TW201317229A - Fused heterocyclic derivatives - Google Patents

Abstract

The subject of present invention is related to a compound or the pharmaceutically acceptable salt thereof having excellent inhibition to DGAT and ingestion inhibition. The solution of present invention is to provide a compound represented by the general formula (I) or the pharmaceutically acceptable salt thereof: [in formula, R1 is hydrogen atom or carboxy group; R2 and R3 each independently represents C1-C6 alkyl group, or R2 and R3 are together with the carbon atom to which they bind to form C3-C6 cycloalkane optionally substituted by one carboxy group or carboxymethyl group; U is nitrogen atom and the like; V is nitrogen atom and the like; W is nitrogen atom and the like; Z is nitrogen atom and the like; R4's each independently represents halogen atom or C1-C6 alkyl group; A is oxygen atom and the like; E is nitrogen atom and the like; J is nitrogen atom and the like; L is nitrogen atom and the like; M is nitrogen atom and the like; m is 0 or 1; n is an integer of 0-2].

Description

Fused heterocyclic derivative

The present invention relates to a compound having a specific chemical structure or a pharmacologically acceptable salt thereof, which has excellent oxime enzyme A: diyl glyceryl thiol transferase (Acyl-CoA: diacylglycerol acyltransferase, hereinafter also referred to as DGAT) hinders and excellent feeding inhibition.

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 (trimercaptoglycerol or triglyceride, hereinafter also referred to as TG), and the result is weight and standard body weight. The state 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 a combination of phospholipids, cholesterol and apolipoprotein, which is secreted in the lymphatics of the gastrointestinal tract by chylomicron. . 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 of the third 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 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 hyperlipidemia caused by obesity, hypertriglyceridemia , abnormal lipid metabolism, insulin resistance A therapeutic or prophylactic agent for sexual 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, digestive tract hormones (CCK, GLP-1, PYY, etc.) secreted in connection with food digestion and absorption (CCK, GLP-1, PYY, etc.) (Non-Patent Document 14), or in response to energy accumulation (fat amount), have been derived from fat cells. Secreted leptin (Non-Patent Document 15) and the like have been clarified as a mechanism for hormonal or neurogenic self-regulation of appetite signals from the distal to the central. 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 hindrance effect, Patent Document 1 discloses that [5-(4-{[(substituted phenyl)carbonyl]amino}phenyl)pyrimidin-2-yl]oxy group and carboxylic acid are stretched. An alkyl-bonded compound, a compound in which [5-(4-{[(substituted phenyl)carbonyl]amino}phenyl)pyrimidin-2-yl]oxy is bonded to cyclopropanecarboxylic acid as an alkylene group. Patent Document 2 describes a compound having (2,3'-bipyridine-6'-yloxy)cyclohexanecarboxylic acid. Further, Patent Document 3, Patent Document 4, and Non-Patent Document 16 describe a compound in which a benzothiazolylbiphenyl group and a cyclopentanecarboxylic acid are bonded to a carbonyl group. Patent Document 3 and Patent Document 4 have described benzene. And a compound in which a thiazolidinylbiphenyl group and a alkylenecarboxylic acid are bonded to a carbonyl group.

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] WO2009/011285

[Patent Document 2] WO2011/031628

[Patent Document 3] US2004/0224997

[Patent Document 4] JP-A-2008-255024

[Non-patent literature]

[Non-Patent Document 1] Ban Yingying II, "STEP Metabolism ‧ Endocrine", Hippocampal 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 Year, Volume 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

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 combination selected from the group consisting of obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism diseases, insulin resistance syndrome, abnormal glucose tolerance, diabetes, and diabetes. Symptoms (including diabetes Peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovarian syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis An effective component of medicine for preventing and/or treating diseases caused by a group consisting of ischemic heart disease and overeating, or as a hyperlipidemia, hypertriglyceridemia, lipid metabolism selected from obesity Abnormal diseases, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataracts, gestational diabetes, non-alcoholic fat Hepatitis, polycystic ovary syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, hypertension, cerebrovascular disease, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, deformed knee joint disease, gout, And medicines for the treatment and/or prevention of diseases of the group consisting of gallstones Ingredients.

The present invention relates to:

(1) a compound represented by the formula (I) or a pharmacologically acceptable salt thereof, Wherein R ¹ represents a hydrogen atom or a carboxyl group; R ² and R ^{3 are} independently represented by a C ₁ -C ₆ alkyl group, or R ² and R ³ together with a bonded carbon atom form a carboxyl group or a carboxymethyl group; Substituted C ₃ -C ₆ naphthenes; 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=; W represents a nitrogen atom or a formula represented by the formula -CH= Z represents a nitrogen atom or a group represented by the formula -CH=; R ^{4 is} independently represented by a halogen atom or a C ₁ -C ₆ alkyl group; A represents an oxygen atom, a sulfur atom or a formula represented by the formula -N(R ⁵ )- R ⁵ represents a hydrogen atom or a C ₁ -C ₆ alkyl group; E represents a nitrogen atom or a group represented by the formula -C(R ⁶ )=; R ⁶ represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkane Or a C ₁ -C ₆ alkoxy group; J represents a nitrogen atom or a group represented by the formula -C(R ⁷ )=; R ⁷ represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C group _{; 6} alkoxy; L represents a nitrogen atom or a group represented by the formula -C(R ⁸ )=; R ⁸ represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group; represents a nitrogen atom or a -C (R ⁹⁾ = represented by the group; R ⁹ represents a hydrogen atom, a halogen atom, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy; m table 0 or 1; n represents an integer of 0-2].

In the present invention, it is preferred that:

(2) A compound according to (1), wherein R ¹ is a carboxyl group, R ² and R ³ are each a methyl group, or R ² and R ³ together with a bonded carbon atom form a cyclopropane, or a pharmacologically acceptable salt thereof; m is 1.

(3) The compound of (1) or a pharmacologically acceptable salt thereof, wherein R ¹ is a hydrogen atom, and R ² and R ³ together with the bonded carbon atom form a 4th position substituted by a carboxymethyl group or a carboxyl group; Cyclohexane, or cyclopentane substituted at the 3rd position with 1 carboxymethyl group, m is 0.

(4) A compound according to any one of (1) to (3) or a pharmacologically acceptable salt thereof, wherein U is a nitrogen atom, V is a group represented by the formula -CH=, and W is a nitrogen atom.

(5) A compound according to any one of (1) to (3) or a pharmacologically acceptable salt thereof, wherein U is a group represented by the formula -CH=, and V is a group represented by the formula -CH= , W is a nitrogen atom.

(6) A compound according to any one of (1) to (5) or a pharmacologically acceptable salt thereof, wherein Z is a group represented by the formula -CH=, and n is 0.

(7) A compound according to any one of (1) to (5), wherein Z is a group represented by the formula -CH=, n is 1, and R ⁴ is a fluorine atom, or a pharmacologically acceptable salt thereof.

(8) A compound, or a pharmacologically acceptable salt thereof, according to any one of (1) to (7), wherein A is an oxygen atom, a sulfur atom, a group represented by the formula -NH- or a formula -N ( CH ₃ ) - the base represented.

(9) A compound, or a pharmacologically acceptable salt thereof, according to any one of (1) to (8), wherein E, J, L and M are a group represented by the formula -CH=.

(10) A compound, or a pharmacologically acceptable salt thereof, according to any one of (1) to (8), wherein E, J and L are a group represented by the formula -CH=, and M is a nitrogen atom, -C(F) = the indicated group or the formula -C(CH ₃ )=.

(11) A compound, or a pharmacologically acceptable salt thereof, according to any one of (1) to (8), wherein E, J and M are a group represented by the formula -CH=, and L is a formula -C ( F) = the indicated base or the formula -C(CH ₃ ) = the indicated group.

(12) A compound, or a pharmacologically acceptable salt thereof, according to any one of (1) to (8), wherein E, L and M are a group represented by the formula -CH=, and J is a formula -C ( F) = the indicated base or the formula -C(CH ₃ ) = the indicated group.

(13) A compound, or a pharmacologically acceptable salt thereof, according to any one of (1) to (8), wherein J, L and M are a group represented by the formula -CH=, and E is a nitrogen atom, -C(F) = the indicated group or the formula -C(CH ₃ )=.

(14) A compound or a pharmacologically acceptable salt thereof, which is selected from the group consisting of: 3-({5-[4-(1,3-benzo) Zin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)-2,2-dimethylpropionic acid, 3-[(5-{4-[(7-fluoro-1,3-) Benzo Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]-2,2-dimethylpropanoic acid, 2,2-dimethyl-3-[(5-{4-[ (7-methyl-1,3-benzophenone Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]propionic acid, 3-({5-[4-(1,3-benzo) Zin-2-ylamino)-3-fluorophenyl]pyrimidin-2-yl}oxy)-2,2-dimethylpropionic acid, {cis--4-[(5-{4-[( 7-methyl-1,3-benzophenone Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid, [cis-4-({5-[4-(1,3-benzo) Zin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid, [cis-4-({5-[4-(1,3-benzo) Zin-2-ylamino)-3-fluorophenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid, [cis-4-({5-[4-(1H-benzimidazole-2) -ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid, {cis-4-[(5-{4-[(1-methyl-1H-benzimidazole-2-) Amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid, {cis-4-[(5-{4-[(5-methyl-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid, {cis-4-[(5-{4-[(6-methyl-1,3-) Benzo Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid, {cis-4-[(5-{4-[(6-fluoro-1,3-benzene) and Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid, {cis-4-[(5-{4-[(5-fluoro-1,3-benzene) and Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid, [cis-3-({5-[4-(1,3-benzo) Zin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclopentyl]acetic acid, [trans-3-({5-[4-(1,3-benzo) Zin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclopentyl]acetic acid, [cis-4-({5-[4-(1,3-benzothiazole-2-) Amino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid, trans-4-({5-[4-(1,3-benzo) Oxazol-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexanecarboxylic acid, {cis-4-[(5-{4-[(7-methyl-1H-benzimidazole) -2-yl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid, 2,2-dimethyl-3-({5-[4-([1,3] Zoxao[4,5-b]pyridin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)propionic acid, 2,2-dimethyl-3-({5-[4-( [1,3] Oxazo[4,5-b]pyridin-2-ylamino)phenyl]pyridin-2-yl}oxy)propionic acid, [cis-4-({5-[4-([1,3) ] Zoxa[4,5-b]pyridin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid, 1-[({5-[4-([1,3]] Zizo[4,5-b]pyridin-2-ylamino)phenyl]pyridin-2-yl}oxy)methyl]cyclopropanecarboxylic acid, [cis-4-({5-[4-( [1,3] Zoxa[4,5-b]pyridin-2-ylamino)phenyl]pyridin-2-yl}oxy)cyclohexyl]acetic acid, [cis-4-({5-[3-fluoro-4] -([1,3] Azolo[4,5-b]pyridin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid, [trans-4-({5-[4-([1 , 3] Zizo[4,5-b]pyridin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid, or [trans-4-({5-[4-( [1,3] Zoxao[4,5-b]pyridin-2-ylamino)phenyl]pyridin-2-yl}oxy)cyclohexyl]acetic acid.

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

(16) A compound or a pharmacologically acceptable salt thereof, which is selected from the group consisting of: {cis-4-[(5-{4-[(7-methyl-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid, {cis-4-[(5-{4-[(1-methyl-1H-benzo) Imidazolyl-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid, {cis-4-[(5-{4-[(5-methyl-1,3-) Benzo Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid, 2,2-dimethyl-3-({5-[4-([1,3] Oxazo[4,5-b]pyridin-2-ylamino)phenyl]pyridin-2-yl}oxy)propionic acid, [cis-4-({5-[4-([1,3) ] Zoxa[4,5-b]pyridin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid, [cis-4-({5-[3-fluoro-4] -([1,3] Zizo[4,5-b]pyridin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid, or [trans-4-({5-[4-( [1,3] Zizo[4,5-b]pyridin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid.

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

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

(19) An ingestion inhibitor and/or an appetite suppressant comprising the compound according to any one of (1) to (17) or a pharmacologically acceptable salt thereof as an active ingredient.

(20) A pharmaceutical composition comprising any one of (1) to (17) A compound or a pharmacologically acceptable salt thereof is used as an active ingredient.

(21) The pharmaceutical composition according to (20), wherein the pharmaceutical composition has an inhibitory effect of 醯Kytozyme A: dimercaptoglycerol hydrazinotransferase.

(22) The pharmaceutical composition according to (20), wherein the pharmaceutical composition has an action of suppressing food intake and/or appetite suppressing.

(23) The pharmaceutical composition according to (20), wherein the pharmaceutical composition is used for the treatment and/or prevention of treatment and/or prevention due to the inhibition of 醯Kystase A: dimercaptoglycerol thiotransferase disease.

(24) The pharmaceutical composition according to (20), wherein the pharmaceutical composition is for treating and/or preventing a disease caused by hyperactivity of 醯Kytozyme A: dimercaptoglycerol thiotransferase activity.

(25) The pharmaceutical composition according to (20), wherein the pharmaceutical composition is used for the treatment and/or prevention of hindering or hindering triglyceride by causing 醯Kytozyme A: dimercaptoglycerol thiol transferase The absorption of the synthetic, triglyceride is inhibited, and the treatment and/or prevention of the disease for the treatment, improvement, alleviation and/or prevention of the symptoms is achieved.

(26) The pharmaceutical composition according to (20), wherein the pharmaceutical composition is used for the treatment and/or prevention of hindering the synthesis of triglyceride by 醯Kystase A: dimercaptoglycerol thiol transferase And to achieve treatment and/or prevention of the treatment, improvement, alleviation and/or prevention of symptoms.

(27) The pharmaceutical composition according to (20), wherein the pharmaceutical composition is for treating and/or preventing obesity, obesity, hyperlipidemia, triglyceride, abnormal lipid metabolism, insulin resistance Syndrome, abnormal sugar tolerance, diabetes, diabetes complications (including diabetic distals) Neurological disorders, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataracts, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovarian syndrome, atherosclerosis, atherosclerosis, diabetic arteriosclerosis Symptoms, ischemic heart disease or overeating.

(28) The pharmaceutical composition according to (20), wherein the pharmaceutical composition is for treating and/or preventing obesity or obesity.

(29) The pharmaceutical composition according to (20), wherein the pharmaceutical composition is for treating and/or preventing diabetes.

(30) The pharmaceutical composition according to (20), wherein the pharmaceutical composition is for treating and/or preventing hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance caused by obesity Symptoms, abnormal glucose tolerance, diabetes, diabetes complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary Syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, hypertension, cerebrovascular disease, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, deformed knee joint disease, gout or gallstones.

(31) The pharmaceutical composition according to (20), wherein the pharmaceutical composition is for treating and/or preventing hyperlipidemia, hypertriglyceridemia, diabetes, arteriosclerosis or hypertension caused by obesity disease.

(32) The pharmaceutical composition according to (20), wherein the pharmaceutical composition is for inhibiting fat absorption from the small intestine.

(33) A compound according to any one of (1) to (17), or a pharmacologically acceptable salt thereof, for use in obesity, obesity, hyperlipidemia, high Triglycerideemia, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), Use in the treatment and/or prevention of cataracts, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, ischemic heart disease or overeating.

(34) A compound according to any one of (1) to (17), or a pharmacologically acceptable salt thereof, for use in the treatment and/or prevention of obesity or obesity.

(35) A compound according to any one of (1) to (17) or a pharmacologically acceptable salt thereof for use in the treatment and/or prevention of diabetes.

(36) A use of a compound according to any one of (1) to (17), or a pharmacologically acceptable salt thereof, for use in the manufacture of a pharmaceutical composition.

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

(38) The use of (36), wherein the pharmaceutical composition is for feeding and/or appetite.

(39) The use according to (36), wherein the pharmaceutical composition is for treating and/or preventing obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, Abnormal sugar tolerance, diabetes, diabetes complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, Atherosclerosis, atherosclerosis, diabetic arteries Sclerosis, ischemic heart disease or overeating.

(40) The use according to (36), wherein the pharmaceutical composition is for treating and/or preventing obesity or obesity.

(41) The use of (36), wherein the pharmaceutical composition is for treating and/or preventing diabetes.

(42) The use according to (36), wherein the pharmaceutical composition is for treating and/or preventing obesity-induced hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, and sugar tolerance Abnormal ability, diabetes, diabetes complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteries Sclerosis, atherosclerosis, diabetic atherosclerosis, hypertension, cerebrovascular disease, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, deformed knee joint disease, gout or gallstones.

(43) The use according to (36), wherein the pharmaceutical composition is for treating and/or preventing hyperlipidemia, hypertriglyceridemia, diabetes, arteriosclerosis or hypertension caused by obesity.

(44) The use according to (36), wherein the pharmaceutical composition is for inhibiting absorption of fat from the small intestine.

(45) A method for inhibiting a ketugase A: dimercaptoglycerol hydrazinotransferase, which is a pharmacologically effective amount of a compound or a pharmacologically active compound thereof according to any one of (1) to (17) Allowable salt is administered to warm-blooded animals.

(46) A method of suppressing food intake and/or appetite suppressing, which comprises administering a pharmacologically effective amount of a compound selected according to any one of (1) to (17) or a pharmacologically acceptable salt thereof. Blood animals.

(47) A method for the treatment and/or prevention of a disease, which comprises administering a pharmacologically effective amount of a compound selected according to any one of (1) to (17) or a pharmacologically acceptable salt thereof. Blood animals.

(48) The method according to (47), 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 retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, atherosclerosis, atherosclerosis, Diabetic atherosclerosis, ischemic heart disease or overeating.

(49) The method according to (47), wherein the disease is obesity or obesity.

(50) The method according to (47), wherein the disease is diabetes.

(51) The method according to (47), wherein the disease is obesity-induced 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 ovarian syndrome, atherosclerosis, atherosclerosis, diabetes Atherosclerosis, hypertension, cerebrovascular disease, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, deformed knee joint disease, gout or gallstones.

(52) The method according to (47), wherein the disease is hyperlipidemia, hypertriglyceridemia, diabetes, arteriosclerosis or hypertension caused by obesity.

(53) A method for inhibiting absorption of fat by the small intestine, which comprises administering a pharmacologically effective amount of the compound according to any one of (1) to (17) or a pharmacologically acceptable salt thereof Blood animals.

(54) An obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes complications (including diabetic peripheral neuropathy, diabetic kidney) Disease, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, ischemic heart A method for the treatment and/or prevention of a disease or a predator, which comprises administering a pharmacologically effective amount of a compound selected according to any one of (1) to (17) or a pharmacologically acceptable salt thereof to warm blood. animal.

(55) The method according to any one of (45) to (54) wherein the warm-blooded animal is a human.

(56) An obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes complications (including diabetic peripheral neuropathy, diabetic kidney) Disease, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, ischemic heart A method for the treatment and/or prevention of a disease or a eclipse, which is characterized by administering a pharmacologically effective amount of a compound according to any one of (1) to (14) or a pharmacologically acceptable salt thereof.

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, 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), more preferably methyl.

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 or hexyloxy. 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 ₃ -C ₆ naphthenic acid" is cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclopropane, cyclopentane or cyclohexane, more preferably cyclohexane.

