TW201139430A - Aromatic compound containing nitrogen atom(s) - Google Patents

Abstract

The present application relates to a compound having excellent glucokinase activation or pharmacologically acceptable salt thereof. The compound represented by general formula (I) or pharmacologically acceptable salt thereof. [In formula, R1 is a nitrogen-containing heterocyclyl group represented by formula (II), which can be independently substituted by one to three group selected from substituent group A; R2 is phenyl, etc., which can be independently substituted by one to five group selected from substituent group B; R3 is C1-C6 halogenated alkoxy, C1-C6 hydroxyalkoxy, etc.; Q is nitrogen atom or a group represented by formula=CH-; U is nitrogen atom or a group represented by formula=CH-; V is nitrogen atom or a group represented by formula=CH-; substituent group A is halogen atom, C1-C6 alkyl, C1-C6 halogenated alkyl, C1-C6 hydroxyalkyl, C1-C6 alkyl substituted by two hydroxyl, etc.; substituent group B is halogen atom, C1-C6 alkyl, C1-C6 halogenated alkyl, C1-C6 alkoxy, C2-C7 alkylcarbonyl, C2-C7 halogenated alkylcarbonyl, C2-C7 alkoxycarbonyl, etc.]

Description

[Technical Field] The present invention relates to a compound which is excellent in glucokinase activation and which can be used as a therapeutic drug for diabetes or the like, or a pharmacologically acceptable salt thereof. [Prior Art] Glucocyanase (sometimes abbreviated as GK; EC2.7.1.1 in the present specification) is one of four hexokinases (hexose kinase IV) found in mammals. Hexokinase, the first stage of the glycolytic system in the cell, catalyzes the conversion of glucose to glucose-6-phosphate, in which the main manifestations of GK are localized to liver and pancreatic beta cells. In pancreatic β-cells, its function is to act as a sensing mechanism for limiting the extracellular glucose concentration of glucose-stimulated insulin secretion. In the liver, the GK enzyme reaction becomes a rate-limiting phase, and the following reactions such as glycolytic and glycogen synthesis are regulated. The GK of the liver and pancreatic β cells differs in the sequence of the 15 amino acids on the terminal side of the sputum due to the difference in splicing, but the enzymatic properties are the same. The three hexokinases (I, II, III) other than GK are saturated with enzyme activity at a glucose concentration of 1 mM or less. In contrast, GK has a low affinity for glucose, and its Km 値 is 8-1 5 mM, which is close to physiological. Blood sugar sputum. Therefore, in the form of changes in blood glucose that respond to postprandial hyperglycemia (10-1 5 mM) from normal blood glucose sputum (5 mM), intracellular glucose metabolism via GK occurs. In the past, the hypothesis that the GK system functions as a glucose sensor in the liver and pancreatic β cells has been advocated (Non-Patent Documents 1 to 3). 201139430 The results of recent studies prove that GK actually plays an important role in maintaining the body's constant glucose, demonstrating the hypothesis. For example, a mouse whose glucokinase gene is destroyed shows obvious hyperglycemia symptoms and death immediately after birth, and GK heterozygous-deficient mice have poor glucose tolerance, and the function of sugar-stimulated insulin secretion is impaired (Non-Patent Document 4). . On the other hand, in a normal mouse in which GK is overexpressed, a decrease in blood glucose sputum, an increase in hepatic glucose content in the liver, and the like are observed, and this phenomenon is similar in the case of a mouse artificially causing diabetes (Non-Patent Document 5). Moreover, recent studies have also found that in humans, GK also functions as a glucose sensor and plays an important role in maintaining glucose constant. In the family of adult-type diabetes mellitus, which is called MODY2 (Maturity Onset Diabetes of the Young), the GK gene was found to be abnormal, and it was found that this case was associated with GK activity (Non-Patent Document 6). On the other hand, there is a family of mutations in which a mutation in G K activity is found, and such a family has observed symptoms of hypoglycemia on a fasting day accompanied by an increase in insulin concentration in plasma (Non-Patent Document 7). From the above report, it can be seen that GK functions as a glucose sensor in humans and the like, and plays an important role in blood sugar regulation. Therefore, among the glucose metabolism diseases including type II diabetes and the like, substances having GK activation are considered to be usable as a drug. In particular, the GK activating substance is expected to have a sugar uptake promoting action and a sugar releasing inhibitory action on the liver and an insulin secretion promoting action on the pancreatic β cells, and therefore it is expected to bring about a potent therapeutic effect that the conventional drug cannot achieve. -5- 201139430 It has been shown in recent years that the performance of pancreatic β-cell type GK is limited to the feeding center of the rat brain (Ventromedial hypothalamus, VMH). It has been known in the past that VMH has a neuron that responds to glucose concentrations. When glucose is administered to the rat brain, the food intake is lowered. On the other hand, if the glucose-like glucosamine is administered and glucose metabolism is inhibited, the food intake is increased (Non-Patent Document 8). It is known from electrophysiological experiments that glucose-responsive neuron is activated in response to changes in physiological glucose concentration (5-20 mM), and glucokinase functions as a glucose sensor as well as peripheral tissue (Non-Patent Document 9) ). Therefore, not only liver sputum and pancreatic β-cells but also glucokinase-activated substances of VMH can be expected to have not only a hypoglycemic effect but also an obesity problem associated with many type 2 diabetes patients. According to the above description, a substance having GK activation can be used as a therapeutic and preventive agent for diabetes or as a treatment and prevention drug for chronic complication of diabetes such as omental disease, kidney disease, neurosis, ischemic heart disease, arteriosclerosis and the like. . A compound having a G Κ activating ability has been reported (Patent Document 1). However, the compound of the present invention has a nitrogen-containing aromatic ring bonded to a 2,5-disubstituted pyridine structure. PRIOR ART DOCUMENT Patent Document Patent Document 1 International Publication No. 2009/09908 No. 0 Non-Patent Document Non-Patent Document 1 Am J Physiol 1984 Sep; 247 (3 Pt 2): R5 2 7 -3 6. 201139430 Non-Patent Literature 2 Diabetes. 1 9 8 6 J a η ; 3 5 (1): 6 1 - 7 . Non-Patent Document 3 Diabetes. 1 9 8 6 Oct; 3 5 ( 1 0) : 1 1 6 3 - 73. Non-patent Document 4 Cell. 1 9 9 5 Oct 6; 8 3 ( 1 ): 6 9 - 7 8. Non-Patent Document 5 Proc Natl Acad Sci USA. 1 996 Jul 9; 93(14): 7225-30. Non-Patent Literature 6 Nature. 1 992 Apr 2 3 ; 3 5 6 (6 3 7 1 ) : 7 2 1 - 2 . Non-Patent Document 7 N Engl J Med. 1 998 Jan 2 2 ; 3 3 8 (4): 2 2 6 - 3 0 . Non-Patent Document 8 Life Sci. 1 9 8 5 Dec 3 0 ; 3 7 ( 2 6): 2 4 7 5 - 8 2 . Non-Patent Document 9 Diabetes. 2 006 F eb ; 5 5 ( 2 ) : 4 1 2 - 2 0 . Erratum in: Diabetes. 2006 Mar; 55(3): 862. [Draft of the Invention] [Technical Problem to be Solved] An object of the present invention is to provide a nitrogen-containing aromatic ring compound or use the same GK activating drugs, especially for the treatment and prevention of diabetes and abnormal sugar tolerance. The inventors of the present invention have diligently studied for compounds having GK activation, and as a result, have found that nitrogen-containing aromatic ring compounds having a specific chemical structure have excellent GK activation. Further, the compound of the present invention has excellent GK selectivity, low toxicity, and few side effects. The inventors of the present invention have found that the nitrogen-containing aromatic ring compound is used for the treatment and/or prevention selected from the group consisting of diabetes, abnormal sugar tolerance, gestational diabetes, chronic diabetic syndrome (including diabetic peripheral neuropathy, diabetic nephropathy, diabetes). It is useful as a pharmaceutical active ingredient of a disease caused by a group consisting of omental disease, diabetic macroangiopathy, and metabolic syndrome. The present invention has been completed based on the above findings. [Technical method for solving the problem] The present invention relates, for example, to: (1) A compound represented by the formula (I) or a pharmacologically acceptable salt thereof:

[wherein R1 represents a nitrogen-containing heterocyclic group represented by the formula (II) which may be independently substituted by 1 to 3 groups selected from the group of the substituent group A,

R2 represents 1 to 5 independently substituted phenyl groups among groups selected from the substituent group B or 1 to 3 independently substituted pyridyl groups among the groups selected from the substituent group B, and R3 Represents a Ci-Cfi halogenated alkoxy group, a Cl_C6 hydroxyalkoxy group, a (C^-Ce alkoxyalkoxy) group or a bis(Cl_c6 alkyl)aminocarbonyl group, and Q represents a nitrogen atom or a formula ==CH - a group represented, U represents a nitrogen atom or a group represented by the formula = CH_, and V represents a nitrogen atom or a group represented by the formula =CH-, but does not contain Q, ϋ, V In the case of a group represented by the formula: CH - -8 - 201139430, the substituent group A represents a group consisting of a halogen atom, a Cl_c6 group, a halogenated alkyl group, a C^Cs hydroxyalkyl group, a Hydroxyl-substituted Ci C6, (Ci-C6), C^-Cg, methoxy, fluorenyl, CyC7 alkylcarbonyl, c2_c7 alkoxycarbonyl, amine, mercapto, monoalkane An aminocarbonyl group, a di-(Cl-C6 alkyl)aminocarbonyl group and a hydroxyl group, and the substituent group B represents a group consisting of a halogen atom, a Cl-C6 group, a C丨-ce halogenated alkyl group, C丨-c6 alkoxy, C2-C7 alkyl , G-C7 halogenated alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 halogenated alkoxycarbonyl, (^-(:6 alkylsulfonyl, CM6 halogenated alkylsulfonyl, C3-C6 Cycloalkylsulfonyl, ((^-(:6 alkoxy)-((:,-(:6 alkylsulfonyl)), halogenated alkoxyalkylsulfonyl)) and a group represented by v-nr4r5 (V represents a carbonyl group or a sulfonyl group, and R4 and R5 are the same or different and each represents a hydrogen atom, a Κ6 alkyl group or a fluorene 6 alkyl group, or R4 and R5 are integrated with a bonded nitrogen atom. a 4 to 6 membered saturated heterocyclic ring which may be independently substituted by 1 or 2 C, -C6 alkyl groups. A 4 to 6 membered saturated heterocyclic ring may further contain 1 oxygen atom or a nitrogen atom)]. In the present invention, (2) A compound represented by the formula (I) or a pharmacologically acceptable salt thereof, wherein the substituent group A is a group consisting of a halogen atom, an alkyl group, C , -C6 halogenated alkyl, h-Ce hydroxyalkyl, Ci-C6, substituted by 2 hydroxy, Ci_C6, oxy, residue, C2_C7, oxycarbonyl, mono-Ci-C6, aminyl , di-(Ci_c6)-based carbonyl group and 201139430 hydroxy 'substituent group B a group consisting of a halogen atom, a C?-C6 alkyl group, an h-C6 halogenated alkyl group, a C2-C7 alkylcarbonyl group, a c2_C7 alkoxycarbonyl group, a Ci-C6 alkylsulfonyl group, and a group represented by V_NR4R5 (V represents a carbonyl group or a sulfonyl group 'R4, R5 are the same or different and represent a hydrogen atom, a Cl-c6 alkyl group or a CrC6 halogenated alkyl group, or R4 and R5 are integrated with a bonded nitrogen atom; The 4 to 6-membered saturated heterocyclic ring which may be independently substituted by 1 or 2 d-Ce alkyl groups is formed, and may further contain 1 oxygen atom or nitrogen atom. (3) A compound represented by the formula (I) or a pharmacologically acceptable salt thereof, wherein the formula (I) is a formula (la)

And R6 is a methyl group (4) such as (1) or (2) which is a compound represented by the formula (I) or a pharmacologically acceptable salt thereof, wherein the formula (I) is a formula (lb) 201139430

(lb) :: R7 is a methyl group, a hydroxymethyl group or a methoxycarbonyl group. (5) A compound represented by the formula (I) or a pharmacologically acceptable salt thereof as in (1) or (2):

