WO2010082601A1

WO2010082601A1 - Novel 2,5-disubstituted pyrrole derivative

Info

Publication number: WO2010082601A1
Application number: PCT/JP2010/050339
Authority: WO
Inventors: 詔大古川; 剛広福崎; 由香利大西; 英樹小林; 哲義松藤; 雄本田
Original assignee: 第一三共株式会社
Priority date: 2009-01-16
Filing date: 2010-01-14
Publication date: 2010-07-22
Also published as: TW201036962A

Abstract

Disclosed is a compound having an excellent glucokinase activating effect, or a pharmacologically acceptable salt thereof. Specifically disclosed is a compound represented by general formula (I) or a pharmacologically acceptable salt thereof. (In the formula, R¹s may be the same or different and each represents a C₁-C₆ alkyl group, a C₁-C₆ halogenated alkyl group, a C₁-C₆ alkyl group substituted by one or two hydroxy groups, or the like; R² represents a phenyl group which may be mono- to penta-substituted independently by a group selected from substituent group A, or a pyridyl group or pyrazinyl group which may be mono- to tri-substituted independently by a group selected from substituent group A; R³ represents an alkyl group which may be mono- to penta-substituted independently by a group selected from substituent group B, or the like; U represents an oxygen atom or a carbonyl group; n represents an integer of 0-3; substituent group A includes halogen atoms, C₁-C₆ alkoxy groups, C₂-C₇ alkylcarbonyl groups, C₂-C₇ halogenated alkylcarbonyl groups, C₂-C₇ alkoxycarbonyl groups and the like; and substituent group B includes halogen atoms, C₂-C₇ alkylcarbonyl groups, C₂-C₇ alkoxycarbonyl groups, a carbamoyl group and the like.)

Description

New 2,5-disubstituted pyrrole derivatives

The present invention relates to a 2,5-disubstituted pyrrole derivative or a pharmacologically acceptable salt thereof that has an excellent glucokinase activating action and is useful as a therapeutic agent for diabetes and the like.

Gluconase (glucokinase, which may be abbreviated as GK in the present specification; EC2.7.1.1) is one of four types of hexokinase (hexokinase IV) found in mammals. Hexokinase is an enzyme that catalyzes the conversion of glucose to glucose-6-phosphate at the initial stage of glycolysis in the cell. Among them, GK is expressed mainly in the liver and pancreatic beta cells. ing. In pancreatic beta cells, it functions as a sensing mechanism of extracellular glucose concentration that regulates glucose-stimulated insulin secretion. In the liver, the GK enzyme reaction becomes the rate-limiting step, and the following reactions such as glycolysis and glycogen synthesis are regulated. GK of liver and pancreatic beta cells differ in the sequence of 15 amino acids on the N-terminal side due to differences in splicing, but have the same enzymatic properties. Three hexokinases (I, II, III) other than GK saturate the enzyme activity at a glucose concentration of 1 mM or less, whereas GK has a low affinity for glucose, and its Km value is 8-15 mM, which is a physiological blood glucose level. Close to value. Therefore, the increase in intracellular glucose metabolism via GK occurs in response to changes in blood glucose from normal blood glucose level (around 5 mM) to postprandial hyperglycemia (10-15 mM).

Since ancient times, the hypothesis that GK functions as a glucose sensor in the liver and pancreatic beta cells has been proposed (Non-Patent Documents 1 to 3).
Recent research results have demonstrated that GK actually plays an important role in maintaining systemic glucose homeostasis, demonstrating the hypothesis. For example, a mouse with a disrupted glucokinase gene died of severe hyperglycemia soon after birth, and a GK hetero-deficient mouse had poor glucose tolerance and impaired insulin secretion due to sugar stimulation (Non-Patent Document) 4). On the other hand, in normal mice overexpressing GK, a decrease in blood glucose level and an increase in glycogen content in the liver were observed, and the same phenomenon was observed in mice that artificially developed diabetes (Non-patent Document 5). ).

In recent human studies, it has been clarified that GK functions as a glucose sensor and plays an important role in maintaining glucose homeostasis. A GK gene abnormality was found in a family with early-onset adult type diabetes called MODY2 (Maturity Onset Diabetes of the Young), and the relationship between this case and GK activity was clarified (Non-patent Document 6). On the other hand, families with mutations that increase GK activity have also been found, and in these families, fasting hypoglycemia symptoms accompanied by an increase in plasma insulin concentration are observed (Non-patent Document 7). From the above reports, GK functions as a glucose sensor in mammals including humans and plays an important role in blood glucose regulation. Therefore, it is considered that a substance having a GK activation action is useful as a drug in sugar metabolism diseases such as type II diabetes. In particular, GK activator can be expected to have the effect of promoting glucose uptake and release of glucose to the liver and insulin secretion of pancreatic beta cells at the same time. is expected.

Recently, it has become clear that pancreatic beta cell type GK is expressed exclusively in the feeding center (Ventromedial hypothalamus, VMH) of rat brain. It has been known that VMH has neurons that respond to glucose concentration. When glucose is administered into the rat ventricle, the amount of food intake decreases, whereas when glucose analog glucosamine is administered to inhibit glucose metabolism, food intake increases (Non-patent Document 8). From electrophysiological experiments, it is known that glucose-responsive neurons are activated in response to physiological glucose concentration changes (5-20 mM). At this time, glucokinase acts as a glucose sensor as in peripheral tissues. It was clarified that it was functioning (Non-Patent Document 9). Therefore, not only the liver and pancreatic beta cells but also substances that bring about activation of VMH glucokinase can be expected not only to lower blood glucose but also to correct obesity, which is a problem associated with many patients with type II diabetes.

From the above description, a substance having a GK activation action is used as a therapeutic and prophylactic agent for diabetes or for the treatment of chronic complications of diabetes such as retinopathy, nephropathy, neurosis, ischemic heart disease, arteriosclerosis and the like. It is useful as a preventive drug.

In addition, although several compounds which have GK activation ability have been reported so far, all have a structure different from the compound of this invention. For example, Patent Document 1 describes a compound that requires an amide structure, but the compound of the present invention requires pyrrole instead of amide. Further, Patent Document 2 describes a compound having a condensed pyrrole, but the compound of the present invention requires a pyrrole that is not condensed. Further, Patent Document 3 describes a compound having 3,5-disubstituted pyrazole or 1,2,4-triazole, which is different from the 2,5-disubstituted pyrrole structure of the present invention. In addition to these, a plurality of compounds having a GK activating action have been reported, but all have structures different from the compounds of the present invention. (For example, Patent Documents 4 to 15, Non-Patent Documents 10 and 11).

International Publication No. 2005/080359 Pamphlet International Publication No. 2007/031739 Pamphlet International Publication No. 2007/061923 Pamphlet International Publication No. 2000/058293 Pamphlet International Publication No. 2003/080585 Pamphlet International Publication No. 2005/066145 Pamphlet International Publication No. 2005/090332 Pamphlet International Publication No. 2006/112549 Pamphlet International Publication No. 2007/007886 Pamphlet International Publication No. 2007/037534 Pamphlet International Publication No. 2007/053765 Pamphlet International Publication No. 2007/117181 Pamphlet International Publication No. 2005/044801 Pamphlet International Publication No. 2007/053662 Pamphlet International Publication No. 2008/136428 Pamphlet

An object of the present invention is to provide a 2,5-disubstituted pyrrole derivative and a GK activator using the derivative, and particularly to provide a therapeutic and prophylactic agent for diabetes and impaired glucose tolerance. As a result of intensive studies on a compound having a GK activation action, the inventors have found that a 2,5-disubstituted pyrrole compound having a specific chemical structure has an excellent GK activation action. In addition, the compound of the present invention has excellent GK selectivity, low toxicity, and few side effects. The present inventors have found that this 2,5-disubstituted pyrrole compound is diabetic, impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic major It was found to be useful as an active ingredient of a medicament for the treatment and / or prevention of a disease selected from the group consisting of (including angiopathy) and metabolic syndrome. The present invention has been completed based on the above findings.

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

[Where:
R ¹ is the same or different and is a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, a C ₁ -C ₆ alkyl group substituted by 1 or 2 hydroxy groups, (C ₁ -C ₆ alkylthio)-(C ₁ -C ₆ alkyl) group, carboxyl group, carbamoyl group, mono-C ₁ -C ₆ alkylaminocarbonyl group or di- (C ₁ -C ₆ alkyl) aminocarbonyl group,
R ² may be independently substituted with 1 to 5 groups independently selected from a group selected from Substituent Group A or 1 to 3 independently substituted with a group selected from Substituent Group A A good pyridyl or pyrazinyl group,
R ³ is a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, a (C ₁ -C ₆ alkyl group) which may be independently substituted with 1 to 5 groups independently selected from the substituent group B , A C ₃ -C ₆ cycloalkyl group and an oxo group) which may be independently substituted by 1 to 3 and may contain one oxygen atom or one nitrogen atom; And a group represented by the formula —NR ⁴ R ⁵ .
R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group, or together with the nitrogen atom to which R ⁴ and R ⁵ are bonded, It forms a 4- to 6-membered heterosaturated ring which may be independently substituted by 1 to 3 groups independently of the group consisting of a C ₁ -C ₆ alkyl group and an oxo group. The 4- to 6-membered heterosaturated ring may further contain one oxygen atom or nitrogen atom.

U represents an oxygen atom or a carbonyl group;
(However, the 2-hydroxy-1-methylethoxy group is excluded from the group represented by the formula -UR ^3. )
n represents an integer of 0 to 3,
Substituent group A includes a halogen atom, C ₁ -C ₆ alkoxy group, C ₂ -C ₇ alkylcarbonyl group, C ₂ -C ₇ halogenated alkylcarbonyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ halogenated alkoxycarbonyl group, C ₁ -C ₆ alkylsulfonyl group, C ₁ -C ₆ halogenated alkylsulfonyl group, C ₃ -C ₆ cycloalkylsulfonyl group, (C ₁ -C ₆ alkoxy)-(C _1- C ₆ alkylsulfonyl) group, (C ₁ -C ₆ halogenated alkoxy)-(C ₁ -C ₆ alkylsulfonyl) group and group represented by the formula —V—NR ⁶ R ⁷ (V is a carbonyl group or a sulfonyl group) are ^shown, R 6, ^{R 7} are the same or different, a hydrogen _atom, or a C 1 -C ₆ alkyl group or a _C 1 -C ₆ halogenated alkyl group, ⁶ and a together with the nitrogen atom to which R ⁷ is bonded, C ₁ -C ₆ alkyl independently one or two substituted or .4 to form a 4 to 6-membered heterocyclic saturated ring or may have 6 membered group The heterosaturated ring may further comprise one oxygen or nitrogen atom)),
Substituent group B includes halogen atom, C ₂ -C ₇ alkylcarbonyl group, C ₂ -C ₇ alkoxycarbonyl group, carbamoyl group, mono-C ₁ -C ₆ alkylaminocarbonyl group, di- (C ₁ -C ₆ An alkyl) aminocarbonyl group, a C ₁ -C ₆ alkylthio group, a C ₁ -C ₆ alkylsulfonyl group, a hydroxy group, and a 3- to 6-membered ring ether. Or a pharmacologically acceptable salt thereof.

In the present invention, preferably,
(2) In (1),
A compound wherein R ¹ is a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, a C ₁ -C ₆ alkyl group substituted with one or two hydroxy groups, or a carbamoyl group, or a pharmacological thereof Top acceptable salt.

(3) In (1) or (2),
A compound or a pharmacologically acceptable salt thereof, wherein the general formula (I) is the general formula (Ia) and R ¹ is a carbamoyl group.

(4) In (1) or (2),
A compound or a pharmacologically acceptable salt thereof, wherein the general formula (I) is the general formula (Ib) and R ¹ is a methyl group, a hydroxymethyl group or a 2-hydroxyethyl group.

(5) In (1) or (2),
A compound in which the general formula (I) is the general formula (Ic) and R ¹ is a methyl group, a fluoromethyl group, a hydroxymethyl group, a 2-hydroxyethyl group or a (1S) -1,2-dihydroxyethyl group Or a pharmacologically acceptable salt thereof.

(6) In any one item selected from (1) to (5),
R ² is a phenyl group substituted at the 4- or 3-position with a group selected from Substituent Group C, and 1 at the 2-position with a group selected from Substituent Group C 5- A compound or a pharmacologically acceptable salt thereof, which is a 2-pyrazinyl group substituted at the 5-position with a pyridyl group or a group selected from substituent group C.

Substituent group C includes a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylsulfonyl group and a group represented by the formula —V—NR ⁶ R ⁷ (V represents a carbonyl group or a sulfonyl group, R ⁶ , R ⁷ is the same or different and represents a hydrogen atom or a C ₁ -C ₆ alkyl group.

(7) In any one item selected from (1) to (5),
R ² represents 3-methoxyphenyl group, 2-methylaminocarbonyl-5-pyridyl group, 4-methylsulfonylphenyl group, 2-methylsulfonyl-5-pyridyl group, 2-methylaminosulfonyl-5-pyridyl group, 5 A compound which is a methylsulfonyl-2-pyrazinyl group or a 5-methylaminosulfonyl-2-pyrazinyl group or a pharmacologically acceptable salt thereof.

(8) In any one item selected from (1) to (7),
R ³ is independently one or two in the group consisting of a C ₁ -C ₆ alkyl group or a (C ₃ -C ₆ cycloalkyl group and an oxo group) which may be independently substituted with 1 to 5 halogen atoms. A compound or a pharmacologically acceptable salt thereof, which is a 3- to 6-membered saturated ring which may be substituted and may contain one oxygen atom or nitrogen atom, and U is an oxygen atom.

(9) In any one item selected from (1) to (7),
R ³ is a C ₁ -C ₆ alkyl group or a group represented by the formula —NR ⁴ R ⁵ (R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or a C ₁ -C ₆ alkyl group). A compound in which U is a carbonyl group or a pharmacologically acceptable salt thereof.

(10) In any one item selected from (1) to (7),
The group represented by the formula -UR ³ is a methoxy group, an ethoxy group, an isopropoxy group, a (1S) -2-fluoro-1-methylethoxy group, a difluoromethoxy group, or a 1,3-difluoro-2-propoxy group. , A compound which is a cyclopentanone-2-yloxy group, tetrahydrofuran-3-yloxy group, 1-cyclopropylpyrrolidin-2-one-3-yloxy group, isopropylcarbonyl group or dimethylaminocarbonyl group, or a pharmacologically acceptable salt thereof salt.

(11) In (1),
[R ¹ is the same or different and is a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, a C ₁ -C ₆ alkyl group substituted with one or two hydroxy groups, (C _1- C ₆ alkylthio)-(C ₁ -C ₆ alkyl) group, carboxyl group, carbamoyl group, mono-C ₁ -C ₆ alkylaminocarbonyl group or di- (C ₁ -C ₆ alkyl) aminocarbonyl group , R ² is independently substituted with 1 to 5 groups independently selected from the substituent group A and independently substituted with 1 to 3 phenyl groups or groups selected from the substituent group A; A C ₁ -C ₆ alkyl group or a C ₂ -C ₆ alkenyl group, wherein R ³ may be independently substituted with 1 to 5 groups independently selected from Substituent Group B _group, C 1 -C ₆ A group consisting of an alkyl group and an oxo group may be independently substituted by 1 to 3 and may contain one oxygen atom or one nitrogen atom. The 3- to 6-membered saturated ring may be bonded to U (carbon atom). Or a group represented by the formula —NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group, Together with the nitrogen atom to which ⁴ and R ⁵ are attached, forms a 4- to 6-membered heterosaturated ring which may be independently substituted with 1 to 3 groups independently of the group consisting of a C ₁ -C ₆ alkyl group and an oxo group To do. The 4- to 6-membered heterosaturated ring may further contain one oxygen atom or nitrogen atom. U represents an oxygen atom or a carbonyl group (provided that a 2-hydroxy-1-methylethoxy group is excluded from the group represented by the formula —UR ³ ), n represents an integer of 0 to 3, Group A is a halogen atom, a C ₂ -C ₇ alkylcarbonyl group, a C ₂ -C ₇ halogenated alkylcarbonyl group, a C ₂ -C ₇ alkoxycarbonyl group, a C ₂ -C ₇ halogenated alkoxycarbonyl group, C ₁ -C ₆ alkylsulfonyl group, C ₁ -C ₆ halogenated alkylsulfonyl group, C ₃ -C ₆ cycloalkylsulfonyl group, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkylsulfonyl) group, (C _1- C ₆ halogenated alkoxy)-(C ₁ -C ₆ alkylsulfonyl) group and a group represented by the formula —V—NR ⁶ R ⁷ (V is a carbonyl group or sulfonyl group) R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ halogenated alkyl group, or a nitrogen to which R ⁶ and R ⁷ are bonded. Together with the atoms, it forms a 4- to 6-membered heterosaturated ring which may be independently substituted with 1 or 2 C ₁ -C ₆ alkyl groups. The substituent group B is a halogen atom, a C ₂ -C ₇ alkylcarbonyl group, a C ₂ -C ₇ alkoxycarbonyl group, a carbamoyl group, a mono- C ₁ -C ₆ alkylaminocarbonyl group, di- (C ₁ -C ₆ alkyl) aminocarbonyl group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ alkylsulfonyl group, hydroxy group and 3-6 membered ring ether Kara Indicating the group. Or a pharmacologically acceptable salt thereof.

(12) In (1),
R ¹ is a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, a C ₁ -C ₆ alkyl group substituted with one or two hydroxy groups, or a carbamoyl group, and R ² is A phenyl group in which one of the 4- or 3-positions is substituted with a group selected from substituent group C, a 5-pyridyl group in which one of the 2-positions is substituted with a group selected from substituent group C, or A 2-pyrazinyl group substituted at the 5-position with a group selected from substituent group C, wherein substituent group C is a C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylsulfonyl group, and From a group represented by —V—NR ⁶ R ⁷ (V represents a carbonyl group or a sulfonyl group, and R ⁶ and R ⁷ are the same or different and represent a hydrogen atom or a C ₁ -C ₆ alkyl group). R ³ is a halogen atom and is independently 1 to 5 An optionally substituted C ₁ -C ₆ alkyl group or a group consisting of (C ₃ -C ₆ cycloalkyl group and oxo group) independently 1 or 2 optionally substituted oxygen atom or nitrogen atom A compound or a pharmacologically acceptable salt thereof, which is a 3- to 6-membered saturated ring which may contain one, U is an oxygen atom, and n is an integer of 0 to 3.

(13) In (1),
R ¹ is a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, a C ₁ -C ₆ alkyl group substituted with one or two hydroxy groups, or a carbamoyl group, and R ² is A phenyl group in which one of the 4- or 3-positions is substituted with a group selected from substituent group C, a 5-pyridyl group in which one of the 2-positions is substituted with a group selected from substituent group C, or A 2-pyrazinyl group substituted at the 5-position with a group selected from substituent group C, wherein substituent group C is a C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylsulfonyl group, and From a group represented by —V—NR ⁶ R ⁷ (V represents a carbonyl group or a sulfonyl group, and R ⁶ and R ⁷ are the same or different and represent a hydrogen atom or a C ₁ -C ₆ alkyl group). Wherein R ³ is a C ₁ -C ₆ alkyl group or a formula A group represented by —NR ⁴ R ⁵ (R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or a C ₁ -C ₆ alkyl group), U is a carbonyl group, and n is 0 A compound which is an integer of 1 to 3, or a pharmacologically acceptable salt thereof.

(14) In (1),
The general formula (I) is the general formula (Ia), R ¹ is a carbamoyl group, R ² is a 3-methoxyphenyl group, 2-methylaminocarbonyl-5-pyridyl group, 4-methylsulfonylphenyl. A 2-methylsulfonyl-5-pyridyl group, a 2-methylaminosulfonyl-5-pyridyl group, a 5-methylsulfonyl-2-pyrazinyl group or a 5-methylaminosulfonyl-2-pyrazinyl group having the formula —U— The group represented by R ³ is a methoxy group, ethoxy group, isopropoxy group, (1S) -2-fluoro-1-methylethoxy group, difluoromethoxy group, 1,3-difluoro-2-propoxy group, cyclopentanone -2-yloxy group, tetrahydrofuran-3-yloxy group, 1-cyclopropylpyrrolidin-2-one-3-yloxy group, Propyl carbonyl group or compound or pharmacologically acceptable salt thereof is a dimethylamino group.

(15) In (1),
The general formula (I) is the general formula (Ib), R ¹ is a methyl group, a hydroxymethyl group or a 2-hydroxyethyl group, R ² is a 3-methoxyphenyl group, 2-methylaminocarbonyl- 5-pyridyl group, 4-methylsulfonylphenyl group, 2-methylsulfonyl-5-pyridyl group, 2-methylaminosulfonyl-5-pyridyl group, 5-methylsulfonyl-2-pyrazinyl group or 5-methylaminosulfonyl-2 A pyrazinyl group, the group represented by the formula -UR ³ is a methoxy group, an ethoxy group, an isopropoxy group, a (1S) -2-fluoro-1-methylethoxy group, a difluoromethoxy group, 1,3- Difluoro-2-propoxy group, cyclopentanone-2-yloxy group, tetrahydrofuran-3-yloxy group, 1-cyclopropylpi 2-one-3-yloxy group, an isopropyl group or a compound or pharmacologically acceptable salt thereof is a dimethylamino group.

(16) In (1),
The general formula (I) is the general formula (Ic), R ¹ is a methyl group, a fluoromethyl group, a hydroxymethyl group, a 2-hydroxyethyl group or a (1S) -1,2-dihydroxyethyl group; R ² represents 3-methoxyphenyl group, 2-methylaminocarbonyl-5-pyridyl group, 4-methylsulfonylphenyl group, 2-methylsulfonyl-5-pyridyl group, 2-methylaminosulfonyl-5-pyridyl group, 5 A methylsulfonyl-2-pyrazinyl group or a 5-methylaminosulfonyl-2-pyrazinyl group, and the group represented by the formula —UR ³ is a methoxy group, an ethoxy group, an isopropoxy group, (1S) -2- Fluoro-1-methylethoxy group, difluoromethoxy group, 1,3-difluoro-2-propoxy group, cyclopentanone-2-yloxy group, Tetrahydrofuran-3-yloxy group, 1-cyclopropyl-2-one-3-yloxy group, an isopropyl group or a compound or a pharmacologically acceptable salt thereof is a dimethylamino group.

(17) A compound having the general formula (I)
{(5R) -2- [5- (3-methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro -1,3-oxazol-5-yl} methanol,
{(5R) -2- [5- (3-Ethoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro -1,3-oxazol-5-yl} methanol,
[(5R) -2- {5- [3- (difluoromethoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrol-2-yl} -4, 5-dihydro-1,3-oxazol-5-yl] methanol,
5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-methoxyphenoxy ) -N-methylpyridine-2-carboxamide,
{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol,
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol,
2-{(5S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethanol,
(1S) -1-{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] Oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethane-1,2-diol,
{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol,
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol,
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyridine-2-sulfonamide,
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyrazine-2-sulfonamide,
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4 -(Methylsulfonyl) phenoxy] benzamide,
3- {5-[(5R) -5- (fluoromethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N-dimethyl-5 -{[6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide,
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide,
N, N-dimethyl-3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide,
{(4R) -2- [5- (3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl) -1H-pyrrole- 2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol,
1-cyclopropyl-3- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 {[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) pyrrolidin-2-one,
2- (3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[6- ( Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) cyclopentanone,
1- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -2-methylpropan-1-one, or
3- (3-methoxyphenoxy) -N, N-dimethyl-5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrole- 2-yl} benzamide or a pharmacologically acceptable salt thereof.

(18) A compound among the compounds described in (17) above or a pharmacologically acceptable salt thereof.

(19) A compound having the general formula (I)
{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol,
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol,
2-{(5S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethanol,
(1S) -1-{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] Oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethane-1,2-diol,
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol,
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyrazine-2-sulfonamide,
3- {5-[(5R) -5- (fluoromethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N-dimethyl-5 -{[6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide, or
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ A compound which is 6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide or a pharmacologically acceptable salt thereof.

(20) A compound described in the above (19) or a pharmacologically acceptable salt thereof.

(21) A glucokinase activator comprising as an active ingredient the compound described in any one of (1) to (20) or a pharmacologically acceptable salt thereof.

(22) A pharmaceutical composition comprising as an active ingredient the compound described in any one of (1) to (20) or a pharmacologically acceptable salt thereof.

(23) The pharmaceutical composition according to (22), wherein the pharmaceutical composition has a glucokinase activating action.

(24) The pharmaceutical composition according to (22), wherein the pharmaceutical composition is for the treatment and / or prevention of a disease which is treated and / or prevented by glucokinase activating action.

(25) The pharmaceutical composition activates glucokinase to achieve maintenance of glucose homeostasis or regulation of blood glucose, thereby treating and / or treating diseases that are treated, ameliorated, reduced and / or prevented. Or the pharmaceutical composition as described in (22) for prevention.

(26) The pharmaceutical composition is diabetes, impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome The pharmaceutical composition according to (22) for treatment and / or prevention.

(27) The pharmaceutical composition according to (22), wherein the pharmaceutical composition is for the treatment and / or prevention of diabetes or impaired glucose tolerance.

(28) Use of the compound described in any one of (1) to (20) or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition.

(29) The use according to (28), wherein the pharmaceutical composition is a composition for activating glucokinase.

(30) Treatment for diabetes, impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome And / or the use according to (28), which is a composition for prevention.

(31) The use according to (28), wherein the pharmaceutical composition is a composition for the treatment and / or prevention of diabetes or impaired glucose tolerance.

(32) A method for activating glucokinase, comprising administering to a warm-blooded animal a pharmacologically effective amount of the compound described in any one of (1) to (20) or a pharmacologically acceptable salt thereof.

(33) Treatment of diseases and / or diseases in which a pharmacologically effective amount of the compound described in any one of (1) to (20) or a pharmaceutically acceptable salt thereof is administered to a warm-blooded animal Prevention method.

(34) The disease is diabetes, impaired glucose tolerance, gestational diabetes, chronic diabetes complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome (33 ) Method.

(35) The method according to (33), wherein the disease is diabetes or impaired glucose tolerance.

(36) The method according to any one of (32) to (35), wherein the warm-blooded animal is a human.

In the present invention, the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferable is a fluorine atom or a chlorine atom, and more preferable is a fluorine atom.

In the present invention, the “C ₁ -C ₆ alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl or 1,2-dimethylbutyl, preferably having 1 to 4 linear or branched alkyl groups (C ₁ -C ₄ alkyl groups), more preferably methyl groups or ethyl groups (C ₁ -C ₂ alkyl groups), and even more preferably , A methyl group.

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

In the present invention, the “C ₁ -C ₆ alkyl group substituted by 1 or 2 hydroxy groups” is a group in which 1 or 2 hydroxy groups are bonded to the “C ₁ -C ₆ alkyl group”. is there. For example, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1,2-dihydroxyethyl or 2,3-dihydroxypropyl group, and preferably one or two hydroxy groups A group bonded to the “C ₁ -C ₄ alkyl group”, more preferably a group in which one or two hydroxy groups are bonded to the “C ₁ -C ₂ alkyl group”, and even more preferably. Is a hydroxymethyl group, a 2-hydroxyethyl group or a 1,2-dihydroxyethyl group.

In the present invention, the “C ₁ -C ₆ alkylthio group” is a group in which one “C ₁ -C ₆ alkyl group” is bonded to a sulfur atom, and is a straight chain or branched chain having 1 to 6 carbon atoms. It is a chain alkylthio group. For example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, 1-ethylpropylthio or hexylthio group, preferably a linear or branched alkylthio group having 1 to 4 carbon atoms (C ₁ -C ₄ alkylthio group), more preferably methylthio or ethylthio group (C ₁ -C ₂ alkylthio group), and still more preferably methylthio group.

In the present invention, “(C ₁ -C ₆ alkylthio)-(C ₁ -C ₆ alkyl) group” means that one “C ₁ -C ₆ alkylthio group” is the above “C ₁ -C ₆ alkyl group”. It is a group bonded to For example, it is a methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl or 2-methylthioethyl group, and preferably one of the “C ₁ -C ₄ alkylthio groups” is the “C 1 _1- C ₄ alkyl group ”((C ₁ -C ₄ alkylthio)-(C ₁ -C ₄ alkyl) group), more preferably one of the above-mentioned“ C ₁ -C ₂ alkylthio groups ”. Group ”is a group ((C ₁ -C ₂ alkylthio)-(C ₁ -C ₂ alkyl) group) bonded to the“ C ₁ -C ₂ alkyl group ”, and more preferably 2-methylthioethyl It is a group.

In the present invention, "mono--C ₁ -C ₆ alkylaminocarbonyl group" is an amino group in which one of the "C ₁ -C ₆ alkyl group" is bonded is a group attached to a carbonyl group. For example, a methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl or butylaminocarbonyl group, preferably an amino group to which one of the above “C ₁ -C ₄ alkyl groups” is bonded is a carbonyl group A group bonded to (mono-C ₁ -C ₄ alkylaminocarbonyl group), more preferably a methylaminocarbonyl group or an ethylaminocarbonyl group (mono-C ₁ -C ₂ alkylaminocarbonyl group), Even more preferred is a methylaminocarbonyl group.

In the present invention, the “di- (C ₁ -C ₆ alkyl) aminocarbonyl group” is a group in which two identical or different “C ₁ -C ₆ alkyl groups” are bonded to a carbonyl group. is there. For example, dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-propylaminocarbonyl or N-butyl-N-methylaminocarbonyl group, preferably An amino group to which two identical or different “C ₁ -C ₄ alkyl groups” are bonded is a group bonded to a carbonyl group (di- (C ₁ -C ₄ alkyl) aminocarbonyl group), more preferably Is a dimethylaminocarbonyl group, a diethylaminocarbonyl group or an N-ethyl-N-methylaminocarbonyl group (di- (C ₁ -C ₂ alkyl) aminocarbonyl group), more preferably a dimethylaminocarbonyl group is there.

In the present invention, the “C ₂ -C ₆ alkenyl group” is a group having 2 to 6 carbon atoms having one double bond in the “C ₁ -C ₆ alkyl group”. For example, ethenyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3 -Butenyl, 1-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl or 5-hexenyl group, preferably an alkenyl group having 2 to 4 carbon atoms (C ₂ -C ₄ alkenyl group) More preferably, it is a 1-methylvinyl group.

In the present invention, the “C ₁ -C ₆ alkoxy group” is a group in which the “C ₁ -C ₆ alkyl group” is bonded to an oxygen atom, and is a linear or branched alkoxy group having 1 to 6 carbon atoms. It is. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, 2-methylbutoxy, 3-ethylpropoxy, neopentoxy, hexyloxy or 2,3-dimethylbutoxy group, Preferred is a linear or branched alkoxy group having 1 to 4 carbon atoms (C ₁ -C ₄ alkoxy group), and more preferred is a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group (C ₁ -C ₃ alkoxy group), even more preferably a methoxy group or an ethoxy group (C ₁ -C ₂ alkoxy group), and particularly preferably a methoxy group.

In the present invention, a “C ₂ -C ₇ alkylcarbonyl group” is a group in which one of the above “C ₁ -C ₆ alkyl groups” is bonded to a carbonyl group. For example, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl or valeryl group, and preferably a group (C ₂ -C ₅ alkyl) in which one said “C ₁ -C ₄ alkyl group” is bonded to a carbonyl group A carbonyl group), more preferably an acetyl group or a propionyl group (C ₂ -C ₃ alkylcarbonyl group), and even more preferably an acetyl group.

In the present invention, the “C ₂ -C ₇ halogenated alkylcarbonyl group” is a group in which one of the above “C ₁ -C ₆ halogenated alkyl groups” is bonded to a carbonyl group. For example, trifluoromethylcarbonyl, trichloromethylcarbonyl, difluoromethylcarbonyl, dichloromethylcarbonyl, fluoromethylcarbonyl, 2,2,2-trifluoroethylcarbonyl, 2,2,2-trichloroethylcarbonyl or 2-fluoroethylcarbonyl group And is preferably a group in which one of the aforementioned “C ₁ -C ₄ halogenated alkyl groups” is bonded to a carbonyl group (C ₂ -C ₅ halogenated alkylcarbonyl group), more preferably 1 The aforementioned “C ₁ -C ₂ halogenated alkyl group” is a group (C ₂ -C ₃ halogenated alkylcarbonyl group) bonded to a carbonyl group, and more preferably a trifluoromethylcarbonyl group.

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

In the present invention, the “C ₁ -C ₆ halogenated alkoxy group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C ₁ -C ₆ alkoxy group”. For example, trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 2-chloroethoxy, 2-fluoroethoxy or A pentafluoroethoxy group, preferably a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C ₁ -C ₄ alkoxy group” (C ₁ -C ₄ halogenated alkoxy group) More preferably, the same or different 1 to 5 “halogen atoms” are groups bonded to the “C ₁ -C ₂ alkoxy group” (C ₁ -C ₂ halogenated alkoxy group), Even more preferred is a trifluoromethoxy group.

In the present invention, a “C ₁ -C ₆ alkylsulfonyl group” is a group in which one of the above “C ₁ -C ₆ alkyl groups” is bonded to a sulfonyl group, and is a straight chain or branched group having 1 to 6 carbon atoms. It is a branched alkylsulfonyl group. For example, a methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, s-butylsulfonyl or pentylsulfonyl group, preferably a linear or branched alkylsulfonyl group having 1 to 4 carbon atoms A group (C ₁ -C ₄ alkylsulfonyl group), more preferably a methylsulfonyl group or an ethylsulfonyl group (C ₁ -C ₂ alkylsulfonyl group), and even more preferably a methylsulfonyl group.

In the present invention, the “C ₁ -C ₆ halogenated alkylsulfonyl group” is a group in which one of the above “C ₁ -C ₆ halogenated alkyl groups” is bonded to a sulfonyl group, and has 1 to 6 carbon atoms. A straight-chain or branched alkylsulfonyl halide group; For example, trifluoromethylsulfonyl, trichloromethylsulfonyl, difluoromethylsulfonyl, dichloromethylsulfonyl, fluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl or 2-fluoroethylsulfonyl group, preferably having 1 carbon atom Or a straight chain or branched chain alkylsulfonyl group having 4 to 4 straight chain or branched chain (C ₁ -C ₄ halogenated alkylsulfonyl group), more preferably a straight chain or branched chain halogenated group having 1 or 2 carbon atoms. An alkylsulfonyl group (C ₁ -C ₂ halogenated alkylsulfonyl group), and even more preferably a trifluoromethylsulfonyl group.

In the present invention, the “C ₃ -C ₆ cycloalkyl group” is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. Preferred is a cyclopropyl group.

In the present invention, the “C ₃ -C ₆ 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, “(C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkylsulfonyl) group” means that one “C ₁ -C ₆ alkoxy group” is the above “C ₁ -C ₆ alkylsulfonyl”. A group bonded to “group”. For example, a methoxymethylsulfonyl, ethoxymethylsulfonyl, propoxymethylsulfonyl, isopropoxymethylsulfonyl, butoxymethylsulfonyl or s-butoxymethylsulfonyl group, and preferably one of the above “C ₁ -C ₄ alkoxy groups” is A group ((C ₁ -C ₄ alkoxy)-(C ₁ -C ₄ alkylsulfonyl) group) bonded to the “C ₁ -C ₄ alkylsulfonyl group”, and more preferably _one “C ₁ -C ₄ alkylsulfonyl group” _{The “1-} C ₂ alkoxy group” is a group ((C ₁ -C ₂ alkoxy)-(C ₁ -C ₂ alkylsulfonyl) group) bonded to the “C ₁ -C ₂ alkylsulfonyl group”, and more preferably Is a methoxymethylsulfonyl group.

In the present invention, “(C ₁ -C ₆ halogenated alkoxy)-(C ₁ -C ₆ alkylsulfonyl) group” means that one “C ₁ -C ₆ halogenated alkoxy group” is the above “C _1- A group bonded to a “C ₆ alkylsulfonyl group”. For example, it is a trifluoromethoxymethylsulfonyl, trichloromethoxymethylsulfonyl, difluoromethoxymethylsulfonyl, dichloromethoxymethylsulfonyl or fluoromethoxymethylsulfonyl group, preferably one of the aforementioned “C ₁ -C ₄ halogenated alkoxy groups” Is a group ((C ₁ -C ₄ halogenated alkoxy)-(C ₁ -C ₄ alkylsulfonyl) group) bonded to the “C ₁ -C ₄ alkylsulfonyl group”, more preferably one A group ((C ₁ -C ₂ halogenated alkoxy)-(C ₁ -C ₂ alkylsulfonyl) group in which the “C ₁ -C ₂ halogenated alkoxy group” is bonded to the “C ₁ -C ₂ alkylsulfonyl group”; And more preferably a trifluoromethoxymethylsulfonyl group.

In the present invention, the “phenyl group which may be independently substituted with 1 to 5 groups selected from the substituent group A” is independently 1 to 5 groups with a phenyl group or a group selected from the substituent group A. This is a phenyl group that is substituted. Preferable is a phenyl group substituted by one at 4-position or 3-position with a group selected from substituent group C, and more preferable is 3-methoxyphenyl group or 4-methylsulfonylphenyl group. .

In the present invention, “a pyridyl group or a pyrazinyl group optionally substituted by 1 to 3 groups independently selected from the substituent group A” is independently a group selected from the pyridyl group and the substituent group A. 1 to 3 substituted pyridyl groups, pyrazinyl groups, or a pyrazinyl group independently substituted with 1 to 3 groups selected from substituent group A. Preferably, a 5-pyridyl group substituted at the 2-position with a group selected from Substituent Group C or 2-pyrazinyl substituted at the 5-position with a group selected from Substituent Group C More preferably a 2-methylaminocarbonyl-5-pyridyl group, a 2-methylsulfonyl-5-pyridyl group, a 2-methylaminosulfonyl-5-pyridyl group, and a 5-methylsulfonyl-2-pyrazinyl group. Or a 5-methylaminosulfonyl-2-pyrazinyl group.

In the present invention, “a C ₁ -C ₆ alkyl group which may be independently substituted with 1 to 5 groups independently selected from the substituent group B” refers to a C ₁ -C ₆ alkyl group or the substituent group B C ₁ -C ₆ alkyl group independently substituted with 1 to 5 selected groups. Preferably, it is a C ₁ -C ₆ alkyl group which may be independently substituted with 1 to 5 halogen atoms, more preferably a methyl group, an ethyl group, an isopropyl group, (1S) -2-fluoro. A 1-methylethyl group, a difluoromethyl group or a 1,3-difluoro-2-propyl group;

In the present invention, the “3- to 6-membered cyclic ether” is oxirane, oxetane, tetrahydrofuran or tetrahydropyran. Tetrahydrofuran is preferred.

In the present invention, the “3- to 6-membered saturated ring optionally containing one oxygen atom or nitrogen atom” is a C ₃ -C ₆ cycloalkyl group, a 3- to 6-membered ring ether, or a 3- to 6-membered ring amine, Cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, aziridine, azetidine, pyrrolidine or piperidine. Preference is given to cyclopentane, tetrahydrofuran or pyrrolidine.

In the present invention, one to three independently substituted oxygen groups or one nitrogen atom may be substituted with a group consisting of “(C ₁ -C ₆ alkyl group, C ₃ -C ₆ cycloalkyl group and oxo group)”. The “3- to 6-membered saturated ring which may be contained” means a 3- to 6-membered saturated ring which may contain one oxygen atom or nitrogen atom, or a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group and an oxo group. A 3- to 6-membered saturated ring which may contain one oxygen atom or one nitrogen atom independently substituted by 1 to 3 groups. For example, the above “3- to 6-membered saturated ring which may contain one oxygen atom or nitrogen atom”, cyclopentanone, cyclohexanone, tetrahydro-2-furanone, tetrahydro-2-pyrone, 2-azetidinone, 2-pyrrolidinone, 2 -Piperidinone, methylcyclopentyl, methylcyclohexyl, methyltetrahydrofuran, methyltetrahydropyran, methylpyrrolidine, methylpiperidine, 1-methyl-2-pyrrolidinone or 1-cyclopropylpyrrolidin-2-one, preferably cyclopropane, cyclo Pentanone, tetrahydrofuran, tetrahydropyran, tetrahydro-2-furanone, 1-methyl-2-pyrrolidinone or 1-cyclopropylpyrrolidin-2-one, more preferably cyclopentanone, tetrahydrofuran Down or 1-cyclopropyl-2-one.

In the present invention, “1 to 3 which may be independently substituted with a group consisting of a C ₁ -C ₆ alkyl group and an oxo group together with the nitrogen atom to which R ⁴ and R ⁵ are bonded may be used. A 4 to 6-membered heterosaturated ring may further contain one oxygen atom or nitrogen atom ”is independently selected from the group consisting of a C ₁ -C ₆ alkyl group and an oxo group. 4 to 6-membered hetero-saturated ring which may be substituted by 3 to 4 (a 4- to 6-membered fully-reduced saturated heterocyclic ring which contains one nitrogen atom and further contains one oxygen atom or nitrogen atom) Group), for example, azetidine, pyrrolidine, piperidine, morpholine, piperazine, 2-azetidinone, 2-pyrrolidinone, 2-piperidinone, dimethylmorpholine, methylpiperazine or dimethylpiperazine, and preferably Zechijin, pyrrolidine or morpholine.

In the present invention, the “group represented by the formula —V—NR ⁶ R ⁷ ” is the “group represented by the formula —C (═O) —NR ⁶ R ⁷ ” or “the formula —SO ₂ —NR ⁶ R ^7” . Group represented ".

In the present invention, “a ^{6 to} 6-membered heterosaturated ring which may be independently substituted with one or two C ₁ -C ₆ alkyl groups together with the nitrogen atom to which R ⁶ and R ⁷ are bonded. The 4- to 6-membered heterosaturated ring may further contain one oxygen atom or nitrogen atom.) ”May be independently substituted with one or two C ₁ -C ₆ alkyl groups. To 6-membered heterosaturated ring (a 4- to 6-membered fully reduced saturated heterocyclic group containing one nitrogen atom and further containing one oxygen atom or nitrogen atom), such as azetidine, pyrrolidine , Piperidine, morpholine, piperazine, dimethylmorpholine, methylpiperazine or dimethylpiperazine, preferably azetidine or 4-methylpiperazine.

In the present invention, R ¹ is preferably a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, a C ₁ -C ₆ alkyl group substituted with one or two hydroxy groups, or a carbamoyl group. And when general formula (I) is general formula (Ia), R ¹ is more preferably a carbamoyl group. When the general formula (I) is the general formula (Ib), more preferable R ¹ is a methyl group, a hydroxymethyl group or a 2-hydroxyethyl group. When the general formula (I) is the general formula (Ic), more preferable R ¹ is a methyl group, a fluoromethyl group, a hydroxymethyl group, a 2-hydroxyethyl group, or a (1S) -1,2-dihydroxyethyl group. is there.

In the present invention, R ² is preferably a phenyl group substituted by one of the 4-position or 3-position with a group selected from Substituent Group C, and one 2-position of a group selected from Substituent Group C. A substituted 5-pyridyl group or a 2-pyrazinyl group substituted at the 5-position with a group selected from Substituent Group C (Substituent Group C is a C ₁ -C ₆ alkoxy group, C _1- A C ₆ alkylsulfonyl group and a group represented by the formula —V—NR ⁶ R ⁷ (V represents a carbonyl group or a sulfonyl group, and R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom or C ₁ -C _6; More preferably R ² represents a 3-methoxyphenyl group, a 2-methylaminocarbonyl-5-pyridyl group, a 4-methylsulfonylphenyl group, a 2-methylsulfonyl-5. -Pyridyl group, 2-methylamino Sulfonyl-5-pyridyl group, a 5-methylsulfonyl-2-pyrazinyl or 5-methyl-aminosulfonyl-2-pyrazinyl group.

In the present invention, when U is an oxygen atom, preferred R ³ is a C ₁ -C ₆ alkyl group or a (C ₃ -C ₆ cycloalkyl group) which may be independently substituted with 1 to 5 halogen atoms. A 3- to 6-membered saturated ring which may be independently substituted by 1 or 2 groups and may contain one oxygen atom or nitrogen atom. When U is a carbonyl group, preferred R ³ is a C ₁ -C ₆ alkyl group or a group represented by the formula —NR ⁴ R ⁵ (R ⁴ and R ⁵ may be the same or different and each represents a hydrogen atom or C ₁ — A C ₆ alkyl group).

In the present invention, the preferred group represented by the formula —NR ⁴ R ⁵ is a dimethylamino group.