In the present invention, "C ₃ -C ₆ naphtheol which may be substituted by one carboxyl group or carboxymethyl group" is preferably cyclopropane, cyclopentane substituted at the third position by one carboxymethyl group, and the fourth position is 1 Carboxymethyl substituted cyclohexane or cyclohexane substituted at the 4th position with 1 carboxyl group, more preferably cyclohexane substituted at the 4th position with 1 carboxymethyl group.

In the present invention, preferred R ^1, R ^2, R ^3, m of compositions based R ¹ is carboxy, R ² and R ³ are each methyl, or R ² and R ³ bonded with the carbon atom form a cyclopropane together m is 1; or R ¹ is a hydrogen atom, and R ² and R ³ together with the bonded carbon atom form a cyclohexane in which the 4th position is substituted by 1 carboxymethyl group or carboxyl group, or the 3rd position is 1 unit. Carboxymethyl substituted cyclopentane, m is 0.

In the present invention, a preferred combination of U, V and W is a nitrogen atom, V is a group represented by the formula -CH=, and W is a nitrogen atom; or U is a group represented by the formula -CH=, and V is The formula -CH= represents the group, and W is a nitrogen atom.

In the present invention, a preferred combination of Z, n and R ⁴ is a group represented by the formula -CH=, n is 0; or Z is a group represented by the formula -CH=, n is 1, and R ⁴ is Fluorine atom.

In the present invention, preferred A is an oxygen atom, a sulfur atom, a group represented by the formula -NH- or a group represented by the formula -N(CH ₃ )-.

In the present invention, preferred combinations E, J, L, and M are E, J, L, and M are groups represented by the formula -CH=; E, J, and L are groups represented by the formula -CH=, M Is a nitrogen atom, a group represented by the formula -C(F)= or a group represented by the formula -C(CH ₃ )=; E, J and M are a group represented by the formula -CH=, and L is a formula -C ( F) = the indicated group or the formula -C(CH ₃ )= represents the group; E, L and M are the groups represented by the formula -CH=, and J is the group represented by the formula -C(F)= or Formula -C(CH ₃ )= represents a group; or J, L and M are a group represented by the formula -CH=, E is a nitrogen atom, a formula -C(F)= represents a group or a formula-C ( CH ₃ ) = the indicated base.

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

The compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof has various isomers because of an asymmetric carbon atom in its molecule. 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 of the present invention may contain an atomic isotope having a non-natural ratio in 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 a salt which is not highly toxic and can be used as a medicine. 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 glycinate, lysate, arginine, and aguanine Amino acid salts such as acid salts, glutamine salts, and aspartic acid salts.

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 for use as 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, abnormal glucose tolerance, diabetes, diabetes Comorbidities (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, atherosclerosis, atherosclerosis a disease consisting of a group consisting of cirrhosis, diabetic atherosclerosis, ischemic heart disease, and overeating; or a hyperlipidemia caused by obesity, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance Symptoms, abnormal glucose tolerance, diabetes, diabetes complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary Syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, hypertension, cerebrovascular disease, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, deformed knee joint disease, gout, and gallstones Group of diseases. 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 as a warm-blooded animal (preferably a mammal, including a human). An active ingredient of a medicine for the prevention and/or treatment of the above diseases. It is preferred to use a medicine for the treatment of the above-mentioned diseases.

[Formation of the Invention]

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

The solvent to be used in the reaction of each step of the following A method and B method is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is, for example, selected from the following solvent groups. The solvent group comprises hydrocarbons such as pentane, hexane, octane, petroleum ether, ligroin, cyclohexane; formamide, N,N-dimethylformamide, N,N-di Indoleamines such as methyl acetamide, 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.

In the following steps of the A method and the B method, the reaction temperature varies depending on the solvent, the starting materials, the reagents, etc., and the reaction time depends on the solvent and the starting materials. , reagents, reaction temperatures, etc. vary.

After the reaction of each step of the following methods A and B, after the reaction is completed, each compound of interest is taken from the reaction mixture according to a usual method. For example, it is suitable to neutralize the reaction mixture, and in the case where insoluble matter is present, after removing by filtration, an organic solvent which does not mix with water and ethyl acetate is added, and the organic layer containing the objective compound is separated and washed with water or the like. After drying, it is dried with anhydrous magnesium sulfate, anhydrous sodium sulfate or the like, filtered, and then obtained by distilling off solvent. The obtained target compound may be appropriately combined with a usual method such as recrystallization, reprecipitation, or the like, usually, a method conventionally used for separation and purification of an organic compound, and subjected to chromatography to be separated and purified by dissolution with a suitable dissolving agent. . The objective compound insoluble in the solvent can be purified by washing the obtained crude product as a solvent. Further, the objective compound of each step may be used as it is without purification.

In the reactions of the following steps A to B, R ¹ , R ² , R ³ , U, V, W, Z, R ⁴ , A, E, J, L, M, m and n are represented as described above. The same meaning. X represents a halogen atom (preferably a bromine atom). Y represents a halogen atom, a nitro group, a C ₁ -C ₆ alkylsulfonyloxy group or a C ₆ -C ₁₀ arylsulfonyloxy group (preferably a halogen atom or a C ₁ -C ₆ alkylsulfonyl group) The oxy group is more preferably a chlorine atom). R ^1a , R ^2a and R ^3a represent a definition of a group of R ¹ , R ² and R ^{3 in} addition to a carboxyl group which the substituent of R ¹ , R ² and R ³ as a substituent is a protectable carboxyl group. The basis is the same base.

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

(A method)

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) and the compound represented by the formula (III) used in the present step are known compounds, or a known compound can be used as a starting material according to a known method or the like. Made easily.

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 azodicarboxylic acid Isopropyl ester (DIAD) or (cyanomethylene) tributylphosphane (CMBP), more preferably 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 carried out by reacting a compound represented by the formula (IV) with a compound represented by the formula (V) in the presence of a solvent, a palladium catalyst and a base to produce a compound represented by the formula (VI). The step of the compound.

The compound represented by the formula (V) used in the present step is a known compound, or is easily produced according to a known method using a known compound as a starting material or the like (for example, WO2005/074603, etc.).

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

The palladium catalyst used in this step is, for example, ruthenium (triphenylphosphine) palladium (0), palladium-activated carbon, palladium (II) acetate, palladium (II) trifluoroacetate, palladium black, palladium bromide ( II), palladium chloride (II), 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), acetonitrile acetone palladium(II), palladium(II) sulfide, dichlorination [1,1 ' -bis(diphenylphosphino)ferrocene]palladium(II), tris(dibenzylideneacetone)dipalladium(0), hydrazine (acetonitrile)palladium(II)tetrafluoroborate or chlorine The divalent palladium catalyst or the zero-valent palladium catalyst such as an aryl palladium dimer 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 such as sodium carbonate, potassium carbonate, lithium carbonate or cesium carbonate, 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 carried out in a solvent, and after reacting the compound represented by the formula (VI) with the compound represented by the formula (VII), the protecting group of the carboxyl group in R ^1a , R ^2a and R ^3a is removed as needed. A step of producing a compound represented by the formula (I).

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

The solvent used in this step is preferably an alcohol, more preferably n-butanol.

The reaction temperature in this step is usually carried out at 20 ° C to 180 ° C, preferably 80 ° C to 140 ° C.

The reaction time in this step is usually from 0.5 to 168 hours, preferably from 8 to 48 hours.

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

(Method B)

B-I step

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

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

The reaction temperature in this step is usually carried out at -20 ° C to 100 ° C, preferably 0 ° C to 40 ° C.

The reaction time in this step is usually from 0.1 to 48 hours, preferably from 0.5 to 8 hours.

B-II step

This step is carried out in a solvent to react a compound represented by the formula (IX) with a compound represented by the formula (X), and then, after reacting the phenyl iodide ethylene compound, R ^1a is removed as needed. And a step of producing a compound represented by the formula (I) by protecting a carboxyl group in R ^2a and R ^3a .

The compound represented by the formula (X) 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 or a halogenated hydrocarbon, more preferably tetrahydrofuran or dichloromethane.

The reaction temperature in this step is usually carried out at -20 ° C to 80 ° C, preferably 20 ° C to 40 ° C.

The reaction time in this step is usually from 0.5 to 72 hours, preferably from 1 to 24 hours.

In the above, the protective group of the "protectable carboxyl group" in the definition of R ^1a , R ^2a and R ^3a means a protective group which can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis. A protecting group generally used for organic synthetic chemistry (for example, see TW Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)).

In the above, the "protecting group" of the "protectable carboxyl group" in the definition of R ^1a , R ^2a and R ^3a 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 "C ₁ -C ₆ alkyl group"; vinyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl or the like "C ₂ -C ₆ alkenyl group"; ethynyl, 1 - "C ₂ -C ₆ alkynyl" such as propynyl, 2-propynyl, 1-methyl-2-propynyl; 2,2,2-trifluoroethyl, 2,2,2 - trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl and the like halo C ₁ -C ₆ alkyl; hydroxymethyl, 2-hydroxyethyl like a C ₁ -C ₆ hydroxyalkyl; (C ₂ -C ₇ alkylcarbonyl)-(C ₁ -C ₆ alkyl) such as ethenylmethyl; benzyl, α-naphthylmethyl, β-naphthyl a C ₁ -C ₆ alkyl group substituted with 1 to 3 aryl groups such as methyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-fluorenylmethyl , 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenyl Methyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl , 4-cyanobenzyl group such C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, nitro, halo, cyano substituted in the aryl ring with 1 to 3 of the aryl group substituted An "aralkyl group" such as a C ₁ -C ₆ alkyl group; or a trimethyl decyl group, a triethyl decyl group, an isopropyl dimethyl decyl group, a t-butyl dimethyl decyl group, a methyl group Tri-(C ₁ -C ₆ alkyl)decyl, bisphenylmethyldecyl, diphenyl, such as isopropyl fluorenyl, methyl di-t-butyl decyl, triisopropyl decyl (C ₁ -C ₆ alkyl)diarylalkyl or bis-(C ₁ -C ₆ alkane) such as butyl decyl, diphenyl isopropyl decyl, phenyl diisopropyl decyl The "nonylalkyl group" of the arylalkyl group or the like is preferably a C ₁ -C ₆ alkyl group or an aralkyl group.

The steps necessary for protection and deprotection are carried out according to known methods (for example, "Protective Groups in Organic Synthesis" (the method described in Theodora W. Greene, Peter GMWuts, 1999, issued by Wiley-Interscience Publication). For example, the deprotection step in the case where the protecting group is a C ₁ -C ₆ alkyl group is as shown below.

This step is carried out in a solvent by reacting a compound having a protecting group with a base.

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

The base used in this step is preferably a quaternary ammonium base, 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 compound of the present invention or a pharmacologically acceptable salt thereof can be administered in various forms. In terms of its administration form, for example, oral administration by a tablet, a capsule, a granule, an emulsion, a pill, a powder, a syrup (liquid), or the like, or an injection (intravenous, Intramuscular, subcutaneous or intraperitoneal administration), drip, suppository (rectal administration), etc. are not administered orally. 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, Ethanol, propanol, monosaccharide syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinyl pyrrolidine a combination of a ketone or the like; dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglycerin a disintegrant such as ester, starch or lactose; a disintegration inhibitor such as white sugar, stearic acid, cocoa butter or hydrogenated oil; an absorption enhancer such as a fourth-order ammonium salt or sodium lauryl sulfate; glycerin, starch, etc. Moisturizer; adsorbent for starch, lactose, kaolin, bentonite, colloidal tannic 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, as the carrier, for example, excipients such as glucose, lactose, cocoa butter, starch, hardened vegetable oil, kaolin, talc, etc.; gum arabic powder, tragacanth powder, gelatin, ethanol, etc. may be used. a binding agent; a disintegrator such as laminaria polysaccharide, agar, or the like.

In the case of use as a suppository, as far as the carrier is concerned, it is widely known in the art, 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 polyoxylated isostearyl alcohol, a polyoxyethylene sorbitan fatty acid ester or the like. In this case, in the preparation of the isotonic solution in the preparation It may contain a sufficient amount of salt, glucose or glycerin, and may also contain a general dissolution aid, a buffer, 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) 3-({5-[4-(1,3-Benzene) Zin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)-2,2-dimethylpropionic acid

(1a) 3-{[5-(4-Isothiocyanate phenyl)pyrimidin-2-yl]oxy}-2,2-dimethylpropanoic acid methyl ester

a solution of 3-{[5-(4-aminophenyl)pyrimidin-2-yl]oxy}-2,2-dimethylpropanoic acid methyl ester (WO2009011285A1) (2.83 g) in tetrahydrofuran (20 mL) Among them, 1,1'-thiocarbonate dipyridine-2(1H)-one (1.02 g) was stirred and concentrated at room temperature for 3 hours. The residue was purified by EtOAc EtOAcjjjjjjj

_{^{1 H NMR (400MHz, CDCl 3}} ): δ (ppm) = 8.69 (1H, s), 7.51 (2H, d, J = 8.6Hz), 7.34 (2H, d, J = 8.6Hz), 4.46 (2H, s), 3.71 (3H, s), 1.37 (6H, s).

(1b) 3-({5-[4-(1,3-Benzene) Oxazol-2-ylamino)phenyl]pyrimidin-2-yl}oxy)-2,2-dimethylpropanoic acid methyl ester

O-Aminophenol (340 mg) was added to a solution of the compound obtained in Example (1a) (1.07 g) in THF (20 mL). The reaction mixture was stirred at room temperature for 30 minutes and then heated at reflux for 1 hour. After cooling to room temperature, triethylamine (0.43 mL) and iodobenzene diacetate (999 mg) were added to the mixture, and the resulting mixture was stirred at room temperature for 3 hr and concentrated. The residue was purified by column chromatography (an automated chromatography apparatus, dichloromethane / ethyl acetate). The obtained compound was heated to EtOAc (EtOAc) (EtOAc)

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 10.8 (1H, s), 8.92 (2H, s), 7.89 (2H, d, J = 8.7Hz), 7.77 (2H, d, J = 8.7 Hz), 7.53-7.48 (2H, m), 7.25 (1H, dd, J = 7.7 and 7.7 Hz), 7.16 (1H, dd, J = 7.6 and 7.6 Hz), 4.38 (2H, s), 3.64 ( 3H, s), 1.27 (6H, s).

(1c) 3-({5-[4-(1,3-Benzene) Zin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)-2,2-dimethylpropionic acid

1,4-two of the compound (744 mg) obtained in the example (1b) To a solution of alkane (10 mL), tetrabutylammonium hydroxide (1 mol/L aqueous solution, 3.6 mL) was added at room temperature. After 3 hours, (concentration of the reaction mixture) was acidified with 1N aqueous hydrochloric acid (20 mL), diluted with ethyl acetate and water, and stirred vigorously for 3 hours, and the precipitated solid was collected by filtration. The solid was stirred with EtOAc EtOAc EtOAc.

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.4 (1H, brs), 10.8 (1H, s), 8.92 (2H, s), 7.89 (2H, d, J = 8.6Hz), 7.77 (2H, d, J = 9.0 Hz), 7.51 (2H, dd, J = 8.6 and 8.6 Hz), 7.25 (1H, dd, J = 7.1 and 7.0 Hz), 7.16 (1H, dd, J = 8.4 and 8.4) Hz), 4.35 (2H, s), 1.24 (6H, s).

MS (ESI) m / z: 405 (M+H) ⁺ .

(Example 2) 3-[(5-{4-[(4-fluoro-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]-2,2-dimethylpropionic acid

The compound (131 mg) obtained in Example (1a) and 2-amino-3-fluorophenol (40 mg) were obtained in the same manner as in Example (1b) to give benzene. Azole (75 mg). Benzo The azole was hydrolyzed in the same manner as in Example (1c) to give the title compound (yield: 35%).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.4 (1H, brs), 11.0 (1H, s), 8.93 (2H, s), 7.88 (2H, d, J = 9.0Hz), 7.79 (2H, d, J = 8.7 Hz), 7.41 (1H, dd, J = 7.4 and 1.5 Hz), 7.16 (1H, d, J = 1.6 Hz), 7.14 (1H, dd, J = 1.8 and 1.8 Hz) , 4.36 (2H, s), 1.24 (6H, s).

MS (ESI) m / z: 422 (M+H) ⁺ .

(Example 3) 3-[(5-{4-[(5-fluoro-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]-2,2-dimethylpropionic acid

In the same manner as in Example (1b), the compound obtained from Example (1a) (364 mg) and 2-amino-4-fluorophenol (135 mg) gave benzo Azole (142 mg). Benzo The azole was hydrolyzed in the same manner as in Example (1c) to give the title compound (yield: 17%).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.4 (1H, brs), 10.9 (1H, s), 8.90 (2H, s), 7.87 (2H, d, J = 8.6Hz), 7.76 (2H, d, J = 9.0 Hz), 7.52 (1H, dd, J = 8.6 and 4.3 Hz), 7.35 (1H, dd, J = 9.2 and 2.5 Hz), 6.99-6.94 (1H, m), 4.32 ( 2H, s), 1.16 (6H, s).

MS (ESI) m / z: 422 (M+H) ⁺ .

(Example 4) 3-[(5-{4-[(6-fluoro-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]-2,2-dimethylpropionic acid

In the same manner as in Example (1b), the compound obtained from Example (1a) (168 mg) and 2-amino-5-fluorophenol (62 mg) gave benzo Azole (149 mg). Benzo The azole was hydrolyzed in the same manner as Example (1c) to give the title compound (yield:

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.4 (1H, brs), 10.8 (1H, s), 8.92 (2H, s), 7.87 (2H, d, J = 9.0Hz), 7.77 (2H, d, J = 8.6 Hz), 7.55 (1H, dd, J = 8.5 and 2.5 Hz), 7.48 (1H, dd, J = 8.6 and 5.1 Hz), 7.13 - 7.08 (1H, m), 4.35 ( 2H, s), 1.24 (6H, s).

MS (ESI) m / z: 422 (M+H) ⁺ .

(Example 5) 3-[(5-{4-[(7-fluoro-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]-2,2-dimethylpropionic acid

The compound (191 mg) obtained in Example (1a) and 2-amino-6-fluorophenol (71 mg) were obtained in the same manner as in Example (1b) to give benzene. Azole (96 mg). Benzo The azole was hydrolyzed in the same manner as Example (1c) to give the title compound (yield: 5%).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.4 (1H, brs), 11.1 (1H, s), 8.92 (2H, s), 7.87 (2H, d, J = 9.0Hz), 7.78 (2H, d, J = 8.6 Hz), 7.35 (1H, d, J = 7.0 Hz), 7.28-7.22 (1H, m), 7.11-7.07 (1H, m), 4.35 (2H, s), 1.23 ( 6H, s).

MS (ESI) m / z: 422 (M+H) ⁺ .