Wherein the general formula (I) is a general formula UO

(lc), R8 is a methyl group or a hydroxymethyl group. (6) The compound represented by the formula (I) or a pharmacologically acceptable salt thereof, according to any one of (1) to (5): wherein R2 is 4-methylxanylphenyl, 2 - Methyl-density group·5·π ratio n-group or 5-methylsulfonyl-2-pyridyl group (7) The formula (I) is represented by any one of (1) to (6) a compound or a pharmacologically acceptable salt thereof: wherein R3 is (lS)-2-methoxy-1-methylethoxy, (lS)-2-hydroxy-1-methylethoxy' (lS) 2-fluoro-1-methylethoxy, dimethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl or diethylaminocarbonyl. 201139430 (8) A compound represented by the formula (1) or a pharmacologically acceptable salt thereof, wherein the formula (1) is a formula (Ia) 'r6 is a methyl group' and R2 is a 4-methyl group. Nonylphenyl, 2-methylsulfonyl-5-pyridyl or 5-methylsulfonyl-2-pyridyl' R3 is (lS)-2-methoxy-1-methylethoxy , 〇S)-2-yl-1-methylethoxy, (lS)-2-fluoro-b-methylethoxy, dimethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl or two Ethylaminocarbonyl. (9) A compound represented by the formula (I) or a pharmacologically acceptable salt thereof, wherein the formula (I) is a formula (lb), and R7 is a methyl group, a hydroxymethyl group or a group Oxycarbonyl, R2 is 4-methylsulfonylphenyl, 2-methylsulfonyl-5-pyridyl or 5-methylsulfonyl-2-pyridyl, and R3 is (lS)-2- Methoxy-1-methylethoxy, (lS)-2-hydroxy-1-methylethoxy, (lS)-2-fluoro-p-methylethoxy, dimethylaminocarbonyl, N-B Base-N-methylaminocarbonyl or diethylaminocarbonyl. (10) A compound represented by the formula (I) or a pharmacologically acceptable salt thereof, wherein (1) is a formula (Ic), and R8 is a methyl group or a hydroxymethyl group, R2 Is 4-methylsulfonylphenyl, 2-methylsulfonyl-5-pyridyl or 5-methylsulfonyl-2-pyridyl, and R3 is (lS)-2-methoxy-1 -methylethyl'oxy, (lS)-2-hydroxy-b-methylethoxy, (lS)-2-fluoro-1-methylethoxy, dimethylaminocarbonyl, N-ethyl-N- Methylaminocarbonyl or diethylaminocarbonyl. (11) One of the following compounds or a pharmacologically acceptable salt thereof: -12- 201139430 4-{[(2S)-l-methoxypropan-2-yl]oxy}-2-{5-[(5S )-5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-111-pyrrol-2-yl}-6-[4-(methylsulfonyl)phenoxy Pyridine, (2S)-2-[(2-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrole-2 -yl}-6-[4-(methylsulfonyl)phenoxy]pyridin-4-yl)oxy]propan-1-ol, 4-{[(2S)-l-methoxypropane-2 -yl]oxy}-2-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1^pyrrol-2-yl}-6 -{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridine, (2S)-2-[(2-{5-[(5S)-5-methyl-4,5-di Hydrogen-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridin-4-yl) Oxy]propan-1-ol, 4-{[(2S)-l-methoxypropan-2-yl]oxy}-2-{5-[(4R)-4-methyl-4,5-di Hydrogen-1,3-oxazol-2-yl]-111-pyrrol-2-yl}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridine, (2S) _2-[(2-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-6-{ [6-(Methylsulfonyl)pyridin-3-yl]oxy}pyridine•4_yl)oxy]propan-1-ol 4-{[(2S)-l-methoxypropan-2-yl]oxy}-2-[5-(5-methyl-1,3,4-oxadiazolyl-2-yl)- 111-pyrrol-2-yl]-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridine, (2S)-2-[(2-[5-(5-methyl) -1,3,4-oxadiazolyl-2-yl)-1Η-pyrrol-2-yl]-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridine- 4-yl)oxy]propan-1-ol, -13- 201139430 > 1, [dimethyl-2-{5-[(53)-5-methyl-4,5-dihydro-1,3 -oxazol-2-yl]-1Η-pyrrol-2-yl}-6-[4-(methylsulfonyl)phenoxy]pyridine-4-carboxamide, 叱:^-dimethyl- 2-{5-[(55)-5-methyl-4,5-dihydro-1,3-oxazol-2yl]-1Η-pyrrol-2-yl}-6-{[6-( Methylsulfonyl)pyridin-3-yl]oxy}pyridine-4-carboxamide, 叱1^-dimethyl-2-{5-[(411)-4-methyl-4,5-di Hydrogen-1,3-oxazol-2-yl]-1Η-pyrrol-2-yl}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridin-4-carboxyindole Amine, methyl(43)-2-[5-(4-{[(23)-1-methoxypropan-2-yl]oxy}-6-{[6-(methylsulfonyl)pyridine- 3-(yl)oxy}pyridin-2-yl)-1 Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-carboxylate, {(4R)-2- [5-(4-{[(2S)-l-methoxypropan-2-yl]oxy) }-6-{[6_(methylsulfonyl)pyridin-3-yl]oxy}pyridin-2-yl)-iH-pyrrol-2-yl]-4,5-dihydro-1,3-anthracene Zyzol-4-yl}methanol, {(5R)-2-[5-(4-{[(2S)-l-methoxypropan-2-yl]oxy}-6-{[6-(methyl) Sulfomethyl)pyridin-3-yl]oxy}pyridin-2-yl)-iH-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol, methyl (4S)-2-[5-(4-{[(2S)-l-fluoropropan-2-yl]oxy}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy }pyridin-2-yl)-1Η-pyrrol-2-yl b 4,5-dihydro-1,3-oxazol-4-carboxylate, {(4 ft)-2-[5-(4- {[(2 3)-1-fluoropropan-2-yl]oxy}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridin-2-yl)-1Η-pyrrole -2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol, or 201139430 {(5R)-2-[5-(4-{[(2S)-l-fluoro) Propane-2-yl]oxy}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridin-2-yl)-1 Η-pyrrole-2-yl]-4,5 - Dihydro-1,3-oxazol-5-yl}methanol (1 2) A compound of the compound (1 1 ) or a pharmacologically acceptable salt thereof. (1 3 ) - a compound such as the following or a pharmacologically acceptable salt thereof: 4-{[(2S)-l-methoxypropan-2-yl]oxy}-2-{5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-111-pyrrol-2-yl}-6-{[6-(methylsulfonyl)pyridine-3 -yl]oxy}pyridine, (2S)-2-[(2-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1 Η-pyrrole-2-yl}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridin-4-yl)oxy]propan-1-ol, 4-{[(2S )-l-methoxypropan-2-yl]oxy}-2-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]- 111-pyrrol-2-yl}-6-{[6-(methylsulfonyl)-U--3-yl]oxy}pyrene ratio, (2S)-2-[(2-{5-[ (4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1 Η-pyrrole-2 -yl} - 6 - {[ 6 -(methylsulfonyl) Pyridine·3-yl]oxy}pyridin-4-yl)oxy]propan-1-ol, (2S)-2-[(2-[5-(5-methyl-1,3,4-曙) Diazolyl-2-yl)-1Η-pyrrol-2-yl]-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridin-4-yl)oxy]propane-1 - alcohol, 1^ dimethyl-2-{5-[(53)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1Η-pyrrol-2-yl }-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridyl -4-carboxyguanamine, -15- 201139430 {(5R)-2-[5-(4-{[(2S)-l-methoxypropan-2-yl]oxy} - 6 - {[ 6 - (methylsulfonyl)pyridin-3-yl]oxy}pyridin-2-yl)-1 Η-pyrrole-2-yl]-4,5-dihydro-1,3-oxazol-5-yl} Methanol, {(4R)-2-[5-(4-{[(2S)-l-fluoropropan-2-yl]oxy}-6-{[6-(methylsulfonyl)pyridine-3- Oxy]pyridin-2-yl)-1Η·pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol, or {(5R)-2-[5 -(4-{[(2S)-l-fluoropropan-2-yl]oxy}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridin-2-yl)- 1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol (14) A compound of the compound (13) or a pharmacologically acceptable salt thereof. (15) A glucokinase activator comprising a compound selected from any one of (1) to (14) or a pharmacologically acceptable salt thereof as an active ingredient. (16) A pharmaceutical composition comprising a compound selected from any one of (1) to (14) or a pharmacologically acceptable salt thereof as an active ingredient. (A) 7) The pharmaceutical composition according to (16), wherein the pharmaceutical composition has glucokinase activation. (18) The pharmaceutical composition according to (16), wherein the pharmaceutical composition is used for the treatment and/or prevention of a disease to be treated and/or prevented by glucokinase activation. (19) The pharmaceutical composition according to (16), wherein the pharmaceutical composition is used for treating and/or preventing symptom treatment, improvement, alleviation and/or prevention by activating glucose kinase to maintain constant glucose or blood glucose regulation. The disease. -16-201139430 (20) The pharmaceutical composition of (16), wherein the pharmaceutical composition is for treating and/or preventing diabetes, abnormal glucose tolerance, gestational diabetes, chronic diabetes syndrome (including diabetic peripheral neuropathy, diabetes) Sexual kidney disease, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome. (2) The pharmaceutical composition according to (16), wherein the pharmaceutical composition is for treating and/or preventing diabetes or an abnormal sugar tolerance. (22) A use of the compound according to any one of (1) to (14) or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition. (2) The use of (22), wherein the pharmaceutical composition is for activating glucokinase. (24) The use of (22), wherein the pharmaceutical composition is for treating and/or preventing diabetes, abnormal glucose tolerance, gestational diabetes, chronic diabetes syndrome (including diabetic peripheral neuropathy, diabetic nephropathy, diabetes) Omental disease, diabetic macroangiopathy) or metabolic syndrome. (2) The use of (22), wherein the pharmaceutical composition is for treating and/or preventing diabetes or an abnormal sugar tolerance. (2 6) A glucokinase activating method, which comprises administering a pharmacologically effective amount of a compound selected from any one of (1) to (14) or a pharmacologically acceptable salt thereof to a warm-blooded animal. (2) A method for the treatment and/or prevention of a disease, which comprises administering a pharmacologically effective amount of a compound selected from any one of (1) to (I4) or a pharmacologically acceptable salt thereof to a warm-blooded animal. Give. -17- 201139430 (2 8) Treatment and/or prevention methods for diseases such as (2 7), wherein the disease is diabetes, abnormal glucose tolerance, gestational diabetes, chronic diabetes syndrome (including diabetic peripheral neuropathy, diabetic kidney) Disease, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome. (2) The method of treating and/or preventing a disease according to (27), wherein the disease is diabetes or an abnormal sugar tolerance. (3) The method of treating and/or preventing a disease according to any one of (2) to (2), wherein the warm-blooded animal is a human. In the present invention, the halogen atom j is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom. In the present invention, "Ci-Ce alkyl group" is a carbon number. 1 to 6 straight or branched alkyl groups. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethyl butyl, 1,1-dimethylbutyl or 1,2-dimethylbutyl, preferably a linear or branched alkyl group having 1 to 4 carbon atoms (CrC4 alkane) More preferably, it is a methyl or ethylalkyl group, and more preferably a methyl group. In the present invention, the "Ci-C6 halogenated compound base" is a group in which one or five of the above-mentioned "halogen atoms" which are the same or different are bonded to the above "(^-C: 6 alkyl group). For example, trifluorocarbon. Methyl, trichloromethyl, difluoromethyl, dichloromethyl, dimethyl methyl, fluoromethyl, 2,2,2-trifluoroethyl '2,2,2-trisylethyl, 2 _ ethyl, 2-chloroethyl or 2-fluoroethyl, preferably the same or different oxime to 5 -18-201139430 The above-mentioned "halogen atom" is bonded to the above "Cl_c4 alkyl" group The group (i.e., Ci-C4 periwinkle base) is preferably a group in which one or five of the above-mentioned "halogen atoms" which are the same or different are bonded to the aforementioned "Ci-c: 2 alkyl group" (Ci_c2 halogenated). Further, the alkyl group ' is more preferably a trifluoromethyl group or a fluoromethyl group, and particularly preferably a fluoromethyl group. In the present invention, "C^-C: 6 hydroxyalkyl group" is a hydroxy group bonded to the above "Ci- a group formed by a group of 6 hydroxy groups, for example, a methyl group, a 2-hydroxymethyl group, a 1-hydroxyethyl group or a 3-hydroxypropyl group, preferably a hydroxyl group bonded to the aforementioned "Ci" The group formed by -C2 fluorenyl group is more preferably a transmethyl group. In the present invention, 'the two hydroxyl groups are taken. The C|-C6 alkyl group is a group in which two hydroxyl groups are bonded to the above "alkyl group". For example, 12-dihydroxyethyl or 2,3-dihydroxypropyl group, preferably 2 The group in which the hydroxy group is bonded to the above-mentioned "Ci-Cz alkyl group" is more preferably a 1,2-dihydroxyethyl group. In the present invention, "(Ci-Ce alkylthio)-((^-C6) The alkyl group is bonded to a group in which the sulfur atom of the above-mentioned "C"C6 alkyl group is bonded to the "CrCe alkyl group". For example, methylthiomethyl or ethylthiocarb. Base, propylthiomethyl, isopropylthiomethyl, butylthiomethyl or 2-methylthioethyl, preferably (C1-C2 thiol)-(Ci-C2) More preferably, it is a methylthioethyl group. In the present invention, the "C丨-C6 alkoxy group" is a group in which the above-mentioned "C丨-c6 alkyl group" is bonded to an oxygen atom, and has a carbon number of 1 to 6 a linear or branched alkoxy group. For example, methoxy, ethoxy 'propoxy, isopropoxy, butoxy, isobutoxy, second butoxy, tert-butoxy, pentane Oxyl, 2-methylbutoxy, 3-ethylpropoxy, neopentyloxy, hexyloxy or 2,3·dimethylbutoxy is preferred The number of 1 to 4 linear or branched alkoxy groups (Ci-C4 alkane-19-201139430 oxy) is more preferably methoxy or ethoxy (C1-C2 decyloxy), but also methoxy. In the present invention, 'Ci-C6 via oxyl group' is a group derived from the group "C^-Ce-houseneoxy group". For example, hydroxymethoxyhydroxyethoxy group, hydroxyethoxy group , 3-hydroxypropyloxy, 2-hydroxy; ethoxy or (1S)-2. thio-1-methylethoxy, preferably 2-; methyl ethoxy or (ls) -2 -transmethyl-1-methylethoxy, more preferably hydroxy-1-methylethoxy. In the present invention, "(Ci-C6-methoxy)-(Ci-C6-oxyl)-based "Ci-C:6 alkoxy" is bonded to the above-mentioned "Ci-q alkoxy group. For example, methoxymethoxy, ethoxymethoxy, propoxy, isopropoxymethoxy, butoxymethoxy, 2-methoxyethyl 2-methoxy-1- Ethyloxy or (1S)-2-methoxy-indole_methyl-ethyl is preferably 2-methoxy-1-methylethoxy or (lS)-2-methoxy-indole-A The group is more preferably (lS)-2-methoxy-1-methylethoxy. In the present invention, "Cz-C?alkylcarbonyl" is one of the aforementioned rc groups bonded to a carbonyl group. Group. For example, 'acetamidinyl, propyl fluorenyl, isobutyl fluorenyl, pentanoyl, valeryl, preferably one of the aforementioned "Ci-C4 hospital bases" is bonded. The group is (C2-C5 alkylcarbonyl), more preferably ethylidene or (C2-C3 alkylcarbonyl), still more preferably ethylidene. In the present invention, the "C2-C7 alkoxy group" is a group in which one alkoxy group J is bonded to a carbonyl group. For example, a methoxycarbonyl group is more preferably a prosthetic group, and a 2-S-1-methyl group is small (lS)-2-" is 1" to form an oxymethoxy group, an L group, and a ethoxy group: 1 - c 6 phenyl, butyl or pentyl carbonyl propyl ketone "c 1 - C 6 group, B-20-201139430 oxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, iso More preferably, the butoxycarbonyl group, the second butoxycarbonyl group or the third butoxycarbonyl group is a group in which one of the aforementioned oxy groups is bonded to a carbonyl group, that is, (c2-c5 alkoxycarbonyl group). Further, it is a methoxycarbonyl group or an ethoxycarbonyl group (c2-c3 alkoxycarbonyl group), and more preferably a methoxycarbonyl group. In the present invention, the "mono-Cl-C6 alkylaminocarbonyl group" is bonded to a group in which an amine group of the above-mentioned "CPC6 alkyl group" is bonded to a carbonyl group. For example, a methylaminocarbonyl group, an ethylaminocarbonyl group, an propylaminocarbonyl group, an isopropylaminocarbonyl group or a butylaminocarbonyl group is preferably a bond in which an amine group of the above-mentioned "CMC4 alkyl group" is bonded to a carbonyl group. The group (monoalkylaminocarbonyl) is more preferably a methylaminocarbonyl group or an ethylaminocarbonyl group (monoalkylaminocarbonyl group), and still more preferably a methylaminocarbonyl group. In the present invention, the "di-(Cl_C6 alkyl)aminocarbonyl group" is a group in which an amine group in which two or more "alkyl groups" having the same or different bonds are bonded to a carbonyl group. For example, dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, ethyl-N-methylaminocarbonyl, N-methyl-N-propylaminocarbonyl or N-butyl-N-methylamino The carbonyl group is preferably a group in which an amine group having the same or different two of the aforementioned alkyl groups is bonded to a carbonyl group, that is, a (di-(()-nonylalkyl)aminocarbonyl group), more preferably More preferably, the dimethylaminocarbonyl group, the diethylaminocarbonyl group or the N-ethyl-N-methylaminocarbonyl group is more preferably a dimethylaminocarbonyl group. In the present invention, the "C2-C7 halogenated alkylcarbonyl group" is a a group in which the aforementioned halogenated alkyl group is bonded to a carbonyl group, for example, a trifluoromethylcarbonyl group, a trichloromethylcarbonyl group, a difluoromethylcarbonyl group, a dichloromethylcarbonyl group, or a fluoromethylcarbonyl-2 1- 201139430, 2,2,2-trifluoroethylcarbonyl, 2,2,2-trichloroethylcarbonyl or 2-fluoroethylcarbonyl, preferably one of the aforementioned "C^-C4 halogenated alkyl" linkages a group formed by a thiol group (C2_C5 halogenated fluorenyl group), more preferably a group of the above-mentioned halogenated alkyl group bonded to a carbonyl group (C2-C3 halogenated; thiol group) More preferably, it is a trifluoromethylcarbonyl group. In the present invention, "C^-C6 The oxime group is a group in which one or five or more of the above-mentioned "halogen atoms" are bonded to the alkoxy group, for example, a trifluoromethoxy group, a trichloromethoxy group, or a difluoro group. Methoxy, dichloromethoxy, dibromomethoxy, fluoromethoxy, 2-fluoro-1-methylethoxy or (lS)-2-fluoro-1-methylethoxy Preferably, the same or different 1 to 5 groups of the above-mentioned "halogen atom" bonded to the aforementioned "Ci-CU alkoxy group" (Crb halogenated alkoxy group) are more preferably 2-fluoro-1- Methylethoxy or (1S)_2_gas-1-methylethoxy, more preferably (lS)-2-propane-1-methylethoxy. In the present invention, "c2-c7 halogenated alkane The oxycarbonyl group is a group in which one of the above-mentioned "C|-C6 halogenated alkoxy groups" is bonded to a carbonyl group. For example, a trifluoromethoxycarbonyl group, a trichloromethoxycarbonyl group, or a difluoromethoxy group. Carbonyl, dichloromethoxycarbonyl, fluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl or 2-fluoroethoxycarbonyl, It is preferably a group in which the above-mentioned "C^-CU halogenated alkoxy group" is bonded to a carbonyl group (C2-C5 halogenated alkoxycarbonyl group). More preferably, a group in which the above-mentioned "Ci-Cz halogenated alkoxy group" is bonded to a carbonyl group is a (C2-C3 halogenated alkoxycarbonyl group), and more preferably a 2-trifluoroethoxycarbonyl group. 22-201139430 In the present invention, the "Cl_C6 alkylsulfonyl group" is a group in which one of the above-mentioned "Cl-C6 alkyl groups" is bonded to a sulfonyl group, and has a carbon number of 1 to 6 straight chains or branches. Alkylsulfonyl. For example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, second A sulfonyl or pentylsulfonyl group, preferably a C 1 to 4 linear or branched alkylsulfonylalkylsulfonyl group, more preferably a methylsulfonyl or ethylsulfonate Further, the alkylsulfonyl group is more preferably a methylsulfonyl group. In the present invention, the "Cl_C6 halogenated alkylsulfonyl group" is a group in which the above-mentioned rCl_C6 halogenated alkyl group is bonded to a sulfonyl group, and is a linear or branched halogenated alkyl group having 1 to 6 carbon atoms. Sulfonyl. For example, trifluoromethylsulfonyl, trichloromethylsulfonyl, difluoromethylsulfonyl, dichloromethylsulfonyl, fluoromethylsulfonyl, 2,2,2-trifluoroethyl A sulfenyl group or a 2-fluoroethylsulfonyl group, preferably a 1 to 4 linear or branched halogenated alkylsulfonyl group (Crh halogenated alkylsulfonyl), more preferably a carbon number of 1 Or 2 linear or branched halogenated alkylsulfonium* halogenated alkylsulfonyl), more preferably trifluoromethylsulfonyl. In the present invention, the "C3-C6 cycloalkylsulfonyl group" is a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group or a cyclohexylsulfonyl group. Preferred is a cyclopropylsulfonyl group. In the present invention, the alkoxyalkylsulfonyl) group is a group in which one of the above alkoxy groups is bonded to the above "(^-(:6 alkylsulfonyl)". For example, Oxymethylsulfonyl, ethoxymethyl-23-201139430 sulfonyl, propoxymethylsulfonyl, isopropoxymethylsulfonyl, butoxymethylsulfonyl or The dibutoxymethylsulfonyl group is preferably a group in which the aforementioned "匸" decyloxy group is bonded to the aforementioned "Cl-C4 alkylsulfonyl group" ((Ci-C4 alkoxy group). _(Cl_c4 alkylsulfonyl) group), more preferably one of the above-mentioned "(^-(^ alkoxy)-bonded to the aforementioned "Cl-C2 alkylsulfonyl" group alkoxy group Further, it is more preferably a methoxymethylsulfonyl group. In the present invention, "(Crb halogenated alkoxy)-((^-(:6 alkylsulfonyl)) The group "" is a group in which the above-mentioned "halogenated alkoxy group" is bonded to the above "C^-Ce alkylsulfonyl group", for example, trifluoromethoxymethylsulfonyl group, three Chloromethoxy. Methylsulfonyl, difluoromethoxymethylsulfonyl, dichloromethoxymethylsulfonyl or fluoromethoxymethylsulfonyl, preferably one of the aforementioned "Ci-CU teeth" a group in which the alkoxy group is bonded to the above-mentioned "Cl-C4 alkylsulfonyl group" ((Ci-C4 halogenated alkoxyalkylsulfonyl) group), more preferably one "C 1 - C2 dentate oxime" is a group bonded to the above-mentioned rc , - c 2 -based dilating group ((C "C2 halogenated alkoxy") (Ci_C2 More preferably, it is a trifluoromethoxymethylsulfonyl group. In the present invention, "is independently represented by the formula (I) by i to 3 substituents selected from the group of the substituent group A The nitrogen-containing heterocyclic group "', for example, may independently be substituted with a group selected from the group of substituent A to 3 substituted pyrazolyl, imidazolyl, oxazolyl, oxazolyl, isoxazolyl , thiazolyl, thiazolinyl. , isothiazolyl, moxadiazolyl, hithiadiazolyltriazolyl, tetrazolyl, thiadiazolyl, pyrazolyl, pyridyl, fluorene, pyrimidine-24-201139430 or pyrazole base. It is preferably 2-pyridyl, 5,6-dihydro-4H-1,3-indol-2-yl, 1, which may be independently substituted by one to three groups selected from the group of the substituent group A. 3-thiazol-2-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazolyl-2-yl, 1,3,4-thiadiazol-2-yl, 4, 5-dihydro-1,3-thiazol-2-yl, 4,5-dihydro-1,3-oxazol-2-yl or 4,5-dihydro-1,3-benzothiazole-2- More preferably, 1,3-thiazol-2-yl, 5-methyl-1,3-thiazol-2-yl, 5-methyl-1,3,4-fl-dioxadiyl. -2 -yl, 4,5-dihydro-1,3-thiazol-2-yl, 4,5-dihydro-1,3-oxazol-2-yl, (53)-5-methyl-4 ,5-dihydro-1,3-oxazol-2-yl, (5R)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl, 5-hydroxymethyl- 4,5-dihydro-1,3-oxazol-2-yl, (5R)-5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-yl, (4R)- 4-methyl-4,5-dihydro-1,3-oxazol-2-yl, (4R)-4-ethyl-4,5-dihydro-1,3-Dfoxazol-2-yl, (4R)-4-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-yl, (4S)-4-[(lR)-l-hydroxyethyl]-4,5- Dihydro-1,3-oxazol-2-yl, (4S)-4-[(lS)-l-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-yl, (411,53)-4,5-dimethyl-4,5-dihydro 1,3 -carbazole · 2-yl, (5 S ) - 4 -hydroxy-5 -methyl-4,5 - two Hydrogen-1,3-B-oxazol-2-yl, (4R,5S)-4-hydroxymethyl-5-methyl-4,5-dihydro-1,3-oxazol-2-yl, ( 4R,5R)-5-hydroxymethyl-4-methyl-4,5-dihydro-1,3-oxazol-2-yl, (4R)-4-methoxycarbonyl-4,5-di Hydrogen-1,3-oxazol-2-yl, 5-carboxy-1,3-thiazol-2-yl, 5-dimethylaminocarbonyl-1,3-thiazol-2-yl, 5-methyl- 1,3,4-thiadiazol-2-yl or 5,6-dihydro-4H-1 , 3-indole-2-yl, more preferably 4,5-dihydro-1,3-oxazol-2-yl, (4R)-4-methyl-4,5-dihydro-1, 3-oxazol-2-yl, (411)-4-ethyl-4,5-dihydro-1,3-oxazol-2-yl, (53)-5-methyl-4,5-di Hydrogen-1,3-oxazol-2-yl, (4R)-4-hydroxymethyl-4,5-dihydro-1,3-oxazol-25- 201139430-2-yl, (5 R)- 5-hydroxymethyl-4,5-dihydro-1,3-indole, oxazol-2-yl, (4S)-4-[(lR)-l-hydroxyethyl]-4,5-dihydro- 1,3 -carbazole-2-yl, (4S)-4-[(lS)-l-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-yl, (4R, 5S)-4,5-Dimethyl-4,5-dihydro-I,3-oxazol-2-yl, (4R,5S)-4-hydroxymethyl-5-methyl-4,5- Dihydro-1,3-oxazol-2-yl, (4R,5R)-5-hydroxymethyl-4-methylindole-4,5-dihydro-1,3-oxazol-2-yl, 1 , 3-thiazol-2-yl, 5-carboxy-1,3-thiazol-2-yl, 5-dimethylaminocarbonyl-1,3-thiazol-2-yl, 5-methyl-1,3, 4-thiadiazole-2-yl, 5-methyl-1,3,4-oxadiazolyl-2-yl, 4,5-dihydro-1,3-thiazol-2-yl, (4R) -4 -Methoxycarbonyl-4,5-dihydro-1,3-oxazol-2-yl or 5,6-dihydro-4H-1,3-indene-2-yl, especially preferably 4 ,5-dihydro-1,3-B Zyridin-2-yl, (411)-4-methyl-4,5-dihydro-1,3-0 oxazol-2-yl, (411)-4-ethyl-4,5-dihydro- 1,3-oxazol-2-yl, (5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl, (411)-4-hydroxymethyl-4, 5-Dihydro-1,3-oxazol-2-yl, (511)-5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-yl, (4S)- 4-[(lR)-l-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-yl, (4S)-4-[(lS)-l-hydroxyethyl]- 4,5-dihydro-1,3-Bfoxazol-2-yl, (4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-yl, (4R,5S)-4-hydroxymethyl-5-methyl-4,5-dihydro-1,3-oxazol-2-yl, (411,511)-5-hydroxymethyl-4-methyl 4-,5-dihydro-1,3-oxazol-2-yl, (4 R)-4-methoxycarbonyl-4,5-dihydro-1,3-oxazol-2-yl Or 5-methyl-1,3,4-oxadiazolyl-2-yl, most preferably (4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl , (5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl, (4R)-4-hydroxymethyl-4,5-dihydro-1,3- Oxazol-2-yl, (5R)-5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-yl, (4R)-4-methoxycarbonyl-4,5- Dihydro-26- 201139430 -1,3-oxazol-2-yl or 5-A The base-1,3,4-卩萼2 D is a base 2_ group. In the present invention, "may independently pass through a group selected from the group of substituents! to 5 substituted phenyl groups", which is a phenyl group or 1 to 5 substituents selected from a group selected from the substituent group β Phenyl. Preferred is L-methylsulfonylphenyl. In the invention, "i to 3 substituted pyridyl groups which may be independently selected from a group selected from the group of substituents" are scheringly steep or independently passed through a group selected from the group of substituents B to Three substituted Ds are steeper than the base. It is preferably a 2-methylmethyl-5-pyridyl group. In the present invention, the "group represented by the formula -V-NR4R5" is a group represented by the formula -c(=o)-nr4r5 or a group represented by the formula _s〇2_nr4r5. "." In the present invention, "R4 and R5 are bonded to a nitrogen atom of a bond to form a 4- to 6-membered saturated heterocyclic ring which may be independently substituted by 1 or 2 Ci-C6 groups. 4 to 6 member saturated heterocyclic ring may be used. Further comprising one oxygen atom or nitrogen atom", which is a * to 6-membered saturated heterocyclic ring (containing one nitrogen atom) which may be independently substituted by one or two groups consisting of C! - C6 alkyl groups. a 4 to 6 member fully reduced saturated heterocyclic group further containing 1 oxygen atom or a nitrogen atom, for example, azetidine, pyrrolidine, piperidine, sormine, piperidine, dimethyl taste The porphyrin, methyl peptin or dimethyl pipe trap is preferably tetrahydroanthracene, pyrrolidine or miso. In the present invention, preferred R1 is 4,5-dihydro-1,3-oxazol-2-yl, (4R)-4-methyl-4,5-dihydro-1,3-oxazole- 2-yl, (4R)-4-ethyl-4,5-dihydro-13-oxazol-2-yl, (5S)-5-methyl-4,5-dihydro-1,3-anthracene Zin-2-yl, (4R)-4-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-yl, (5R)-5-hydroxymethyl-27- 201139430 -4, 5-dihydro-1,3-oxazol-2-yl, (4S)-4-[(lR)-l-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2- , (43)-4-[(13)-1-hydroxyethyl]-4,5-dihydro-1,3-Pfoxazol-2-yl, (4R,5S)-4,5-dimethyl 4-,5-dihydro-1,3-oxazol-2-yl, (4R,5S)-4-hydroxymethyl-5-methyl-4,5-dihydro-1,3-oxazole -2-yl, (4R,5R)-5-hydroxymethyl-4-methyl-4,5-dihydro-1,3-oxazol-2-yl, (4R)-4-methoxy Carbonyl-4,5-dihydro-1,3-oxazol-2-yl or 5-methyl-1,3,4-oxadiazolyl-2-yl, more preferably 111 (411)-4 -Methyl-4,5-dihydro-1,3-oxazol-2-yl, (5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl, ( 4R)-4-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-yl, (511)-5-hydroxymethyl-4,5-dihydro-1,3-oxazole -2-yl, (4R)-4-methoxycarbonyl·4,5-dihydro -1,3-oxazol-2-yl or 5-methyl-1,3,4-oxadiazolyl-2-yl. In the present invention, preferred R2 is 4-methylsulfonylphenyl, 4-(1-tetrahydroindenyl)carbonyl-2-fluorophenyl, 2-fluoro-4-(1-pyrrolidinyl) Carbophenyl, 5-(1-tetrahydroindenyl)carbonyl-3-chloro-2-pyridyl, 2-methylsulfonyl-5-pyridyl '2-methylaminocarbonyl-5-pyridine Or 2-methylaminosulfonyl-5-pyridyl, more preferably R2 is 4-methylsulfonylphenyl, 2-methylsulfonyl-5-pyridyl or 5-methylsulfonium Base-2-pyridyl. In the present invention, preferred R3 is methoxy, ethoxy, isopropoxy, (lS)-2-methoxy-1-methylethoxy, (lS)-2-hydroxy-1- Methyl ethoxy, (lS)-2-fluoro-1-methylethoxy, difluoromethoxy, 1,3-difluoro-2-propoxy, dimethylaminocarbonyl, N-B Further, R-3 is (lS)-2-methoxy-1-methylethoxy, (lS)-2-hydroxy-1-methyl, benzyl-N-methylaminocarbonyl or diethylaminocarbonyl Ethoxy, (lS)-2-fluoro (-1-methylethoxy, dimethylamino, N-ethyl-N-methylaminocarbonyl or diethylaminocarbonyl. -28- 201139430 In the present invention, preferred Q is a group represented by the formula: CH-. In the present invention, preferred U is a group represented by the formula = CH -. In the present invention, preferred V is nitrogen. The compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof has all of the isomers (keto-enol isomer, non-image isomer, optical isomer, rotation) The compound represented by the formula (I) or a pharmacologically acceptable salt thereof of the present invention has various kinds of impurities due to the presence of an asymmetric carbon atom in the molecule. In the compound of the present invention, the isomers and the mixture of the isomers are represented by a single formula, that is, the formula (I). Therefore, the present invention also includes all of the isomers and the like. a mixture of isomers in any ratio. As the above stereoisomers, it is possible to use an optically active starting material compound, or to synthesize a compound of the invention using an asymmetric synthetic or asymmetric derivatization method' or to synthesize the inventive The compound is obtained by a single optical separation method or a separation method. The compound represented by the formula (I) or a pharmacologically acceptable salt thereof of the present invention constitutes one or more atoms of the compound. It may contain an atomic isotope in an unnatural ratio, such as 氖(2 Η ), 氤(3 Η ), iodine-1 2 5 (12 5 Ι) or carbon _14 (14C), etc. Further, the aforementioned compound Radiolabeling can be carried out using radioisotopes such as cesium (3H), iodine-125 (125I) or carbon-14 ("C"). Radioactively calibrated compounds are used as therapeutic or prophylactic agents, for example, for analytical reagents, And diagnostic agents A diagnostic imaging agent is useful. All isotopically variable substances of the compounds of the present invention, whether or not they are radioactive, are included in the scope of the present invention. -29- 201139430 "The pharmacologically acceptable salt" means no significant toxicity. a salt to be used as a medicine. The compound represented by the formula (I) of the present invention can be reacted with an acid to form a salt when having a basic group, and can be reacted with a base when having an acidic group. And as a salt based on a basic group, for example, a hydrohalide such as a hydrofluoride, a hydrochloride, a hydrobromide or a hydroiodide; for example, a nitrate, a perchlorate, a mineral acid salt such as a sulfate or a phosphate; a CPC6 alkyl sulfonate such as a methanesulfonate, a trifluoromethanesulfonate or an ethanesulfonate; an aryl group such as a besylate or a p-toluenesulfonate; a sulfonate; an acid salt such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate; and such as glycinate , aminate, arginine, alanine, glutamate, aspartate The amino acid hydrochloride. On the other hand, in the case of an acid group-based salt, for example, an alkali metal salt such as a sodium salt or a potassium salt 'lithium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt: a metal salt such as an aluminum salt or an iron salt. An inorganic salt such as an ammonium salt; such as a third octylamine salt, a dibenzylamine salt, a miso salt, a glucosamine salt, an alkyl phenylglycine salt, an ethylenediamine salt, an N-methyl reduced glucose Glucamine salt, sulfonium salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, procaine chloride salt, procaine An amine salt such as a salt, a diethanolamine salt, an N-benzylphenethylamine salt, a piperazine salt, a tetramethylammonium salt, an organic salt of a hydroxymethylaminomethane salt; and a glycinate, Amino acid salt of an amine salt, arginine salt, alanine salt, glutamate salt, and aspartate. -30-201139430 The compound represented by the formula (I) or a pharmacologically acceptable salt thereof of the present invention absorbs water and is accompanied by adsorbed water and sometimes becomes a hydrate due to being placed in the atmosphere or recrystallized. Such a hydrate is also included in the present invention, which is a compound represented by the formula (I) or a pharmacologically acceptable salt thereof, and sometimes absorbs another solvent to form a solvate, such a solvent The substance is also included in the salt of the present invention. The compound represented by the formula (I) or a pharmacologically acceptable salt thereof in the present invention is preferably a compound represented by the formula (I) of the present invention. In the present invention, "metabolic syndrome" refers to a pathological condition in which a plurality of coronary vascular risk factors are accumulated based on insulin resistance, and the risk of coronary artery disease is significantly increased (hyperlipidemia, diabetes, obesity, high in lifestyle-related diseases). Blood pressure, etc.) (Diabetes, Obesity and Metabolism, 9, 2007, 246-258, Journal of the American Medical Association, 2 8 5: 2486-2497 (2001), Diabet.  Med. , 15: 539-5 53 (1998)). [Effect of the Invention] The compound represented by the formula (I) or a pharmacologically acceptable salt thereof of the present invention has excellent GK activation action and is used for preventing and/or treating warm-blooded animals (preferably mammals). Animals, including humans, are selected from the group consisting of diabetes, abnormal glucose tolerance, gestational diabetes, chronic dysplasia of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) and metabolic syndrome. The medicine in the group is useful for medicine. Further, the novel compound 201139430 represented by the formula (I) or a pharmacologically acceptable salt thereof provided by the present invention has an excellent GK for preventing and/or treating a warm-blooded animal (preferably a mammalian disease 4) The active ingredient of the medicine is useful. The preferred disease or sugar tolerance is abnormal. It is preferred to treat the above-mentioned condition [Embodiment] [Best Embodiment of the Invention] The present invention is represented by the general formula (I) The compound can be produced by the method A to E. The reaction of each step of the following methods A to E can be carried out by using a solvent group which does not hinder the reaction and which dissolves the starting material to some extent, for example, may be selected from the following solvent groups. The solvent group consists of: polyoctane, petroleum ether, ligroin, amine of cyclohexane, hydrazine, hydrazine-dimethylformamide, N,N-dimethylacetamide N-methyl-2-pyrrolidone), N-methyl (N - methy 1 - 2 - pyrr ο 1 idi η ο ne), hexamethyl phosphate; such as diethyl ether, diisopropyl ether, tetrahydrofuran, diterpenes Ethane, diethylene glycol dimethyl ether, ether of cyclopentyl methyl ether; n-propanol, isopropanol, n-butanol 2-butanol, 2-methylbutanol, isoamyl alcohol, diethylene glycol 'glycerol' octanol, alcohols of the ring sulphate; quinones of dimethyl hydrazine; such as cyclobutyl acetonitrile, C A nitrile of nitrile, butyronitrile or isobutyronitrile; for example, formate, propyl acetate, butyl acetate, diethyl carbonate, butanone, 4-methyl-2-pentanone, methyl isobutyl ketone , the activation of the Buddha, the disease, including the human) disease, is used for the medical treatment of diabetes. According to the solvent described below, there is no special pentyl pentane, hexane, or hydrocarbon; for example, formazan, N-methyl-2-H, and 2-pyrrolidone tridecylamine, amidoxime, Dimethoxymethanol, ethanol, -1 -propanol, trihexyl alcohol, methyl oxime; such as ethyl ester, ethyl acetate; acetone, 2-ketone, cyclohexanone -32-201139430 a ketone; a nitro compound such as nitroethane or nitrobenzene; a halogenated hydrocarbon such as dichloromethane, hydrazine, 2-dichloroethane, chlorobenzene, dichlorobenzene, chloroform or carbon tetrachloride. An aromatic hydrocarbon such as benzene, toluene or xylene; a carboxylic acid such as acetic acid, formic acid, propionic acid, butyric acid or trifluoroacetic acid; such as N-methyl porphyrin, triethylamine, tripropylamine, tributylamine , diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 2,6-lutidine, 4-pyrrolidinylpyridine, picoline, 4·dimethylaminopyridine, 2,6_bis(t-butyl)·4-methylpyridine, quinoline, anthracene, fluorene-dimethylaniline, anthracene, oxime-diethylaniline, ;,,5-diazabicyclo[43 〇] 壬-5-ene (DBN), 1,4-diazabicyclo[2. 2. 2] Octane (DABCO), 1,8-diazabicyclo[5. 4. 0] eleven-7-ene (DBU), an amine of piperidine; water; and a mixed solvent of these. The base used in the reaction of the following steps to the various steps of the hydrazine method, for example, sodium carbonate, potassium carbonate, lithium carbonate, alkali metal carbonates of carbonic acid; such as sodium hydrogencarbonate, potassium hydrogencarbonate, lithium hydrogencarbonate Alkali metal hydrogencarbonates; such as sodium acetate, potassium acetate, lithium acetate, alkali metal acetates of acetic acid; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; such as sodium hydroxide, potassium hydroxide , alkali metal hydroxides of lithium hydroxide; inorganic bases such as sodium fluoride, alkali metal fluorides of potassium fluoride; such as sodium methoxide, sodium ethoxide, sodium butoxide, potassium methoxide, potassium ethoxide, An alkali metal alkoxide of potassium butoxide or lithium methoxide; an alkali metal trialkyl sulfonium oxide such as trimethylsulfonium oxide, trimethylsulfonium oxide, or trimethylsulfonium oxide; such as sulfur methanol Sodium, sodium thioethanolate thiol alkali metal; N-methyl sulphate, triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine, dicyclohexylamine, N-methyl Piperidine, pyr-33- 201139430 pyridine, 2,6-lutidine, 4-pyrrolidylpyridine, picoline, 4-dimethylamine Pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, n,N-dimethylaniline, anthracene, fluorene-diethylaniline, 1,5-diazabicyclo [4. 3. 0] 壬-5-ene (0; 8 > 〇, 1,4-diazabicyclo [2_2. 2] Octane (〇8-8:0), 1,8-diazabicyclo[5. 4. 0] an organic base of eleven-7-ene (DBU); an organometallic base such as n-butyllithium, lithium diisopropylguanidinium, lithium bis(trimethyldecyl)guanamine; or Amino acid of amino acid. to. The condensing agent used in the following steps to the various steps of the hydrazine process, for example, 0-fluorene-azabenzotriazol-1-yl)-7V, 7V, tetramethyluron hexafluorophosphate (HATU), 1-propanesulfonic acid cyclic anhydride (T3P), dicyclohexylcarbonyldiimide (DCCD), 1-ethyl-3-(3-dimethylaminopropyl) mineral di-imine hydrochloride ( WSCI·HC1), 1-ethyl-3-(3-dimethylaminopropyl)carbonyldiimide (WSCI), 4-(4,6-dimethoxy-1,3,5-three Well-2-yl)-4-methyl-sodium chlorate η hydrate (DMT-MM), isobutyl chloroformate (iBCF), 1,1'·carbonylbis-1Η-imidazole (CDI), cyano Diethyl phosphonate (DEPC), diphenylphosphoric acid azide (DPPA), N-hydroxysuccinimide, Ν-hydroxy-5-norz-2,3-dicarboxy quinone imine or dipyridine Dithioether, if desired, can also be hydrazine-hydroxybenzodiazepine (HOBt) or 1-p-benzobenzotrione monohydrate (HOBt.  H20) Coexistence Palladium catalyst used in the following steps from the A method to the E method, for example, ruthenium (triphenylphosphine) palladium (0), palladium-activated carbon, palladium acetate (II), trifluoroacetic acid (II), palladium black, palladium (II) bromide, palladium (II) chloride, palladium iodide (n), cesium cyanide (11), palladium nitrate (11), palladium oxide (11), palladium sulfate ( 11), dichlorobis(acetonitrile) -34- 201139430 palladium (II), dichlorobis(benzonitrile)palladium(II), dichloro(1,5-cyclooctadiene)palladium (11), acetamidine P-acetone palladium (II), palladium (II) sulfide, [1,1,_bis(diphenylphosphino)ferrocene]palladium(II) dichloride, ginseng (dibenzylideneacetone) dipalladium ( 〇), hydrazine (acetonitrile) palladium (11) tetrafluoroborate or arsenic palladium dimer as a rhodium palladium catalyst or a divalent palladium catalyst. In the reaction of each step of the following A to E methods, the reaction temperature varies depending on the solvent, the starting material, the reagent, and the like, and the reaction time varies depending on the solvent, the starting material, the reagent, the reaction temperature, and the like. In the reaction of each step of the following A to E methods, after completion of the reaction, each compound of interest is taken from the reaction mixture by a usual method. For example, the reaction mixture may be appropriately neutralized, and after being removed by filtration in the presence of insoluble matter, an organic solvent such as water and ethyl acetate which is not mixed is added, and the organic layer containing the objective compound is separated, and washed with water or the like. It is obtained by drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., filtering, and distilling off a solvent. The desired compound to be obtained may be appropriately combined with a conventional method such as recrystallization or reprecipitation, such as recrystallization or reprecipitation, by a conventional method, and subjected to chromatography to be separated and purified by elution with an appropriate solvent. For the objective compound insoluble in a solvent, the obtained crude product of the solid can be washed and purified with a solvent. Further, the compound of each step may be used in the next reaction without purification. In the respective steps of the following methods A to E, R2, Q, U and V have the same meanings as defined above, and R31 represents a halogenated alkoxy group of 113, a hydroxyalkoxy group or (Ci-Q alkoxy alkoxy group). a group after removal of an oxygen atom at the terminal end, R61' R71, R72, R81 and R82 represent a hydrogen atom -35-201139430 or a group of one of the substituent groups A, and R9 represents a Ci-Q alkyl group (Comparative) Preferably, it is a methyl group or an ethyl group.), and X represents a halogen atom (preferably a chlorine atom, a bromine atom or an iodine atom, more preferably a chlorine atom or an iodine atom), and Y represents a γ atom, a nitro group, and a C^- group. Cealkylsulfonyloxy, alkoxysulfonyloxy or C6-C1()arylsulfonyloxy (preferably a halogen atom or a nitro group, more preferably a fluorine atom, a chlorine atom or a nitro group). , the ruler 2!* indicates that the group of R2 is defined as a group other than the amine group, the hydroxyl group and/or the carboxyl group which are contained as a substituent in the group of R2, which is a protected amine group, a hydroxyl group and/or a carboxyl group. The same groups, R61a, R71a, R72a, R81a and R82a are represented by the case of an amine group, a hydroxyl group and/or a carboxyl group, in addition to a protected amine group, a hydroxyl group and/or a carboxyl group, and R6 1. The groups of R71, R72, R81 and R82 are the same group, and Bn represents a benzyl group. A method for producing a compound represented by the formula (I), 113 is 1 ^ 6 halogenated alkoxy, Ci-Ce hydroxyalkoxy or d-Ce alkoxy)-((^-(:6 courtyard oxygen) And R 1 is a compound of the formula (Ie) which can be independently substituted with 1 to 3 groups selected from the group A of the substituent group A, 4,5-dihydro-1,3-oxazol-2-yl Method of the indicated compound. (Method A) -36- 201139430