In the present invention, preferable groups represented by the formula -UR ³ are methoxy group, ethoxy group, isopropoxy group, (1S) -2-fluoro-1-methylethoxy group, difluoromethoxy group, 1,3- A difluoro-2-propoxy group, a cyclopentanone-2-yloxy group, a tetrahydrofuran-3-yloxy group, a 1-cyclopropylpyrrolidin-2-one-3-yloxy group, an isopropylcarbonyl group or a dimethylaminocarbonyl group.

In the present invention, the preferred group represented by the formula —NR ⁶ R ⁷ is a methylamino group.

In the present invention, n is preferably 1.

In the present invention, the preferred substituent group A includes a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylsulfonyl group, and a group represented by the formula —V—NR ⁶ R ⁷ (V is a carbonyl group or a sulfonyl group) R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom or a C ₁ -C ₆ alkyl group.), And more preferred substituent group A includes a methoxy group, a methylaminocarbonyl group, a methyl group A sulfonyl group or a methylaminosulfonyl group.

In the present invention, a preferred substituent group B is a halogen atom, and a more preferred substituent group B is a fluorine atom.

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

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

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

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

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

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

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

The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof absorbs moisture by being left in the atmosphere or recrystallized, and adsorbs water, or hydrates. Such hydrates are also included in the salts of the present invention.

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

The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is preferably a compound having the general formula (I) of the present invention.

In the present invention, “metabolic syndrome” is based on insulin resistance, and a state in which the risk of coronary artery disease is significantly increased by accumulation of a plurality of coronary risk factors (lifestyle-related diseases such as hyperlipidemia, diabetes, Obesity, hypertension, etc. (Diabetes, Obesity and Metabolism, 9, 2007, 246-258, Journal of the American Medical Association, oci285: 2486-2497 (2001), Diabet. Med., 15: 539-553 ( 1998)).

The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent GK activation action, and is a warm-blooded animal (preferably a mammal, including humans). Diseases selected from the group consisting of diabetes, impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) and metabolic syndrome It is useful as a medicament for the prevention and / or treatment. Further, the novel compound represented by the general formula (I) provided by the present invention or a pharmacologically acceptable salt thereof has an excellent GK activation action, and is a warm-blooded animal (preferably a mammalian animal). And is useful as an active ingredient of a medicament for the prevention and / or treatment of the above-mentioned diseases (including humans). Preferred diseases are diabetes or impaired glucose tolerance. Suitably, it can be used as a medicament for the treatment of the above-mentioned diseases.

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

The solvent used in the reaction in each step of the following methods A to U is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, and is selected from the following solvent group, for example. Solvent groups include hydrocarbons such as pentane, hexane, octane, petroleum ether, ligroin, cyclohexane; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methyl Amides such as -2-pyrrolidinone and hexamethylphosphoric triamide; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and cyclopentyl methyl ether; methanol, ethanol, n-propanol, i -Propanol, n-butanol, 2-butanol, 2-methyl-1-propanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, Alcohols such as methyl cellosolve; sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane; nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ethyl formate, ethyl acetate, propyl acetate, Esters such as butyl acetate and diethyl carbonate; ketones such as acetone, 2-butanone, 4-methyl-2-pentanone, methyl isobutyl ketone, isophorone and cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; dichloromethane, Halogenated hydrocarbons such as 1,2-dichloroethane, chlorobenzene, dichlorobenzene, chloroform and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene and xylene; acetic acid, formic acid, propionic acid, Carboxylic acids such as lauric acid and trifluoroacetic acid; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 2,6-lutidine, 4-pyrrolidinopyridine , Picoline, 4-dimethylaminopyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3 .0] nona-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), An amine such as piperidine; water; and a mixed solvent thereof.

The base used in the reaction of each step of the following methods A to U is, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate; sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate Alkali metal bicarbonates such as sodium acetate, potassium acetate, lithium acetate, alkali metal acetates such as cesium acetate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; Alkali metal hydroxides such as sodium, potassium hydroxide, barium hydroxide, lithium hydroxide; inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxy Sodium-t-butoxide, potassium methoxide, Alkali metal alkoxides such as lithium ethoxide, potassium tert-butoxide, lithium methoxide; alkali metal trialkylsiloxides such as sodium trimethylsiloxide, potassium trimethylsiloxide, lithium trimethylsiloxide; sodium thiomethoxide Mercaptan alkali metals such as sodium thioethoxide; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, N, N-diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 2,6-lutidine, 4-pyrrolidinopyridine, picoline, 4-dimethylaminopyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-die Ruaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4. 0] Organic bases such as undec-7-ene (DBU); organometallic bases such as n-butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide; or amino acids such as proline.

The condensing agent used in the reaction in each step of the following methods A to U is, for example, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexa Fluorophosphate (HATU), 1-propanephosphonic acid cyclic anhydride (T3P), dicyclohexylcarbodiimide (DCCD), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCI · HCl), 1-ethyl -3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAC), 4- (4,6-dimethoxy-1,3,5- Triazin-2-yl) -4-methylmorpholinium chloride n-hydrate (DMT-MM), isobutyl chloroformate IBCF), 1,1′-carbonylbis-1H-imidazole (CDI), diethyl cyanophosphonate (DEPC), diphenyl phosphate azide (DPPA), N-hydroxysuccinimide, N-hydroxy-5-norbornene-2, It is 3-dicarboximide or dipyridyl disulfide, and 1-hydroxybenzotriazole (HOBt) or 1-hydroxybenzotriazole monohydrate (HOBt · H ₂ O) can be coexisted as necessary.

Examples of the demethylating agent used in the reaction of each step of the following methods A to U include sodium thiomethoxide, sodium thioethoxide, sodium thiophenoxide, iodotrimethylsilane, aluminum chloride, aluminum bromide, and three odors. Boron iodide, boron triiodide, methylmagnesium iodide, and hydrogen bromide.

The palladium catalyst used in the reaction in each step of the following methods A to U is, for example, tetrakis (triphenylphosphine) palladium (0), palladium-activated carbon, palladium acetate (II), palladium trifluoroacetate (II) , Palladium black, palladium (II) bromide, palladium (II) chloride, palladium (II) iodide, palladium (II) cyanide, palladium (II) nitrate, palladium (II) oxide, palladium (II) sulfate, dichlorobis (Acetonitrile) palladium (II), dichlorobis (benzonitrile) palladium (II), dichloro (1,5-cyclooctadiene) palladium (II), acetylacetone palladium (II), palladium (II) sulfide, [1,1 ' -Bis (diphenylphosphino) ferrocene] Zero-valent or divalent palladium catalysts such as palladium (II) dichloride, tris (dibenzylideneacetone) dipalladium (0), tetrakis (acetonitrile) palladium (II) tetrafluoroborate or arylpalladium chloride dimer. .

The oxidizing agent used in the reaction of each step of the following methods A to U is an inorganic oxidizing agent such as m-chloroperbenzoic acid, hydrogen peroxide solution, oxone or manganese dioxide.

In the reaction of each step of the following methods A to U, the reaction temperature varies depending on the solvent, starting material, reagent, etc., and the reaction time varies depending on the solvent, starting material, reagent, reaction temperature, and the like.

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

In the reaction of each step of the following methods A to U, Me represents a methyl group, iPr represents an isopropyl group, Ac represents an acetyl group, Bn represents a benzyl group, and Boc represents a t-butoxycarbonyl group.

Method A is a method for producing a compound having the general formula (Id) in which U is an oxygen atom among the compounds having the general formula (I).

In the present invention, R ² and R ³ are as defined above, R ⁸ represents a C ₁ -C ₆ alkyl group (preferably a methyl group or an ethyl group), R ⁹ , R ¹⁰ , R ¹¹ and R ¹² represent a hydrogen atom or one group of R ¹ , and X is a halogen atom (preferably a chlorine atom, a bromine atom or an iodine atom, more preferably a bromine atom Y represents a halogen atom, a C ₁ -C ₆ alkylsulfonyloxy group, a C ₁ -C ₆ alkoxysulfonyloxy group or a C ₆ -C ₁₀ arylsulfonyloxy group (preferably a halogen atom) R ^2a , R ^3a , R ^9a , R ^10a , R ^11a, and R ^12a are R, and more preferably a fluorine atom or a chlorine atom, and even more preferably a fluorine atom. ^2, ^{R 3} R ^{9, R} ^10, amino group contained as a substituent group of R ¹¹ and R ^12, hydroxy and / or carboxyl groups, addition is a protected amino group which may, hydroxyl and / or carboxyl group, The group similar to the group in the definition of group of R < ² >, R < ³ >, R < ⁹ >, R < ¹⁰ >, R < ¹¹ > and R < ¹² > is shown.

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

This step is performed by reacting a compound having the general formula (II) with a demethylating agent in a solvent.

The compound having the general formula (II) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.

The solvent used in this step is preferably an amide, more preferably N, N-dimethylformamide or N-methyl-2-pyrrolidinone.

The demethylating agent used in this step is preferably sodium thiomethoxide.

The reaction temperature in this step is usually 50 ° C. to 140 ° C., preferably 80 ° C. to 120 ° C.

The reaction time in this step is usually 0.5 to 12 hours, preferably 1 to 5 hours.

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

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

The compound having the general formula (IV) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.

The solvent used in this step is preferably an amide or a nitrile, and more preferably N, N-dimethylformamide or acetonitrile.

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

The reaction temperature in this step is usually −10 ° C. to 140 ° C., preferably 0 ° C. to 120 ° C.

The reaction time in this step is usually 0.5 to 72 hours, preferably 1 to 48 hours.

Step A3 This step is a step of producing a compound having the general formula (VI).

This step is performed by reacting a compound having the general formula (V) with a demethylating agent in a solvent.

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

The demethylating agent used in this step is preferably boron tribromide.

The reaction temperature in this step is usually −100 ° C. to 40 ° C., preferably −78 ° C. to 25 ° C.

The reaction time in this step is usually 1 hour to 72 hours, preferably 12 hours to 36 hours.

Step A4 This step is a step of producing a compound having the general formula (VII).

This step is performed by reacting a compound having the general formula (VI) with bis (pinacolato) diboron in a solvent in the presence of a palladium catalyst and an inorganic base.

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

The palladium catalyst used in this step is preferably a divalent palladium catalyst, more preferably [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex. .

The inorganic base used in this step is preferably an alkali metal acetate, and more preferably potassium acetate.

The reaction temperature in this step is usually 50 ° C to 130 ° C, preferably 70 ° C to 110 ° C.

The reaction time in this step is usually 1 to 24 hours, preferably 2 to 10 hours.

Step A5 This step is a step of producing a compound having the general formula (IX).

This step is performed by reacting a compound having the general formula (VII) with a compound having the general formula (VIII) in the presence of triphenylphosphine and diethyl azodicarboxylate in a solvent.

The compound having the general formula (VIII) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.

The solvent used in this step is preferably an ether, an aromatic hydrocarbon, or a mixed solvent thereof, more preferably tetrahydrofuran, toluene, or a mixed solvent of tetrahydrofuran and toluene.

The reaction temperature in this step is usually −20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.

The reaction time in this step is usually 0.5 to 72 hours, preferably 1 to 36 hours.

Step A6 This step is a step of producing a compound having the general formula (XI).

This step is performed by reacting a compound having the general formula (IX) with a compound having the general formula (X) in a solvent in the presence of a palladium catalyst and an inorganic base.

The solvent used in this step is preferably an ether, alcohol, aromatic hydrocarbon or a mixed solvent thereof, more preferably dioxane, ethanol, toluene or a mixed solvent thereof. Even more preferred is dioxane or a mixed solvent of ethanol and toluene.

The inorganic base used in this step is preferably an alkali metal carbonate, more preferably potassium carbonate, and even more preferably an aqueous potassium carbonate solution.

The reaction temperature in this step is usually 25 ° C to 100 ° C, preferably 40 ° C to 70 ° C.

Step A7 This step is a step of producing a compound having the general formula (XII).

This step is performed by reacting a compound having the general formula (XI) with an acid in a solvent.

Examples of the acid used in this step include hydrogen halides such as hydrogen chloride gas and hydrogen bromide gas; mineral acids such as sulfuric acid, hydrobromic acid and hydrochloric acid; methanesulfonic acid and p-toluenesulfonic acid , Organic sulfonic acids such as pyridinium p-toluenesulfonate (PPTS), camphorsulfonic acid and trifluoromethanesulfonic acid; carboxylic acids such as acetic acid, formic acid and trifluoroacetic acid; aluminum chloride, zinc chloride, zinc iodide, tetra Lewis acids such as tin chloride, titanium trichloride, boron trifluoride, boron tribromide; or acidic ion exchange resins, preferably carboxylic acids, and more preferably trifluoroacetic acid.

The reaction temperature in this step is usually −20 ° C. to 60 ° C., preferably 0 ° C. to 40 ° C.

The reaction time in this step is usually 0.1 to 5 hours, preferably 0.5 to 3 hours.

Step A8 This step is a step of producing a compound having the general formula (XIII).

This step is performed by reacting a compound having the general formula (XII) with a base in a solvent.

The solvent used in this step is preferably an alcohol, and more preferably ethanol.

The base used in this step is preferably an alkali metal hydroxide, more preferably sodium hydroxide, and even more preferably an aqueous sodium hydroxide solution.

The reaction temperature in this step is usually 25 ° C to 100 ° C, preferably 50 ° C to 80 ° C.

The reaction time in this step is usually 0.1 to 24 hours, preferably 0.5 to 6 hours.

Step A9 This step is a step of producing a compound having the general formula (XV).

This step is performed by reacting a compound having the general formula (XIII) with a compound having the general formula (XIV) in a solvent in the presence of a condensing agent, in the presence or absence of a base.

The compound having the general formula (XIV) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.

The solvent used in this step is preferably an alcohol, a halogenated hydrocarbon, an amide or a mixed solvent thereof, more preferably methanol, dichloromethane, N, N-dimethylformamide or dichloromethane. It is a mixed solvent of N, N-dimethylformamide.

The condensing agent used in this step is preferably DMT-MM, HATU or WSCI · HCl. When WSCI · HCl is used, HOBt or HOBT · H ₂ O can coexist if necessary.

The base used in this step is preferably an organic base, and more preferably N-methylmorpholine, N, N-diisopropylethylamine or 4-dimethylaminopyridine.

The reaction temperature in this step is usually −20 ° C. to 60 ° C., preferably 0 ° C. to 30 ° C.

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

Step A10 This step is a step of producing a compound having the general formula (Id).

In this step, a compound having the general formula (XV) is reacted with a base and methanesulfonic anhydride or bis (2-methoxyethyl) aminosulfur trifluoride in a solvent, and then optionally R ^2a , R ^3a , R ^9a , R ^10a , R ^11a and R ^12a are carried out by removing amino, hydroxy and / or carboxyl protecting groups.

When the methanesulfonic anhydride is used, the solvent used in this step is preferably an ether, and more preferably tetrahydrofuran or dimethoxyethane. When bis (2-methoxyethyl) aminosulfur trifluoride is used, it is preferably a halogenated hydrocarbon, and more preferably dichloromethane.

When the methanesulfonic anhydride is used, the base used in this step is preferably an organic base, and more preferably triethylamine. When bis (2-methoxyethyl) aminosulfur trifluoride is used, it is preferably an alkali metal carbonate, more preferably potassium carbonate.

The reaction temperature in this step is usually −100 ° C. to 85 ° C., and when methanesulfonic anhydride is used, it is preferably 10 ° C. to 60 ° C. When bis (2-methoxyethyl) aminosulfur trifluoride is used, it is preferably −78 ° C. to 30 ° C.

Method B is a method for producing a compound having the general formula (Id) in which U is an oxygen atom among the compounds having the general formula (I).

In the present invention, R ² , R ³ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ^2a , R ^3a , R ^9a , R ^10a , R ^11a , R ^12a , X and Y are as described above. It shows the same meaning as the thing.

Step B1 This step is a step of producing a compound having the general formula (XVI).

This step comprises reacting the compound having the general formula (V) obtained in Step A2 Step A2 with bis (pinacolato) diboron in a solvent in the presence of a palladium catalyst and an inorganic base. This is performed in the same manner as in step A4.

Step B2 This step is a step of producing a compound having the general formula (XVII).

In this step, the compound having the general formula (XVI) is reacted with the compound having the general formula (X) in the presence of a palladium catalyst and an inorganic base in a solvent in the same manner as in step A6 of the method A. Done.

Step B3 This step is a step of producing a compound having the general formula (XVIII).

This step is performed in the same manner as in Step A8 of Method A above by reacting a compound having the general formula (XVII) with a base in a solvent.

Step B4 This step is a step of producing a compound having the general formula (XIX).

This step is performed by reacting a compound having the general formula (XVIII) with a compound having the general formula (XIV) in a solvent in the presence of a condensing agent, in the presence or absence of a base, and Performed in the same manner as in step A9.

Step B5 This step is a step of producing a compound having the general formula (XX).

In this step, the compound having the general formula (XIX) is reacted with a base and methanesulfonic anhydride or bis (2-methoxyethyl) aminosulfur trifluoride in a solvent to form the step A10 of the above method A. The same is done.

Step B6 This step is a step of producing a compound having the general formula (XXI).

This step is performed in the same manner as in Step A3 of Method A above by reacting a compound having the general formula (XX) with a demethylating agent in a solvent.

Step B7 This step is a step of producing a compound having the general formula (Id).

In this step, the compound having the general formula (XXI) is reacted with the compound having the general formula (VIII) in the presence of triphenylphosphine and diethyl azodicarboxylate in a solvent, whereby the A5 After being carried out in the same manner as in the step, it is carried out by removing amino, hydroxy and / or carboxyl protecting groups in R ^2a , R ^3a , R ^9a , R ^10a , R ^11a and R ^12a as desired.

Step B8 This step is a step of producing a compound having the general formula (Id).

This step is carried out by reacting a compound having the general formula (XXI) with a compound having the general formula (XXII) in a solvent in the presence of a base, and then optionally R ^2a , R ^3a , R ^9a , R ^10a , R ^11a and R ^12a are carried out by removing the protective group for the amino group, hydroxy group and / or carboxyl group.

The compound having the general formula (XXII) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.

The solvent used in this step is preferably an amide or a ketone, and more preferably N, N-dimethylformamide or 2-butanone.

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

The reaction temperature in this step is usually 25 ° C to 120 ° C, preferably 40 ° C to 80 ° C.

The reaction time in this step is usually 1 hour to 72 hours, preferably 6 hours to 48 hours.

Method C is a method for producing a compound having the general formula (Id) in which U is an oxygen atom among the compounds having the general formula (I).

In the present invention, R ² , R ³ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ^2a , R ^3a , R ^9a , R ^10a , R ^11a , R ^12a , X and Y are the same as described above. Show significance.

Step C1 This step is a step of producing a compound having the general formula (XXIII).

This step comprises reacting the compound having the general formula (III) obtained in the above-mentioned Method A, Step A1 with a compound having the general formula (XXII) in a solvent in the presence of a base, thereby Performed in the same manner as in step B8.

Step C2 This step is a step of producing a compound having the general formula (XXIV).

This step is performed in the same manner as in Step A1 of Method A above by reacting a compound having the general formula (XXIII) with a demethylating agent in a solvent.

Step C3 This step is a step of producing a compound having the general formula (XXV).

This step is carried out in the same manner as in Step A4 of Method A above by reacting a compound having the general formula (XXIV) with bis (pinacolato) diboron in a solvent in the presence of a palladium catalyst and an inorganic base.

Step C4 This step is a step of producing a compound having the general formula (XXVII).

In this step, the compound having the general formula (XXV) is reacted with the compound having the general formula (XXVI) in the presence of a palladium catalyst and an inorganic base in a solvent in the same manner as in Step A6 of the above Method A. Done.

The compound having the general formula (XXVI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.

Step C5 This step is a step of producing a compound having the general formula (XXVIII).

This step is performed in the same manner as in Step A7 of Method A above by reacting a compound having the general formula (XXVII) with an acid in a solvent.

Step C6 This step is a step of producing a compound having the general formula (XXIX).

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

The base used in this step is preferably an organic base, and more preferably triethylamine or a mixed base of triethylamine and 4-dimethylaminopyridine.

The reaction temperature in this step is usually −10 ° C. to 40 ° C., preferably 0 ° C. to 30 ° C.

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

Step C7 This step is a step of producing a compound having the general formula (XXX).

This step is performed by reacting a compound having the general formula (XXIX) in a solvent in a hydrogen atmosphere in the presence of a palladium catalyst.

The solvent used in this step is preferably an ether, alcohol, ester or a mixed solvent thereof, more preferably tetrahydrofuran, methanol, ethanol, ethyl acetate or a mixed solvent of ethanol and ethyl acetate. It is.

The palladium catalyst used in this step is preferably a zero-valent palladium catalyst, and more preferably palladium-activated carbon.

Step C8 This step is a step of producing a compound having the general formula (XXXI).

This step is performed by reacting a compound having the general formula (XXX) with a compound having the general formula (XIV) in a solvent in the presence of a condensing agent, in the presence or absence of a base. Performed in the same manner as in step A9.

Step C9 This step is a step of producing a compound having the general formula (XXXII).

This step comprises reacting the compound having the general formula (XXXI) with a base and methanesulfonic anhydride or bis (2-methoxyethyl) aminosulfur trifluoride in a solvent, The same is done.

Step C10 This step is a step of producing a compound having the general formula (XXXIII).

This step is performed by reacting a compound having the general formula (XXXII) with tetrabutylammonium fluoride in a solvent.

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

The reaction time in this step is usually 0.1 to 12 hours, preferably 0.5 to 3 hours.

Step C11 This step is a step of producing a compound having the general formula (Id).

This step is carried out in the same manner as in Step A2 of Method A above by reacting a compound having the general formula (XXXIII) with a compound having the general formula (IV) in the presence of a base in a solvent. If necessary, the amino group, hydroxy group and / or carboxyl group-protecting group in R ^2a , R ^3a , R ^9a , R ^10a , R ^11a and R ^12a is removed.

Method D is a method for producing a compound having the general formula (XIII) used in the above-mentioned Method A, Step A9.

In the present invention, R ^2a , R ^3a , X and Y have the same meaning as described above.

Step D1 This step is a step of producing a compound having the general formula (XXXIV).

This step is performed in (i) or (ii).

(I) In this step, in the presence of triphenylphosphine and diethylazodicarboxylate in a solvent, the compound having the general formula (VI) obtained in the above-mentioned Method A, Step A3 is converted to the compound having the general formula (VIII). Is carried out in the same manner as in step A5 of the method A.

(Ii) This step is carried out in the same manner as in Step B8 of Method B above by reacting a compound having the general formula (VI) with a compound having the general formula (XXII) in the presence of a base in a solvent. Is called.

Step D2 This step is a step of producing a compound having the general formula (XXXV).

In this step, a compound having the general formula (XXXIV) is converted into benzyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl in a solvent in the presence of a palladium catalyst and an inorganic base. ) -1H-pyrrole-2-carboxylate.

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

Step D3 This step is a step of producing a compound having the general formula (XIII).

This step is performed in the same manner as in Step C7 of Method C above by reacting a compound having the general formula (XXXV) in a solvent in a hydrogen atmosphere in the presence of a palladium catalyst.

Method E is a method for producing a compound having the general formula (XIII) used in the above-mentioned Method A, Step A9.

In the present invention, R ⁸ , R ^2a , R ^3a , X and Y have the same meaning as described above.

Step E1 This step is a step of producing a compound having the general formula (XXXVI).

This step comprises reacting a compound having the general formula (XXV) obtained in the above-mentioned Method C, Step C3 with a compound having the general formula (X) in a solvent in the presence of a palladium catalyst and an inorganic base. This is performed in the same manner as in step A6 of method A.

Step E2 This step is a step of producing a compound having the general formula (XXXVII).

This step is performed in the same manner as in Step A7 of Method A above by reacting a compound having the general formula (XXXVI) with an acid in a solvent.

Step E3 This step is a step of producing a compound having the general formula (XXXVIII).

This step is carried out in the same manner as in Step A2 of Method A above by reacting a compound having the general formula (XXXVII) with a compound having the general formula (IV) in the presence of a base in a solvent.

Step E4 This step is a step of producing a compound having the general formula (XIII).

This step is performed in the same manner as in Step A8 of Method A above by reacting a compound having the general formula (XXXVIII) with a base in a solvent.

Method F is a method for producing a compound having the general formula (XIII) used in the above-mentioned Method A, Step A9.

In the present invention, R ^2a , R ^3a and Y have the same meaning as described above.

Step F1 This step is a step of producing a compound having the general formula (XXXV).

In this step, the compound having the general formula (XXVIII) obtained in the above-mentioned Method C, Step C5 is reacted with the compound having the general formula (IV) in a solvent in the presence of a base, thereby This is performed in the same manner as in step A2.

Step F2 This step is a step of producing a compound having the general formula (XIII).

Method G is a method for producing a compound having the general formula (XVIII) used in Method B, Step B4.

In the present invention, R ^2a , X and Y are as defined above.

Step G1 This step is the step of producing compound (XXXIX).

This step comprises reacting the compound having the general formula (III) obtained in Step A1 Step A1 with bis (pinacolato) diboron in a solvent in the presence of a palladium catalyst and an inorganic base. This is performed in the same manner as in step A4.

Step G2 This step is a step of producing compound (XL).

This step is carried out in the same manner as in Step A6 of Method A above by reacting compound (XXXIX) with a compound having the general formula (XXVI) in the presence of a palladium catalyst and an inorganic base in a solvent.

Step G3 This step is a step of producing a compound having the general formula (XLI).

This step is performed in the same manner as in Step A2 of Method A above by reacting compound (XL) with a compound having the general formula (IV) in a solvent in the presence of a base.

Step G4 This step is a step of producing a compound having the general formula (XLII).

This step is performed in the same manner as in Step A7 of Method A above by reacting a compound having the general formula (XLI) with an acid in a solvent.

Step G5 This step is a step of producing a compound having the general formula (XVIII).

This step is performed in the same manner as in Step C7 of Method C above by reacting a compound having the general formula (XLII) in the presence of a palladium catalyst in a solvent under a hydrogen atmosphere.

Method H is a method for producing a compound having the general formula (XXVIII) used in Step C6 of Method C.

In the present invention, R ^3a and X are as defined above.

Step H1 This step is a step of producing a compound having the general formula (XXVIII).

In this step, in the presence of a palladium catalyst and an inorganic base in a solvent, the compound having the general formula (XXIV) obtained in the above-mentioned Method C, Step C2 is converted to benzyl 5- (4,4,5,5-tetramethyl-1, The reaction is carried out in the same manner as in Step D2 of Method D above by reacting with 3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate.

Method I is a method for producing a compound having the general formula (XXIV) used in the above-mentioned Method C, Step C3.

In the present invention, R ^3a and X are as defined above.

Step I1 This step is a step of producing a compound having the general formula (XLIV).

In this step, the compound having the general formula (XLIII) is reacted with the compound having the general formula (IV) in the presence of triphenylphosphine and diethyl azodicarboxylate in a solvent, whereby the A5 of the above method A It is performed in the same manner as the process.

The compound having the general formula (XLIII) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.

Step I2 This step is a step of producing a compound having the general formula (XXIV).

This step is performed by reacting a compound having the general formula (XLIV) with trimethyl borate in a solvent in the presence of a base, and further with acetic acid and an oxidizing agent.

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

The base used in this step is preferably an organometallic base, and more preferably n-butyllithium.

The oxidizing agent used in this step is preferably an inorganic oxidizing agent, and more preferably 30% hydrogen peroxide solution.

The reaction temperature in this step is usually −120 ° C. to 40 ° C., preferably −78 ° C. to 25 ° C.

The reaction time in this step is usually 1 hour to 48 hours, preferably 6 hours to 24 hours.

Method J is a method for producing a compound having the general formula (Ie) in which U is a carbonyl group among the compounds having the general formula (I).

In the present invention, R ² , R ³ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ^2a , R ^9a , R ^10a , R ^11a , R ^12a , X and Y are the same as described above. Show significance.

Step J1 This step is a step of producing a compound having the general formula (XLVI).

This step is performed in the same manner as in Step A2 of Method A above by reacting a compound having the general formula (XLV) with a compound having the general formula (IV) in a solvent in the presence of a base.

The compound having the general formula (XLV) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.

Step J2 This step is a step of producing a compound having the general formula (XLVIII).

This step is performed by reacting a compound having the general formula (XLVI) with a compound having trifluoromethanesulfonic anhydride (XLVII) in a solvent in the presence of a base.

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

The reaction time in this step is usually 0.5 to 12 hours, preferably 1 to 6 hours.

Step J3 This step is a step of producing a compound having the general formula (XLIX).

This step is carried out in the same manner as in Step A4 of Method A above by reacting a compound having the general formula (XLVIII) with bis (pinacolato) diboron in the presence of a palladium catalyst and an inorganic base in a solvent.

Step J4 This step is a step of producing a compound having the general formula (L).

In this step, the compound having the general formula (XLIX) is reacted with the compound having the general formula (XXVI) in the presence of a palladium catalyst and an inorganic base in a solvent in the same manner as in Step A6 of the above Method A. Done.

Step J5 This step is a step of producing a compound having the general formula (LI).

This step is performed in the same manner as in Step A7 of Method A above by reacting a compound having the general formula (L) with an acid in a solvent.

Step J6 This step is a step of producing a compound having the general formula (LII).

This step is performed in the same manner as in Step C7 of Method C above by reacting a compound having the general formula (LI) in a solvent in a hydrogen atmosphere in the presence of a palladium catalyst.

Step J7 This step is a step of producing a compound having the general formula (LIII).

This step is performed by reacting a compound having the general formula (LII) with a compound having the general formula (XIV) in a solvent in the presence of a condensing agent or in the presence or absence of a base. Performed in the same manner as in step A9.

Step J8 This step is a step of producing a compound having the general formula (LIV).

In this step, the compound having the general formula (LIII) is reacted with a base and methanesulfonic anhydride or bis (2-methoxyethyl) aminosulfur trifluoride in a solvent to obtain the step A10 of the above-mentioned method A; The same is done.

Step J9 This step is a step of producing a compound having the general formula (Ie).

In this step, R ⁸ O of the compound having the general formula (LIV) is converted to R ^3a (R ^3a is as defined above), and then R ^2a , R ^3a , R ^{9a as} desired. , R ^10a , R ^11a and R ^12a are carried out by removing the protective group for the amino group, hydroxy group and / or carboxyl group.

The L method described below is an example of the J9th step.

Method K is a method for producing a compound having the general formula (Ie) in which U is a carbonyl group among the compounds having the general formula (I).

Step K1 This step is a step of producing a compound having the general formula (LVII).

This step is performed by reacting 3,5-dimethoxybenzaldehyde (LV) with a compound having the general formula (LVI) in a solvent.

The compound having the general formula (LVI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.

The reaction temperature in this step is usually −110 ° C. to 40 ° C., preferably −80 ° C. to 25 ° C.

Step K2 This step is a step of producing a compound having the general formula (LVIII).

This step is performed by reacting a compound having the general formula (LVII) with an oxidizing agent in a solvent.

The oxidizing agent used in this step is preferably an inorganic oxidizing agent, and more preferably manganese dioxide.

The reaction temperature in this step is usually 0 ° C. to 60 ° C., preferably 25 ° C. to 40 ° C.

The reaction time in this step is usually 6 hours to 72 hours, preferably 12 hours to 36 hours.

Step K3 This step is a step of producing a compound having the general formula (LIX).

This step is performed in the same manner as in Step A1 of Method A above by reacting a compound having the general formula (LVIII) with a demethylating agent in a solvent.

Step K4 This step is a step of producing a compound having the general formula (LX).

This step is performed in the same manner as in Step A2 of Method A above by reacting a compound having the general formula (LIX) with a compound having the general formula (IV) in a solvent in the presence of a base.

Step K5 This step is a step of producing a compound having the general formula (LXI).

This step is performed in the same manner as in Step A3 of Method A above by reacting a compound having the general formula (LX) with a demethylating agent in a solvent.

Step K6 This step is a step of producing a compound having the general formula (LXII).

In this step, the compound having the general formula (LXI) is reacted with the compound having trifluoromethanesulfonic anhydride (XLVII) in the presence of a base in a solvent in the same manner as in Step J2 of Method J above. Done.

Step K7 This step is a step of producing a compound having the general formula (LXIII).

This step is performed in the same manner as in Step A4 of Method A above by reacting a compound having the general formula (LXII) with bis (pinacolato) diboron in the presence of a palladium catalyst and an inorganic base in a solvent.

Step K8 This step is a step of producing a compound having the general formula (LXIV).

In this step, the compound having the general formula (LXIII) is reacted with the compound having the general formula (XXVI) in the presence of a palladium catalyst and an inorganic base in a solvent in the same manner as in Step A6 of Method A above. Done.

Step K9 This step is a step of producing a compound having the general formula (LXV).

This step is performed in the same manner as in Step A7 of Method A above by reacting a compound having the general formula (LXIV) with an acid in a solvent.

Step K10 This step is a step of producing a compound having the general formula (LXVI).

This step is performed in the same manner as in Step C7 of Method C above by reacting a compound having the general formula (LXV) in a solvent in a hydrogen atmosphere in the presence of a palladium catalyst.

Step K11 This step is a step of producing a compound having the general formula (LXVII).

This step comprises reacting a compound having the general formula (LXVI) with a compound having the general formula (XIV) in a solvent in the presence of a condensing agent, in the presence or absence of a base, Performed in the same manner as in step A9.

Step K12 This step is a step of producing a compound having the general formula (Ie).

In this step, the compound having the general formula (LXVII) is reacted with a base and methanesulfonic anhydride or bis (2-methoxyethyl) aminosulfur trifluoride in a solvent to obtain the step A10 of the above-mentioned method A; The same is done.

Method L is a method for producing a compound having the general formula (If) wherein U is a carbonyl group and R ³ is a group represented by the formula —NR ⁴ R ⁵ among the compounds having the general formula (I). It is.

In the present invention, R ² , R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ^2a , R ^9a , R ^10a , R ^11a and R ^12a are as defined above. R ^4a and R ^{5a each} represents an amino group contained as a substituent in the groups of R ⁴ and R ⁵ which may be protected, and groups in the definition of the groups of R ⁴ and R ^5. Similar groups are shown.

Step L1 This step is a step of producing a compound having the general formula (LXVIII).

This step is performed by reacting a compound having the general formula (LIV) obtained in the above-mentioned J method, step J8, with a base in a solvent.

The solvent used in this step is preferably ethers or alcohols, and more preferably tetrahydrofuran or ethanol.

The base used in this step is preferably an alkali metal hydroxide, more preferably sodium hydroxide or lithium hydroxide, and still more preferably an aqueous sodium hydroxide solution or hydroxide. Lithium aqueous solution.

The reaction temperature in this step is usually 0 ° C. to 100 ° C., preferably 25 ° C. to 70 ° C.

The reaction time in this step is usually 0.5 to 24 hours, preferably 1 to 12 hours.

Step L2 This step is a step of producing a compound having the general formula (If).

In this step, a compound having the general formula (LXVIII) is reacted with a compound having the general formula (LXIX) in a solvent in the presence of a condensing agent, in the presence or absence of a base, and then optionally R ^2a , R ^4a , R ^5a , R ^9a , R ^10a , R ^11a and R ^12a are carried out by removing amino, hydroxy and / or carboxyl protecting groups.

The compound having the general formula (LXIX) used in this step is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.

The solvent used in this step is preferably amides, alcohols or halogenated hydrocarbons, and more preferably N, N-dimethylformamide, methanol or dichloromethane.

The condensing agent used in this step is preferably WSCI · HCl, DMT-MM or HATU.

The base used in this step is preferably an organic base, and more preferably triethylamine, diisopropylethylamine or a combination of triethylamine and 4-dimethylaminopyridine.

The reaction time in this step is usually 1 hour to 72 hours, preferably 6 hours to 36 hours.

Method M is a method for producing a compound having the general formula (LI) used in the J method, J6 step.

In the present invention, R ⁸ and R ^2a have the same meaning as described above.

Step M1 This step is a step of producing a compound having the general formula (LI).

In this step, a compound having the general formula (XLVIII) obtained in the above-mentioned Method J, Step J2 in the presence of a palladium catalyst and an inorganic base in a solvent is converted to benzyl 5- (4,4,5,5-tetramethyl-1, The reaction is carried out in the same manner as in Step D2 of Method D above by reacting with 3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate.

Method N is a method for producing a compound having the general formula (X) used in Method A, Step A6, Method B, Step B2, and Method E, Step E1.

In the present invention, R ⁸ and X are as defined above.

Step N1 This step is a step of producing a compound having the general formula (LXXI).

This step is performed by reacting a compound having the general formula (LXX) with a halogenating agent in a solvent.

The compound having the general formula (LXX) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.

The solvent used in this step is preferably ethers or a mixed solvent of ethers and alcohols, more preferably tetrahydrofuran or a mixed solvent of tetrahydrofuran and methanol.

The halogenating agent used in this step is, for example, an inorganic acid such as hydrochloric acid, hydrogen bromide or hydrogen iodide; a halogen molecule such as chlorine, bromine or iodine, or N-chlorosuccinimide, N-bromo. Succinimides such as succinimide and N-iodosuccinimide, preferably succinimide, and more preferably N-bromosuccinimide.

The reaction time in this step is usually 0.5 to 48 hours, preferably 1 to 24 hours.

Step N2 This step is a step of producing a compound having the general formula (X).

This step is performed by reacting a compound having the general formula (LXXI) with di-t-butyl dicarbonate in the presence of a base in a solvent.

The base used in this step is preferably an organic base, more preferably triethylamine, 4-dimethylaminopyridine, or a mixed base thereof, and still more preferably triethylamine and 4-dimethyl. A mixed base of aminopyridine.

Method O is a method for producing a compound having the general formula (XXVI) used in Step C, Step C4, Method G, Step G2, Step J, Step J4 and Method K, Step K8.

In the present invention, X has the same meaning as described above.

Step O1 This step is a step of producing a compound having the general formula (LXXIII).

This step is carried out in the same manner as the Nth step of the N method by reacting pyrrole-1-carboxylate t-butyl (LXXII) with a halogenating agent in a solvent.

The pyrrole-1-carboxylic acid t-butyl (LXXII) used in this step is easily produced according to a known method or a similar method using a known compound as a starting material.

Step O2 This step is a step of producing a compound having the general formula (XXVI).

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

The compound having the general formula (LXXIV) used in this step is a known compound, or is easily produced according to a known method or a similar method using the known compound as a starting material.

Method P is benzyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl used in Method D, Step D2, Method H, Step H1 and Method M, Step M1. ) -1H-pyrrole-2-carboxylate (LXXVIII).

In the present invention, Y has the same meaning as described above.

Step P1 This step is a step for producing benzyl 1H-pyrrole-2-carboxylate (LXXVII).

This step is performed by reacting pyrrole-2-carboxylic acid (LXXV) with a compound having the general formula (LXXVI) in a solvent in the presence of a base.

The pyrrole-2-carboxylic acid (LXXV) used in this step is easily produced according to a known method or a similar method using a known compound as a starting material.

The compound having the general formula (LXXVI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.

The reaction temperature in this step is usually −10 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.

Step P2 This step is a step for producing benzyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate (LXXVIII). .

In this step, benzyl 1H-pyrrole-2-carboxylate (LXXVII) is converted to bis (pinacolato) diboron in the presence of an iridium catalyst and 4,4′-di-t-butyl-2,2′-dipyridyl in a solvent. By reacting with.

The solvent used in this step is preferably a hydrocarbon, and more preferably hexane.

The iridium catalyst used in this step is preferably methoxy (cyclooctadiene) iridium (I) dimer.

The reaction temperature in this step is usually 0 ° C. to 70 ° C., preferably 25 ° C. to 60 ° C.

The reaction time in this step is usually 0.1 to 12 hours, preferably 0.5 to 6 hours.

Method Q is a method for producing a compound having the general formula (Id) in which U is an oxygen atom among the compounds having the general formula (I).

In the present invention, R ² , R ³ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ^2a , R ^3a , R ^9a , R ^10a , R ^11a , R ^12a and Y are as described above. Shows the same significance.

Step Q1 This step is a step of producing a compound having the general formula (LXXX).

In this step, in the presence of a condensing agent and a base in a solvent, the compound having the general formula (XIII) obtained in the above-mentioned Method A, Step A8 is reacted with a compound having the general formula (LXXIX), thereby This is carried out in the same manner as in step A9 of the law.

The compound having the general formula (LXXIX) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.

Step Q2 This step is a step of producing a compound having the general formula (Id).

In this step, a compound having the general formula (LXXX) is reacted with a base in a solvent, and then optionally, an amino group, a hydroxy group, and R ^2a , R ^3a , R ^9a , R ^10a , R ^11a and R ^12a It is carried out by removing the protecting group of the carboxyl group.

The base used in this step is preferably an alkali metal hydride, and more preferably sodium hydride.

Method R is a method for producing a compound having the general formula (LI) used in Method J, Step J6.

In the present invention, R ⁸ , R ^2a and X are as defined above.

Step R1 This step is a step of producing a compound having the general formula (LXXXII).

In this step, a compound having the general formula (LXXXI) is converted into benzyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl in a solvent in the presence of a palladium catalyst and an inorganic base. ) By reacting with -1H-pyrrole-2-carboxylate, the reaction is performed in the same manner as in Step D2 of Method D above.

The compound having the general formula (LXXXI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.

Step R2 This step is a step of producing a compound having the general formula (LI).

This step is performed by reacting a compound having the general formula (LXXXII) with a compound having the general formula (LXXXIII) in the presence of a copper catalyst, a base and molecular sieves 4A in a solvent.

The compound having the general formula (LXXXIII) used in this step is a known compound, or is easily produced according to a known method or a similar method using the known compound as a starting material.

The copper catalyst used in this step is preferably copper (II) acetate.

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

The reaction time in this step is usually 12 hours to 360 hours, preferably 24 hours to 240 hours.

Method S is a method for producing a compound having the general formula (LXVI) used in Method K, Step K11.

In the present invention, R ^2a and R ^3a have the same meaning as described above.

Step S1 This step is a step of producing a compound having the general formula (LXXXIV).

In this step, a compound having the general formula (LXII) obtained in Step K6, Step K6 in the presence of a palladium catalyst and an inorganic base in a solvent is converted to methyl 5- (4,4,5,5-tetramethyl-1, Performed by reacting with 3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate.

Step S2 This step is a step of producing a compound having the general formula (LXVI).

This step is performed by reacting a compound having the general formula (LXXXIV) with a base in a solvent.

The base used in this step is preferably an alkali metal hydroxide, more preferably lithium hydroxide, and even more preferably an aqueous lithium hydroxide solution.

Method T is a method for producing a compound having the general formula (LXXXIV) used in Step S2 of Method S.

In the present invention, R ^2a , R ^3a and X are as defined above.

Step T1 This step is a step of producing a compound having the general formula (LXXXVII).

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

The compound having the general formula (LXXXV) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.

The compound having the general formula (LXXXVI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.

The base used in this step is preferably an alkali metal carbonate, and more preferably cesium carbonate.

The reaction temperature in this step is usually 60 ° C to 180 ° C, preferably 100 ° C to 150 ° C.

The reaction time in this step is usually 1 hour to 48 hours, preferably 12 hours to 36 hours.

Step T2 This step is a step of producing a compound having the general formula (LXXXIV).

In this step, a compound having the general formula (LXXXVII) is converted into methyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl in a solvent in the presence of a palladium catalyst and an inorganic base. ) By reacting with -1H-pyrrole-2-carboxylate, the reaction is carried out in the same manner as in Step S1 of Method S.

Method U is a method for producing a compound having the general formula (LXXXIV) used in Step S2 of Method S.

Step U1 This step is a step of producing a compound having the general formula (LXXXIX).

This step is performed by reacting a compound having the general formula (LXXXVIII) with acetic anhydride in the presence of an acid.

The compound having the general formula (LXXXVIII) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.

Examples of the acid used in this step include hydrogen halides such as hydrogen chloride gas and hydrogen bromide gas; mineral acids such as sulfuric acid, hydrobromic acid and hydrochloric acid; acetic acid, formic acid and trifluoroacetic acid. Carboxylic acids, preferably mineral acids, and more preferably sulfuric acid.

Step U2 This step is a step of producing a compound having the general formula (LXL).

This step is performed by reacting a compound having the general formula (LXXXIX) with a chlorinating agent.

The chlorinating agent used in this step is, for example, an inorganic acid such as hydrochloric acid; a halogen molecule such as chlorine; a phosphorus reagent such as phosphorus trichloride, phosphorus pentachloride, or phosphorus oxychloride; Oxalic acid chlorides; sulfinic acid reagents such as thionyl chloride; or sulfonic acid reagents such as sulfonyl chloride and toluenesulfonic acid chloride, preferably sulfinic acid reagents or oxalate chlorides More preferred is thionyl chloride or oxalyl chloride, and even more preferred is thionyl chloride.