(Example 6) 2,2-dimethyl-3-[(5-{4-[(4-methyl-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]propionic acid

In the same manner as in Example (1b), the compound obtained from Example (1a) (380 mg) and 2-amino-3-methylphenol (136 mg) gave benzene. Azole (358 mg). Benzo The azole was hydrolyzed in the same manner as Example (1c) to give 297mg (yield:

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.5 (1H, brs), 10.8 (1H, s), 8.93 (2H, s), 7.92 (2H, d, J = 9.0Hz), 7.78 (2H, d, J = 8.6 Hz), 7.34 - 7.32 (1H, m), 7.09 - 7.03 (2H, m), 4.35 (2H, s), 2.49 (3H, s), 1.24 (6H, s).

MS (ESI) m / z: </RTI> (M+H) ⁺ .

(Example 7) 2,2-dimethyl-3-[(5-{4-[(5-methyl-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]propionic acid

In the same manner as in Example (1b), the compound obtained from Example (1a) (380 mg) and 2-amino-4-methylphenol (136 mg) gave benzene. Azole (381 mg). Benzo The azole was hydrolyzed in the same manner as Example (1c) to give 372 mg (yield:

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.5 (1H, brs), 10.8 (1H, s), 8.92 (2H, s), 7.88 (2H, d, J = 8.6Hz), 7.88 (2H, d, J = 8.6 Hz), 7.39 (1H, d, J = 8.2 Hz), 7.30 (1H, s), 6.96 (1H, dd, J = 8.5 and 1.3 Hz), 4.35 (2H, s) , 2.38 (3H, s), 1.24 (6H, s).

MS (ESI) m / z: </RTI> (M+H) ⁺ .

(Example 8) 2,2-dimethyl-3-[(5-{4-[(6-methyl-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]propionic acid

In the same manner as in Example (1b), the compound obtained from Example (1a) (343 mg) and 2-amino-5-methylphenol (123 mg) gave benzene. Azole (340 mg). Benzo The azole was hydrolyzed in the same manner as Example (1c) to give 263 mg (yield:

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.4 (1H, brs), 10.7 (1H, s), 8.92 (2H, s), 7.87 (2H, d, J = 8.6Hz), 7.76 (2H, d, J = 9.0 Hz), 7.36 (2H, m), 7.06 (1H, dd, J = 8.6 and 1.5 Hz), 4.35 (2H, s), 2.40 (3H, s), 1.24 (6H, s). MS (ESI) m/z: 419 (M+H) ⁺ .

(Example 9) 2,2-dimethyl-3-[(5-{4-[(7-methyl-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]propionic acid

In the same manner as in Example (1b), the compound obtained from Example (1a) (343 mg) and 2-amino-6-methylphenol hydrochloride (159 mg) afforded benzene. Azole (227 mg). Benzo The azole was hydrolyzed in the same manner as in Example (1c) to give the title compound 192 mg (46%, step 2).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.4 (1H, brs), 10.8 (1H, s), 8.92 (2H, s), 7.89 (2H, d, J = 9.0Hz), 7.76 (2H, d, J = 9.0 Hz), 7.31 (1H, d, J = 7.8 Hz), 7.14 (1H, dd, J = 7.7 and 7.6 Hz), 6.98 (1H, d, J = 7.5 Hz), 4.35 (2H, s), 2.45 (3H, s), 1.24 (6H, s).

MS (ESI) m / z: </RTI> (M+H) ⁺ .

(Example 10) 3-[(5-{4-[(6-methoxy-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]-2,2-dimethylpropionic acid

The compound (343 mg) obtained in Example (1a) and 2-amino-5-methoxyphenol (175 mg) were obtained in the same manner as in Example (1b). Azole (382 mg). Benzo The azole was hydrolyzed in the same manner as Example (1c) to give 343 mg (yield:

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.4 (1H, brs), 10.7 (1H, s), 8.91 (2H, s), 7.86 (2H, d, J = 8.6Hz), 7.75 (2H, d, J = 9.0 Hz), 7.38 (1H, d, J = 8.6 Hz), 7.21 (1H, d, J = 2.3 Hz), 6.84 (1H, dd, J = 8.6 and 2.8 Hz), 4.35 (2H, s), 3.80 (3H, s), 1.24 (6H, s).

MS (ESI) m / z: 435 (M+H) ⁺ .

(Example 11) 3-[(5-{4-[(5-methoxy-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]-2,2-dimethylpropionic acid

The compound (343 mg) obtained in Example (1a) and 2-amino-4-methoxyphenol (139 mg) were obtained in the same manner as in Example (1b). Azole (74 mg). Benzo The azole was hydrolyzed in the same manner as Example (1c) to give the title compound (yield:

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.4 (1H, brs), 10.8 (1H, s), 8.92 (2H, s), 7.87 (2H, d, J = 9.0Hz), 7.76 (2H, d, J = 8.6 Hz), 7.40 (1H, d, J = 8.6 Hz), 7.10 (1H, d, J = 2.4 Hz), 6.71 (1H, dd, J = 8.8 and 2.6 Hz), 4.35 (2H, s), 3.79 (3H, s), 1.24 (6H, s).

MS (ESI) m / z: 435 (M+H) ⁺ .

(Example 12) 3-({5-[4-(1,3-Benzene) Zin-2-ylamino)-2-methylphenyl]pyrimidin-2-yl}oxy)-2,2-dimethylpropionic acid

(12a) 3-{[5-(4-Isothiocyanate-2-methylphenyl)pyrimidin-2-yl]oxy}-2,2-dimethylpropanoic acid methyl ester

In the same manner as in the embodiment (1a), from 3-{[5-(4-amino-2-methylphenyl)pyrimidin-2-yl]oxy}-2,2-dimethylpropanoic acid Methyl ester (WO 2009 011 285) (2.72 g) and 1,1'- thiocarbazide dipyridine-2(1H)-one (2.00 g).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ (ppm) = 8.47 (2H, s), 7.20-7.19 (1H, m), 7.17-7.16 (2H, m), 4.45 (2H, s), 3.73 (3H , s), 2.28 (3H, s), 1.38 (6H, s).

IR (KBr) cm ^-1 : 2087,1728.

(12b) 3-({5-[4-(1,3-Benzene) Zin-2-ylamino)-2-methylphenyl]pyrimidin-2-yl}oxy)-2,2-dimethylpropionic acid

The compound (343 mg) obtained from Example (12a) and o -aminophenol (102 mg) were obtained in the same manner as in the Example (1b). Azole (347 mg). Benzo The azole was hydrolyzed in the same manner as Example (1c) to give 183 mg (yield: 47%).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.4 (1H, brs), 10.7 (1H, s), 8.63 (2H, s), 7.75 (1H, dd, J = 8.4 and 2.1Hz) , 7.69 (1H, d, J = 2.0 Hz), 7.52-7.48 (2H, m), 7.30 (1H, d, J = 8.2 Hz), 7.24 (1H, dd, J = 7.7 and 7.7 Hz), 7.15 ( 1H, dd, J=7.9 and 7.9 Hz), 4.35 (2H, s), 2.30 (3H, s), 1.25 (6H, s).

MS (ESI) m / z: </RTI> (M+H) ⁺ .

(Example 13) 3-({5-[4-(1,3-Benzene) Zin-2-ylamino)-2-chlorophenyl]pyrimidin-2-yl}oxy)-2,2-dimethylpropanoic acid

(13a) 3-{[5-(4-Amino-2-chlorophenyl)pyrimidin-2-yl]oxy}-2,2-dimethylpropanoic acid methyl ester

3-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (507 mg) and 3-[(5-bromopyrimidine-2) -yl)oxy]-2,2-dimethylpropionic acid methyl ester (WO2009011285) (578 mg), tetrakis(triphenylphosphine)palladium(0) (116 mg), and potassium carbonate (553 mg) , 4-two A suspension of alkane/water (7:3, 20 mL) was heated at 80 ° C for 3.5 hours. The reaction mixture was diluted with EtOAcq. The residue was purified by chromatography EtOAcjjjjjjjjj

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 8.59 (2H, s), 7.13 (1H, d, J = 8.2Hz), 6.75 (1H, d, J = 2.3Hz), 6.62 (1H , dd, J = 8.4 and 2.2 Hz), 5.63 (2H, brs), 4.36 (2H, s), 3.63 (3H, s), 1.26 (6H, s).

(13b) 3-{[5-(2-Chloro-4-isothiocyanate phenyl)pyrimidin-2-yl]oxy}-2,2-dimethylpropanoic acid methyl ester

The compound (298 mg) obtained from Example (13a) and 1,1'-thiocarbazide dipyridine-2(1H)-one (207 mg) were obtained as a white solid. The title compound was 260 mg (78%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.59 (2H, s), 7.40 (1H, d, J = 2.4 Hz), 7.31 (1H, d, J = 8.3 Hz), 7.23 (1H, Dd, J = 8.2 and 2.3 Hz), 4.46 (2H, s), 3.72 (3H, s), 1.37 (6H, s).

(13c)3-({5-[4-(1,3-Benzene) Zin-2-ylamino)-2-chlorophenyl]pyrimidin-2-yl}oxy)-2,2-dimethylpropanoic acid

The compound (260 mg) obtained from the compound (13b) and o -aminophenol (75 mg) were obtained in the same manner as in the the compound (1b). Azole (255 mg). Benzo The azole was hydrolyzed in the same manner as Example (1c) to give the title compound 226 mg (yield: ^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.5 (1H, brs), 11.0 (1H, s), 8.71 (2H, s), 8.14 (1H, d, J = 2.3Hz), 7.77 (1H, dd, J = 8.4 and 2.1 Hz), 7.55 (2H, d, J = 8.6 Hz), 7.55 (m, 1H), 7.27 (1H, dd, J = 7.6 and 7.6 Hz), 7.19 (1H, Dd, J = 7.6 and 7.6 Hz), 4.36 (2H, s), 1.25 (6H, s).

MS (ESI) m / z: 437 (M+H) ⁺ .

(Example 14) 3-({5-[4-(1,3-Benzene) Zin-2-ylamino)-2-fluorophenyl]pyrimidin-2-yl}oxy)-2,2-dimethylpropionic acid

(14a) 3-{[5-(4-Amino-2-fluorophenyl)pyrimidin-2-yl]oxy}-2,2-dimethylpropanoic acid methyl ester

In the same manner as in the embodiment (13a), from 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (474 mg) And 3-[(5-Bromopyrimidin-2-yl)oxy]-2,2-dimethylpropanoic acid methyl ester (WO2009011285) (578 mg). .

_{^{1 H NMR (400MHz, CDCl 3}} ): δ (ppm) = 8.62 (2H, s), 7.16 (1H, dd, J = 8.4 and 8.5Hz), 6.55 (1H, dd , J = 8.2 and 2.4Hz), 6.50 (1H, dd, J = 12.3 and 2.1 Hz), 4.43 (2H, s), 3.71 (3H, s), 1.36 (6H, s).

(14b) 3-{[5-(2-Fluoro-4-isothiocyanate phenyl)pyrimidin-2-yl]oxy}-2,2-dimethylpropanoic acid methyl ester

The compound (430 mg) obtained from Example (14a) and 1,1'-thiocarbazide dipyridine-2(1H)-one (469 mg) were obtained as a white solid. The title compound was 300 mg (62%).

(14c) 3-({5-[4-(1,3-Benzene) Zin-2-ylamino)-2-fluorophenyl]pyrimidin-2-yl}oxy)-2,2-dimethylpropionic acid

The compound (299 mg) obtained from Example (14b) and o -aminophenol (90 mg) were obtained in the same manner as in Example (1b). Azole (275 mg). Benzo The azole was hydrolyzed in the same manner as Example (1c) to give the title compound (yield:

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.4 (1H, brs), 11.1 (2H, s), 8.81 (1H, s), 7.93 (1H, dd, J = 13.3 and 1.9Hz) , 7.67 (1H, dd, J = 8.6 and 8.6 Hz), 7.60 (1H, dd, J = 8.6 and 2.4 Hz), 7.56-7.53 (2H, m), 7.27 (1H, dd, J = 7.6 and 7.6 Hz) ), 7.19 (1H, dd, J = 7.8 and 7.8 Hz), 4.36 (2H, s), 1.25 (6H, s).

MS (ESI) m / z: 422 (M+H) ⁺ .

(Example 15) 3-({5-[4-(1,3-Benzene) Zin-2-ylamino)-3-methylphenyl]pyrimidin-2-yl}oxy)-2,2-dimethylpropionic acid

(15a) 3-{[5-(4-Amino-3-methylphenyl)pyrimidin-2-yl]oxy}-2,2-dimethylpropanoic acid methyl ester

In the same manner as in the embodiment (13a), from 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline ( US20050171131) (1.73g) and 3-[(5-Bromopyrimidin-2-yl)oxy]-2,2-dimethylpropanoic acid methyl ester (WO2009011285) (2.14g) gave the title as a yellow solid Compound 281 mg (9%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.64 (2H, s), 7.22 - 7.18 (1H, m), 7.21. (1H, s), 6.79 (1H, d, J = 7.8 Hz), 4.43 (2H, s), 3.71 (3H, s), 2.25 (3H, s), 1.36 (6H, s).

(15b) 3-{[5-(4-Isothiocyanate-3-methylphenyl)pyrimidin-2-yl]oxy}-2,2-dimethylpropanoic acid methyl ester

The compound (281 mg) obtained from Example (15a) and 1,1'-thiocarbazide dipyridine-2(1H)-one (207 mg) were obtained as a white solid. The title compound was 268 mg (84%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ (ppm) = 8.68 (2H, s), 7.36-7.32 (2H, m), 7.31 (1H, s), 4.46 (2H, s), 3.72 (3H, s ), 2.47 (3H, s), 1.37 (6H, s).

(15c)3-({5-[4-(1,3-Benzene) Zin-2-ylamino)-3-methylphenyl]pyrimidin-2-yl}oxy)-2,2-dimethylpropionic acid

The compound (268 mg) obtained from Example (15b) and o -aminophenol (82 mg) were obtained in the same manner as in Example (1b). Azole (235 mg). Benzo The azole was hydrolyzed in the same manner as Example (1c) to give 188 mg (yield:

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.4 (1H, brs), 9.81 (1H, s), 8.93 (2H, s), 8.02 (1H, d, J = 8.2Hz), 7.65 (1H, s), 7.63 (1H, dd, J = 10.9 and 2.8 Hz), 7.48 (1H, d, J = 7.8 Hz), 7.40 (1H, d, J = 7.0 Hz), 7.21 (1H, dd, J = 7.6 and 7.6 Hz), 7.12 (1H, dd, J = 7.9 and 7.9 Hz), 4.36 (2H, s), 2.39 (3H, s), 1.25 (6H, s).

MS (ESI) m / z: </RTI> (M+H) ⁺ .

(Example 16) 3-({5-[4-(1,3-Benzene) Zin-2-ylamino)-3-fluorophenyl]pyrimidin-2-yl}oxy)-2,2-dimethylpropionic acid

(16a) 3-{[5-(4-Amino-3-fluorophenyl)pyrimidin-2-yl]oxy}-2,2-dimethylpropanoic acid methyl ester

In the same manner as in the embodiment (13a), from 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (474 mg) And 3-[(5-Bromopyrimidin-2-yl)oxy]-2,2-dimethylpropanoic acid methyl ester (WO2009011285) (578 mg). ).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ (ppm) = 8.63 (2H, s), 7.17 (1H, dd, J = 11.8 and 2.0Hz), 7.11 (1H, dd , J = 8.0 and 2.1Hz), 6.87 (1H, dd, J = 8.6 and 8.6 Hz), 4.43 (2H, s), 3.87 (2H, brs), 3.71 (3H, s), 1.37 (6H, s).

(16b) 3-{[5-(3-Fluoro-4-isothiocyanate phenyl)pyrimidin-2-yl]oxy}-2,2-dimethylpropanoic acid methyl ester

The compound (510 mg) obtained from Example (16a) and 1,1'-thiocarbazinium dipyridin-2 (1H)-one (372 mg) were obtained as white solid. The title compound was 473 mg (82%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.69 (2H, s), 7.34 - 7.26 (3H, m), 4.46 (2H, s), 3.72 (3H, s), 1.37 (6H, s ).

IR (KBr) cm ^-1 : 2147,1724.

(16c)3-({5-[4-(1,3-Benzene) Zin-2-ylamino)-3-fluorophenyl]pyrimidin-2-yl}oxy)-2,2-dimethylpropionic acid

The compound (141 mg) obtained from Example (15b) and o -aminophenol (43 mg) were obtained in the same manner as in Example (1b). Azole (139 mg). Benzo The azole was hydrolyzed in the same manner as Example (1c) to give the title compound 112 mg (yield: 67%).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.4 (1H, brs), 10.6 (1H, brs), 8.98 (2H, s), 8.39 (1H, t, J = 8.6Hz), 7.79 (1H, dd, J = 12.5 and 2.4 Hz), 7.67 (1H, dd, J = 8.4 and 1.8 Hz), 7.52 (1H, d, J = 7.5 Hz), 7.48 (1H, d, J = 7.8 Hz) , 7.25 (1H, dd, J = 7.7 and 7.7 Hz), 7.17 (1H, dd, J = 7.7 and 7.7 Hz), 4.36 (2H, s), 1.24 (6H, s).

MS (ESI) m / z: 422 (M+H) ⁺ .

(Example 17) 1-[({5-[4-(1,3-Benzene) Zin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)methyl]cyclopropanecarboxylic acid

(17a) 1-({[5-(4-Isothiocyanato)phenyl)pyrimidin-2-yl]oxy}methyl)cyclopropanecarboxylic acid ethyl ester

Ethyl 1-({[4-aminophenyl)pyrimidin-2-yl]oxy}methyl)cyclopropanecarboxylate (WO2009011285A1) (1.12) in the same manner as in Example (1a) g) and 1,1'-thiocarbonyldiimidazole (637 mg).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 8.70 (2H, s), 7.51 (2H, d, J = 8.6Hz), 7.35 (2H, d, J = 8.6Hz), 4.59 (2H , s), 4.15 (2H, q, J = 7.1 Hz), 1.41 (2H, q, J = 4.3 Hz), 1.21 (3H, t, J = 7.0 Hz), 1.08 (2H, q, J = 4.5 Hz) ).

IR (KBr) cm ^-1 : 2120, 1709.

(17b)1-[({5-[4-(1,3-Benzene) Zin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)methyl]cyclopropanecarboxylic acid

The compound (359 mg) obtained from Example (17a) and o -aminophenol (111 mg) were obtained in the same manner as in Example (1b) to give benzene. Azole (226 mg). Benzo The azole was hydrolyzed in the same manner as in Example (1c) to give the title compound 160 mg (40%, 2 steps) as a pale brown solid.

¹ H-NMR (500 MHz, DMSO-d6): δ (ppm) = 12.44 (1H, br), 10.82 (1H, s), 8.92 (2H, s), 7.89 (2H, d, J = 8.8 Hz) , 7.77 (2H, d, J = 8.3 Hz), 7.53 - 7.49 (2H, m), 7.25 (1H, t, J = 7.6 Hz), 7.16 (1H, t, J = 7.6 Hz), 4.45 (2H, s), 1.24-1.21 (2H, m), 1.08-1.06 (2H, m).