A-IV -►

R82

Step A-1 This step is a step of producing a compound represented by the formula (V). This step is carried out by reacting a compound represented by the formula (III) with a compound represented by the formula (IV) in the presence of a base in a solvent. The compound represented by the formula (III) and the compound represented by the formula (IV) used in this step may be a known compound or may be easily produced by a known method or the like using a known compound as a starting material. The solvent used in this step is preferably an ether, more preferably tetrahydrofuran. -37- 201139430 The base used in this step is preferably an alkali metal hydride type, more preferably sodium hydroxide. The reaction temperature in this step 'usually is -20 ° C to 80 ° C, preferably 0 t: to 60 ° C. The reaction time in the step 'usually 〇. 5 hours to 48 hours' is preferably from 1 hour to 24 hours. Step A-11 This step is a step of producing a compound represented by the formula (VI1). This step is carried out by reacting a compound represented by the formula (V) with a compound represented by the formula (VI) in the presence of a base in a solvent. The compound represented by the formula (VI) used in this step may be a known compound or may be easily produced by a known method or the like using a known compound as a starting material. The solvent used in this step is preferably a nitrile or a guanamine, more preferably acetonitrile or N,N-dimethylformamide. The base used in this step is preferably an alkali metal carbonate, more preferably potassium carbonate or carbonic acid planer. The reaction temperature in this step is usually -10 ° C to 160 ° C, preferably 0 ° C to 140 ° C. The reaction time in this step is usually from 0.5 to 7 2 hours, preferably from 1 hour to 48 hours. -38- 201139430 A-III Step This step is a step of producing a compound represented by the formula (VIII). This step is carried out in a solvent, in the presence of a palladium catalyst and an inorganic base, by using a compound represented by the formula (VII) with 5-(4,4,5,5·tetramethyl- 1,3, The reaction is carried out by reacting benzyl 2-dioxaborolan-2-yl)-1Η-pyrrole-2-carboxylate. The solvent used in this step is preferably a mixed solvent of an ether and water, more preferably a mixed solvent of dioxane and water. The palladium catalyst used in this step is preferably a II-valent palladium catalyst, more preferably [i,:r-bis(diphenylphosphino)ferrocene]palladium dichloride (π) dichloromethane. Compound. The inorganic base used in this step is preferably an alkali metal carbonate, more preferably potassium carbonate, more preferably an aqueous potassium carbonate solution. The reaction temperature in this step is usually from 25 ° C to 100 ° C, preferably from 40 ° C to 70 ° C. The reaction time in this step is usually from 0.5 to 7 2 hours, preferably from 1 hour to 24 hours. A-IV step This step is a step of producing a compound represented by the formula (IX). This step is carried out in (i) or (ii). (i) This step is carried out by reacting a compound represented by the formula (VIII) in the presence of a palladium catalyst in a hydrogen atmosphere under a solvent. The solvent used in this step is preferably an ether, an alcohol, an ester or a mixed solvent of these, and more preferably tetrahydrofuran, methanol, ethanol, ethyl acetate or a mixed solvent of ethanol and ethyl acetate. -39- 201139430 The palladium catalyst used in this step is preferably a palladium catalyst of valence, more preferably palladium-activated carbon. The reaction temperature in this step is usually "Ot to 40 ° C, preferably 〇 ° C to 30 ° C. The reaction time in this step is usually from 1 hour to 72 hours, preferably 〇. · 5 hours to 24 hours. (ii) This step is carried out by reacting a compound represented by the formula (VIU) with a base in a solvent. The solvent used in this step is preferably an ether and water. The mixed solvent is more preferably a mixed solvent of tetrahydrofuran and water. The base used in this step is preferably an alkali metal hydroxide, more preferably lithium hydroxide. The reaction temperature in this step is usually 10. (: to 100 °c, preferably 25. (: to 80 ° C » The reaction time in this step 'usually 〇 1 hour to 48 hours, preferably 0.5 hours to 24 hours. A - V step this step A step of producing a compound represented by the formula (XI). This step is carried out in a solvent in the presence of a condensing agent, in the presence or absence of a base (preferably in the presence), by The compound represented by IX) is reacted with a compound represented by the formula (X). This step is used. The compound represented by the formula (X) can be easily produced by a known compound or a known compound as a starting material according to a known method or the like. -40- 201139430 The solvent ii used in this step is preferably an alcohol, _hydrocarbons, acid amines or a mixed solvent of these 'more preferably methanol, dichloromethane, hydrazine, hydrazine dimethyl dimethyl hydrazine or methylene chloride and hydrazine, hydrazine-dimethylformamide Mixed solvent. The condensing agent used in this step is preferably DMT-MM, HATU, WSCI or WSCI. HC1. When using WSCI or WSCI. HC1, HOBt or HOBT·Η20 may be coexisted as needed. Preferably, HOBt is used. · Η20 coexist. The base used in this step is preferably an organic base, more preferably Ν-methyl porphyrin, hydrazine, hydrazine-diisopropylethylamine or 4-dimethylaminopyridine. The temperature is usually -2 ° C to 6 ° C, preferably from or 30 C. The reaction time in this step is usually from 0.5 to 7 hours, preferably from 1 to 24 hours. A - VI Step This step is a step of producing a compound represented by the formula (Ie). This step is carried out by (i) or (ii). (i) This step After reacting the compound represented by the formula (XI) with a base and methanesulfonic anhydride in a solvent, the amine group, the hydroxyl group and the hydroxyl group in R2a, R71a, R72a, and 81; 1 and 11823 are removed as desired. The solvent used in the step is preferably an ether, more preferably tetrahydrofuran or dimethoxyethane. The base used in this step is preferably an organic base, more preferably triethylamine. The reaction temperature in this step is usually -100 ° C to 85 ° C, preferably 10 t to 60 ° C. -41· 201139430 The reaction time in this step is usually from 0.5 to 72 hours, preferably from 1 to 24 hours. (Π) This step is carried out by reacting a compound represented by the formula (XI) with a base and bis(2-methoxyethyl)aminosulfur trifluoride in a solvent, and then removing R as expected. 23. A protecting group for an amine group, a hydroxyl group and/or a carboxyl group in R.713, R72a, 813 and R82a. The solvent used in this step is preferably a halogenated hydrocarbon, preferably dichloromethane. The base used in this step is preferably an alkali metal carbonate ‘more preferably potassium carbonate. The reaction temperature in this step is usually from _100 «c to 85 ° C', preferably from -78 ° C to 30 ° C. The reaction time in this step is usually from 5 hours to 72 hours, preferably from 1 hour to 24 hours. The B method is a method of producing a compound represented by the formula (Ie). (Method B) -42- 201139430

B-lll

B-VI (XVI)

Step B-1 This step is a step of producing a compound represented by the formula (XII). This step is carried out in the same manner as in the above, in the presence of a base, by reacting the compound represented by the formula (V) with benzyl alcohol in the same manner as the A-oxime step of the above-mentioned A method. Step B-11 This step is a step of producing a compound represented by the formula (ΧΠΙ). This step is carried out in a solvent, in the presence of a palladium catalyst and an inorganic base, by using -43-201139430 as a compound of the formula (ΧΠ) and 5-(4,4,5,5-tetramethyl- The reaction of benzyl i,3,2-dioxaborolan-2-yl)-1 -pyrrole-2-carboxylate is carried out in the same manner as in the A-III step of the above a method. Step B - III This step is a step of producing a compound represented by the formula (XIV). This step is carried out in a solvent by the reaction of the compound represented by the formula (XIIU with a base, in the same manner as the A-IV step (ii) of the above-mentioned A method. The B-IV step is carried out by the general formula. Step of the compound represented by (XV). This step is carried out in a solvent, in the presence of a condensing agent, in the presence or absence of a base (preferably in the presence), and the compound represented by the formula (XIV) is The compound represented by the formula (X) is reacted in the same manner as the AV step of the above-mentioned A method. The BV step is a step of producing a compound represented by the formula (XVI). i) or (ii) carried out. (i) This step is carried out in a solvent by reacting a compound represented by the formula (XV) with a base and methanesulfonic anhydride, and the A-VI step of the aforementioned method A. (i) is carried out in the same manner. (Π) This step is 'in a solvent' by using a compound represented by the formula (XV) with a base and bis(2-methoxyethyl)aminosulfur trifluoride. The reaction is carried out in the same manner as in the above-mentioned A-VI step (ii) of the method A. -44- 201139430 Β-VI step This step is produced by the general formula Χνπ) The step of the compound represented by the method A. The reaction of the compound represented by the formula (XVI) in the presence of a palladium catalyst in a hydrogen atmosphere and in the solvent, and the A method A Step (i) is carried out in the same manner. Step B-VII This step is a step of producing a compound represented by the formula (le). This step is carried out in a solvent in the presence of a base by using a formula (XVII). The compound represented by the formula (XVIII) is reacted with the compound represented by the formula (XVIII), and after the same procedure as in the A-II step of the above-mentioned A method, the amine group in R2a, R71a, R72a, R8la and R82a is removed as desired. The compound represented by the formula (VIII) is used as a known compound in the present step, or can be easily produced by a known method or the like using a known compound as a starting material. The method of producing the compound represented by the formula (XII) used in the above step B-B step B-II is carried out by the method (C method).

-45- (III) 201139430 C-ΙStep This step is a step of producing a compound represented by the formula. This step is carried out in the same manner as in the above-mentioned A-oxime step of the A method, in which a compound represented by the formula (III) is reacted with benzyl alcohol in the presence of a base. Step C-II This step is a step of producing a compound represented by the formula (ΧΠ). This step is carried out in the same manner as in the above-mentioned A method of the A method, by reacting the compound represented by the formula (XIX) with the compound represented by the formula (Iv) in the presence of a base. In the D method, a compound represented by the formula (I) is produced, and R3 is a Ci-C6 halogenated alkoxy group, an h-C6 hydroxyalkoxy group or a (Ci_C6-homoyloxy group)-(Ci-C6-homoyloxy group). The group 'R1' is a method of a compound represented by the formula (If) which can be substituted with a group selected from the group of the substituent group a, I3,4.oxadiazolyl-2-yl. (D method)

-46- 201139430 D-ΙStep This step is a step of producing a compound represented by the formula (XXI). This step is carried out in a solvent, in the presence or absence of a condensing agent, preferably in the presence or absence (preferably in the presence), by the compound represented by the formula (IX) and the formula (XX). The compound reaction was carried out in the same manner as the AV step of the above A method. The compound represented by the formula (XX) used in this step is a known compound, or can be easily produced by a known method or the like using a known compound as a starting material. Step D-11 This step is a step of producing a compound represented by the formula (If). This step 'in a solvent' allows the compound represented by the formula (X XI) to be removed as a result of reacting with a base and p-toluenesulfonyl chloride or methanesulfonyl chloride (preferably p-toluene) The protecting group for the amine group, the hydroxyl group and the sulfhydryl group in R2a and R61a is preferably used. The solvent used in this step is preferably a halogenated hydrocarbon, more preferably dichloro φ. The base used in this step is preferably an organic base. More preferably, it is triethylamine. The reaction temperature in this step is usually -100 ° C to 85 ° C, preferably 10 〇 C to 60 ° C. The reaction time in this step is usually 0.5 hour to 72 hours. , ^ _ is 1 hour to 24 hours.

In the method of E, the compound represented by the formula (I), R3 stomach di-(Ci-C6 alkyl)aminocarbonyl, R1 is independently separable from the group selected from the group A-47-201139430 A method in which one to three substituted 4,5-dihydro-1,3-oxazol-2-yl groups of the group are represented by the formula (Ig). (E law) 0 〇

E-ΙStep This step is a step of producing a compound represented by the formula (XX III). This step is carried out in the same manner as in the case of a base, and the compound represented by the formula (XXII) is reacted with the compound represented by the formula (VI) in the same manner as in the above-mentioned A-II step of the A method. . -48- 201139430 This step is a compound represented by the formula (XXII), which is a known compound, or can be easily produced by a known method or the like using a known compound as a starting material. Step E -11 This step is a step of producing a compound represented by the formula (XXIV). This step is carried out in a solvent, in the presence of a palladium catalyst and an inorganic base, by using a compound represented by the formula (XXIII) with 5-(4,4,5,5-tetramethyl-1,3,2 The reaction with benzyl dioxaborane-2·yl)-1Η-pyrrole-2·carboxylate is carried out in the same manner as in the above-mentioned step A-III of the a method. Step E - 111 This step is a step of producing a compound represented by the formula (XXV). This step is carried out in the same manner as in the above-mentioned A-IV step (i) of the method A, by reacting the compound represented by the formula (XXIV) in the presence of a palladium catalyst in a hydrogen atmosphere. E-IV step This step is a step of producing a compound represented by the formula (XXVI). This step is carried out in a solvent in the presence of a 'condensing agent, in the presence or absence of a base (preferably in the presence), by the compound represented by the formula (XXV) and represented by the formula (X) The compound reaction 'is carried out in the same manner as the A_v step of the above A method. E-V step This step is a step of producing a compound represented by the formula (XXVI1). This step is performed by (i) or (U). -49- 201139430 (i) This step is carried out in the same manner as in the above-mentioned A-VI step (1) of the A method by reacting a compound represented by the formula (XXVI) with a base and methanesulfonic anhydride. (ii) This step is carried out in a solvent by reacting a compound represented by the formula (XXVI) with a base and bis(2-methoxyethyl)aminosulfur trifluoride with the aforementioned A method A -VI step (ii) is carried out in the same manner. E-VI Step This step is a step of producing a compound represented by the formula (XXVIII). This step is carried out in the same manner as in the above-mentioned A-IV step (ii) of the A method, by reacting the compound represented by the formula (XXVII) with a base in a solvent. E - V II step This step is a step of producing a compound represented by the formula (Ig). This step is carried out in a solvent, in the presence of a condensing agent, in the presence or absence of a base, by reacting a compound represented by the formula (XXVIII) with a compound represented by the formula (XXIX), and then removing it as desired. The protecting group of the amine group, the hydroxyl group and/or the carboxyl group in Rh, R7la, R72a, 813 and 11823 is carried out. This step is carried out by using a compound represented by the formula (XXIX), a known compound, or a known compound as a starting material, which can be easily produced according to a known method or the like. The solvent used in this step is preferably a guanamine, an alcohol or a sulfonated hydrocarbon, more preferably N,N-dimethylformamide, methanol or a dichlorocarbyl. -50- 201139430 The condensing agent used in this step is preferably WSCI, WSCI·HCl, DMT-MM or HATU. The base used in this step is preferably an organic base, more preferably triethylamine, diisopropylethylamine or a combination of triethylamine and 4-dimethylaminopyridine. The reaction temperature in this step is usually -20 ° C to 4 (TC, preferably 〇. (: to 25 ° C. The reaction time in this step is usually from 1 hour to 72 hours, preferably from 6 hours to 3 hours). 6 hours. In the above, the definition of R2a, R61a 'R71a, R"a, R81a and R82a "protected limb base", "protectable base" and "protectable residue" The term "protecting group" refers to a protecting group which can be cleaved by a chemical method such as hydrodecomposition, hydrolysis, electrolysis, photolysis, and represents a protecting group which can be generally used in organic synthetic chemistry (for example, refer to TW Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1 999)) In the above, the "protective hydroxyl group" in the definition of R2a, R613, R71a, R72a, R81a and R82a The substituent of the hydroxyl group used in the field of organic synthetic chemistry is not particularly limited, and examples thereof include, for example, a formazan group, the aforementioned "CrC7 alkylcarbonyl group", and the above "c2-c7-alkylcarbonyl group J, A. Alkoxyalkylcarbonyl, propylene fluorenyl "Alkylcarbonyl" such as propioloyl, methacryl fluorenyl, crotonyl, isocrotonyl, (E)-2-methyl-2-butenyl hydrazyl unsaturated alkylcarbonyl An arylcarbonyl group such as a benzamidine group, an α-naphthylmethyl group, a β-naphthylmethyl group, or a halogenated aryl group such as 2--5 1-201139430 bromobenzylidene group or 4-chlorobenzylidene group; a carbonyl group, such as an alkylated arylcarbonyl group of 2,4,6-trimethylbenzylidene, 4-tolylmethyl, a CrCU alkoxylated arylcarbonyl such as 4-methoxybenzhydryl, Such as 4-nitrobenzhydryl, 2-nitrobenzhydryl-nitrolated arylcarbonyl, such as 2-(methoxycarbonyl)benzylidene-based C2-C7 alkoxycarbonylated aryl An "arylcarbonyl group" such as a carbonyl group or an arylated arylcarbonyl group such as a phenyl benzhydryl group; a "C2-C7 alkoxycarbonyl group" as described above, a 2,2,2-trichloroethoxycarbonyl group, 2 - "Alkoxycarbonyl" such as c2-C7 alkoxycarbonyl substituted by halogen or trialkyl) fluorenyl group of trimethylsulfonylethoxycarbonyl: tetrahydropyran-2-yl, 3-bromo Tetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4·methoxytetrahydro "tetrahydropyranyl or tetrahydrothiopyranyl" of piperidin-4-yl; "tetrahydrofuranyl or tetrahydrothiofuranyl" such as tetrahydrofuran-2-yl or tetrahydrofuran-2-yl; Trimethyl decyl, triethyl decyl, isopropyl dimethyl fluorenyl, tert-butyl dimethyl fluorenyl, methyl diisopropyl decyl, methyl di-tert-butyl fluorenyl , triisopropyl decyltris-alkyl) fluorenyl, diphenylmethyl fluorenyl, diphenylbutyl fluorenyl, diphenyl isopropyl fluorenyl, phenyl diisopropyl fluorenyl "Ci-Ce alkyl" diaryl fluorenyl or di-alkyl) aryl fluorenyl and the like "indenyl"; such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl , ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, a third butoxymethyl (CrC^ alkoxy)methyl group, such as 2-methoxy (C^-Ce alkoxyalkoxy)methyl group of ethoxymethyl group, such as 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl (C , -C6 halogenated alkoxy) methyl and the like "alkoxymethyl"; such as 1-ethoxyethyl, 1-(isopropoxy)ethyl-52-201139430 (C[-C6 "Substituted ethyl" such as benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenyl-ethyl, such as a halogenated ethyl group of 2,2,2-trichloroethyl; a C^-Ce alkyl group substituted with 1 to 3 aryl groups, such as 4-methylbenzyl group, 2, 3-phenylmethyl, α-naphthyldiphenylmethyl, 9-fluorenylmethyl ,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl , 4-nitrobenzyl, 4-chlorobenzyl, 4·bromobenzyl, 4-cyanobenzyl, substituted by Cl-C6 alkyl 'Cl-C6 alkoxy, nitro, halogen, cyano An "aralkyl group" such as a Cl-C6 alkyl group substituted by 1 to 3 aryl groups of the base ring; an "oxycarbonyl group" such as an ethylene oxycarbonyl group or an allyloxycarbonyl group; such as a benzyloxycarbonyl group or a 4-methoxy group. The benzyloxycarbonyl group, the 3,4-dimethoxybenzyloxycarbonyl group, the 2-nitrobenzyloxycarbonyl group, the 4-nitrobenzyloxycarbonyl group may have 1 or 2 Ci-Cs alkoxy groups. Or an "aralkyloxycarbonyl group" of a nitro-substituted aryl ring, preferably an alkylcarbonyl group, a fluorenyl group or an aralkyl group. In the above, the "protecting group" of the "protectable carboxyl group" in the definition of R2a, R61a, R71a, R72a, R81a, and R82a 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 aforementioned "Ci-Ce Institute Base", which is described as "C2-C6' thin base", B-base, 1-propyl block, 2-propynyl, b-methyl-2-propynyl, and C^C:6 alkynyl group of alkynyl group; the above-mentioned "C丨-C6 halogenated alkyl group"; such as hydroxymethyl group, 2-hydroxyl ethyl group Cl_Cf via a base group; such as ethyl ethyl group (C2-C7) The above-mentioned "aralkyl group"; or the aforementioned "aralkyl group"; or the above-mentioned "mercapto group", preferably (^-(^院基或芳院基. -53- 201139430 above, R2a, R61a, R713, The "protecting group" of the "protectable amine group" in the definition of R72a, R81a and R"a is not particularly limited as long as it is a protecting group for an amine group used in the field of organic synthetic chemistry, for example, "Alkylcarbonyl" in the protecting group of a hydroxy group; "arylcarbonyl"; "alkoxycarbonyl"; "fluorenyl"; "aralkyl"; "alkenyloxycarbonyl"; The same group of "aralkyloxycarbonyl", or such as N,N-dimethylaminomethylene, sub-nodal '4-methoxyarylene-based group, 4-nitro-subunit group, arsenic "Substituted methylene group forming a S chi ff base", 5-chlorosalicylidene, diphenylmethylene, (5-chloro-2-hydroxyphenyl)phenylmethylene Preferably, it is an alkylcarbonyl group, an arylcarbonyl group or an alkoxycarbonyl group, more preferably an alkoxycarbonyl group. Protection and deprotection are essential steps in accordance with known methods (for example, 'Protective Groups in Organic Synthesis' (Theodora W The method described in Greene, Peter GMWuts, 1999, issued by Wiley-Interscience Publication, etc.) The compound of the present invention or a pharmacologically acceptable salt thereof can be administered in various forms. , tablets, capsules, granules, emulsions, nine doses, powders, syrups (liquid preparations), etc. by oral administration, or injection (intravenous, intramuscular, subcutaneous or intraperitoneal administration), drip, Suppositories (rectal administration), etc. are administered by parenteral administration. According to the usual method, an auxiliary agent which can be generally used in the field of pharmaceutical preparations such as excipients, adhesives, disintegrating agents, lubricants, flavoring agents, dissolution aids, suspending agents, and coating agents is formulated. -54- 201139430 When used in the form of tablets, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate 'kaolin, crystalline cellulose, citric acid and the like; water, ethanol, propanol , single syrup 'glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and other bonding agents; dry starch, sodium alginate, loam powder, kelp Sugar (laminaran) powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and other disintegrating agents; white sugar, tristearic acid glycerin Emulsification inhibitors such as ester (steari η), cocoa butter, hydrogenated oil; absorption enhancers such as 4-grade ammonium salts and sodium lauryl sulfate; humectants such as glycerin and starch; starch, lactose , kaolin, bentonite, colloidal citrate and other adsorbents; refined talc, stearate, boric acid powder, polyethylene glycol and other lubricants. Further, if necessary, a lozenge treated with a coating may be prepared, 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. When used in the form of nine doses, the carrier is, for example, an excipient such as glucose, lactose, cocoa butter, starch, hardened vegetable oil, kaolin, talc; gum arabic powder, gelatin powder, gelatin, ethanol, etc.; , agar and other disintegration agents. When used in the form of a suppository, the carrier can be widely used in the prior art, such as polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like. When used in the form of an injection, it can be used in the form of a liquid, an emulsion or a suspension. These liquids, emulsions or suspensions should be sterilized and are isotonic with blood-55-201139430. The solvent used for the preparation of the liquid, emulsion or suspension may be used as a diluent for medical use, and is not particularly limited as water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylipid. Alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. Further, the preparation may contain a sufficient amount of glucose or glycerin required for preparing an isotonic solution, and may contain a usual solubilizing aid, a pain reliever, and the like. Further, the above preparation may contain a coloring agent, a preservative, a flavor, a sweetener or the like as necessary, and may further contain other pharmaceuticals. The amount of the active ingredient compound to be contained in the above-mentioned preparation is not particularly limited. It is appropriately selected in a wide range, but it is usually contained in the total composition of 0.70% by weight, preferably 1 to 30% by weight. The amount of use varies depending on the age of the patient (warm-blooded animals, especially humans). In the case of oral administration, for adults, 2000 mg (preferably 100 mg) per sputum, the lower limit is 〇.lmg (compared Preferably, it is 1 mg, 10 m g), and it is desirable to administer the symptoms 1 to 6 times a day. EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples and test examples, and the scope of the invention is not limited thereto.