The reaction temperature in this step is usually −20 ° C. to 100 ° C., preferably 25 ° C. to 80 ° C.

Step U3 This step is a step of producing a compound having the general formula (LXLII).

This step is performed by reacting a compound having the general formula (LXL) with a compound having the general formula (LXLI) in a solvent.

The compound having the general formula (LXLI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.

Step U4 This step is a step of producing a compound having the general formula (LXLIII).

In this step, a compound having the general formula (LXLII) is converted into methyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl in a solvent in the presence of a palladium catalyst and an inorganic base. ) By reacting with -1H-pyrrole-2-carboxylate, the reaction is carried out in the same manner as in Step S1 of Method S.

Step U5 This step is a step of producing a compound having the general formula (LXXXIV).

This step is performed in the same manner as in Step A2 of Method A above by reacting a compound having the general formula (LXLIII) with a compound having the general formula (IV) in a solvent in the presence of a base.

In the above, R ^2a , R ^3a , R ^4a , R ^5a , R ^9a , R ^10a , R ^11a and R ^{12a in} the definition of “amino group which may be protected”, “hydroxy group which may be protected” and “ The protecting group of “optionally protected carboxyl group” means a protecting group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis, and is generally used in organic synthetic chemistry. Protecting groups are indicated (see, for example, TW Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)).

In the above, “protective group” of “optionally protected hydroxy group” in the definition of R ^2a , R ^3a , R ^9a , R ^10a , R ^11a and R ^12a is a hydroxy group used in the field of synthetic organic chemistry The protecting group is not particularly limited, and examples thereof include a formyl group, the “C ₂ -C ₇ alkylcarbonyl group”, the “C ₂ -C ₇ halogenated alkylcarbonyl group”, and an alkoxyalkyl such as methoxyacetyl. “Alkylcarbonyl groups” such as carbonyl groups, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, unsaturated alkylcarbonyl groups such as (E) -2-methyl-2-butenoyl; benzoyl, α-naphthoyl, β-naphthoyl Arylcarbonyl groups such as 2-bromobenzoyl, 4-chloro Halogenated arylcarbonyl groups such as Nzoiru, 2,4,6-trimethylbenzoyl, _4-C 1 -C ₆ alkylated ants such as toluoyl - ylcarbonyl group, _C 1 -C ₆ alkoxy such as 4-anisoyl Arylcarbonyl groups, 4-nitrobenzoyl, nitrated arylcarbonyl groups such as 2-nitrobenzoyl, C ₂ -C ₇ alkoxycarbonylated arylcarbonyl groups such as 2- (methoxycarbonyl) benzoyl, 4-phenylbenzoyl An “arylcarbonyl group” such as an arylated arylcarbonyl group; a halogen such as the aforementioned “C ₂ -C ₇ alkoxycarbonyl group”, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, or tri- ( C ₁ -C ₆ alkyl) silyl An “alkoxycarbonyl group” such as a C ₂ -C ₇ alkoxycarbonyl group substituted with a group; tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothio “Tetrahydropyranyl or tetrahydrothiopyranyl group” such as pyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; “tetrahydrofuranyl such as tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl” or tetrahydrothiofuranyl group "; trimethylsilyl, triethylsilyl, isopropyl dimethylsilyl, t- butyl dimethylsilyl, methyl diisopropylsilyl, methyldi -t- butylsilyl, tri as triisopropylsilyl - (C ₁ -C ₆ alkyl) "Silyl groups such as (C ₁ -C ₆ alkyl) aryl silyl group - Lil group, diphenylmethyl silyl, diphenyl butylsilyl, diphenyl isopropylsilyl, (C ₁ -C ₆ alkyl) diarylsilyl or di- such as phenyl diisopropylsilyl A (C ₁ -C ₆ alkoxy) methyl group such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, 2-methoxy such as ethoxymethyl _(C 1 -C ₆ alkoxy) - _(C 1 -C ₆ alkoxy) methyl group, 2,2,2-trichloroethoxymethyl, such as bis (2-chloroethoxy) methyl _{(C 1} - C ₆ halogenated alkoxy) "alkoxymethyl group" such as methyl; 1 Ethoxyethyl, 1- (isopropoxy) such as ethyl _(C 1 -C ₆ alkoxy) ethyl group, "substituted ethyl group" such as a halogenated ethyl group such as 2,2,2-trichloroethyl; benzyl, alpha A C ₁ -C ₆ alkyl group substituted by 1 to 3 aryl groups such as naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl , 4-bromobenzyl, C ₁ -C ₆ alkyl such as 4-cyanobenzyl, C ₁ -C ₆ alkoxy, nitro (B) an aralkyl group such as a C ₁ -C ₆ alkyl group substituted with 1 to 3 aryl groups in which the aryl ring is substituted with a halogen, cyano group; vinyloxycarbonyl, allyloxycarbonyl Such as “alkenyloxycarbonyl group”; 1 or 2 such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl An “aralkyloxycarbonyl group” in which the aryl ring may be substituted with a C ₁ -C ₆ alkoxy group or a nitro group, preferably an alkylcarbonyl group, a silyl group, or an aralkyl group.

In the above, “protective group” of “optionally protected carboxyl group” in the definition of R ^2a , R ^3a , R ^9a , R ^10a , R ^11a and R ^12a is a carboxyl group used in the field of synthetic organic chemistry The protecting group is not particularly limited, but for example, the “C ₁ -C ₆ alkyl group”; the “C ₂ -C ₆ alkenyl group”; ethynyl, 1-propynyl, 2-propynyl, 1-methyl- A C ₂ -C ₆ alkynyl group such as 2-propynyl and 1-butynyl; the aforementioned “C ₁ -C ₆ halogenated alkyl group”; a C ₁ -C ₆ hydroxyalkyl group such as hydroxymethyl and 2-hydroxyethyl; (C ₂ -C ₇ alkylcarbonyl)-(C ₁ -C ₆ alkyl group) such as acetylmethyl; said “aralkyl group”; or “silyl group” And preferably a C ₁ -C ₆ alkyl group or an aralkyl group.

In the above, “protecting group” of “amino group which may be protected” in the definition of R ^2a , R ^3a , R ^4a , R ^5a , R ^9a , R ^10a , R ^11a and R ^12a is a field of synthetic organic chemistry. There is no particular limitation as long as it is an amino-protecting group used in the above, for example, “alkylcarbonyl group”; “arylcarbonyl group”; “alkoxycarbonyl group”; A group similar to the “aralkyloxycarbonyl group” or N, N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, Salicylidene, 5-chlorosalicylidene, diphenylmethylene, (5-chloro-2-hydroxyphenyl) E) a “substituted methylene group forming a Schiff base” such as phenylmethylene, preferably an alkylcarbonyl group, an arylcarbonyl group or an alkoxycarbonyl group, and more preferably an alkoxycarbonyl group .

Processes that require protection / deprotection are described in known methods (eg “Protective Groups Organic Synthesis” (written by Theodora W. Greene, Peter G. M.Wuts, W1999, published by Wiley-Interscience Publication)). Method).

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

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

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

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

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

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

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

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

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

Elution in the column chromatography of the examples was performed under observation by TLC (Thin Layer Chromatography). In the TLC observation, the TLC plate silica gel 60F ₂₅₄ manufactured by Merck or the NH-TLC plate manufactured by Fuji Silysia Chemical Co. was used as the TLC plate, and the solvent used as the elution solvent in the column chromatography was used as the detection method. A UV detector was adopted. As silica gel for the column, silica gel SK-85 (230-400 mesh) manufactured by Merck or silica gel FL100B manufactured by Fuji Silysia Chemical Ltd. was used. In addition to the usual column chromatography, an automatic chromatography device (Purif-α2) manufactured by Moritex and a disposable column (Purif-pack SI series or NH series) were appropriately used. The purification by preparative TLC manufactured by Merck silica gel _60F 254, 0.5 mm thick, was used plates 20 × 20 cm. The abbreviations used in the examples have the following significance.
mg: milligram, g: gram, mL: milliliter, MHz: megahertz, HATU: O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate WSCI.HCl: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HOBT.H ₂ O: 1-hydroxybenzotriazole monohydrate, DMT-MM: 4- (4,6-dimethoxy -1,3,5-triazin-2-yl) -4-methylmorpholinium chloride n hydrate.

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

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

Example 1
2- [5- (3-{[(2S) -1-fluoropropan-2-yl] oxy} -5- [4- (methylsulfonyl) phenoxy] phenyl) -1H-pyrrol-2-yl] -4 , 5-Dihydro-1,3-oxazole

(1a) 3-Bromo-5-methoxyphenol 1-Bromo-3,5-dimethoxybenzene (18.74 g, 86.3 mmol) was dissolved in 1-methyl-2-pyrrolidone (100 mL), and sodium thiomethoxide ( 6.74 g, 96.2 mmol) was added, and the mixture was stirred at 100 ° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 1N hydrochloric acid (200 mL) was added, and the mixture was extracted with diethyl ether (500 mL). The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% to 25%) to give the target compound (15.03 g, Yield 86%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ3.77 (3H, s), 4.82 (1H, s), 6.33 (1H, t, J = 2.4 Hz), 6.61 (1H, t, J = 2.0 Hz) , 6.66 (1H, t, J = 2.0 Hz).
(1b) 1-Bromo-3-methoxy-5- [4- (methylsulfonyl) phenoxy] benzene The compound synthesized in Example (1a) (10.45 g, 60.0 mmol) was converted to N, N-dimethylformamide (100 mL). ), Potassium carbonate (25.00 g, 181 mmol) was added, and the mixture was stirred at 100 ° C. for 36 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, potassium carbonate was removed by celite filtration, 0.1N hydrochloric acid (500 mL) was added, and the mixture was extracted twice with diethyl ether (400 mL) and ethyl acetate (100 mL). The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting solid was washed with diethyl ether to obtain the target compound (18.30 g, yield 79%) as a light brown solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ3.07 (3H, s), 3.80 (3H, s), 6.56 (1H, t, J = 2.4 Hz), 6.81 (1H, t, J = 2.0 Hz) , 6.92 (1H, t, J = 2.0 Hz), 7.12 (2H, d, J = 9.0 Hz), 7.92 (2H, d, J = 9.0 Hz).
(1c) 3-Bromo-5- [4- (methylsulfonyl) phenoxy] phenol The compound (18.29 g, 51.2 mmol) synthesized in Example (1b) was dissolved in methylene chloride (400 mL) and dissolved at −78 ° C. Then, boron tribromide (1.0 mol / L methylene chloride solution, 100 mL, 100 mmol) was added over 30 minutes using a dropping funnel under a nitrogen atmosphere. After stirring at −78 ° C. for 2 hours, the temperature was naturally raised and stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added while cooling in an ice bath to neutralize the reaction solution, and the mixture was extracted twice with a mixed solvent of methylene chloride (500 mL) and methanol (50 mL). The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound (16.89 g, yield 96%) as a pale yellow solid.
¹ H-NMR (DMSO-D ₆ , 400 MHz): δ 3.19 (3H, s), 6.49 (1H, t, J = 2.1 Hz), 6.77 (1H, t, J = 2.0 Hz), 6.84 (1H, t, J = 2.0 Hz), 7.23 (2H, d, J = 8.6 Hz), 7.94 (2H, d, J = 9.0 Hz), 10.27 (1H, s).

(1d) 3- [4- (Methylsulfonyl) phenoxy] -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol Synthesized in Example (1c) The compound (10.10 g, 29.4 mmol) was dissolved in N, N-dimethylformamide (100 mL) and bis (pinacolato) diboron (11.09 g, 43.7 mmol), [1,1′-bis (diphenylphosphino) ) Ferrocene] palladium (II) dichloride A dichloromethane complex (722 mg, 0.884 mmol) and potassium acetate (14.92 g, 152 mmol) were added, and the mixture was stirred at 90 ° C. for 5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (400 mL), and insolubles were removed by celite filtration. Water (400 mL) was added to the filtrate for liquid separation, and the organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 30% -50%) to give the target compound (11.88 g, Yield ˜100%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.33 (12H, s), 3.06 (3H, s), 5.16 (1H, s), 6.69 (1H, t, J = 2.4 Hz), 7.06-7.12 (4H , m), 7.87 (2H, t, J = 9.0 Hz).
(1e) 2- {3-[(1S) -2-methoxy-1-methylethoxy] -5- [4- (methylsulfonyl) phenoxy] phenyl} -4,4,5,5-tetramethyl-1, 3,2-Dioxaborolane The compound (13.20 g, 33.8 mmol) synthesized in Example (1d) was dissolved in tetrahydrofuran (300 mL), and (R)-(−)-1-methoxy-2-propanol (3. 70 mL, 37.8 mmol) and triphenylphosphine (9.78 g, 37.3 mmol) were added and cooled to 0 ° C. Under a nitrogen atmosphere, diethyl azodicarboxylate (40% toluene solution, 16.2 mL, 37.2 mmol) was added dropwise over 10 minutes, stirred at 0 ° C. for 30 minutes, then allowed to warm naturally and stirred overnight at room temperature. . Water (300 mL) and ethyl acetate (300 mL) were added for liquid separation. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 20% -40%) to give the desired compound (11.94 g, Yield 76%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.31 (3H, d, J = 6.7 Hz), 1.33 (12H, s), 3.05 (3H, s), 3.40 (3H, s), 3.48 (1H, dd, J = 10.2, 4.3 Hz), 3.57 (1H, dd, J = 10.2, 5.9 Hz), 4.58-4.62 (1H, m), 6.76 (1H, t, J = 2.4 Hz), 7.05-7.09 (3H , m), 7.24 (1H, d, J = 2.4 Hz), 7.87 (2H, d, J = 9.0 Hz).
(1f) Ethyl 5-bromo-1H-pyrrole-2-carboxylate Ethyl 1H-pyrrole-2-carboxylate (5.10 g, 30.7 mmol) was dissolved in a mixed solvent of tetrahydrofuran (120 mL) and methanol (60 mL). Cooled to 0 ° C. N-bromosuccinimide (6.52 g, 30.7 mmol) was added, and the mixture was stirred at room temperature for 18 hours under a nitrogen atmosphere. Water (150 mL) and ethyl acetate (200 mL) were added for liquid separation. 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 (elution solvent: ethyl acetate / hexane = 5% -30%) to give the target compound (3.20 g, 3.20 g, Yield 40%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.36 (3H, t, J = 7.1 Hz), 4.32 (2H, q, J = 7.1 Hz), 6.21 (1H, dd, J = 3.9, 2.7 Hz) , 6.82 (1H, dd, J = 3.9, 2.7 Hz), 9.21 (1H, brs).

(1 g) 1-tert-butyl 2-ethyl 5-bromo-1H-pyrrole-1,2-dicarboxylate The compound synthesized in Example (1f) (3.20 g, 14.7 mmol) was dissolved in methylene chloride (100 mL). Di-t-butyl dicarbonate (3.85 g, 17.6 mmol), triethylamine (4.10 mL, 19.4 mmol) and 4-dimethylaminopyridine (180 mg, 1.47 mmol) were added, and the mixture was added at room temperature under a nitrogen atmosphere. For 1 hour. Water (100 mL) was added and extracted with methylene chloride (100 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 resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 20%) to give a colorless oily target compound (4.37 g, Yield 94%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.34 (3H, t, J = 7.0 Hz), 1.63 (9H, s), 4.30 (2H, q, J = 7.0 Hz), 6.23 (1H, d, J = 3.9 Hz), 6.83 (1H, d, J = 3.9 Hz).
(1h) 1-tert-butyl 2-ethyl 5- {3-[(1S) -2-methoxy-1-methylethoxy] -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-1 , 2-Dicarboxylate Compound (8.73 g, 18.9 mmol) synthesized in Example (1e) and compound (8.37 g, 26.3 mmol) synthesized in Example (1 g) were combined with toluene (180 mL). Dissolved in a mixed solvent of ethanol (77 mL), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (770 mg, 0.94 mmol), aqueous potassium carbonate solution (2 mol / L, 23. 7 mL, 47.2 mmol) was added and the mixture was stirred at 100 ° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (400 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: ethyl acetate / hexane = 10% -50%) to give the target compound (9.44 g) as a pale yellow oil. Yield 84%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.31 (3H, d, J = 6.3 Hz), 1.35 (3H, t, J = 7.0 Hz), 1.46 (9H, s), 3.05 (3H, s) , 3.39 (3H, s), 3.48 (1H, dd, J = 10.2, 4.3 Hz), 3.57 (1H, dd, J = 10.2, 5.9 Hz), 4.32 (2H, q, J = 7.0 Hz), 4.53 ( 1H, m), 6.22 (1H, d, J = 3.9 Hz), 6.65 (1H, m), 6.73 (1H, m), 6.88 (1H, m), 6.89 (1H, d, J = 3.9 Hz), 7.12 (1H, d, J = 9.0 Hz), 7.89 (2H, d, J = 9.0 Hz).
(1i) Ethyl 5- {3-[(1S) -2-methoxy-1-methylethoxy] -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2-carboxylate Example (1h) ) (9.44 g, 16.5 mmol) was dissolved in methylene chloride (90 mL) and cooled to 0 ° C. While stirring in a nitrogen atmosphere, trifluoroacetic acid (45 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the mixture was diluted with ethyl acetate (300 mL), and a saturated aqueous sodium hydrogen carbonate solution (200 mL) was added to separate the layers. 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: ethyl acetate / hexane = 10% -50%) to give the target compound (6.34 g) as a pale yellow solid. Yield 81%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.33 (3H, d, J = 6.3 Hz), 1.37 (2H, t, J = 7.0 Hz), 3.07 (3H, s), 3.41 (3H, s) , 3.51 (1H, dd, J = 10.2, 3.9 Hz), 3.60 (1H, dd, J = 10.2, 6.3 Hz), 4.34 (2H, q, J = 7.0 Hz), 4.58 (1H, m), 6.51 ( 1H, dd, J = 4.0, 2.5 Hz), 6.58 (1H, m), 6.86 (1H, m), 6.93 (1H, dd, J = 4.0, 2.5 Hz), 7.01 (1H, m), 7.13 (2H , d, J = 8.8 Hz), 7.91 (2H, d, J = 8.8 Hz), 9.41 (1H, brs).
MS (ESI) m / z: 474.16048 (M + H) ^<+> .

(1j) 5- {3-[(1S) -2-Methoxy-1-methylethoxy] -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2-carboxylic acid Example (1i) The compound synthesized in step (4.36 g, 9.2 mmol) was dissolved in ethanol (100 mL), 4N aqueous sodium hydroxide solution (23 mL, 92 mmol) was added, and the mixture was heated to reflux for 1 hour under a nitrogen atmosphere. The reaction solution was neutralized with 2N hydrochloric acid (45 mL), and the solvent was distilled off under reduced pressure. The mixture was acidified with 1N hydrochloric acid and extracted 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 to obtain the desired product (4.06 g, yield 99%) as a white solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.34 (3H, d, J = 6.3 Hz,), 3.07 (3H, s), 3.46 (3H, s), 3.55 (1H, dd, J = 10.4, 4.2 Hz), 3.66 (1H, dd, J = 10.5, 6.3 Hz), 4.70-4.75 (1H, m), 6.53 (1H, dd, J = 3.9, 2.6 Hz), 6.59 (1H, t, J = 2.0 Hz), 6.91 (1H, t, J = 1.6 Hz,), 7.04 (1H, dd, J = 3.9, 2.3 Hz), 7.25 (1H, m), 7.14 (2H, d, J = 8.9 Hz), 7.91 (2H, d, J = 8.8 Hz), 10.13 (1H, brs).
(1k) N- (2-chloroethyl) -5- {3-[(1S) -2-methoxy-1-methylethoxy] -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2 -Carboxamide Compound (150 mg, 0.34 mmol) synthesized in Example (1j), 2-chloroethylamine hydrochloride (78 mg, 0.68 mmol) and 4-dimethylaminopyridine (41 mg, 0.34 mmol) were dissolved in methylene chloride (15 mL). ), WSCI · HCl (71 mg, 0.37 mmol) was added at room temperature, and the mixture was stirred under a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with methylene chloride (150 mL), washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% to 60%) to give the desired product (105 mg, yield 62%) as a white solid. )
¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.33 (3H, d, J = 6.3 Hz), 3.07 (3H, s), 3.42 (3H, s), 3.51 (1H, dd, J = 10.3, 4.0 Hz ), 3.59 (1H, dd, J = 10.4, 6.1 Hz), 3.70 (2H, t, J = 5.4 Hz), 3.77 (2H, t, J = 5.4 Hz), 4.55-4.59 (1H, m), 6.26 -6.29 (1H, brm), 6.50 (1H, dd, J = 3.9, 2.9 Hz), 6.58 (1H, t, J = 2.2 Hz), 6.63 (1H, dd, J = 3.8, 2.5 Hz), 6.83 ( 1H, t, J = 1.7Hz), 6.99 (1H, t, J = 2.0 Hz), 7.14 (2H, d, J = 8.8 Hz), 7.91 (2H, d, J = 8.8 Hz), 9.52 (1H, brs).
(1l) 2- (5- {3-[(1S) -2-Methoxy-1-methylethoxy] -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrol-2-yl) -4 , 5-Dihydro-1,3-oxazole The compound synthesized in Example (1k) (177 mg, 0.349 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to 0 ° C. Sodium hydride (40 mg, 0.917 mmol) was added, and the mixture was warmed to room temperature and stirred for 19 hours. The reaction mixture was cooled to 0 ° C., water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 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 resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 50% to 100%) to give the target compound (118 mg, yield) as a white solid. 72%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.33 (3H, d, J = 6.3 Hz), 3.07 (3H, s), 3.41 (3H, s), 3.50 (1H, dd, J = 10.2, 3.9 Hz), 3.59 (1H, dd, J = 10.2, 6.3 Hz), 3.98 (2H, t, J = 9.4 Hz), 4.40 (2H, t, J = 9.4 Hz), 4.56 (1H, m), 6.50 ( 1H, d, J = 3.9 Hz), 6.56 (1H, brt, J = 2.0 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.83 (1H, brt, J = 2.0 Hz), 7.00 (1H, brt, J = 2.0 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.90 (2H, d, J = 9.0 Hz).
MS (ESI) m / z: 471.16050 (M + H) ^<+> .

(1m) (2S) -2- {3- [5- (4,5-Dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) ) Phenoxy] phenoxy} propan-1-ol The compound synthesized in Example (1l) (3.17 g, 6.74 mmol) was dissolved in methylene chloride (100 mL) and cooled to -78 ° C. Boron bromide (1.0 mol / L methylene chloride solution, 7.07 mL, 7.07 mmol) was added. The mixture was naturally warmed and stirred at room temperature for 30 minutes, and then a saturated aqueous sodium hydrogen carbonate solution was added to neutralize the reaction solution, followed by extraction with methylene chloride (200 mL). The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was washed with ethyl acetate (100 mL) and ethanol (50 mL) to obtain the desired product (1.96 g, yield 64%) as a white solid.
¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.29 (3H, d, J = 6.3 Hz), 3.06 (3H, s), 3.79 (2H, d, J = 5.9 Hz), 4.00 (2H, t, J = 9.3 Hz), 4.42 (2H, t, J = 9.4 Hz), 4.58-4.63 (1H, m), 6.40 (1H, t, J = 2.2 Hz), 6.47 (1H, d, J = 3.9 Hz) , 6.75 (1H, d, J = 3.8 Hz), 6.79 (1H, t, J = 1.7 Hz), 6.94 (1H, t, J = 1.8 Hz), 7.09 (2H, d, J = 8.8 Hz), 7.88 (2H, d, J = 8.8 Hz).
MS (ESI) m / z: 457.14357 (M + H) ⁺ .
(1n) 2- [5- (3-{[(2S) -1-fluoropropan-2-yl] oxy} -5- [4- (methylsulfonyl) phenoxy] phenyl) -1H-pyrrol-2-yl ] -4,5-dihydro-1,3-oxazole The compound synthesized in Example (1m) (80 mg, 0.175 mmol) was dissolved in methylene chloride (10.0 mL), and N, N-diethylaminosulfur trifluoride was dissolved. (0.05 mL, 0.378 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 2 and a half hours under a nitrogen atmosphere. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with methylene chloride (20 mL). The organic layer was washed with 1N aqueous sodium hydroxide solution (10 mL) and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% -75%) to give the target compound (48 mg, yield) as a white solid. 60%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.32 (3H, dd, J = 6.5, 1.4 Hz), 3.04 (3H, s), 3.97 (2H, t, J = 9.4 Hz), 4.38 (2H, t , J = 9.4 Hz), 4.43 (1H, d, J = 4.7 Hz), 4.54 (1H, d, J = 5.1 Hz), 4.60-4.68 (1H, m), 6.48 (1H, d, J = 3.9 Hz) ), 6.53 (1H, t, J = 2.2 Hz), 6.73 (1H, d, J = 3.9 Hz), 6.80 (1H, t, J = 1.8 Hz), 6.94 (1H, t, J = 1.8 Hz), 7.10 (2H, d, J = 9.0 Hz), 7.88 (2H, d, J = 9.0 Hz).
MS (ESI) m / z: 459.13825 (M + H) ^<+> .

(Example 2)
2- (5- {3- [4- (Methylsulfonyl) phenoxy] -5- (1-propen-2-yloxy) phenyl} -1H-pyrrol-2-yl) -4,5-dihydro-1,3 -Oxazole

(2a) (2S) -2- {3- [5- (4,5-Dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) ) Phenoxy] phenoxy} propyl methanesulfonate The compound (106 mg, 0.23 mmol) synthesized in Example (1m) was dissolved in tetrahydrofuran (5.0 mL), methanesulfonic anhydride (65 mg, 0.37 mmol), triethylamine ( 0.06 mL, 0.43 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (30 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 resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% to 100%) to give the target compound (109 mg, yield) as a white solid. 88%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.40 (3H, d, J = 6.3 Hz), 3.06 (3H, s), 3.08 (3H, s), 4.00 (2H, t, J = 9.4 Hz), 4.35 (2H, ddd, J = 21.6, 11.0, 5.2 Hz), 4.41 (2H, t, J = 9.4 Hz), 4.67-4.75 (1H, m), 6.52 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.0 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.86 (1H, t, J = 1.6 Hz), 6.98 (1H, t, J = 1.8 Hz), 7.14 (2H , dt, J = 9.4, 2.5 Hz), 7.92 (2H, dt, J = 9.4, 2.4 Hz).
(2b) 2- [5- (3-{[(2S) -1-iodopropan-2-yl] oxy} -5- [4- (methylsulfonyl) phenoxy] phenyl) -1H-pyrrol-2-yl ] -4,5-dihydro-1,3-oxazole The compound synthesized in Example (2a) (504 mg, 0.94 mmol) was dissolved in acetone (15.0 mL), and sodium iodide (320 mg, 2.13 mmol) was dissolved. Was added, and the mixture was stirred for one day with heating under reflux in a nitrogen atmosphere. Water (40 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (50 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 (elution solvent: ethyl acetate / hexane = 40-100%) to give the target compound (443 mg, yield 83) as a white solid. %).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.48 (3H, d, J = 6.3 Hz), 3.08 (3H, s), 3.32 (1H, dd, J = 10.4, 6.1 Hz), 3.39 (1H, dd , J = 10.4, 4.9 Hz), 4.00 (2H, t, J = 9.2 Hz), 4.40-4.44 (1H, m), 4.41 (2H, t, J = 9.6 Hz), 6.52 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.84 (1H, t, J = 1.8 Hz), 6.94 (1H, t, J = 1.8 Hz ), 7.14 (2H, dd, J = 6.6, 2.0 Hz), 7.92 (2H, dd, J = 6.6, 2.0 Hz).
(2c) 2- (5- {3- [4- (Methylsulfonyl) phenoxy] -5- (1-propen-2-yloxy) phenyl} -1H-pyrrol-2-yl) -4,5-dihydro- 1,3-oxazole The compound (93 mg, 0.16 mmol) synthesized in Example (2b) was dissolved in N, N-dimethylformamide (10.0 mL), sodium ethoxide (500 mg, 7.34 mmol) was added, The mixture was stirred at 80 ° C. for 1 day under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution (50 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (30 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 resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0-2%) to give the target compound (34 mg, yield 47) as a yellow solid. %).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.99 (3H, s), 3.07 (3H, s), 4.01 (2H, t, J = 9.2 Hz), 4.19 (1H, s), 4.33 (1H, s ), 4.43 (2H, t, J = 9.2 Hz), 6.53 (1H, d, J = 3.9 Hz), 6.67 (1H, s), 6.77 (1H, d, J = 3.9 Hz), 7.00 (1H, s ), 7.09 (1H, s), 7.14 (2H, d, J = 8.6 Hz), 7.92 (2H, d, J = 8.6 Hz).
MS (ESI) m / z: 439.13042 (M + H) ^<+> .

(Example 3)
2- [5- (3-{[(2S) -1- (methylsulfanyl) propan-2-yl] oxy} -5- [4- (methylsulfonyl) phenoxy] phenyl) -1H-pyrrol-2-yl ] -4,5-dihydro-1,3-oxazole

The compound synthesized in Example (2a) (56 mg, 0.11 mmol) was dissolved in tetrahydrofuran (10 mL), sodium thiomethoxide (25 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (30 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 resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% to 70%) to give the target compound as a white solid (31 mg, yield). 61%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.42 (3H, d, J = 5.9 Hz), 2.18 (3H, s), 2.70 (1H, dd, J = 13.5, 6.1 Hz), 2.85 (1H, dd , J = 13.7, 5.5 Hz), 3.07 (3H, s), 3.97 (2H, t, J = 9.0 Hz), 4.40 (2H, t, J = 9.4 Hz), 4.55 (1H, br s), 6.50 ( 1H, d, J = 3.5 Hz), 6.53 (1H, s), 6.75 (1H, d, J = 3.5 Hz), 6.83 (1H, s), 6.96 (1H, s), 7.13 (2H, d, J = 8.6 Hz), 7.91 (2H, d, J = 8.2 Hz).
MS (ESI) m / z: 487.13473 (M + H) ^<+> .

Example 4
2- [5- (3- [4- (Methylsulfonyl) phenoxy] -5-{[(2S) -1- (methylsulfonyl) propan-2-yl] oxy} phenyl) -1H-pyrrol-2-yl ] -4,5-dihydro-1,3-oxazole

The compound synthesized in Example 3 (150 mg, 0.31 mmol) was dissolved in methylene chloride (5.0 mL), and m-chloroperbenzoic acid (about 65%, 170 mg, about 0.64 mmol) was added at 0 ° C. In addition, the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (10 mL) was added, and the mixture was extracted with methylene chloride (15 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 (elution solvent: ethyl acetate / hexane = 40% -90%) to give the desired compound (95 mg, yield) as a white solid. 60%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.45 (3H, d, J = 6.3 Hz), 3.01 (3H, s), 3.08 (3H, s), 3.16 (1H, dd, J = 15.1, 1.8 Hz ), 3.54 (1H, dd, J = 15.1, 8.8 Hz), 3.98 (2H, t, J = 9.2 Hz), 4.41 (2H, t, J = 9.4 Hz), 4.99-5.06 (1H, m), 6.52 (1H, d, J = 3.9 Hz), 6.58 (1H, d, J = 2.0 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.89 (1H, t, J = 1.8 Hz), 7.02 (1H , t, J = 1.8 Hz), 7.14 (2H, d, J = 8.6 Hz), 7.92 (2H, d, J = 9.0 Hz).
MS (ESI) m / z: 519.12522 (M + H) ^<+> .

(Example 5)
2- (5- {3-methoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrol-2-yl) -4,5-dihydro-1,3-oxazole

(5a) 2- {3-methoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -4,4,5,5-tetramethyl-1,3,2-dioxaborolane Synthesized in Example (1b) Compound (22.8 g, 63.8 mmol), bis (pinacolato) diboron (24.3 g, 95.7 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (1. 56 g, 1.91 mmol) and potassium acetate (31.3 g, 319 mmol) were used to obtain the target compound (24.8 g, yield 96%) as a pale yellow oil in the same manner as in Example (1d).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.33 (12H, s), 3.05 (3H, s), 3.84 (3H, s), 6.73 (1H, t, J = 2.4 Hz), 7.07 (2H, d, J = 9.0Hz), 7.08 (1H, m), 7.20 (1H, d, J = 2.8Hz), 7.87 (2H, d, J = 9.0Hz).
(5b) 1-tert-butyl 2-ethyl 5- {3-methoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-1,2-dicarboxylate synthesized in Example (5a) Compound (24.8 g, 61.3 mmol), compound synthesized in Example (1 g) (20.1 g, 63.2 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride Using a dichloromethane complex (2.50 g, 3.06 mmol) and an aqueous potassium carbonate solution (2 mol / L, 80.0 mL, 160 mmol), the target compound (23.9 g, yield) was obtained in the same manner as in Example (1h). 76%).
¹ H-NMR (CDCl ₃ , 400MHz): δ1.35 (3H, t, J = 7.0Hz), 1.46 (9H, s), 3.05 (3H, s), 3.81 (3H, s), 4.32 (2H, q, J = 7.0Hz), 6.22 (1H, d, J = 3.9Hz), 6.62 (1H, t, J = 2.4Hz), 6.74 (1H, t, J = 2.0Hz), 6.85 (1H, t, J = 2.4Hz), 6.89 (1H, d, J = 3.9 Hz), 7.12 (1H, d, J = .9.0 Hz), 7.89 (2H, d, J = 9.0 Hz).
(5c) 5- {3-methoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2-carboxylic acid Compound synthesized in Example (5b) (23.9 g, 46.4 mmol) Was dissolved in ethanol (100 mL), 5N aqueous sodium hydroxide solution (100 mL) was added, and the mixture was heated to reflux for 2 hours under a nitrogen atmosphere. 2N hydrochloric acid (260 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (300 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product (18.3 g, yield˜100%) as a white solid.

(5d) N- (2-hydroxyethyl) -5- {3-methoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2-carboxamide Compound synthesized in Example (5c) ( 10.36 g, 26.7 mmol) was dissolved in methanol (250 mL), 2-aminoethanol (3.23 mL, 53.5 mmol) and DMT-MM (11.7 g, 42.3 mmol) were added, and the mixture was added at room temperature under a nitrogen atmosphere. For 19 hours. The solvent was distilled off under reduced pressure, water (200 mL) was added, and the mixture was extracted twice with ethyl acetate (100 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 resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 80% to 100%) to obtain the desired product (11.6 g, yield) as a white solid. To 100%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ3.07 (3H, s), 3.59 (2H, dd, J = 5.1, 10.2 Hz), 3.80 (2H, t, J = 5.1 Hz), 3.84 (3H, s), 6.49 (2H, m), 6.54 (1H, t, J = 2.4Hz), 6.61 (1H, d, J = 3.5Hz), 6.84 (1H, brs), 6.94 (1H, brs), 7.13 ( 2H, d, J = 9.0Hz), 7.90 (2H, d, J = 9.0Hz), 9.73 (1H, brs).
(5e) 2- (5- {3-methoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrol-2-yl) -4,5-dihydro-1,3-oxazole Examples The compound synthesized in 5d) (11.5 g, 26.7 mmol) was dissolved in tetrahydrofuran (200 mL), methanesulfonic anhydride (7.00 g, 40.2 mmol) and triethylamine (15.0 mL, 108 mol) were added, The mixture was stirred at room temperature for 50 hours under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (200 mL) was added, and the mixture was extracted twice with ethyl acetate (100 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 (elution solvent: ethyl acetate / hexane = 50% -90%) to give the desired product as a white solid (8.90 g, Yield 81%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ3.07 (3H, s), 3.84 (3H, s), 3.99 (2H, t, J = 9.4 Hz), 4.41 (2H, t, J = 9.4 Hz) , 6.52 (1H, d, J = 3.9Hz), 6.54 (1H, t, J = 2.4Hz), 6.76 (1H, d, J = 3.9Hz), 6.83 (1H, t, J = 2.4Hz), 6.94 (1H, t, J = 2.4Hz), 7.13 (2H, d, J = 9.0 Hz), 7.91 (2H, d, J = 9.0Hz).
MS (ESI) m / z: 413.11712 (M + H) ^<+> .

(Example 6)
Methyl 2- {3- [5- (4,5-dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) phenoxy] phenoxy} propanoate

(6a) 3- [5- (4,5-Dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) phenoxy] phenol Examples ( 5e) was dissolved in methylene chloride (70 mL), and boron tribromide (1.0 mol / L methylene chloride solution, 23.0 mL, 23.0 mmol) was dissolved at 0 ° C. ) And stirred at room temperature for 4 days under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (100 mL) was added, and the mixture was extracted 3 times with tetrahydrofuran (100 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 (elution solvent: methanol / methylene chloride = 3% to 10%) to give the desired product as a white solid (2.70 g, Yield 95%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ3.07 (3H, s), 4.07 (2H, t, J = 9.4 Hz), 4.52 (2H, t, J = 9.4 Hz), 6.44 (1H, t, J = 2.0Hz), 6.47 (1H, d, J = 3.9Hz), 6.78 (1H, d, J = 3.9Hz), 6.85 (1H, t, J = 2.0Hz), 7.15 (2H, d, J = 9.0 Hz), 7.31 (1H, m), 7.91 (2H, d, J = 9.0Hz).
(6b) Methyl 2- {3- [5- (4,5-dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) phenoxy] Phenoxy} propanoate The compound synthesized in Example (6a) (600 mg, 1.51 mmol) was dissolved in 2-butanone (20 mL), methyl 2-bromopropanoate (340 μL, 3.05 mmol), potassium carbonate (625 mg, 4.52 mmol) was added, and the mixture was refluxed for 19 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, and insoluble matters were removed by celite filtration. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 50% -100%) to give the desired product (302 mg, yield) as a white solid. 41%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.64 (3H, d, J = 6.7 Hz), 3.07 (3H, s), 3.77 (3H, s), 3.97 (2H, t, J = 9.4 Hz) , 4.40 (2H, t, J = 9.4Hz), 4.80 (1H, q, J = 6.7Hz), 6.48 (1H, brs), 6.50 (1H, d, J = 3.9Hz), 6.76 (1H, d, J = 3.9Hz), 6.86 (1H, brs), 6.94 (1H, brs), 7.13 (2H, d, J = 9.0 Hz), 7.91 (2H, d, J = 9.0Hz).
MS (ESI) m / z: 485.13825 (M + H) ^<+> .

(Example 7)
3- {3- [5- (4,5-Dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) phenoxy] phenoxy} butane- 2-on

Using the compound (200 mg, 0.502 mmol) synthesized in Example (6a), 3-bromo-2-butanone (110 μL, 1.05 mmol), and potassium carbonate (210 mg, 1.52 mmol), The target product (31.0 mg, yield 13%) as a white solid was obtained in the same manner.
¹ H-NMR (CDCl ₃ , 400MHz): δ1.52 (3H, d, J = 7.0Hz), 2.20 (3H, s), 3.08 (3H, s), 3.97 (2H, t, J = 9.4Hz) , 4.40 (2H, t, J = 9.4Hz), 4.66 (1H, q, J = 7.0Hz), 6.46 (1H, t, J = 2.4Hz), 6.50 (1H, d, J = 3.9Hz), 6.75 (1H, d, J = 3.9Hz), 6.87 (1H, t, J = 2.0Hz), 6.91 (1H, t, J = 2.0Hz), 7.12 (2H, d, J = 9.0 Hz), 7.91 (2H , d, J = 9.0Hz).
MS (ESI) m / z: 469.14333 (M + H) ^<+> .

(Example 8)
2- (5- {3-Isopropoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrol-2-yl) -4,5-dihydro-1,3-oxazole

The compound (340 mg, 0.853 mmol) synthesized in Example (6a) was dissolved in N, N-dimethylformamide (10 mL), 2-bromopropane (160 μL, 1.70 mmol), potassium carbonate (360 mg, 2.60 mmol). ) And stirred at 80 ° C. under a nitrogen atmosphere for 2 days. The mixture was cooled to room temperature, and insoluble matters were removed by celite filtration. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 50% -90%) to give the desired product (318 mg, yield) as a white solid. 85%).
¹ H-NMR (CDCl ₃ , 400MHz): δ1.34 (6H, d, J = 6.3Hz), 3.07 (3H, s), 3.95 (2H, t, J = 9.4Hz), 4.39 (2H, t, J = 9.4Hz), 4.55 (1H, m), 6.50 (1H, m), 6.75 (1H, d, J = 3.5Hz), 6.81 (1H, t, J = 2.0Hz), 6.94 (1H, t, J = 2.0Hz), 7.12 (2H, d, J = 8.6 Hz), 7.90 (2H, d, J = 8.6Hz).
MS (ESI) m / z: 441.14842 (M + H) ^<+> .

Example 9
3- {3- [5- (4,5-Dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) phenoxy] phenoxy} dihydrofuran -2 (3H) -ON

Using the compound (220 mg, 0.552 mmol) synthesized in Example (6a), α-bromo-γ-butyrolactone (110 μL, 1.19 mmol), potassium carbonate (230 mg, 1.66 mmol), and Example (6b) The target product (175 mg, 66% yield) was obtained in the same manner as a white solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.48 (1H, m), 2.72 (1H, m), 3.07 (3H, s), 3.93 (2H, t, J = 9.4Hz), 4.36 (1H, m), 4.38 (2H, t, J = 9.4Hz), 4.52 (1H, m), 4.99 (1H, t, J = 7.8Hz), 6.51 (1H, d, J = 3.9Hz), 6.66 (1H, t, J = 2.4Hz), 6.74 (1H, d, J = 3.9Hz), 6.92 (1H, t, J = 2.4Hz), 7.08 (1H, t, J = 2.0Hz), 7.12 (2H, d, J = 9.0 Hz), 7.90 (2H, d, J = 9.0 Hz).
MS (ESI) m / z: 483.12260 (M + H) ^<+> .

(Example 10)
2- (5- {3- [4- (Methylsulfonyl) phenoxy] -5- (tetrahydrofuran-3-yloxy) phenyl} -1H-pyrrol-2-yl) -4,5-dihydro-1,3-oxazole

Tetrahydro-3-furanol (130 μL, 1.61 mmol) and triphenylphosphine (410 mg, 1.56 mmol) are dissolved in tetrahydrofuran (10 mL), and at 0 ° C. diethyl azodicarboxylate (40% toluene solution, 720 μL, 1). 58 mmol) was added dropwise. The compound synthesized in Example (6a) (250 mg, 0.627 mmol) was dissolved in tetrahydrofuran (10 mL) and added to the reaction solution, followed by stirring at room temperature for 14 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 50% -80%) to give the desired product (277 mg, yield) as a white solid. 94%).
¹ H-NMR (CDCl ₃ , 400MHz): δ2.11-2.25 (2H, m), 3.07 (3H, s), 3.87-4.02 (4H, m), 3.94 (2H, t, J = 9.4Hz), 4.39 (2H, t, J = 9.4Hz), 4.92 (1H, m), 6.48 (1H, brs), 6.50 (1H, d, J = 3.9Hz), 6.75 (1H, d, J = 3.9Hz), 6.86 (1H, brs), 6.92 (1H, brs), 7.12 (2H, d, J = 8.6 Hz), 7.90 (2H, d, J = 8.6 Hz).
MS (ESI) m / z: 469.14333 (M + H) ^<+> .

Example 11
2- (5- {3- [4- (Methylsulfonyl) phenoxy] -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl} -1H-pyrrol-2-yl) -4,5-dihydro-1 , 3-Oxazole

(3R) -tetrahydro-3-furanol (76.0 μL, 0.946 mmol), triphenylphosphine (250 mg, 0.953 mmol), diethyl azodicarboxylate (40% toluene solution, 430 μL, 0.946 mmol), Example ( Using the compound (150 mg, 0.376 mmol) synthesized in 6a), a white solid target product (130 mg, yield 74%) was obtained in the same manner as in (Example 10).
¹ H-NMR (CDCl ₃ , 400 MHz): δ2.12-2.25 (2H, m), 3.07 (3H, s), 3.88-4.03 (6H, m), 4.40 (2H, t, J = 9.4Hz), 4.93 (1H, m), 6.48 (1H, t, J = 2.4Hz), 6.50 (1H, d, J = 3.9Hz), 6.75 (1H, d, J = 3.9Hz), 6.84 (1H, t, J = 2.0Hz), 6.91 (1H, t, J = 2.0Hz), 7.13 (2H, d, J = 9.0 Hz), 7.91 (2H, d, J = 9.0Hz).
MS (ESI) m / z: 469.14333 (M + H) ^<+> .