(Example 18) 1-{[(5-{4-[(7-methyl-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]methyl}cyclopropanecarboxylic acid

The compound (113 mg) obtained in Example (17a) and 2-amino-6-methylphenol hydrochloride (51 mg) were obtained in the same manner as in Example (1b) to afford benzene. Azole (83 mg). Benzo The azole was hydrolyzed in the same manner as Example (1c) to give the title compound (yield: 46%).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.4 (1H, brs), 10.8 (1H, s), 8.92 (2H, s), 7.89 (2H, d, J = 8.6Hz), 7.76 (2H, d, J = 9.0 Hz), 7.31 (1H, d, J = 7.4 Hz), 7.14 (1H, dd, J = 7.9 and 7.8 Hz), 6.98 (1H, d, J = 7.5 Hz), 4.45 (2H, s), 2.45 (3H, s), 1.22 (2H, q, J = 3.9 Hz), 1.07 (2H, q, J = 4.1 Hz).

MS (ESI) m / z: 417 (M+H) ⁺ .

(Example 19) {cis-4-[(5-{4-[(7-methyl-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid

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

To a solution of (trans-4-hydroxycyclohexyl)acetic acid methyl ester (WO2009119534) (2.58g) and 5-bromopyrimidin-2-ol (1.74g) in toluene (30mL), cyanosyl at room temperature Methyltributylphosphine (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 EtOAcjjjj:

_{^{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).

(19b) (cis-4-{[5-(4-Aminophenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid methyl ester

The compound obtained in Example (19a) (1.67 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.11 g) ), tetrakis(triphenylphosphine)palladium(0) (295 mg), and potassium carbonate (1.41 g) of 1,4-two A solution of alkane/water (7:3, 30 mL) was heated at 80 °C for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and evaporated. 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).

(19c) (cis-4-{[5-(4-isothiocyanate phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid methyl ester

The compound (439 mg) obtained from Example (19b) and 1,1'-thiocarbazide dipyridine-2(1H)-one (299 mg) were obtained in the same manner as in Example (1a). The title compound was 432 mg (88%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ (ppm) = 8.69 (2H, s), 7.51 (2H, d, J = 7.5Hz), 7.34 (2H, d, J = 8.2Hz), 5.32 (1H, Brs), 3.68 (3H, s), 2.30 (2H, d, J = 7.1 Hz), 2.13 - 2.09 (2H, m), 1.98 - 1.92 (1H, m), 1.74-1.58 (6H, m).

IR(KBr)cm ^-1 : 2134,1733.

(19d) {cis-4-[(5-{4-[(7-methyl-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid

The compound (767 mg) obtained in Example (19c) and 2-amino-6-methylphenol (252 mg) were obtained in the same manner as in Example (1b). Azole (786 mg). Benzo The azole was hydrolyzed in the same manner as in Example (1c) to give the title compound 745 mg (81%, 2 step).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.0 (1H, brs), 10.9 (1H, s), 8.90 (2H, s), 7.89 (2H, d, J = 8.9Hz), 7.75 (2H, d, J = 9.0 Hz), 7.75 (1H, d, J = 9.0 Hz), 7.14 (1H, dd, J = 7.6 and 7.6 Hz), 6.99 (1H, d, J = 7.9 Hz), 5.22 -5.21(1H,m), 2.45(3H,s), 2.19(2H,d,J=7.1Hz),1.98-1.94(2H,m),1.87-1.80(1H,m),1.72-1.64(2H , m), 1.62-1.57 (2H, m), 1.43-1.33 (2H, m).

MS (ESI) m / z: 459 (M+H) ⁺ .

(Example 20) [cis-4-({5-[4-(1,3-Benzene) Zin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid

In the same manner as in Example (1b), the compound obtained in Example (19c) (1.22 g) and o -aminophenol (347 mg) afforded benzo. Azole (1.20 g). Similarly combining the other batches of benzene prepared Azole, using 2.51 g of benzoxene The azole is hydrolyzed. Benzo The azole (2.51 g) was hydrolyzed in the same manner as Example (1c) to give the title compound 1.

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.1 (1H, brs), 10.8 (1H, s), 8.90 (2H, s), 7.89 (2H, d, J = 9.0Hz), 7.76 (2H, d, J = 8.7 Hz), 7.52 (1H, d, J = 7.9 Hz), 7.50 (1H, d, J = 7.8 Hz), 7.25 (1H, dt, J = 10.4 and 3.7 Hz), 7.16 (1H, dt, J = 10.7 and 3.9 Hz), 5.22 - 5.21 (1H, m), 2.19 (2H, d, J = 7.0 Hz), 1.98-1.94 (2H, m), 1.87-1.80 (1H, m ), 1.72-1.64 (2H, m), 1.61-1.57 (2H, m), 1.43-1.34 (2H, m).

MS (ESI) m / z: 445 (M+H) ⁺ .

(Example 21) [cis-4-({5-[4-(1,3-benzo) Zin-2-ylamino)phenyl]pyridin-2-yl}oxy)cyclohexyl]acetic acid

(21a) {cis-4-[(5-bromopyridin-2-yl)oxy]cyclohexyl}acetic acid methyl ester

In the same manner as in the embodiment (19a), (trans-4-hydroxycyclohexyl)acetic acid methyl ester (WO2009119534) (2.58 g) and 5-bromopyridin-2-ol (1.74 g), cyania Methyl tributylphosphine (CMBP) (3.93 mL) gave the title compound 2.

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).

(21b) (cis-4-{[5-(4-aminophenyl)pyridin-2-yl]oxy}cyclohexyl)acetic acid methyl ester

The compound (2.76 g) obtained from the example (21a) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboride in the same manner as in the compound (19b). Pentacyclo-2-yl)aniline (1.84 g) gave the title compound 2.37 g (83%).

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).

(21c) (cis-4-{[5-(4-isothiocyanate phenyl)pyridin-2-yl]oxy}cyclohexyl)acetic acid methyl ester

The title compound (546 mg) (yield: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> .

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.34 (1H, d, J = 2.7 Hz), 7.75 (1H, dd, J = 8.6 and 2.3 Hz), 7.50 (2H, d, J = 9.0 Hz), 7.30 (2H, d, J = 8.6 Hz), 6.81 (1H, d, J = 8.6 Hz), 5.31-5.29 (1H, m), 3.69 (3H, s), 2.30 (2H, d, J = 7.5 Hz), 2.07-2.03 (2H, m), 1.99-1.91 (1H, m), 1.71-1.58 (4H, m), 1.53-1.43 (2H, m).

IR (KBr) cm ^-1 : 2095, 1735.

(21d) [cis--4-({5-[4-(1,3-benzo) Zin-2-ylamino)phenyl]pyridin-2-yl}oxy)cyclohexyl]acetic acid

The compound (149 mg) obtained from Example (21c) and o -aminophenol (43 mg) were obtained in the same manner as in Example (1b). Azole (124 mg). Benzo The azole was hydrolyzed in the same manner as in Example (1c) to give the title compound (yield: 47%).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 10.8 (1H, s), 8.46 (1H, d, J = 3.1Hz), 7.99 (1H, dd, J = 8.6 and 2.7Hz), 7.86 (2H, d, J = 8.6 Hz), 7.69 (2H, d, J = 9.0 Hz), 7.52 (1H, d, J = 7.8 Hz), 7.49 (1H, d, J = 7.8 Hz), 7.25 (1H) , dd, J = 7.6 and 7.6 Hz), 7.15 (1H, dd, J = 7.7 and 7.7 Hz), 6.88 (1H, d, J = 8.6 Hz), 5.24 - 5.23 (1H, m), 2.18 (2H, d, J = 7.0 Hz), 1.95-1.90 (2H, m), 1.86-1.80 (1H, m), 1.68-1.64 (2H, m), 1.62-1.55 (2H, m), 1.43-1.33 (2H, m).

MS (ESI) m / z: 444 (M+H) ⁺ .

(Example 22) [cis-4-({5-[4-(1,3-benzo) Zin-2-ylamino)phenyl]pyridinium -2-yl}oxy)cyclohexyl]acetic acid

(22a){cis--4-[(5-bromopyridyl) 2-yl)oxy]cyclohexyl}acetic acid methyl ester

In the same manner as in the embodiment (19a), methyl (trans-4-hydroxycyclohexyl)acetate (WO2009119534) (694 mg) and 5-bromopyridinium 2-Phenol (470 mg), cyanomethylenetributylphosphine (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).

(22b) (cis-4-{[5-(4-aminophenyl)pyridinium Methyl-2-yl]oxy}cyclohexyl)acetate

The compound (633 mg) obtained from Example (22a) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) were obtained in the same manner as in Example (19b). Cyclo-2-yl)aniline (421 mg) ield EtOAc (EtOAc)

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).

(22c) (cis-4-{[5-(4-isothiocyanate phenyl)pyrene Methyl-2-yl]oxy}cyclohexyl)acetate

The compound (63 mg) obtained from Example (22b) and 1,1'-thiocarbazide dipyridine-2(1H)-one (43 mg) were obtained in the same manner as in Example (1a). The title compound was 50 mg (70%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.47 (1H, d, J = 1.6 Hz), 8.25 (1H, d, J = 1.5 Hz), 7.91 (2H, d, J = 9.0 Hz) , 7.33 (2H, d, J = 9.0 Hz), 5.31-5.29 (1H, m), 3.69 (3H, s), 2.31 (2H, d, J = 7.0 Hz), 2.08-2.03 (2H, m), 1.98-1.93 (1H, m), 1.72-1.55 (4H, m), 1.52-1.46 (2H, m).

(22d) [cis--4-({5-[4-(1,3-benzo) Zin-2-ylamino)phenyl]pyridinium -2-yl}oxy)cyclohexyl]acetic acid

In the same manner as in Example (1b), the compound (50 mg) obtained from Example (22c) and o -aminophenol (14 mg) afforded benzo. Azole (45 mg). Benzo The azole was hydrolyzed in the same manner as Example (1c) to give the title compound 36 mg (yield: 63%).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.1 (1H, brs), 10.8 (1H, s), 8.75 (1H, d, J = 1.6Hz), 8.33 (1H, d, J = 1.5 Hz), 8.05 (2H, d, J = 9.0 Hz), 7.88 (2H, d, J = 8.6 Hz), 7.53 (1H, d, J = 7.8 Hz), 7.51 (1H, d, J = 7.8 Hz) ), 7.25 (1H, dd, J = 7.6 and 7.7 Hz), 7.16 (1H, dd, J = 7.8 and 7.9 Hz), 5.24 - 5.23 (1H, m), 2.19 (2H, d, J = 7.1 Hz) , 1.97-1.93 (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: 445 (M+H) ⁺ .

(Example 23) [cis-4-({5-[4-(1,3-benzo) Zin-2-ylamino)-2-methylphenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid

(23a) (cis-4-{[5-(4-Amino-2-methylphenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid methyl ester

The compound (658 mg) obtained from the compound (19a), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2, - dioxolan-2-yl) aniline (466 mg) ield:

_{^{1 H NMR (400MHz, CDCl 3}} ): δ (ppm) = 8.44 (2H, s), 6.99 (1H, d, J = 8.2Hz), 6.65-6.60 (2H, m), 5.30-5.28 (1H, m ), 3.68 (3H, s), 2.29 (2H, d, J = 7.4 Hz), 2.22 (3H, s), 2.14-2.10 (2H, m), 1.98-1.92 (1H, m), 1.73-1.53 ( 6H, m).

(23b) (cis-4-{[5-(4-isothiocyanate-2-methylphenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid methyl ester

The compound (178 mg) obtained from Example (23a) and 1,1'-thiocarbazide dipyridin-2(1H)-one (116 mg) were obtained as colorless in the same manner as in Example (1a). The title compound was 157 mg (79%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.45 (2H, s), 7.19-7.13 (3H, m), 5.32-5.31 (1H, m), 3.68 (3H, s), 2.31 (3H) , s), 2.30 (2H, d, J = 7.9 Hz), 2.14-2.10 (2H, m), 1.99-1.92 (1H, m), 1.75-1.56 (6H, m).

(23c) [cis--4-({5-[4-(1,3-benzo) Zin-2-ylamino)-2-methylphenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid

The compound (157 mg) obtained from Example (23b) and o -aminophenol (43 mg) were obtained in the same manner as in Example (1b) to give benzene. Azole (161 mg). Benzo The azole was hydrolyzed in the same manner as in Example (1c) to give the title compound 121 mg (yield: 67%).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.1 (1H, brs), 10.7 (1H, s), 8.61 (2H, s), 7.75 (1H, dd, J = 8.4 and 2.1Hz) , 7.68 (1H, d, J = 1.9 Hz), 7.51 (1H, d, J = 9.0 Hz), 7.49 (1H, d, J = 7.8 Hz), 7.31 (1H, d, J = 8.2 Hz), 7.24 (1H, dd, J=7.6 and 7.7 Hz), 7.15 (1H, dd, J=7.9 and 7.9 Hz), 5.22-5.21 (1H, m), 2.30 (3H, s), 2.20 (2H, d, J) =7.1 Hz), 1.99-1.94 (2H, m), 1.88-1.81 (1H, m), 1.72-1.64 (2H, m), 1.62-1.58 (2H, m), 1.44-1.35 (2H, m).

MS (ESI) m / z: 459 (M+H) ⁺ .

(Example 24) [cis-4-({5-[4-(1,3-benzo) Zin-2-ylamino)-3-fluorophenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid

(24a) (cis-4-{[5-(4-Amino-2-methylphenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid methyl ester

The compound (771 mg) obtained from the compound (19a), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- The title compound 533 mg (63%) was obtained as a pale yellow solid.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ (ppm) = 8.62 (2H, s), 7.16 (1H, dd, J = 11.7 and 2.0Hz), 7.11 (1H, dd , J = 8.3 and 1.5Hz), 6.87 (1H, dd, J=9.0 and 8.3 Hz), 5.30-5.28 (1H, m), 3.68 (3H, s), 2.29 (2H, d, J = 7.1 Hz), 2.12-2.08 (2H, m) , 1.98-1.89 (1H, m), 1.72-1.51 (6H, m).

(24b) (cis-4-{[5-(3-fluoro-4-isothiocyanate phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid methyl ester

The compound (214 mg) obtained from Example (24a) and 1,1'-thiocarbazide dipyridine-2(1H)-one (138 mg) were obtained in the same manner as in Example (1a). The title compound was 197 mg (82%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.67 (2H, s), 7.34 - 7.25 (3H, m), 5.33-5.31 (1H, m), 3.68 (3H, s), 2.29 (2H) , d, J = 7.0 Hz), 2.13 - 2.08 (2H, m), 2.00-1.92 (1H, m), 1.74-1.54 (6H, m).

(24c) [cis-4-({5-[4-(1,3-benzo) Zin-2-ylamino)-3-fluorophenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid

The compound (197 mg) obtained from Example (24b) and o -aminophenol (54 mg) were obtained in the same manner as in Example (1b). Azole (201 mg). Benzo The azole was hydrolyzed in the same manner as Example (1c) to give 181 mg (yield:

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.1 (1H, brs), 10.6 (1H, brs), 8.96 (2H, s), 8.39 (1H, dd, J = 8.6 and 8.6Hz) , 7.77 (1H, dd, J = 12.3 and 2.2 Hz), 7.66 (1H, dd, J = 8.4 and 1.3 Hz), 7.52 (1H, d, J = 7.8 Hz), 7.48 (1H, d, J = 7.9) Hz), 7.25 (1H, dd, J = 7.6 and 7.6 Hz), 7.16 (1H, dd, J = 7.7 and 7.7 Hz), 5.24 - 5.22 (1H, m), 2.19 (2H, d, J = 7.0 Hz) ), 1.98-1.94 (2H, m), 1.86-1.81 (1H, m), 1.72-1.64 (2H, m), 1.62-1.57 (2H, m), 1.43-1.33 (2H, m).

MS (ESI) m / z: 467 (M+H) ⁺ .

(Example 25) [cis-4-({5-[6-(1,3-Benzene) Zin-2-ylamino)pyridin-3-yl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid

(25a) 3-{[5-(6-Aminopyridin-3-yl)pyrimidin-2-yl]oxy}-2,2-dimethylpropanoic acid methyl ester

In the same manner as in the embodiment (19b), from 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (440 mg) And cis -4-[(5-bromopyrimidin-2-yl)oxy]cyclohexyl}acetic acid methyl ester (289 mg) afforded the title compound 245 mg (87%).

_{^{1 H NMR (500MHz, CDCl 3}} ): δ (ppm) = 8.61 (2H, s), 8.23 (1H, s), 7.58 (1H, d, J = 8.4Hz), 6.61 (1H, d, J = 8.4 Hz), 5.29 (1H, brs), 4.60 (2H, brs), 3.68 (3H, s), 2.29 (2H, d, J = 7.3 Hz), 2.12 - 2.05 (2H, m), 2.12 - 2.05 (1H , m), 2.12-2.05 (6H, m).

(25b) (cis-4-{[5-(6-isothiocyanate)pyridin-3-yl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid

The compound (200 mg) obtained from Example (25a) and 1,1'-thiocarbazide dipyridin-2(1H)-one (136 mg) were obtained in the same manner as in Example (1a). The title compound was 189 mg (85%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.70 (2H, s), 8.61 (1H, d, J = 2.3 Hz), 7.86 (1H, dd, J = 8.2 and 2.3 Hz), 7.22 ( 1H,d,J=7.8Hz), 5.34-5.32(1H,m), 3.68(3H,s), 2.29(2H,d,J=7.5Hz),2.13-2.09(2H,m),1.98-1.93 (1H, m), 1.75-1.51 (6H, m).

(25c)[cis--4-({5-[6-(1,3-benzo) Zin-2-ylamino)pyridin-3-yl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid

In the same manner as in Example (1b), the compound (100 mg) obtained from Example (25b) and o -aminophenol (28 mg) afforded benzo. Azole (94 mg). Benzo The azole was hydrolyzed in the same manner as in Example (1c) to give the title compound (yield: 70%).

1H NMR (400MHz, DMSO-d6): δ (ppm) = 11.5 (1H, brs), 8.97 (2H, s), 8.73 (1H, d, J = 2.0 Hz), 8.38 (1H, d, J = 9.0 Hz), 8.25 (1H, dd, J = 8.8 and 2.6 Hz), 7.55 (2H, t, J = 6.8 Hz), 7.28 (1H, t, J = 7.6 Hz), 7.20 (1H, t, J = 7.6) Hz), 5.23 (1H, brs), 2.19 (2H, d, J = 7.0 Hz), 1.99-1.94 (2H, m), 1.87-1.81 (1H, m), 1.72-1.57 (4H, m), 1.72 -1.57 (2H, m).

(Example 26) 3-({5-[4-(1H-Benzimidazol-2-ylamino)phenyl]pyrimidin-2-yl}oxy)-2,2-dimethylpropanoic acid

The compound (50 mg) obtained from Example (1a) and o -phenylenediamine (16 mg) were obtained in the same manner as in Example (1b) to give the benzimidazole (52 mg). This benzimidazole body was hydrolyzed in the same manner as in the Example (1c) to give the title compound 23 mg (40%, 2 steps) as a yellow solid.