The elution in column chromatography of the examples was carried out by observation under TLC (Thin I Chromatography). In the TLC observation, the plate was prepared by using Merck Co., Ltd., 60F 2 5 4 , and the solvent used in the solvent chromatography was used as a solvent for the elution solvent. The detection method was UV, and only the salt was used. Fragrance, can be 5 to, the age is better but this / ayer TLC column inspection -56- 201139430. For the column, the silicone rubber SK-8 5 (230-400 mesh) manufactured by Merck & Co., Ltd., or silicone rubber FL100B manufactured by Fuji Silysia Chemical Co., Ltd. was used. In addition to the usual column chromatography, Moritex's automatic chromatography apparatus (Purif-a2) and disposable pipe (Purif-pack) can also be used suitably. It was refined by preparative TLC using a silicone rubber 60F 2 5 4 made of Merck, 0.5 mm thick, and 2 〇 x 20 cm. Further, the abbreviations used in the examples have the following meanings. Mg: mg, g: g, mL: ml, MHz: megahertz, HATU: 〇-(7-azabenzotriazol-1-yl)-indole, hydrazine, Ν'Ν'-tetramethylurea hexafluoro Phosphate, WSCI*HC1:1-ethyl-3-(dimethylaminopropyl)carbonyldiimide hydrochloride, HOBT. H20: 1-hydroxybenzotriazole monohydrate, DMT-MM: 4-(4,6-Dimethoxy-1,3,5-triton-2-yl)-4-methyl-glymphine chloride η hydrate. In the following examples, the nuclear magnetic resonance (hereinafter, 1H-NMR) spectrum is based on tetramethyl decane as a standard material, and the chemical shift 値 is described in δ 値 (ppm). Regarding the split pattern, a single line is represented by s, a double line is represented by d, a reference line is represented by t, four lines are represented by q, a plurality of lines are represented by m, and a broad line is represented by br. The mass analysis (hereinafter, MS) was carried out by FAB (Fast Atom Bombardment) method, El (Electron Ionization) method, or ESI (Electron Spray Ionization) method. (Example 1) 4-{[(2S)-l-methoxypropan-2-yl]oxy}-2-{5-[(5S)-5-methyl-4,5-dihydro-1 , 3-oxazol-2-yl]-111-pyrrol-2-yl}-6-[4-(methylsulfonyl)phenoxy]pyridine-57- 201139430

:^° (la) 2,6-Dichloro- 4-{[(2S)-l-methoxypropan-2-yl]oxy}pyridine makes sodium hydride (about 63% '980mg, about 25.7mm〇l After suspending in tetrahydrofuran (60 mL), (S)-(+)-2-methoxy-1-propanol (2.55 mL, 26.0 mmol) was added dropwise under nitrogen atmosphere, stirring at 0 ° 20 minute. 2,6-Dichloro-4-nitropyridine (4.02 g, 20-8 mmol) in which tetrahydrofuran (2 mL) was dissolved was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. Water (3 mL) was added and extracted twice with ethyl acetate (300 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent solvent: ethyl acetate/hexane = 〇% to 10%) to obtain the objective compound (4.65 g , yield 95%). 'H-NMR (CDC13, 400ΜΗζ): δ 1.33 (3Η, d, J = 6.6 Hz), 3.39 (3H, s), 3.50 (1 H, dd, J = 10.4, 3.7 Hz), 3.55 (1H, dd , J - 10.6, 6.3 Hz), 4.57-4.65 ( 1 H, m), 6.81 (2H, s) (lb) 2-Chloro 4-{[(2S)-l-methoxypropan-2-yl Oxy}-6-[4-(methylsulfonyl)phenoxy]pyridine The compound synthesized in Example (la) (835 mg, 3.54 mmol) and 4-(methylsulfanyl)benzene The hydrazine (520 mg, 3.71 mmol) was dissolved in acetonitrile (20 mL), and then the mixture was poured to the mixture (1.20 g, 3.68 mmol), and the mixture was stirred under reflux in a nitrogen atmosphere for one day. The mixture was extracted twice with ethyl acetate (100 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified eluting eluting eluting eluting eluting eluting eluting This was dissolved in methylene chloride (10 mL), and m-chloroperbenzoic acid (about 65%, 1.16 g, 4.4 mmol) was slowly added at 0 ° C, and stirred at 〇 ° C for 30 minutes under a nitrogen atmosphere. A saturated aqueous solution of bicarbonic acid (50 mL) was added and dichloromethane was evaporated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue obtained was purified using silica gel column chromatography (eluent solvent: ethyl acetate / hexane = 5% to 25%) to obtain the objective compound (7 6 0 mg, yield 5 8 %). 'H-NMR (CDClj, 500 ΜΗζ): δ 1.35 (3Η, d, J = 6.3 Hz), 3.07 (3H, s), 3.40 (3H, s), 3.51 (1H, dd, J = 10.3, 3.9 Hz ), 3.57 (1H, dd, J - 10.7, 6.3 Hz), 4.60-4.66 (1H, m), 6.42 (1H, d, J = 2.0 Hz), 6.71 (1H, d, J = 2.0 Hz), 7.30 (2H, dt, J = 9.3, 2.3 Hz), 7.95 (2H, dt, J = 9.3, 2.3 Hz) (lc) 5-(4-{[(2S)-l-methoxypropan-2-yl) Oxy}-6-[4-(methylsulfonyl)phenoxy]pyridin-2-yl)-1Η-pyrrole-2-carboxylic acid vinegar. Compound synthesized in Example (lb) (76 Omg , 2.0 4m mol) dissolved in a mixed solvent of 1.4-dioxane (15mL) and water (4.0mL), and added 5-(4,4,5,5-tetramethyl) which is known (International Publication No. W02009/099080) _i,3,2-dioxaboron-2 -yl)-1Η -indolebi-2-residual acid vinegar (i.〇5g, 3.21mmol), [1,1'-bis(diphenyl Phosphinyl) ferrocene] palladium dichloride (π) dichloromethane - 59-201139430 (90mg, O.llmmol), potassium carbonate (1.25g, 9.04mmol), under nitrogen atmosphere Stir at 50 ° C for one night. After the reaction mixture was cooled to room temperature, water (50 mL) was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent solvent: ethyl acetate / hexane = 5% to 30%) to obtain the desired compound (1). 0 3 g, yield 9 4%) ° 'H-NMR (CDC13, 4 00 ΜΗζ): δ 1.37 (3Η, d, J = 6.6 Hz), 3.10 (3H, s), 3.41 (3H, s), 3.53 (1H, dd, J = 10.6, 3.9 Hz), 3.60 (1H, dd, J = 10.2, 6.3 Hz), 4.66-4.71 (1H, m), 5.28 (2H, s), 6.36 (1 H, d, J = 1.6 Hz), 6.63 (1 H, dd, J = 3.9, 2.3 Hz), 6.94 (1H, dd, J = 4.1, 2.5 Hz), 6.97 (1H, d, J = 2.0 Hz), 7.29 (2H, dt, J = 9.4, 2.4 Hz), 7.33-7.41 (5H, m), 7.97 (2H, dt, J = 9.5, 2·3 Hz), 9.7 1 (1H, s). (1 <1) Heart [(2 ft)-2-hydroxypropyl]-5-(4-{[(23)-1-methoxypropan-2-yl]oxy}-6_[4-(A The compound synthesized in the example (lc) (1. 〇3 g, 1.92 mmol) was dissolved in ethyl acetate (m.p.) phenoxy]pyridin-2-yl)-1 H-pyrrole-2-carboxycarboxamide. 30 m L), palladium on carbon (23 Omg) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. After filtration through celite, the solvent was evaporated under reduced pressure to give a white solid. The obtained compound was dissolved in dichloromethane (20 mL), (R)-(-)-l-amino-2-propanol (0.20 mL, 2.54 mmol), WSCI. HCl (5 00 mg, 2.61 mmol) HOBT. H2 〇 (400 mg, 2.61 mmol), -60-201139430 N-methyl sulphate (O.WmL, 4.09 mmol) was stirred overnight at room temperature under a nitrogen atmosphere. Saturated aqueous sodium hydrogencarbonate (5 mL) was added and the mixture was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent solvent: methanol / dichloromethane = 1% to 5%) Yield 74%). 'H-NMR (CDC13, 400ΜΗζ): δ 1.23 (3Η, d, J = 6.3 Hz), 1.38 (3H, d, J = 6.3 Hz), 2.45 (1H, d, J = 4.3 Hz), 3.14 (3H, s), 3.24 (1H, ddd, J = 14.1, 7.6, 5.3 Hz), 3.42 (3H, s), 3.54 (1H, dd, J = 10.6, 3.9 Hz), 3.61 (1H, dd, J = 10.2, 6.3 Hz), 3.71-3.80 (1H, m), 3.95-4.02 ( 1 H, m), 4.65-4.71 (1H, m), 6.25 (1 H, t, J = 6.1 Hz), 6.37 ( 1H, d, J = 2.0 Hz), 6.58 (1H, dd, J = 4.1, 2.5 Hz), 6.62 (1H, dd, J = 3.9, 2.7 Hz), 6.95 (1H, d, J = 2.0 Hz), 7.29 (2H, dt, J = 9.6, 2.4 Hz), 7.97 (2H, dt, J = 9.4, 2.4 Hz), 9.78 (1H, s) (le) 4-{[(2S)-l-methoxy Propane-2-yl]oxy}-2-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrole-2- The compound synthesized in Example (Id) (72 Omg, 1.43 mmol) was dissolved in tetrahydrofuran (10 mL), and methane was added at 0 ° C. Sulfonic acid anhydride (450 mg, 2.58 mmol) and triethylamine (〇. 60 mL, 4.30 mmol) were stirred at 50 ° C overnight under a nitrogen atmosphere. Water (20 mL) was added and the mixture was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent solvent ethyl acetate / hexane = 20% to 70%) to give the title compound (400 mg). Rate 58%). 'H-NMR (CDClj, 400ΜΗζ): δ 1.37 (3Η, d, J = 6.3 Hz), 1.39 (3H, d, J = 5.9 Hz), 3.11 (3H, s), 3.42 (3H, s), 3.47 -3.56 (2H, m), 3.60 (1H, dd, J = 10.4, 6.1 Hz), 4.03 (1H, dd, J = 14.1, 9.0 Hz), 4.64-4.72 (1H, m), 4.73-4.83 (1H , m), 6.34 (1H, d, J = 2.0 Hz), 6.64 (1H, d, J = 3.9 Hz), 6.73 (1H, d, J = 3.9 Hz), 6.96 (1H, d, J = 2.0 Hz) ), 7.29 (2H, d, J = 8.6 Hz), 7.97 (2H, d, J = 9.0 Hz), 9.73 (1H, br s). MS (ESI) m/z: 486.1 688 1 (M + H) +. (Example 2) (2S)-2-[(2-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H·pyrrole -2-yl}-6-[4-(methylsulfonyl)phenoxy]pyridin-4-yl)oxy]propyl-1-ol

The compound synthesized in Example (le) (346 mg, 0.713 mmol) was dissolved in dichloromethane (5.0 mL), and boron tribromide (1. 〇m〇l/L dichloromethane solution was added dropwise at -78 °C. 0.90 mL), and stirred at 〇 ° C for 2 hours under a nitrogen atmosphere. A saturated aqueous solution of sodium hydrogencarbonate (10 mL) was added and the mixture was evaporated to dichloromethane. The organic layer was washed with a 1N aqueous sodium hydroxide solution and brine (br. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography ( eluting solvent: methanol / methylene chloride = 1% to 5%) to give the title compound (258 mg, yield 77%). *H-NMR (CDC13, 500 ΜΗζ): δ 1.35 (3Η, d, J - 6.3 Hz), 1.39 (3H, d, J = 5.9 Hz), 2.15 (1H, br s), 3.11 (3H, s ), 3.50 (1H, dd, J = 14.2, 7.3 Hz), 3.79 (2H, d, J = 4.9 Hz), 4.04 (1H, dd, J = 14.2, 9.3 Hz), 4.59-4.66 ( 1 H, m ), 4.75 -4.8 3 ( 1 H, m), 6.32 (1H, d, J = 2.0 Hz), 6.64 (1H, d, J = 3.9 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.92 (1H, s), 7.31 (2H, dt, J = 9.4, 2.4 Hz), 7.98 (2H, dt, J = 9.1, 2.4 Hz) MS (ESI) m/z: 472.1 5477 (M + H)+0 (Example 3) 4-{[(2S)-l-methoxypropan-2-yl]oxy}-2-{5-[(53)-5-methyl-4,5-dihydro-1 , 3-oxazol-2-yl]-111-pyrrol-2-yl}-6-{[6-(methylsulfonyl)pyrene-deep-3-yl]oxy} Π ratio D

(3a) 2-Chloro-4-{[(2S)-l-methoxypropan-2-yl]oxy}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy} Pyridine The compound synthesized in Example (la) (2.4〇g 'l〇.2mmol) is known to be 6-(methylsulfonyl)pyridin-3-yl-63- (International Publication No. WO2007/0079 10) 201139430 Alcohol (2.20 g, 12.7 mmol) was dissolved in N,N-dimethylformamide (30 mL). EtOAc (EtOAc:EtOAc:EtOAc A 1 N aqueous solution of hydrochloric acid (100 mL) was added, and ethyl acetate (200 mL) The organic layer was washed twice with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent solvent: ethyl acetate / hexane = 10% to 50%) to obtain the objective compound (1.94 g , yield 51%). ^-NMR (CDC13, 400ΜΗζ): δ 1.37 (3Η, d, J = 6.3 Hz), 3.25 (3H, s), 3.41 (3H, s), 3.53 (1H, dd, J = 10.4, 3.7 Hz), 3.59 (1H, dd, J = 10.4, 6.5 Hz), 4.61-4.68 (1H, m), 6.48 (1H, d, J = 1.6 Hz), 6.73 (1H, d, J = 2.0 Hz), 7.75 (1H , dd, J = 8.6, 2.7 Hz), 8.13 (1H, d, J = 8.6 Hz), 8.58 (1H, d, J = 2.7 Hz) (3b) 5-(4-{[(2S)-l- Methoxypropan-2-yl]oxy}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridin-2-yl)-1Η-pyrrole-2-carboxylic acid benzyl ester The compound synthesized in Example (3a) (490 mg, 1.31 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-111- Benzyl pyrrole-2-carboxylate (7550 mg, 2.29 mm 〇l), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (Π) dichloromethane complex (89 mg, O. ll mmol), potassium carbonate (91_5 mg, 6.62 mm), Compound Compound (561 mg, yield: 80%). 'H-NMR (CDC13, 400ΜΗζ): δ 1.39 (3Η, d, J = 6.3 Hz), 3.26 (3H, s), 3.42 (3H, s), 3.54 (1H, dd, J = 10.6, 3.9 Hz) , -64- 201139430 3.61 (1H, dd, J = 10.2, 6.3 Hz), 4.66-4.73 ( 1 H, m), 5.29 (2H, s), 6.43 (1H, d, J = 2.0 Hz), 6.64 ( 1H, dd, J = 3.9, 2.3 Hz), 6.94 (1H, dd, J = 3.9, 2.7 Hz), 6.99 (1H, d, J = 2.0 Hz), 7.3 3 -7.43 (5 H, m), 7.72 (1H, dd, J = 8.6, 2.3 Hz), 8.13 (1H, d, J = 8.6 Hz), 8.60 (1H, d, J = 2.3 Hz), 9.63 (1H, br s) (3c)5-( 4-{[(2S)-l-methoxypropan-2-yl]oxy}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridin-2-yl)- 1Η-pyrrol-2-carboxylic acid The compound (561 mg, 1.4 mmol) synthesized in Example (3b) was dissolved in a mixed solvent of ethyl acetate (5.0 mL) and ethanol (5.0 mL), and palladium carbon (1) was added. 90 mg), stirred at room temperature for 4 hours under a hydrogen atmosphere. After filtration of the celite, the solvent was evaporated to dryness to give the title compound (yield: ield: 90%). 'H-NMR (CDC13, 400ΜΗζ): δ 1.40 (3Η, d, J = 6.3 Hz), 3.28 (3H, s), 3.43 (3H, s), 3.56 (1H, dd, J = 10.4, 3.7 Hz) , 3.63 (1H, dd, J = 10.4, 6.5 Hz), 4.68-4.76 ( 1 H, m), 6.45 (1H, d, J = 2.0 Hz), 6.66 (1H, dd, J = 3.9, 2.3 Hz) , 6.99 (1H, dd, J = 3.9, 2.7 Hz), 7.02 (1H, d, J = 1.6 Hz), 7.74 (1H, dd, J = 8.4, 2.5 Hz), 8.16 (1H, d, J = 8.6 Hz), 8.62 (1H, d, J = 2.7 Hz), 9.66 (1H, s). (3d) N-[(2R)-2-Hydroxypropyl]-5-(4-{[(2S)-l-methoxypropan-2-yl]oxy}-6-{[6-(A The compound synthesized by the example (3c) (419 mg, 0.94 mmol) was dissolved in the compound (3c), which was dissolved in the compound (3c). Dichloromethane (10 mL), (R)-(-)-l-amino-2-propanol (0.15 mL, 1.91 mmol), WSCI. HCl (2 80 mg, 1 · 4 6 mm) ο 1), Η BT BT · H2 〇 (240 mg, 1.57 mmol), Ν-methyl morpholine (0.25 mL, 2.27 mmol), stirred under a nitrogen atmosphere for one night. Water (20 mL) was added to the mixture and the mixture was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent solvent: methanol/dichloromethane = 1% to 6%) to obtain a white foamy compound (340 mg). Rate 72%). 'H-NMR (CDC13, 400ΜΗζ): δ 1.23 (3Η, d, J = 6.3 Hz), 1.39 (3H, d, J = 6.3 Hz), 3.21-3.28 (1H, m), 3.29 (3H, s) , 3.43 (3H, s), 3.55 (1H, dd, J = 10.4, 3.7 Hz), 3.62 (1H, dd, J = 10.2, 6.3 Hz), 3.72 -3.7 9 ( 1 H, m), 3.9 5 - 4.04 ( 1 H, m), 4.67-4.7 2 ( 1 H, m), 6.30 (1H, t, J = 5.5 Hz), 6.42 (1H, d, J = 1.6 Hz), 6.58 (1H, dd, J = 4.1, 2.5 Hz), 6.63 (1H, dd, J = 3.9, 2.7 Hz), 6.97 (1H, d, J = 2.0 Hz), 7.72 (1H, dd, J = 8.6, 2.7 Hz), 8.14 (1H , d, J = 8.6 Hz), 8.60 (1H, d, J = 2.7 Hz), 9.76 (1H, s) (3e)4-{[(2S)-l-methoxypropan-2-yl]oxy }-2-{5-[(5S)-5-Methyl-4,5-dihydro-1,3-Dfoxazol-2-yl]-1H-pyrrol-2-yl}-6-{[6 -(Methylsulfonyl)pyridin-3-yloxy}pyridine The compound synthesized using Example (3d) (34 mg, 0.67 mmol), methanesulfonic anhydride (278 mg, 1.6 mmol), three Ethylamine (〇40 mL, 2.87 mmol), -66 - 201139430 The title compound (2900 mg > • H-NMR (CDC13) 400ΜΗζ): δ 1.35 (6Η, d, J = 6.3 Hz), 3.24 (3H, s), 3.39 (3H, s), 3.47 (1H, dd, J = 13.9, 7.2 Hz) , 3.51 (1 H, dd, J = 10.2, 3 .5 Hz), 3.58 ( 1 H, dd, J = 10.6, 6.3 Hz), 4.00 (1H, dd, J = 14.1, 9.0 Hz), 4.63 -4.69 ( 1 H, m), 4.72-4.8 0 ( 1 H, m), 6.36 (1H, d, J = 2.0 Hz), 6.60 (1H, d, J = 3.9 Hz), 6.69 (1H, d, J = 3.9 Hz), 6.94 (1H, d, J = 2.0 Hz), 7.70 (1H, dd, J = 8.6, 2.3 Hz), 8.10 (1H, d, J = 8.6 Hz), 8.57 (1 H, d, J = 2.7 Hz) MS (ESI) m/z: 48 7.1 6 5 07 (M + H)+. (Example 4) (2S)-2-[(2-{5-[(5S)-5-methyl-4,5-dihydro-1,3-Dfoxazol-2-yl]-1 H - Pyrrolo-2-yl}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridin-4-yl)oxy]propan-1-ol

The compound synthesized in Example (3e) (280 mg, 0.575 mmol), boron tribromide (1.0 mol/L dichloromethane solution, 0.72 mL) was used in the same manner as in Example 2 The title compound was obtained as a white solid (23Omg, yield: 5%) 〇^-NMR (CDC13, 400 ΜΗζ): δ 1.35 (3 Η, d, J = 6.3 Hz), -67- 201139430 1.40 (3H, d, J = 6.3 Hz), 2.48 (1H, br s), 3.28 (3H, s), 3.51 (1H, dd, J = 14.1, 7.4 Hz), 3.78 (2H, d, J = 5.1 Hz), 4.05 (1H, Dd, J = 14.1, 9.0 Hz), 4.56-4.63 (lH, m), 4.75-4.85 (1H, m), 6.35 (1H, s), 6.61 (1H, d, J = 4.3 Hz), 6.74 (1H , d, J = 3.9 Hz), 6.88 (1H, s), 7.78 (1H, dd, J = 8.8, 1.8 Hz), 8.16 (1H, d, J = 8.2 Hz), 8.62 (1H, d, J = 2.3 Hz) MS (ESI) m/z: 473.1 4948 (M + H) + (Example 5) 4-{[(2S)-l-methoxypropan-2-yl]oxy}-2- {5-[(4R)-4 -Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1^pyrrol-2-yl}-6-{[6-(methyl Sulfomethyl)pyridin-3-yl]oxy}pyridine