(Example 12)
2- (5- {3- [2-Fluoro-1- (fluoromethyl) ethoxy] -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrol-2-yl) -4,5-dihydro -1,3-oxazole

1,3-difluoro-2-propanol (100 μL, 1.29 mmol), triphenylphosphine (330 mg, 1.26 mmol), diethyl azodicarboxylate (40% toluene solution, 570 μL, 1.26 mmol), Example (6a) Using the compound synthesized in Step (200 mg, 0.502 mmol), the target product (178 mg, yield 74%) was obtained as a white solid in the same manner as in Example 10.
¹ H-NMR (CDCl ₃ , 400 MHz): δ3.07 (3H, s), 3.94 (2H, t, J = 9.4 Hz), 4.39 (2H, t, J = 9.4 Hz), 4.57-4.76 (5H, m), 6.51 (1H, d, J = 3.5Hz), 6.60 (1H, t, J = 2.4Hz), 6.75 (1H, d, J = 3.5Hz), 6.90 (1H, t, J = 2.0Hz) , 7.02 (1H, t, J = 2.0Hz), 7.12 (2H, d, J = 8.6Hz), 7.91 (2H, d, J = 8.6Hz).
MS (ESI) m / z: 477.12957 (M + H) ^<+> .

(Example 13)
(2R, 3S) -3- {3- [5- (4,5-Dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) Phenoxy] phenoxy} butan-2-ol

(1R, 2R) -2-hydroxy-1-methylpropyl benzoate (270 mg, 1.39 mmol), tritium of {Tetrahedron Letters, Vol. 38, No. 5, Item 773-776 (1997)} Phenylphosphine (360 mg, 1.37 mmol) was dissolved in tetrahydrofuran (5 mL), and diethyl azodicarboxylate (40% toluene solution, 630 μL, 1.39 mmol) was added dropwise at 0 ° C. The compound synthesized in Example (6a) (220 mg, 0.552 mmol) was dissolved in tetrahydrofuran (10 mL) and added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 50% -80%).

The obtained crude product was dissolved in methanol (10 mL), potassium carbonate (230 mg, 1.66 mmol) was added, and the mixture was heated to reflux for 1 hour under a nitrogen atmosphere. Insoluble matter was removed by Celite filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 70% to 100%) to give white A solid target product (154 mg, yield 59%) was obtained.
¹ H-NMR (CDCl ₃ , 400MHz): δ1.28 (3H, d, J = 6.3Hz), 1.29 (3H, d, J = 6.3Hz), 3.06 (3H, s), 3.93 (2H, t, J = 9.4Hz), 4.03 (1H, m), 4.38 (2H, t, J = 9.4Hz), 4.41 (1H, m), 6.44 (1H, d, J = 3.9Hz), 6.45 (1H, m) , 6.73 (1H, d, J = 3.9Hz), 6.83 (1H, t, J = 2.0Hz), 7.01 (1H, t, J = 2.0Hz), 7.06 (2H, d, J = 9.0 Hz), 7.87 (2H, d, J = 9.0Hz).
MS (ESI) m / z: 471.15898 (M + H) ^<+> .

(Example 14)
(3S) -3- {3- [5- (4,5-Dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) phenoxy] Phenoxy} butan-1-ol

{2R) -4-{[(1,1-dimethylethyl) diphenylsilyl] oxy} -2-butanol (460 mg, 1.40 mmol) of {{Synthesis 9], 1357-1360 (2003)} ), Triphenylphosphine (360 mg, 1.37 mmol) was dissolved in tetrahydrofuran (5 mL), and diethyl azodicarboxylate (40% toluene solution, 630 μL, 1.39 mmol) was added dropwise at 0 ° C. The compound synthesized in Example (6a) (220 mg, 0.552 mmol) was dissolved in tetrahydrofuran (10 mL) and added to the reaction solution, and the mixture was stirred at room temperature for 6 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 50% -80%).

The obtained crude product was dissolved in tetrahydrofuran (10 mL), tetrabutylammonium fluoride (1M tetrahydrofuran solution, 560 μL, 0.560 mmol) was added, and the mixture was stirred at room temperature for 1 hour in a nitrogen atmosphere. Water (10 mL) was added and extracted twice with ethyl acetate (20 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 resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 70% to 100%) to give the target compound (121 mg, yield) as a white solid. 47%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.33 (3H, d, J = 6.3 Hz), 1.85 (1H, m), 2.04 (1H, m), 3.06 (3H, s), 3.77-3.88 ( 2H, m), 3.94 (2H, t, J = 9.4Hz), 4.38 (2H, t, J = 9.4Hz), 4.63 (1H, m), 6.44-6.48 (2H, m), 6.73 (1H, d , J = 3.5Hz), 6.83 (1H, t, J = 2.0Hz), 7.03 (1H, brs), 7.10 (2H, d, J = 9.0 Hz), 7.88 (2H, d, J = 9.0Hz).
MS (ESI) m / z: 471.15898 (M + H) ^<+> .

(Example 15)
2- [5- (3-{[(1S) -3-Fluoro-1-methylpropyl] oxy} -5- [4- (methylsulfonyl) phenoxy] phenyl) -1H-pyrrol-2-yl] -4 , 5-Dihydro-1,3-oxazole

The compound synthesized in Example 14 (72.5 mg, 0.154 mmol) was dissolved in methylene chloride (5 mL), and bis (2-methoxyethyl) aminosulfur trifluoride (70 μL, 0.534 mmol) at 0 ° C. Was added. After stirring at room temperature for 4 hours, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with methylene chloride (10 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 resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 70% to 100%) to give the desired compound (47.3 mg, Yield 65%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.37 (3H, d, J = 6.3 Hz), 2.00-2.13 (2H, m), 3.07 (3H, s), 3.98 (2H, t, J = 9.4 Hz), 4.41 (2H, t, J = 9.4Hz), 4.50-4.72 (3H, m), 6.51 (1H, d, J = 3.9Hz), 6.53 (1H, t, J = 2.0Hz), 6.76 ( 1H, d, J = 3.9Hz), 6.83 (1H, brs), 6.96 (1H, brs), 7.13 (2H, d, J = 8.6 Hz), 7.91 (2H, d, J = 8.6Hz).
MS (ESI) m / z: 473.15464 (M + H) ^<+> .

(Example 16)
{(5R) -2- [5- (3-methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro -1,3-oxazol-5-yl} methanol

(16a) 5-Chloro-2- (methylsulfonyl) pyridine 2,5-dichloropyridine (1.49 g, 10.1 mmol) was dissolved in N, N-dimethylformamide (10 mL), and the resulting solution was at 0 ° C. under a nitrogen atmosphere. Sodium thiomethoxide (783 mg, 11.2 mmol) was added and stirred for 1 hour. Water (100 mL) was added and extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a colorless oily compound (1.58 g).

This was dissolved in methylene chloride (50 mL), m-chloroperbenzoic acid (about 65%, 5.25 g, about 20 mmol) was slowly added at 0 ° C., and the mixture was stirred at 0 ° C. for 2 hours under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (200 mL) was added, and the mixture was extracted with methylene chloride (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 25% -45%) to give the target compound (1.63 g, yield) as a white solid. 84%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.24 (3H, s), 7.95 (1H, dd, J = 8.2, 2.3 Hz), 8.06 (1H, d, J = 8.2 Hz), 8.69 (1H, d , J = 2.3 Hz).
MS (ESI) m / z: 191.98866 (M + H) ⁺ .
(16b) 3-Methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol The compound synthesized in Example (1a) (5.05 g, 24. 9 mmol), bis (pinacolato) diboron (9.47 g, 37.3 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (634 mg, 0.776 mmol), potassium acetate ( The target compound (4.49 g, yield 72%) as a colorless oil was obtained in the same manner as in Example (1d) using 12.24 g, 125 mmol).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.34 (12H, s), 3.80 (3H, s), 4.91 (1H, s), 6.53 (1H, t, J = 2.3 Hz), 6.86 (1H, d , J = 2.3 Hz), 6.92 (1H, d, J = 2.3 Hz).
MS (FAB) m / z: 251 (M + H) ⁺ .
(16c) t-butyl 2,5-dibromo-1H-pyrrole-1-carboxylate t-butyl 1-pyrrole carboxylate (46.68 g, 279 mmol) was dissolved in tetrahydrofuran (500 mL) and cooled to -78 ° C. To this was added N-bromosuccinimide (100.48 g, 565 mmol) in portions over 1 hour. The reaction was allowed to warm naturally and stirred at room temperature for 18 hours. The reaction mixture was cooled to 0 ° C., sodium sulfite (36.43 g) was added, and the mixture was stirred for 30 min. Hexane (200 mL) was added, and the resulting precipitate was removed by celite filtration. The solvent of the filtrate was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1% to 5%) to give the objective compound (52. 69 g, yield 58%).
¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.65 (9H, s), 6.25 (2H, s).
MS (EI) m / z: 323 (M ⁺ ).

(16d) 2-Benzyl 1-t-butyl 5-bromo-1H-pyrrole-1,2-dicarboxylate The compound synthesized in Example (16c) (10.98 g, 33.8 mmol) was converted into diethyl ether (135 mL). And cooled to -78 ° C. n-Butyllithium (2.77 mol / L hexane solution, 12.8 mL, 35.5 mmol) was slowly added dropwise and stirred for 1 hour. To the reaction solution, benzyl chloroformate (6.25 mL, 44.0 mmol) was slowly added dropwise and stirred for 30 minutes. The reaction solution was stirred for 1 hour while gradually warming to room temperature. A saturated aqueous ammonium chloride solution (200 mL) and diethyl ether (300 mL) were added to the reaction solution to separate the layers. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1% to 9%) to give the desired compound (8.80 g) as a red-brown oil. Yield 68%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.56 (9H, s), 5.26 (2H, s), 6.21 (1H, d, J = 3.9 Hz), 6.85 (1H, d, J = 3.9 Hz), 7.28-7.39 (5H, m).
MS (FAB) m / z: 380 (M + H) ⁺ .
(16e) 2-Benzyl 1-t-butyl 5- (3-hydroxy-5-methoxyphenyl) -1H-pyrrole-1,2-dicarboxylate Compound (7.78 g, 20) synthesized in Example (16d) 0.5 mmol) and the compound (4.26 g, 17.0 mmol) synthesized in Example (16b) were dissolved in a mixed solvent of 1,4-dioxane (80 mL) and water (20 mL), and [1,1′-bis (Diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (420 mg, 0.514 mmol) and potassium carbonate (5.93 g, 42.9 mmol) were added, and the mixture was stirred at 55 ° C. for 6 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 5% -30%) to give the target compound (5.20 g) as a red-brown oil. Yield 72%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.41 (9H, s), 3.78 (3H, s), 5.05 (1H, s), 5.31 (2H, s), 6.19 (1H, d, J = 3.5 Hz ), 6.41 (1H, t, J = 2.2 Hz), 6.49 (1H, dd, J = 2.2, 1.4 Hz), 6.55 (1H, dd, J = 2.2, 1.4 Hz), 6.95 (1H, d, J = 3.5 Hz), 7.30-7.43 (5H, m).
MS (FAB) m / z: 424 (M + H) ⁺ .
(16f) Benzyl 5- (3-methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxylate Compound synthesized in Example (16e) ( 2.96 g, 6.99 mmol) and the compound synthesized in Example (16a) (1.39 g, 7.25 mmol) were dissolved in N, N-dimethylformamide (35 mL), and cesium carbonate (6.86 g, 21.20 mmol) was dissolved. 1 mmol) was added, and the mixture was stirred at 100 ° C. for 2.5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.

The obtained residue was dissolved in methylene chloride (20 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and then 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: ethyl acetate / hexane = 25% -50%) to give the desired compound (1.23 g, Yield 37%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.23 (3H, s), 3.85 (3H, s), 5.33 (2H, s), 6.53 (1H, dd, J = 3.9, 2.7 Hz), 6.56 (1H , t, J = 2.2 Hz), 6.86 (1H, t, J = 1.8 Hz), 6.96 (1H, t, J = 1.8 Hz), 6.99 (1H, dd, J = 3.7, 2.5 Hz), 7.35-7.45 (6H, m), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.27 (1H, br s).

(16 g) 5- (3-Methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxylic acid Compound (1) synthesized in Example (16f) .22 g, 2.55 mmol) was dissolved in ethyl acetate (50 mL), 10% palladium carbon catalyst (872 mg) was added, and the mixture was stirred at room temperature for 2 and a half hours under a hydrogen atmosphere. After filtration through Celite, the solvent was distilled off under reduced pressure to obtain the target compound (954 mg, yield 96%) as a white solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.23 (3H, s), 3.87 (3H, s), 6.56-6.60 (2H, m), 6.89 (1H, t, J = 1.6 Hz), 7.01 (1H , t, J = 1.6 Hz), 7.07 (1H, dd, J = 3.7, 2.5 Hz), 7.46 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz), 9.44 (1H, br s).
MS (FAB) m / z: 389 (M + H) ⁺ .
(16h) N-[(2S) -2,3-dihydroxypropyl] -5- (3-methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole- 2-Carboxamide Compound (946 mg, 2.44 mmol) synthesized in Example (16 g), (S)-(−)-3-amino-1,2-propanediol (574 mg, 6.30 mmol), DMT-MM ( Using 1.98 g, 6.32 mmol), the white solid target product (949 mg, 84%) was obtained in the same manner as in Example (5d).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.16-3.24 (2H, m), 3.23 (3H, s), 3.48-3.60 (4H, m), 3.79-3.86 (1H, m), 3.84 (3H, s), 6.46-6.51 (2H, m), 6.55 (1H, t, J = 2.2 Hz), 6.64 (1H, dd, J = 3.9, 2.3 Hz), 6.87 (1H, t, J = 1.8 Hz), 6.98 (1H, t, J = 1.8 Hz), 7.42 (1H, dd, J = 8.6, 2.7 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.88 (1H, br s).
MS (FAB) m / z: 462 (M + H) ⁺ .
(16i) N-{(2S) -2-hydroxy-3-[(triisopropylsilyl) oxy] propyl} -5- (3-methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] Oxy} phenyl) -1H-pyrrole-2-carboxamide The compound synthesized in Example (16h) (940 mg, 2.04 mmol) was dissolved in methylene chloride (30 mL), triethylamine (0.85 mL, 6.13 mmol), Isopropylsilyl chloride (525 μL, 2.45 mmol) and 4-dimethylaminopyridine (258 mg, 2.11 mmol) were added, and the mixture was stirred under a nitrogen atmosphere for 21 hours. The reaction mixture was diluted with methylene chloride (100 mL), washed with water and 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 (elution solvent: ethyl acetate / hexane = 40% -75%) to give the desired product (1.05 g, 83%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.05-1.15 (21H, m), 3.11 (1H, d, J = 4.3 Hz), 3.23 (3H, s), 3.36-3.43 (1H, m), 3.65 -3.91 (4H, m), 3.85 (3H, s), 6.35 (1H, t, J = 5.7 Hz), 6.51 (1H, t, J = 3.3 Hz), 6.54 (1H, t, J = 2.0 Hz) , 6.61 (1H, dd, J = 3.7, 2.5 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.96 (1H, t, J = 1.8 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.52 (1H, br s).
MS (FAB) m / z: 618 (M + H) ^<+> .

(16j) 5- (3-Methoxy-5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -2- (methylsulfonyl) pyridine The compound synthesized in Example (16i) (1.04 g, 1.68 mmol) was dissolved in tetrahydrofuran (20 mL) and methanesulfonic anhydride (594 mg, 3.41 mmol) and triethylamine (1.05 mL, 7.57 mmol) were added, and the mixture was stirred at 60 ° C. for 2 hours under a nitrogen atmosphere, and then heated to reflux for 1 hour. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0.5% to 3%) to give the target compound (955 mg) as a pale yellow solid. 94% yield).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.02-1.14 (21H, m), 3.23 (3H, s), 3.83-3.91 (3H, m), 3.85 (3H, s), 4.00 (1H, dd, J = 14.3, 9.6 Hz), 4.73-4.79 (1H, m), 6.51 (1H, d, J = 3.9 Hz), 6.53 (1H, t, J = 2.2 Hz), 6.73 (1H, d, J = 3.9 Hz), 6.83 (1H, t, J = 1.8 Hz), 6.95 (1H, t, J = 2.0 Hz), 7.43 (1H, dd, J = 8.6, 2.7 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
MS (FAB) m / z: 600 (M + H) ⁺ .
(16k) {(5R) -2- [5- (3-methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4, 5-Dihydro-1,3-oxazol-5-yl} methanol The compound (943 mg, 1.57 mmol) synthesized in Example (16j) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (1.0 mol / mol) was dissolved. L tetrahydrofuran solution, 1.70 mL, 1.70 mmol) was added, and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 7%) to give the target compound (596 mg, yield) as a white solid. 86%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.00 (1H, br s), 3.23 (3H, s), 3.68-3.83 (3H, m), 3.85 (3H, s), 4.03 (1H, dd, J = 14.3, 10.0 Hz), 4.75-4.82 (1H, m), 6.45 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.67 (1H, d, J = 3.9 Hz) ), 6.83 (1H, t, J = 1.8 Hz), 6.95 (1H, t, J = 1.8 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz) ), 8.49 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 444.12012 (M + H) ^<+> .

(Example 17)
{(5R) -2- [5- (3-Ethoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro -1,3-oxazol-5-yl} methanol

(17a) 1-Bromo-3-ethoxy-5-methoxybenzene The compound synthesized in Example (1a) (4.10 g, 20.2 mmol) was dissolved in N, N-dimethylformamide (100 mL), and iodoethane ( 2.43 mL, 30.4 mmol) and potassium carbonate (7.00 g, 50.6 mmol) were added, and the mixture was stirred at 60 ° C. for 25 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, potassium carbonate was removed by celite filtration, 1N hydrochloric acid (100 mL) was added, and the mixture was extracted twice with diethyl ether (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 5% -30%) to give the target compound (4.75 g, Yield ˜100%).
¹ H-NMR (CDCl ₃ , 400MHz): δ1.40 (3H, t, J = 7.0Hz), 3.77 (3H, s), 3.99 (2H, q, J = 7.0Hz), 6.38 (1H, m) , 6.65 (1H, m), 6.66 (1H, m).
(17b) 3-Bromo-5-ethoxyphenol Using the compound synthesized in Example (17a) (4.75 g, 20.6 mmol) and sodium thiomethoxide (1.56 g, 22.3 mmol), Example (1a ) To give the target compound (4.19 g, 94% yield) as a white solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.40 (3H, t, J = 7.0 Hz), 3.98 (1H, q, J = 7.0 Hz), 6.32 (1H, t, J = 2.0 Hz), 6.60 (1H, brs), 6.64 (1H, t, J = 2.0Hz).
(17c) 3-Ethoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol The compound synthesized in Example (17b) (4.19 g, 19. 3 mmol), bis (pinacolato) diboron (7.35 g, 28.9 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (790 mg, 0.967 mmol), potassium acetate ( (9.47 g, 96.5 mmol) was used to obtain the target compound (3.22 g, yield 63%) as a white solid in the same manner as in Example (1d).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.33 (12H, s), 1.39 (3H, t, J = 7.0 Hz), 4.04 (2H, q, J = 7.0 Hz), 6.52 (1H, t, J = 2.4Hz), 6.83 (1H, t, J = 2.4Hz), 6.92 (1H, t, J = 2.0Hz).

(17d) Ethyl 5- (3-ethoxy-5-hydroxyphenyl) -1H-pyrrole-2-carboxylate Compound (3.22 g, 12.2 mmol) synthesized in Example (17c) and Example (1 g) The compound synthesized in step (4.66 g, 14.6 mmol) was dissolved in a mixed solvent of 1,4-dioxane (45 mL) and water (15 mL), and [1,1′-bis (diphenylphosphino) ferrocene] palladium ( II) Dichloride Dichloromethane complex (300 mg, 0.367 mmol) and potassium carbonate (3.40 g, 24.6 mmol) were added, and the mixture was stirred at 50 ° C. for 19 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted 3 times with diethyl ether (50 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.

The obtained residue was dissolved in methylene chloride (30 mL), and trifluoroacetic acid (30 mL) was added dropwise. After stirring at room temperature for 1 hour in a nitrogen atmosphere, the solvent was distilled off under reduced pressure. The mixture was diluted with methylene chloride (50 mL), and a saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to separate the layers. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% to 40%) to give the target compound (3.18 g) as a pale yellow solid. Yield 95%).
¹ H-NMR (CDCl ₃ , 400MHz): δ1.39 (3H, t, J = 7.0Hz), 1.43 (3H, t, J = 7.0Hz), 4.05 (2H, q, J = 7.0Hz), 4.36 (2H, q, J = 7.0Hz), 6.38 (1H, m), 6.50 (1H, t, J = 2.7Hz), 6.69 (1H, brs), 6.77 (1H, m), 6.94 (1H, t, J = 2.7Hz), 9.73 (1H, brs).
(17e) Ethyl 5- (3-ethoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxylate Compound synthesized in Example (17d) ( 3.18 g, 11.6 mmol) was dissolved in N, N-dimethylformamide (80 mL). The compound synthesized in Example (16a) (2.43 g, 12.7 mmol) and cesium carbonate (11.3 g, 34.7 mmol) were added, and the mixture was stirred at 100 ° C. for 17 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted 3 times with diethyl ether (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% to 60%) to give the target compound (3.13 g, Yield 63%) was obtained.
¹ H-NMR (CDCl ₃ , 400MHz): δ1.38 (3H, t, J = 7.0Hz), 1.45 (3H, t, J = 7.0Hz), 3.24 (3H, s), 4.07 (2H, q, J = 7.0Hz), 4.35 (2H, q, J = 7.0Hz), 6.53 (1H, m), 6.55 (1H, m), 6.86 (1H, brs), 6.94 (1H, m), 6.97 (1H, brs), 7.45 (1H, dd, J = 2.7, 8.6Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.24 (1H, brs).
(17f) N-[(2S) -2,3-dihydroxypropyl] -5- (3-ethoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole- 2-Carboxamide The compound synthesized in Example (17e) (3.18 g, 7.39 mmol) was dissolved in ethanol (50 mL), 5N aqueous sodium hydroxide solution (20 mL) was added, and the mixture was heated to reflux for 2 hours under a nitrogen atmosphere. . 2N Hydrochloric acid (50 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (50 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.

The obtained residue was dissolved in methanol (100 mL), (S)-(−)-3-amino-1,2-propanediol (1.70 g, 18.7 mmol), DMT-MM (5.20 g, 28 .8 mmol) was used to obtain the desired product (972 mg, yield 28%) as a white solid in the same manner as in Example (5d).
¹ H-NMR (CDCl ₃ , 400MHz): δ1.44 (3H, t, J = 7.0Hz), 3.23 (3H, s), 3.52-3.63 (4H, m), 3.84 (1H, m), 4.06 ( 2H, q, J = 7.0Hz), 6.41 (1H, brs), 6.51 (1H, m), 6.54 (1H, brs), 6.64 (1H, m), 6.85 (1H, brs), 6.97 (1H, brs ), 7.44 (1H, dd, J = 2.4, 8.6Hz), 8.04 (1H, d, J = 8.6Hz), 8.47 (1H, d, J = 2.4Hz), 9.72 (1H, brs).

(17 g) 5- (3-Ethoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -N-{(2S) -2-hydroxy-3-[(triisopropylsilyl) Oxy] propyl} -1H-pyrrole-2-carboxamide The compound synthesized in Example (17f) (972 mg, 2.05 mmol) was dissolved in methylene chloride (40 mL), triisopropylsilyl chloride (483 μL, 2.26 mmol), Triethylamine (860 μL, 6.17 mol) and 4-dimethylaminopyridine (250 mg, 2.05 mmol) were added, and the mixture was stirred at room temperature for 50 hours under a nitrogen atmosphere. Water (40 mL) was added and extracted twice with methylene chloride (30 mL). The organic layer was washed with saturated brine and then 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: ethyl acetate / hexane = 40% -60%) to give the desired product (975 mg, yield) as a white solid. 75%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.01-1.14 (21H, m), 1.44 (3H, t, J = 7.0 Hz), 3.23 (3H, s), 3.38 (1H, m), 3.60- 3.78 (3H, m), 3.86 (1H, m), 4.05 (2H, q, J = 7.0Hz), 6.43 (1H, brs), 6.48-6.53 (2H, m), 6.61 (1H, dd, J = 2.4, 3.9Hz), 6.87 (1H, brs), 6.99 (1H, brs), 7.43 (1H, dd, J = 2.7, 8.6Hz), 8.04 (1H, d, J = 8.6Hz), 8.48 (1H, d, J = 2.7Hz), 9.90 (1H, brs).
(17h) 5- (3-Ethoxy-5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -2- (methylsulfonyl) pyridine Compound synthesized in Example (17 g) (975 mg, 1.55 mmol), methanesulfonic anhydride (540 mg, 3.10 mmol), triethylamine (1.08 mL, 7.75 mol) was used to obtain the white solid target product (856 mg, yield 90%) in the same manner as in Example (5e).
¹ H-NMR (CDCl ₃ , 400MHz): δ0.95-1.12 (21H, m), 1.42 (3H, t, J = 7.0Hz), 3.23 (3H, s), 3.80-3.88 (3H, m), 3.94 (1H, m), 4.04 (2H, q, J = 7.0Hz), 4.74 (1H, m), 6.49-6.51 (2H, m), 6.71 (1H, d, J = 3.9Hz), 6.84 (1H , brs), 6.90 (1H, brs), 7.42 (1H, dd, J = 2.7, 8.6Hz), 8.03 (1H, d, J = 8.6Hz), 8.47 (1H, d, J = 2.7Hz).
(17i) {(5R) -2- [5- (3-Ethoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4, 5-Dihydro-1,3-oxazol-5-yl} methanol Compound (856 mg, 1.39 mmol) synthesized in Example (17h), tetrabutylammonium fluoride (1M tetrahydrofuran solution, 2.80 mL, 2.80 mmol) Was used to give the target compound (538 mg, yield 84%) as a white solid in the same manner as in Example (16k).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.43 (3H, t, J = 7.0 Hz), 3.22 (3H, s), 3.67 (1H, dd, J = 5.1, 12.5 Hz), 3.72 (1H, dd, J = 7.0, 14.1Hz), 3.79 (1H, dd, J = 3.1, 12.5Hz), 3.98 (1H, dd, J = 9.8, 14.1Hz), 4.05 (2H, q, J = 7.0Hz), 4.74 (1H, m), 6.40 (1H, d, J = 3.5Hz), 6.50 (1H, t, J = 2.0Hz), 6.61 (1H, d, J = 3.5Hz), 6.83 (1H, t, J = 2.0Hz), 6.97 (1H, t, J = 2.0Hz), 7.42 (1H, dd, J = 2.7, 9.0Hz), 8.01 (1H, d, J = 9.0Hz), 8.47 (1H, d, J = 2.7Hz).
MS (ESI) m / z: 458.13858 (M + H) ^<+> .

(Example 18)
[(5R) -2- {5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- (2,2,2-trifluoroethoxy) phenyl] -1H-pyrrole- 2-yl} -4,5-dihydro-1,3-oxazol-5-yl] methanol

(18a) 1-bromo-3-methoxy-5- (2,2,2-trifluoroethoxy) benzene The compound synthesized in Example (1a) (4.10 g, 20.2 mmol) was converted to N, N-dimethyl. Dissolve in formamide (100 mL), add 1,1,1-trifluoro-2-iodoethane (2.99 mL, 30.3 mmol) and potassium carbonate (7.00 g, 50.6 mmol) at 60 ° C. under nitrogen atmosphere. Stir for 25 hours. Further, 1,1,1-trifluoro-2-iodoethane (2.99 mL, 30.3 mmol) was added and stirred at 100 ° C. for a day. The reaction mixture was cooled to room temperature, potassium carbonate was removed by celite filtration, 1N hydrochloric acid (100 mL) was added, and the mixture was extracted twice with diethyl ether (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 5% -30%) to give the target compound (5.84 g, Yield ˜100%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ3.79 (3H, s), 4.31 (2H, q, J = 8.2 Hz), 6.44 (1H, t, J = 2.4 Hz), 6.69 (1H, t, J = 2.0Hz), 6.76 (1H, t, J = 2.0Hz).
(18b) 3-Bromo-5- (2,2,2-trifluoroethoxy) phenol The compound synthesized in Example (18a) (5.76 g, 20.2 mmol), sodium thiomethoxide (1.56 g, 22 .3 mmol) was used to obtain the target compound (3.57 g, yield 65%) as a white solid in the same manner as in Example (1a).
¹ H-NMR (CDCl ₃ , 400MHz): δ4.31 (2H, q, J = 8.2Hz), 6.40 (1H, t, J = 2.0Hz), 6.69 (1H, t, J = 2.0Hz), 6.72 (1H, t, J = 2.0Hz).
(18c) 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5- (2,2,2-trifluoroethoxy) phenol In Example (18b) Synthesized compound (3.57 g, 13.2 mmol), bis (pinacolato) diboron (5.02 g, 19.8 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex ( 540 mg, 0.661 mmol) and potassium acetate (6.48 g, 66.0 mmol) were used to obtain the target compound (4.11 g, yield 98%) as a white solid in the same manner as in Example (1d).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.34 (12H, s), 4.35 (2H, q, J = 8.2 Hz), 6.59 (1H, t, J = 2.4 Hz), 6.90 (1H, d, J = 2.4Hz), 6.94 (1H, d, J = 2.4Hz).

(18d) Ethyl 5- [3-hydroxy-5- (2,2,2-trifluoroethoxy) phenyl] -1H-pyrrole-2-carboxylate Compound (4.11 g, 12) synthesized in Example (18c) 0.9 mmol), the compound synthesized in Example (1g) (4.93 g, 15.5 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (320 mg, 0.392 mmol) ), Potassium carbonate (3.60 g, 26.0 mmol), trifluoroacetic acid (30 mL), and the target compound (3.38 g, yield 80%) as a pale yellow solid was obtained in the same manner as in Example (17d) It was.
¹ H-NMR (CDCl ₃ , 400MHz): δ1.40 (3H, t, J = 7.0Hz), 4.38 (2H, q, J = 7.0Hz), 4.38 (2H, q, J = 7.8Hz), 6.43 (1H, t, J = 2.4Hz), 6.52 (1H, dd, J = 2.7, 3.9Hz), 6.73 (1H, t, J = 2.0Hz), 6.90 (1H, brs), 6.95 (1H, dd, J = 2.4, 3.9Hz), 9.84 (1H, brs).
(18e) Ethyl 5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- (2,2,2-trifluoroethoxy) phenyl] -1H-pyrrole-2-carboxylate The compound (3.38 g, 10.3 mmol) synthesized in Example (18d) was dissolved in N, N-dimethylformamide (80 mL). The compound (2.16 g, 11.3 mmol) synthesized in Example (16a) and cesium carbonate (10.0 g, 30.7 mmol) were added, and the mixture was stirred at 100 ° C. for 17 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted 3 times with diethyl ether (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% -60%) to give the target compound (3.53 g) as a pale brown solid. Yield 71%).
¹ H-NMR (CDCl ₃ , 400MHz): δ1.38 (3H, t, J = 7.0Hz), 3.24 (3H, s), 4.35 (2H, q, J = 7.0Hz), 4.41 (2H, q, J = 7.8Hz), 6.55 (1H, t, J = 3.9Hz), 6.61 (1H, t, J = 2.0Hz), 6.95 (1H, dd, J = 2.4, 3.9Hz), 6.97 (1H, brs) , 7.02 (1H, brs), 7.47 (1H, dd, J = 2.7, 8.6Hz), 8.08 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.31 (1H, brs).
(18f) N-[(2S) -2,3-dihydroxypropyl] -5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- (2,2,2-tri Fluoroethoxy) phenyl] -1H-pyrrole-2-carboxamide The compound (3.53 g, 7.29 mmol) synthesized in Example (18e) was dissolved in ethanol (50 mL), and 5N aqueous sodium hydroxide solution (20 mL) was added. In addition, the mixture was heated to reflux for 2 hours under a nitrogen atmosphere. 2N Hydrochloric acid (50 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (50 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.

The obtained residue was dissolved in methanol (100 mL), and (S)-(−)-3-amino-1,2-propanediol (1.70 g, 18.7 mmol), DMT-MM (5.20 g, 28 8 mmol) was used to obtain the desired product (729 mg, yield 19%) as a white solid in the same manner as in Example (5d).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.17 (3H, s), 3.29 (1H, m), 3.34-3.50 (3H, m), 3.37 (1H, m), 4.40 (2H, q, J = 8.2Hz), 6.36 (1H, m), 6.50 (1H, brs), 6.64 (1H, m), 6.98 (1H, brs), 7.08 (1H, brs), 7.34 (1H, dd, J = 2.7, 8.6Hz), 7.93 (1H, d, J = 8.6Hz), 8.36 (1H, d, J = 2.7Hz), 10.99 (1H, brs).

(18 g) N-{(2S) -2-hydroxy-3-[(triisopropylsilyl) oxy] propyl} -5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5 -(2,2,2-trifluoroethoxy) phenyl] -1H-pyrrole-2-carboxamide The compound (729 mg, 1.38 mmol) synthesized in Example (18f) was dissolved in methylene chloride (30 mL) and triisopropyl Silyl chloride (325 μL, 1.52 mmol), triethylamine (578 μL, 4.15 mol) and 4-dimethylaminopyridine (170 mg, 1.39 mmol) were added, and the mixture was stirred at room temperature for 50 hours under a nitrogen atmosphere. Water (30 mL) was added and extracted twice with methylene chloride (30 mL). The organic layer was washed with saturated brine and then 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: ethyl acetate / hexane = 40% -60%) to give the desired product (583 mg, yield) as a white solid. 62%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.00-1.14 (21H, m), 3.23 (3H, s), 3.34 (1H, m), 3.60-3.76 (3H, m), 3.84 (1H, m ), 4.38 (2H, q, J = 8.2Hz), 6.50 (1H, m), 6.56 (1H, brs), 6.62 (1H, m), 7.01 (1H, brs), 7.07 (1H, brs), 7.42 (1H, dd, J = 2.7, 8.6Hz), 8.03 (1H, d, J = 8.6Hz), 8.46 (1H, d, J = 2.7Hz), 10.58 (1H, brs).
(18h) 2- (Methylsulfonyl) -5- [3- (2,2,2-trifluoroethoxy) -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy] pyridine The compound synthesized in Example (18 g) (583 mg, 0.851 mmol), methanesulfonic anhydride Product (300 mg, 1.72 mmol) and triethylamine (600 μL, 4.30 mol) were used to obtain the desired product (531 mg, 93% yield) as a white solid in the same manner as in Example (5e).
¹ H-NMR (CDCl ₃ , 400 MHz): δ0.98-1.12 (21H, m), 3.23 (3H, s), 3.78-3.92 (4H, m), 4.37 (2H, q, J = 8.2Hz), 4.72 (1H, m), 6.51 (1H, d, J = 3.9Hz), 6.57 (1H, t, J = 2.4Hz), 6.71 (1H, d, J = 3.9Hz), 6.95 (1H, t, J = 2.0Hz), 7.00 (1H, t, J = 2.0Hz), 7.43 (1H, dd, J = 2.7, 8.6Hz), 8.04 (1H, d, J = 8.6Hz), 8.46 (1H, d, J = 2.7Hz).
(18i) [(5R) -2- {5- [3 {[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (2,2,2-trifluoromethoxy) phenyl] -1H- Pyrrole-2-yl} -4,5-dihydro-1,3-oxazol-5-yl] methanol Compound (531 mg, 0.795 mmol) synthesized in Example (18h), tetrabutylammonium fluoride (1M tetrahydrofuran solution) , 1.60 mL, 1.60 mmol), and the target compound (270 mg, 66% yield) was obtained in the same manner as in Example (16k).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.24 (3H, s), 3.71 (1H, dd, J = 5.1, 12.5 Hz), 3.76 (1H, dd, J = 7.4, 14.1 Hz), 3.84 ( 1H, dd, J = 3.1, 12.5Hz), 4.04 (1H, dd, J = 9.4, 14.1Hz), 4.41 (2H, q, J = 8.2Hz), 4.79 (1H, m), 6.45 (1H, d , J = 3.9Hz), 6.58 (1H, brs), 6.66 (1H, d, J = 3.9Hz), 6.94 (1H, brs), 7.02 (1H, brs), 7.46 (1H, dd, J = 2.7, 8.6Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz).
MS (ESI) m / z: 512.11031 (M + H) ^<+> .

Example 19
[(5R) -2- {5- [3- (difluoromethoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrol-2-yl} -4, 5-Dihydro-1,3-oxazol-5-yl] methanol

(19a) 5- (3-Bromo-5-methoxyphenoxy) -2- (methylsulfonyl) pyridine The compound synthesized in Example (1a) (10.8 g, 53.2 mmol) was converted to N, N-dimethylformamide (300 mL). ). The compound synthesized in Example (16a) (11.2 g, 58.4 mmol) and cesium carbonate (52.5 g, 161 mmol) were added, and the mixture was stirred at 100 ° C. for 3 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (300 mL) was added, and the mixture was extracted 3 times with diethyl ether (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% -50%) to give the target compound (17.9 g, 17.9 g, Yield 94%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ3.23 (3H, s), 3.81 (3H, s), 6.58 (1H, t, J = 2.4 Hz), 6.83 (1H, t, J = 2.4 Hz) , 6.96 (1H, t, J = 2.4Hz), 7.44 (1H, dd, J = 2.7, 8.6Hz), 8.07 (1H, d, J = 8.6Hz), 8.46 (1H, d, J = 2.7Hz) .
(19b) 3-Bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenol The compound synthesized in Example (19a) (17.9 g, 50.0 mmol), boron tribromide ( Using 1.0 mol / L methylene chloride solution, 100 mL, 100 mmol), a white solid target product (17.2 g, yield˜100%) was obtained in the same manner as in Example (1c).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.24 (3H, s), 6.53 (1H, t, J = 2.0 Hz), 6.81 (1H, t, J = 2.0 Hz), 6.92 (1H, t, J = 2.0Hz), 7.46 (1H, dd, J = 2.4, 8.6 Hz), 8.07 (1H, d, J = 8.6Hz), 8.46 (1H, d, J = 2.4Hz).
(19c) 5- [3-Bromo-5- (difluoromethoxy) phenoxy] -2- (methylsulfonyl) pyridine The compound synthesized in Example (19b) (3.77 g, 11.0 mmol) was converted to N, N— It melt | dissolved in dimethylformamide (100 mL), methyl chloro (difluoro) acetate (1.74 mL, 16.5 mmol) and potassium carbonate (2.28 g, 16.5 mmol) were added, and it stirred at 80 degreeC by nitrogen atmosphere for 20 hours. The reaction mixture was cooled to room temperature, potassium carbonate was removed by celite filtration, 1N hydrochloric acid (100 mL) was added, and the mixture was extracted twice with diethyl ether (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% to 40%) to give the target compound (2.32 g, 2.3%, Yield 54%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.24 (3H, s), 6.54 (1H, t, J = 72.3 Hz), 6.84 (1H, t, J = 2.0 Hz), 7.09 (1H, t, J = 2.0Hz), 7.21 (1H, t, J = 2.0Hz), 7.49 (1H, dd, J = 2.7, 8.6 Hz), 8.11 (1H, d, J = 8.6Hz), 8.48 (1H, d, J = 2.7Hz).

(19d) Benzyl 1H-pyrrole-2-carboxylate benzyl bromide (20 mL, 168 mmol) was dissolved in N, N-dimethylformamide (200 mL), and potassium carbonate (37.32 g, 270 mmol) was added. While stirring at room temperature under a nitrogen atmosphere, pyrrole-2-carboxylic acid (5.03 g, 45.3 mmol) was added little by little, and the mixture was further stirred for 16 hours. Ethyl acetate (150 mL) was added for dilution, and insolubles were removed by celite filtration. Water (400 mL) and diethyl ether (200 mL) were added for liquid separation, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and diisopropyl ether (25 mL) and hexane (75 mL) were added to the resulting residue and washed to obtain the desired product (22.70 g, 67%) as a white solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 6.28 (1H, q, J = 3.0 Hz), 6.95-6.99 (2H, m), 7.32-7.44 (5H, m), 9.14 (1H, br s).
(19e) Benzyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate Compound (25) synthesized in Example (19d) 0.0 g, 124 mmol) in hexane (370 mL), bis (pinacolato) diboron (16.0 g, 63.0 mmol), 4,4′-di-t-butyl-2,2′-dipyridyl (500 mg, 1.86 mmol) and methoxy (cyclooctadiene) iridium (I) dimer (617 mg, 0.931 mmol) were added, and the mixture was stirred at 50 ° C. for 1 hour. Ethyl acetate (300 mL) was added to the reaction solution, washed twice with water (150 mL), washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was washed with diisopropyl ether (200 mL) to obtain the desired product (32.71 g, 81%) as a pale pink solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.32 (12H, s), 5.32 (2H, s), 6.77 (1H, dd, J = 3.7, 2.3 Hz), 6.96 (1H, dd, J = 3.9, 2.3 Hz), 7.32-7.44 (5H, m), 9.45 (1H, br s).
MS (EI) m / z: 327 (M ⁺ ).
(19f) Benzyl 5- [3- (difluoromethoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrole-2-carboxylate synthesized in Example (19c) Compound (2.32 g, 5.89 mmol), compound synthesized in Example (19e) (2.50 g, 7.64 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride Using a dichloromethane complex (145 mg, 0.178 mmol) and potassium carbonate (2.44 g, 17.7 mmol) in the same manner as in Example (16e), the target compound (2.37 g, yield 78%) was obtained as a pale yellow solid. Got.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.24 (3H, s), 5.34 (2H, s), 6.56 (1H, dd, J = 2.7, 3.9Hz), 6.58 (1H, t, J = 72.7 Hz), 6.80 (1H, t, J = 2.4Hz), 7.00 (1H, dd, J = 2.4, 3.9Hz), 7.11 (1H, t, J = 2.4Hz), 7.20 (1H, t, J = 1.6 Hz), 7.35-7.45 (5H, m), 7.48 (1H, dd, J = 2.7, 8.6 Hz), 8.09 (1H, d, J = 8.6Hz), 8.50 (1H, d, J = 2.7Hz).

(19g) 5- [3- (Difluoromethoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -N-[(2S) -2,3-dihydroxypropyl] -1H -Pyrrole-2-carboxamide The compound (2.37 g, 4.61 mmol) synthesized in Example (19f) was dissolved in tetrahydrofuran (50 mL), 10% palladium carbon catalyst (1.00 g) was added, and room temperature was added under a hydrogen atmosphere. For 1 hour. The palladium carbon catalyst was removed by Celite filtration and washed with ethyl acetate. The solvent was distilled off under reduced pressure.

The obtained residue was dissolved in methanol (50 mL), (S)-(−)-3-amino-1,2-propanediol (840 mg, 9.22 mmol), DMT-MM (3.20 g, 11.6 mmol). ) Was used to obtain the white solid target product (1.93 g, yield 84%) in the same manner as in Example (5d).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.25 (3H, s), 3.57-3.67 (4H, m), 3.87 (1H, m), 6.37 (1H, brs), 6.56 (1H, t, J = 3.1Hz), 6.60 (1H, t, J = 72.7Hz), 6.65 (1H, t, J = 3.1Hz), 6.81 (1H, t, J = 2.4Hz), 7.11 (1H, brs), 7.21 ( 1H, brs), 7.49 (1H, dd, J = 2.7, 8.6 Hz), 8.10 (1H, d, J = 8.6Hz), 8.50 (1H, d, J = 2.7Hz), 9.66 (1H, brs).
(19h) 5- [3- (Difluoromethoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -N-{(2S) -2-hydroxy-3-[(tri Isopropylsilyl) oxy] propyl} -1H-pyrrole-2-carboxamide Compound (1.93 g, 3.88 mmol) synthesized in Example (19 g) was dissolved in methylene chloride (40 mL) and N, N-dimethylformamide (2 mL). Dissolve in the mixed solvent, add triisopropylsilyl chloride (1.08 mL, 5.05 mmol), triethylamine (1.62 mL, 11.6 mol), 4-dimethylaminopyridine (480 mg, 3.93 mmol), and add nitrogen at room temperature. For 21 hours. Water (40 mL) was added and extracted three times with methylene chloride (40 mL). The organic layer was washed with saturated brine and then 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: ethyl acetate / hexane = 40% -60%) to give the desired product as a white solid (2.08 g, Yield 82%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.04-1.16 (21H, m), 3.07 (1H, t, J = 3.9 Hz), 3.39 (1H, m), 3.67 (1H, dd, J = 6.3 , 9.8Hz), 3.72 (1H, m), 3.78 (1H, dd, J = 9.8, 10.2Hz), 3.87 (1H, m), 6.42 (1H, m), 6.54 (1H, t, J = 3.5Hz ), 6.58 (1H, t, J = 72.7Hz), 6.63 (1H, t, J = 3.5Hz), 6.78 (1H, brs), 7.12 (1H, brs), 7.21 (1H, brs), 7.48 (1H , dd, J = 2.7, 8.6Hz), 8.09 (1H, d, J = 8.6Hz), 8.50 (1H, d, J = 2.7Hz), 9.76 (1H, brs).