1H NMR (400MHz, DMSO-d6): δ (ppm) 8.93 (2H, s), 7.84 (2H, d, J = 8.6 Hz), 7.75 (2H, d, J = 8.6 Hz), 7.37 (2H, dd , J = 5.9 and 3.1 Hz), 7.08 (2H, dd, J = 5.1 and 3.1 Hz), 4.35 (2H, s), 1.25 (6H, s).

(Example 27) 2,2-Dimethyl-3-[(5-{4-[(1-methyl-1H-benzimidazol-2-yl)amino]phenyl}pyrimidin-2-yl Oxy]propionic acid

In the same manner as in Example (1b), the compound (50 mg) obtained from Example (1b) and N-methylbenzene-1,2-diamine 2 hydrochloride (29 mg) afforded the benzimidazole. (34mg). This benzimidazole body was hydrolyzed in the same manner as in the Example (1c) to give the title compound 13 mg (yield: 21%).

1H NMR (400MHz, DMSO-d6): δ (ppm) = 9.13 (1H, brs), 8.92 (2H, s), 8.02 (2H, d, J = 8.6 Hz), 7.72 (2H, d, J = 8.6 Hz), 7.43-7.41 (1H, m), 7.35-7.32 (1H, m), 7.09-7.07 (2H, m), 4.35 (2H, s), 3.74 (3H, s), 1.25 (6H, s) .

(Example 28) 3-({5-[4-(1,3-benzothiazol-2-ylamino)phenyl]pyrimidin-2-yl}oxy)-2,2-dimethylpropane acid

3-{[5-(4-Aminophenyl)pyrimidin-2-yl]oxy}-2,2-dimethylpropanoic acid methyl ester (WO2009011285A1) (301 mg) and 2-chloro-1, A solution of 3-benzothiazole (169 mg) in 1-butanol (6 mL) was heated at 100 °C for 13 h. The mixture was concentrated, diluted with ethyl acetate, washed with water and evaporated. The residue was purified by column chromatography (yield chromatography, methylene chloride/ethyl acetate: 100:0:75:25) to afford 330 mg (76%) of benzothiazole as a yellow amorphous material. This benzothiazolyl was hydrolyzed in the same manner as Example (1c) to give 299 mg (yield:

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.4 (1H, brs), 10.7 (1H, s), 8.93 (2H, s), 7.93 (2H, d, J = 8.6Hz), 7.84 (1H, d, J = 8.2 Hz), 7.76 (2H, d, J = 8.6 Hz), 7.65 (1H, d, J = 8.6 Hz), 7.36 (1H, dd, J = 8.2 and 8.2 Hz), 7.19 (1H, dd, J = 6.8 and 6.9 Hz), 4.35 (2H, s), 1.24 (6H, s).

MS (ESI) m / z: 421 (M+H) ⁺ .

(Example 29) 2,2-Dimethyl-3-[(5-{4-[(6-methyl-1,3-benzothiazol-2-yl)amino]phenyl}pyrimidine-2 -yloxy]propionic acid

In the same manner as in the embodiment (28), methyl 3-{[5-(4-aminophenyl)pyrimidin-2-yl]oxy}-2,2-dimethylpropanoate (WO2009011285) A1) (301 mg) and 2-chloro-6-methyl-1,3-benzothiazole (183 mg) gave the benzothiazole (311 mg). This benzothiazole body was hydrolyzed in the same manner as in the Example (1c) to give 276 mg (yield:

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.4 (1H, brs), 10.6 (1H, s), 8.92 (2H, s), 7.91 (2H, d, J = 8.6Hz), 7.75 (2H, d, J = 8.7 Hz), 7.63 (1H, dd, J = 0.9 and 1.0 Hz), 7.53 (1H, d, J = 8.2 Hz), 7.16 (1H, dd, J = 8.8 and 1.7 Hz) , 4.35 (2H, s), 2.37 (3H, s), 1.24 (6H, s)

MS (ESI) m / z: 435 (M+H) ⁺ .

(Example 30) 3-[(5-{4-[(6-fluoro-1,3-benzothiazol-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]-2, 2-dimethylpropionic acid

In the same manner as in Example (28), from methyl 3-{[5-(4-aminophenyl)pyrimidin-2-yl]oxy}-2,2-dimethylpropanoate (WO2009011285A1) (301 mg) and 2-chloro-6-fluoro-1,3-benzothiazole (187 mg) gave the benzothiazole (136 mg). This benzothiazole body was hydrolyzed in the same manner as in Example (1c) to give the title compound 111 mg (26%, 2 steps).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.4 (1H, brs), 10.7 (1H, s), 8.92 (2H, s), 7.90 (2H, d, J = 8.7Hz), 7.79 -7.75 (1H, m), 7.76 (2H, d, J = 9.0 Hz), 7.64 (1H, dd, J = 8.8 and 4.9 Hz), 7.19 (1H, m), 4.35 (2H, s), 1.24 ( 6H, s).

MS (ESI) m / z: 437 (M+H) ⁺ .

(Example 31) [cis-4-({5-[4-(1H-benzimidazol-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid

The compound (100 mg) obtained from the compound (19c) and o -phenylenediamine (28 mg) were obtained in the same manner as in the compound (1b) to obtain the benzimidazole (82 mg). This benzimidazole body (80 mg) was hydrolyzed in the same manner as Example (1c) to give the title compound 70 mg (64%, 2 step).

1H NMR (400MHz, DMSO-d6): δ (ppm) = 12.0 (1H, brs), 11.0 (1H, brs), 9.64 (1H, brs), 8.88 (2H, s), 7.90 (2H, d, J) = 9.0 Hz), 7.69 (2H, d, J = 9.0 Hz), 7.34 (2H, brs), 7.04-7.00 (2H, m), 5.21 (1H, brs), 2.19 (2H, d, J = 7.1 Hz) ), 1.99-1.94 (2H, m), 1.86-1.81 (1H, m), 1.71-1.57 (4H, m), 1.43-1.34 (2H, m).

(Example 32) {cis-4-[(5-{4-[(1-methyl-1H-benzimidazol-2-yl)amino]phenyl}pyrimidin-2-yl)oxy] Cyclohexyl}acetic acid

In the same manner as in Example (1b), the compound obtained in Example (19c) (1.29 g) and N-methylbenzene-1,2-diamine 2 hydrochloride (411 mg) afforded benzimidazole. Body (668 mg). This benzimidazole body (591mg) The title compound ( 591 mg (39%, 2 steps) was obtained as a pale brown solid.

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.1 (1H, brs), 9.12 (1H, s), 8.90 (2H, s), 8.02 (2H, d, J = 8.9Hz), 7.71 (2H,d,J=9.0Hz), 7.44-7.40(1H,m),7.34-7.31(1H,m),7.10-7.06(2H,m),5.22-5.21(1H,m),3.74(3H , s), 2.20 (2H, d, J = 7.1 Hz), 1.98-1.94 (2H, m), 1.87-1.79 (1H, m), 1.71-1.64 (2H, m), 1.61-1.57 (2H, m ), 1.43-1.34 (2H, m).

MS (ESI) m / z: 458 (M+H) ⁺ .

(Example 33) {cis-4-[(5-{4-[(4-methyl-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid

The compound (100 mg) obtained in Example (19c) and 2-amino-3-methylphenol (32 mg) were obtained in the same manner as in Example (1b). Azole (111 mg). Benzo The azole (105 mg) was hydrolyzed to give the title compound (yield: 78%).

1H NMR (500MHz, DMSO-d6): δ (ppm) = 12.1 (1H, brs), 10.7 (1H, brs), 8.90 (2H, s), 7.90 (2H, d, J = 6.8 Hz), 7.76 ( 2H,d,J=8.3Hz), 7.32(1H,d,J=7.4Hz),7.07-7.03(2H,m),5.21(1H,brs),2.49(3H,s),2.19(2H,d , J = 6.8 Hz), 1.99-1.94 (2H, m), 1.86-1.70 (1H, m), 1.57-1.42 (4H, m), 1.39-1.34 (2H, m).

(Example 34) {cis-4-[(5-{4-[(5-methyl-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid

The compound (767 mg) obtained in Example (19c) and 2-amino-4-methylphenol (246 mg) were obtained in the same manner as in Example (1b). Azole (740 mg). Benzo The azole (740 mg) was hydrolyzed to give the title compound (yield: 76%).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.1 (1H, brs), 10.8 (1H, s), 8.91 (2H, s), 7.87 (2H, d, J = 8.6Hz), 7.76 (2H, d, J = 9.0 Hz), 7.39 (1H, d, J = 8.2 Hz), 7.30 (1H, s), 6.96 (1H, d, J = 8.2 Hz), 5.23-5.21 (1H, m) , 2.39 (3H, s), 2.19 (2H, d, J = 7.0 Hz), 1.98-1.94 (2H, m), 1.86-1.81 (1H, m), 1.72-1.64 (2H, m), 1.62-1.57 (2H,m), 1.43-1.33 (2H, m).

MS (ESI) m / z: 459 (M+H) ⁺ .

(Example 35) {cis-4-[(5-{4-[(6-methyl-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid

The compound (100 mg) obtained in Example (19c) and 2-amino-5-methylphenol (321 mg) were obtained in the same manner as in Example (1b). Azole (117 mg). Benzo The azole (117 mg) was hydrolyzed to give the title compound (yield: 78%).

1H NMR (400MHz, DMSO-d6): δ (ppm) 12.1 (1H, brs), 10.7 (1H, s), 8.90 (2H, s), 7.87 (2H, d, J = 8.6 Hz), 7.75 (2H) , d, J = 8.6 Hz), 7.36 (1H, d, J = 8.2 Hz), 7.35 (1H, s), 7.06 (1H, d, J = 7.8 Hz), 5.21 (1H, brs), 2.40 (3H) , s), 2.19 (2H, d, J = 7.1 Hz), 1.98-1.94 (2H, m), 1.87-1.80 (1H, m), 1.71-1.57 (4H, m), 1.42-1.34 (2H, m ).

(Example 36) [trans-4-({5-[4-(1,3-benzo) Zin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid

(36a) {trans-4-[(5-bromopyrimidin-2-yl)oxy]cyclohexyl}acetic acid methyl ester

In the same manner as in Example (19a), 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) ⁺ .

(36b) (trans-4-{[5-(4-aminophenyl)pyrimidin-2-yl]oxy}cyclohexylacetic acid methyl ester

The compound (475 mg) obtained from Example (36a) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron in the same manner as in Example (19b). ring 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).

(36c) (trans-4-{[5-(4-isothiocyanate phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid methyl ester

The compound (449 mg) obtained from Example (36b) and 1,1'-thiocarbazide dipyridine-2(1H)-one (306 mg) were obtained in the same manner as in Example (1a). The title compound was 504 mg (93%). 1H-NMR (500 MHz, CDCl ₃ ): δ (ppm) = 8.67 (2H, s), 7.50 (2H, d, J = 8.3 Hz), 7.34 (2H, d, J = 8.3 Hz), 5.01-4.94 (1H, m), 3.69 (3H, s), 2.27-2.20 (4H, m), 1.92-1.84 (3H, m), 1.65-1.57 (2H, m), 1.25-1.16 (2H, m).

(36d) [trans-4-({5-[4-(1,3-benzo) Zin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid

The compound (235 mg) obtained from Example (36c) and 2-aminophenol (67 mg) were obtained in the same manner as in Example (1b) to give benzene. Azole (306 mg). Benzo The azole (302 mg) was hydrolyzed to give the title compound 276 mg (94%, 2 steps) as a pale brown solid.

¹ H-NMR (500 MHz, DMSO-d6): δ (ppm) = 12.10 (1H, brs), 10.80 (1H, brs), 8.91 (2H, s), 7.88 (2H, d, J = 8.8 Hz) , 7.75 (2H, d, J = 8.8 Hz), 7.52 - 7.48 (2H, m), 7.24 (1H, t, J = 7.8 Hz), 7.15 (1H, t, J = 7.8 Hz), 4.94 - 4.88 ( 1H,m), 3.18-3.14(1H,m), 2.16-2.11(3H,m),1.83-1.80(2H,m),1.50-1.46(2H,m),1.33-1.29(1H,m), 1.18-1.12 (2H, m).

(Example 37) [trans-4-({5-[4-(1,3-benzo) Zin-2-ylamino)phenyl]pyridin-2-yl}oxy)cyclohexyl]acetic acid

(37a) {trans-4-[(5-bromopyridin-2-yl)oxy]cyclohexyl}acetic acid methyl ester

In the same manner as in the embodiment (19a), methyl (cis-4-hydroxycyclohexyl)acetate (WO2009119534) (3.43 g), 5-bromopyridin-2-ol (2.78 g), and cyano group Methylene tributylphosphine (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).

(37b) (trans-4-{[5-(4-Aminophenyl)pyridin-2-yl]oxy}cyclohexyl)acetic acid methyl ester

The compound (1.47 g) obtained from Example (37a) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboride were obtained in the same manner as in Example (19b). 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).

(37c) (trans-4-{[5-(4-isothiocyanate phenyl)pyridin-2-yl]oxy}cyclohexyl)acetic acid methyl ester

The title compound (872 mg) (yield: 86%) ).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.33 (1H, d, J = 3.1 Hz), 7.74 (1H, dd, J = 8.8 and 2.6 Hz), 7.50 (2H, d, J = 8.7) Hz), 7.30 (2H, d, J = 9.0 Hz), 6.77 (1H, d, J = 8.6 Hz), 5.04-4.96 (1H, m), 3.69 (3H, s), 2.26 (2H, d, J =6.6 Hz), 2.21-2.17 (2H, m), 1.90- 1.84 (3H, m), 1.57-1.45 (2H, m), 1.27-1.16 (2H, m).

IR (KBr) cm ^-1 : 2134,1740.

(37d) [trans-4-({5-[4-(1,3-benzo) Zin-2-ylamino)phenyl]pyridin-2-yl}oxy)cyclohexyl]acetic acid

The compound (229 mg) obtained from Example (37c) and 2-aminophenol (65 mg) were obtained in the same manner as in the Example (1b). Azole (238 mg). Benzo The azole (238 mg) was hydrolyzed in the same manner as in Example (1c) to give the title compound 230 mg (yield: 86%).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 10.8 (1H, s), 8.47 (1H, d, J = 2.8Hz), 7.99 (1H, dd, J = 8.6 and 2.8Hz), 7.86 (2H, d, J = 8.6 Hz), 7.69 (2H, d, J = 8.6 Hz), 7.52 (1H, d, J = 7.4 Hz), 7.49 (1H, dd, J = 7.9 and 0.8 Hz), 7.24 (1H, dt, J = 10.6 and 3.8 Hz), 7.15 (1H, dt, J = 10.7 and 3.9 Hz), 6.84 (1H, dd, J = 8.6 and 0.8 Hz), 4.99 - 4.91 (1H, m), 2.16 (2H, d, J = 7.0 Hz), 2.13 - 2.09 (2H, m), 1.82-1.78 (2H, m), 1.74-1.68 (1H, m), 1.47-1.37 (2H, m), 1.19- 1.09 (2H, m).

MS (ESI) m / z: 444 (M+H) ⁺ .

(Example 38) {cis-4-[(5-{4-[(7-fluoro-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid

The compound (60 mg) obtained in Example (19c) and 2-amino-6-fluorophenol (20 mg) were obtained in the same manner as in Example (1b). Azole (52 mg). Benzo The azole (52 mg) was hydrolyzed to give the title compound (25%, m.

1H NMR (500MHz, DMSO-d6): δ (ppm) = 12.0 (1H, brs), 11.1 (1H, s), 8.90 (2H, d, J = 2.5 Hz), 7.85 (2H, d, J = 6.3 Hz), 7.76 (2H, d, J = 6.8 Hz), 7.34 (1H, d, J = 7.8 Hz), 7.26-7.22 (1H, m), 7.08 (1H, t, J = 9.6 Hz), 5.23 5.19 (1H, m), 2.19 (2H, d, J = 6.9 Hz), 1.97-1.94 (2H, m), 1.86-1.80 (1H, m), 1.70-1.57 (6H, m).

(Example 39) {cis-4-[(5-{4-[(6-fluoro-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid

The compound (60 mg) obtained in Example (19c) and 2-amino-5-fluorophenol (20 mg) were obtained in the same manner as in Example (1b). Azole (58 mg). Benzo The azole (58 mg) was hydrolyzed in the same manner as Example (1c) to give the title compound 40 mg (55%, 2 step).

1H NMR (500MHz, DMSO-d6): δ (ppm) = 12.1 (1H, brs), 10.8 (1H, brs), 8.89 (2H, s), 7.85 (2H, d, J = 6.8 Hz), 7.75 ( 2H, d, J = 8.8 Hz), 7.55 (1H, d, J = 8.8 Hz), 7.47 (1H, dd, J = 8.3 and 4.9 Hz), 7.10 (1H, t, J = 9.5 Hz), 5.21 ( 1H, brs), 2.19 (2H, d, J = 6.8 Hz), 1.95 (2H, d, J = 13.2 Hz), 1.87-1.79 (1H, m), 1.70-1.57 (6H, m).

(Example 40) {cis-4-[(5-{4-[(4-fluoro-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid

The compound (60 mg) obtained in Example (19c) and 2-amino-3-fluorophenol (20 mg) were obtained in the same manner as in Example (1b). Azole (52 mg). Benzo The azole (52 mg) was hydrolyzed to give the title compound (yield: 50%).

1H NMR (400MHz, DMSO-d6): δ (ppm) = 11.0 (1H, s), 8.91 (2H, s), 7.88 (2H, d, J = 9.0 Hz), 7.78 (2H, d, J = 9.0 Hz), 7.41 (1H, dd, J = 7.2 and 1.8 Hz), 7.20-7.12 (2H, m), 5.24-5.20 (1H, m), 2.19 (2H, d, J = 7.1 Hz), 2.00-1.80 (1H, m), 1.72-1.56 (4H, m), 1.43-1.40 (2H, m).

(Example 41) {cis-4-[(5-{4-[(5-fluoro-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid

The compound (200 mg) obtained in Example (19c) and 2-amino-4-fluorophenol (70 mg) were obtained in the same manner as in Example (1b). Azole (187 mg). Benzo The azole (185 mg) was hydrolyzed to give the title compound (yield: 24%).

1H NMR (400MHz, DMSO-d6): δ (ppm) = 10.9 (1H, s), 8.91 (2H, s), 7.87 (2H, d, J = 8.6 Hz), 7.76 (2H, d, J = 9.0 Hz), 7.53 (1H, dd, J = 8.8 and 4.5 Hz), 7.36 (1H, dd, J = 9.0 and 2.3 Hz), 7.00-6.95 (1H, m), 5.22-5.20 (1H, m), 2.19 (2H, d, J = 7.1 Hz), 1.99-1.93 (2H, m), 1.87-1.80 (1H, m), 1.72-1.56 (4H, m), 1.43-1.33 (2H, m).

(Example 42) [cis-3-({5-[4-(1,3-Benzene) Zin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclopentyl]acetic acid

(42a) cis-{3-[(5-bromopyrimidin-2-yl)oxy]cyclopentyl}acetic acid methyl ester

In the same manner as in the example (19a), p-(3-hydroxycyclopentyl)acetic acid methyl ester (WO2009119534) (899 mg) and 5-bromopyrimidin-2-ol (875 mg) were obtained as a colorless solid. 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).