(53) 1^-[(211)-1-hydroxypropan-2-yl]-5-(4-{[(23)-1-methoxypropan-2-yl]oxy}-6-{[ 6-(Methylsulfonyl)pyridin-3-yl]oxy}pyridin-2-yl)-1Η-pyrrole-2-carboxyguanamine The compound synthesized in Example (3c) (592 mg, 1.32 mmol), D -Aminopropanol (〇18 mL, 2.30 mmol), WSCI. HCl (393 mg, 2.05 mmol), HOBT·H2 〇 (335 mg, 2.19 mmol), N-methyl-Mineline (0.45 mL, 4.09 mmol), Example (3d) The title compound (575 mg, yield: 86%) -68- 201139430 •H-NMR (CDC13, 4 00ΜΗζ): δ 1.26 (3H, d, J = 6.6 Hz), 1.39 (3H, d, J = 6.3 Hz), 2.50 ( 1 H, br s), 3.29 (3H, s), 3.43 (3H, s), 3.55 (1H, dd, J = 10.2, 3.9 Hz), 3.62 (1H, dd, J = 10.2, 6.3 Hz), 3.71-3.81 (2H, m), 4.16-4.24 (1H, m), 4.67- 4.74 ( 1 H, m), 6.00 (1H, d, J = 7.0 Hz), 6.42 (1H, d, J =2.0 Hz), 6.56 (1 H, dd, J = 3.9, 2.7 Hz), 6.62 (1 H, dd, J = 4.1, 2.5 Hz), 6.97 (1H, d, J = 2.0 Hz), 7.71 (1H, dd, J - 8.6, 2.7 Hz), 8.14 (1H, d, J = 9.0 Hz), 8.59 (1H, d, J = 3.1 Hz), 9.73 ( 1 H, br s) (5b) 4-{[(2S)-l-methoxypropane-2 -yl]oxy}-2-{5-[(4 ft)-4-methyl- 4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl b 6 -{[6-(Methylsulfonyl)pyridin-3-yl]oxy}pyridine The compound synthesized in Example (5a) (575 mg, 1.14 mmol), methanesulfonic acid anhydride (400 mg, 2.30 mmol), triethylamine (0.65 mL, 4.66 mmol), m. m. H-NMR (CDC13,400ΜΗζ): δ 1_31 (3H, d, J = 6.6 Hz), 1.39 (3H, d, J = 6.3 Hz), 3.27 (3H, s), 3.42 (3H, s), 3.55 (1H, dd, J = 10.6, 3.9 Hz), 3.62 (1H, dd, J = 10.4, 6.1 Hz), 3.8 6-3.94 ( 1 H, m), 4.2 5 -4.3 6 ( 1 H, m), 4.43-4.51 (1H, m), 4.67- 4.75 ( 1 H, m), 6.40 (1H, d, J = 2.0 Hz), 6.65 (1H, d, J = 3.9 Hz), 6.76 (1H, d, J = 3.5 Hz), 7.00 (1H, s), 7.71 (1H, dd, J = 8.6, 2.7 Hz), 8.14 (1H, dd, J = 8.6, 0.8 Hz), 8.60 (1H, d, J = 2.7 Hz) ) -69- 201139430 MS (ESI) m/z: 4 8 7.1 65 08 (M + H)+. (Example 6) (2S)-2-[(2-{5-[(4R)-4-methyl-4,5-dihydro-i,3-oxazol-2-yl]-1 H-pyrrole -2 -yl} - 6 - {[ 6 -(methylsulfonyl)pyridine · 3 yl]oxy}pyridin-4-yl)oxy]propan-1-ol

The compound (389 mg, 0.800 mmol) synthesized by the example (5b) and boron tribromide (1.0 m ο 1 / L dichloromethane solution, 1. 〇〇m L) were used in the same manner as in (Example 2). The title compound was obtained as a white solid (365 mg, yield: 7%). 'H-NMR (CDC1 3, 5 00 ΜΗζ): δ 1.29 (3 Η, d, J = 6.3 Hz), 1.32 (3H, d, J = 6.8 Hz), 3.28 (3H, s), 3.6 8 -3.7 7 (2H, m), 3.9 0-3.9 8 ( 1 H, m), 3.92 (1H, t, J = 7.8 Hz), 4.28-4.3 6 ( 1 H, m), 4.41-4.47 (1H, m), 4.50 (1H, t, J = 8.5 Hz), 6.20 (1H, d, J = 1.5 Hz), 6.54 (1H, d, J = 3.4 Hz ), 6.68 (1H, s), 6.75 (1H, d, J = 3.9 Hz), 7.85 (1H, dd, J = 8.8, 2.4 Hz), 8.17 (1H, d, J = 8.8 Hz), 8.60 (1H , d, J = 2.4 Hz), 9.94 (1H, br s) MS (ESI) m/Z: 473.1 4925 (M + H)+. (Example 7) 4-{[(2S)-l-methoxypropan-2-yl]oxy}-2-[5-(5-methyl-1,3,4-Dfdiazolyl-2 -yl)-1Η-pyrrol-2-yl]-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridine-70- 201139430 ο-^γ0

ο (7a) N'-Ethyl-5-(4-{[(2S)-l-methoxypropan-2-yl]oxy} - 6 - {[ 6 -(methylsulfonyl)pyridine -3 -yl]oxy}pyridin-2-yl)-1 Η-pyrrole-2-carboindole The compound synthesized in Example (3c) (6 mg, 1.34 mmol), acetonitrile (159 mg, 2.15) Ment), WSCI· HCl (395 mg, 2.06 mmol), Η Ο BT . Η 2 Ο ( 3 3 5 mg, 2 · 1 9 mm ο 1) ' n · Methyl porphyrin (〇· 4 5 m L, 4.09 The title compound (5 30 mg, yield 79%) was obtained as a yellow solid. ^-NMR (CDC13j 400ΜΗζ): δ 1.38 (3Η, d, J = 6.3 Hz), 2.04 (3H, s), 3.26 (3H, s), 3.42 (3H, s), 3.54 (1H, dd, J = 10-4, 3.7 Hz), 3.61 (1H, dd, J = 10.6, 6.3 Hz), 4.67-4.74 (1H, m), 6.40 (1H, d, J = 2.0 Hz), 6.60 (1H, dd, J = 3.9, 2.7 Hz), 6.74 (1H, dd, J = 3.9, 2.7 Hz), 6.96 (1H, d, J - 2.0 Hz), 7 72 〇H, dd, J = 8.6, 2.7 Hz), 8.11 ( 1H, d, J = 8.6 Hz), 8.58 (1H, d, j = 2.7 Hz), 8.66 (1H, s), 9.05 (1H, s), 9.76 (1H, s) (7b)4-{[( 2S)-l-methoxypropan-2-yl]oxy}-2-[5·(5-methyl-1,3,4-oxadiazolyl-indhrylpyrazine-2-pyrrol-2-yl (Methylsulfonyl) indole D-but-3-yloxy}pyridine The compound synthesized in Example (7a) (530 mg, 1. 5 mmol) was dissolved in dichloromethane (10 mL) at 0 ° C Add p-toluenesulfonyl chloride (400 mg, 201139430 2.10 mmol), triethylamine (0.60 mL, 4.30 mmol), and stir overnight at room temperature under nitrogen. Water (2OmL), (3OmL) The organic layer was washed with saturated brine and dried. The solvent was evaporated under reduced pressure, and the obtained residue was used for elution (eluent solvent: methanol / dichloromethane = 〇%) 2%) The objective compound (445 mg, yield 87%) of purified solid. [H-NMR (CDC13, 400 ΜΗζ): δ 1.40 (3 Η, d, 2.57 (3H, s), 3.31 (3H, s), 3.43 ( 3H, s), 3.56 10.6, 3.9 Hz), 3.63 (1H, dd, J = 10.6, 6.3 Hz (1H, m), 6.44 (1H, d, J = 2.0 Hz), 6.71 (1 H, dd, Hz ), 6.85 (1H, dd, J = 3.9, 2.7 Hz), 7.01 (1H, d, 7.70 (1H, dd, J = 8.6, 2.7 Hz), 8.16 (1H, d, J = 8 (1H, d, J = 2.7 Hz), 9.71 (1H, br s) MS (ESI) m/z: 486.1 445 9 (M + H)+. (Example 8) (28)-2-[(2-[5-(5-Methyl-1,3,4-oxadiazolyl-2-!-2-yl]-6-{[6- (Methylsulfonyl)pyridin-3-yl]oxy}pyridin-1-ol in an atmosphere of methylene chloride anhydrous magnesium sulfate in a septum column to obtain a yellow J = 6.6 Hz), (1 H, dd, J = ), 4.68-4.75 J = 3.9, 2.7 J = 2.0 Hz), .6 Hz), 8.6 1 S ) - 1 H -pyrrol-4-yl)oxy]propyl

The compound synthesized in Example (7b) (426 mg, 0. boron tribromide (1.0 mol/L dichloromethane solution, 1.15 mL), | 8 7 7 mm ο 1), U Example 2) -72- 201139430 The title compound (29 5 mg, yield 71%) was obtained as white solid. 'H-NMR (CDC13, 400ΜΗζ): δ 1.39 (3Η, d, J = 6.3 Hz), 2.57 (3H, s), 3.31 (3H, s), 3.82 (2H, d, J = 5.5 Hz), 4.63 -4.72 ( 1 H, m), 6.43 (1H, d, J = 2.0 Hz), 6.72 (1H, dd, J = 3.9, 2.3 Hz), 6.86 (1H, dd, J = 3.9, 2.7 Hz), 6.99 (1H, d, J = 2.0 Hz), 7.71 (1H, dd, J = 8.6, 2.7 Hz), 8.17 (1H, d, J = 8.6 Hz), 8.62 (1H, d, J = 2.3 Hz), 9.80 (1H, br s) MS (ESI) m/z: 472.1 29 1 0 (M + H)+. (Example 9) 4-{[(2S)-l-methoxypropan-2-yl]oxy}-2-{5-[(5S)-5-methyl-4,5-dihydro-1 , 3-oxazol-2-yl]-111-pyrrol-2-yl}-6-{[5-(methylsulfonyl)pyridin-2-yl]oxy}pyridine

(9a) 2-(Benzyloxy)-6-chloro-4-{[(2S)-l-methoxypropan-2-yl]oxy}pyridine gives sodium hydride (about 63%, 260 mg, about 6.83 mmol) After suspension in tetrahydrofuran (20 mL), benzyl alcohol (0.65 mL, 6.25 mmol) was added dropwise at 0 ° under a nitrogen atmosphere and stirred at 0 ° for 15 min. A solution of the compound (1. 7 g, 4.96 mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 2 hours and a half under a nitrogen atmosphere, -73-201139430 at 60°. C is stirred for 3 hours and a half. Water (50 mL) was added, and extracted twice with ethyl acetate (100 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent solvent: ethyl acetate/hexane = 〇% to 10%) to obtain the objective compound (1.28) as colorless oil. g, yield 84%). 'H-NMR (CDC 13, 4 00ΜΗζ): δ 1.31 (3Η, d, J = 6.3 Hz), 3.38 (3H, s), 3.47 (1H, dd, J = 10.4, 4.1 Hz), 3.54 (1H, Dd, J = 10.4, 6.1 Hz), 4.51-4.59 (1H, m), 5.33 (2H, s), 6.20 (1H, d, J = 2.0 Hz), 6.54 (1H, d, J = 2.0 Hz), 7.3 2-7.40 (3 H, m), 7.4 3 -7.47 (2H, m) (9b) 5-[6-(Benzyloxy)-4-{[(2S)-l-methoxypropane-2 -Based on the benzyl 2-oxo-pyridyl-2-carboxylic acid benzyl ester. The compound synthesized in Example (9a) (1.28 g, 4.16 mmol), 5-(4,4,5,5) - tetramethyl-1,3,2-dioxaborolan-2-yl)-1 -pyrrole-2-carboxylic acid benzyl ester (2.25 g, 6.88 mm 〇l), [1, K-double (two Phenylphosphino)ferrocene]palladium dichloride (methane) dichloromethane complex (18 mg, 0.22 mmol), potassium carbonate (3.25 g, 23.5 1 mmol), and Example (lc) The objective compound (1.42 g, yield 72%) was obtained as a brown oil. iH-NMR (CDC13, 500 ΜΗζ): δ 1.33 (3H, d, J = 6.3 Hz), 3.40 (3H, s), 3.49 (1H, dd, J = 10.3, 3.9 Hz), 3.58 (1H, dd, J = 10.5, 6.1 Hz), 4.59-4.63 (1H, m), 5.35 (2H, s), 5.41 (2H, s), 6.19 (1H, d, J = 2.0 Hz), 6.60 (1H, dd, J = 3.9, 2.4 Hz), 6.81 (1H, d, J = 2.0 Hz), 6.97 (1H, dd, J = 3.9, 2.9 Hz), 7.29-7.47 (1 0H, m), 9.92 (1H, br s) -74- 201139430 (9c) 5-[6-(Benzyloxy)-4-{[(2S)-l-methoxypropan-2-yl]oxy}pyridin-2-yl]-N-[ (2R)-2-Hydroxypropyl]-1H-pyrrole-2-carboxamide The compound synthesized in Example (9b) (1.41 g, 2.98 mmol) was dissolved in tetrahydrofuran (20 mL) and water (6 mL) Lithium hydroxide-hydrate (1.23 g, 29.3 mmol) was added at room temperature and stirred at 60 ° C for one day under a nitrogen atmosphere. 2N hydrochloric acid was added to the reaction mixture until the pH became about 3, and extracted with ethyl acetate (8 mL) three times. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained compound was dissolved in dichloromethane (10 mL), and (R)-(-)-l-amino-2-propanol (0.30 mL, 3.81 mmol), WSCI · HCl (750 mg, 3.91 mmol) was added at room temperature. ), HOBT · H 2 O (620 mg, 4.05 mmol), N-methyl sulphate (〇. 65 mL, 5.91 mmol), and stirred under nitrogen atmosphere overnight. Water (50 mL) was added to the mixture and the mixture was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent solvent: methanol/dichloromethane = 1% to 4%) to give the desired compound (1.1 〇g Rate 99%). *H-NMR (CDC13, 40 0ΜΗζ): δ 1.25 (3Η, d, J = 6.3 Hz), 1.33 (3H, d, J = 6.3 Hz), 2.73 (1H, br s), 3.30 (1H, ddd, J = 13.2, 7.3, 5,8 Hz), 3.40 (3H, s), 3.49 (1H, dd, J = 1 0.6, 4.3 Hz), 3.58 (1H, dd, J = 10.6, 5.9 Hz), 3.63 ( 1H, ddd, J = 14.1, 7.0, 2.3 Hz), 3.99-4.07 ( 1 H, m), 4.56-4.64 ( 1 H, m), 5.41 (2H, s), 6.18 (1H, d, J = 2.0 Hz), 6.35-6.38 (1H, br m), -75- 201139430 6.58-6.61 (2H, m), 6.79 (1H, d, J = 2.0 Hz), 7.31 (1H, t, J = 7.4 Hz), 7.39 (2H, t, J = 7.6 Hz), 7.49 (2H, d, J = 7.4 Hz), 10.08 (1 H, br s) ° (9d) 2-(Benzyloxy-methoxypropen-2-yl) Oxygen}-6-{5-[(5S)-5-methyl-4,5-dihydro-l,3-0f 哩-2-yl]-1H-U ratio D-2-yl}pyridine The compound (1.10 g, 2.5 〇mm〇1), formazanic acid anhydride (890 mg, 5.11 mmol), and triethylamine (1.50 mL, 10.76 mmol) synthesized in the same manner as in Example (9) were used. The title compound was obtained as a colorless oil (yield: 940 mg, yield: s.). <'>H-NMR (CDC13, 400 ΜΗζ): δ 1.33 (3 Η, d, J = 6.3 Hz), 1.44 (3H, d, J = 6.3 Hz), 3.40 (3H, s), 3.49 (1H, Dd, J = 10.4, 4.1 Hz), 3.5 5 - 3.62 (2H, m), 4.13 (1H, dd, J = 14.1, 9.0 Hz), 4.5 6-4.64 ( 1 H, m), 4.7 9-4.89 ( 1 H, m), 5.42 (2H, s), 6.16 (1H, d, J = 2.0 Hz), 6.62 (1H, d, J = 3.9 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.81 (1H, d, J = 2.0 Hz), 7.2 9- 7.3 4 ( 1 H, m), 7.37-7.42 (2H, m), 7.47-7.51 (2H, m), 9.89 (1H, br s) MS ( ESI) m/z: 422.208 0 1 (M + H) + (9e) 4-{[(2S)-; l-methoxypropan-2-yl]oxy}-6-{5-[(53) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1{1-pyrrol-2-yl}pyridin-2-ol The compound synthesized in Example (9d) was used ( The title compound (622 mg, yield: 83%) was obtained from white crystals. -76- 201139430 'H-NMR (CDC13, 400ΜΗζ): δ 1.38 (3H, d, J = 6.3 Hz), 1.50 (3H, d, J = 5.9 Hz), 3.41 (3H, s), 3.51 (1H, Dd, J = 10.2, 4.3 Hz), 3.61 (1H, dd, J = 10.4, 5.7 Hz), 3.65 (1H, dd, J = 14.3, 7.6 Hz), 4.18 (1H, dd, J = 13.9, 9.2 Hz ), 4.58-4.65 (1H, m), 4.86-4.9 8 ( 1 H, m), 5.99 (1H, d, J = 2.0 Hz), 6.43 (1H, s), 6.77 (1H, s), 6.83 ( 1H, s) MS (ESI) m/z: 3 3 2.1 6 1 1 9 (M + H) + (9f) 4-{[(2S)-l-methoxypropan-2-yl]oxy}- 2-{5-[(5S)-5-methyl-4,5-dihydro-1,3-Dfoxazol-2-yl]-1H-pyrrol-2-yl}-6-{[5-( Methylsulfonyl)pyridin-2-yl]oxy}pyridine The compound synthesized in Example (9e) (100 mg, 0.302 mmol) and 2-chloro-5- known (International Publication No. WO2002/05 1 83 6) (Methylsulfonyl) The mouth was steep (80 mg, 0.417 mmol) dissolved in acetonitrile (5.0 mL), and then evaporated (150 mg, 0.660 mmol). The reaction solution was cooled to room temperature, water (30 mL) was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted %). 'H-NMR (CDC13, 400ΜΗζ): δ 1.38 (3Η, d, J = 6.3 Hz), 1.40 (3H, d, J = 5.9 Hz), 3.14 (3H, s), 3.42 (3H, s), 3.5 0-3.5 3 ( 1 H, m), 3.54 (1H, dd, J = 10.6, 3.9 Hz), 3.61 (1H, dd, J = 10.4, 6.1 Hz), 4.05 (1H, dd, J = 14.1, 9.4 Hz), •77- 201139430 4.66-4.72 ( 1 H, m), 4.75-4.84 ( 1 H, m), 6.47 (1H, d, J = 2.0 Hz), 6.66 (1H, d, J = 3.5 Hz) , 6.75 (1H, d, J = 3.9 Hz), 7.06 (1H, s), 7.19 (1H, d, J = 8.6 Hz), 8.24 (1H, dd, J = 8.8, 2.5 Hz), 8.79 (1H, Dd, J = 2.3, 0.8 Hz). MS (ESI) m/z: 487.1 6500 (M + H)+. (Example 1 0) (2S)-2-[(2-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1Η- Pyrrol-2-yl}-6-{[5-(methylsulfonyl)pyridin-2-yl]oxy}pyridin-4-yl)oxy]propan-1-ol

The compound (135 mg, 〇.277 mmol) and boron tribromide (l_〇mol/L dichloromethane solution, 0.35 mL) synthesized in Example (9f) were used to obtain white solids in the same manner as in (Example 2). The compound of interest (74 mg, yield 57%). 'H-NMR (CDC13, 400ΜΗζ): δ 1.36 (3Η, d, J = 6.3 Hz), 1.40 (3H, d, J = 6.3 Hz), 2.20 (1H, br s), 3.14 (3H, s), 3.52 (1H, dd, J = 13.9, 7.2 Hz), 3.79 (2H, d, J = 5.1 Hz), 4.06 (1H, dd, J = 14.1, 9.4 Hz), 4.61-4.67 (1H, m), 4.76 -4.84 (1H, m), 6.45 (1H, d, J = 2.0 Hz), 6.66 (1H, d, J = 3.9 Hz), 6.76 (1H, d, J = 3.9 Hz), 7.02 (1H, s) , 7.20 (ih, dd, J = 8.6, 0.8 Hz), 8.25 (1H, dd, J = 8.6, 2.3 Hz), 8.79 (1H, d, J = 2.7 Hz) MS (ESI) m/z: 47 3.1 48 8 0 (M + H) + 〇-78- 201139430 (Example 11) 2-{.[(2S)-l-methoxypropan-2-yl]oxy}-4-{5-[(5S )-5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-111-pyrrol-2-yl b-6-[4-(methylsulfonyl)phenoxy] Pyridine

(11&) 2-chloro-4-iodo-6-{[(23)-1-methoxypropan-2-yl]oxy}pyridine using sodium hydride (about 63%, 350 mg, about 9-19 mmol), (S)-(+)-2-methoxy-l-propanol (0.90 mL, 9·19 mmol), 2,6-dichloro-4-deuterium ratio (2.00 g, 7.30 mmol), and implementation Example (la) The objective compound (1. 94 g, yield 81%) was obtained as a colorless transparent liquid. 'H-NMR (CDC13, 500 ΜΗζ): δ 1.32 (3Η, d, J = 6.3 Hz), 3.39 (3H, s), 3.50 (1H, dd, J = 10.7, 3.9 Hz), 3.55 (1H, dd , J = 10.3, 5.9 Hz), 5.3 3 -5.3 8 ( 1 H, m), 7.08 (1H, d, J = 1.5 Hz), 7.24 (1H, d, J = 1.5 Hz) (llb) 4-iodine 2-{[(2S)-l-methoxypropan-2-yl]oxy}-6-[4-(methylsulfonyl)phenoxy]pyridinium was synthesized using Example (lla) Compound (2.65 g, 8.09 mmol), 4-(methylsulfanyl)phenol (1 37 g, 9 7 7 mm〇1), carbonic acid (5 65 g, 17.34 mmol), m-chloroperbenzoic acid (about 65%, The title compound (268 mg, yield 7%) was obtained as a white solid. -79- 201139430 Ή-NMR (CDC13, 400ΜΗζ): δ 1.17 (3H, d, J = 6.3 Hz), 3.08 (3H, s), 3.32 (3H, s), 3.38 (1 H, dd, J = 10.6 , 3.9 Hz), 3.45 (1H, dd, J = 10.4, 6.1 Hz), 4.92 -4.99 ( 1 H, m), 6.89 (1H, d, J = 1.2 Hz), 6.95 ( 1 H, d, J = 1.2 Hz), 7.29 (2H, dt, J = 9.4, 2.4 Hz), 7.95 (2H, dt, J = 9.1, 2.3 Hz) (llc) 5-(2-{[(2S)-l-A Benzyl oxypropan-2-yl]oxy.}-6-[4-(methylsulfonyl)phenoxy]pyridin-4-yl)-1 oxime-pyrrole-2-carboxylate Example (lib) Synthetic compound (268 mg, 0.578 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Η-pyrrole-2-carboxylate Benzyl methacrylate (293 mg, 0.896 mmol), [1,1'-bis(diphenylphosphino)ferrocene]-chlorinated IG(II)-chloromethyl compound (35 mg, 0.043 mmol), carbonic acid The title compound (321 mg, yield ~ 100%) was obtained as white crystals. 'H-NMR (CDC13, 400ΜΗζ): δ 1.20 (3Η, d, J = 5.9 Hz), 3.08 (3H, s), 3.33 (3H, s), 3.41 (1H, dd, J = 10.6, 3.9 Hz) , 3.48 (1H, dd, J = 11.0, 5.9 Hz), 4.99-5.05 ( 1 H, m), 5.34 (2H, s), 6.65 (1H, dd, J = 3.9, 2.7 Hz), 6.69 (2H, d, J = 〇-8 Hz), 7.00 (1H, dd, J = 3.9, 2.3 Hz), 7.30 (2H, dt, J = 9.4, 2.4 Hz), 7.3 5-7.44 (5H, m), 7.95 ( 2H, dt, J = 9.5, 2.3 Hz), 9.49 (1H, s) ° (lld) N-[(2R)-2-hydroxypropyl]-5_(2-{[(2S)-l-methoxy Propane-2-yl]oxy}·6-[4-(methylsulfonyl)phenoxy]pyridin-4-yl)-1 Η-pyrrole-2-carboxyguanamine-80-201139430 Example of use (lie) Synthetic compound (321 mg, 〇.598 mmol), IG carbon (120 mg), (R)-(-)-l-amino-2-propanol (0.07 mL, 〇.89 mmol), WSCI · HCl ( 155 mg, 0.809 mmol), HOBT·H2O (130 mg, 0.849 mmol), N-methyl- s. Rate 62%) » 'H-NMR (CDC13, 5 00ΜΗζ): δ 1.25 (3Η, d, J = 5.9 Hz), 1.27 (3H, d, J = 6.8 Hz), 3.08 (3H, s), 3.29 ( 1H, d Dd, J = 14.0, 7.7, 5.2 Hz), 3.34 (3H, s), 3.43 (1H, dd, J = 10.3, 3.9 Hz), 3.47 -3.5 2 ( 1 H, m), 3.65 (1H, ddd, J = 14.2, 6.8, 2.9 Hz), 4.01-4.06 (1H, m), 5.01-5.07 (1H, m), 6.42 (1H, t, J = 5.9 Hz), 6.64 (2H, d, J = 2.4 Hz) ), 6.69 (1H, d, J = 1.0 Hz), 6.7 1 (1H, d, J = 1.0 Hz), 7.31 (2H, dt, J = 9.3, 2.3 Hz), 7.95 (2H, dt, J = 9.3 , 2.3 Hz), 9.97 (1H, br s) (lle)2-{[(2S)-l-methoxypropan-2-yl]oxy}-4-{5-[(53)-5-A 4-,5-dihydro-1,3-Dfoxazol-2-yl]-1H-pyrrol-2-yl}-6-[4-(methyl-propenyl)phenoxy]pyrene The compound synthesized by the example (lid) (188 mg, 0.373 mmol), decyl anhydride (141 mg, 0.809 mmol), triethylamine (〇25 mL, 1.7 9 mm 〇l) was obtained in the same manner as in Example (le). The title compound was white solid (1 16 mg, yield 46%). 'H-NMR (CDC13, 400ΜΗζ): δ 1.22 (3Η, d, J = 6.3 Hz), 1.43 (3H, d, J = 6.3 Hz), 3.09 (3H, s), 3.34 (3H, s), 3.43 (1H, dd, J = 10.4, 4.1 Hz), 3.47-3.52 ( 1 H, m), 3.55 (1H, dd, -81- 201139430 J = 13.9, 7.6 Hz), 4.09 (1H, dd, J = 14.1 , 9.4 Hz), 4.80-4.87 (1H, m), 5.00- 5.08 ( 1 H, m), 6.65 (1H, d, J = 3.9 Hz), 6.66 (1H, d, J = 4.7 Hz), 6.70 ( 1H, s), 6.77 (1H, d, J = 3.9 Hz), 7.3 1 (2H, d, J = 8.6 Hz), 7.95 (2H, d, J = 8.6 Hz) MS (ESI) m/z: 4 8 6.1 6 96 8 (M + H)+. (Example 12) (2S)-2-[(4-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H- Pyrrol-2-yl}-6-[4-(methylsulfonyl)phenoxy]pyridin-2-yl)oxy]propan-1-ol