(19i) 5- [3- (Difluoromethoxy) -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy] -2- (methylsulfonyl) pyridine The compound synthesized in Example (19h) (2.08 g, 3.18 mmol), methanesulfonic anhydride (1.17 g) , 6.72 mmol) and triethylamine (2.22 mL, 15.9 mol) were used to obtain the white solid target product (1.45 g, yield 72%) in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.03-1.12 (21H, m), 3.24 (3H, s), 3.81-3.91 (3H, m), 4.00 (1H, dd, J = 9.4, 14.5Hz ), 4.76 (1H, m), 6.53 (1H, d, J = 3.9Hz), 6.57 (1H, t, J = 72.7Hz), 6.73 (1H, d, J = 3.9Hz), 6.75 (1H, brs ), 7.10 (1H, t, J = 2.0Hz), 7.20 (1H, brs), 7.48 (1H, dd, J = 2.7, 8.6Hz), 8.08 (1H, d, J = 8.6Hz), 8.50 (1H , d, J = 2.7Hz).
(19j) [(5R) -2- {5- [3- (Difluoromethoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrol-2-yl} -4,5-dihydro-1,3-oxazol-5-yl] methanol Compound (1.45 g, 2.28 mmol) synthesized in Example (19i), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 2 .74 mL, 2.74 mmol) was used to obtain the target compound (1.00 g, yield 91%) as a white solid in the same manner as in Example (16k).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.24 (3H, s), 3.68-3.80 (2H, m), 3.85 (1H, d, J = 12.1Hz), 4.01 (1H, m), 4.80 ( 1H, m), 6.47 (1H, brs), 6.58 (1H, t, J = 73.1Hz), 6.67 (1H, brs), 6.77 (1H, brs), 7.09 (1H, brs), 7.20 (1H, brs ), 7.48 (1H, dd, J = 2.7, 8.6Hz), 8.08 (1H, d, J = 8.6Hz), 8.50 (1H, d, J = 2.7Hz).
MS (ESI) m / z: 480.10409 (M + H) ^<+> .

(Example 20)
[(5R) -2- {5- [3- (cyclopropyloxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrol-2-yl} -4 , 5-Dihydro-1,3-oxazol-5-yl] methanol

(20a) 1,3-dibromo-5- (2-chloroethoxy) benzene 3,5-dibromophenol (7.00 g, 27.8 mmol) was dissolved in toluene (200 mL), and 2-chloroethanol (2.23 mL) was dissolved. 33.4 mmol) and triphenylphosphine (8.02 g, 30.6 mmol) were added. Diethyl azodicarboxylate (40% toluene solution, 15.2 mL, 33.4 mmol) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Diethyl ether was added to the residue obtained by evaporating the solvent under reduced pressure, and the resulting insoluble material was removed by filtration. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: hexane) to give the target compound (9.72 g, yield ˜100%) as a pale yellow oil. It was.
¹ H-NMR (CDCl ₃ , 400 MHz): δ3.80 (2H, t, J = 5.9 Hz), 4.20 (2H, t, J = 5.9 Hz), 7.02 (2H, d, J = 2.0 Hz), 7.29 (1H, t, J = 2.0Hz).
(20b) 1,3-dibromo-5- (vinyloxy) benzene The compound (8.74 g, 27.8 mmol) synthesized in Example (20a) was dissolved in tetrahydrofuran (200 mL), and potassium t-butoxide was dissolved at 0 ° C. (4.10 g, 36.5 mmol) was added. After stirring at room temperature for 1 hour under a nitrogen atmosphere, water (200 mL) was added, and the mixture was extracted with diethyl ether (200 mL). The solvent was distilled off under reduced pressure, and the resulting insoluble material was removed by filtration and washed with diethyl ether. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: hexane) to give the desired product (7.06 g, yield 91%) as a pale yellow oil. .
¹ H-NMR (CDCl ₃ , 400 MHz): δ4.57 (1H, dd, J = 2.0, 5.9 Hz), 4.86 (1H, dd, J = 2.0, 13.7 Hz), 6.55 (1H, dd, J = 5.9 13.7Hz), 7.10 (2H, d, J = 2.0Hz), 7.38 (1H, t, J = 2.0Hz).
(20c) 1,3-Dibromo-5- (cyclopropyloxy) benzene The compound synthesized in Example (20b) (9.72 g, 33.3 mmol) was dissolved in 1,2-dichloroethane (300 mL), and -78 Chloro (iodo) methane (14.8 mL, 203 mmol), diethyl zinc (1.09 M hexane solution, 100 mL, 109 mmol), and trifluoroacetic acid (800 μL, 10.4 mmol) were added at ° C. The mixture was stirred for 1 hour while gradually warming to room temperature in a nitrogen atmosphere, and further stirred at 70 ° C. for 17 hours. The reaction station was cooled to room temperature, 1N hydrochloric acid (200 mL) was added, and the mixture was extracted twice with diethyl ether (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: hexane) to give the desired product (5.62 g, yield 58%) as a pale yellow oil. .
¹ H-NMR (CDCl ₃ , 400 MHz): δ0.75-0.83 (4H, m), 3.71 (1H, m), 7.14 (2H, dd, J = 0.8, 1.6 Hz), 7.26 (1H, m).

(20d) 3-Bromo-5- (cyclopropyloxy) phenol The compound (5.62 g, 19.2 mmol) synthesized in Example (20c) was dissolved in diethyl ether (150 mL), and butyllithium was dissolved at -78 ° C. (1.65 mol / L hexane solution, 12.8 mL, 21.1 mmol) was added. After stirring at −78 ° C. for 1 hour, trimethyl borate (3.64 mL, 32.6 mmol) was added, and the mixture was stirred for 1.5 hours while gradually warming to room temperature. The reaction mixture was cooled to 0 ° C., and acetic acid (3.63 mL, 63.4 mmol) and 30% aqueous hydrogen peroxide (7.40 mL, 65.3 mmol) were added dropwise in this order. After stirring at room temperature for 21 hours, water (100 mL) was added to separate the layers. The organic layer was washed successively with a saturated aqueous sodium thiosulfate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% to 40%) to give the target compound (4.90 g, 4.90 g, Yield ˜100%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ0.74-0.80 (4H, m), 3.69 (1H, m), 5.16 (1H, m), 6.47 (1H, t, J = 2.4Hz), 6.63 ( 1H, t, J = 2.4Hz), 6.81 (1H, t, J = 2.4Hz).
(20e) 5- [3-Bromo-5- (cyclopropyloxy) phenoxy] -2- (methylsulfonyl) pyridine The compound (4.41 g, 19.2 mmol) synthesized in Example (20d) was converted to N, N— Dissolved in dimethylformamide (200 mL). The compound synthesized in Example (16a) (4.00 g, 20.9 mmol) and potassium carbonate (8.00 g, 57.9 mmol) were added, and the mixture was stirred at 100 ° C. for 20 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted twice with diethyl ether (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 30% -60%) to give the target compound (6.00 g) as a pale yellow oil. Yield 81%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ0.78-0.83 (4H, m), 3.23 (3H, s), 3.72 (1H, m), 6.70 (1H, t, J = 2.4 Hz), 6.84 ( 1H, t, J = 2.4Hz), 7.26 (1H, m), 7.45 (1H, dd, J = 2.7, 8.6Hz), 8.07 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7Hz).
(20f) Benzyl 5- [3- (cyclopropyloxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrole-2-carboxylate in Example (20e) Synthesized compound (6.00 g, 15.6 mmol), compound synthesized in Example (19e) (6.64 g, 20.3 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) Using the dichloride dichloromethane complex (390 mg, 0.478 mmol) and potassium carbonate (6.47 g, 46.8 mmol) in the same manner as in Example (16e), the target compound (6.23 g, yield 79%) was obtained as a pale yellow solid. )
¹ H-NMR (CDCl ₃ , 400 MHz): δ0.78-0.85 (4H, m), 3.23 (3H, s), 3.77 (1H, m), 5.33 (2H, s), 6.53 (1H, dd, J = 2.7, 3.9Hz), 6.73 (1H, t, J = 2.0Hz), 6.87 (1H, t, J = 2.0Hz), 6.99 (1H, dd, J = 2.7, 3.9Hz), 7.10 (1H, t , J = 2.0Hz), 7.34-7.47 (6H, m), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, brs), 9.35 (1H, brs).

(20 g) 5- [3- (Cyclopropoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -N-[(2S) -2,3-dihydroxypropyl] -1H -Pyrrole-2-carboxamide The compound (2.62 g, 5.19 mmol) synthesized in Example (20f) was dissolved in tetrahydrofuran (50 mL), 10% palladium carbon catalyst (1.50 g) was added, and room temperature was added under a hydrogen atmosphere. For 4.5 hours. The palladium carbon catalyst was removed by Celite filtration and washed with ethyl acetate. The solvent was distilled off under reduced pressure.

The obtained residue was dissolved in methanol (50 mL) and (S)-(−)-3-amino-1,2-propanediol (710 mg, 7.79 mmol), DMT-MM (3.59 g, 13.0 mmol) ) Was used to obtain the white solid target product (2.14 g, yield 85%) in the same manner as in Example (5d).
¹ H-NMR (CDCl ₃ , 400 MHz): δ0.78-0.82 (4H, m), 3.22 (3H, s), 3.41-3.56 (5H, m), 3.76 (1H, m), 3.78 (1H, m ), 6.46 (1H, dd, J = 2.7, 3.9Hz), 6.65 (1H, dd, J = 2.4, 3.9Hz), 6.59 (1H, t, J = 2.0Hz), 6.70 (1H, m), 6.90 (1H, t, J = 2.0Hz), 7.12 (1H, t, J = 2.0Hz), 7.42 (1H, dd, J = 2.7, 8.6Hz), 8.01 (1H, d, J = 8.6Hz), 8.45 (1H, d, J = 2.7Hz), 10.20 (1H, brs).
(20h) 5- [3- (Cyclopropyloxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -N-{(2S) -2-hydroxy-3-[( Triisopropylsilyl) oxy] propyl} -1H-pyrrole-2-carboxamide The compound (2.14 g, 4.39 mmol) synthesized in Example (20 g) was dissolved in methylene chloride (50 mL), and triisopropylsilyl chloride (1 .22 mL, 5.70 mmol), triethylamine (1.84 mL, 13.2 mol) and 4-dimethylaminopyridine (540 mg, 4.42 mmol) were added, and the mixture was stirred at room temperature for 18 hours under a nitrogen atmosphere. Water (50 mL) was added and extracted twice with methylene chloride (50 mL). The organic layer was washed with saturated brine and then 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: ethyl acetate / hexane = 40% -60%) to give the desired product (2.00 g, Yield 71%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ0.80-0.85 (4H, m), 1.05-1.15 (21H, m), 3.11 (1H, d, J = 4.3Hz), 3.24 (3H, s), 3.40 (1H, m), 3.68 (1H, dd, J = 6.3, 10.2Hz), 3.71-3.80 (3H, m), 3.87 (1H, m), 6.38 (1H, t, J = 3.9Hz), 6.51 (1H, t, J = 3.1Hz), 6.62 (1H, dd, J = 2.4, 3.9Hz), 6.70 (1H, t, J = 2.4Hz), 6.87 (1H, brs), 7.46 (1H, dd, J = 2.7, 8.6Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.58 (1H, brs).

(20i) 5- [3- (cyclopropyloxy) -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazole- 2-yl] -1H-pyrrol-2-yl} phenoxy] -2- (methylsulfonyl) pyridine The compound synthesized in Example (20h) (2.00 g, 3.11 mmol), methanesulfonic anhydride (1. 14 g, 6.54 mmol) and triethylamine (2.17 mL, 15.6 mol) were used to obtain the target product (1.79 g, yield 92%) as a white solid in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 400 MHz): δ0.80-0.84 (4H, m), 1.02-1.12 (21H, m), 3.23 (3H, s), 3.77 (1H, m), 3.82-3.91 (3H , m), 4.00 (1H, dd, J = 9.8, 14.1Hz), 4.76 (1H, m), 6.50 (1H, d, J = 3.9Hz), 6.67 (1H, t, J = 2.4Hz), 6.73 (1H, d, J = 3.9Hz), 6.87 (1H, t, J = 1.6Hz), 7.14 (1H, t, J = 1.6Hz), 7.46 (1H, dd, J = 2.7, 8.6Hz), 8.05 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz).
(20j) [(5R) -2- {5- [3- (Cyclopropyloxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrol-2-yl } -4,5-dihydro-1,3-oxazol-5-yl] methanol The compound synthesized in Example (20i) (1.79 g, 2.86 mmol), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, The target compound (1.26 g, 94% yield) was obtained in the same manner as in Example (16k) using 3.43 mL, 3.43 mmol).
¹ H-NMR (CDCl ₃ , 400 MHz): δ0.79-0.84 (4H, m), 3.23 (3H, s), 3.68-3.79 (3H, m), 3.85 (1H, dd, J = 3.1, 12.5 Hz ), 4.03 (1H, dd, J = 9.8, 14.1Hz), 4.79 (1H, m), 6.47 (1H, d, J = 3.9Hz), 6.69 (1H, t, J = 2.4Hz), 6.71 (1H , d, J = 3.9Hz), 6.87 (1H, t, J = 1.6Hz), 7.13 (1H, t, J = 1.6Hz), 7.45 (1H, dd, J = 2.7, 8.6Hz), 8.04 (1H , d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz).
MS (ESI) m / z: 470.13858 (M + H) ^<+> .

(Example 21)
5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-methoxyphenoxy ) Methyl pyridine-2-carboxylate

(21a) Benzyl 5- (3-hydroxy-5-methoxyphenyl) -1H-pyrrole-2-carboxylate Compound (5.00 g, 24.6 mmol) synthesized in Example (1a), Example (19e) Synthesized compound (8.46 g, 25.9 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (600 mg, 0.74 mmol), potassium carbonate (6.81 g, 49 3 mmol) was used to obtain the target compound (5.83 g, yield 73%) as a brown solid in the same manner as in Example (16e).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.83 (3H, s), 5.16 (1H, s), 5.34 (2H, s), 6.36 (1H, t, J = 2.3 Hz), 6.51 (1H, dd , J = 3.9, 2.7 Hz), 6.66 (2H, d, J = 2.3 Hz), 6.99 (1H, dd, J = 3.9, 2.3 Hz), 7.45-7.35 (5H, m), 9.32 (1H, s) .
(21b) 5- (3-Hydroxy-5-methoxyphenyl) -1H-pyrrole-2-carboxylic acid The compound synthesized in Example (21a) (2.00 g, 6.19 mmol) was dissolved in ethyl acetate (40 mL). Then, 10% palladium carbon catalyst (0.50 g) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The palladium carbon catalyst was removed by Celite filtration and washed with tetrahydrofuran. The solvent was distilled off under reduced pressure to obtain the target compound (1.42 g, 99%) as a white solid.
¹ H-NMR (CD ₃ OD, 400 MHz): δ 3.87 (3H, dt, J = 91.6, 32.7 Hz), 6.44 (1H, t, J = 2.2 Hz), 6.56 (1H, d, J = 4.4 Hz) , 6.91 (2H, d, J = 2.0 Hz), 6.93 (1H, d, J = 3.9 Hz).
(21c) N-[(2S) -2,3-dihydroxypropyl] -5- (3-hydroxy-5-methoxyphenyl) -1H-pyrrole-2-carboxamide Compound (500 mg, synthesized in Example (21b)) 2.14 mmol), N-methylmorpholine (0.47 ml, 4.29 mmol) was dissolved in N, N-dimethylformamide (10 mL), and WSCI · HCl (493 mg, 2.57 mmol), (S)-( −)-3-Amino-1,2-propanediol (215 μL, 2.36 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 14 hours. The reaction mixture was diluted with ethyl acetate (60 mL), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 10%) to give the target compound (400 mg, 61%) as a white solid. Got.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.39 (2H, dd, J = 13.9, 6.6 Hz), 3.51-3.58 (3H, m), 3.79-3.82 (4H, m), 6.29 (1H, t, J = 2.2 Hz), 6.48 (1H, d, J = 3.9 Hz), 6.69 (1H, t, J = 1.7 Hz), 6.75 (1H, t, J = 1.7 Hz), 6.84 (1H, d, J = 3.9 Hz).

(21d) N-{(2S) -2-dihydroxy-3-[(triisopropylsilyl) oxy] propyl} -5- {3-methoxy-5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrole -2-Carboxamide The compound synthesized in Example (21c) (400 mg, 1.31 mmol) was dissolved in N, N-dimethylformamide (10 mL), triethylamine (0.91 mL, 6.53 mmol), triisopropylsilyl chloride ( 0.84 mL, 3.92 mmol) and 4-dimethylaminopyridine (239 mg, 1.96 mmol) were added, and the mixture was stirred for 15 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water and 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: ethyl acetate / hexane = 0% -50%) to give the desired product (619 mg, 77%) as a white solid. )
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.07-1.13 (36H, m), 1.25-1.31 (6H, m), 3.42 (1H, ddd, J = 13.9, 7.1, 5.1 Hz), 3.69 (1H, dd, J = 10.0, 6.1 Hz), 3.74 (1H, td, J = 7.0, 3.3 Hz), 3.78 (1H, dd, J = 9.8, 4.9 Hz), 3.82 (3H, s), 3.89 (1H, br s), 6.33 (1H, t, J = 5.6 Hz), 6.38 (1H, t, J = 2.2 Hz), 6.47 (1H, t, J = 3.2 Hz), 6.61 (1H, dd, J = 3.7, 2.7 Hz), 6.68 (2H, dd, J = 4.2, 2.2 Hz), 9.42 (1H, br s).
(21e) (5R) -2- (5- {3-methoxy-5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrol-2-yl) -5-{[(triisopropylsilyl) oxy] Methyl} -4,5-dihydro-1,3-oxazole Compound (619 mg, 1.00 mmol) synthesized in Example (21d), methanesulfonic anhydride (348 mg, 2.00 mmol), triethylamine (0.42 mL, 3.0 mmol) and the white solid target compound (298 mg, yield 50%) was obtained in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.05 (18H, d, J = 5.5 Hz), 1.11 (19H, d, J = 6.6 Hz), 1.23-1.32 (6H, m), 3.81 (3H, s ), 3.91-3.84 (3H, m), 4.02 (1H, dd, J = 14.1, 9.8 Hz), 4.73-4.78 (1H, m), 6.36 (1H, t, J = 2.2 Hz), 6.47 (1H, d, J = 3.9 Hz), 6.70 (2H, d, J = 2.0 Hz), 6.74 (1H, d, J = 3.5 Hz).
(21f) 3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-methoxyphenol Using the compound (297 mg, 0.50 mmol) synthesized in Example (21e) and tetrabutylammonium fluoride (1.0 mol / L tetrahydrofuran solution, 1.09 mL, 1.09 mmol), the same as in Example (16k) The target compound as a white solid (102 mg, yield 72%) was obtained by the method.
¹ H-NMR (CD ₃ OD, 400 MHz): δ 3.78 (1H, dd, J = 12.3, 5.3 Hz), 3.82 (3H, s), 3.93-3.99 (2H, m), 4.17 (1H, dd, J = 13.7, 9.8 Hz), 4.94-4.87 (1H, m), 6.31 (1H, t, J = 2.2 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.68 (1H, t, J = 1.8 Hz ), 6.80 (1H, d, J = 3.9 Hz), 7.06 (1H, t, J = 1.8 Hz), 10.98 (1H, s).

(21 g) Methyl 5-hydroxypyridine-2-carboxylate 2-Bromo-5-fluoropyridine (3.80 g, 21.6 mmol) was dissolved in methanol (50 mL) and N, N-dimethylformamide (50 mL). Palladium (484 mg, 2.16 mmol), 1,1′-bis (diphenylphosphino) ferrocene (2.39 g, 4.32 mmol), triethylamine (6.0 mL, 43.2 mmol) were added, and under a carbon monoxide atmosphere, After stirring at room temperature for 3 days, insoluble matters in the reaction solution were filtered. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% -50%) to give the target compound (2.87 g) as a pale yellow solid. Yield 86%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 4.01 (3H, s), 7.54 (1H, dt, J = 8.6, 3.9 Hz), 8.20 (1H, dd, J = 8.6, 4.7 Hz), 8.59 (1H , d, J = 2.7 Hz).
(21h) 5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -Methoxyphenoxy) methyl pyridine-2-carboxylate The compound synthesized in Example (21f) (420 mg, 1.45 mmol) and the compound synthesized in Example (21 g) (224 mg, 1.44 mmol) were combined with N, N- It was dissolved in dimethylformamide (5 mL), cesium carbonate (723 mg, 2.22 mmol) was added, and the mixture was stirred at 100 ° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (330 mg, yield) as a white solid. 54%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.73 (1H, dd, J = 12.2, 5.4 Hz), 3.80 (1H, dd, J = 14.4, 7.6 Hz), 3.85 (3H, s), 3.88 (1H , dd, J = 12.5, 3.2 Hz), 4.01 (3H, s), 4.05 (1H, dd, J = 14.2, 9.8 Hz), 4.85-4.79 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.77 (1H, d, J = 3.9 Hz), 6.87 (1H, t, J = 1.7 Hz), 6.98 (1H, s), 7.37 (1H, dd, J = 8.8, 2.9 Hz), 8.13 (1H, d, J = 8.3 Hz), 8.54 (1H, d, J = 2.4 Hz).
MS (ESI) m / z: 424.15078 (M + H) ^<+> .

(Example 22)
5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-methoxyphenoxy ) -N-methylpyridine-2-carboxamide

(22a) 5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -Methoxyphenoxy) pyridine-2-carboxylic acid The compound (300 mg, 0.71 mmol) synthesized in Example (21h) was dissolved in tetrahydrofuran (10 mL), methanol (10 mL), water (4 mL), lithium hydroxide monohydrate A Japanese product (89 mg, 2.13 mmol) was added, followed by stirring at 60 ° C. for 1.5 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature and acidified with 2N hydrochloric acid. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 5% to 10%) to give the target compound (290 mg, yield 100) as a white solid. %).
¹ H-NMR (CD ₃ OD, 400 MHz): δ 3.81 (1H, dd, J = 13.2, 3.4 Hz), 3.89 (3H, s), 4.05-4.11 (2H, m), 4.23 (1H, t, J = 10.5 Hz), 5.51-5.47 (1H, m), 6.81 (1H, t, J = 2.2 Hz), 6.92 (1H, d, J = 3.9 Hz), 7.20 (1H, t, J = 1.7 Hz), 7.32 (1H, t, J = 1.7 Hz), 7.41 (1H, d, J = 4.4 Hz), 7.57 (1H, dd, J = 8.5, 2.7 Hz), 8.19 (1H, d, J = 8.8 Hz), 8.43 (1H, d, J = 2.4 Hz).
(22b) 5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -Methoxyphenoxy) -N-methylpyridine-2-carboxamide The compound synthesized in Example (22a) (70 mg, 0.17 mmol) was dissolved in N, N-dimethylformamide (1 mL), and HOBt · H ₂ O (29 mg) was dissolved. 0.19 mmol), methylamine hydrochloride (23 mg, 0.34 mmol) and WSCI.HCl (39 mg, 0.21 mmol) were added, and the mixture was stirred under a nitrogen atmosphere for 14 hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 3% to 10%) to give the target compound (24 mg, yield 35) as a white solid. %).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.03 (3H, d, J = 5.4 Hz), 3.69 (1H, dd, J = 12.2, 5.4 Hz), 3.77 (1H, dd, J = 14.2, 7.3 Hz) ), 3.84-3.86 (4H, m), 4.02 (1H, dd, J = 13.9, 10.0 Hz), 4.75-4.80 (1H, m), 6.47 (1H, d, J = 3.4 Hz), 6.51 (1H, t, J = 2.0 Hz), 6.71 (1H, d, J = 3.4 Hz), 6.84 (1H, t, J = 2.0 Hz), 6.95 (1H, t, J = 2.0 Hz), 7.39 (1H, dd, J = 8.5, 2.7 Hz), 7.87 (1H, d, J = 4.9 Hz), 8.16 (1H, d, J = 8.3 Hz), 8.30 (1H, d, J = 2.4 Hz).
MS (ESI) m / z: 423.16652 (M + H) ^<+> .

(Example 23)
1- [5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -Methoxyphenoxy) pyridin-2-yl] ethanone

(23a) 5-Fluoro-N-methoxy-N-methylpyridine-2-carboxamide 5-Fluoro-2-pyridinecarboxylic acid (200 mg, 1.42 mmol) was dissolved in methylene chloride (10 mL), and HOBt · H ₂ O was dissolved. (239 mg, 1.56 mmol), N, O-dimethylhydroxylamine hydrochloride (277 mg, 2.83 mmol), WSCI.HCl (543 mg, 2.83 mmol), triethylamine (0.98 mL, 7.09 mmol) were added, and nitrogen was added. Stir for 15 hours under atmosphere. The reaction mixture was diluted with ethyl acetate (20 mL), washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 50%) to give the target compound (214 mg, yield 82) as a white solid. %).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.44 (3H, s), 3.79 (3H, s), 7.52 (1H, td, J = 8.5, 2.9 Hz), 7.77 (1H, s), 8.50 (1H , d, J = 2.9 Hz).
(23b) 1- (5-Fluoropyridin-2-yl) ethanone The compound (213 mg, 1.16 mmol) synthesized in Example (23a) was dissolved in tetrahydrofuran (5 mL) and cooled to -78 ° C. Under a nitrogen atmosphere, methylmagnesium iodide (3.0 mol / L tetrahydrofuran solution, 0.58 mL, 1.74 mmol) was added, and the mixture was returned to room temperature and stirred for 2 hours. The reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 5%) to give the target compound (70 mg, yield) as a colorless oily liquid. 44%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.74 (3H, s), 7.54 (1H, td, J = 8.3, 2.0 Hz), 8.14 (1H, dd, J = 8.5, 4.6 Hz), 8.54 (1H , d, J = 2.4 Hz).
(23c) 1- [5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl } -5-methoxyphenoxy) pyridin-2-yl] ethanone The compound (63 mg, 0.46 mmol) synthesized in Example (23b) and the compound (125 mg, 0.43 mmol) synthesized in Example (21f) were mixed with N , N-dimethylformamide (2 mL), potassium carbonate (120 mg, 0.87 mmol) was added, and the mixture was stirred at 80 ° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (30 mg, yield) as a white solid. 17%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.70 (3H, s), 3.72 (1H, dd, J = 12.1, 5.5 Hz), 3.82 (4H, td, J = 8.4, 5.3 Hz), 3.89 (1H , dd, J = 12.1, 3.1 Hz), 4.05 (1H, dd, J = 14.5, 9.8 Hz), 4.79-4.85 (1H, m), 6.49 (1H, d, J = 3.9 Hz), 6.53 (1H, s), 6.76 (1H, d, J = 3.9 Hz), 6.86 (1H, s), 6.96 (1H, s), 7.35 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.43 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 408.15504 (M + H) ^<+> .

(Example 24)
5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-methoxyphenoxy ) -N-methylpyridine-2-sulfonamide

(24a) 5-Chloropyridine-2-thiol In a nitrogen atmosphere, 2,5-dichloropyridine (5.00 g, 33.8 mmol) was dissolved in dimethyl sulfoxide (35 mL), and sodium disulfide nonahydrate (9. (00 g, 37.2 mmol) was added, followed by stirring at 120 ° C. for 2 hours. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was neutralized with 5N hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and hexane, and the obtained solid was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 10%) to give a yellow solid. The target compound (2.28 g, yield 46%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz) δ 2.63 (1H, s), 7.34 (1H, dd, J = 9.0, 2.2 Hz), 7.41 (1H, d, J = 9.3 Hz), 7.70 (1H, s) .
(24b) 5-Chloro-N-methylpyridine-2-sulfonamide The compound synthesized in Example (24a) (1.00 g, 6.87 mmol) was dissolved in methylene chloride (30 mL) / 1N hydrochloric acid (30 mL). Cooled to -5 ° C. While maintaining the reaction solution at 0 ° C. or lower, ice-cooled 5% aqueous sodium perchlorate solution (30 mL) was added dropwise, and the mixture was stirred as it was for 15 minutes. The organic layer was extracted with a separatory funnel previously cooled with ice, cooled to −78 ° C., and a commercially available 40% methylamine / methanol solution (1.33 mL, 17.2 mmol) in methylene chloride (10 mL) was added. The temperature was raised to ° C and stirred for 2 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then 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: ethyl acetate / hexane = 30% -80%) to give the target compound (889 mg, yield) as a white solid. 63%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.77 (3H, d, J = 4.9 Hz), 4.81 (1H, s), 7.90 (1H, dd, J = 8.3, 2.4 Hz), 7.97 (1H, d , J = 8.3 Hz), 8.65 (1H, d, J = 2.4 Hz).
(24c) 5-chloro-N- (4-methoxybenzyl) -N-methylpyridine-2-sulfonamide The compound synthesized in Example (24b) (889 mg, 4.30 mmol) was converted to N, N-dimethylformamide (15 mL). ) And sodium hydride (172 mg, 4.30 mmol) was added. After cooling with ice, p-methoxybenzyl chloride (0.70 mL, 5.16 mmol) was added, and the mixture was warmed to room temperature and stirred for 3 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 0% -20%) to give the desired compound (817 mg, yield) as a colorless oily liquid. 58%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.79 (3H, s), 3.81 (3H, s), 4.36 (2H, s), 6.87 (2H, dt, J = 9.4, 2.4 Hz), 7.25 (2H , d, J = 7.3 Hz), 7.88 (1H, dd, J = 8.3, 2.4 Hz), 7.94 (1H, d, J = 8.3 Hz), 8.66 (1H, d, J = 2.4 Hz).

(24d) 5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -Methoxyphenoxy) -N- (4-methoxybenzyl) -N-methylpyridine-2-sulfonamide Compound (105 mg, 0.32 mmol) synthesized in Example (24c) and compound synthesized in Example (21f) (139 mg, 0.48 mmol) was dissolved in N, N-dimethylformamide (1.5 mL), cesium carbonate (314 mg, 0.96 mmol) was added, and the mixture was stirred at 100 ° C. for 1.5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 1% to 5%) to give the desired compound (90 mg, yield) as a white solid. 49%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.79 (3H, s), 3.74 (2H, td, J = 12.1, 5.5 Hz), 3.80 (3H, s), 3.86-3.89 (4H, m), 4.04 (1H, dd, J = 14.3, 9.6 Hz), 4.37 (2H, s), 4.78-4.84 (1H, m), 6.51 (1H, d, J = 3.9 Hz), 6.55 (1H, t, J = 2.2 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.86-6.88 (3H, m), 6.98 (1H, s), 7.27 (2H, d, J = 8.2 Hz), 7.41 (1H, dd, J = 8.6, 2.7 Hz), 7.94 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
(24e) 5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -Methoxyphenoxy) -N-methylpyridine-2-sulfonamide In a nitrogen atmosphere, the compound synthesized in Example (24d) (81 mg, 0.14 mmol) was added to trifluoroacetic acid (0.5 mL) and methylene chloride (5 mL). Dissolved and stirred for 16 hours. Saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted twice with methylene chloride (20 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (43 mg, yield) as a white solid. 67%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.76 (3H, d, J = 3.4 Hz), 3.72 (1H, dd, J = 12.7, 4.9 Hz), 3.76-3.81 (1H, m), 3.86-3.89 (4H, m), 4.04 (1H, dd, J = 14.2, 9.8 Hz), 4.81 (1H, s), 5.05 (1H, br s), 6.51 (1H, d, J = 3.9 Hz), 6.54 (1H , t, J = 2.2 Hz), 6.76 (1H, d, J = 3.4 Hz), 6.87 (1H, t, J = 1.7 Hz), 6.99 (1H, s), 7.41 (1H, dd, J = 8.5, 2.7 Hz), 7.96 (1H, d, J = 8.8 Hz), 8.45 (1H, d, J = 2.4 Hz).
MS (ESI) m / z: 459.13442 (M + H) ^<+> .

(Example 25)
{(5R) -2- [5- (3-{[6- (azetidin-1-ylsulfonyl) pyridin-3-yl] oxy} -5-methoxyphenyl) -1H-pyrrol-2-yl] -4 , 5-Dihydro-1,3-oxazol-5-yl} methanol

(25a) 2- (azetidin-1-ylsulfonyl) -5-chloropyridine The compound (1.00 g, 6.87 mmol) synthesized in Example (24a) was dissolved in methylene chloride (30 mL) / 1N hydrochloric acid (30 mL). And cooled to -5 ° C. While maintaining the reaction solution at 0 ° C. or lower, an ice-cooled 7% sodium perchlorate aqueous solution (30 mL) was added dropwise, and the mixture was stirred as it was for 15 minutes. The organic layer was extracted with a separatory funnel previously cooled with ice, cooled to −78 ° C., and a commercial maze of azetidine hydrochloride (2.24 mg, 17.2 mmol) in methylene chloride (10 mL) was added. The temperature was raised and the mixture was stirred for 30 minutes. Water (30 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then 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: ethyl acetate / hexane = 5% -60%) to give the target compound (735 mg, yield) as a white solid. 46%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.19-2.25 (2H, m), 4.10 (4H, t, J = 7.8 Hz), 7.91 (1H, dd, J = 8.3, 2.0 Hz), 7.95 (1H , d, J = 7.8 Hz), 8.72 (1H, d, J = 2.0 Hz).
(25b) {(5R) -2- [5- (3-{[6- (azetidin-1-ylsulfonyl) pyridin-3-yl] oxy} -5-methoxyphenyl) -1H-pyrrol-2-yl ] -4,5-dihydro-1,3-oxazol-5-yl} methanol The compound synthesized in Example (25a) (100 mg, 0.43 mmol) and the compound synthesized in Example (21f) (161 mg, 0 .56 mmol) was dissolved in N, N-dimethylformamide (3 mL), cesium carbonate (280 mg, 0.86 mmol) was added, and the mixture was stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 1% to 5%) to give the desired compound (111 mg, yield) as a white solid. 53%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.18-2.24 (2H, m), 3.72 (1H, dd, J = 12.2, 5.4 Hz), 3.79 (1H, dd, J = 14.2, 7.8 Hz), 3.86 -3.89 (4H, m), 4.05 (1H, dd, J = 14.2, 9.8 Hz), 4.10 (4H, t, J = 7.8 Hz), 4.82 (1H, s), 6.51 (1H, d, J = 3.4 Hz), 6.55 (1H, t, J = 2.0 Hz), 6.76 (1H, s), 6.88 (1H, d, J = 1.5 Hz), 6.99 (1H, s), 7.43 (1H, dd, J = 8.5 , 2.7 Hz), 7.95 (1H, d, J = 8.8 Hz), 8.54 (1H, d, J = 2.4 Hz).
MS (ESI) m / z: 485.14698 (M + H) ^<+> .

(Example 26)
[(5R) -2- {5- [3-methoxy-5-({6-[(methoxymethyl) sulfonyl] pyridin-3-yl} oxy) phenyl] -1H-pyrrol-2-yl} -4, 5-Dihydro-1,3-oxazol-5-yl] methanol

(26a) 5-Chloro-2-[(methoxymethyl) thio] pyridine The compound synthesized in Example (24a) (200 mg, 1.37 mmol) was dissolved in methanol (5 mL), and a 28% sodium methoxide / methanol solution was obtained. (0.30 mL, 1.55 mmol) and methoxymethyl chloride (0.23 mL, 3.01 mmol) were added, and the mixture was stirred at 50 ° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 0% -20%) to give the target compound (188 mg, yield) as a colorless oily liquid. 74%).
¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.51 (3H, s), 3.37 (2H, s), 7.22 (1H, d, J = 10.2 Hz), 7.47 (1H, dd, J = 3.1, 8.6 Hz) , 8.40 (1H, d, J = 2.7 Hz).
(26b) 5-chloro-2-[(methoxymethyl) sulfonyl] pyridine The compound synthesized in Example (26a) (187 mg, 0.99 mmol) was dissolved in methylene chloride (10 mL), and m-chloroperbenzoic acid ( (524 mg, 1.97 mmol) was added, and the mixture was stirred at 0 ° C. for 75 minutes under a nitrogen atmosphere. Water (30 mL) was added to the reaction mixture, and the mixture was extracted twice with methylene chloride (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 35%) to give the target compound (187 mg, yield) as a white solid. 85%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.66 (3H, s), 4.88 (2H, s), 7.98 (1H, dd, J = 8.3, 2.4 Hz), 8.12 (1H, d, J = 8.3 Hz ), 8.75 (1H, d, J = 2.0 Hz).
(26c) [(5R) -2- {5- [3-methoxy-5-({6-[(methoxymethyl) sulfonyl] pyridin-3-yl} oxy) phenyl] -1H-pyrrol-2-yl} -4,5-dihydro-1,3-oxazol-5-yl] methanol The compound synthesized in Example (26b) (185 mg, 0.83 mmol) and the compound synthesized in Example (21f) (360 mg, 1. 25 mmol) was dissolved in N, N-dimethylformamide (3 mL), potassium carbonate (231 mg, 1.67 mmol) was added, and the mixture was stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0.5% -4%) to give the desired compound (229 mg, Yield 58%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.67 (3H, s), 3.75 (1H, dd, J = 12.2, 5.4 Hz), 3.82 (1H, dd, J = 14.6, 7.3 Hz), 3.86-3.91 (4H, m), 4.08 (1H, dd, J = 14.2, 9.8 Hz), 4.81-4.87 (3H, m), 6.53 (1H, d, J = 3.9 Hz), 6.57 (1H, t, J = 2.2 Hz), 6.77 (1H, d, J = 3.9 Hz), 6.89 (1H, d, J = 1.5 Hz), 7.01 (1H, s), 7.47 (1H, dd, J = 8.3, 2.9 Hz), 8.11 ( 1H, d, J = 8.3 Hz), 8.55 (1H, d, J = 2.9 Hz).
MS (ESI) m / z: 474.13312 (M + H) ^<+> .

(Example 27)
{(5R) -2- [5- (3-{[6- (Cyclopropylsulfonyl) pyridin-3-yl] oxy} -5-methoxyphenyl-1H-pyrrol-2-yl] -4,5-dihydro -1,3-oxazol-5-yl} methanol

(27a) 5-Chloro-2-[(3-chloropropyl) thio] pyridine The compound synthesized in Example (24a) (600 mg, 4.12 mmol) was dissolved in methanol (15 mL), and 28% sodium methoxide / A methanol solution (0.95 mL, 4.94 mmol) and 1-bromo-3-chloropropane (0.61 mL, 6.18 mmol) were added, and the mixture was stirred at 60 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature, water (40 mL) was added, and the mixture was extracted twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, followed by vacuum drying to obtain the target compound (846 mg, yield 92%) as a colorless oily liquid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.21-2.14 (2H, m), 3.30 (2H, t, J = 6.8 Hz), 3.67 (2H, t, J = 6.3 Hz), 7.13 (1H, dd , J = 8.6, 0.8 Hz), 7.45 (1H, dd, J = 8.6, 2.3 Hz), 8.37 (1H, dd, J = 5.1, 3.1 Hz).
(27b) 5-Chloro-2-[(3-chloropropyl) sulfonyl] pyridine The compound synthesized in Example (27a) (846 mg, 3.80 mmol) was dissolved in methylene chloride (20 mL). -Chloroperbenzoic acid (2.02 g, 7.62 mmol) was added and stirred as such for 1 hour. Saturated aqueous sodium hydrogen carbonate solution (40 mL) was added to the reaction mixture, and the mixture was extracted twice with methylene chloride (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 0% -20%) to give the target compound (733 mg, yield) as a colorless oily liquid. 76%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.26-2.31 (2H, m), 3.55-3.58 (2H, m), 3.67 (2H, t, J = 6.3 Hz), 7.96 (1H, dd, J = 8.3, 2.0 Hz), 8.06 (1H, d, J = 7.8 Hz), 8.70 (1H, d, J = 2.4 Hz).

(27c) 5-Chloro-2- (cyclopropylsulfonyl) pyridine The compound synthesized in Example (27b) (732 mg, 3.05 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to −30 ° C., potassium-t -Butoxide (582 mg, 5.18 mmol) was added and stirred as such for 30 minutes. A saturated aqueous ammonium chloride solution (40 mL) was added to the reaction mixture, and the mixture was extracted twice with methylene chloride (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 25%) to give the desired compound (397 mg, yield) as a white solid. 60%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.07-1.12 (2H, m), 1.37-1.41 (2H, m), 2.76-2.83 (1H, m), 7.91 (1H, dd, J = 8.2, 2.3 Hz), 7.98 (1H, d, J = 8.2 Hz), 8.71 (1H, dd, J = 2.3, 0.8 Hz).
(27d) {(5R) -2- [5- (3-{[6- (cyclopropylsulfonyl) pyridin-3-yl] oxy} -5-methoxyphenyl-1H-pyrrol-2-yl] -4, 5-dihydro-1,3-oxazol-5-yl} methanol Compound (266 mg, 1.22 mmol) synthesized in Example (27c) and compound (440 mg, 1.53 mmol) synthesized in Example (21f) It was dissolved in N, N-dimethylformamide (3 mL), potassium carbonate (338 mg, 2.44 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 3 hours at 100 ° C. The reaction mixture was cooled to room temperature and water (30 mL) was added. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) gave the target compound (96 mg, 17% yield) as a white solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.06-1.11 (2H, m), 1.37-1.41 (2H, m), 2.80 (1H, tt, J = 8.2, 4.3 Hz), 3.70-3.89 (6H, m), 4.04 (1H, dd, J = 14.3, 10.0 Hz), 4.85-4.78 (1H, m), 6.51 (1H, d, J = 3.5 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.76 (1H, d, J = 3.5 Hz), 6.87 (1H, t, J = 1.8 Hz), 6.99 (1H, t, J = 2.0 Hz), 7.42 (1H, dd, J = 8.6, 2.7 Hz), 7.98 (1H, d, J = 9.4 Hz), 8.52 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 470.13790 (M + H) ^<+> .

(Example 28)
{(5R) -2- [5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5- Dihydro-1,3-oxazol-5-yl} methanol

(28a) 1-Bromo-3-isopropoxy-5-methoxybenzene The compound synthesized in Example (1a) (31.62 g, 155.74 mmol) was dissolved in N, N-dimethylformamide (200 mL), and 2- Bromopropane (29.25 mL, 311.48 mmol) and potassium carbonate (64.57 g, 467.22 mmol) were added, and the mixture was stirred at 60 ° C. for 3 hours under a nitrogen atmosphere. 1N Hydrochloric acid (200 mL) was added, and the mixture was extracted with diethyl ether (1.0 L). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 10%) to give a colorless oily target compound (33.95 g, Yield 89%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.29 (6H, d, J = 5.9 Hz), 3.73 (3H, s), 4.41-4.50 (1H, m), 6.33 (1H, t, J = 2.3 Hz ), 6.59-6.62 (2H, m).
(28b) 3-Bromo-5-isopropoxyphenol The compound (33.95 g, 138.51 mmol) synthesized in Example (28a) and sodium thiomethoxide (10.68 g, 152.36 mmol) were used. A pale yellow oily target compound (31.52 g, yield 98%) was obtained in the same manner as in 1a).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.32 (6H, d, J = 5.9 Hz), 4.43-4.52 (1H, m), 5.14 (1H, s), 6.31 (1H, t, J = 2.0 Hz ), 6.58 (1H, t, J = 2.0 Hz), 6.63 (1H, t, J = 2.0 Hz).
(28c) 3-Isopropoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol The compound synthesized in Example (28b) (31.52 g, 136 .4 mmol), bis (pinacolato) diboron (51.96 g, 204.6 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (3.34 g, 4.09 mmol), The target compound (33.36 g, yield 88%) as a yellow oil was obtained using potassium acetate (66.93 g, 682.0 mmol) in the same manner as in Example (1d).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.31 (6H, d, J = 6.3 Hz), 1.33 (12H, s), 4.51-4.60 (1H, m), 5.00 (1H, s), 6.51 (1H , t, J = 2.3 Hz), 6.82 (1H, d, J = 2.3 Hz), 6.92 (1H, d, J = 2.3 Hz).