(42b) cis-(3-{[5-(4-Aminophenyl)pyrimidin-2-yl]oxy}cyclopentyl)acetic acid methyl ester

The compound (812 mg) obtained from Example (42a) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron in the same manner as in Example (19b). </RTI> </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt;

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).

(42c) cis-methyl (3-{[5-(4-isothiocyanate)phenyl)pyrimidin-2-yl]oxy}cyclopentyl) acetate

The compound (155 mg) obtained from Example (42b) and 1,1'-thiocarbazide dipyridine-2(1H)-one (110 mg) were obtained as colorless in the same manner as in the Example (1a). The title compound was 159 mg (91%).

¹ H-NMR (500 MHz, CDCl ₃ ): δ (ppm) = 8.68 (2H, s), 7.50 (2H, d, J = 8.3 Hz), 7.34 (2H, d, J = 8.3 Hz), 5.46- 5.42 (1H, m), 3.67 (3H, s), 2.52-2.36 (4H, m), 2.03-1.91 (3H, m), 1.60-1.53 (2H, m).

(42d) [cis-3-({5-[4-(1,3-benzo) Zin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclopentyl]acetic acid

The compound (150 mg) obtained from Example (42c) and 2-aminophenol (45 mg) were obtained in the same manner as in Example (1b). Azole (185 mg). Benzo The azole was hydrolyzed in the same manner as in Example (1c) to give the title compound 151 mg (86%, 2 steps) as pale brown solid.

¹ H-NMR (500 MHz, DMSO-d6): δ (ppm) = 12.04 (1H, br), 10.79 (1H, s), 8.91 (2H, s), 7.88 (2H, d, J = 8.8 Hz) , 7.76 (2H, d, J = 8.7 Hz), 7.52-7.48 (2H, m), 7.24 (1H, t, J = 7.6 Hz), 7.15 (1H, t, J = 8.3 Hz), 5.37-5.33 ( 1H, m), 2.40-2.21 (3H, m), 2.03-1.94 (1H, m), 1.89-1.81 (1H, m), 1.60-1.54 (1H, m), 1.47-1.39 (2H, m), 1.35-1.27 (1H, m).

(Example 43) [trans-3-({5-[4-(1,3-benzo) Zin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclopentyl]acetic acid

(43a) trans-{3-[(5-bromopyrimidin-2-yl)oxy]cyclopentyl}acetic acid methyl ester

In the same manner as in Example (19a), from cis-(3-hydroxycyclopentyl)acetic acid methyl ester (WO2009119534) (1.91 g) and 5-bromopyrimidin-2-phenol (1.75 g), 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).

(43b) trans-(3-{[5-(4-Aminophenyl)pyrimidin-2-yl]oxy}cyclopentyl)acetic acid methyl ester

The compound (1.70 g) obtained from Example (43a) 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 1.46 g (83%).

_{^{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).

(43c) trans-methyl (3-{[5-(4-isothiocyanate)phenyl)pyrimidin-2-yl]oxy}cyclopentyl) acetate

The compound (159 mg) obtained from Example (43b) and 1,1'-thiocarbazinium dipyridin-2 (1H)-one (113 mg) were obtained as colorless in the same manner as in the Example (1a). The title compound was 177 mg (99%).

¹ H-NMR (500 MHz, CDCl ₃ ): δ (ppm) = 8.68 (2H, s), 7.50 (2H, d, J = 8.8 Hz), 7.34 (2H, d, J = 8.3 Hz), 5.50- 5.46(1H,m), 3.67(3H,s), 2.72-2.62(1H,m), 2.40-2.38(2H,m), 2.26-2.08(3H,m),1.97-1.90(1H,m), 1.68-1.62 (1H, m), 1.35-1.28 (1H, m).

(43d) [trans-3-({5-[4-(1,3-benzo) Zin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclopentyl]acetic acid

The compound (172 mg) obtained from Example (43c) and 2-aminophenol (51 mg) were obtained in the same manner as in Example (1b) to give benzene. Azole (146 mg). Benzo The azole (146 mg) was hydrolyzed in the same manner as in Example (1c) to give the title compound 129 mg (64%, 2 steps) as pale brown solid.

¹ H-NMR (500 MHz, DMSO-d6): δ (ppm) = 12.10 (1H, br), 10.80 (1H, brs), 8.90 (2H, s), 7.88 (2 H, d, J = 8.8 Hz ), 7.76 (2H, d, J = 8.7 Hz), 7.52-7.48 (2H, m), 7.24 (1H, t, J = 7.8 Hz), 7.15 (1H, t, J = 7.8 Hz), 5.42-5.38 (1H, m), 2.32-2.29 (2H, m), 2.21-2.14 (1H, m), 2.03-1.94 (2H, m), 1.78-1.72 (1H, m), 1.62-1.57 (1H, m) , 1.34-1.22 (2H, m).

(Example 44) [cis-4-({5-[4-(1,3-benzothiazol-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid

The compound (176 mg) obtained from Example (19b) and 2-chloro-1,3-benzothiazole (85 mg) were obtained in the same manner as in Example (28) to afford benzothiazole (60 mg). This benzothiazole body was hydrolyzed in the same manner as in Example (1c) to give the title compound (yield: 23%).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 10.7 (1H, brs), 8.91 (2H, s), 7.92 (2H, d, J = 8.6Hz), 7.84 (1H, dd, J = 7.8 and 0.8 Hz), 7.75 (2H, d, J = 8.9 Hz), 7.65 (1H, d, J = 7.4 Hz), 7.37-7.33 (1H, m), 7.21-7.17 (1H, m), 5.22 5.21(1H,m), 2.19 (2H,d,J=7.0Hz), 1.98-1.94(2H,m),1.86-1.81(1H,m),1.72-1.64(2H,m),1.61-1.57( 2H, m), 1.43-1.34 (2H, m). MS (ESI) m/z: 461 (M+H) ⁺ .

(Example 45) trans-4-({5-[4-(1,3-Benzene) Zin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexanecarboxylic acid

(45a) trans-4-[(5-bromopyrimidin-2-yl)oxy]cyclohexanecarboxylic acid methyl ester

In the same manner as in Example (19a), from cis-4-hydroxycyclohexanecarboxylic acid methyl ester (WO2009119534) (1.13 g) and 5-bromopyrimidin-2-ol (1.00 g), a colorless oil was obtained. The title compound 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).

(45b) trans-4-{[5-(4-aminophenyl)pyrimidin-2-yl]oxy}cyclohexanecarboxylic acid methyl ester

The compound (341 mg) obtained in Example (45a) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) were obtained in the same manner as in the Example (1b). Cyclo-2-yl)aniline (240 mg) gave 293 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).

(45c) trans-4-{[5-(4-isothiocyanate phenyl)pyrimidin-2-yl]oxy}cyclohexanecarboxylic acid methyl ester

The compound (273 mg) obtained from Example (45b) and 1,1'-thiocarbazide dipyridin-2 (1H)-one (196 mg) were obtained as colorless in the same manner as in Example (1a). The title compound was 254 mg (82%).

¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) = 8.69 (2H, s), 7.52 (2H, d, J = 8.8 Hz), 7.34 (2H, d, J = 8.3 Hz), 5.07-5.01 (1H,m), 3.70(3H,s),2.43-2.37(1H,m), 2.28-2.26(2H,m),2.13-2.11(2H,m),1.71-1.58(4H,m).

(45d) trans-4-({5-[4-(1,3-benzo) Zin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexanecarboxylic acid

The compound (254 mg) obtained in Example (45c) and 2-aminophenol (75 mg) were obtained in the same manner as in Example (1b) to give benzene. Azole (299 mg). Benzo The azole (299 mg) was hydrolyzed in the same manner as in the Example (1c) to give the title compound 252 mg (yield: 70%).

¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) = 12.13 (1H, brs), 10.80 (1H, s), 8.92 (2H, s), 7.89 (2H, d, J = 8.8 Hz), 7.76 (2H, d, J = 8.8 Hz), 7.53-7.49 (2H, m), 7.25 (1H, t, J = 7.6 Hz), 7.16 (1H, t, J = 7.1 Hz), 4.97-4.91 (1H, m), 2.34 - 2.28 (1H, m), 2.19 - 2.14 (2H, m), 2.03-1.97 (2H, m), 1.56-1.46 (4H, m).

(Example 46) cis-4-({5-[4-(1,3-Benzene) Zin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexanecarboxylic acid

(46a) cis-4-[(5-bromopyrimidin-2-yl)oxy]cyclohexanecarboxylic acid methyl ester

In the same manner as in the embodiment (19a), a trans-form-4-hydroxycyclohexanecarboxylic acid methyl ester (WO2009119534) (1.00 g) and 5-bromopyrimidin-2-ol (1.08 g) were obtained as a colorless solid. The title compound was 1.80 g (16%).

¹ H-NMR (500 MHz, CDCl ₃ ): δ (ppm) = 8.50 (2H, s), 5.15-5.11 (1H, m), 3.68 (3H, s), 2.46-2.42 (1H, m), 2.15 -1.98 (4H, m), 1.80-1.69 (4H, m).

(46b) cis-4-{[5-(4-Aminophenyl)pyrimidin-2-yl]oxy}cyclohexanecarboxylic acid methyl ester

The compound (473 mg) obtained from Example (46a) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron in the same manner as in Example (19b). Cyclo-2-yl)aniline (330 mg) afforded 499 mg (yield of quantitative) of the title compound as a pale yellow solid.

¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) = 8.65 (2H, s), 7.34 (2H, d, J = 8.3 Hz), 6.81 (2H, d, J = 8.3 Hz), 5.27-5.23 (1H, m), 3.83 (2H, brs), 3.72 (3H, s), 2.51-2.46 (1H, m), 2.14-2.06 (4H, m), 1.86-1.74 (4H, m).

(46c) cis-4-{[5-(4-Isothiocyanate phenyl)pyrimidin-2-yl]oxy}cyclohexanecarboxylic acid methyl ester

The compound (497 mg) obtained from Example (46b) and 1,1'-thiocarbazide dipyridin-2(1H)-one (354 mg) were obtained in the same manner as in Example (1a). The title compound was 470 mg (84%).

¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) = 8.68 (2H, s), 7.51 (2H, d, J = 8.3 Hz), 7.34 (2H, d, J = 8.8 Hz), 5.27-5.24 (1H, m), 3.69 (3H, s), 2.50-2.40 (1H, m), 2.12-2.03 (4H, m), 1.84-1.72 (4H, m).

(46d) cis-4-({5-[4-(1,3-Benzene) Zin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexanecarboxylic acid

The compound (240 mg) obtained in Example (46c) and 2-aminophenol (82 mg) were obtained in the same manner as in Example (1b). Azole (217 mg). Benzo The azole (215 mg) was hydrolyzed in the same manner as in Example (1c) to give the title compound 187 mg (47%, 2 steps) as a pale brown solid.

¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) = 12.15 (1H, brs), 10.79 (1H, s), 8.90 (2H, s), 7.88 (2H, d, J = 8.8 Hz), 7.76 (2H, d, J = 8.8 Hz), 7.52-7.48 (2H, m), 7.24 (1H, t, J = 7.5 Hz), 7.15 (1H, t, J = 7.6 Hz), 5.19-5.15 (1H, m), 2.44-2.39 (1H, m), 1.92-1.69 (8H, m).

(Example 47) [cis-4-({5-[4-(1H-benzimidazol-2-ylamino)phenyl]pyridin-2-yl}oxy)cyclohexyl]acetic acid

In the same manner as in Example (1b), the compound (76 mg) obtained from Example (21c) and o -phenylenediamine (22 mg) afforded the benzimidazole (77 mg). This benzimidazole body (77 mg) was hydrolyzed in the same manner as Example (1c) to give the title compound 47 mg (yield: 53%).

1H NMR (500MHz, DMSO-d6): δ (ppm) = 11.9 (1H, brs), 9.89 (1H, brs), 8.45 (1H, s), 7.98 (1H, d, J = 8.8 Hz), 7.79 ( 2H,d,J=7.4Hz), 7.66(2H,d,J=8.3Hz), 7.36-7.34(2H,m),7.07(2H,brs),6.87(1H,d,J=8.3Hz), 5.23(1H,brs), 2.19(2H,d,J=7.3Hz),1.94-1.91(2H,m),1.86-1.79(1H,m),1.67-1.62(2H,m),1.58-1.56( 2H, m), 1.43-1.33 (2H, m).

(Example 48) {cis-4-[(5-{4-[(1-methyl-1H-benzimidazol-2-yl)amino]phenyl}pyridin-2-yl)oxy] Cyclohexyl}acetic acid

The compound (76 mg) obtained in Example (21c) and N-methylbenzene-1,2-diamine (24 mg) were obtained in the same manner as in Example (1b) to give the benzimidazole (43 mg). This benzimidazole body (43 mg) was hydrolyzed in the same manner as in Example (1c) to give the title compound (yield: 28%).

1H NMR (400MHz, DMSO-d6): δ (ppm) = 12.0 (1H, s), 9.07 (1H, brs), 8.45 (1H, d, J = 3.1 Hz), 7.99-7.96 (3H, m), 7.64(2H,d,J=8.6Hz), 7.42-7.40(1H,m),7.34-7.32(1H,m),7.09-7.06(2H,m),6.87(1H,d,J=8.6Hz) , 5.23 (1H, brs), 3.73 (3H, s), 2.18 (2H, d, J = 7.1 Hz), 1.95-1.79 (2H, m), 1.68-1.64 (1H, m), 1.61-1.55 (4H , m), 1.43-1.36 (2H, m).

(Example 49) {cis-4-[(5-{4-[(7-methyl-1H-benzimidazol-2-yl)amino]phenyl}pyrimidin-2-yl)oxy] Cyclohexyl}acetic acid

The compound (100 mg) obtained from Example (19c) and 3-methylbenzene-1,2-diamine (32 mg) were obtained in the same manner as in Example (1b) to give the benzimidazole (78 mg). This benzimidazole body (78 mg) was hydrolyzed in the same manner as Example (1c) to give the title compound 47 mg (40%, 2 steps) as a pale brown solid.

1H NMR (400MHz, DMSO-d6): δ (ppm) = 12.0 (1H, brs), 9.84 (1H, brs), 8.91 (2H, s), 7.82 (2H, d, J = 8.3 Hz), 7.74 ( 2H, d, J = 8.6 Hz), 7.19 (1H, d, J = 7.8 Hz), 6.99 (1H, t, J = 7.2 Hz), 6.91 (1H, d, J = 7.4 Hz), 5.24-5.20 ( 1H,m), 2.47(3H,s), 2.19(2H,d,J=7.1Hz), 1.98-1.94(2H,m),1.87-1.80(1H,m),1.72-1.64(2H,m) , 1.62-1.57 (2H, m), 1.43-1.34 (2H, m).

(Example 50) {cis-4-[(5-{4-[(6-fluoro-1H-benzimidazol-2-yl)amino]phenyl}pyrimidin-2-yl)oxy] ring Hexyl acetate

The compound (100 mg) obtained in Example (19c) and 4-fluorobenzene-1,2-diamine (32 mg) were obtained in the same manner as in Example (1b) to give the benzimidazole (93 mg). This benzimidazole body (92 mg) was hydrolyzed in the same manner as Example (1c) to give the title compound 54 mg (45%, 2 step).

1H NMR (400MHz, DMSO-d6): δ (ppm) = 11.0 (1H, brs), 8.95 (2H, s), 7.85 (2H, d, J = 8.6 Hz), 7.66 (2H, d, J = 8.6 Hz), 7.40 (1H, dd, J=9.0 and 4.6 Hz), 7.25 (1H, dd, J=9.0 and 2.8 Hz), 7.10-7.05 (1H, m), 5.25-5.21 (1H, m), 2.20 (2H,d,J=7.0Hz), 1.99-1.94(2H,m),1.87-1.81(1H,m),1.73-1.65(2H,m),1.62-1.56(2H,m),1.43-1.33 (2H, m).

(Example 51) {cis-4-[(5-{4-[(7-fluoro-1H-benzimidazol-2-yl)amino]phenyl}pyrimidin-2-yl)oxy] ring Hexyl acetate

The compound (100 mg) obtained from the compound (19c) and 3-fluorobenzene-1,2-diamine (33 mg) were obtained in the same manner as in the Example (1b) to obtain the benzimidazole (55 mg). This benzimidazole body (55 mg) was hydrolyzed in the same manner as Example (1c) to give the title compound 30 mg (25%, 2 steps) as a pale brown solid.

1H NMR (400MHz, DMSO-d6): δ (ppm) = 10.2 (1H, brs), 8.92 (2H, s), 7.81 (2H, d, J = 8.6 Hz), 7.76 (2H, d, J = 8.6 Hz), 7.20 (1H, d, J = 7.8 Hz), 7.10-7.05 (1H, m), 7.00-6.94 (1H, m), 5.23-5.20 (1H, m), 2.20 (2H, d, J = 7.1 Hz), 1.99-1.93 (2H, m), 1.87-1.80 (1H, m), 1.72-1.64 (2H, m), 1.61-1.57 (2H, m), 1.43-1.34 (2H, m).

(Example 52) [cis-4-({5-[4-(1H-benzimidazol-2-ylamino)-2-methylphenyl]pyrimidin-2-yl}oxy)cyclohexyl Acetic acid

The compound (100 mg) obtained from Example (23b) and benzene-1,2-diamine (27 mg) were obtained in the same manner as in Example (1b) to give the benzimidazole (84 mg). This benzimidazole body (83 mg) was hydrolyzed in the same manner as Example (1c) to give the title compound 62 mg (55%, 2 steps).

1H NMR (400MHz, DMSO-d6): δ (ppm) = 11.9 (1H, brs), 9.99 (1H, brs), 8.62 (2H, s), 7.68-7.66 (1H, m), 7.59-7.58 (1H , m), 7.37-7.35 (2H, m), 7.30 (1H, d, J = 8.2 Hz), 7.10-7.08 (2H, m), 5.24 - 5.22 (1H, m), 2.30 (3H, s), 2.20(2H,d,J=7.1Hz), 1.99-1.95(2H,m),1.87-1.81(1H,m),1.73-1.65(2H,m),1.62-1.58(2H,m),1.44- 1.35 (2H, m).

(Example 53) {cis-4-[(5-{2-methyl-4-[(1-methyl-1H-benzimidazol-2-yl)amino]phenyl}pyrimidin-2- Alkyloxy]cyclohexyl}acetic acid

The compound (100 mg) obtained in Example (23b) and N-methylbenzene-1,2-diamine (30 mg) were obtained in the same manner as in Example (1b) to give the benzimidazole (66 mg). This benzimidazole body (65 mg) was hydrolyzed in the same manner as Example (1c) to give the title compound (yield: 5%).