Using the compound synthesized by the example (lie) (78 mg, 〇. 161 mmol), boron tribromide (l. 〇mol/L digastric solution, 0.17 mL), and (Example 2), white was obtained in the same manner. The title compound (59 mg, yield 78%). 'H-NMR (CDCb, 400ΜΗζ): δ 1.22 (3Η, d, J = 6.3 Hz), 1.44 (3H, d, J = 6.3 Hz), 2.57 (1H, br s), 3.09 (3H, s), 3.57 (1H, dd, J = 14.1, 7.4 Hz), 3.64-3.69 (2H, m), 4.11 (1H, dd, J = 13.9, 9.2 Hz), 4.83 -4.90 ( 1 H, m), 4.91-4.97 (1H, m), 6.65 (1H, d, J = 3.9 Hz), 6.67 (2H, d, J = 2.7 Hz), 6.79 (1H, d, J = 3.9 Hz), 7.30 (2H, d, J = 8.6 Hz), 7.96 (2H, d, J = 9.0 Hz) MS (ESI) m/z: 472 · 1 5 5 1 0 (M + H) + 〇-82- 201139430 (Example 1 3 ) 2-{ [(2S)-l-methoxypropan-2-yl]oxy}-6-{5-[(5S)-5-methyl•4,5-dihydro-1,3-oxazol-2- [-]-111-pyrrol-2-yl}-4-[4-(methylsulfonyl)phenoxy]pyridine

〇' '〇(13a) 4-(benzyloxy)-2,6-dichloropyridine using sodium hydride (about 63%, 4 40 mg, about 1 1 · 5 mm ο 1), benzyl alcohol (1 2 0 m L 1 11.5 mmol), 2,6-dichloro-4-nitro D is determined by the ratio of U (2.00 g, 1 〇 -4 mmol), which is obtained in the same manner as in Example (1 a). Compound (2.30 g, yield 87%). 'H-NMR (CDC13, 400ΜΗζ): δ 5.11 (2Η, s), 6.86 (2H, s), 7.3 7 -7.45 (5H, m). (13b) 4-(Benzyloxy)-2-chloro- 6-{[(2S)-l-methoxypropan-2-yl]oxy}pyridine using sodium hydride (about 63% '170 mg, about 4 · 4 6 mm ο 1), (S) - (+)-2-methoxy-1·propanol (0.44 mL, 4.49 mmol), and the compound synthesized in Example (13a) (1.0 g, 3.94 mmol) were obtained in the same manner as in Example (9a). Oily compound of interest (6 02 mg, yield 50%). 'H-NMR (CDC 1 3, 5 0 0ΜΗζ): δ 1.32 (3Η, d, J = 6.3 Hz), 3.40 (3H, s), 3.51 (1H, dd, J = 10.7, 3.9 Hz), 3.55 (1H, dd, J = 10.5, 5.6 Hz), 5.04 (2H, s), 5.34-5.40 ( 1 H, m), 6.21 (1H, -83- 201139430 d, J = 1.5 Hz), 6.55 (1H, d, J = 2.0 Hz), 7.33-7.41 (5H, m) (13c) Benzyl 5-[4-(benzyloxy)_6-{[(2S)-l-methoxypropan-2-yl] Oxy}pyridin-2-yl]-1H-pyrrole-2-carboxylate The compound synthesized in Example (13b) (602 mg, 1.96 mmol), 5-(4,4,5,5-tetramethyl·1) , 3,2·dioxaborolan-2-yl)-1Η-pyrrole-2-carboxylic acid benzyl ester (98 0 mg, 3.00 mmol), [1, 1, bis(diphenylphosphinyl) ferrocene Iron] palladium (II) dichloride methylene chloride complex (85 mg, 0.1 mmol), potassium carbonate (1.20 g, 8.68 mmol), the title compound 722 mg, yield 78%). *H-NMR (CDC13, 400ΜΗζ): δ 1.37 (3Η, d, J = 6.3 Hz), 3.42 (3H, s), 3.55 (1H, dd, J = 10.4, 4.1 Hz), 3.62 (1 H, dd , J = 10.6, 5.5 Hz), 5.08 (2H, s), 5.34 (2H, s), 5.44-5.5 0 ( 1 H, m), 6.21 (1H, d, J = 2.0 Hz), 6.61 (1H, Dd, J - 3.9, 2.7 Hz), 6.85 (1H, d, J = 2.0 Hz), 6.97 (1H, dd, J = 3.9, 2.7 Hz), 7.34-7.45 (1 0H, m), 9.94 (1H, Br s). (13d) 5-[4-(Benzyloxy)-6-{[(2S)-l-methoxypropan-2-yl]oxy}pyridin-2-yl]-N-[(2R)-2 -Hydroxypropyl]-1H-pyrrole-2-carboxyguanamine The compound synthesized in Example (13c) (722 mg, 1-53 mmol), lithium hydroxide monohydrate (615 mg, 14.7 mmol), (R)-(-) -l-amino-2-propanol (0.15 mL, 1.91 mmol), WSCI. HCl (380 mg, 1.98 mmol), HOBT. H2O (310 mg, '2.02 mmol), N-methyl- The title compound (5 60 x ng, yield 83%) was obtained as a pale yellow foam. -84- 201139430 JH-NMR (CDC 13, 500 ΜΗζ): δ 1.25 (3H, d, J = 6.3 Hz), 1.37 (3H, d, J = 6.3 Hz), 2.52 (1H, br s), 3.30 (1H, ddd, J = 14.0, 7.4, 5.5 Hz), 3.42 (3H, s), 3.56 (1H, dd, J = 10.3, 3.9 Hz), 3.6 0-3.6 5 (2H, m), 4.00-4.07 ( 1 H, m), 5.08 (2H, s), 5.49-5.55 ( 1 H, m), 6.20 (1H, d, J = 2.0 Hz), 6.27-6.3 3 ( 1 H, br m), 6.60 ( 2H, d, J = 2.4 Hz), 6.83 (1H, d, J = 2.0 Hz), 7.3 3 - 7.42 (5 H, m), 10.05 (1H, br s) (13e) 4-(benzyloxy) -2-{[(2S)-l-methoxypropan-2-yl]oxy}-6-{5-[(5S)-5-methyl-4,5-dihydro-1,3-Df The compound synthesized by the application of Example (13d) (560 mg, 1.27 mmol), methanesulfonic anhydride (450 mg, 2.58 mmoI), triethylamine (by carbazol-2-yl)-1H-pyrrole-2-yl}pyrene The title compound (4.99 mg, yield: 3%) was obtained as a white solid. • H-NMR (CDC 1 3) 5 00ΜΗζ): δ 1.37 (3Η, d, J = 6.3 Hz), 1.43 (3H, d, J = 5.9 Hz), 3.43 (3H, s), 3.53 (1H, dd , J = 10.3, 4.4 Hz), 3.58 (1H, dd, J = 14.2, 7.3 Hz), 3.63 (1H, dd, J = 10.3, 5.4 Hz), 4.11 (1H, dd, J = 14.2, 9.3 Hz) , 4.79-4.86 (1H, m), 5.08 (2H, s), 5.49- 5.5 7 ( 1 H, m), 6.18 (1H, d, J = 2.0 Hz), 6.61 (1H, d, J = 3.9 Hz ), 6.76 (1H, d, J = 3.9 Hz), 6.83 (1H, d, J = 2.0 Hz), 7.33-7.42 (5H, m), 10.00 (1H, br s) MS (ESI) m/z: 422.2 07 6 3 (M + H)+. -85- 201139430 -methoxypropan-2-yloxyx 6{5[(5S)5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H- Pyrrole-2-yl}D ratio St. 4· alcohol The compound (480 mg, i 14 mm〇1) and IG carbon catalyst (〇.59 g) synthesized in the same manner as in Example (13e) were treated in the same manner as in Example (3c). The title compound (3 63 mg, 96%) was obtained as pale yellow solid. 'H-NMR (CDC13) 400ΜΗζ): δ 1.33 (3Η, dj j = 6 6 Hz) 1.48 (3H, d, J = 6-3 Hz), 3.40 (3H, s), 3.51.3.66 (3H, m ), 4.17 (1H, dd, J — 13.9, 9.2 Hz), 4.87-4.95 (1H m) 5.45-5.53 (1H, m), 6.05 (1H, d, J = 1.6 Hz), 6.70 (1H d J = 3.9 Hz), 6.77 (1H, d, J = 3.9 Hz), 6.89 (1H, d, J = 1.6 Hz), 10.61 (1 H, br s) - MS (FAB) m/z: 3 3 2 (M + H) + (13g) 2-{[(2S)-l-methoxypropan-2-yl]oxy}-6.{5.[(5S)_5_methyl-4,5-dihydro-1 , 3-oxazol-2-yl]-1H-pyrrol-2-yl}_4-[4-(methylsulfonyl)phenoxy]pyridine The compound synthesized in Example (13f) (102 mg, 0.308 mmol 4, 4-fluorophenylmethyl hydrazine (162 mg, 0.930 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then added with carbonic acid (409 mg, 1.26 mmol) in a nitrogen atmosphere at 90 Stir at °C for 15 hours. Water (20 mL) was added, and then ethyl acetate (30 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent solvent: ethyl acetate / hexane = 45% to 65%) to give the title compound (4 8.8 mg , yield 33%). -86- 201139430 Ή-NMR (CDCIs, 400ΜΗζ): δ 1.37 (3H, d, J = 6.3 Hz), 1.44 (3H, d, J = 6.3 Hz), 3.09 (3H, s), 3.42 (3H, s ), 3.51-3.64 (3H, m), 4.12 (1H, dd, J = 14.1, 9.8 Hz), 4.8 0-4.8 8 ( 1 H, m), 5.5 3 -5.60 ( 1 H, m), 6.11 ( 1H, d, J = 2.0 Hz), 6.63 (1H, d, J = 3.9 Hz), 6.77 (1H, d, J = 3.9 Hz), 6.86 (1H, d, J = 2.0 Hz), 7.25 (2H, d, J - 9.0 Hz), 7.98 (2H, d, J = 9.0 Hz) MS (ESI) m/z: 48 6.1 69 5 0 (M + H)+. (Example 14) 1^,1^-dimethyl-2-{5-[(53)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H -pyrrole_2-yl}-6-[4-(methylsulfonyl)phenoxy]pyridine-4-carboxamide

〇···'〇(Ma) 2-chloro-6-[4-(methylsulfonyl)phenoxy]pyridine-4-carboxylic acid ethyl ester using ethyl 2,6-dichloroisonicotinate (5.27g, 23.9mm〇l), 4-(methylsulfanyl)phenol (3.55g, 25.3mm〇l), carbonic acid planer (8.35g, 25.6mmol), m-benzoic acid (about 65%, The title compound (5.63 g, yield 66%) was obtained. -8 7-201139430 H-NMR (CDC13, 400ΜΗζ): δ 1.42 (3H, t, J = 7.0 Hz), 3.10 (3H, s), 4.44 (2H, q, J = 7.2 Hz), 7.34 (2H, Dt, J = 9.4, 2.4 Hz), 7.48 (1H, d, J = 1.2 Hz), 7.66 (1H, d, J = 1.2 Hz), 8.00 (2H, dt, J = 9.4, 2.4 Hz) (14b) Ethyl 2-{5-[(benzyloxy)carbonyl; 1_1H-pyrrol-2-yl}-6-[4-(methylsulfonyl)phenoxy]pyridine-4-carboxylate 14a) Synthetic compound (5.63 g, 15.8 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-111-pyrrole-2 - Benzyl carboxylate (8.07 g, 24.7 mmol), bis(diphenylphosphino)ferrocene] - ruthenium chloride δ (Π) - chloroformine complex (520 mg, 〇. 64 mmol), potassium carbonate ( The title compound (5.09 g, yield 62%) was obtained. 'H-NMR (CDCI3, 400ΜΗζ): δ 1.44 (3Η, t, J = 7.2 Hz), 3.12 (3H, s), 4.45 (2H, q, J = 7.2 Hz), 5.29 (2H, s), 6.80 (1H, dd, J = 3.9, 2.7 Hz), 6.96 (1H, dd, J = 3.9, 2.7 Hz), 7-33 (2H, dt, J = 8.7, 2.1 Hz), 7.3 4- 7.42 (6H, m), 7.91 (1H, d, J = 0.8 Hz), 8.01 (2H, dt, J = 9.3, 2.3 Hz), 9.69 (1H, s) (14c) 2-(5-{[(2R)-2 Ethyl hydroxypropyl]aminocarbazide}-iH-pyrrol-2-yl)-6-[4-(methylsulfonyl)phenoxy]pyridine-4-carboxylate Example (14b) Synthetic compound (5. 9 g, 9.78 mmol), fine carbon (1.15 g), (R)-(-)-l-amino-2-propanol (〇.92 mL, 11.7 mmol), WS c 1 . H Cl (2 · 60 g, 13.56 mmol), Η BT BT. H2 0 (2 · 1 Og, 13.7 mmol), N-methyl sulline (2.40 mL, 21.8 mmol), and Example (Id) The title compound (3.76 g, Yield: 79%) -88- 201139430 *H-NMR (CDC 13 , 500 ΜΗζ): δ 1.28 (3H, d, J = 6.3 Hz), 1.45 (3H, t, J = 7.1 Hz), 3.14 (3H, s), 3.3 8-3.46 (1H, m),

3.65 (1H,d, J = 14.2 Hz), 4.13-4.21 (ih, m), 4.46 (2H,q, J -7.2 Hz), 6.85 (1H, s), 7.00-7.06 (ih, m), 7.34 (1H, s), 7.39 (2H, dd, J = 9.0, 2.7 Hz), 8.03 (2H, d, J = 8.3 Hz), 8.07 (IH, d, J = 4.4 Hz), 11.08 (1H, br s ). (14d) 2-{5-[(5S)-5-Methyl-4,5-dihydro-;1,3_indol-2-yl]-1H-pyrrol-2-yl}_6-[4 -(Methylsulfonyl)phenoxy]oxime ratio steep_4_residual acid ethyl acetonate The compound synthesized in Example (14c) (3.76 g, 7.71 mm〇i), methanesulfonic anhydride (2.25 g, 12-9 mmol) The title compound (3.46 g, yield 96 ° /.) was obtained as a pale yellow solid (yield: EtOAc). 'H-NMR (CDC13, 400ΜΗζ): δ 1.40 (3Η, d, J = 6.3 Hz), 1.44 (3H, t, J = 7.2 Hz), 3.13 (3H, s), 3.51 (1H, dd, J = 14.1, 7.4 Hz), 4.05 (1H, dd, J = 14.1, 9.4 Hz), 4.45 (2H, q, J = 7.0 Hz), 4.76-4.85 ( 1 H, m), 6.76 (1H, d, J = 3.9 Hz), 6.81 (1H, d, J = 3.9 Hz), 7.32 (2H, dt, J = 8.6, 2.0 Hz), 7.3 4-7.3 5 ( 1 H, m), 7.90 (1H, s), 8.01 (2H, dt, J = 9.4, 2.4 Hz) MS (ESI) m/z: 470.1 3 83 6 (M + H) + (14e) 2-{5-[(5S)-5 -methyl-4, 5-dihydro-l,3-oxazol-2-yl]-1H-indolebi-2-yl}-6-[4-(methylglycosyl)phenoxy]pyreneidine-4 - citric acid The compound synthesized in Example (14d) (938 mg, 2.00 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 〇m L) and water (5.0 mL), and hydrogen peroxide was added at room temperature -89-201139430 The monohydrate (250 mg, 5 - 96 mmol) was stirred at room temperature for 2 min under a nitrogen atmosphere. Ethyl acetate (20 mL) was added to the reaction mixture, and then 2N hydrochloric acid was added until the pH became about 6 to obtain a precipitate. The precipitate was collected by chromatography,yield eluted eluted eluted eluted eluted eluted 'H-NMR (CDC13, 400 ΜΗζ): δ 1.59 (3Η, d, J - 6.3 Hz) s 3.12 (3H, s), 3.74 (1H, dd, J = 12.5, 7.8 Hz), 4.25 (1 H, Dd, J = 12.5, 9.4 Hz), 5.09-5.18 (1H, m), 6.88 (1H, dd, J = 4.1, 2.2 Hz), 7.02 (1 H, dd, J = 3.9, 2.3 Hz), 7.44 ( 2H,dt,J = 9.4 2.4 Hz), 7.46 (1H, d, J = 0.8 Hz), 8.00 (2H, dt, J = 9.3, 2.4 Hz), 9.23 (1H, s) MS (ESI) m/z : 442.1 07 3 9 (M + H) + (14f)N,N-Dimethyl-2-{5-[(5S)-5-methyl-4,5-dihydro-1,3-ordazole 2-yl]-1H-pyrrol-2-yl}-6-[4-(methylsulfonyl)phenoxy]pyridin-4-carboxyguanamine The compound synthesized in Example (14e) 151 mg, 0.34 mmol) was dissolved in dichloromethane (10 mL), dimethylamine (2.0 mol/L tetrahydrofuran solution, 〇.55 mL), WSCI · HCl (110 mg, 0.57 mmol), and stirred at room temperature under nitrogen atmosphere. one night. Water (10 m L) was added to the mixture and the mixture was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluting eluted eluted eluted eluted eluted eluted eluted eluted eluted Rate 44%). -90- 201139430 !H-NMR (CDC13, 400ΜΗζ): δ 1.40 (3H, d, J = 6.3 Hz), 3.03 (3H, s), 3.12 (3H, s), 3.14 (3H, s), 3.51 ( 1H, dd, J = 13.9, 7.2 Hz), 4.05 (1H, dd, J = 14.3, 9.2 Hz), 4.76-4.86 (1H, m), 6.71 (1H, d, J = 3.9 Hz), 6.75 (1H , d, J = 3.9 Hz), 6.77 (1H, s), 7.33 (2H, d, J = 8.6 Hz), 7.3 4- 7.3 6 ( 1 H, m), 8.01 (2H, d, J = 8.6 Hz MS (ESI) m/z: 469.1 5 43 4 (M + H)+. (Example 15) N-ethyl-N-methyl-2-{5-[(5S)-5-methyl-4,5-dihydro-1,3-Dfoxazol-2-yl]-1H -pyrrol-2-yl}-6-[4-(methyl-propenyl)phenoxy]pyridine_4_carboxamide

The compound synthesized in Example (14e) (95 mg, 0.215 mmol) was dissolved in a solvent mixture of tetrahydrofuran (3.0 mL) and dichloromethane (5 〇mL), and N-ethylmethylamine (〇.25 mL, 2.92 mmol) was added. HATU (100 mg, 0.263 mmol), N,N-isopropylethylamine (20 mL, 1.15 mmol) was stirred at room temperature under nitrogen atmosphere for 4 hr. Saturated aqueous sodium hydrogencarbonate (20 mL) was added and the mixture was evaporated. The organic layer was washed with brine and dried over anhydrous sulfur-magnes. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent solvent: ethyl acetate /hexane = 30% to 80%) 4mg, yield ~ 1 0 0%). 201139430 'H-NMR (CDC13,400ΜΗζ): δ 0.86 (2/5x3H, t, J = 6.8 Hz), 1.17 (3/5x3H, t5 J = 7.0 Hz), 1.38 (3H, d, J = 6.3 Hz) , 2.96 (2/5 x 3 H, s), 3.08 (3/5 x3H5 s), 3.11 (3H, s), 3.31 (3/5 x2H, q, J = 7.0 Hz), 3.49 (1H, dd, J = 14.3, 7.2 Hz), 3.59 (2/5x2H, q, J = 7.0 Hz), 4.02 (1H, dd, J = 14.3, 9.2 Hz), 4.73-4.82 (1H, m), 6.69 (1H, dd , J = 5.5, 3.9 Hz), 6.71-6.74 (2H, m), 7.2 9 - 7.3 4 (3 H, m), 7.99 (2H, dt, J = 9.1, 2.3 Hz) MS (ESI) m/z : 4 8 3 . 1 6990 (M + H)+. (Example 16) N,N-Diethyl-2-{5-[(5S)-5-methyl-4,5-dihydro-1,3-Bfoxazol-2-yl]-1H-pyrrole -2-yl}-6-[4-(methylsulfonyl)phenoxy]pyridine-4-carboxyguanamine

The compound (90 mg, 0.204 mmol), diethylamine (〇.25 mL, 2.42 mmol), H ATU (100 mg, 〇.263 mmol), hydrazine, hydrazine-diisopropylethylamine (0.20). The title compound (92 mg, yield 91%) was obtained from m. *H-NMR (CDC1 3, 4 00 ΜΗζ): δ 1.17 (3Η, t, J = 7.0 Hz), 1.28 (3H, t, J = 7.4 Hz), 1.40 (3H, d, J = 6.3 Hz), 3.13 (3H, s), 3.30 (2H, q, J = 7.0 Hz), 3.50 (1H, dd, J = 14.1, 7.4 Hz), 3.57 (2H, q, J = 7.2 Hz), 4.04 (1H, dd , J = 14.3, 9.2 Hz), -92- 201139430 4.7 5 -4.8 4 ( 1 H, m), 6.71 (1H, d, J = 3.9 Hz), 6.7 3 -6.7 5 (2H, m), 7.3 1 (1H, d, J = 0.8 Hz), 7.34 (2H, dt, J = 9.1, 2.3 Hz), 8.01 (2H, dt, J = 9.1, 2.3 Hz) MS (ESI) m/z: 497.1 8 58 6 (M + H)+. (Example 17) >1,:^Dimethyl-2-{5-[(53)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]·1 Η-pyrrole-2-yl}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridine-4-carboxamide