(28d) 2-Benzyl 1-t-butyl 5- (3-hydroxy-5-isopropoxyphenyl) -1H-pyrrole-1,2-dicarboxylate Compound synthesized in Example (28c) (20.17 g, 72.51 mmol), the compound synthesized in Example (16d) (28.95 g, 76.14 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (2.96 g, 3.63 mmol) and potassium carbonate (49.11 g, 355.32 mmol) were used to obtain the target compound (27.53 g, yield 84%) as a brown oil in the same manner as in Example (16e).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.31 (6H, d, J = 5.9 Hz), 1.40 (9H, s), 4.46-4.55 (1H, m), 5.30 (2H, s), 5.58 (1H , s), 6.16 (1H, d, J = 3.9 Hz), 6.39 (1H, t, J = 2.0 Hz), 6.46 (1H, t, J = 2.0 Hz), 6.51 (1H, d, J = 2.0 Hz) ), 6.94 (1H, t, J = 3.9 Hz), 7.30-7.43 (5H, m).
(28e) Benzyl 5- (3-hydroxy-5-isopropoxyphenyl) -1H-pyrrole-2-carboxylate Compound (9.97 g, 22.08 mmol) synthesized in Example (28d) was dissolved in methylene chloride (100 mL). Dissolved in. Trifluoroacetic acid (40 mL) was added dropwise with stirring at room temperature under a nitrogen atmosphere. After stirring for 30 minutes, the solvent was distilled off under reduced pressure. The mixture was diluted with ethyl acetate (400 mL), and a saturated aqueous sodium hydrogen carbonate solution (200 mL) was added to separate the layers. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% -35%) to give the target compound (6.20 g) as a pale brown solid. , Yield 80%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.34 (6H, d, J = 5.9 Hz), 4.51-4.58 (1H, m), 5.35 (2H, s), 6.38 (1H, t, J = 2.3 Hz ), 6.49 (1H, dd, J = 2.7, 3.9 Hz), 6.69 (1H, t, J = 2.0 Hz), 6.81 (1H, t, J = 2.0 Hz), 6.86 (1H, brs), 6.99 (1H , dd, J = 2.3, 3.9 Hz), 7.32-7.46 (5H, m).
(28f) Benzyl 5- (3-isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxylate Compound synthesized in Example (28e) (6.20 g, 17.64 mmol), the compound synthesized in Example (16a) (3.48 g, 18.17 mmol) was dissolved in N, N-dimethylformamide (100 mL), and cesium carbonate (17.25 g, 52 .93 mmol) was added, and the mixture was stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with diethyl ether (400 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 30% -50%) to give the desired compound (6.21 g, 6.21 g, Yield 69%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.36 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 4.52-4.61 (1H, m), 5.33 (2H, s), 6.51-6.54 (2H, m), 6.84 (1H, t, J = 2.0 Hz), 6.96 (1H, t, J = 2.0 Hz), 6.99 (1H, dd, J = 2.3, 3.9 Hz), 7.34-7.45 (6H, m), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.33 (1H, brs).

(28 g) 5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxylic acid Compound synthesized in Example (28f) ( 6.21 g, 12.26 mmol) was dissolved in a mixed solvent of ethyl acetate (70 mL) and ethanol (20 mL), 10% palladium carbon catalyst (1.17 g) was added, and the mixture was stirred under a hydrogen atmosphere for 2 hours. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (5.20 g, yield ˜100%) as a pale orange solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.37 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 4.54-4.63 (1H, m), 6.54-6.57 (2H, m), 6.87 (1H, s), 7.00 (1H, s), 7.07 (1H, dd, J = 2.3, 3.9 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.49 (1H, brs).
(28h) N-[(2S) -2,3-dihydroxypropyl] -5- (3-isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole -2-Carboxamide Compound (1.83 g, 4.39 mmol) synthesized in Example (28 g), (S)-(−)-3-amino-1,2-propanediol (1.00 g, 10.99 mmol) , DMT-MM (2.09 g, 6.59 mmol) was used to give the target compound (0.79 g, 37%) as a white solid in the same manner as in Example (5d).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.36 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 3.55-3.63 (4H, m), 3.82-3.86 (1H, m), 4.54 -4.60 (1H, m), 6.39-6.43 (1H, br m), 6.48-6.52 (2H, m), 6.63 (1H, s), 6.84 (1H, s), 6.96 (1H, s), 7.43 ( 1H, dd, J = 2.9, 8.8 Hz), 8.03 (1H, d, J = 8.3 Hz), 8.47 (1H, s).
(28i) N-{(2S) -2-hydroxy-3-[(triisopropylsilyl) oxy] propyl} -5- (3-isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl ] Oxy} phenyl) -1H-pyrrole-2-carboxamide The compound (0.79 g, 1.61 mmol) synthesized in Example (28h) was dissolved in methylene chloride (20 mL), and triisopropylsilyl chloride (0.52 mL, 2.42 mmol), triethylamine (1.12 mL, 8.07 mol) and 4-dimethylaminopyridine (0.30 g, 2.42 mmol) were added, and the mixture was stirred at room temperature for 22 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 30% -60%) to give the desired product (779 mg, yield) as a white solid. 75%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.04-1.16 (21H, m), 1.37 (6H, d, J = 5.9 Hz), 3.12 (1H, d, J = 4.3 Hz), 3.23 (3H, s ), 3.36-3.44 (1H, m), 3.65-3.79 (3H, m), 3.84-3.90 (1H, m), 4.54-4.61 (1H, m), 6.33 (1H, t, J = 5.1 Hz), 6.49-6.52 (2H, m), 6.61 (1H, dd, J = 2.3, 3.9 Hz), 6.82 (1H, t, J = 1.6 Hz), 6.94 (1H, d, J = 1.6 Hz), 7.44 (1H , dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.41 (1H, brs).

(28j) 5- (3-Isopropoxy-5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazol-2-yl ] -1H-pyrrol-2-yl} phenoxy) -2- (methylsulfonyl) pyridine The compound synthesized in Example (28i) (779 mg, 1.21 mmol), methanesulfonic anhydride (420 mg, 2.41 mmol), Using triethylamine (0.67 mL, 4.82 mmol), the target product (695 mg, yield 92%) was obtained as a pale yellow solid in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.03-1.12 (21H, m), 1.36 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 3.83-3.91 (4H, m), 4.54 -4.59 (1H, m), 4.73-4.78 (1H, m), 6.49-6.51 (2H, m), 6.73 (1H, d, J = 3.4 Hz), 6.80 (1H, t, J = 1.5 Hz), 6.93 (1H, t, J = 1.5 Hz), 7.44 (1H, dd, J = 2.9, 8.8 Hz), 8.05 (1H, d, J = 8.8 Hz), 8.49 (1H, d, J = 2.9 Hz).
(28k) {(5R) -2- [5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4 , 5-Dihydro-1,3-oxazol-5-yl} methanol Compound (921 mg, 1.47 mmol) synthesized in Example (28j), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 1.61 mL, 1 .61 mmol) was used to obtain the target compound (538 mg, yield 78%) as a white solid in the same manner as in Example (16k).
¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.36 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 3.69-3.79 (2H, m), 3.84 (1H, dd, J = 3.4, 12.7 Hz), 4.03 (1H, dd, J = 9.8, 14.2 Hz), 4.53-4.61 (1H, m), 4.76-4.82 (1H, m), 6.46 (1H, d, J = 3.9 Hz), 6.51 ( 1H, t, J = 2.4 Hz), 6.69 (1H, d, J = 3.9 Hz), 6.81 (1H, t, J = 2.0 Hz), 6.95 (1H, t, J = 2.0 Hz), 7.44 (1H, dd, J = 2.9, 8.8 Hz), 8.04 (1H, d, J = 8.8 Hz), 8.48 (1H, d, J = 2.9 Hz).
MS (ESI) m / z: 472.15594 (M + H) ^<+> .

(Example 29)
5- (3-Isopropoxy-5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy)- 2- (Methylsulfonyl) pyridine

(29a) N-[(1R) -2-hydroxy-1-methylethyl] -5- (3-isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrole-2-carboxamide Compound (530 mg, 1.27 mmol) synthesized in Example (28 g), D-alaninol (0.15 mL, 1.91 mmol), HOBT.H ₂ O (206 mg, 1.53 mmol), N -Methylmorpholine (0.28 mL, 2.55 mmol) was dissolved in N, N-dimethylformamide (12 mL), WSCI · HCl (268 mg, 1.40 mmol) was added at room temperature, and the mixture was stirred under a nitrogen atmosphere for 20 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 60% to 100%) to give the target compound (538 mg, 89%) as a white solid. )
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.27 (3H, d, J = 6.3 Hz), 1.36 (6H, d, J = 6.3 Hz), 2.83-2.87 (1H, m), 3.23 (3H, s ), 3.59-3.65 (1H, m), 3.73-3.78 (1H, m), 4.21-4.28 (1H, br m), 4.52-4.60 (1H, m), 6.09 (1H, d, J = 7.4 Hz) , 6.49 (1H, t, J = 3.1 Hz), 6.51 (1H, t, J = 2.0 Hz), 6.61 (1H, dd, J = 2.3, 3.9 Hz), 6.83 (1H, t, J = 2.0 Hz) , 6.95 (1H, d, J = 2.0 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz) , 9.69 (1H, br s).
(29b) 5- (3-Isopropoxy-5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} Phenoxy) -2- (methylsulfonyl) pyridine Compound (538 mg, 1.14 mmol) synthesized in Example (29a), methanesulfonic anhydride (408 mg, 2.27 mmol), triethylamine (0.63 mL, 4.54 mmol) Was used to give the target compound (395 mg, yield 76%) as a white solid in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.32 (3H, d, J = 6.6 Hz), 1.36 (6H, d, J = 6.3 Hz), 3.23 (3H, s), 3.92 (1H, t, J = 7.8 Hz), 4.27-4.37 (1H, m), 4.49 (1H, dd, J = 8.2, 9.0 Hz), 4.57 (1H, q, J = 5.9 Hz), 6.50-6.52 (2H, m), 6.75 (1H, d, J = 3.9 Hz), 6.81 (1H, t, J = 1.8 Hz), 6.96 (1H, t, J = 1.8 Hz), 7.42 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
MS (EI) m / z: 455.1517 (M ^<+> ).

(Example 30)
{2- [5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1, 3-oxazol-4-yl} methanol

(30a) Methyl N-{[5- (3-isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] carbonyl} selinate Examples Compound (2.00 g, 4.80 mmol) synthesized in (28 g), DL-serine methyl ester hydrochloride (0.82 g, 5.28 mmol), HOBT.H ₂ O (0.71 g, 5.28 mmol), N -The target compound (2.36 g, 95%) of white solid was prepared in the same manner as in Example (29a) using methylmorpholine (1.06 mL, 9.60 mmol) and WSCI.HCl (1.10 g, 5.76 mmol). )
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.36 (6H, d, J = 5.9 Hz), 2.84 (1H, t, J = 6.1 Hz), 3.24 (3H, s), 3.80 (3H, s), 3.98-4.09 (2H, m), 4.57 (1H, q, J = 5.9 Hz), 4.80-4.84 (1H, m), 6.50-6.52 (2H, m), 6.74 (1H, dd, J = 2.7, 3.9 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.93 (1H, d, J = 7.4 Hz), 6.97 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.77 (1H, br s).
(30b) Methyl 2- [5- (3-isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro -1,3-oxazole-4-carboxylate Compound (2.36 g, 4.41 mmol) synthesized in Example (30a), methanesulfonic anhydride (1.58 g, 8.81 mmol), triethylamine (2.46 mL) , 17.63 mmol) and the white solid target compound (1.52 g, yield 69%) was obtained in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.37 (6H, d, J = 6.3 Hz), 3.24 (3H, s), 3.82 (3H, s), 4.55-4.61 (2H, m), 4.66 (1H , t, J = 8.2 Hz), 4.91 (1H, dd, J = 7.8, 10.6 Hz), 6.51-6.53 (2H, m), 6.80-6.82 (2H, m), 6.95 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.44 (1H, br s).
(30c) {2- [5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro -1,3-oxazol-4-yl} methanol The compound synthesized in Example (30b) (498 mg, 1.00 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (114 mg, 2.99 mmol) was added at 0 ° C. ) Was added. After stirring for 30 minutes under a nitrogen atmosphere, water (0.12 mL), 5N aqueous sodium hydroxide solution (0.12 mL), and water (0.36 mL) were added in this order, and the mixture was stirred for 10 minutes. Ethyl acetate (40 mL) was added and stirred for 5 minutes, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 4%) to give the desired compound (295 mg, 63%) as a white solid. )
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.37 (6H, d, J = 6.3 Hz), 3.23 (3H, s), 3.62 (1H, dd, J = 4.3, 11.7 Hz), 3.90 (1H, dd , J = 2.7, 11.7 Hz), 4.13 (1H, t, J = 7.0 Hz), 4.33-4.39 (1H, m), 4.39-4.43 (1H, m), 4.57 (1H, q, J = 5.9 Hz) , 6.43 (1H, d, J = 3.9 Hz), 6.51 (1H, t, J = 2.0 Hz), 6.60 (1H, d, J = 3.9 Hz), 6.85 (1H, t, J = 1.8 Hz), 6.99 (1H, t, J = 1.8 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 472.15279 (M + H) ^<+> .

(Example 31)
2- [5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3 -Oxazole-4-carboxylic acid

The compound synthesized in Example (30b) (620 mg, 1.24 mmol) was dissolved in ethanol (12 mL), 2N aqueous sodium hydroxide solution (6.21 mL) was added, and the mixture was heated to reflux for 1 hour under a nitrogen atmosphere.
The reaction solution was neutralized with 2N hydrochloric acid, and the solvent was distilled off under reduced pressure. Water (50 ml) was added and extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound (600 mg, yield 100%) as a white solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.36 (6H, d, J = 6.3 Hz), 3.21 (3H, s), 4.63 (1H, q, J = 5.9 Hz), 4.88-4.98 (2H, m ), 5.01-5.07 (1H, m), 6.58 (1H, s), 6.62 (1H, s), 7.14 (1H, s), 7.26 (1H, s), 7.36 (1H, s), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.02 (1H, d, J = 8.6 Hz), 8.51 (1H, d, J = 2.7 Hz), 13.72 (1H, br s).
MS (ESI) m / z: 486.13511 (M + H) ^<+> .

(Example 32)
2- [5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -N, N-dimethyl-4,5 -Dihydro-1,3-oxazole-4-carboxamide

Compound synthesized in Example 31 (156 mg, 0.32 mmol), dimethylamine hydrochloride (78 mg, 0.96 mmol), WSCI · HCl (123 mg, 0.64 mmol), 4-dimethylaminopyridine (118 mg, 0. 96 mmol) was used to obtain the target compound (111 mg, yield 67%) as a white solid in the same manner as in Example (1k).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.36 (6H, d, J = 5.9 Hz), 2.97 (3H, s), 3.23 (3H, s), 3.25 (3H, s), 4.40-4.47 (1H , m), 4.55 (1H, q, J = 5.9 Hz), 5.00-5.07 (2H, m), 6.49-6.51 (2H, m), 6.77 (1H, d, J = 3.9 Hz), 6.80 (1H, t, J = 1.6 Hz), 6.94 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.70 (1H, br s).
MS (ESI) m / z: 513.18300 (M + H) ^<+> .

(Example 33)
2- [5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3 -Oxazole-4-carboxamide

The compound synthesized in (Example 31) (200 mg, 0.41 mmol) was dissolved in methylene chloride (10 mL), an aqueous ammonia solution (28%, 0.13 mL, 2.06 mmol), WSCI · HCl (95 mg, 0.49 mmol). ), HOBT.H ₂ O (61 mg, 0.45 mmol) was added, and the mixture was stirred at room temperature for 5 hours under a nitrogen atmosphere. The reaction mixture was diluted with methylene chloride (30 mL), washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 4%) to give the target compound (145 mg, yield) as a white solid. 73%).
¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.37 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 4.55-4.66 (3H, m), 4.78 (1H, dd, J = 8.3, 10.3 Hz), 5.59 (1H, br s), 6.54 (2H, s), 6.60 (1H, br s), 6.83-6.85 (2H, m), 6.98 (1H, s), 7.45 (1H, dd, J = 2.9, 8.8 Hz), 8.05 (1H, d, J = 8.8 Hz), 8.48 (1H, d, J = 2.9 Hz), 9.49 (1H, br s).
MS (ESI) m / z: 485.14881 (M + H) ^<+> .

(Example 34)
2- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -5-[(4-methylpiperazin-1-yl) carbonyl] pyrazine

(34a) 2-Chloro-5-[(4-methylpiperazin-1-yl) carbonyl] pyrazine 5-hydroxypyrazine-2-carboxylic acid (5.00 g, 39.0 mmol) was dissolved in thionyl chloride (64 mL). After adding a few drops of N, N-dimethylformamide, the mixture was heated to reflux for 5 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was diluted with methylene chloride (50 mL). Diisopropylethylamine (18.7 mL, 107 mmol) and 1-methylpiperazine (4.37 mL, 39.2 mmol) were added while cooling in an ice bath, and the mixture was stirred at room temperature for 3 days under a nitrogen atmosphere. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 3% to 5%) to give the target compound (5.32 g, 5.3%, Yield 62%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.34 (3H, s), 2.44 (2H, t, J = 5.1 Hz), 2.53 (2H, t, J = 5.1 Hz), 3.64 (2H, t, J = 5.1 Hz), 3.84 (2H, t, J = 4.9 Hz), 8.55 (1H, d, J = 1.2 Hz), 8.76 (1H, d, J = 1.6 Hz).
(34b) (2R) -1-{[t-Butyl (dimethyl) silyl] oxy} propan-2-ol (R)-(−)-1,2-propanediol (21.23 g, 279.01 mmol) Dissolve in methylene chloride (300 ml) and add triethylamine (58.33 mL, 418.52 mmol), 4-dimethylaminopyridine (3.41 g, 27.90 mmol), t-butyldimethylchlorosilane (42.05 g, 279.01 mmol). In addition, the mixture was stirred overnight at room temperature. The mixture was diluted with methylene chloride (200 mL), and washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 20%) to give a colorless oil. The target compound (43.75 g, 82%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 0.08 (6H, s), 0.91 (9H, s), 1.12 (3H, d, J = 6.3 Hz), 2.46 (1H, br s), 3.35 (1H, dd, J = 7.8, 10.2 Hz), 3.59 (1H, dd, J = 3.5, 10.2 Hz), 3.78-3.86 (1H, m).
(34c) {[(2S) -2- (3-Bromo-5-methoxyphenoxy) propyl] oxy} (t-butyl) dimethylsilane Compound synthesized in Example (1a) (33.47 g, 164.9 mmol) The compound synthesized in Example (34b) (37.7 g, 197.82 mmol), triphenylphosphine (47.74 g, 181.3 mmol), diethyl azodicarboxylate (40% toluene solution, 79.00 mL, 181.34 mmol) ) To give a colorless oily target compound (57.19 g, yield 92%) in the same manner as in Example (20a).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 0.04 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.27 (3H, d, J = 6.3 Hz), 3.63 (1H, dd , J = 5.1, 10.6 Hz), 3.74-3.78 (1H, m), 3.76 (3H, s), 4.34-4.41 (1H, m), 6.39 (1H, t, J = 2.3 Hz), 6.64 (1H, t, J = 1.6 Hz), 6.69 (1H, t, J = 1.6 Hz).

(34d) 3-Bromo-5-[(1S) -2-{[t-butyl (dimethyl) silyl] oxy} -1-methylethoxy] phenol Compound (57.19 g, 152 mmol) synthesized in Example (34c) ) And sodium thiomethoxide (11.56 g, 160 mmol), and the target compound (45.50 g, yield 83%) was obtained as a pale yellow oil in the same manner as in Example (1a).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 0.04 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.27 (3H, d, J = 6.3 Hz), 3.63 (1H, dd , J = 5.1, 10.6 Hz), 3.75 (1H, dd, J = 5.9, 10.6 Hz), 4.40-4.33 (1H, m), 6.34 (1H, t, J = 2.0 Hz), 6.58 (1H, s) , 6.66 (1H, s).
(34e) Benzyl 5- {3-[(1S) -2-{[t-butyl (dimethyl) silyl] oxy} -1-methylethoxy] -5-hydroxyphenyl} -1H-pyrrole-2-carboxylate Compound (45.50 g, 126 mmol) synthesized in Example (34d), compound (43.26 g, 132 mmol) synthesized in Example (19e), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II ) Dichloride Dichloromethane complex (5.14 g, 6.30 mmol) and potassium carbonate (87.01 g, 630 mmol) were used in the same manner as in Example (16e), and the target compound (56.70 g, yield: 93%) was obtained. )
¹ H-NMR (CDCl ₃ , 400 MHz): δ 0.05 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.30 (3H, d, J = 6.3 Hz), 3.64 (1H, dd , J = 5.5, 10.6 Hz), 3.80 (1H, dd, J = 5.9, 10.6 Hz), 4.40-4.48 (1H, m), 5.35 (2H, s), 6.41 (1H, t, J = 2.0 Hz) , 6.48 (1H, dd, J = 2.7, 3.9 Hz), 6.66 (1H, br s), 6.71 (1H, t, J = 1.6 Hz), 6.80 (1H, t, J = 1.6 Hz), 6.99 (1H , dd, J = 2.7, 3.9 Hz), 7.32-7.46 (5H, m), 9.92 (1H, s).
(34f) Benzyl 5- {3-hydroxy-5-[(1S) -2-hydroxy-1-methylethoxy] phenyl} -1H-pyrrole-2-carboxylate Compound (34.) synthesized in Example (34e). 12 g, 70.84 mmol), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 79.00 mL, 79.00 mmol), and the target compound (22.00 g) as a pale yellow oil in the same manner as in Example (16k). Yield 85%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.27 (3H, d, J = 6.3 Hz), 3.70-3.79 (2H, m), 4.47-4.54 (1H, m), 5.34 (2H, s), 6.40 (1H, t, J = 2.0 Hz), 6.47 (1H, dd, J = 2.7, 3.9 Hz), 6.53 (1H, br s), 6.70 (1H, t, J = 1.6 Hz), 6.76 (1H, t , J = 1.6 Hz), 6.98 (1H, dd, J = 2.3, 3.9 Hz), 7.32-7.46 (5H, m), 9.83 (1H, br s).

(34 g) Benzyl 5- {3-[(1S) -2-fluoro-1-methylethoxy] -5-hydroxyphenyl} -1H-pyrrole-2-carboxylate Compound (4.) synthesized in Example (34f). 81 g, 13.09 mmol) was dissolved in 1,2-dimethoxyethane (100 mL), and bis (2-methoxyethyl) aminosulfur trifluoride (3.14 mL, 17.02 mmol) was added dropwise at -78 ° C. After stirring for 30 minutes under a nitrogen atmosphere, the temperature was naturally raised, and bis (2-methoxyethyl) aminosulfur trifluoride (3.00 mL, 16.27 mmol) was added again at 0 ° C., followed by stirring for 30 minutes. The mixture was naturally warmed up and stirred at room temperature for 2 hours. Further, bis (2-methoxyethyl) aminosulfur trifluoride (4.80 mL, 26.03 mmol) was added, and the mixture was stirred overnight. Ethanol (10 mL) was added and the mixture was stirred for 10 min, and water (40 mL) was added. The mixture was extracted with ethyl acetate (200 mL), and 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 (elution solvent: ethyl acetate / hexane = 20% -40%) to give the target compound (4.00 g, 4.00 g, 83%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.35 (3H, dd, J = 1.6, 6.3 Hz), 4.41-4.69 (3H, m), 5.35 (2H, s), 6.32 (1H, br s), 6.41 (1H, t, J = 2.0 Hz), 6.49 (1H, dd, J = 2.7, 3.9 Hz), 6.73 (1H, t, J = 1.6 Hz), 6.81 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.3, 3.9 Hz), 7.33-7.46 (5H, m), 9.81 (1H, s).
(34h) Benzyl 5- {3-[(1S) -2-fluoro-1-methylethoxy] -5-({5-[(4-methylpiperazin-1-yl) carbonyl] pyrazin-2-yl} oxy ) Phenyl} -1H-pyrrole-2-carboxylate Compound (1.50 g, 4.06 mmol) synthesized in Example (34 g) and compound (0.96 g, 3.98 mmol) synthesized in (34a) were mixed with acetonitrile ( 40 mL), potassium carbonate (1.68 g, 12.18 mmol) was added, and the mixture was stirred at 80 ° C. for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (80 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 5%) to give the target compound (2.20 g, Yield 94%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.37 (3H, dd, J = 1.6, 6.3 Hz), 2.34 (3H, s), 2.43-2.46 (2H, br m), 2.51-2.54 (2H, br m), 3.69-3.73 (2H, br m), 3.81-3.85 (2H, br m), 4.43-4.72 (3H, m), 5.32 (2H, s), 6.52 (1H, dd, J = 2.7, 4.3 Hz), 6.68 (1H, t, J = 2.0 Hz), 6.96 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.3, 4.3 Hz), 7.03 (1H, t, J = 1.6 Hz), 7.32-7.44 (5H, m), 8.35 (1H, d, J = 1.6 Hz), 8.53 (1H, d, J = 1.2 Hz), 9.31 (1H, br s).

(34i) 5- {3-[(1S) -2-Fluoro-1-methylethoxy] -5-({5-[(4-methylpiperazin-1-yl) carbonyl] pyrazin-2-yl} oxy) Phenyl} -1H-pyrrole-2-carboxylic acid The compound (2.20 g, 3.84 mmol) synthesized in Example (34h) was dissolved in methanol (35 mL), and 10% palladium carbon catalyst (2.4 g) was added. And stirred for 6 hours under a hydrogen atmosphere. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (1.54 g, yield 83%) as a pale yellow solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.30 (3H, s), 2.38 (3H, s), 2.53-2.67 (4H, br m), 3.68-3.88 (4H, br m), 4.37-4.70 ( 3H, m), 6.43 (1H, s), 6.60 (1H, s), 6.79 (1H, s), 7.00-7.11 (2H, m), 8.24 (1H, s), 8.47 (1H, s), 10.41 (1H, br s).
(34j) 2- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -5-[(4-methylpiperazin-1-yl) carbonyl] pyrazine The compound synthesized in Example (34i) (500 mg, 1.03 mmol), (R ) -1-amino-2-propanol (194 mg, 2.59 mmol) and 4-dimethylaminopyridine (505 mg, 4.14 mmol) were dissolved in methylene chloride (20 mL), and WSCI.HCl (496 mg, 2.59 mmol) was dissolved at room temperature. And stirred for 15 hours under a nitrogen atmosphere. The reaction mixture was diluted with methylene chloride (60 mL), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 5%).

Using the obtained white solid compound (360 mg), methanesulfonic anhydride (185 mg, 1.02 mmol) and triethylamine (285 μL, 2.03 mmol), in the same manner as in Example (16j), the purpose of the white solid was The compound (242 mg, yield 49%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.37 (3H, dd, J = 1.6, 6.3 Hz), 1.43 (3H, d, J = 6.3 Hz), 2.34 (3H, s), 2.44-2.48 (2H , br m), 2.51-2.55 (2H, br m), 3.55 (1H, dd, J = 7.4, 14.1 Hz), 3.70-3.74 (2H, br m), 3.81-3.86 (2H, br m), 4.09 (1H, dd, J = 9.4, 14.1 Hz), 4.44-4.72 (3H, m), 4.80-4.88 (1H, m), 6.52 (1H, d, J = 3.9 Hz), 6.65 (1H, t, J = 2.3 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.95 (1H, t, J = 1.6 Hz), 7.04 (1H, t, J = 1.6 Hz), 8.35 (1H, d, J = 1.6 Hz), 8.54 (1H, d, J = 1.2 Hz).
MS (ESI) m / z: 523.24603 (M + H) ^<+> .

(Example 35)
{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol

(35a) Benzyl 5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2 -Carboxylate Compound (924 mg, 2.50 mmol) synthesized in Example (34 g) and compound (503 mg, 2.63 mmol) synthesized in Example (16a) were dissolved in N, N-dimethylformamide (20 mL). Cesium carbonate (2.44 g, 7.50 mmol) was added, and the mixture was stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with diethyl ether (200 mL). The organic layer was washed with saturated brine and then 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: ethyl acetate / hexane = 10% -50%) to give the target compound (1.67 g) as a pale yellow solid. Yield 62%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H, dd, J = 1.6, 6.3 Hz), 3.23 (3H, s), 4.45-4.70 (3H, m), 5.33 (2H, s), 6.52 (1H, dd, J = 3.1, 3.9 Hz), 6.59 (1H, t, J = 2.3 Hz), 6.88 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.3, 3.9 Hz) , 7.01 (1H, t, J = 1.6 Hz), 7.33-7.46 (6H, m), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.33 (1H, br s).
(35b) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2- Carboxylic acid The compound (1.67 g, 3.18 mmol) synthesized in Example (35a) was dissolved in a mixed solvent of ethyl acetate (30 mL) and ethanol (5 mL), 10% palladium carbon catalyst (820 mg) was added, and hydrogen was added. Stir for 5 hours under atmosphere. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (1.31 g, yield 95%) as a white solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.35 (3H, d, J = 6.3 Hz), 3.21 (3H, s), 4.43-4.74 (3H, m), 6.51 (1H, s), 6.60 (1H , s), 6.91 (1H, s), 7.01 (1H, s), 7.05 (1H, s), 7.44 (1H, d, J = 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, s), 9.67 (1H, br s).
(35c) N-[(2S) -2,3-dihydroxypropyl] -5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridine- 3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide Compound (1.31 g, 3.02 mmol) synthesized in Example (35b), (S)-(−)-3-amino-1,2 Using propanediol (0.69 g, 7.54 mmol) and DMT-MM (2.39 g, 7.54 mmol) in the same manner as in Example (5d), the target compound (1.27 g, 83% )
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.35 (3H, dd, J = 1.6, 6.3 Hz), 3.23 (3H, s), 3.47-3.60 (4H, m), 3.79-3.83 (1H, br m ), 4.44-4.73 (3H, m), 6.48 (1H, dd, J = 2.3, 3.9 Hz), 6.54 (1H, t, J = 6.3 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.64 (1H, dd, J = 2.0, 3.9 Hz), 6.89 (1H, t, J = 2.0 Hz), 7.03 (1H, t, J = 2.0 Hz), 7.43 (1H, dd, J = 2.7, 8.6 Hz) , 8.03 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz), 10.03 (1H, br s).

(35d) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -N-{(2S) -2-Hydroxy-3-[(triisopropylsilyl) oxy] propyl} -1H-pyrrole-2-carboxamide The compound (1.27 g, 2.50 mmol) synthesized in Example (35c) was added to methylene chloride (25 mL). Dissolve, add triisopropylsilyl chloride (0.80 mL, 3.75 mmol), triethylamine (1.74 mL, 12.51 mol), 4-dimethylaminopyridine (0.46 g, 3.75 mmol), and add nitrogen at room temperature. Stir for 22 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% to 70%) to give the desired product (1.46 g, Yield 88%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.04-1.13 (21H, m), 1.36 (3H, dd, J = 6.3, 1.6 Hz), 3.13 (1H, d, J = 4.7 Hz), 3.23 (3H , s), 3.34-3.42 (1H, m), 3.64-3.78 (3H, m), 3.83-3.90 (1H, br m), 4.44-4.73 (3H, m), 6.38 (1H, t, J = 5.9 Hz), 6.50 (1H, dd, J = 2.7, 3.9 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.61 (1H, dd, J = 2.3, 3.9 Hz), 6.88 (1H, t, J = 1.6 Hz), 7.01 (1H, d, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.72 (1H, s).
(35e) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5 -Dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -2- (methylsulfonyl) pyridine Compound synthesized in Example (35d) (1.46 g, 2.20 mmol) , Methanesulfonic anhydride (790 mg, 4.40 mmol) and triethylamine (1.23 mL, 8.80 mmol) in the same manner as in Example (16j), the target compound (1.25 g, yield) 88%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.03-1.14 (21H, m), 1.36 (3H, dd, J = 1.6, 6.3 Hz), 3.82-3.94 (4H, m), 4.44-4.71 (3H, m), 4.72-4.79 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.56 (1H, t, J = 2.3 Hz), 6.73 (1H, d, J = 3.9 Hz), 6.85 ( 1H, t, J = 1.6 Hz), 6.99 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 ( (1H, d, J = 2.7 Hz).
(35f) {(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl ) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol Compound (1.25 g, 1.94 mmol) synthesized in Example (35e), tetrabutylammonium The target compound (830 mg, yield 88%) was obtained as a pale yellow solid in the same manner as in Example (16k) using fluoride (1 mol / L tetrahydrofuran solution, 2.32 mL, 2.32 mmol).
¹ H-NMR (CDCl ₃ , 500 MHz): δ1.36 (3H, dd, J = 1.6, 6.3 Hz), 3.23 (3H, s), 3.34 (1H, br s), 3.67-3.77 (2H, m) , 3.82 (1H, dd, J = 3.1, 12.1 Hz), 4.01 (1H, dd, J = 9.8, 13.7 Hz), 4.44-4.72 (3H, m), 4.74-4.81 (1H, m), 6.43 (1H , d, J = 3.9 Hz), 6.56 (1H, t, J = 2.3 Hz), 6.65 (1H, d, J = 3.9 Hz), 6.85 (1H, t, J = 1.6 Hz), 7.00 (1H, t , J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 490.14446 (M + H) ^<+> .

(Example 36)
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -2- (methylsulfonyl) pyridine

(36a) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -N-[(1R) -2-Hydroxy-1-methylethyl] -1H-pyrrole-2-carboxamide Compound (150 mg, 0.35 mmol) synthesized in Example (35b), D-alaninol (80 μL, 1.04 mmol), DMT-MM ( 273 mg, 0.86 mmol) was used to give the target compound (124 mg, 73%) as a white solid in the same manner as in Example (5d).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.26 (3H, d, J = 7.0 Hz), 1.35 (3H, dd, J = 1.6, 6.3 Hz), 2.92 (1H, t, J = 5.5 Hz), 3.23 (3H, s), 3.57-3.63 (1H, m), 3.72-3.78 (1H, m), 4.20-4.27 (1H, br m), 4.45-4.72 (3H, m), 6.11 (1H, d, J = 7.4 Hz), 6.48 (1H, t, J = 3.5 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.60 (1H, dd, J = 2.3, 3.9 Hz), 6.87 (1H, t, J = 1.6 Hz), 7.01 (1H, t, J = 1.6 Hz), 7.43 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.87 (1H, br s).
(36b) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -2- (methylsulfonyl) pyridine The compound synthesized in Example (36a) (124 mg, 0.25 mmol), methanesulfonic anhydride (91 mg, 0.50 mmol) ) And triethylamine (0.14 mL, 1.01 mmol) were used to obtain the target compound (84 mg, 70%) as a white solid in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.33 (3H, d, J = 6.6 Hz), 1.36 (3H, d, J = 6.3 Hz), 3.24 (3H, s), 3.93 (1H, t, J = 7.8 Hz), 4.28-4.37 (1H, m), 4.45-4.72 (4H, m), 6.52 (1H, d, J = 3.5 Hz), 6.56 (1H, t, J = 2.0 Hz), 6.76 (1H , d, J = 3.5 Hz), 6.85 (1H, s), 7.00 (1H, s), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 474.14763 (M + H) ^<+> .

(Example 37)
5- {3-[(1S) -2-fluoro-1-methylethoxy] -5- (5-{[(4R) -4- [2- (methylthio) ethyl] -4,5-dihydro-1, 3-Oxazol-2-yl} -1H-pyrrol-2-yl) phenoxy} -2- (methylsulfonyl) pyridine

(37a) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -N-[(1R) -1- (Hydroxymethyl) -3- (methylthio) propyl] -1H-pyrrole-2-carboxamide Compound synthesized in Example (35b) (150 mg, 0.35 mmol), D-methioninol (51 mg, 0.38 mmol) , HOBT · H ₂ O (51 mg, 0.38 mmol), N-methylmorpholine (76 μL, 0.69 mmol), WSCI · HCl (79 mg, 0.41 mmol) and colorless in the same manner as in Example (29a) An oily target compound (174 mg, 91%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.37 (3H, dd, J = 1.6, 6.3 Hz), 1.90-2.00 (2H, m), 2.14 (3H, s), 2.62 (2H, t, J = 6.6 Hz), 3.24 (3H, s), 3.72-3.82 (2H, m), 4.21-4.29 (1H, br m), 4.45-4.74 (3H, m), 6.41 (1H, d, J = 8.2 Hz) , 6.51 (1H, dd, J = 2.7, 3.9 Hz), 6.58 (1H, d, J = 2.0 Hz), 6.64 (1H, dd, J = 2.3, 3.9 Hz), 6.86 (1H, t, J = 1.8 Hz), 7.00 (1H, t, J = 1.8 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz) 9.49 (1H, br s).
(37b) 5- {3-[(1S) -2-Fluoro-1-methylethoxy] -5- (5-{[(4R) -4- [2- (methylthio) ethyl] -4,5-dihydro -1,3-oxazol-2-yl} -1H-pyrrol-2-yl) phenoxy} -2- (methylsulfonyl) pyridine Compound (178 mg, 0.32 mmol) synthesized in Example (37a), methanesulfonic acid The target compound (88 mg, 51%) was obtained as a white solid in the same manner as in Example (16j) using anhydride (116 mg, 0.65 mmol) and triethylamine (0.22 mL, 1.61 mmol).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.34 (3H, dd, J = 1.6, 6.3 Hz), 1.75-1.90 (2H, m), 2.03 (3H, s), 2.49-2.63 (2H, m) , 3.23 (3H, s), 4.03 (1H, t, J = 7.8 Hz), 4.24-4.32 (1H, m), 4.42-4.68 (4H, m), 6.51 (1H, d, J = 3.9 Hz), 6.55 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.88 (1H, t, J = 1.6 Hz), 7.02 (1H, t, J = 1.6 Hz), 7.42 ( 1H, dd, J = 2.7, 8.6 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
MS (FAB ^<+> ) m / z: 534.1534 (M + H) ^<+> .

(Example 38)
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol

(38a) Methyl N-{[5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrole-2-yl] carbonyl} -L-serineate Compound (1.10 g, 2.53 mmol) synthesized in Example (35b), L-serine methyl ester hydrochloride (0.43 g, 2.79 mmol), HOBT H ₂ O (0.38 g, 2.79 mmol), N-methylmorpholine (0.56 mL, 5.06 mmol) was dissolved in a mixed solvent of methylene chloride (20 mL) and N, N-dimethylformamide (8 mL), WSCI · HCl (0.58 g, 3.04 mmol) was added at room temperature, and the mixture was stirred for 20 hours under a nitrogen atmosphere. The reaction mixture was diluted with methylene chloride (200 mL), washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and 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 (elution solvent: ethyl acetate / hexane = 50% -80%) to give the desired compound (1.21 g, 89%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H, dd, J = 1.6, 6.6 Hz), 3.23 (3H, s), 3.81 (3H, s), 3.99-4.09 (2H, m), 4.44 -4.72 (3H, m), 4.80-4.85 (1H, m), 6.51 (1H, dd, J = 2.7, 3.9 Hz), 6.58 (1H, t, J = 2.0 Hz), 6.74 (1H, dd, J = 2.3, 3.9 Hz), 6.86 (1H, br s), 6.88 (1H, t, J = 1.6 Hz), 7.02 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.75 (1H, br s).
(38b) Methyl (4S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl ) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazole-4-carboxylate The compound synthesized in Example (38a) (910 mg, 1.70 mmol) was added to methylene chloride (20 mL). After dissolution, bis (2-methoxyethyl) aminosulfur trifluoride (0.39 mL, 2.12 mmol) was added dropwise at −78 ° C. After stirring for 30 minutes under a nitrogen atmosphere, potassium carbonate (0.35 g, 2.55 mmol) was added, and the mixture was stirred at 0 ° C. for 10 minutes, allowed to warm naturally and stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added, and the mixture was extracted with methylene chloride (50 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 (elution solvent: ethyl acetate / hexane = 30% -70%) to give the target compound (811 mg, 92%) as a white solid. )
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.37 (3H, dd, J = 1.6, 6.6 Hz), 3.24 (3H, s), 3.82 (3H, s), 4.45-4.73 (5H, m), 4.91 (1H, dd, J = 7.8, 10.9 Hz), 6.52 (1H, d, J = 3.9 Hz), 6.59 (1H, t, J = 2.0 Hz), 6.82 (1H, d, J = 3.9 Hz), 6.87 (1H, t, J = 1.6 Hz), 7.03 (1H, s), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
(38c) {(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl ) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol The compound (950 mg, 1.84 mmol) synthesized in Example (38b) was added to tetrahydrofuran (20 mL). Dissolved and lithium aluminum hydride (140 mg, 3.67 mmol) was added at 0 ° C. After stirring for 30 minutes under a nitrogen atmosphere, water (0.14 mL), 5N aqueous sodium hydroxide solution (0.14 mL) and water (0.45 mL) were added in this order, and the mixture was stirred for 10 minutes. Ethyl acetate (70 mL) was added and stirred for 5 minutes, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (602 mg, 67%) as a white solid. )
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.38 (3H, dd, J = 1.6, 6.6 Hz), 3.23 (3H, s), 3.61 (1H, dd, J = 3.1, 12.5 Hz), 3.98 (1H , dd, J = 2.0, 12.5 Hz), 4.11-4.16 (1H, m), 4.31-4.41 (2H, m), 4.45-4.72 (3H, m), 6.37 (1H, d, J = 3.9 Hz), 6.47 (1H, d, J = 3.9 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.89 (1H, t, J = 1.6 Hz), 7.04 (1H, t, J = 1.6 Hz), 7.46 ( 1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 490.14356 (M + H) ^<+> .

(Example 39)
2-{(5S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethanol

(39a) N-{(2R) -2- (benzyloxy) -4-[(triisopropylsilyl) oxy] butyl} -5- (3-[(1S) -2-fluoro-1-methylethoxy]- 5-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide Compound (2.50 g, 5.75 mmol) synthesized in Example (35b), known {J . Org. Chem. (Journal of Organic Chemistry) Vol. 60, No. 12, 3910-3915 (1995)} (2R) -2- (benzyloxy) -4-[(triisopropylsilyl) oxy] butan-1-amine (2 0.04 g, 5.80 mmol) and DMT-MM (3.98 g, 14.4 mmol) were used to obtain the target product (4.23 g, yield 96%) as a white solid in the same manner as in Example (5d). It was.
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.04-1.13 (21H, m), 1.37 (3H, dd, J = 1.6, 6.3Hz), 1.77 (1H, m), 1.89 (1H, m), 3.24 (3H, s), 3.49 (1H, td, J = 5.9, 14.1Hz), 3.72 (1H, ddd, 4.3, 5.9, 14.1Hz), 3.84 (2H, t, J = 5.9Hz), 3.85 (1H , m), 4.47 (1H, d, J = 5.1Hz), 4.56 (1H, d, J = 11.7Hz), 4.59 (1H, d, J = 5.1Hz), 4.65 (1H, d, J = 11.7Hz) ), 4.67 (1H, m), 6.22 (1H, t, J = 5.9Hz), 6.44 (1H, dd, J = 2.7, 3.9Hz), 6.48 (1H, dd, J = 2.7, 3.9Hz), 6.57 (1H, t, J = 2.4Hz), 6.86 (1H, t, J = 2.4Hz), 7.01 (1H, t, J = 2.0Hz), 7.28-7.37 (5H, m), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6Hz), 8.50 (1H, d, J = 2.7Hz), 9.60 (1H, brs).
(39b) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -N-{(2R) -2-Hydroxy-4-[(triisopropylsilyl) oxy] butyl} -1H-pyrrole-2-carboxamide The compound synthesized in Example (39a) (4.23 g, 5.51 mmol) was dissolved in acetic acid (80 mL). Then, 10% palladium carbon catalyst (1.70 g) was added, and the mixture was stirred at room temperature for 7 hours in a hydrogen atmosphere. The palladium carbon catalyst was removed by Celite filtration and washed with ethyl acetate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 40% -60%) to give the desired product (2.28 g, Yield 61%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.04-1.17 (21H, m), 1.37 (3H, dd, J = 1.6, 6.3Hz), 1.62-1.84 (2H, m), 3.23 (3H, s ), 3.34 (1H, m), 3.68 (1H, ddd, J = 3.9, 6.3, 14.1Hz), 3.93-4.09 (3H, m), 4.46 (1H, d, = 4.7Hz), 4.58 (1H, d , J = 4.7Hz), 4.68 (1H, m), 6.48 (1H, m), 6.50 (1H, dd, J = 2.7, 3.9Hz), 6.57 (1H, t, J = 2.4Hz), 6.64 (1H , dd, J = 2.7, 3.9Hz), 6.88 (1H, t, J = 2.0Hz), 7.03 (1H, t, J = 2.0Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.76 (1H, brs).