1H NMR (400MHz, DMSO-d6): δ (ppm) = 12.0 (1H, brs), 8.63 (2H, s), 7.80-7.75 (1H, m), 7.68-7.66 (1H, m), 7.42-7.40 (2H, m), 7.31 (1H, d, J = 8.6 Hz), 7.16-7.14 (2H , m), 5.25-5.21 (1H, m), 3.75 (3H, s), 2.31 (3H, s), 2.20 (2H, d, J = 7.1 Hz), 1.99-1.94 (2H, m), 1.87- 1.81 (1H, m), 1.72-1.65 (2H, m), 1.62-1.58 (2H, m), 1.44-1.35 (2H, m).

(Example 54) {cis-4-[(5-{4-[(6-methyl-1H-benzimidazol-2-yl)amino]phenyl}pyrimidin-2-yl)oxy] Cyclohexyl}acetic acid

The compound (100 mg) obtained in Example (19c) and 4-methylbenzene-1,2-diamine (96 mg) were obtained in the same manner as in Example (1b) to give the benzimidazole (96 mg). This benzimidazole (96 mg) was hydrolyzed in the same manner as Example (1c) to give the title compound (yield: 51%).

1H NMR (500MHz, DMSO-d6): δ (ppm) = 12.5 (1H, brs), 12.0 (1H, brs), 10.6 (1H, brs), 8.93 (2H, s), 7.80 (2H, d, J =7.8 Hz), 7.68 (2H, d, J = 7.8 Hz), 7.28 (1H, d, J = 8.3 Hz), 7.20 (1H, s), 7.01 (1H, d, J = 8.3 Hz), 5.22 ( 1H, brs), 2.39 (3H, s), 2.19 (2H, d, J = 7.3 Hz), 1.99-1.94 (2H, m), 1.86-1.82 (1H, m), 1.71-1.66 (2H, m) , 1.61-1.57 (2H, m), 1.42-1.35 (2H, m).

(Example 55) {cis-4-[(5-{4-[(1,6-dimethyl-1H-benzimidazol-2-yl)amino]phenyl}pyrimidin-2-yl) Oxy]cyclohexyl}acetic acid

The compound (100 mg) obtained in Example (19c) and N ² ,4-dimethylbenzene-1,2-diamine (35 mg) were obtained in the same manner as in the the the (43mg). This benzimidazole body (43 mg) was hydrolyzed in the same manner as in Example (1c) to give the title compound (32%,

1H NMR (500MHz, DMSO-d6): δ (ppm) = 10.2 (1H, brs), 8.93 (2H, s), 7.82 (2H, d, J = 8.3 Hz), 7.75 (2H, d, J = 8.3) Hz), 7.34 (1H, s), 7.28 (1H, d, J = 8.3 Hz), 7.05 (1H, d, J = 7.8 Hz), 5.24-5.20 (1H, m), 3.76 (3H, s), 2.43 (3H, s), 2.19 (2H, d, J = 6.8 Hz), 1.99-1.95 (2H, m), 1.87-1.81 (1H, m), 1.71-1.66 (2H, m), 1.60-1.58 ( 2H, m), 1.42-1.35 (2H, m).

(Example 56) {cis-4-[(5-{4-[(1,5-dimethyl-1H-benzimidazol-2-yl)amino]phenyl}pyrimidin-2-yl) Oxy]cyclohexyl}acetic acid

In the same manner as in Example (1b), from Example (19C) compound (93 mg) and the obtained N ^1, 4- dimethylbenzene-1,2-diamine (33mg), obtained body-benzimidazole (42 mg). This benzimidazole body (42 mg) was hydrolyzed in the same manner as in Example (1c) to give the title compound 17 mg (15%, 2 steps) as a brown solid.

1H NMR (400MHz, DMSO-d6): δ (ppm) = 12.0 (1H, brs), 9.19 (1H, brs), 8.90 (2H, s), 7.95 (2H, d, J = 8.6 Hz), 7.72 (2H, d, J = 8.6 Hz), 7.24 - 7.22 (2H, m), 6.92 (1H, d, J = 7.9 Hz), 5.24 - 5.19 (1H, m), 3.71 (3H, s), 2.38 (3H, s), 2.19 (2H, d, J = 7.1 Hz), 1.99-1.94 (2H, m ), 1.87-1.79 (1H, m), 1.72-1.64 (2H, m), 1.61-1.57 (2H, m), 1.44-1.34 (2H, m).

(Example 57) {cis-4-[(5-{4-[(1,7-dimethyl-1H-benzimidazol-2-yl)amino]phenyl}pyrimidin-2-yl) Oxy]cyclohexyl}acetic acid

The compound (87 mg) obtained in Example (19c) and N ² ,3-dimethylbenzene-1,2-diamine (31 mg) were obtained in the same manner as in the Example (1b) to obtain the benzimidazole. (25mg). This benzimidazole body (25 mg) was hydrolyzed in the same manner as Example (1c) to give the title compound 16 mg (15%).

1H NMR (400MHz, DMSO-d6): δ (ppm) = 11.9 (1H, brs), 9.72 (1H, brs), 8.93 (2H, s), 7.78 (4H, s), 7.24 (1H, d, J) =7.6 Hz), 7.06 (1H, t, J = 7.6 Hz), 6.93 (1H, d, J = 7.6 Hz), 5.23-5.21 (1H, m), 3.96 (3H, s), 2.70 (3H, s ), 2.20 (2H, d, J = 7.0 Hz), 1.99-1.94 (2H, m), 1.87-1.80 (1H, m), 1.72-1.64 (2H, m), 1.61-1.57 (2H, m), 1.43-1.34 (2H, m).

(Example 58) (cis-4-{[4'-(1,3-Benzene) Zin-2-ylamino)biphenyl-4-yl]oxy}cyclohexyl)acetic acid

(58a) cis-4-[(5-Bromopyrimidin-2-yl)oxy]cyclohexanecarboxylic acid methyl ester

In the same manner as in Example (19a), p-trans-4-hydroxycyclohexanecarboxylic acid methyl ester (WO2009119534) (2.07 g) and 5-bromopyrimidin-2-ol (1.73 g) were obtained as pale yellow. The title compound of the oil was 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).

(58b) {cis-4-[(4'-Aminobiphenyl-4-yl)oxy]cyclohexyl}acetic acid methyl ester

The compound (2.07 g) obtained from Example (58a) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboride were obtained in the same manner as in the compound (19b). 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).

(58c) {cis-4-[(4'-isothiocyanatebiphenyl-4-yl)oxy]cyclohexyl}acetic acid methyl ester

Obtained from Example (58b) in the same manner as in Example (1a) Compound (339 mg) and 1,1'-thiocarbonyldiimidazole (178 mg) gave 332 mg (87%)

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 7.53 (2H, d, J = 8.6 Hz), 7.48 (2H, d, J = 9.0 Hz), 7.27 (2H, d, J = 8.6 Hz) , 6.98 (2H, d, J = 9.0 Hz), 4.58-4.57 (1H, m), 3.68 (3H, s), 2.29 (2H, d, J = 7.1 Hz), 2.07-2.02 (2H, m), 1.96-1.89 (1H, m), 1.66-1.47 (6H, m).

(58d) (cis-4-{[4'-(1,3-benzo) Zin-2-ylamino)biphenyl-4-yl]oxy}cyclohexyl)acetic acid

The compound (332 mg) obtained from Example (58c) and 2-aminophenol (95 mg) were obtained in the same manner as in Example (1b) to give benzene. Azole (297 mg). Benzo The azole (297 mg) was hydrolyzed in the same manner as in Example (1c) to give the title compound 276 mg (72%, 2 steps).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.0 (1H, brs), 10.7 (1H, s), 7.82 (2H, d, J = 8.6Hz), 7.64 (2H, d, J = 9.0 Hz), 7.57 (2H, d, J = 8.6 Hz), 7.51 (1H, d, J = 7.5 Hz), 7.48 (1H, d, J = 7.0 Hz), 7.26 - 7.22 (1H, m), 7.17 -7.12 (1H, m), 7.03 (2H, d, J = 9.0 Hz), 4.62-4.61 (1H, m), 2.17 (2H, d, J = 7.0 Hz), 1.92-1.88 (2H, m), 1.84-1.78 (1H, m), 1.64-1.60 (2H, m), 1.57-1.51 (2H, m), 1.42-1.32 (2H, m).

MS (ESI) m / z: 443 (M+H) ⁺ .

(Example 59) 2,2-dimethyl-3-({5-[4-([1,3] Zoxao[4,5-b]pyridin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)propanoic acid

(59a) 2,2-dimethyl-3-({5-[4-([1,3] Methylazo[4,5-b]pyridin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)propanoate

In tetrahydrofuran compound (343 mg) of the obtained (1a) (10mL) solution of Example, was added at room temperature o -2- aminopyridine-3-ol (110mg). The reaction mixture was stirred at room temperature for 1 hour and then heated under reflux for 15 hours. After cooling to room temperature, triethylamine (0.14 mL) and iodobenzene diacetate (322 mg) were added to the mixture, and the resulting mixture was stirred at room temperature for 1.5 hr and concentrated. The residue was purified by column chromatography eluting elut elut elut elut eluting

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 11.1 (1H, s), 8.94 (2H, s), 8.26 (1H, m), 7.90 (2H, d, J = 8.6Hz), 7.90 (1H, m), 7.80 (2H, d, J = 9.0 Hz), 7.17-7.13 (1H, m), 4.39 (2H, s), 3.64 (3H, s), 1.28 (6H, s).

(59b) 2,2-dimethyl-3-({5-[4-([1,3] Zoxao[4,5-b]pyridin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)propanoic acid

1,4-two of the compound (131 mg) obtained in Example (59a) In a solution of alkane (4 mL), tetrabutylammonium hydroxide (1 mol/L aqueous solution, 0.63 mL) was added at room temperature. After 2 hours, the reaction mixture was evaporated, evaporated, evaporated, evaporated, evaporated The title compound was obtained as a white solid (yield: 79%).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.4 (1H, brs), 11.1 (1H, s), 8.94 (2H, s), 8.26 (1H, dd, J = 5.1 and 1.6Hz) , 7.91-7.88 (3H, m), 7.81 (2H, d, J = 9.0 Hz), 7.16 (1H, dd, J = 8.2 and 5.1 Hz), 4.36 (2H, s), 1.25 (6H, s).

MS (FAB) m / z: 406 (M + H) ⁺ .

(Example 60) 2,2-dimethyl-3-({5-[2-methyl-4-([1,3] Zoxao[4,5-b]pyridin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)propanoic acid

The compound (420 mg) obtained from Example (12a) and o -2-aminopyridin-3-ol (129 mg) were obtained as a purple solid [1,3]. Imidazo[4,5-b]pyridin-2-ylamine substrate 197 mg. This [1,3] The oxazolo[4,5-b]pyridin-2-ylamine (197 mg) was obtained in the title compound (yield: 4%).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 11.0 (1H, brs), 8.64 (2H, s), 8.26 (1H, d, J = 3.9Hz), 7.88 (1H, dd, J = 7.8 and 1.5 Hz), 7.73-7.71 (2H, m), 7.34 (1H, d, J = 9.0 Hz), 7.15 (1H, dd, J = 8.0 and 5.2 Hz), 4.35 (2H, s), 2.31 ( 3H, s), 1.25 (6H, s). MS (ESI) m/z: 420 (M+H) ⁺ .

(Example 61) 2,2-dimethyl-3-({5-[4-([1,3] Zoxao[4,5-b]pyridin-2-ylamino)phenyl]pyridin-2-yl}oxy)propionic acid

(61a) 3-{[5-(4-Isothiocyanate phenyl)pyridin-2-yl]oxy}-2,2-dimethylpropanoic acid methyl ester

In the same manner as in the embodiment (1a), methyl 3-{[5-(4-aminophenyl)pyridin-2-yl]oxy}-2,2-dimethylpropanoate (WO2009011285) (985 mg) and 1,1'- thiocarbonium dipyridine-2(1H)-one (762 mg) gave 546 mg (75%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.34 (1H, d, J = 2.0 Hz), 7.76 (1H, dd, J = 8.6 and 2.7 Hz), 7.50 (2H, d, J = 8.7) Hz), 7.30 (2H, d, J = 8.6 Hz), 6.82 (1H, d, J = 8.6 Hz), 4.38 (2H, s), 3.71 (3H, s), 1.33 (6H, s).

IR (KBr) cm ^-1 : 2121, 1733.

(61b) 2,2-dimethyl-3-({5-[4-([1,3] Zoxao[4,5-b]pyridin-2-ylamino)phenyl]pyridin-2-yl}oxy)propionic acid

The compound (576 mg) obtained from Example (61a) and o -2-aminopyridin-3-ol (185 mg) were obtained as a pale yellow solid [1,3]. ] Azolo[4,5-b]pyridin-2-ylamine substrate 316 mg. This [1,3] The oxazolo[4,5-b]pyridin-2-ylamine ( </RTI></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.4 (1H, brs), 11.1 (1H, brs), 8.48 (1H, d, J = 3.1Hz), 8.25 (1H, dd, J = 5.1 and 1.6 Hz), 8.02 (1H, dd, J = 8.6 and 2.7 Hz), 7.88 (1H, dd, J = 8.0 and 1.4 Hz), 7.86 (2H, d, J = 9.0 Hz), 7.73 (2H, d, J = 9.0 Hz), 7.14 (1H, dd, J = 7.8 and 5.1 Hz), 6.89 (1H, d, J = 8.6 Hz), 4.29 (2H, s), 1.22 (6H, s).

MS (ESI) m / z: 405 (M+H) ⁺ .

(Example 62) [cis-4-({5-[4-([1,3] Zoxao[4,5-b]pyridin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid

The compound (275 mg) obtained from Example (19c) and o -2-aminopyridin-3-ol (79 mg) were obtained as a pale yellow solid [1,3]. ] Imidazo[4,5-b]pyridin-2-ylamine matrix 199 mg. This [1,3] The oxazolo[4,5-b]pyridin-2-ylamine ( 199 mg) was obtained by the title compound (yield:

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.1 (1H, brs), 11.1 (1H, s), 8.92 (2H, s), 8.26 (1H, dd, J = 5.1 and 1.6Hz) , 7.89 (2H, d, J = 9.0 Hz), 7.89 (1H, d, J = 9.0 Hz), 7.79 (2H, d, J = 9.0 Hz), 7.16 (1H, dd, J = 7.8 and 5.1 Hz) , 5.22 - 5.22 (1H, m), 2.19 (2H, d, J = 7.0 Hz), 1.98-1.94 (2H, m), 1.86-1.81 (1H, m), 1.72-1.64 (2H, m), 1.61 -1.57(2H,m), 1.43-1.34(2H,m).

MS (ESI) m / z: s446 (M+H) ⁺ .

(Example 63) 1-[({5-[4-([1,3] Zoxa[4,5-b]pyridin-2-ylamino)phenyl]pyridin-2-yl}oxy)methyl]cyclopropanecarboxylic acid

(63a) Ethyl 1-({[5-(4-isothiocyanate)phenyl)pyridin-2-yl]oxy}methyl)cyclopropanecarboxylic acid

Ethyl l-({[5-(4-aminophenyl)pyridin-2-yl]oxy}methyl)cyclopropanecarboxylate (WO2009011285A1) (376 mg, in the same manner as in Example (1a) And 1,1'- thiocarbonium dipyridine-2(1H)-one (279 mg) gave 303 mg (71%)

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.33 (1H, d, J = 2.3 Hz), 7.77 (1H, dd, J = 8.6 and 2.8 Hz), 7.51 (2H, d, J = 9.0 Hz), 7.31 (2H, d, J = 9.0 Hz), 6.85 (1H, d, J = 8.6 Hz), 4.52 (2H, s), 4.17 (2H, q, J = 7.0 Hz), 1.38 (2H, Dd, J = 7.3 and 4.1 Hz), 1.22 (3H, t, J = 7.1 Hz), 1.05 (2H, dd, J = 7.3 and 4.5 Hz).

IR (KBr) cm ^-1 : 2096,1709.

(63b)1-[({5-[4-([1,3] Zoxa[4,5-b]pyridin-2-ylamino)phenyl]pyridin-2-yl}oxy)methyl]cyclopropanecarboxylic acid

The compound (303 mg) obtained from Example (63a) and o -2-aminopyridin-3-ol (94 mg) were obtained as a pale yellow solid [1,3]. ] Imidazo[4,5-b]pyridin-2-ylamine matrix 194 mg. This [1,3] The oxazolo[4,5-b]pyridin-2-ylamine (193 mg) was hydrolyzed to give the title compound 156 mg (45%, 2 step).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.4 (1H, brs), 11.1 (1H, s), 8.48 (1H, d, J = 2.7Hz), 8.26 (1H, dd, J = 5.1 and 1.2 Hz), 8.03 (1H, dd, J = 8.6 and 2.4 Hz), 7.90-7.86 (1H, m), 7.87 (2H, d, J = 9.0 Hz), 7.74 (2H, d, J = 8.6) Hz), 7.15 (1H, dd, J = 7.8 and 5.1 Hz), 6.93 (1H, d, J = 8.6 Hz), 4.40 (2H, s), 1.20 (2H, q, J = 3.9 Hz), 1.04 ( 2H, q, J = 3.9Hz).

MS (FAB) m / z: 403 (M + H) ⁺ .

(Example 64) [cis-4-({5-[4-([1,3] Zoxao[4,5-b]pyridin-2-ylamino)phenyl]pyridin-2-yl}oxy)cyclohexyl]acetic acid

(64a) {cis-4-[(5-bromopyridin-2-yl)oxy]cyclohexyl}acetic acid methyl ester

In the same manner as in the embodiment (19a), methyl (trans-4-hydroxycyclohexyl)acetate (WO2009119534) (2.58 g) and 5-bromopyridin-2-ol (1.74 g), cyania Methyl tributylphosphine (CMBP) (3.93 mL) gave the title compound 2.

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).

(64b) (cis-4-{[5-(4-aminophenyl)pyridin-2-yl]oxy}cyclohexyl)acetic acid methyl ester

The compound (2.76 g) obtained from Example (64a) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboride were obtained in the same manner as in the compound (19b). Penal ring Benzylamine (1.84 g) gave the title compound 2.37 g (83%).

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).

(64c) (cis-4-{[5-(4-isothiocyanate phenyl)pyridin-2-yl]oxy}cyclohexyl)acetic acid methyl ester

The title compound (546 mg) (yield: </RTI> </ RTI> </ RTI> </ RTI> </ RTI> .

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.34 (1H, d, J = 2.7 Hz), 7.75 (1H, dd, J = 8.6 and 2.3 Hz), 7.50 (2H, d, J = 9.0 Hz), 7.30 (2H, d, J = 8.6 Hz), 6.81 (1H, d, J = 8.6 Hz), 5.31-5.29 (1H, m), 3.69 (3H, s), 2.30 (2H, d, J = 7.5 Hz), 2.07-2.03 (2H, m), 1.99-1.91 (1H, m), 1.71-1.58 (4H, m), 1.53-1.43 (2H, m). IR (KBr) cm ^-1 : 2095 , 1735.