(17a) Methyl 2-chloro-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridine-4-carboxylate 2,6-dichloroisonicotinate methyl ester ( 2.07g, 10.1mmol) and 6-(methylsulfonyl)pyridin-3-ol (2.06g, 11.9mmol) were dissolved in N,N-dimethylformamide (20mL), and added with carbonic acid (5.02g) , 15.4 mmol), and stirred at 60 ° C for 5 hours under a nitrogen atmosphere. Water (100 mL) was added, and extracted twice with diethyl ether (200 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted Yield 30%). ^-NMR (CDC13, 400ΜΗζ): δ 3.27 (3Η, s), 4.00 (3H, s), 7.54 (1H, d, J = 0.8 Hz), 7.70 (1H, d, J = 1.2 Hz), 7.81 ( 1H, -93- 201139430 dd, J = 8.6, 2.7 Hz), 8.17 (1H, dd, J = 8.6, 0.8 Hz), 8.63 (1H, d, J = 3.1 Hz) (171〇2-{5-[ (Benzyloxy)carbonyl]-;^-pyrrol-2-yl}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridine·4 · Carboxylic acid methyl ester for use in implementation The compound synthesized in Example (173) (1.29§, 3.761111111〇1), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1Η- Benzyl pyrrole-2-carboxylate (1.90g' 5.81mmol), [1,1,-bis(diphenylphosphino)ferrocene]-chlorinated (II)-chloromethyl compound (178mg) , 〇.22mmol), cesium carbonate (2.65g ' 19.17mmol), the title compound (2.05 §, yield ~100%) obtained as an orange liquid in the same manner as in Example (lc). 'H-NMR (CDClj, 400ΜΗζ) ): δ 3.28 (3Η, s), 4.01 (3H, s), 5.30 (2H, s), 6.81 (1H, dd, J = 3.9, 2.3 Hz), 6.97 (1H, dd, J = 4.1, 2.5 Hz) ), 7.34-7.43 (6H, m), 7.75 (1H, dd, J = 8.6, 2.3 Hz), 7.95 (1H, d, J = 1.2 Hz), 8.17 (1H, d, J = 8.6 Hz), 8.63 (1H , d, J = 2.7 Hz), 9.61 (1H, br s). (17c) 2-(5-{[(2R)-2-Hydroxypropyl]aminemethanyl}-lH-pyrrol-2-yl Methyl-6-{[6·(methylsulfonyl)pyridin-3-yl]oxy}pyridine-4-carboxylate was used in the compound (1. 7 g, 4.04 mmol). Palladium carbon (l. 〇 5g), (R)-(-)-i-amino-2-propanol (0.40mL, 5.08mm 〇l), WSCI· HCl (1.15g, 6.00mmol), HOBT*H2O ( The title compound (1.43 g, yield: 75%) was obtained as a yellow solid (yield: EtOAc) 94- 201139430 'H-NMR (CDC13, 400ΜΗζ): δ 1.23 (3H, d, J = 6.6 Hz), 2.54 (1 H, br s), 3.24 ( 1 H, ddd, J = 13.9, 7.6, 5.3 Hz ), 3.30 (3H, s), 3.60 (1H, ddd, J = 14.1, 6.5, 2.9Hz), 3.96-4.03 ( 1 H, m), 4.01 (3 H, s), 6.41 (1 H, t, J = 5.7 Hz), 6.63 (1H, dd, J = 4.1, 2.5 Hz), 6.78 (1H, dd, J = 3.9, 2.7 Hz), 7.40 (1H, d, J = 0.8 Hz), 7.75 ( 1H, dd, J = 8.6, 2.7 Hz), 7.92 (1H, d, J = 1.2 Hz), 8.17 (1H, d, J = 8.6 Hz), 8.62 (1H, d, J = 2.7 Hz), 9.8 1 (1H, s). (17d) 2-{5-[(5S)-5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-6-{[ Methyl 6-(methylsulfonyl)pyridin-3-yl]oxy}pyridine-4-carboxylate The compound synthesized in Example (17c) (1.43 g, 3.01 mmol), A. g, 6.31 mmol), triethylamine (1.90 mL, 13.6 mmol). 'H-NMR (CDC13,500ΜΗζ): δ 1.40 (3H,d,J = 5.9 Hz), 3.29 (3H, s), 3.51 (1H, dd, J = 14.2, 7.3 Hz), 4.01 (3H, s) , 4.05 (1H, dd, J = 14.2, 9.3 Hz), 4.78-4.84 (1H, m), 6.76 (1H, d, J = 3.9 Hz), 6.80 (1H, d, J - 3.9 Hz), 7.39 ( 1H, s), 7.76 (1 H, dd, J = 8.8, 1.5 Hz), 7.92 (1 H, s), 8.18 (1 H, d, J = 8.8 Hz), 8.64 (1H, d, J = 2.0 Hz) MS (ESI) m/z: 4 5 7.1 1 8 29 (M + H) + (17e) 2-{5-[(5S)-5 -methyl-4,5-dihydro-1 ,3-oxazole-2-yl]-1H-pyrrol-2-yl}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridine-4-carboxylic acid-95- 201139430 The compound (i. 〇 4g, 2.28 mmol) and lithium hydroxide monohydrate (280 mg, 6.67 mmol) which were synthesized from the compound of (17d) were obtained. 913 mg, yield 91%). 'H-NMR (CDC1 3, 400 ΜΗζ): δ1 .61 (3Η, d, J = 6.3 Hz), 3.29 (3H, s), 3.74 (1H, dd, J = 12.5, 7.4 Hz), 4.25 (1H , dd, J = 12.3, 9.6 Hz), 5.09-5.19 (1H, m), 6.82 (1H, dd, J = 3.9, 2.0 Hz), 7.01 (1H, dd, J = 3.9, 1.6 Hz), 7.50 ( 1H, s), 7.91 (1H, dd, J = 8.6, 2.7 Hz), 8.18 (1H, d, J = 8.6 Hz), 8.75 (1H, d, J = 2.3 Hz), 9.25 (1H, s) ( 17f) N,N-Dimethyl-2-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrole-2- The compound synthesized by the method (17e) (913 mg, 2.06 mmol), dimethyl, was used in the compound (17e). Amine (2.0 mol/L tetrahydrofuran solution, 2.60 mL), WSCI· HCl (715 mg, 3.73 mm, EtOAc) 'H-NMR (CDC13, 400ΜΗζ): δ 1.40 (3Η, d, J = 6.3 Hz), 3.04 (3H, s), 3.16 (3H, s), 3.29 (3H, s), 3.51 (1H, dd, J = 14.3, 7.2 Hz), 4.05 (1H, dd, J = 14.3, 9.2 Hz), 4.75-4.84 (1H, m), 6.71 (1H, d, J = 3.9 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.84 (1H, d, J = 1.2 Hz), 7.37 (1H, s), 7.77 (1H, dd, J = 8.6, 2.7 Hz), 8.18 (1H, d, J = 8.6 Hz), 8.65 (1H, d, J = 2.3 Hz) MS (ESI) m/z: 47 0.1 4996 (M + H)+. -96-201139430 (Example 1 8) Ratio to 1 dimethyl-2-{5_[(411)_4.methyl-4,5-dihydro-1,3-oxazol-2-yl]-1 Η -pyrrole-2 _yl}_ 6 - {[ 6 -(methylsulfonyl)pyridin-3-yl]oxy}pyridine-4-carboxamide

(18a) 2-(5-{[(2R)-l-hydroxypropan-2-yl]amine-carbamoyl}-1Η-pyrrol-2-yl)-6-{[6-(methylsulfonyl) Methyl pyridin-3-yl]oxy}pyridine-4-carboxylate The compound (721 mg, 1.42 mmol), palladium carbon (200 mg), D-aminopropanol (0.161111), used in the compound (17b). 2.05111111〇1), \¥3 (:1· HCl (410 mg, 2.14 mmol), HOBT·H20 (3 5 5 mg, 2.32 mmol), N-methyl sulline (0.40 mL, 3.64 mmol), and examples ( Id) The title compound (5 23 mg, yield 78%) was obtained as a yellow solid. [H-NMR (CDCls, 5 00 ΜΗζ): δ 1.30 (3 Η, d, J = 6.8 Hz), 2.54 (1H, Br s), 3.33 (3H, s), 3.62 -3.6 7 ( 1 H, m), 3.75-3.80 (1H, m), 4.04 (3H, s), 4.21-4.26 (1H, m), 6.06 (1H , d, J = 6.8 Hz), 6.62 (1H, dd, J = 3.7, 2.7 Hz), 6.82 (1H, dd, J = 3.9, 2.9 Hz), 7.44 (1H, s), 7.78 (1H, dd, J = 8.3, 2.4 Hz), 7.95 (1H, s), 8.21 (1H, d, J = 8.8 Hz), 8.65 (1H, d, J = 2.4 Hz), 9.76 (1H, br s) (18b) 2 -{5-[(4R)-4 -Methyl-4,5-dihydro-1,3··卩foxa-2-yl]-1H·pyrrol-2-yl}-6-{[6- (methylsulfonyl)pyridin-3-yl]oxy}pyridine-4-carboxylic acid A -97-201139430 The compound (523 mg, 1.0 mmol), methanesulfonic anhydride (380 mg, 2.18 mmol), triethylamine (0.65 mL, 4.66 mmol), used in Example (18a), and Example (le) The title compound (215 mg, yield 43%) was obtained as a yellow solid. <H-NMR (CDClj, 400 ΜΗζ): δ 1.31 (3 Η, d, J = 6.6 Hz), 3.29 (3H, s), 3.90 (1H , t, J = 7.8 Hz), 4.01 (3H, s), 4.26-4.3 6 ( 1 H, m), 4.47 (1H, t, J = 8.6 Hz), 6.77 (1H, d, J = 3.9 Hz) , 6.81 (1H, d, J = 3.9 Hz), 7.39 (1H, d, J = 0.8 Hz), 7.75 (1H, dd, J = 8.6, 2.3 Hz), 7.93 (1H, s), 8.18 (1H, d, J = 8.6 Hz), 8.64 (1H, d, J = 2.0 Hz) (18〇1^,1^-dimethyl-2-{5-[(411)-4-methyl-4,5 -dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridine-4 Carboxylamidine The compound (419 mg, 0.918 mmol), lithium hydroxide monohydrate (120 mg, 2.86 mmol), which was obtained from the compound (18b), was obtained as a white solid. The obtained compound was dissolved in dichloromethane (10 mL), dimethylamine (2.0 mol/L tetrahydrofuran solution, 1.0 mL), HATU (5 50 mg, 1.45 mmol), diisopropylethylamine (0.38 mL, 2.18 mmol), stirred at room temperature for 4 hours under a nitrogen atmosphere. Water (20 mL) was added to the mixture and the mixture was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent solvent: ethyl acetate /hexane = 30% to 90%) Rate 81%). -98- 201139430 'H-NMR (CDCls, 500MHz) : 61.32 (3H, d, J = 6.3 Hz), 3.05 (3H, s), 3.16 (3H, s), 3.28 (3H, s), 3.8 6- 3.9 8 ( 1 H, m), 4.28-4.3 7 ( 1 H, m), 4.44-4.5 3 ( 1 H, m), 6.72 (1H, d, J = 3.9 Hz), 6.78 (1H, s), 6.85 (1H, s), 7.40 (1H, s), 7.76 (1H, dd, J = 8.3, 2.4 Hz), 8.18 (1H, d, J = 8.3 Hz), 8.63 (1H, d, J = 2.9 Hz) MS (ESI) m/z: 470.1 49 84 (M + H)+. (Example 19) (4S)-2-[5-(4-{[(2S)-l-methoxypropan-2-yl]oxy} _ 6 - {[ 6 -(methylsulfonyl) Pyridine-3-yl-oxy}pyridin-2-yl)- 1 Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazole-4-carboxylic acid methyl ester

(19a) N-{[5-(4-{[(2S)-l-methoxypropan-2-yl]oxy}-6-{[6-(methylsulfonyl)pyridin-3-yl Methyloxy}pyridin-2-yl)-1 Η-pyrrol-2-yl]carbonyl}-L-serinate The compound synthesized in Example (3c) (550 mg, 1.23 mmol), L-serine Methyl ester hydrochloride (260 mg, l_67 mmol), WSCI.HCl (360 mg, 1.88 mmol), HOBT. H2O (290 mg, 1.89 mmol), N-methyl s. The title compound (5 9 1 mg, 8 8 %) was obtained in the same manner in the same manner. -99-201139430 'H-NMR (CDC13, 4 00 ΜΗζ): δ 1.39 (3H, d, J = 6.3 Hz), 2.43 (1H, t, J = 5.9 Hz), 3.28 (3H, s), 3.43 (3H, s), 3.55 (1H, dd, J = 10.2, 3.9 Hz), 3.62 (1 H, dd, J = 10.2 , 6.3 Hz), 3.82 (3H, s), 3.9 7 -4.0 8 (2H, m), 4.66-4.73 (1 H, m), 4.77-4.80 (1H, m), 6.43 (1H, d, J = 2.0 Hz), 6.65 (1H, dd, J = 3.9, 2.7 Hz), 6.70 (1H, dd, J = 3.9, 2.7 Hz), 6.73 (1H, d, J - 7.4 Hz), 6.98 (1H, d, J = 2.0 Hz), 7.71 (1H, dd, J = 8.6, 2.7 Hz), 8.14 (1H, d, J = 8.6 Hz), 8.59 (1H, d, J = 2.7 Hz), 9.71 (1H, s) (19b) (4S)-2-[5-(4-{[(2S)-l-A Propane-2-yl]oxy}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridin-2-yl)-1Η-pyrrol-2-yl]-4,5 -Dihydro-1,3-Dfazole-4-carboxylic acid methyl ester The compound synthesized in Example (19a) (591 mg, 1.08 mmol) was dissolved in dichloromethane (10 mL), and 2-methoxyethyl)aminosulfur trifluoride (0.3 OmL, 1.7 1 mmol). After stirring at -78 ° C for 30 minutes under a nitrogen atmosphere, potassium carbonate (280 mg, 2.03 mmol) was added at -78 ° C, stirred at 0 ° C for 20 minutes, warmed naturally, and stirred at room temperature for 3 hours and a half. . A saturated aqueous solution of sodium hydrogencarbonate (10 mL) was added and the mixture was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted .). 'H-NMR (CDC13, 400 ΜΗζ): δ 1.39 (3Η, d, J = 6.3 Hz), 3.27 (3H, s), 3.42 (3H, s), 3.55 (1H, dd, J = 10.6, 3.9 Hz ), -100- 201139430

3.62 (1H, dd, J = 1〇_6, 6.3 Hz), 3.80 (3H, s), 4.50-4.57 (1H m), 4.60-4.66 ( 1 H, m), 4.67-4.73 ( 1 H, m ), 4.86 (1H, dd, J = 10.6, 7.8 Hz), 6.42 (1H, d, J = 2.0 Hz), 6.65 (1H, d, J = 1.6 Hz), 6.81 (1H, s), 7.00 (1H , s), 7.69 (1H, dd, J = 8.8, 2.5 Hz), 8.13 (1H, d, J = 8.6 Hz), 8.59 (1H, d, J = 2.3 Hz), 9.68 (1 H, br s) MS (ESI) m/z: 53 1 · 1 5434 (M + H)+. (Example 20) {(4R)-2-[5-(4-{[(2S)-l-methoxypropan-2-yl]oxy}-6-{[6-(methylsulfonyl) Pyridin-3-yl]oxy}pyridin-2-yl)_1Η_卩bido-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol

The compound (480 mg, 0.9 lmm〇i) synthesized in Example (19b) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (42 mg, hexane) was added at 0 ° C under a nitrogen atmosphere at 30 ° C. After a minute, water (1.0 mL), 5 equivalents of aqueous sodium hydroxide (1.0 mL), water (3. 〇mL) were added, and stirred for 10 minutes, and the resulting white precipitate was separated under reduced pressure. Filtration was carried out, and water (20 mL) was added to the filtrate, and the mixture was evaporated to ethyl acetate (30 mL). After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by column chromatography (eluent solvent: methanol) /Methylene chloride = 0% to 5%), whereby the title compound (350 mg, 77%) was obtained as a yellow solid. -10 1-201139430 1 Η - NMR (CDC 13,4 0 0 Μ Η z): δ 1 . 4 0 ( 3 Η,d,J = 6.3 Η z ), 3.27 (3Η, s), 3.43 (3H, s), 3.45 - 3.49 ( 1 H, m), 3.55 (1 H, dd, J = 10.2, 3.9 Hz), 3.62 ( 1 H, dd, J = 10.2, 6.3 Hz), 3.85 ( 1 H, dd, J = 11.5, 2.9 Hz), 4.20 (1H, t, J = 7.0 Hz), 4.26- 4.38 (2H, m), 4.6 8 -4.7 3 ( 1 H, m), 6.41 (1H, d, J - 2.0 Hz), 6.57 (2H, s), 6.98 (1 H, d, J = 2.0 Hz), 7.77 ( 1 H, dd, J = 8.6, 2.7 Hz), 8.14 (1 H, d, J = 8.6 Hz), 8.60 (1H, d, J = 2.3 Hz), 9.91 (1 H, Br s) MS (ESI) m/z: 5 0 3.1 5 92 8 (M + H) + (Example 21) (2S)-2-[(2-{5-[(4R)-4-( Hydroxymethyl)-4,5-dihydro-1,3-Pfoxazol-2-yl]-1H-pyrrol-2-yl}-6-{[6-(methylsulfonyl)pyridin-3-yl Oxy} pyridin-4-yl)oxy]propan-1-ol

The compound synthesized by the method (Example 20) (143 mg, 0-285 mmol), boron tribromide (1.0 mol/L dichloromethane solution, 0.35 mL) was obtained in the same manner as (Example 2). (54 mg, yield 39%). *H-NMR (DMSO-d6, 400 ΜΗζ): δ 1.27 (3Η, d, J = 6.3 Hz), 3.30 (3H, s), 3.31-3.47 (2H, m), 3.54-3.62 (2H, m), 4.19 (1 H, dd, J = 7.4, 7.0 Hz), 4.22-4.29 ( 1 H, m), 4.3 7 (1 H, -102- 201139430 dd, J = 8.8, 7.2 Hz), 4.71-4.79 (1H , m), 4.8 2 (1H, t, J = 5.5 Hz), 4.97 (1H, t, J = 5.7 Hz), 6.52 (1H, d, J = 2.0 Hz), 6.56 (2H, dd, J = 8.8 , 3.7 Hz), 7.59 (1H, d, J = 2.0 Hz), 7.98 (1H, dd, J = 8.6, 2.7 Hz), 8.11 (1H, dd, J = 8.6, 0.8 Hz), 8.71 (1H, d , J = 3.1 Hz), 11.90 (1 H, br s) MS (ESI) m/z: 4 8 9.1 43 48 (M + H)+. (Example 2 2 ) {(5R)-2-[5-(4-{[(2S)-l-methoxypropan-2-yl]oxy} - 6 - {[ 6 -(methylsulfonate) Pyridin-3-yl]oxy}pyridin-2-yl)-1 Ηpyrrole-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol

(22a) N-[(2S)-2,3-dihydroxypropyl]-5-(4-{[(2S)-l-methoxypropan-2-yl]oxy}_6-{[6- (Methylsulfonyl)pyridin-3-yl]oxy}pyridin-2-yl)-1Η-pyrrole-2-carboxyguanamine used in the compound synthesized in Example (3 c). (5 5 3 mg, 1 2 4 mm 〇丨), (S)-(-)-3-Amino-1,2-propanediol (180 mg, 1.98 mmol), HOBT. H2 〇 (300 mg, 1.96 mmol), WSCI. HCl (365 mg The title compound (570 mg, 88%) was obtained as white crystals (yield: 1.90mm). 'H-NMR (CDC13, 400ΜΗζ): δ 1.39 (3Η, d, J = 6.3 Hz), 2.87 (1H, br s), 2.95 (1H, br s), 3.28 (3H, s), 3.43 (3H, s), -103- 201139430 3.49-3.64 (6H, m), 3.81-3.85 (1H, m), 4.6 7 -4.7 3 ( 1 H, m), 6.33 (1H, t, J = 5.9 Hz), 6.42 (1H, d, J = 2.0 Hz), 6.60 (1H, dd, J = 3.9, 2.7 Hz), 6.63 (1H, dd, J = 3.9, 2.7 Hz), 6.98 (1H, d, J = 2.0 Hz) , 7.71 (1H, dd, J = 8.6, 2.7 Hz), 8.15 (1H, d, J = 8.6 Hz), 8.60 (1H, d, J = 2.7 Hz), 9.73 (1H, s) (22b)N- {(2S)-2-hydroxy-3_[(tripropion-2-ylindenyl)oxy]propyl}-5-(4-{[(2S)-l-methoxypropan-2-yl]oxy }_6_{[6_(Methylsulfonyl)pyridin-3-yl]oxy}pyridin-2-yl)-1 η-pyrrole-2-carboxycarboxamide The compound synthesized in Example (22a) (57 mg I.〇9mmol) dissolved in Qijiayuan (2〇mL) 'Add diethylamine (〇.5〇mL, 3.59mmol) at room temperature, triisopropyl sulfhydryl atmosphere (0.35mL, 1.64mmol) And 4-dimethylaminopyridine (83 mg '0.68 mmol) was stirred at room temperature for 3 Torr under a nitrogen atmosphere. Water (30 mL) was added to the reaction mixture to extract with dichloromethane (4 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified eluting eluted eluted eluted eluted eluted eluted eluted eluted elution %). 'H-NMR (CDC13, 400ΜΗζ): δ 1.06 (18H, d, J = 5.5 Hz), 1.09-1.15 (3H, m), 1.39 (3H, d, J = 6.3 Hz), 3.10 (1H, br s ), 3.29 (3H, s), 3.35 (1H, ddd, J = 14.0, 7.3, 4.8 Hz), 3.43 (3H, s), 3.55 (1H, dd, J = 10.6, 3.9 Hz), 3.5 9 -3.7 8 (4H, m), 3.81-3.88 (1H, m), 4.67-4.73 ( 1 H, m), 6.30 (1H, t, J = 5.7 Hz), 6.42 (1H, d, J = 1.6 Hz), 6.56 (1H, dd, J = 3.9, 2.7 Hz), -10 4- 201139430 6.63 (1H, dd, J = 3.9, 2.7 Hz), 6.97 (1H, d, J = 2.0 Hz), 7.71 (1H, dd , J = 8.6, 2.3 Hz), 8.14 (1H, d, J = 8.6 Hz), 8.59 (1H, d, J = 2.3 Hz), 9.72 (1H, s). (22〇) 4-{[(2 5)-1-methoxypropan-2-yl]oxy}-2-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-6 -{5-[(511)-5-{[(tripropen-2-ylindenyl)oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-111- Pyrrole-2-yl}pyridine was used in the compound synthesized in Example (22b) (531 mg, 0.78 mmol), methanesulfonic anhydride (220 mg, 1.26 mm ο 1), triethylamine (0.40 mL, 2.87 mmol), and Example (le) The title compound (506 mg, 98%) was obtained. 'H-NMR (CDClj, 400ΜΗζ): δ 1.02 (18Η, d, J = 5.5 Hz), 1.05-1.11 (3H, m), 1.39 (3H, d, J = 6.3 Hz), 3.27 (3H, s) , 3.42 (3H, s), 3.54 (1H, dd, J = 10.2, 3.9 Hz), 3.62 (1H, dd, J = 10.4, 6.1 Hz), 3.80-3.88 (3H, m), 3.97 (1H, dd , J = 14.3, 9.6 Hz), 4.67-4.74 (2H, m), 6.40 (1H, d, J = 2.0 Hz), 6.63 (1H, d, J = 3.9 Hz), 6.71 (1H, d, J = 3.9 Hz), 6.98 (1H, s), 7.70 (1H, dd, J = 8.6, 2.7 Hz), 8.13 (1H, d, J = 8.6 Hz), 8.59 (1H, d, J = 3.1 Hz), 9.62 (1H, br s) (22d) {(5R)-2-[5-(4-{[(2S)-l-methoxypropan-2-yl]oxy}-6-{[6-(A Sulfosyl)pyridin-3-yl]oxy}pyridin-2-yl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol Example (22〇) synthesized compound (48 011^, 0.73111111〇1) was dissolved in tetrahydrofuran (5. 〇mL)' to add tetrabutylammonium fluoride (1.0 mol/L tetrahydrofuran-105-201139430 solution, 0.90 mL), stirred at room temperature for 30 minutes under a nitrogen atmosphere. Water (20 mL) was added to the reaction mixture, and extracted with dichloromethane (2 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography ( eluting solvent: methanol / methylene chloride = 1% to 5%) to give the title compound (333 mg, yield 91%). 'H-NMR (CDC13, 400ΜΗζ): δ 1.39 (3H, d, J = 6.3 Hz), 2.09 (1H, br s), 3.28 (3H, s), 3.43 (3H, s), 3.55 (1H, dd , J =10.6, 3.9 Hz), 3.62 (1H, dd, J = 10.2, 6.3 Hz), 3.66-3.75 (2H, m), 3.8 3 (1H, dd, J = 12.3, 2.9 Hz), 4.01 (1H , dd, J = 14.5, 9.8 Hz), 4.67-4.8 0 (2H, m), 6.41 (1H, d, J = 2.0 Hz), 6.64 (1H, d, J = 3.9 Hz), 6.76 (1H, d , J = 3.9 Hz), 6.97 (1H, d, J = 1.6 Hz), 7.73 (1H, dd, J = 8.6, 2.7 Hz), 8.15 (1H, d, J - 8.6 Hz), 8.60 (1H, d , J = 2.3 Hz), 9.64 (1H, br s) MS (ESI) m/z: 503.1 6054 (M + H) + 〇 (Example 23) (23)-2-[(2-{5-[ (5 ft)-5-(hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-6-{[6-(methyl Sulfomethyl)pyridin-3-yl]oxy}pyridin-4-yl)oxy]propan-1-ol

-106-201139430 The compound (106 mg, 0-211 mmol) and boron tribromide (1.0 mol/L dichloromethane solution, 0.25 mL) synthesized in Example (22d) were used to obtain a white solid in the same manner as (Example 2). The compound of interest (66 mg, yield 64%). 'H-NMR (CDC13, 400MHz): 5 1.36 (3Η, d, J = 6.3 Hz), 2.07 (1 H, br s), 2.47 (1H, br s), 3.29 (3H, s), 3.67- 3.8 0 (4H, m), 3.85 (1 H, dd, J = 12.3, 2.9 Hz), 4.02 ( 1 H, dd, J = 14.5, 9.8 Hz), 4.5 7-4.64 ( 1 H, m), 4.7 6 -4.8 3 ( 1 H, m), 6.36 (1H, d, J = 1.6 Hz), 6.62 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.9 Hz), 6.91 (1H, s), 7.77 (1H, dd, J = 8.6, 2.7 Hz), 8.16 (1H, dd, J = 8.6, 0.8 Hz), 8.61 (1H, dd, J = 2.7, 0.8 Hz), 9.85 (1H, brs MS (ESI) m/z: 48 9.1 4427 (M + H)+. (Example 24) (4S)-2-[5-(4-{[(2S)-l-fluoropropan-2-yl]oxy}-6-{[6-(methylsulfonyl)pyridine- 3 -yl]oxy}pyridin-2-yl)-1 Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazole-4-carboxylic acid methyl ester