(39c) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(5S) -5- {2-[(triisopropylsilyl) oxy] ethyl} -4 , 5-Dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -2- (methylsulfonyl) pyridine The compound synthesized in Example (39b) (2.28 g, 3. 36 mmol), methanesulfonic anhydride (1.46 g, 8.38 mmol), and triethylamine (2.81 mL, 20.2 mol) in the same manner as in Example (16j), and the target product (2. 10 g, yield 95%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.02-1.15 (21H, m), 1.37 (3H, dd, J = 0.8, 6.3Hz), 1.86 (1H, m), 1.96 (1H, m), 3.23 (3H, s), 3.66 (1H, dd, J = 7.8, 14.1Hz), 3.87 (1H, m), 3.89 (1H, m), 4.08 (1H, m), 4.46 (1H, d, J = 4.7Hz), 4.58 (1H, d, J = 4.7Hz), 4.67 (1H, m), 4.91 (1H, m), 6.50 (1H, d, J = 3.5Hz), 6.56 (1H, t, J = 2.0Hz), 6.73 (1H, d, J = 3.5Hz), 6.88 (1H, brs), 7.03 (1H, brs), 7.45 (1H, dd, J = 2.7, 8.6Hz), 8.05 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz).
(39d) 2-{(5S) -2- [5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy } Phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethanol Compound (2.10 g, 3.18 mmol) synthesized in Example (39c), tetra Using butylammonium fluoride (1 mol / L tetrahydrofuran solution, 3.82 mL, 3.82 mmol), the target compound (1.15 g, yield 72%) as a white solid was obtained in the same manner as in Example (16k). .
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.34 (3H, d, J = 6.3 Hz), 1.90 (1H, m), 1.98 (1H, m), 3.22 (3H, s), 3.61 (1H, dd, J = 7.4, 14.1Hz), 3.85 (2H, t, J = 6.3Hz), 4.05 (1H, dd, J = 9.4, 14.1Hz), 4.44 (1H, d, J = 4.7Hz), 4.56 ( 1H, d, J = 4.7Hz), 4.66 (1H, m), 4.86 (1H, m), 6.50 (1H, d, J = 3.9Hz), 6.55 (1H, t, J = 2.0Hz), 6.73 ( 1H, d, J = 3.9Hz), 6.90 (1H, brs), 7.05 (1H, brs), 7.43 (1H, dd, J = 2.7, 8.6Hz), 8.03 (1H, d, J = 8.6Hz), 8.47 (1H, d, J = 2.7Hz).
MS (ESI) m / z: 504.16046 (M + H) ^<+> .

(Example 40)

2-{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} ethanol

(40a) (2S) -4- (benzyloxy) -1-[(triisopropylsilyl) oxy] butan-2-ol (2S) -4- (benzyloxy) butane-1,2-diol (3.00 g , 15.3 mmol) in methylene chloride (150 mL), triisopropylsilyl chloride (3.60 mL, 16.8 mmol), triethylamine (6.40 mL, 45.9 mol), 4-dimethylaminopyridine (1.87 g, 15.3 mmol) was added, and the mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. Water (150 mL) was added and extracted twice with methylene chloride (100 mL). The organic layer was washed with saturated brine and then 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: ethyl acetate / hexane = 10% -30%) to give the desired product as a colorless oil (5.64 g, Yield ˜100%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.02-1.12 (21H, m), 1.72-1.84 (2H, m), 2.86 (1H, d, J = 3.1Hz), 3.58 (1H, dd, J = 6.7, 9.8Hz), 3.62-3.72 (3H, m), 3.86 (1H, m), 4.52 (2H, s), 7.28-7.35 (5H, m).
(40b) 2-[(1R) -3- (Benzyloxy) -1-{[(triisopropylsilyl) oxy] methyl} propyl] -1H-isoindole-1,3 (2H) -dione Example (40a) ) Compound (5.64 g, 16.0 mmol) was dissolved in tetrahydrofuran (150 mL), and phthalimide (2.59 g, 17.6 mmol) and triphenylphosphine (4.62 g, 17.6 mmol) were added. Diethyl azodicarboxylate (40% toluene solution, 8.00 mL, 17.6 mmol) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% -30%) to give the target compound (4.87 g) as a pale yellow oil. Yield 63%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ0.92-1.08 (21H, m), 2.06 (1H, m), 2.37 (1H, m), 3.46-3.58 (2H, m), 3.94 (1H, dd , J = 6.3, 9.8Hz), 4.14 (1H, t, J = 9.8Hz), 4.39 (2H, s), 4.59 (1H, m), 7.18-7.27 (5H, m), 7.65-7.70 (2H, m), 7.76-7.80 (2H, m).
(40c) (2R) -4- (Benzyloxy) -1-[(triisopropylsilyl) oxy] butan-2-amine The compound (4.87 g, 10.1 mmol) synthesized in Example (40b) was added to ethanol ( 100 mL). Hydrazine monohydrate (4.90 mL, 101 mmol) was added, and the mixture was heated to reflux for 3 hours under a nitrogen atmosphere. Insoluble material was removed by filtration, saturated aqueous sodium hydrogen carbonate solution (100 mL) was added, and the mixture was extracted twice with diethyl ether (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a colorless oily target product (3.34 g, yield 94%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.03-1.12 (21H, m), 1.72-1.80 (2H, m), 3.03 (1H, m), 3.47 (1H, dd, J = 7.0, 9.8Hz ), 3.58-3.68 (2H, m), 3.67 (1H, dd, J = 4.3, 9.4Hz), 4.51 (2H, s), 7.27-7.35 (5H, m).

(40d) N-{(1R) -3- (benzyloxy) -1-{[(triisopropylsilyl) oxy] methyl} propyl] -5- (3-[(1S) -2-fluoro-1-methyl Ethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide Compound (1.90 g, 4.37 mmol) synthesized in Example (35b), Using the compound (1.75 g, 4.98 mmol) synthesized in Example (40c) and DMT-MM (3.63 g, 13.1 mmol), the target product (white solid) was obtained in the same manner as in Example (5d). 2.33 g, 69% yield).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.03-1.13 (21H, m), 1.37 (3H, d, J = 6.3 Hz), 2.00-2.06 (2H, m), 3.24 (3H, s), 3.64 (1H, m), 3.71-3.77 (2H, m), 3.88 (1H, dd, J = 2.7, 9.7Hz), 4.29 (1H, m), 4.46 (1H, d, J = 5.1Hz), 4.51 (2H, s), 4.58 (1H, d, J = 5.1Hz), 4.67 (1H, m), 6.23 (1H, t, J = 3.5Hz), 6.40 (1H, t, J = 3.5Hz), 6.57 (1H, brs), 6.73 (1H, brd, J = 8.2Hz), 6.85 (1H, brs), 6.99 (1H, brs), 7.27-7.37 (5H, m), 7.45 (1H, dd, J = 2.7 , 8.6 Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.54 (1H, brs).
(40e) N-{(1R) -3- (benzyloxy) -1- (hydroxymethyl) propyl] -5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[ 6- (Methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide Compound (2.32 g, 3.02 mmol) synthesized in Example (40d), tetrabutylammonium fluoride (1 mol) / L tetrahydrofuran solution, 6.35 mL, 6.35 mmol) was used to obtain the desired product (1.43 g, yield 77%) as a white solid in the same manner as in Example (16k).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.37 (3H, dd, J = 1.6, 6.7 Hz), 1.93-2.07 (2H, m), 3.23 (3H, s), 3.61 (1H, dd, J = 4.3, 7.4Hz), 3.68-3.80 (4H, m), 4.22 (1H, m), 4.46 (1H, d, J = 5.1Hz), 4.54 (2H, s), 4.58 (1H, d, J = 5.1Hz), 4.68 (1H, m), 6.23 (1H, dd, J = 2.4, 3.9Hz), 6.37 (1H, dd, J = 3.1, 3.9Hz), 6.57 (1H, t, J = 2.4Hz) , 6.85 (1H, t, J = 2.0Hz), 6.99 (1H, t, J = 2.0Hz), 7.05 (1H, brd, J = 6.7Hz), 7.32-7.40 (5H, m), 7.45 (1H, dd, J = 2.7, 8.6Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.54 (1H, brs).

(40f) 5- {3- (5-{(4R) -4- [2- (benzyloxy) ethyl] -4,5-dihydro-1,3-oxazol-2-yl} -1H-pyrrole-2 -Yl) -5-[(1S) -2-fluoro-1-methylethoxy] phenoxy} -2- (methylsulfonyl) pyridine The compound synthesized in Example (40e) (1.43 g, 2.34 mmol), methane Using sulfonic anhydride (1.02 g, 5.86 mmol) and triethylamine (1.96 mL, 14.1 mol), the target product (1.29 g, yield) was obtained in the same manner as in Example (16j). 93%).
¹ H-NMR (CDCl ₃ , 400MHz): δ1.34 (3H, dd, J = 1.2, 6.3Hz), 1.82-1.92 (2H, m), 3.22 (3H, s), 3.55-3.61 (2H, m ), 4.07 (1H, t, J = 7.8), 4.33 (1H, m), 4.38-4.49 (4H, m), 4.55 (1H, d, J = 4.7Hz), 4.63 (1H, m), 6.50 ( 1H, d, J = 3.9Hz), 6.54 (1H, t, J = 2.4Hz), 6.73 (1H, d, J = 3.9Hz), 6.88 (1H, t, J = 2.0Hz), 7.03 (1H, t, J = 2.0Hz), 7.24-7.34 (5H, m), 7.41 (1H, dd, J = 2.7, 8.6Hz), 8.02 (1H, d, J = 8.6Hz), 8.46 (1H, d, J = 2.7Hz).
(40 g) 2-{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy } Phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} ethanol The compound (1.29 g, 2.17 mmol) synthesized in Example (40f) was chlorinated. After dissolving in methylene (30 mL), boron tribromide (1.0 mol / L methylene chloride solution, 2.61 mL, 2.61 mmol) was added at −78 ° C., and the mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted twice with methylene chloride (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the desired product (984 mg, yield) as a white solid. 90%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.38 (3H, dd, J = 1.6, 6.3 Hz), 1.73-1.96 (2H, m), 3.23 (3H, s), 3.82-3.95 (2H, m ), 4.04 (1H, t, J = 7.8Hz), 4.41 (1H, m), 4.46 (1H, d, J = 5.1Hz), 4.56 (1H, m), 4.58 (1H, d, J = 5.1Hz) ), 4.70 (1H, m), 6.52 (1H, d, J = 3.9Hz), 6.57 (1H, t, J = 2.0Hz), 6.78 (1H, d, J = 3.9Hz), 6.91 (1H, brs ), 7.08 (1H, brs), 7.46 (1H, dd, J = 2.7, 8.6Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz).
MS (ESI) m / z: 504.16046 (M + H) ^<+> .

(Example 41)
(1S) -1-{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] Oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethane-1,2-diol

(41a) N-{(2S) -2-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] -2-hydroxyethyl} -5- (3-[(1S)- 2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide Compound (1.1) synthesized in Example (35b). 54 g, 3.54 mmol), known {Chem. Res. Toxicol. (Chemical Research Intoxicology) Vol. 14, No. 4, 379-388 (2001)}, (1S) -2-amino-1-[(4S) -2,2-dimethyl-1,3-dioxolane-4 -Il] ethanol (690 mg, 4.28 mmol) and DMT-MM (2.45 g, 8.85 mmol) were used in the same manner as in Example (5d) to give the desired product (1.65 g, yield 80) %).
¹ H-NMR (CDCl ₃ , 400MHz): δ1.37 (3H, d, J = 6.3Hz), 1.38 (3H, s), 1.46 (3H, s), 2.72 (1H, brd, J = 5.1Hz) , 3.24 (3H, s), 3.43 (1H, ddd, J = 5.1, 6.3, 14.1Hz), 3.68 (1H, m), 3.90 (1H, m), 3.95 (1H, d, J = 12.1Hz), 4.05-4.15 (2H, m), 4.46 (1H, d, J = 4.7Hz), 4.58 (1H, d, J = 4.7Hz), 4.68 (1H, m), 6.44 (1H, brt, J = 5.1Hz ), 6.50 (1H, t, J = 3.1Hz), 6.58 (1H, t, J = 2.4Hz), 6.61 (1H, t, J = 3.1Hz), 6.87 (1H, brs), 7.01 (1H, brs) ), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.65 (1H, brs).
(41b) (1S) -1-{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridine-3 -Yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethane-1,2-diol The compound synthesized in Example (41a) ( 1.64 g, 2.84 mmol) was dissolved in tetrahydrofuran (40 mL), methanesulfonic anhydride (1.24 g, 7.12 mmol) and triethylamine (2.38 mL, 17.1 mol) were added, and the mixture was added at 50 ° C. under a nitrogen atmosphere. For 22 hours. Water (40 mL) was added and extracted twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.

The obtained residue was dissolved in a mixed solvent of acetic acid (30 mL) and water (10 mL), and stirred at 50 ° C. for 16 hours under a nitrogen atmosphere. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 8%) to give the desired compound (854 mg, yield) as a white solid. 58%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.36 (3H, dd, J = 1.6, 6.7 Hz), 3.13 (1H, brd, J = 1.2 Hz), 3.23 (3H, s), 3.69 (1H, dd, J = 5.9, 11.3Hz), 3.81 (1H, dd, J = 3.5, 11.3Hz), 3.88 (1H, m), 3.93-4.01 (2H, m), 4.46 (1H, d, J = 4.7Hz ), 4.58 (1H, d, J = 4.7Hz), 4.67 (1H, m), 4.68 (1H, d, J = 5.5Hz), 6.49 (1H, d, J = 3.9Hz), 6.57 (1H, t , J = 2.4Hz), 6.73 (1H, d, J = 3.9Hz), 6.88 (1H, t, J = 2.0Hz), 7.04 (1H, t, J = 2.0Hz), 7.45 (1H, dd, J = 2.7, 8.6Hz), 8.05 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz).
MS (ESI) m / z: 520.15537 (M + H) ^<+> .

(Example 42)
(1R) -1-{(4S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] Oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} ethane-1,2-diol

(42a) (1S) -2-{[t-Butyl (diphenyl) silyl] oxy} -1-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] ethanol Known {J. Am. Chem. Soc. (Journal of American Chemical Society) 123, 24, 5695-5702 (2001)}, (1S) -1-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] Ethane-1,2-diol (7.34 g, 45.3 mmol) was dissolved in methylene chloride (300 mL), t-butyldiphenylsilyl chloride (14.2 mL, 54.6 mmol), triethylamine (15.8 mL, 113 mmol). 4-dimethylaminopyridine (560 mg, 4.58 mmol) was added, and the mixture was stirred at room temperature for 23 hours under a nitrogen atmosphere. Water (300 mL) was added and extracted twice with methylene chloride (200 mL). The organic layer was washed with saturated brine and then 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: ethyl acetate / hexane = 10% -30%) to give the desired product as a colorless oil (17.2 g, Yield 95%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.06 (9H, s), 1.37 (3H, s), 1.41 (3H, s), 2.43 (1H, d, J = 5.5 Hz), 3.63-3.72 ( 3H, m), 3.81 (1H, dd, J = 7.0, 8.2Hz), 4.00 (1H, dd, J = 6.3, 8.6Hz), 4.21 (1H, m), 7.37-7.47 (6H, m), 7.64 -7.68 (4H, m).
(42b) (1R) -2-{[t-Butyl (diphenyl) silyl] oxy} -1-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] ethyl 4-nitrobenzoate Compound (8.65 g, 21.6 mmol) synthesized in Example (42a), 4-nitrobenzoic acid (5.42 g, 32.4 mmol), triphenylphosphine (7.93 g, 30.2 mmol), azodicarboxylic acid Using diethyl (40% toluene solution, 14.7 mL, 32.3 mmol) in the same manner as in Example (20a), the target compound (10.7 g, yield 90%) was obtained as a pale yellow oil.
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.02 (9H, s), 1.31 (3H, s), 1.36 (3H, s), 3.97 (2H, d, J = 3.5 Hz), 4.05 (1H, dd, J = 7.0, 8.6Hz), 4.13 (1H, m), 4.48 (1H, m), 5.34 (1H, m), 7.23-7.44 (6H, m), 7.60 (4H, t, J = 7.8Hz ), 8.20 (2H, d, J = 8.2Hz), 8.31 (2H, d, J = 8.2Hz).
(42c) (1R) -2-{[t-Butyl (diphenyl) silyl] oxy} -1-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] ethanol Example (42b) ) (10.7 g, 19.4 mmol) was dissolved in methylene chloride (200 mL), and diisopropylaluminum hydride (1.02 mol / L toluene solution, 48.0 mL, 50.0 mmol) was dissolved at −78 ° C. Was dripped. The mixture was stirred at −20 ° C. for 1.5 hours under a nitrogen atmosphere, 1N aqueous sodium hydroxide solution (100 mL) was added, and the mixture was extracted twice with methylene chloride (200 mL). The organic layer was washed with saturated brine and then 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: ethyl acetate / hexane = 10% -30%) to give the desired product as a colorless oil (6.87 g, Yield 88%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.07 (9H, s), 1.33 (3H, s), 1.34 (3H, s), 2.50 (1H, d, J = 4.7 Hz), 3.68 (1H, m), 3.75 (1H, dd, J = 5.5, 10.2Hz), 3.82 (1H, dd, J = 3.9, 10.2Hz), 3.98 (1H, m), 4.04-4.10 (2H, m), 7.36-7.46 (6H, m), 7.64-7.68 (4H, m).

(42d) 2-{(1S) -2-{[t-Butyl (diphenyl) silyl] oxy} -1-[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] ethyl} -1H-isoindole-1,3 (2H) -dione The compound synthesized in Example (42c) (6.87 g, 17.2 mmol), phthalimide (2.78 g, 18.9 mmol), triphenylphosphine (4. 96 g, 18.9 mmol) and diethyl azodicarboxylate (40% toluene solution, 8.60 mL, 18.9 mmol) were used in the same manner as in Example (20a) to obtain the target compound (8.65 g, yield) as a pale yellow oil. 95%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.03 (9H, s), 1.13 (3H, s), 1.14 (3H, s), 3.67-3.81 (3H, m), 3.94 (1H, dd, J = 6.3, 8.6Hz), 4.08 (1H, m), 4.24 (1H, m), 7.27-7.44 (6H, m), 7.59-7.78 (8H, m).
(42e) (1S) -2-{[t-Butyl (diphenyl) silyl] oxy} -1-[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] ethanamine Example (42d) ) (8.65 g, 16.3 mmol) was dissolved in ethanol (150 mL). Hydrazine monohydrate (7.92 mL, 163 mmol) was added, and the mixture was heated to reflux for 1.5 hours under a nitrogen atmosphere. Insoluble material was removed by filtration, saturated aqueous sodium hydrogen carbonate solution (150 mL) was added, and the mixture was extracted twice with diethyl ether (150 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% -50%) to give the target compound (5.85 g) as a pale yellow oil. Yield 90%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.06 (9H, s), 1.27 (3H, s), 1.31 (3H, s), 2.76 (1H, dd, J = 2.7, 3.9Hz), 3.64 ( 1H, m), 3.66 (1H, dd, J = 6.7, 8.2Hz), 3.99 (1H, dd, J = 6.3, 8.2Hz), 4.18 (1H, m), 7.36-7.47 (6H, m), 7.64 -7.70 (4H, m).
(42f) N-{(1S) -2-{[t-butyl (diphenyl) silyl] oxy} -1-[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] ethyl} -5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide The compound (1.55 g, 3.57 mmol) synthesized in Example (35b), the compound (1.71 g, 4.28 mmol) synthesized in Example (42e), and DMT-MM (2.47 g, 8.93 mmol) were used. In the same manner as in Example (5d), the white solid target product (2.67 g, yield 92%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.06 (9H, s), 1.33 (6H, s), 1.37 (3H, dd, J = 1.6, 6.3 Hz), 3.24 (3H, s), 3.46 ( 1H, td, J = 5.9, 14.1Hz), 3.65 (1H, m), 3.71-3.81 (2H, m), 4.01 (1H, dd, J = 6.3, 8.2Hz), 4.11 (1H, m), 4.47 (1H, d, J = 4.7Hz), 4.59 (1H, d, J = 4.7Hz), 4.67 (1H, m), 5.86 (1H, dd, J = 2.4, 3.9Hz), 6.14 (1H, brt, J = 5.9Hz), 6.39 (1H, dd, J = 2.7, 3.9Hz), 6.57 (1H, t, J = 2.4Hz), 6.83 (1H, t, J = 2.0Hz), 6.97 (1H, t, J = 2.4Hz), 7.30-7.50 (7H, m), 7.63-7.71 (4H, m), 8.07 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.38 ( 1H, brs).

(42g) N-{(1S) -1-[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] -2-hydroxyethyl} -5- (3-[(1S)- 2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide The compound synthesized in Example (42f) (2. 67 g, 3.27 mmol) and tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 4.43 mL, 4.43 mmol) were used in the same manner as in Example (16k) to obtain the target compound (1.56 g, Yield 83%) was obtained.
¹ H-NMR (CDCl ₃ , 400MHz): δ1.36 (3H, s), 1.37 (3H, dd, J = 1.7, 6.3Hz), 1.43 (3H, s), 3.23 (3H, s), 3.48 ( 1H, td, J = 5.9, 14.1Hz), 3.72-3.82 (2H, m), 3.88 (1H, brs), 3.98-4.15 (3H, m), 4.47 (1H, d, J = 4.7Hz), 4.59 (1H, d, J = 4.7Hz), 4.68 (1H, m), 6.42 (1H, brt, J = 5.5Hz), 6.51 (1H, dd, J = 2.7, 3.9Hz), 6.59 (1H, t, J = 2.4Hz), 6.64 (1H, dd, J = 2.4, 3.9Hz), 6.87 (1H, t, J = 2.0Hz), 7.01 (1H, t, J = 2.0Hz), 7.45 (1H, dd, J = 2.7, 8.6Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.58 (1H, brs).
(42h) (1R) -1-{(4S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridine-3 -Yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} ethane-1,2-diol Compound synthesized in Example (42g) ( 1.56 g, 2.70 mmol) was dissolved in tetrahydrofuran (40 mL), methanesulfonic anhydride (1.18 g, 6.77 mmol) and triethylamine (2.26 mL, 16.2 mol) were added, and the mixture was added at 50 ° C. under a nitrogen atmosphere. For 16 hours. Water (40 mL) was added and extracted twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.

The obtained residue was dissolved in a mixed solvent of acetic acid (30 mL) and water (10 mL), and stirred at 50 ° C. for 17 hours under a nitrogen atmosphere. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 8%) to give the target compound (710 mg, yield) as a white solid. 54%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.35 (3H, dd, J = 1.6, 6.3 Hz), 3.22 (3H, s), 3.68-3.71 (3H, m), 3.80 (1H, dd, J = 7.4, 14.1Hz), 3.98 (1H, dd, J = 10.2, 14.1Hz), 4.45 (1H, d, J = 4.7Hz), 4.57 (1H, d, J = 4.7Hz), 4.62-4.70 (2H , m), 6.38 (1H, d, J = 3.9Hz), 6.54 (1H, t, J = 2.4Hz), 6.61 (1H, d, J = 3.9Hz), 6.86 (1H, t, J = 2.0Hz) ), 7.02 (1H, t, J = 2.0Hz), 7.42 (1H, dd, J = 2.7, 8.6Hz), 8.02 (1H, d, J = 8.6Hz), 8.45 (1H, d, J = 2.7Hz) ).
MS (ESI) m / z: 520.15537 (M + H) ^<+> .

(Example 43)
{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol

(43a) 5- (Methylsulfanyl) pyrazin-2-amine 2-Aminopyrazine (50.8 g, 0.53 mmol) was dissolved in methylene chloride (1.0 L), and N-bromosuccinimide (97.9 g, 0 .55 mol) was added at 0 ° C. over 30 minutes, and the mixture was stirred at 0 ° C. for 2.5 hours under a nitrogen atmosphere. The reaction solution was returned to room temperature, and the precipitate was filtered off. The precipitate separated by filtration was washed with ethyl acetate. The mother liquor was collected and the solvent was distilled off under reduced pressure. The mother liquor obtained by repeating this operation twice was evaporated under reduced pressure to give a yellow oily compound.

This was dissolved in N, N-dimethylformamide (300 mL), sodium thiomethoxide (75.0 g, 1.07 mol) was added, and the mixture was stirred at 100 ° C. for 3 hours under nitrogen atmosphere. The reaction solution was returned to room temperature, water (1.5 L) was added, and the mixture was extracted with ethyl acetate (1.0 L). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% -30%) to give the target compound (42.5 g, Yield 56%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.52 (3H, s), 4.41 (2H, br s), 7.92 (1H, d, J = 1.6 Hz), 7.98 (1H, d, J = 1.6 Hz) .
(43b) 2-chloro-5- (methylsulfanyl) pyrazine sodium nitrite (50.9 g, 0.74 mol) is dissolved in water (150 mL),
The mixture was added dropwise to 5N hydrochloric acid (1.0 L) at 0 ° C. over 1 hour. Thereafter, the compound (40.4 g, 0.28 mol) synthesized in Example (43a) was added at 0 ° C. over 40 minutes, and the mixture was stirred at 0 ° C. for 1 hour. The reaction solution was returned to room temperature, water (500 mL) was added, and the mixture was extracted with ethyl acetate (1.0 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% to 20%) to give the target compound (11.9 g, Yield 26%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.57 (3H, s), 8.24 (1H, d, J = 1.2 Hz), 8.39 (1H, d, J = 1.2 Hz).
(43c) 2-Chloro-5- (methylsulfonyl) pyrazine The compound (10.82 g, 67.4 mmol) synthesized in Example (43b) was dissolved in methylene chloride (200 mL), and m-chloroperbenzoic acid (about 65%, 37.4 g, about 140 mmol) was slowly added at 0 ° C., and the mixture was stirred at 0 ° C. for 1.5 hours under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (300 mL) was added, and the mixture was extracted with methylene chloride (400 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% -50%) to give the target compound (10.1 g, yield) as a white solid. 78%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.27 (3H, s), 8.70 (1H, d, J = 1.2 Hz), 9.09 (1H, d, J = 1.2 Hz).

(43d) Benzyl 5- {3-[(1S) -2-fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrole-2-carboxylate Example (34g) (9.72 g, 26.31 mmol), triethylamine (11.00 mL, 78.94 mmol) and 4-dimethylaminopyridine (4.82 g, 39.47 mmol) were dissolved in methylene chloride (250 mL) at room temperature. Added triisopropylsilyl chloride (8.45 mL, 39.47 mmol) and stirred for 5 hours under nitrogen atmosphere. The reaction mixture was diluted with methylene chloride (300 mL), washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 15%) to give the desired product (13.32 g, 96%) as a colorless oil. )
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.10-1.13 (18H, m), 1.22-1.30 (3H, m), 1.35 (3H, dd, J = 1.6, 6.3 Hz), 4.41-4.66 (3H, m), 5.33 (2H, s), 6.42 (1H, t, J = 2.0 Hz), 6.48 (1H, dd, J = 2.7, 3.9 Hz), 6.68 (1H, t, J = 1.6 Hz), 6.70 ( 1H, t, J = 1.6 Hz), 6.98 (1H, dd, J = 2.3, 3.9 Hz), 7.32-7.46 (5H, m), 9.17 (1H, br s).
(43e) 5- {3-[(1S) -2-Fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrole-2-carboxylic acid In Example (43d) The synthesized compound (13.65 g, 25.96 mmol) was dissolved in ethanol (400 mL), 10% palladium carbon catalyst (2.00 g) was added, and the mixture was stirred under a hydrogen atmosphere for 40 minutes. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (10.37 g, yield 92%) as a white solid.
¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.11-1.14 (18H, m), 1.23-1.31 (3H, m), 1.35 (3H, dd, J = 1.5, 6.3 Hz), 4.43-4.67 (3H, m), 6.44 (1H, t, J = 2.0 Hz), 6.51 (1H, t, J = 2.9 Hz), 6.71 (1H, s), 6.74 (1H, s), 7.07 (1H, t, J = 2.4 Hz), 9.32 (1H, br s).
(43f) N-[(2S) -2,3-dihydroxypropyl] -5- {3-[(1S) -2-fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrole-2-carboxamide Compound (3.52 g, 8.08 mmol) synthesized in Example (43e), (S)-(−)-3-amino-1,2-propanediol (1.84 g, 20.20 mmol) and DMT-MM (6.40 g, 20.20 mmol) were used to give the target compound (3.83 g, 94%) as a white solid in the same manner as in Example (5d).
¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.10-1.13 (18H, m), 1.23-1.29 (3H, m), 1.34 (3H, dd, J = 1.6, 6.3 Hz), 3.51-3.66 (4H, m), 3.84-3.89 (1H, m), 4.41-4.67 (3H, m), 6.40 (1H, t, J = 2.0 Hz), 6.45 (1H, t, J = 3.5 Hz), 6.54 (1H, t , J = 5.9 Hz), 6.65 (1H, dd, J = 2.7, 3.9 Hz), 6.71 (1H, t, J = 1.6 Hz), 6.76 (1H, t, J = 1.6 Hz), 9.81 (1H, br s).

(43 g) 5- {3-[(1S) -2-Fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -N-{(2S) -2-hydroxy-3- [ (Triisopropylsilyl) oxy] propyl} -1H-pyrrole-2-carboxamide The compound synthesized in Example (43f) (3.83 g, 7.53 mmol) was dissolved in methylene chloride (70 mL), and triisopropylsilyl chloride ( 2.42 mL, 11.29 mmol), triethylamine (5.25 mL, 37.64 mol) and 4-dimethylaminopyridine (1.38 g, 11.29 mmol) were added, and the mixture was stirred at room temperature for 8 hours under a nitrogen atmosphere. The reaction mixture was diluted with methylene chloride (100 mL), washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 20% -50%) to give the desired compound (5.01 g, Yield 100%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.05-1.14 (42H, m), 1.35 (3H, dd, J = 1.2, 6.3 Hz), 3.38-3.45 (1H, m), 3.66-3.79 (3H, m), 3.85-3.91 (1H, br m), 4.42-4.66 (3H, m), 6.30-6.35 (1H, br m), 6.40 (1H, t, J = 2.0 Hz), 6.46 (1H, t, J = 2.7 Hz), 6.60 (1H, dd, J = 2.3, 3.9 Hz), 6.69 (1H, t, J = 1.6 Hz), 6.71 (1H, t, J = 1.6 Hz), 9.38 (1H, br s ).
(43h) (5R) -2- (5- {3-[(1S) -2-Fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrol-2-yl ) -5-{[(Triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazole Compound (5.01 g, 7.52 mmol) synthesized in Example (43 g), methanesulfonic anhydride Product (2.70 g, 15.04 mmol) and triethylamine (4.19 mL, 30.07 mmol) were used in the same manner as in Example (16j) to give the target product (4.15 g, yield 85%) as an orange oil. Obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.03-1.15 (39H, m), 1.24-1.29 (3H, m), 1.34 (3H, dd, J = 1.2, 6.3 Hz), 3.84-3.90 (3H, m), 4.01 (1H, dd, J = 9.4, 14.1 Hz), 4.40-4.65 (3H, m), 4.71-4.78 (1H, m), 6.39 (1H, t, J = 3.5 Hz), 6.46 (1H , d, J = 3.9 Hz), 6.72-6.68 (2H, m), 6.74 (1H, d, J = 3.9 Hz).

(43i) 3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Il] -1H-pyrrol-2-yl} phenol Compound (4.15 g, 6.41 mmol) synthesized in Example (43h), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 13.50 mL, 13. The target compound (2.02 g, yield 94%) as a white solid was obtained in the same manner as in Example (16k).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.35 (3H, dd, J = 1.2, 6.3 Hz), 3.78 (1H, dd, J = 5.5, 12.1 Hz), 3.93-3.99 (2H, m), 4.18 (1H, dd, J = 9.8, 13.3 Hz), 4.42-4.69 (3H, m), 4.87-4.94 (1H, m), 6.34 (1H, t, J = 2.3 Hz), 6.48 (1H, d, J = 3.9 Hz), 6.70 (1H, t, J = 1.6 Hz), 6.79 (1H, d, J = 3.9 Hz), 7.08 (1H, t, J = 1.6 Hz), 10.99 (1H, br s).
(43j) {(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl ) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol Compound (120 mg, 0.36 mmol) synthesized in Example (43i), Example (43c) The compound synthesized in (69 mg, 0.36 mmol) was dissolved in acetonitrile (3 mL), potassium carbonate (99 mg, 0.72 mmol) was added, and the mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. Water (10 mL) was added and extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the desired compound (132 mg, yield) as a white solid. 75%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.34 (3H, dd, J = 1.2, 6.3 Hz), 3.22 (3H, s), 3.64-3.73 (2H, m), 3.80 (1H, dd, J = 3.1, 12.5 Hz), 3.94 (1H, dd, J = 9.8, 14.1 Hz), 4.43-4.69 (3H, m), 4.70-4.77 (1H, m), 6.42 (1H, d, J = 3.9 Hz), 6.62-6.64 (2H, m), 6.96 (1H, t, J = 1.6 Hz), 7.06 (1H, t, J = 1.6 Hz), 8.45 (1H, s), 8.77 (1H, s).
MS (ESI) m / z: 491.13903 (M + H) ^<+> .

(Example 44)
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol

(44a) Methyl N-[(5- {3-[(1S) -2-fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrol-2-yl) carbonyl ] -L-Selinate Compound (7.01 g, 16.09 mmol) synthesized in Example (43e), L-serine methyl ester hydrochloride (2.75 g, 17.70 mmol), HOBT.H ₂ O (2.39 g) , 17.70 mmol), N-methylmorpholine (3.54 mL, 32.19 mmol), WSCI.HCl (3.70 g, 19.31 mmol), and the target compound as a white solid in the same manner as in Example (29a) (7.88 g, 91% yield) was obtained.
¹ H-NMR (CDCl ₃ , 500 MHz): δ1.12 (18H, d, J = 7.4 Hz), 1.22-1.32 (3H, m), 1.35 (3H, dd, J = 1.6, 6.3 Hz), 3.82 ( 3H, s), 3.99-4.10 (2H, m), 4.41-4.66 (3H, m), 4.82-4.86 (1H, m), 6.41 (1H, t, J = 2.3 Hz), 6.48 (1H, dd, J = 2.7, 3.9 Hz), 6.70 (1H, t, J = 1.6 Hz), 6.72-6.75 (2H, m), 6.83 (1H, d, J = 7.0 Hz), 9.57 (1H, br s).
(44b) Methyl (4S) -2- (5- {3-[(1S) -2-Fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrole-2- Ile-4,5-dihydro-1,3-oxazole-4-carboxylate Compound (7.77 g, 14.48 mmol) synthesized in Example (44a), bis (2-methoxyethyl) aminosulfur trifluoride (3 .47 mL, 18.8 mmol) and potassium carbonate (3.00 g, 21.72 mmol) were used to obtain the target compound (7.21 g, 96%) as a white solid in the same manner as in Example (38b).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.12 (18H, d, J = 7.3 Hz), 1.23-1.31 (3H, m), 1.35 (3H, dd, J = 1.5, 6.3 Hz), 3.82 (3H , s), 4.42-4.68 (5H, m), 4.91 (1H, dd, J = 7.8, 10.7 Hz), 6.40 (1H, t, J = 2.0 Hz), 6.47 (1H, d, J = 3.9 Hz) , 6.71-6.73 (2H, m), 6.81 (1H, d, J = 3.9 Hz).
(44c) [(4R) -2- (5- {3-[(1S) -2-Fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrole-2- Yl) -4,5-dihydro-1,3-oxazol-4-yl} methanol The compound (7.21 g, 13.90 mmol) synthesized in Example (44b) was dissolved in tetrahydrofuran (150 mL) at 0 ° C. Lithium aluminum hydride (1.06 g, 27.80 mmol) was added. After stirring for 30 minutes under a nitrogen atmosphere, water (1.0 mL), 5N aqueous sodium hydroxide solution (1.0 mL), and water (3.0 mL) were added in this order, and the mixture was stirred for 10 minutes. Ethyl acetate (70 mL) was added and stirred for 5 minutes, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% to 70%) to give the target compound (3.73 g, 3.73 g, Yield 55%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.13 (18H, d, J = 7.4 Hz), 1.23-1.32 (3H, m), 1.36 (3H, d, J = 6.3 Hz), 3.65 (1H, d , J = 12.5 Hz), 4.04 (1H, d, J = 12.5 Hz), 4.17-4.23 (1H, m), 4.31-4.40 (2H, m), 4.42-4.66 (3H, m), 6.33 (1H, d, J = 3.9 Hz), 6.39 (1H, t, J = 2.0 Hz), 6.45 (1H, d, J = 3.9 Hz), 6.76 (2H, br s).

(44d) 3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenol Compound (3.73 g, 7.60 mmol) synthesized in Example (44c), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 8.36 mL, 8. 36 mmol), and the target compound (2.05 g, yield 81%) was obtained as a pale orange solid in the same manner as in Example (16k).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.35 (3H, dd, J = 1.6, 6.3 Hz), 3.80 (1H, dd, J = 3.9, 11.3 Hz), 3.99 (1H, dd, J = 3.1, 11.3 Hz), 4.31-4.67 (6H, m), 6.47-6.50 (2H, m), 6.73 (1H, t, J = 1.6 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.07 (1H, t, J = 1.6 Hz), 11.03 (1H, br s).
(44e) {(4R) -2- [5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl ) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol Compound (250 mg, 0.75 mmol) synthesized in Example (44d), Example (43c) The compound synthesized in step (144 mg, 0.75 mmol) was dissolved in acetonitrile (8 mL), potassium carbonate (207 mg, 1.50 mmol) was added, and the mixture was stirred at room temperature for 8 hours under a nitrogen atmosphere. Water (10 mL) was added and extracted with ethyl acetate (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (320 mg, 87%) as a white solid. )
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.39 (3H, dd, J = 1.6, 6.3 Hz), 3.24 (3H, s), 3.64 (1H, dd, J = 3.5, 12.1 Hz), 3.97 (1H , dd, J = 2.7, 11.7 Hz), 4.21 (1H, t, J = 6.6 Hz), 4.33-4.44 (2H, m), 4.45-4.73 (3H, m), 6.41 (1H, d, J = 3.9 Hz), 6.56 (1H, d, J = 3.9 Hz), 6.66 (1H, t, J = 2.2 Hz), 6.97 (1H, t, J = 1.8 Hz), 7.09 (1H, t, J = 1.8 Hz) , 8.50 (1H, d, J = 1.2 Hz), 8.81 (1H, d, J = 1.2 Hz).
MS (ESI) m / z: 491.13903 (M + H) ^<+> .

(Example 45)
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyrazine-2-carboxamide

(45a) 5-chloro-N-methylpyrazine-2-carboxamide 5-chloropyrazine-2-carboxylic acid (1.99 g, 12.6 mmol) was dissolved in N, N-dimethylformamide (10 mL), and HOBt · H _{2 O (2.11g, 13.8mmol),} WSCI · HCl (2.89g, 15.1mmol), N- methylmorpholine (2.76mL, 25.1mmol), 40% methylamine / methanol solution (2.92 mL 37.6 mmol) and stirred for 18 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 75%) to give the target compound (585 mg, yield) as a white solid. 27%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.03 (3H, d, J = 4.9 Hz), 7.60 (1H, br s), 8.09 (1H, d, J = 1.5 Hz), 8.93 (1H, d, J = 1.0 Hz).
(45b) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3- Oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyrazine-2-carboxamide with the compound (170 mg, 0.99 mmol) synthesized in Example (45a) and Example (44d) The synthesized compound (331 mg, 0.99 mmol) was dissolved in N, N-dimethylformamide (3 mL), potassium carbonate (274 mg, 1.88 mmol) was added, and the mixture was stirred at 90 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 3%) to give the target compound (445 mg, yield) as a white solid. 92%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.39 (3H, dd, J = 6.3, 1.5 Hz), 3.05 (3H, d, J = 4.9 Hz), 3.62 (1H, dd, J = 12.2, 3.4 Hz), 3.97 (1H, d, J = 12.2 Hz), 4.17 (1H, t, J = 6.3 Hz), 4.32-4.39 (2H, m), 4.46-4.51 (1H, m), 4.55-4.61 (1H , m), 4.63-4.70 (1H, m), 6.38 (1H, d, J = 3.9 Hz), 6.51 (1H, d, J = 3.4 Hz), 6.67 (1H, t, J = 2.2 Hz), 6.98 (1H, t, J = 1.7 Hz), 7.06 (1H, s), 7.63 (1H, q, J = 4.9 Hz), 8.31 (1H, d, J = 1.5 Hz), 8.94 (1H, d, J = 1.5 Hz), 10.26 (1H, br s).
MS (ESI) m / z: 470.18368 (M + H) ^<+> .

(Example 46)
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyridine-2-sulfonamide

(46a) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3- Oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -N- (4-methoxybenzyl) -N-methylpyridine-2-sulfonamide Compound synthesized in Example (24c) (379 mg, 1. 10 mmol) and the compound synthesized in Example (44d) (368 mg, 1.10 mmol) were dissolved in N, N-dimethylformamide (5 mL), cesium carbonate (718 mg, 2.20 mmol) was added, and nitrogen atmosphere was added. Stir at 90 ° C. for 3 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (520 mg, yield) as a white solid. 76%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.38 (3H, dd, J = 6.3, 1.6 Hz), 2.78 (3H, s), 3.64 (1H, dd, J = 11.9, 3.3 Hz), 3.80 (3H , s), 3.96 (1H, d, J = 11.3 Hz), 4.19-4.22 (1H, m), 4.35-4.43 (4H, m), 4.47 (1H, d, J = 5.1 Hz), 4.59 (1H, d, J = 4.7 Hz), 4.63-4.72 (1H, m), 6.43 (1H, s), 6.58 (2H, t, J = 2.0 Hz), 6.87 (2H, d, J = 8.6 Hz), 6.90 ( 1H, t, J = 2.0 Hz), 7.04 (1H, t, J = 1.6 Hz), 7.27 (2H, d, J = 7.0 Hz), 7.43 (1H, dd, J = 8.6, 2.7 Hz), 7.95 ( 1H, d, J = 9.4 Hz), 8.48 (1H, d, J = 3.1 Hz).
(46b) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3- Oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyridine-2-sulfonamide Under nitrogen atmosphere, the compound (540 mg, 0.86 mmol) synthesized in Example (46a) was treated with trifluoro Dissolved in acetic acid (3 mL) and stirred at 45 ° C. for 5 hours. The solvent was distilled off under reduced pressure, a small amount of methylene chloride and triethylamine were added to the residue, and the solvent was distilled off again under reduced pressure. The obtained residue was purified using silica gel column chromatography (eluent: methanol / methylene chloride = 0% -4%) to give the target compound (257 mg, yield 59%) as a white solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.39 (3H, dd, J = 6.3, 1.6 Hz), 2.69 (3H, d, J = 3.5 Hz), 3.62 (1H, dd, J = 12.1, 5.5 Hz) ), 3.84 (1H, dd, J = 11.9, 2.9 Hz), 4.13 (1H, t, J = 7.8 Hz), 4.33-4.39 (1H, m), 4.42-4.48 (2H, m), 4.57-4.60 ( 1H, m), 4.66-4.74 (1H, m), 6.46 (1H, d, J = 3.9 Hz), 6.61 (1H, t, J = 2.7 Hz), 6.68 (1H, d, J = 3.9 Hz), 6.98 (1H, s), 7.06 (1H, t, J = 1.6 Hz), 7.52 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.44 (1H, d , J = 3.3 Hz).
MS (ESI) m / z: 505.15374 (M + H) ^<+> .