(64d)[cis--4-({5-[4-([1,3] Zoxao[4,5-b]pyridin-2-ylamino)phenyl]pyridin-2-yl}oxy)cyclohexyl]acetic acid

The compound (391 mg) obtained from Example (64c) and o -2-aminopyridin-3-ol (113 mg) were obtained in the same manner as in Example (1b). ] Imidazo[4,5-b]pyridin-2-ylamine matrix 199 mg. This [1,3] The oxazolo[4,5-b]pyridin-2-ylamine base (199 mg) was hydrolyzed to give the title compound 177 mg (yield: 39%).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.1 (1H, brs), 11.1 (1H, brs), 8.47 (1H, d, J = 3.1Hz), 8.25 (1H, dd, J = 5.1 and 1.6 Hz), 8.00 (1H, dd, J = 8.6 and 2.3 Hz), 7.88-7.85 (1H, m), 7.86 (2H, d, J = 8.6 Hz), 7.72 (2H, d, J = 8.6) Hz), 7.14 (1H, dd, J = 7.8 and 5.1 Hz), 6.88 (1H, d, J = 8.6 Hz), 5.25-5.23 (1H, m), 2.17 (2H, d, J = 7.1 Hz), 1.95-1.90 (2H, m), 1.86-1.78 (1H, m), 1.69-1.54 (4H, m), 1.42-1.33 (2H, m).

MS (ESI) m / z: 445 (M+H) ⁺ .

(Example 65) [cis-4-({5-[3-fluoro-4-([1,3] Zoxao[4,5-b]pyridin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid

(65a) (cis-4-{[5-(4-Amino-3-fluorophenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid methyl ester

The compound (5.95 g) obtained from Example (4a) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2) were obtained in the same manner as in Example (19b). - Dioxaborolan-2-yl)phenylamine (4.28 g), m.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ (ppm) = 8.62 (2H, s), 7.17 (1H, dd, J = 12.2 and 1.9Hz), 7.11 (1H, dd , J = 8.1 and 1.8Hz), 6.87 (1H, dd, J = 8.6 and 8.6 Hz), 5.30-5.28 (1H, m), 3.86 (2H, brs), 3.86 (3H, s), 2.29 (2H, d, J = 7.0 Hz), 2.13 -2.08 (2H, m), 1.98-1.91 (1H, m), 1.73-1.52 (6H, m).

(65b) (cis-4-{[5-(3-fluoro-4-isothiocyanate phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid methyl ester

The compound (202 mg) obtained from Example (65a) and 1,1'-thiocarbazide dipyridine-2(1H)-one (131 mg) were obtained in the same manner as in Example (1a). The title compound was 136 mg (60%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.68 (2H, s), 7.34 - 7.26 (3H, m), 5.33-5.31 (1H, m), 3.68 (3H, s), 2.29 (2H) , d, J = 7.0 Hz), 2.13 - 2.09 (2H, m), 1.99 - 1.92 (1H, m), 1.74-1.53 (6H, m).

(65c)[cis--4-({5-[3-fluoro-4-([1,3] Zoxao[4,5-b]pyridin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid

The compound (135 mg) obtained from Example (65b) and o -2-aminopyridin-3-ol (37 mg) were obtained in the same manner as in Example (1b). 83 mg of oxazo[4,5-b]pyridin-2-ylamine substrate. This [1,3] The oxazolo[4,5-b]pyridin-2-ylamine (83 mg) was obtained by the title compound (yield: 47%).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.0 (1H, brs), 10.9 (1H, brs), 8.98 (2H, s), 8.30 (1H, dd, J = 8.2 and 8.2Hz) , 8.24 (1H, d, J = 5.1 Hz), 7.86 (1H, d, J = 7.4 Hz), 7.79 (1H, dd, J = 12.5 and 2.0 Hz), 7.68 (1H, dd, J = 8.6 and 1.6) Hz), 7.13 (1H, dd, J = 8.0 and 4.9 Hz), 5.24 - 5.23 (1H, m), 2.20 (2H, d, J = 7.1 Hz), 2.20 - 1.99 (2H, m), 1.87-1.80 (1H, m), 1.72-1.64 (2H, m), 1.61-1.57 (2H, m), 1.43-1.33 (2H, m).

MS (FAB) m / z: 463 (M + H) ⁺ .

(Example 66) 1-[({5-[4-([1,3] Zoxao[4,5-b]pyridin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)methyl]cyclopropanecarboxylic acid

The compound (456 mg) obtained from Example (17a) and o -2-aminopyridin-3-ol (145 mg) were obtained as a pale brown solid [1,3]. ] Azolo[4,5-b]pyridin-2-ylamine substrate 215 mg. This [1,3] The oxazolo[4,5-b]pyridin-2-ylamine (215 mg) was hydrolyzed to give the title compound (yield: 31%, 2 steps) as a pale brown solid.

¹ H NMR (500 MHz, DMSO-d6): δ (ppm) = 12.44 (1H, brs), 11.14 (1H, s), 8.94 (2H, s), 8.25 (1H, d, H = 4.9 Hz), 7.90-7.88(3H,m), 7.81(2H,d,J=8.3 Hz), 7.17-7.14(1H,d,J=5.3 Hz), 4.45(2H,s),1.24-1.22(2H,m) , 1.08-1.06 (2H, m).

(Example 67) [trans-4-({5-[4-([1,3]] Zoxao[4,5-b]pyridin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid

The compound (118 mg) obtained from Example (36c) and o -2-aminopyridin-3-ol (36 mg) were obtained as a pale brown solid [1,3]. ] 93 mg of oxazo[4,5-b]pyridin-2-ylamine substrate. This [1,3] The oxazo[4,5-b]pyridin-2-ylamine (93 mg) was hydrolyzed to give the title compound (yield:

1H-NMR (500 MHz, DMSO-d6): δ (ppm) = 12.08 (1H, brs), 11.15 (1H, s), 8.92 (2H, s), 8.27 (1H, d, J = 5.4 Hz), 7.91-7.88 (3H, m), 7.79 (2H, d, J = 6.4 Hz), 7.17-7.14 (1H, m), 4.95-4.89 (1H, m), 3.18-3.15 (1H, m), 2.17- 2.12 (3H, m), 1.83-1.70 (2H, m), 1.60-1.43 (2H, m), 1.35-1.11 (2H, m), 0.95-0.92 (1H, m).

(Example 68) [trans-4-({5-[4-([1,3]] Zoxao[4,5-b]pyridin-2-ylamino)phenyl]pyridin-2-yl}oxy)cyclohexyl]acetic acid

The compound (440 mg) obtained in Example (37c) and 2-aminopyridin-3-ol (127 mg) were obtained in the same manner as in Example (1b) to obtain [1,3]. Azolo[4,5-b]pyridin-2-ylamine substrate (223 mg). This [1,3] The oxazolo[4,5-b]pyridin-2-ylamine (223 mg) was hydrolyzed to give the title compound 207 mg (yield: 40%).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.1 (1H, brs), 11.1 (1H, brs), 8.48 (1H, d, J = 3.2Hz), 8.25 (1H, dd, J = 5.0 and 1.5 Hz), 8.00 (1H, dd, J = 8.6 and 2.8 Hz), 7.89 (1H, d, J = 1.2 Hz), 7.86 (2H, d, J = 8.6 Hz), 7.72 (2H, d, J = 8.6 Hz), 7.14 (1H, dd, J = 7.8 and 5.1 Hz), 6.84 (1H, d, J = 8.6 Hz), 4.99 - 4.92 (1H, m), 2.15 (2H, d, J = 6.6) Hz), 2.13-2.09 (2H, m), 1.82-1.79 (2H, m), 1.74-1.68 (1H, m), 1.47-1.37 (2H, m), 1.19-1.09 (2H, m).

MS (ESI) m / z: 445 (M+H) ⁺ .

(Example 69) [cis-4-({5-[4-([1,3] Zoxao[4,5-c]pyridin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid

The compound (383 mg) obtained from Example (19c) and 3-aminopyridin-4-ol (110 mg) were obtained as a pale yellow solid [1,3]. Zymbolo[4,5-b]pyridin-2-ylamine matrix 279 mg. This [1,3] The oxazolo[4,5-b]pyridin-2-ylamine (279 mg) was obtained in the title compound (1%).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.0 (1H, brs), 11.3 (1H, s), 8.92 (2H, s), 8.88 (1H, s), 8.48 (1H, d, J = 5.5 Hz), 7.89 (2H, d, J = 9.0 Hz), 7.83 - 7.79 (3H, m), 5.22 - 5.20 (1H, m), 2.20 (2H, d, J = 7.1 Hz), 1.98- 1.94 (2H, m), 1.86-1.81 (1H, m), 1.71-1.64 (2H, m), 1.61-1.57 (2H, m), 1.43-1.33 (2H, m).

MS (ESI) m / z: 446 (M+H) ⁺ .

(Example 70) [cis-4-({5-[4-([1,3] Zoxao[5,4-b]pyridin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid

The compound (383 mg) obtained from Example (19c) and 3-aminopyridin-2-ol (110 mg) were obtained as a white solid [1,3]. 61 mg of oxazo[4,5-b]pyridin-2-ylamine base. This [1,3] The oxazolo[4,5-b]pyridin-2-ylamine base (61 mg) was crystallized from the title compound (1%).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.1 (1H, brs), 11.1 (1H, brs), 8.92 (2H, s), 8.04 (1H, dd, J = 5.1 and 1.5Hz) , 7.88 (2H, d, J = 8.6 Hz), 7.87 (1H, dd, J = 7.4 and 1.6 Hz), 7.78 (2H, d, J = 9.0 Hz), 7.32 (1H, dd, J = 7.8 and 5.1) Hz), 5.23-5.21 (1H, m), 2.19 (2H, d, J = 7.0 Hz), 1.98-1.94 (2H, m), 1.86-1.80 (1H, m), 1.71-1.64 (2H, m) , 1.61-1.57 (2H, m), 1.43-1.33 (2H, m).

MS (ESI) m / z: 446 (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

A reaction solution of the following composition [175 mM Tris-HCl (pH 8.0), 8 mM MgCl ₂ , 1 mg/ml BSA, 0.3 mM 1,2-dioleyl-sn-glycerol (addition of 10% 10-fold concentration of EtOH) Solution), 10 μM [ ¹⁴ C]-oleryl-CoA (about 50 mCi/mmol), 0.5% triton X-100, DGAT1 enzyme (10 μg) obtained in Test Example 1 (1), test compound or vehicle (DMSO) /MeOH, 7:3 solution, 5% addition), total volume 50 μl], and incubated at room temperature (23 ° C) for 30 minutes. A reaction stop solution (70 μl) containing isopropanol / 1-heptane / water (80:20:2, v / v / v) was added to the reaction solution and stirred, and then, water (30 μl) and 1-g by weight were added. Alkane (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 triglyceride fraction 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 to 5, 7 to 14, 16 to 52, 54 to 59 and 61 to 70 showed an inhibition ratio of 50% or more in the test compound concentration of 0.1 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. (5 mL/kg) vehicle (0.5% methylcellulose) or each test compound (1 to 10 mg/kg) suspended in vehicle. After a certain period of time, intraperitoneal administration (5 mL / kg) lipoprotein lipase inhibitor (Pluronic-F127: Sigma-Aldrich (strand), 1 g / kg, dissolved in physiological saline at 20% by weight) Immediately thereafter, the vehicle group 1 was orally administered with distilled water, and 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). . 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 plasma was rapidly separated and recovered. The neutral fat concentration in the plasma was measured using a commercially available kit (triglyceride E TEST WAKO: and Light Pure Chemical Industry Co., Ltd.) 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, 5, 9, 16, 19, 20, 24, 31, 32, 34, 35, 39, 42 to 45, 49, 61 to 65, 67 and 68 are shown in an amount of less than 1 mg/kg. More than or equal to neutral fat absorption inhibitory activity.

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

(Test Example 3)

Male C57BL/6N mice (7-12 weeks old, body weight 17-25 g, Charles River, Japan) were individually fed and fertilized for 1 week or more with high fat food (fat content: 45 kcal%: Research diet D12451). Animals were equally distributed in the experimental group based on the amount of prey during the period, and after one day of fasting, the groups were orally administered (10 mL/kg) vehicle (0.5% methylcellulose) or suspended in vehicle. Test compound (1 to 10 mg/kg). 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 compounds of Examples 1 and 62 exhibited a food intake inhibiting activity of 25% or more in an amount of 10 mg/kg or less.

From the above results, it is understood that the compound of the present invention has an excellent food suppressing action.

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

Compound of Example 1 or 2 50mg

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.

[Industrial availability]

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 as a medicine.

Claims (27)

a compound represented by the formula (I) or a pharmacologically acceptable salt thereof, Wherein R ¹ represents a hydrogen atom or a carboxyl group; R ² and R ^{3 are} independently represented by a C ₁ -C ₆ alkyl group, or R ² and R ³ together with a bonded carbon atom form a carboxyl group or a carboxymethyl group; Substituted C ₃ -C ₆ naphthenes; 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=; W represents a nitrogen atom or a formula represented by the formula -CH= Z represents a nitrogen atom or a group represented by the formula -CH=; R ^{4 is} independently represented by a halogen atom or a C ₁ -C ₆ alkyl group; A represents an oxygen atom, a sulfur atom or a formula represented by the formula -N(R ⁵ )- R ⁵ represents a hydrogen atom or a C ₁ -C ₆ alkyl group; E represents a nitrogen atom or a group represented by the formula -C(R ⁶ )=; R ⁶ represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkane Or a C ₁ -C ₆ alkoxy group; J represents a nitrogen atom or a group represented by the formula -C(R ⁷ )=; R ⁷ represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C group _{; 6} alkoxy; L represents a nitrogen atom or a group represented by the formula -C(R ⁸ )=; R ⁸ represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group; Represents a nitrogen atom or a group represented by the formula -C(R ⁹ )=; R ⁹ represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group; 0 or 1; n represents an integer from 0 to 2. A compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein R ¹ is a carboxyl group, R ² and R ³ are each a methyl group, or R ² and R ³ together with a bonded carbon atom form a cyclopropane, m is 1. The compound of claim 1 or a pharmacologically acceptable salt thereof, wherein R ¹ is a hydrogen atom, and R ² and R ³ together with the bonded carbon atom form a 4th position substituted by a carboxymethyl group or a carboxyl group; Cyclohexane, or cyclopentane substituted at the 3rd position with 1 carboxymethyl group, m is 0. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein U is a nitrogen atom, V is a group represented by the formula -CH=, and W is a nitrogen atom. The compound or a pharmacologically acceptable salt thereof, wherein U is a group represented by the formula -CH=, V is a group represented by the formula -CH=, and W is a nitrogen. atom. The compound of any one of claims 1 to 5, wherein Z is a group represented by the formula -CH=, and n is 0, or a pharmacologically acceptable salt thereof. The compound of any one of claims 1 to 5, wherein Z is a group represented by the formula -CH=, n is 1, and R ⁴ is a fluorine atom, or a pharmacologically acceptable salt thereof. The compound of any one of claims 1 to 7 or a pharmacologically acceptable salt thereof, wherein A is an oxygen atom, a sulfur atom, a group represented by the formula -NH- or a formula -N(CH ₃ )- The basis of the representation. The compound of any one of claims 1 to 8 or a pharmacologically acceptable salt thereof, wherein E, J, L and M are a group represented by the formula -CH=. The compound of any one of claims 1 to 8 or a pharmacologically acceptable salt thereof, wherein E, J and L are a group represented by the formula -CH=, M is a nitrogen atom, and the formula -C(F) ) = the base represented by or the formula -C(CH ₃ )= represents the group. The compound of any one of claims 1 to 8 or a pharmacologically acceptable salt thereof, wherein E, J and M are a group represented by the formula -CH=, and L is a formula -C(F)= The base or formula -C(CH ₃ )= represents the group. The compound of any one of claims 1 to 8 or a pharmacologically acceptable salt thereof, wherein E, L and M are a group represented by the formula -CH=, and J is a formula -C(F)= The base or formula -C(CH ₃ )= represents the group. The compound of any one of claims 1 to 8 or a pharmacologically acceptable salt thereof, wherein J, L and M are a group represented by the formula -CH=, E is a nitrogen atom, and the formula -C(F) ) = the base represented by or the formula -C(CH ₃ )= represents the group. a compound which is {cis-4-[(5-{4-[(7-methyl-1,3-benzo) Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid, {cis-4-[(5-{4-[(1-methyl-1H-benzo) Imidazolyl-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid, {cis-4-[(5-{4-[(5-methyl-1,3-) Benzo Zin-2-yl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid, 2,2-dimethyl-3-({5-[4-([1,3] Oxazo[4,5-b]pyridin-2-ylamino)phenyl]pyridin-2-yl}oxy)propionic acid, [cis-4-({5-[4-([1,3) ] Zoxa[4,5-b]pyridin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid, [cis-4-({5-[3-fluoro-4] -([1,3] Zizo[4,5-b]pyridin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid, or [trans-4-({5-[4-([ 1,3] Zizo[4,5-b]pyridin-2-ylamino)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid. A ketamine enzyme A: a dimercaptoglycerol hydrazinotransferase inhibitor containing the compound of any one of claims 1 to 14 or a pharmacologically acceptable salt thereof as an active ingredient. An ingestion inhibitor and/or an appetite suppressant comprising the compound of any one of claims 1 to 14 or a pharmacologically acceptable salt thereof as an active ingredient. A pharmaceutical composition containing the compound of any one of claims 1 to 14 or a pharmacologically acceptable salt thereof as an active ingredient. The pharmaceutical composition according to claim 17, wherein the pharmaceutical composition has the action of 醯Kytozyme A: dimercaptoglycerol hydrazinotransferase. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition has an action of suppressing food intake and/or appetite suppressing. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is hindered by 醯Kytozyme A: dimercaptoglycerol hydrazinotransferase, hinders synthesis of triglyceride, absorption of triglyceride A pharmaceutical composition for the treatment and/or prevention of a disease which is inhibited and which is a treatment, amelioration, amelioration and/or prevention of symptoms. For example, the pharmaceutical composition of claim 17 wherein the pharmaceutical composition is hindered by the reaction of the Kiev enzyme A: dimercaptoglycerol thiol transferase, and the synthesis of the triglyceride is hindered, and the symptom treatment is achieved. A pharmaceutical composition for the treatment and/or prevention of diseases that improve, alleviate and/or prevent. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is used for obesity, obesity, hyperlipidemia, triglyceride, abnormal lipid metabolism, insulin resistance syndrome, abnormal sugar tolerance, Diabetes, diabetes complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataracts, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, atherosclerosis, Treatment and/or prevention of atherosclerosis, diabetic atherosclerosis, ischemic heart disease or overeating. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is for the treatment and/or prevention of obesity or obesity. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is for the treatment and/or prevention of diabetes. A use of a compound according to any one of claims 1 to 14 or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition Things. For example, the use of the pharmaceutical composition for obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, diabetes Diabetes mellitus (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, arteries Treatment and/or prevention of atherosclerosis, diabetic atherosclerosis, ischemic heart disease or overeating. An obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetes) Auricular membrane, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, ischemic heart disease, or A method of treating and/or preventing overeating, characterized by administering a pharmacologically effective amount of a compound selected from any one of claims 1 to 14 or a pharmacologically acceptable salt thereof.