(24a) 5-(4-{[(2S)-l-hydroxypropan-2-yl]oxy}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridine-2 -Based -1 -pyridole-2-carboxylic acid benzyl ester -107 - 201139430 The compound synthesized in Example (3b) (188 mg, 〇35 mm〇1), boron dibromide (1.0 mol/L two gas The title compound (55 mg, yield 30%) was obtained as a white solid. 'H-NMR (CDC13, 500 ΜΗζ): δ 1.38 (3Η, d, J = 6.3 Hz), 1-86 (1H, t, J = 6.3 Hz), 3.27 (3H, s), 3.8 0- 3.8 4 (2 H, m), 4.64-4.69 (1H, m), 5.30 (2H, s), 6.4.3 (1H, d, J = 2.0 Hz), 6.65 (1H, dd, J = 3.9, 2.4 Hz) , 6.94 (1H, dd, J = 3.9, 2.9 Hz), 6-98 (1H, d, J = 2.0 Hz), 7.31-7.42 (5H, m), 7.73 (1H, dd, J = 8.3, 2.4 Hz ), 8.14 (1H, d, J = 8.8 Hz), 8.60 (1H, d, J = 2.9 Hz), 9.58 (1H, br s) (24b) 5-(4-{[(2S)-l-Fluorine Propane-2-yl]oxy}-6-{[6-(methylsulfonic acid) fluorene ratio D--3-yl]oxy}pyrene ratio D-but-2-yl)-1Η -卩比略-2 -Acidic acid to vinegar The compound synthesized in Example (24a) (3.05 g &gt; 5.83 mmol) was dissolved in dichloromethane (100 mL), and (2-methoxyethyl)aminotrifluoro was added dropwise at -78 °C. Sulfur (5.0 mL, 28.48 mmol). After stirring for 5 hours at room temperature under a nitrogen atmosphere, saturated sodium bicarbonate water (100 m L) was added. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted 64%). 'H-NMR (CDC1 3, 5 00ΜΗζ): δ1.42 (3Η, dd, J = 6.6, 1.2 Hz), 3.27 (3H, s), 4.51 (1H, d, J = 4.9 Hz), 4.61 (1H , d, J = 4.9 Hz), 4.7 7-4.8 5 ( 1 H, m), 5.29 (2H, s), 6.42 (1H, d, J = -108- 201139430 2.0 Hz), 6.65 (1H, dd, J = 4.2, 2.7 Hz), 6.94 (1H, dd, J = 3.9, 2.4 Hz), 6.98 (1H, d, J = 2.0 Hz), 7.31-7·43 (5H, m), 7 73 (1H, Dd, J = 8.5, 2.7 Hz), 8.14 (1H, d, J = 8.8 HZ), 8.60 (1H, d, J = 2.4 Hz), 9.57 (1H, br s) (24c)5-(4 -{[(2S)-l-fluoropropan-2-yl]oxy}-6][6-(methylsulfonyl)pyridin-3-yl]oxy}pyridin-2-yl)-1Η-pyrrole-2 - Carboxy-the compound (2.9 〇g '5_52 mm()1)' palladium carbon (1. 〇3g), which was obtained in the same manner as in Example (3c), was obtained as a white solid (2.42 g, ~1 0 0 % ) ° *H-NMR (CDC 1 3, 5 0 0ΜΗζ): δ1.43 〇H, dd, J = 6-3, 15 Hz), 3.28 (3H, s), 4.52 (1H, d, J = 4.9 Hz), 4.62 (1H, d, J = 4.4 Hz), 4.7 8 -4.8 6 ( 1 H, m), 6.45 (1H, d, J = 2.0 Hz), 6 68 (1H, dd , J = 3.9, 2.4 Hz), 7.00-7.02 (2H, m), 7.74 (1H, dd, J = 8.5, 2.7 Hz), 8.1 8 (1H, d, J = 8.8 Hz), 8.62 (1H, d, J = 2.4 Hz), 9.58 (1 H, br s). (2 4(1)1^-{[5-(4-{[(23)-1-fluoropropan-2-yl]oxy}-6-{[6-(methylsulfonyl)pyridine-3 Methyl-oxy}pyridin-2-yl)-1 Η-pyrrol-2-yl]carbonyl}-L-serine methyl ester The compound synthesized in Example (24c) (1.17 g, 2.69 mmol), L- Methyl methinate hydrochloride (590 mg, 3.79 mmol), WSCI.HCl (790 mg, 4.12 mmol), HOBT. H.sub.2 (630 mg, 4.11 mmol), N-methyl s. Example (3d) The title compound (1. 2 6 g, 8 7 %) was obtained as a white solid. -109-201139430 'H-NMR (CDC13s 400 ΜΗζ): δ 1.42 (3H, dd, J = 6.5, 1.4 Hz), 3.29 (3H, s), 3.82 (3H, s), 4.03 (2H, ddd, J = 25.0, 11.3, 3.5 Hz), 4.50 (1H, d, J = 4.3 Hz), 4.62 (1H, d, J = 4.7

Hz), 4.76-4.8 7 (2H, m), 6.42 (1H, s), 6.6 5 -6.7 6 (3 H, m), 6.98 (1H, s), 7.72 (1H, d, J = 7.0 Hz) , 8.15 (1H, d, J = 8.6

Hz), 8.60 (1H, s), 9.74 (1H, br s) (24e) (4S)-2-[5-(4-{[(2S)-l-fluoropropan-2-yl]oxy} 6 - {[ 6 -(Methylsulfonyl)pyridin-3-yl]oxy}pyridin-2-yl)-1 Η-pyrrol-2-yl]-4,5-dihydro-1,3-anthracene Methyl azole-4-carboxylate The compound synthesized in Example (24d) (1.26 g, 2.35 mmol), bis(2-methoxyethyl)aminosulfur trifluoride (〇.65 mL, 3.70 mmol) The title compound (1.17 g, 96%) was obtained as a white solid (yield: </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 3Η, d, J = 6.3 Hz), 3.27 (3H, s), 3.80 (3H, s), 4.50-4.56 (2H, m), 4.5 9-4.65 (2H, m), 4.76-4.8 5 ( 1 H , m), 4.86 (1H, dd, J = 10.0, 8.5 Hz), 6.41 (1H, d, J = 1.5 Hz), 6.66 (1H, t, J = 2.9 Hz), 6.81 (1H, s), 6.99 (1H, s), 7.70 (1H, dd, J = 8.5, 2.7 Hz), 8.14 (1H, d, J = 8.8 Hz), 8.59 (1H, d, J = 2.4 Hz), 9.65 (1H, br s MS (ESI) m/z: 5 1 9.1 3 48 8 (M + H) + ° (Example 25) {(4R)-2-[5-(4-{[(2S)-l-fluoropropyl)院-2-yl]oxy}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridin-2-yl)-1 Η-pyridyl 2 - yl] -4,5 - 1,3-dihydro-4-yl} methanol fathoms 201139430

The compound (i.iig, 2.14 mmol), and lithium aluminum hydride (98 mg, 2.58 mmol), which were obtained from the compound (24e), were obtained as the title compound (646 mg, 62%). ). ^-NMR (CDC13, 400ΜΗζ): δ 1.43 (3Η, dd, J = 6.6, 1.6 Hz), 3.27 (3H, s), 3.44 (1H, dd, J = 11.1, 2.5 Hz), 3.87 (1H, dd , J = 11.9, 2.9 Hz), 4.23 (1H, t, J = 7.0 Hz), 4.27-4.34 (1H, m), 4.37 (1H, dd, J = 9.0, 7.0 Hz), 4.51 (1H, d, J = 5.1 Hz), 4.63 (1H, d, J = 4.7 Hz), 4.77-4.89 ( 1 H, m), 6.41 (1H, d, J = 2.0 Hz), 6.57 (2H, s), 7.00 (1H , s), 7.80 (1H, dd, J = 8.6, 2.7 Hz), 8.14 (1H, dd, J = 8.6, 0.8 Hz), 8.60 (1H, d, J = 2.7 Hz), 10.11 (1H, br s MS (ESI) m/z: 49 1.1 4 08 2 (M + H)+. (Example 26) {(5R)-2-[5-(4-{[(2S)-l-fluoropropan-2-yl]oxy}-6-{[6-(methylsulfonyl)pyridine -3-yl]oxy}pyridin-2-yl)-111-pyrrol-2-yl]_4,5-dihydro-1,3-oxazole-5-yl}methanol

-111- 201139430 (26a) N-[(2S)-2,3-dihydroxypropyl]-5-(4-{[(2S)-l-fluoropropan-2-yl]oxy}-6-{ [6-(Methylsulfonyl)pyridin-3-yl]oxy}pyridin-2-yl)-1Η-pyrrole-2-carboxyguanamine The compound synthesized in Example (24c) (1.23 g, 2.82 mmol) ), (S)-(-)-3-Amino-1,2-propanol (410 mg, 4.50 mmol), HOBT. H2 〇 (690 mg &gt; 4.51 mmol), WSCI · HCl (860 mg, 4.49 mmol) The title compound (1.24 g, 87%) was obtained from white crystals. 'H-NMR (CDC 13, 400ΜΗζ): δ 1.42 (3Η, dd, J = 6.5, 1.4 Hz), 2.83 (1H, br s), 2.90 (1H, br s), 3.29 (3H, s), 3.47 -3.63 (4H, m), 3.81-3.86 (1H, m), 4.51 (1H, d, J = 4.7

Hz), 4.62 (1H, d, J = 4.7 Hz), 4.7 7-4.8 5 ( 1 H, m), 6.30 (1H, s), 6.42 (1H, d, J = 2.0 Hz), 6.60 (1H, Dd, J = 3.9, 2.7 Hz), 6.65 (1H, dd, J = 3.9, 2.7 Hz), 6.97 (1H, d, J = 2.0 Hz), 7.72 (1H, dd, J = 8.6, 2.7 Hz), 8.16 (1H, d, J = 8.6 Hz), 8.61 (1H, d, J = 2.0 Hz), 9.70 (1H, s) (26b) 5-(4-{[(2S)-l-fluoropropyl- 2-yl]oxy}-6-{[6-(methyl-fluorenyl)pyridin-3-yl]oxy}pyridin-2-yl)-N-{(2S)-2-hydroxy-3--[( Triprop-2-ylindenyl)oxy]propyl}-1Η-pyrrole-2-carboxyguanamine The compound synthesized in Example (26a) (i.24 g, 2.44 mmol), triethylamine (1.1 mL) ' 7.89 mmol), triisopropyl sandyl chloride (〇.8 mL, 3.74 mmol), 4-dimethylaminopyridine (300 mg, 2.46 mmol), obtained in the same manner as in Example (2 2 b) The compound of interest (1.21 g, 7 5%). 201139430 'H-NMR (CDC13j 400ΜΗζ): δ 1.06 (18H, d, J = 5.5 Hz), 1.09-1.15 (3H, m), 1.42 (3H, dd, J = 6.3, 1.6 Hz), 3.29 (3H, s), 3.35 (1H, ddd, J = 14.1, 7.4, 5.1 Hz), 3.66 (1H, dd, J = 9.8, 6.3 Hz), 3.6 8 - 3.74 ( 1 H, m), 3.76 (1H, dd, J = 10.0, 4.9

Hz), 3.8 2-3.8 8 ( 1 H, m), 4.50 (1H, d, J = 4.7 Hz), 4.62 (1H, d, J = 4.7 Hz), 4.77-4.85 (1H, m), 6.33 ( 1H, s), 6.41 (1H, d, J = 2.0 Hz), 6.57 (1H, dd, J = 3.9, 2.7 Hz), 6.65 (1H, dd, J = 3.9, 2.7 Hz), 6.97 (1H, d , J = 2.0 Hz), 7.72 (1H, dd, J = 8.6, 2.3 Hz), 8.15 (1H, d, J = 8.6 Hz), 8.6 0 (1H, d, J = 2.3

Hz), 9.78 (1H, s). (26c) 4-{[(2S)-l-fluoropropan-2-yl]oxy}-2-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-6-{5- [(5R)-5-{[(Tripropen-2-ylindenyl)oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-1 -pyrrole- 2-Based ratio|] The compound (l 21g, i 82mm〇i) synthesized in the example (26b), a potentanic anhydride (520 mg '2.99 mmol), triethylamine (0.90 mL, 6.46 mmol) The title compound (1.10 g, 93%) was obtained as a yellow foam. • H-NMR (CDCI3, 500ΜΗζ): δ 1.02 (18Η, d, J = 6.3 Hz), 1.04-1.10 (3H, m), 1.42 (3H, d, J = 6.3 Hz), 3.28 (3H, s) , 3.81-4.04 (4H, m), 4.52 (1H, d, J = 4.9 Hz), 4.61 (1H, d, J = 4.9 Hz), 4.69-4.90 (2H, m), 6.40 (1H, s), 6.66 (1H, d, J = 3.4 Hz), 6.74 (1H, s), 7.00 (1H, s), 7.72 (1H, d, J = 8.8 Hz), 8.14 (1H, d, J = 8.3 Hz), 8.60 (1H, d, J = 2.4 Hz), 9.55 (1H, brs) -113- 201139430 (26d){(5R)-2-[5-(4-{[(2S)-l-fluoropropane-2 ·yloxy] - 6 - {[ 6 -(methylsulfonyl)pyridin-3-yl]oxy}pyridine-2 ·yl)-1 Η-pyrrol-2-yl]-4,5-dihydro -1,3-oxazol-5-yl}methanol used in the compound synthesized in Example (26c) (ii〇g, i, 7〇mmol), tetrabutylammonium fluoride (1. 〇mol/L tetrahydrofuran solution The title compound (800 mg, yield: 96%) was obtained as white solid. 'H-NMR (CDClj, 400ΜΗζ): δ 1.42 (3Η, dd, J = 6.3, 1.6 Hz), 2.13 (1H, br s), 3.28 (3H, s), 3.67- 3.79 (2H, m), 3.85 (1H, d, J = 12.5 Hz), 4.02 (1H, dd, J = 14.1, 9.8 Hz), 4.51 (1H, d, J = 4.7 Hz), 4.63 (1H, d, J = 4.7 Hz), 4.76 -4.8 8 (2H, m), 6.41 (1H, d, J = 2.0 Hz), 6.65 (1H, d, J = 3.5 Hz), 6.79 (1H} d, J = 3.9 Hz), 7.00 (1H, d , J = 3.5 Hz), 7.75 (1H, dd, J = 8.4, 2.5 Hz), 8.16 (1H, d, J = 8.6 Hz), 8.61 (1H, d, J = 2.7 Hz), 9.70 (1H, br s) MS (ESI) m/z: 49 1.1 4004 (M + H)+. (Test Example 1) (1) Preparation of GK cDNA (GenBank Accssion N〇.NM_000 1 62 human glucokinase, variantl) encoding human pancreatic-type GK polypeptide was polymerase chain reaction from a human cDNA library (polymerase chain) Reaction: hereinafter referred to as "PCR"), and introduced glutathione S transferase (hereinafter referred to as GST) fusion protein expression vector (GEX4T, GE Healthcare -114- 201139430

Bioscience). The vector was introduced into Escherichia coli (BL21, Invitrogen), and the transformed coliform was cultured at 37 ° C for one night and the cells were recovered. The recovered cells were frozen and melted, and then suspended in a phosphate buffer containing Triton-X to a final concentration of 1%, and disrupted by an ultrasonic breaker. The supernatant after homogenization by low-speed centrifugation (10,00 〇xg, 30 minutes) was centrifuged at high speed (100, OOOxg, 10 minutes) and the supernatant was recovered, using the GST fusion protein purification system (Bulk GST). Purification module, GE Healthcare Bioscience) Refined fusion protein. The GK fusion protein was divided into small volumes and stored at -80 °C. (2) GK activity test GK activity was measured using (1) purified GK. Specifically, a solution 1 of a glucose measuring kit (D-glucose UV method, Roche Diagnostics) was added to (1) purified GK and glucose-6-phosphate dehydrogenase (Sigma) to prepare an enzyme solution. The enzyme solution, the test compound diluent, and glucose (final concentration: 5 mM) were mixed on a 96-well plate for ELISA, and reacted at room temperature for 30 minutes. After the end of the reaction, the absorbance at a wavelength of 340 nm was measured using SpectraMaxPlus (Molecular Probe). Further, the absorbance of unreacted (when no glucose was added) was used as the background 値. The activation rate of G K is represented by the number represented by the equation (absorbance after 30 minutes of reaction in the case of adding a test compound) / (absorbance after 30 minutes of reaction without adding a test compound). The compounds of Examples 1 to 26 showed a GK activation ratio of 1.5 times or more at the concentration of the test compound ΙμΜ. -115- 201139430 Formulation Example 1: Capsules Compound of Example 1 5 0 η ig Lactose 128 ng ng Corn starch 70 η ig Magnesium stearate 2 mg 2 5 0 m g The powder was mixed with the above-prepared powder and passed through a 60-mesh sieve. Into 21 2 3 4 〇mg gelatin glued to make a gelatin agent. Formulation Example 2: Lozenge Compound of Example 1 5 0 mg Lactose 1 2 6 mg Corn starch 2 3 mg Magnesium stearate 1 mg granules, after drying, the agent can be used as needed; Chronic-116-100 mg 2 Mix the powder of the above prescription, and use a corn starch paste to make a tablet ingot to make a tablet of 200 mg. This is a sugar-coated garment. 3 [Industrial use possibility] 4 The compound represented by the formula (I) or a salt thereof of the present invention has excellent GK activation, can be used as a warm-blooded type of diabetes, has abnormal glucose tolerance, gestational diabetes, and 201139430 syndrome ( A therapeutic or prophylactic agent (especially a therapeutic agent) comprising a diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, or metabolic syndrome (especially diabetes or abnormal glucose tolerance). [Simple description of the diagram] None. [Main component symbol description] None. -117-

Claims (1)

201139430 VII. Patent application scope: A compound represented by the formula (1) or a pharmacologically acceptable salt thereof /〇R〆(I) [wherein, R1 represents a nitrogen-containing heterocyclic T represented by the formula (11) which can be independently substituted with i to 3 substituents selected from the group of the substituent group A) (II) R represents a pyridyl group which may be independently substituted by a group selected from the substituent group B to 5 substituted groups or may be independently substituted with 1 to 3 groups selected from the group of the substituent group B; The formula C C-C6 halogenated alkoxy, Cl_C6 hydroxyalkoxy, (Ci_c6 alkoxy MCl-c: 6 alkoxy) or di-(Ci_C6 alkyl) aminocarbonyl; Q represents a nitrogen atom or a group represented by formula = CH -; U represents a nitrogen atom or a group represented by the formula = CH -; V represents a nitrogen atom or a group represented by the formula =CH-; And V is a case of a group represented by the formula: CH-; -118- 201139430 The substituent group A is represented by a halogen atom, an alkyl group, a C^-Ce halogenated alkyl group, a Ci-Ce hydroxyalkyl group, 2 hydroxy-substituted Ci-Ce alkyl, (Ci-Ce alkylthio)-((^-(:6 alkyl)), (^-(:6 alkoxy, carboxy, C2-C7 alkylcarbonyl) , C2-C7 alkoxycarbonyl, aminemethanyl, mono-CrCe alkylaminocarbonyl, di-(Ck a group consisting of a CU alkyl)aminocarbonyl group and a hydroxyl group; the substituent group B is represented by a halogen atom, a Ci-6 group, a Ci-C6 halogenated alkyl group, a fluorene 6 alkoxy group, or a c2-c7 alkylcarbonyl group. , C2-C7 halogenated alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 halogenated alkoxycarbonyl, CrCe alkylsulfonyl, C^-Ce halogenated alkylsulfonyl, C3-C6 cycloalkyl Sulfosyl, (C^-C^ alkoxy MCi-Ce alkylsulfonyl) group, (C^-Ce halogenated alkoxyalkylsulfonyl) group and represented by the formula -V-NR4R5 a group (V represents a carbonyl group or a sulfonyl group, and R4 and R5 are the same or different and each represents a hydrogen atom, a Ct-Ce alkyl group or a CrQ halogenated alkyl group, or R4 and R5 are integrated with a bonded nitrogen atom to form an independent group. a group consisting of 1 or 2 (^-(6-alkyl substituted 4 to 6-membered saturated heterocyclic ring; 4 to 6-membered saturated heterocyclic ring may further contain 1 oxygen atom or nitrogen atom). A compound represented by the formula (1) or a pharmacologically acceptable salt thereof, wherein the substituent group A is a halogen atom, (^-(:6 alkyl, (^-) (:6 halogenated alkyl, (^-(:6 hydroxyalkyl, via 2 hydroxy groups) a group of substituted Ci-Ce alkyl, CrCe alkoxy, carboxyl, C2-C7 alkoxycarbonyl, monoalkylaminocarbonyl, di-(Cl-C6 alkyl)aminocarbonyl, and hydroxyl; The group B is composed of a halogen atom 'Ci-Ce alkyl group, -119-201139430 Ci-Ce halogenated alkyl group, C2-C7 alkylcarbonyl group, c2_c7 alkoxycarbonyl group, C|_c6 alkylsulfonyl group, and a group represented by V-NR4R5 (v represents a carbonyl group or a sulfonyl group), and r4 and r5 are the same or different and represent a hydrogen atom, a Cl_C6 alkyl group or a Ci_C6 halogenated alkyl group, or R4 and R5 and a bonded nitrogen atom become a group consisting of 4 to 6 membered saturated heterocyclic rings which may be independently substituted by 1 or 2 c^-cu alkyl groups; 4 to 6 membered saturated heterocyclic rings may further contain 1 oxygen atom or nitrogen atom . 3. A compound represented by the formula (I) or a pharmacologically acceptable salt thereof according to the first or second aspect of the patent application, wherein the formula (I) is a formula (la) /0 R〆 (la) and R6 is a methyl group. 4. A compound represented by the formula (I) or a pharmacologically acceptable salt thereof according to the first or second aspect of the patent application, wherein the formula (I) is a formula (lb) And R7 is a methyl group, a hydroxymethyl group or a methoxycarbonyl group-120-201139430 5. The compound represented by the formula (I) or a pharmacologically acceptable salt thereof according to the first or second aspect of the patent application, Wherein the formula (I) is of the formula (1C) (10) and R8 is a methyl group or a hydroxymethyl group. 6. The compound represented by the formula (1) or a pharmacologically acceptable salt thereof, according to any one of the claims 1-5 to 5, wherein R2 is 4-methyl-purinylphenyl, 2- Methylsulfonyl-5-pyridyl or 5·methylsulfonyl-2-? is a steep base. 7. The compound represented by the formula (I) or a pharmacologically acceptable salt thereof, wherein R3 is (lS)-2-methoxy-1-, according to any one of claims 1 to 6. Methyl ethoxy, (lS)-2-hydroxy-1-methylethoxy, fluoro·1·methylethoxy, dimethylaminocarbonyl, N-ethyl-fluorenylmethylaminocarbonyl or Diethylaminocarbonyl. 8. A compound such as the following or a pharmacologically acceptable salt thereof: 4-{[(2S)-; l-methoxypropan-2-yl]oxy}-2-{5-[(5S)- 5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1^1-pyrrol-2-yl}-6-{[6-(methylsulfonyl)pyridine- 3-(yl)oxy}pyridine, (2 S ) - 2 - [ (2 - { 5 - [ ( 5 S ) - 5 -methyl-4,5 -dihydro · 1,3 -oxazol-2-yl -1H-pyrrol-2-yl}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridin-4-yl)oxy]propane-1·ol, -121- 201139430 4-{[(2S)-l-methoxypropan-2-yl]oxy}-2-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazole -2-yl]-111-pyrrol-2-yl}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridine, (2S)-2-[(2-{5 -[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-6-{[6-(methylsulfonate) ()pyridin-3-yl]oxy}pyridin-4-yl)oxy]propane·!--ol, (2S)-2-[(2-[5-(5-methyl-1,3,4- Oxalazolyl-2-yl)-1Η-pyrrol-2-yl]-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridin-4-yl)oxy] -1 -Alcohol, 叱1 dimethyl-2-{5-[(53)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrole-2 -基}-6-{[6-(A Sulfhydryl)pyridin-3-yl]oxy}pyridine-4-carboxamide, {(5R)-2-[5-(4-{[(2S)-l-methoxypropan-2-yl] Oxygen}-6-{[6-(methylsulfonyl)pyridin-3-yl]oxy}pyridin-2-yl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3 -carbazol-5-yl}methanol, {(4R)-2-[5-(4-{[(2S)-l-fluoropropan-2-yl]oxy}-6-{[6-(methyl) Sulfomethyl)pyridin-3-yl]oxy}pyridin-2-yl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol, or {(5R)-2-[5-(4-{[(2S)-l-fluoropropan-2-yl]oxy}-6-{[6-(methylsulfonyl)pyridin-3-yl] Oxy}pyridin-2-yl)-1 Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol. -122-201139430 9 - A glucokinase activator containing a compound selected from any one of claims 1 to 8 or a pharmacologically acceptable salt thereof as an effective ingredient. A pharmaceutical composition comprising a compound selected from any one of claims 1 to 8 or a pharmacologically acceptable salt thereof as an active ingredient. II. A pharmaceutical composition as claimed in claim 10, which has glucokinase activation. 1 2 A pharmaceutical composition according to claim 10 of the patent application, which utilizes glucokinase activation for the treatment and/or prevention of a disease to be treated and/or prevented. 1 3. A pharmaceutical composition according to claim 10, which activates glucokinase and achieves constant glucose maintenance or blood glucose regulation, while treating and/or preventing symptomatic treatment, improvement, alleviation and/or prevention. The disease. 1 4. The pharmaceutical composition of claim 10, which is used for the treatment and/or prevention of diabetes, abnormal glucose tolerance, gestational diabetes, chronic diabetes syndrome (including diabetic peripheral neuropathy, diabetic nephropathy) , diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome. The pharmaceutical composition of claim 1 is for use in the treatment and/or prevention of diabetes or an abnormality in sugar tolerance. The use of a compound of any one of claims 1 to 8 or a pharmacologically acceptable salt thereof is used for the manufacture of a pharmaceutical composition. -1 23-201139430 17. The use of claim 16, wherein the pharmaceutical composition is for activating glucokinase. 1 8 · For the use of Article 16 of the patent application, the pharmaceutical composition is used for the treatment and/or prevention of diabetes, abnormal glucose tolerance, gestational diabetes, chronic diabetes syndrome (including diabetic peripheral neuropathy, diabetic kidney) Disease, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome. 19. The use of claim 16 wherein the pharmaceutical composition is for the treatment and/or prevention of diabetes or an abnormal glucose tolerance. A glucokinase activating method which comprises administering to a warm-blooded animal a pharmacologically effective amount of a compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof. A method for the treatment and/or prevention of a disease, which comprises administering to a warm-blooded animal a pharmaceutically effective amount of a compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof. 2 2. The method for treating and/or preventing diseases according to item 21 of the patent application, wherein the disease is diabetes, abnormal sugar tolerance, gestational diabetes, chronic diabetes syndrome (including diabetic peripheral nerves, menstrual disorders, diabetic kidneys) Disease, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome. 2 3. The method for treating and/or preventing diseases according to claim 24, wherein the disease is diabetes or abnormal in sugar tolerance. 24. The method of treating and/or preventing a disease according to any one of claims 20 to 23, wherein the warm-blooded animal is a human. -1 24- 201139430 IV. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the representative figure: None 0. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: (I)