(Example 47)
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyrazine-2-sulfonamide

(47a) 5-Bromopyrazine-2-thiol 2,5-Dibromopyrazine (300 mg, 1.26 mmol) was dissolved in dimethyl sulfoxide (3 mL) under a nitrogen atmosphere, and sodium disulfide nonahydrate (454 mg, 1. 89 mmol) and then stirred at 100 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was neutralized with 5N hydrochloric acid. The resulting precipitate was collected by filtration and washed with water. The obtained solid was dissolved in diethyl ether / tetrahydrofuran, and insoluble matter was filtered off. The target compound (163 mg, yield 68%) as an orange solid was obtained by evaporating the solvent under reduced pressure and drying in vacuo.
¹ H-NMR (CDCl ₃ , 400 MHz) δ 3.19 (1H, s), 7.97 (1H, d, J = 1.0 Hz), 8.34 (1H, d, J = 1.0 Hz).
(47b) 5-Bromo-N-methylpyrazine-2-sulfonamide The compound (988 mg, 5.17 mmol) synthesized in Example (47a) was dissolved in methylene chloride (15 mL) / 1N hydrochloric acid (15 mL), and −10 Cooled to ° C. While maintaining the reaction solution at −5 ° C. or lower, ice-cooled 7% sodium perchlorate aqueous solution (15 mL) was added dropwise and stirred as it was for 1 hour. The organic layer was separated with an ice-cooled separatory funnel, cooled to 0 ° C., added with a commercially available 40% methylamine / methanol solution (1.00 mL, 12.9 mmol), returned to room temperature, and stirred for 17 hours. . Saturated aqueous ammonium chloride solution (30 mL) was added to the reaction mixture, and the mixture was extracted twice with methylene chloride (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 30%) to give the target compound (147 mg, yield) as a white solid. 11%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.83 (3H, d, J = 5.5 Hz), 4.80 (1H, s), 8.76 (1H, d, J = 1.6 Hz), 8.96 (1H, d, J = 1.2 Hz).
(47c) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3- Oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyrazine-2-sulfonamide The compound synthesized in Example (47b) (103 mg, 0.41 mmol) and Example (44d) The compound synthesized in (1) (130 mg, 0.39 mmol) was dissolved in N, N-dimethylformamide (2 mL), potassium carbonate (107 mg, 0.78 mmol) was added, and the mixture was stirred at room temperature for 15 hours under a nitrogen atmosphere. Water (20 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 3.5%) to give the target compound (131 mg, Yield 66%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.39 (3H, dd, J = 6.3, 1.5 Hz), 2.81 (3H, d, J = 4.9 Hz), 3.64 (1H, dd, J = 11.7, 3.4 Hz) ), 3.95 (1H, dd, J = 11.2, 2.9 Hz), 4.23 (1H, s), 4.36-4.45 (2H, m), 4.49 (1H, dd, J = 4.6, 2.2 Hz), 4.59 (1H, dd, J = 4.4, 2.4 Hz), 4.65-4.72 (1H, m), 5.10 (1H, br s), 6.44 (1H, s), 6.61 (1H, s), 6.68 (1H, t, J = 2.2 Hz), 6.98 (1H, t, J = 1.5 Hz), 7.09 (1H, t, J = 1.7 Hz), 8.47 (1H, d, J = 1.0 Hz), 8.73 (1H, d, J = 1.0 Hz) .
MS (ESI) m / z: 506.14859 (M + H) ^<+> .

(Example 48)
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4 -(Methylsulfonyl) phenoxy] benzamide

(48a) Methyl 3- [4- (methylsulfonyl) phenoxy] -5-{[(trifluoromethyl) sulfonyl] oxy} benzoate Methyl 3,5-dihydroxybenzoate (9.10 g, 54.1 mmol) and 4 -Fluorophenylmethylsulfone (7.10 g, 40.8 mmol) was dissolved in N, N-dimethylformamide (80 mL), potassium carbonate (30.0 g, 217 mmol) was added, and the mixture was stirred at 100 ° C. for 15 hours under a nitrogen atmosphere. . The reaction mixture was cooled to room temperature, 1N hydrochloric acid (500 mL) was added, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% to 70%) to obtain a white solid compound.

This was dissolved in methylene chloride (100 mL), pyridine (7.50 mL, 92.7 mmol) and trifluoromethanesulfonic anhydride (7.80 mL, 46.4 mmol) were added at 0 ° C., and 3 ° C. was added at 0 ° C. under a nitrogen atmosphere. Stir for half an hour. The reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution (200 mL) was added, and the mixture was extracted with methylene chloride (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% to 60%) to give the desired compound (9.58 g, yield) as a white solid. 52%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.10 (3H, s), 3.95 (3H, s), 7.17 (2H, dd, J = 7.0, 2.2 Hz), 7.22 (1H, t, J = 2.3 Hz ), 7.74 (1H, dd, J = 2.2, 1.4 Hz), 7.77 (1H, dd, J = 2.3, 1.6 Hz), 7.98 (2H, dd, J = 7.0, 2.2 Hz).
(48b) Methyl 3- [4- (methylsulfonyl) phenoxy] -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate In Example (48a) Synthesized compound (9.58 g, 21.1 mmol), bis (pinacolato) diboron (7.45 g, 29.3 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex ( Using 850 mg, 1.04 mmol) and potassium acetate (10.6 g, 108 mmol), the target compound (6.83 g, yield 75%) was obtained as a pale red solid in the same manner as in Example (1d).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.35 (12H, s), 3.07 (3H, s), 3.93 (3H, s), 7.07 (2H, dd, J = 6.8, 2.0 Hz), 7.69 (1H , dd, J = 2.3, 0.8 Hz), 7.83 (1H, dd, J = 2.3, 1.6 Hz), 7.90 (2H, dd, J = 6.8, 2.0 Hz), 8.33 (1H, dd, J = 1.6, 0.8 Hz).
(48c) 2-Benzyl 1-t-butyl 5- {3- (methoxycarbonyl) -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-1,2-dicarboxylate Example (16d) ) (9.40 g, 24.7 mmol), the compound synthesized in Example (48b) (6.58 g, 15.2 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium ( II) Dichloride Dichloromethane complex (1.10 g, 1.35 mmol) and potassium carbonate (8.70 g, 63.0 mmol) were used in the same manner as in Example (16e) to give the desired compound (7.79 g, yield) as a brown oil. 85%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.24 (9H, s), 3.07 (3H, s), 3.92 (3H, s), 5.32 (2H, s), 6.29 (1H, d, J = 3.5 Hz ), 6.96 (1H, d, J = 3.9 Hz), 7.14 (2H, d, J = 9.0 Hz), 7.26-7.29 (1H, m), 7.31-7.44 (5H, m), 7.71-7.72 (1H, m), 7.92 (2H, d, J = 9.0 Hz), 7.95-7.96 (1H, m).

(48d) 5- {3- (methoxycarbonyl) -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2-carboxylic acid The compound synthesized in Example (48c) (7.79 g, 12 .9 mmol) was dissolved in trifluoroacetic acid (15.0 mL) and stirred at room temperature for 45 minutes. After evaporating the solvent under reduced pressure, triethylamine (5 mL) was added, and the mixture was stirred for 5 minutes. A pale yellow solid was obtained by distilling off triethylamine under reduced pressure.

This was dissolved in ethyl acetate (100 mL), palladium carbon (1.50 g) was added, and the mixture was stirred at room temperature for 1 day in a hydrogen atmosphere. After filtration through celite, the solvent was distilled off under reduced pressure, diethyl ether was added, and the precipitated solid was collected by filtration to obtain the target compound (3.50 g, yield 66%) as a white solid.
¹ H-NMR (CD ₃ OD, 500 MHz): δ 3.13 (3H, s), 3.94 (3H, s), 6.65 (1H, d, J = 3.9 Hz), 6.93 (1H, d, J = 3.9 Hz) , 7.23 (2H, d, J = 8.8 Hz), 7.57 (1H, s), 7.74 (1H, s), 7.85 (2H, d, J = 2.4 Hz), 7.97 (2H, d, J = 8.8 Hz) , 8.23 (1H, s).
MS (FAB) m / z: 415 (M ⁺ ).
(48e) Methyl 3- (5-{[(2R) -2-hydroxypropyl] carbamoyl} -1H-pyrrol-2-yl) -5- [4- (methylsulfonyl) phenoxy] benzoate Example (48d) The compound synthesized in step (2.86 g, 6.88 mmol) was dissolved in a mixed solvent of methylene chloride (70 mL) and N, N-dimethylformamide (45 mL), and (R)-(−)-1-amino-2- Propanol (1.20 g, 15.98 mmol), WSCI.HCl (2.80 g, 14.61 mmol) and 4-dimethylaminopyridine (900 mg, 7.37 mmol) were added, and the mixture was stirred at room temperature for 3 days under a nitrogen atmosphere. The solvent was evaporated under reduced pressure, brine (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0 to 3%) to give the target compound (2.24 g, yield) as a yellow solid. Yield 69%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.26 (3H, d, J = 6.3 Hz), 2.41 (1H, br s), 3.09 (3H, s), 3.27-3.34 (1H, m), 3.61- 3.67 (1H, m), 3.95 (3H, s), 4.03 (1H, br s), 6.33 (1H, s), 6.60 (1H, t, J = 3.3 Hz), 6.64 (1H, dd, J = 3.9 , 2.3 Hz), 7.12-7.15 (2H, m), 7.44 (1H, t, J = 2.2 Hz), 7.61 (1H, t, J = 1.8 Hz), 7.92-7.95 (2H, m), 8.07 (1H , t, J = 1.6 Hz), 9.57 (1H, s).
(48f) 3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4- (methyl [Sulfonyl) phenoxy] methyl benzoate Compound synthesized in Example (48e) (2.24 g, 4.74 mmol), methanesulfonic anhydride (1.25 g, 7.17 mmol), triethylamine (2.00 mL, 14.3 mmol) ) Was used to obtain the target compound (1.99 g, yield 92%) as a yellow solid in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.43 (3H, d, J = 6.3 Hz), 3.08 (3H, s), 3.53 (1H, dd, J = 13.5, 6.8 Hz), 3.94 (3H, s ), 4.06 (1H, dd, J = 14.9, 10.2 Hz), 4.80-4.88 (1H, m), 6.61 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.5 Hz), 7.13 (2H, dt, J = 9.4, 2.4 Hz), 7.44 (1H, t, J = 1.8 Hz), 7.58 (1H, t, J = 1.8 Hz), 7.93 (2H, dt, J = 9.3, 2.4 Hz) , 8.06 (1H, t, J = 1.6 Hz).
MS (ESI) m / z: 455.13005 (M + H) ^<+> .

(48 g) 3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4- (methyl Sulfonyl) phenoxy] benzoic acid The compound synthesized in Example (48f) (820 mg, 1.80 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (2 mL), and lithium hydroxide monohydrate (200 mg, 4 .77 mmol) at room temperature and stirred at 50 ° C. for 5 hours. 5N hydrochloric acid (3 mL) was added, and the resulting precipitate was collected by filtration. The obtained solid was washed with diethyl ether (20 mL) to obtain the target compound (810 mg, yield˜100%) as a white solid.
MS (FAB) m / z: 441 (M + H) ⁺ .
(48h) N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -[4- (Methylsulfonyl) phenoxy] benzamide The compound (78 mg, 0.18 mmol) synthesized in Example (48 g) was dissolved in methylene chloride (10 mL), and dimethylamine hydrochloride (170 mg, 2.08 mmol), WSCI -HCl (140 mg, 0.73 mmol) and triethylamine (0.40 mL, 2.87 mmol) were added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (30 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the desired compound (35 mg, yield) as a white solid. 43%).
¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.41 (3H, d, J = 6.3 Hz), 2.97 (3H, s), 3.07 (3H, s), 3.11 (3H, s), 3.48 (1H, dd , J = 13.9, 7.6 Hz), 4.00 (1H, dd, J = 14.1, 9.4 Hz), 4.76-4.85 (1H, m), 6.55 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.97 (1H, t, J = 1.0 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.29 (1H, t, J = 1.8 Hz), 7.45 (1H, t, J = 1.4 Hz), 7.90 (2H, dd, J = 6.5, 5.3 Hz).
MS (ESI) m / z: 468.15943 (M + H) ^<+> .

(Example 49)
N-ethyl-N-methyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 [4- (Methylsulfonyl) phenoxy] benzamide

The compound (97 mg, 0.22 mmol) synthesized in Example (48 g) was dissolved in methylene chloride (10.0 mL), and N-ethylmethylamine (0.10 mL, 1.16 mmol), HATU (250 mg, 0.66 mmol) was dissolved. ), N, N-diisopropylethylamine (0.20 mL, 1.15 mmol) was added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 3%) to give the desired compound (77 mg, yield) as a white solid. 73%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.11-1.27 (3H, m), 1.43 (3H, d, J = 6.3 Hz), 2.97 (3H, br s), 3.08 (3H, s), 3.32 ( 1H, br s), 3.54 (1H, dd, J = 14.3, 7.2 Hz), 3.58 (1H, br s), 4.08 (1H, dd, J = 13.9, 9.2 Hz), 4.80-4.88 (1H, m) , 6.56 (1H, d, J = 3.5 Hz), 6.77 (1H, d, J = 3.5 Hz), 6.95 (1H, s), 7.15 (2H, d, J = 9.0 Hz), 7.26 (1H, s) , 7.42 (1H, s), 7.92 (2H, d, J = 9.0 Hz).
MS (ESI) m / z: 482.17604 (M + H) ^<+> .

(Example 50)
(3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4- (methylsulfonyl) Phenoxy] phenyl) (pyrrolidin-1-yl) methanone

Compound (102 mg, 0.23 mmol) synthesized in Example (48 g), pyrrole (0.15 mL, 2.16 mmol), HATU (250 mg, 0.66 mmol), N, N-diisopropylethylamine (0.20 mL, 1. 15 mmol) was used to give the target compound (61 mg, 53% yield) as a white solid in the same manner as in (Example 49).
¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.43 (3H, d, J = 6.3 Hz), 1.89-1.94 (2H, m), 1.95-2.01 (2H, m), 3.08 (3H, s), 3.45 (2H, t, J = 6.3 Hz), 3.55 (1H, dd, J = 13.9, 7.1 Hz), 3.65 (2H, t, J = 7.1 Hz), 4.09 (1H, dd, J = 13.9, 9.0 Hz) , 4.79-4.88 (1H, m), 6.56 (1H, d, J = 3.9 Hz), 6.77 (1H, d, J = 3.4 Hz), 7.08 (1H, s), 7.14 (2H, d, J = 8.8 Hz), 7.26 (1H, s), 7.54 (1H, s), 7.92 (2H, d, J = 8.8 Hz).
MS (ESI) m / z: 494.17477 (M + H) ^<+> .

(Example 51)
(3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4- (methylsulfonyl) Phenoxy] phenyl) (morpholin-4-yl) methanone

Compound (102 mg, 0.23 mmol) synthesized in Example (48 g), morpholine (0.15 mL, 1.72 mmol), HATU (250 mg, 0.66 mmol), N, N-diisopropylethylamine (0.20 mL, 1. 15 mmol) was used to obtain the target compound (121 mg, yield˜100%) as a white solid in the same manner as in (Example 49).
¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.43 (3H, d, J = 5.9 Hz), 3.08 (3H, s), 3.18 (2H, q, J = 7.3 Hz), 3.44-3.88 (6H, m ), 3.55 (1H, dd, J = 14.2, 7.3 Hz), 4.08 (1H, dd, J = 13.7, 9.3 Hz), 4.81-4.91 (1H, m), 6.56 (1H, d, J = 3.9 Hz) , 6.78 (1H, d, J = 3.4 Hz), 6.97 (1H, d, J = 1.5 Hz), 7.15 (2H, dt, J = 9.4, 2.4 Hz), 7.28 (1H, s), 7.43 (1H, s), 7.93 (2H, dt, J = 9.4, 2.4 Hz).
MS (ESI) m / z: 510.16861 (M + H) ⁺ .

(Example 52)
N-methoxy-N-methyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 [4- (Methylsulfonyl) phenoxy] benzamide

Compound (152 mg, 0.35 mmol) synthesized in Example (48 g), N, O-dimethylhydroxylamine hydrochloride (170 mg, 1.74 mmol), HATU (325 mg, 0.86 mmol), N, N-diisopropylethylamine ( 0.30 mL, 1.72 mmol) was used to obtain the target compound as a white solid (132 mg, yield 79%) in the same manner as in Example 49.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.43 (3H, d, J = 6.3 Hz), 3.08 (3H, s), 3.38 (3H, s), 3.47-3.57 (1H, m), 3.58 (3H , s), 4.10 (1H, dd, J = 14.3, 9.2 Hz), 4.82-4.89 (1H, m), 6.58 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.5 Hz) , 7.14 (2H, dt, J = 9.4, 2.4 Hz), 7.29 (1H, s), 7.33 (1H, s), 7.72 (1H, s), 7.92 (2H, dt, J = 9.4, 2.4 Hz).
MS (ESI) m / z: 484.15489 (M + H) ^<+> .

(Example 53)
Azetidin-1-yl (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4 -(Methylsulfonyl) phenoxy] phenyl) methanone

Compound (80 mg, 0.18 mmol) synthesized in Example (48 g), azetidine hydrochloride (120 mg, 1.28 mmol), WSCI · HCl (100 mg, 0.52 mmol), triethylamine (0.10 mL, 0.72 mmol) The target compound (12 mg, 14% yield) was obtained as a white solid in the same manner as in Example (48h).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.43 (3H, d, J = 6.3 Hz), 2.33-2.40 (2H, m), 3.08 (3H, s), 3.56 (1H, dd, J = 14.1, 7.4 Hz), 3.73-3.78 (1H, m), 4.20-4.28 (2H, m), 4.28-4.35 (2H, m), 4.81-4.89 (1H, m), 6.57 (1H, d, J = 3.9 Hz ), 6.78 (1H, d, J = 3.9 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.16 (1H, s), 7.32 (1H, s), 7.67 (1H, s), 7.93 (2H , d, J = 9.0 Hz).
MS (ESI) m / z: 480.15870 (M + H) ⁺ .

(Example 54)
3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N-dimethyl-5 -[4- (Methylsulfonyl) phenoxy] benzamide

(54a) Methyl 3- (5-{[(2S) -2,3-dihydroxypropyl] carbamoyl} -1H-pyrrol-2-yl) -5- [4- (methylsulfonyl) phenoxy] benzoate Example (48d) The compound synthesized (1.58 g, 3.80 mmol) is suspended in a mixed solvent of methanol (30 mL) and tetrahydrofuran (30 mL), and (S)-(−)-3-amino-1,2-propanediol is suspended. (544 mg, 5.97 mmol) and DMT-MM (2.56 g, 8.18 mmol) were added, and the mixture was stirred under a nitrogen atmosphere for 6 hours. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The extract 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 (elution solvent: methanol / methylene chloride = 2% to 10%) to give the desired product (1.25 g, 67%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.08 (3H, s), 3.12 (1H, t, J = 6.3 Hz), 3.19 (1H, d, J = 5.9 Hz), 3.51-3.65 (4H, m ), 3.83-3.90 (1H, m), 3.94 (3H, s), 6.50 (1H, t, J = 6.3 Hz), 6.59 (1H, dd, J = 3.9, 2.7 Hz), 6.67 (1H, dd, J = 3.7, 2.5 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.46 (1H, t, J = 2.0 Hz), 7.59 (1H, dd, J = 2.3, 1.6 Hz), 7.92 (2H, d, J = 9.0 Hz), 8.09 (1H, t, J = 1.6 Hz), 9.97 (1H, br s).
MS (FAB) m / z: 489 (M + H) ⁺ .
(54b) Methyl 3- [5-({(2S) -2-hydroxy-3-[(triisopropylsilyl) oxy] propyl} carbamoyl) -1H-pyrrol-2-yl] -5- [4- (methyl [Sulfonyl) phenoxy] benzoate The compound synthesized in Example (54a) (1.25 g, 2.56 mmol) was dissolved in methylene chloride (25 mL), triethylamine (1.05 mL, 7.57 mmol), triisopropylsilyl chloride (610 μL). , 2.85 mmol) and 4-dimethylaminopyridine (314 mg, 2.57 mmol) were added and stirred under a nitrogen atmosphere for 5 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water and 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: ethyl acetate / hexane = 40% -60%) to give the desired product (1.16 g, 70%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.05-1.16 (21H, m), 3.08 (3H, s), 3.11 (1H, d, J = 4.7 Hz), 3.37-3.43 (1H, m), 3.65 -3.80 (3H, m), 3.85-3.90 (1H, m), 3.95 (3H, s), 6.40 (1H, t, J = 5.7 Hz), 6.60 (1H, dd, J = 3.9, 2.7 Hz), 6.64 (1H, dd, J = 3.9, 2.3 Hz), 7.14 (2H, d, J = 9.0 Hz), 7.46 (1H, t, J = 2.0 Hz), 7.60 (1H, t, J = 2.0 Hz), 7.93 (2H, d, J = 9.0 Hz), 8.09 (1H, t, J = 1.6 Hz), 9.74 (1H, br s).
MS (FAB) m / z: 645 (M + H) ⁺ .
(54c) Methyl 3- [4- (methylsulfonyl) phenoxy] -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3- Oxazol-2-yl] -1H-pyrrol-2-yl} benzoate Compound (1.16 g, 1.80 mmol) synthesized in Example (54b), methanesulfonic anhydride (633 mg, 3.63 mmol), triethylamine ( The target compound (1.11 g, yield 98%) was obtained as a pale yellow solid in the same manner as in Example (16j) using 0.99 mL, 7.14 mmol).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.02-1.14 (21H, m), 3.08 (3H, s), 3.83-3.92 (3H, m), 3.94 (3H, s), 4.01 (1H, dd, J = 14.5, 9.8 Hz), 4.73-4.80 (1H, m), 6.60 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 7.13 (2H, d, J = 8.6 Hz), 7.45 (1H, t, J = 1.8 Hz), 7.58 (1H, t, J = 1.6 Hz), 7.93 (2H, d, J = 9.0 Hz), 8.08 (1H, t, J = 1.6 Hz) .
MS (FAB) m / z: 627 (M + H) ⁺ .

(54d) 3- [4- (Methylsulfonyl) phenoxy] -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazole -2-yl] -1H-pyrrol-2-yl} benzoic acid The compound synthesized in Example (54c) (1.01 g, 1.75 mmol) was dissolved in ethanol (15 mL), and 2N aqueous sodium hydroxide solution was dissolved. (5 mL) was added and stirred at 70 ° C. for 1 hour. Water (100 mL) was added to the reaction solution, followed by ice cooling, 1N hydrochloric acid (15 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound (951 mg, yield 89%) as an orange solid.
MS (FAB) m / z: 613 (M + H) ⁺ .
(54e) 3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N- Dimethyl-5- [4- (methylsulfonyl) phenoxy] benzamide The compound synthesized in Example (54d) (944 mg, 1.54 mmol) was dissolved in N, N-dimethylformamide (15 mL) and dimethylamine hydrochloride (289 mg). 3.54 mmol), HATU (1.21 g, 3.18 mmol) and N, N-diisopropylethylamine (1.08 mL, 6.18 mmol) were added, and the mixture was stirred at room temperature for 15 hours under a nitrogen atmosphere. Water (50 mL) and 1N hydrochloric acid (15 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL), washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0.5% to 5%) to give an orange oily compound (1.20 g). )

This was dissolved in tetrahydrofuran (15 mL), tetrabutylammonium fluoride (1.0 mol / L tetrahydrofuran solution, 1.60 mL, 1.60 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hr. A saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 7%) to give the target compound (514 mg, yield) as a white solid. 69%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.99 (3H, br s), 3.07 (3H, s), 3.11 (3H, br s), 3.66 (1H, dd, J = 12.3, 5.3 Hz), 3.75 (1H, dd, J = 14.1, 7.4 Hz), 3.83 (1H, dd, J = 12.5, 3.1 Hz), 4.00 (1H, dd, J = 14.5, 9.8 Hz), 4.75-4.81 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.73 (1H, d, J = 3.5 Hz), 6.96 (1H, dd, J = 2.3, 1.6 Hz), 7.13 (2H, dt, J = 9.5, 2.3 Hz ), 7.28 (1H, t, J = 2.0 Hz), 7.40 (1H, t, J = 1.6 Hz), 7.91 (2H, dt, J = 9.5, 2.3 Hz).
MS (ESI) m / z: 484.15459 (M + H) ^<+> .

(Example 55)
3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N-dimethyl-5 -{[6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide

(55a) Methyl 3-hydroxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} benzoate The compound (17.4 g, 90.8 mmol) synthesized in Example (16a) was converted to N, N— Dissolved in dimethylformamide (500 mL). Methyl 3,5-dihydroxybenzoate (30.5 g, 181 mmol) and potassium carbonate (37.7 g, 273 mmol) were added, and the mixture was stirred at 100 ° C. for 5.5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (500 mL) was added, and the mixture was extracted 3 times with diethyl ether (400 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% -60%) to give the target compound (18.9 g, 18.9 g, Yield 64%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.24 (3H, s), 3.91 (3H, s), 6.36 (1H, brs), 6.82 (1H, t, J = 2.4 Hz), 7.28 (1H, brs), 7.43 (1H, brs), 7.44 (1H, dd, J = 2.7, 8.6Hz), 8.06 (1H, d, J = 8.6Hz), 8.46 (1H, d, J = 2.7Hz).
(55b) Methyl 3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5-{[(trifluoromethyl) sulfonyl] oxy} benzoate Compound (18.9 g) synthesized in Example (55a) , 58.5 mmol) was dissolved in methylene chloride (500 mL). Trifluoromethanesulfonic anhydride (13.8 mL, 82.0 mmol) and pyridine (14.2 mL, 176 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. Water (400 mL) was added and extracted twice with methylene chloride (400 mL). The organic layer was washed with saturated brine and then 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: ethyl acetate / hexane = 20% -50%) to give the target compound (20.9 g, Yield 79%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.26 (3H, s), 3.96 (3H, s), 7.28 (1H, m), 7.52 (1H, dd, J = 2.7, 8.6Hz), 7.75 ( 1H, brt, J = 2.4Hz), 7.83 (1H, brt, J = 2.4Hz), 8.14 (1H, d, J = 8.6 Hz), 8.51 (1H, d, J = 2.7Hz).
(55c) Benzyl 5- [3- (methoxycarbonyl) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrole-2-carboxylate synthesized in Example (55b) Compound (20.9 g, 45.9 mmol), compound synthesized in Example (19e) (18.0 g, 55.0 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride Using the dichloromethane complex (1.13 g, 1.38 mmol) and potassium carbonate (12.7 g, 91.9 mmol), the target compound (19.3 g, yield 83%) was obtained in the same manner as in Example (16e). )
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.24 (3H, s), 3.96 (3H, s), 5.35 (2H, s), 6.63 (1H, dd, J = 2.4, 3.9Hz), 7.01 ( 1H, dd, J = 2.4, 3.9Hz), 7.35-7.47 (6H, m), 7.48 (1H, brs), 7.62 (1H, m), 8.08 (1H, d, J = 8.9Hz), 8.11 (1H , brs), 8.50 (1H, d, J = 2.9Hz), 9.49 (1H, brs).

(55d) Methyl 3- [5-({(2S) -2-hydroxy-3-[(triisopropylsilyl) oxy] propyl} carbamoyl) -1H-pyrrol-2-yl] -5-{[6- ( Methylsulfonyl) pyridin-3-yl] oxy} benzoate The compound synthesized in Example (55c) (19.3 g, 38.1 mmol) was dissolved in a mixed solvent of ethyl acetate (200 mL) and tetrahydrofuran (200 mL), and 10% A palladium carbon catalyst (7.80 g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 3.5 hours. The palladium carbon catalyst was removed by Celite filtration and washed with ethyl acetate. The solvent was distilled off under reduced pressure.

The obtained residue was dissolved in methanol (300 mL), and (S)-(−)-3-amino-1,2-propanediol (5.00 g, 54.9 mmol), DMT-MM (26.4 g, 95) was dissolved. .4 mmol) was added, and the mixture was stirred at room temperature for 19 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, water (200 mL) was added, and the mixture was extracted 10 times with ethyl acetate (100 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.

The obtained residue was dissolved in methylene chloride (300 mL), triisopropylsilyl chloride (12.2 mL, 57.0 mmol), triethylamine (16.0 mL, 115 mol), 4-dimethylaminopyridine (4.66 g, 38.1 mmol). And stirred at room temperature for 17 hours under a nitrogen atmosphere. Water (200 mL) was added and extracted twice with methylene chloride (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 40% to 70%) to give the desired product as a white solid (19.4 g, Yield 79%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.03-1.16 (21H, m), 3.12 (1H, d, J = 4.7 Hz), 3.24 (3H, s), 3.39 (1H, ddd, J = 4.7 , 7.0, 14.1Hz), 3.67 (1H, dd, J = 6.3, 9.8Hz), 3.74 (1H, ddd, J = 3.1, 7.0, 14.1Hz), 3.78 (1H, dd, J = 4.7, 10.2Hz) , 3.87 (1H, m), 3.95 (1H, s), 6.44 (1H, brt, J = 6.3Hz), 6.61 (1H, dd, J = 2.7, 3.9Hz), 6.64 (1H, dd, J = 2.4 , 3.9Hz), 7.44 (1H, dd, J = 2.7, 8.6Hz), 7.49 (1H, t, J = 2.4Hz), 7.59 (1H, t, J = 2.0Hz), 8.07 (1H, d, J = 8.6Hz), 8.12 (1H, t, J = 2.0Hz), 8.49 (1H, d, J = 2.7Hz), 9.92 (1H, brs).
(55e) methyl 3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5 -Dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} benzoate The compound synthesized in Example (55d) (19.4 g, 30.0 mmol), methanesulfonic anhydride (11. 0 g, 63.1 mmol) and triethylamine (21.0 mL, 151 mol) were used to obtain the desired product (15.6 g, yield 83%) as a white solid in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.03-1.13 (21H, m), 3.25 (3H, s), 3.83-3.93 (3H, m), 3.95 (3H, s), 4.02 (1H, dd , J = 9.8, 14.5Hz), 4.77 (1H, m), 6.61 (1H, d, J = 3.9Hz), 6.76 (1H, d, J = 3.9Hz), 7.45 (1H, dd, J = 2.7, 8.6Hz), 7.46 (1H, t, J = 2.4Hz), 7.58 (1H, t, J = 2.4Hz), 8.08 (1H, d, J = 8.6Hz), 8.10 (1H, t, J = 1.6Hz) ), 8.50 (1H, d, J = 2.7Hz).

(55f) N, N-dimethyl-3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl } -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} benzamide The compound (4.02 g, 6.40 mmol) synthesized in Example (55e) was dissolved in ethanol (100 mL). ), 2N aqueous sodium hydroxide solution (50 mL) was added, and the mixture was heated to reflux for 1 hour under a nitrogen atmosphere. 2N Hydrochloric acid (55 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (100 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.

The obtained residue was dissolved in methanol (70 mL), and dimethylamine (2.0 mol / L methanol solution, 8.00 mL, 16.0 mmol) and DMT-MM (4.43 g, 16.0 mmol) were used. The target compound (1.84 g, yield 45%) was obtained as a white solid in the same manner as in (5d).
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.02-1.13 (21H, m), 3.02 (3H, s), 3.12 (3H, s), 3.24 (3H, s), 3.82-3.92 (3H, m ), 4.00 (1H, m), 4.76 (1H, m), 6.55 (1H, d, J = 3.9Hz), 6.75 (1H, d, J = 3.9Hz), 6.99 (1H, brs), 7.29 (1H , t, J = 2.0Hz), 7.45-7.50 (2H, m), 8.07 (1H, d, J = 8.6Hz), 8.50 (1H, d, J = 2.4Hz).
(55 g) 3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N- Dimethyl-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide Compound (1.84 g, 2.87 mmol) synthesized in Example (55f), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran) Using the solution, 3.45 mL, 3.45 mmol), the target compound (1.27 g, yield 91%) as a white solid was obtained in the same manner as in Example (16k).
¹ H-NMR (CDCl ₃ , 400 MHz): δ2.98 (3H, s), 3.12 (3H, s), 3.24 (3H, s), 3.65 (1H, dd, J = 4.7, 12.5Hz), 3.74 ( 1H, dd, J = 7.4, 14.1Hz), 3.83 (1H, dd, J = 3.1, 12.5Hz), 4.00 (1H, dd, J = 9.8, 14.1Hz), 4.78 (1H, m), 6.49 (1H , d, J = 3.9Hz), 6.71 (1H, d, J = 3.9Hz), 6.97 (1H, brs), 7.29 (1H, brs), 7.40 (1H, brs), 7.44 (1H, dd, J = 2.4, 9.0Hz), 8.05 (1H, d, J = 9.0Hz), 8.48 (1H, d, J = 2.4Hz).
MS (ESI) m / z: 485.14948 (M + H) ^<+> .

(Example 56)
3- {5-[(5R) -5- (fluoromethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N-dimethyl-5 -{[6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide

The compound (563 mg, 1.16 mmol) synthesized in Example (55 g) was dissolved in 1,2-dimethoxyethane (15 mL), and bis (2-methoxyethyl) aminosulfur trifluoride (0. 32 mL, 1.7 mmol) was added dropwise. The temperature was naturally raised to room temperature, and bis (2-methoxyethyl) aminosulfur trifluoride (0.32 mL, 1.7 mmol) was added on the way, followed by stirring for 7 hours. Methanol (2 mL) was added, and the mixture was stirred for 10 min, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then 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: ethyl acetate / hexane = 60% -100%) to give the target compound (105 mg, 19%) as a white solid. )
¹ H-NMR (CDCl ₃ , 500 MHz): δ 3.02 (3H, br s), 3.12 (3H, br s), 3.24 (3H, s), 3.82 (1H, dd, J = 14.6, 7.3 Hz), 4.06 -4.11 (1H, m), 4.44-4.66 (2H, m), 4.86-4.95 (1H, m), 6.57 (1H, d, J = 3.4 Hz), 6.81 (1H, d, J = 3.9 Hz), 6.99 (1H, dd, J = 2.4, 1.5 Hz), 7.30 (1H, t, J = 2.0 Hz), 7.45-7.49 (2H, m), 8.07 (1H, d, J = 8.3 Hz), 8.50 (1H , d, J = 2.4 Hz).
MS (ESI) m / z: 487.14624 (M + H) ^<+> .

(Example 57)
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (Methylsulfonyl) pyridin-3-yl] oxy} benzamide

(57a) 5- [3- (Methoxycarbonyl) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrole-2-carboxylic acid Synthesized in Example (55c) The compound (2.29 g, 4.52 mmol) was dissolved in tetrahydrofuran (150 mL), 10% palladium carbon catalyst (2.53 g) was added, and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. The palladium carbon catalyst was removed by Celite filtration and washed with ethyl acetate. The solvent was distilled off under reduced pressure to obtain the target compound (1.52 g, 81%) as a gray solid.
¹ H-NMR (DMSO-D6, 400 MHz) δ: 3.28 (3H, s), 3.89 (3H, s), 6.80 (2H, s), 7.55 (1H, dd, J = 2.2, 1.4 Hz), 7.69 ( 1H, dd, J = 8.6, 2.7 Hz), 8.07 (1H, d, J = 9.0 Hz), 8.09 (1H, t, J = 2.0 Hz), 8.34 (1H, t, J = 1.4 Hz), 8.66 ( 1H, d, J = 2.7 Hz), 12.26 (1H, br s).
(57b) Methyl 3- (5-{[(2R) -2-hydroxypropyl] carbamoyl} -1H-pyrrol-2-yl) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} Benzoate Compound synthesized in Example (57a) (1.52 g, 3.65 mmol), (R)-(−)-1-amino-2-propanol (450 μL, 5.69 mmol), DMT-MM (2.80 g) , 8.94 mmol), and the white solid target product (1.28 g, 74%) was obtained in the same manner as in Example (5d).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.25 (3H, d, J = 6.3 Hz), 3.24 (3H, s), 3.26-3.32 (1H, m), 3.59-3.65 (1H, m), 3.95 (3H, s), 4.00-4.04 (1H, m), 6.41 (1H, t, J = 5.5 Hz), 6.60 (1H, dd, J = 3.9, 2.7 Hz), 6.65 (1H, dd, J = 3.9 , 2.7 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 7.48 (1H, t, J = 2.2 Hz), 7.60 (1H, dd, J = 2.3, 1.6 Hz), 8.07 (1H, d , J = 8.6 Hz), 8.12 (1H, t, J = 1.4 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.96 (1H, br s).
MS (FAB) m / z: 474 (M + H) ^<+> .

(57c) Methyl 3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} benzoate Compound (1.26 g, 2.67 mmol) synthesized in Example (57b), methanesulfonic anhydride (936 mg, 5.37 mmol), triethylamine (1.5 mL) , 11 mmol), and the target compound (0.92 g, yield 76%) was obtained as a pale yellow solid in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.43 (3H, d, J = 6.3 Hz), 3.24 (3H, s), 3.55 (1H, dd, J = 14.1, 7.4 Hz), 3.95 (3H, s ), 4.08 (1H, dd, J = 14.1, 9.4 Hz), 4.80-4.87 (1H, m), 6.62 (1H, d, J = 3.9 Hz), 6.77 (1H, d, J = 3.9 Hz), 7.44 -7.48 (2H, m), 7.58 (1H, dd, J = 2.3, 1.6 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.12 (1H, t, J = 1.4 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 456.12143 (M + H) ⁺ .
(57d) N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -{[6- (Methylsulfonyl) pyridin-3-yl] oxy} benzamide The compound (920 mg, 2.02 mmol) synthesized in Example (57c) was dissolved in ethanol (15 mL), and 2N aqueous sodium hydroxide solution was dissolved. (5 mL) was added and stirred at 70 ° C. for 1 hour. Water (100 mL) was added to the reaction solution, followed by ice cooling, 1N hydrochloric acid (10 mL) was added, and the precipitated white solid (730 mg) was collected by filtration.

This was suspended in N, N-dimethylformamide (8 mL), dimethylamine hydrochloride (283 mg, 3.47 mmol), HATU (1.25 g, 3.28 mmol), N, N-diisopropylethylamine (1.15 mL, 6.58 mmol) was added, and the mixture was stirred at room temperature for 6 hours under a nitrogen atmosphere. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL), washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 1.5% to 6%) to give the target compound (676 mg, Yield 71%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.42 (3H, d, J = 6.3 Hz), 3.02 (3H, br s), 3.12 (3H, br s), 3.24 (3H, s), 3.54 (1H , dd, J = 14.1, 7.4 Hz), 4.07 (1H, dd, J = 14.1, 9.0 Hz), 4.79-4.88 (1H, m), 6.56 (1H, d, J = 3.5 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.99 (1H, dd, J = 2.2, 1.4 Hz), 7.29 (1H, t, J = 2.0 Hz), 7.46-7.49 (2H, m), 8.07 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 469.15449 (M + H) ^<+> .

(Example 58)
N, N-dimethyl-3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (Methylsulfonyl) pyridin-3-yl] oxy} benzamide

(58a) Methyl 3- (5-{[(1R) -2-hydroxy-1-methylethyl] carbamoyl} -1H-pyrrol-2-yl) -5-{[6- (methylsulfonyl) pyridine-3- Yl] oxy} benzoate Using the compound synthesized in Example (57a) (1.53 g, 3.67 mmol), D-alaninol (570 μL, 7.36 mmol), DMT-MM (2.89 g, 9.23 mmol), The target product (1.00 g, yield 58%) was obtained as a white solid in the same manner as in Example (5d).
¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.28 (3H, d, J = 6.8 Hz), 2.75 (1H, br s), 3.24 (3H, s), 3.60-3.66 (1H, m), 3.74- 3.80 (1H, m), 3.95 (3H, s), 4.22-4.30 (1H, m), 6.11 (1H, d, J = 7.3 Hz), 6.59 (1H, dd, J = 3.9, 2.9 Hz), 6.63 (1H, dd, J = 3.9, 2.4 Hz), 7.44 (1H, dd, J = 8.8, 2.9 Hz), 7.48 (1H, t, J = 2.0 Hz), 7.59 (1H, dd, J = 2.4, 1.5 Hz), 8.07 (1H, d, J = 8.8 Hz), 8.12 (1H, t, J = 1.5 Hz), 8.49 (1H, d, J = 2.9 Hz), 9.96 (1H, br s).
MS (FAB) m / z: 474 (M + H) ⁺ .
(58b) Methyl 3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} benzoate Compound synthesized in Example (58a) (990 mg, 2.09 mmol), methanesulfonic anhydride (730 mg, 4.19 mmol), triethylamine (1.2 mL, 8 .7 mmol) was used to obtain the target compound (899 mg, 94% yield) as a yellow solid in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.34 (3H, d, J = 6.3 Hz), 3.25 (3H, s), 3.92-3.97 (1H, m), 3.95 (3H, s), 4.30-4.39 (1H, m), 4.52 (1H, dd, J = 9.2, 8.0 Hz), 6.62 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 7.47 (1H, t, J = 2.2 Hz), 7.59 (1H, dd, J = 2.3, 1.2 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.12 (1H, t, J = 1.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (FAB) m / z: 456 (M + H) ⁺ .
(58c) N, N-dimethyl-3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -{[6- (Methylsulfonyl) pyridin-3-yl] oxy} benzamide Compound (899 mg, 1.97 mmol) synthesized in Example (58b), 2N aqueous sodium hydroxide solution (5 mL), dimethylamine hydrochloride (208 mg, 2.55 mmol), HATU (927 mg, 2.44 mmol) and N, N-diisopropylethylamine (850 μL, 4.87 mmol) were used in the same manner as in Example (57d) to give the target compound (353 mg) as a white solid. Yield 38%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.32 (3H, d, J = 6.6 Hz), 3.02 (3H, br s), 3.12 (3H, br s), 3.24 (3H, s), 3.94 (1H , t, J = 7.8 Hz), 4.28-4.37 (1H, m), 4.50 (1H, t, J = 8.6 Hz), 6.56 (1H, d, J = 3.9 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.99 (1H, dd, J = 2.3, 1.6 Hz), 7.30 (1H, t, J = 2.0 Hz), 7.46-7.49 (2H, m), 8.07 (1H, d, J = 8.6 Hz) , 8.50 (1H, d, J = 2.3 Hz).
MS (ESI) m / z: 469.15449 (M + H) ^<+> .

(Example 59)
2-Methyl-1- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [ 4- (Methylsulfonyl) phenoxy] phenyl) propan-1-one

(59a) 1- (3,5-Dimethoxyphenyl) -2-methylpropan-1-ol 3,5-dimethoxybenzaldehyde (6.67 g, 40.1 mmol) was dissolved in tetrahydrofuran (40 mL) and isopropylmagnesium bromide ( 0.72 mol / L tetrahydrofuran solution, 90 mL, 64.8 mmol) was added dropwise at −78 ° C., and the mixture was stirred at room temperature for 4 hours and a half in a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% to 40%) to give the target compound as a colorless liquid (3.79 g, yield). 45%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 0.82 (3H, d, J = 6.6 Hz), 1.00 (3H, d, J = 6.6 Hz), 1.81 (1H, d, J = 3.1 Hz), 1.89- 1.98 (1H, m), 3.80 (6H, s), 4.29 (1H, dd, J = 7.0, 3.1 Hz), 6.37 (1H, t, J = 2.3 Hz), 6.48 (2H, d, J = 2.0 Hz ).
(59b) 1- (3,5-dimethoxyphenyl) -2-methylpropan-1-one The compound synthesized in Example (59a) (3.79 g, 18.2 mmol) was dissolved in methylene chloride (200 mL). Manganese dioxide (15.0 g, 173 mmol) was added at room temperature, and the mixture was stirred for one day with heating under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature and then filtered through celite. The mother liquor was evaporated under reduced pressure to give the target compound (2.55 g, yield 67%) as a colorless liquid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.21 (6H, d, J = 7.0 Hz), 3.46-3.53 (1H, m), 3.84 (6H, s), 6.65 (1H, t, J = 2.2 Hz ), 7.09 (2H, d, J = 2.0 Hz).
(59c) 1- {3-methoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -2-methylpropan-1-one Compound synthesized in Example (59b) (2.55 g, 12.2 mmol) Was dissolved in 1-methyl-2-pyrrolidone (30 mL), sodium thiomethoxide (1.75 g, 25.0 mmol) was added at room temperature, and the mixture was stirred at 100 ° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 2N hydrochloric acid (150 mL) was added, and the mixture was extracted with diethyl ether (300 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.

The obtained residue was dissolved in N, N-dimethylformamide (30 mL), 4-fluorophenylmethylsulfone (4.40 g, 25.3 mmol) and potassium carbonate (7.05 g, 51.0 mmol) were added at room temperature, The mixture was stirred at 100 ° C. overnight under a nitrogen atmosphere. The reaction solution was cooled to room temperature, water (150 mL) was added, and the mixture was extracted with diethyl ether (300 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The product was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 5% to 40%) to obtain the target compound (3.98 g, yield 94%) as a yellow solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.21 (6H, d, J = 6.8 Hz), 3.07 (3H, s), 3.42-3.47 (1H, m), 3.86 (3H, s), 6.81 (1H , t, J = 2.2 Hz), 7.12 (2H, dd, J = 9.3, 2.4 Hz), 7.22 (1H, t, J = 1.7 Hz), 7.35 (1H, dd, J = 2.4, 1.5 Hz), 7.91 (2H, dd, J = 9.5, 2.2 Hz).

(59d) 1- {3-Hydroxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -2-methylpropan-1-one Compound synthesized in Example (59c) (3.78 g, 10.9 mmol) Was dissolved in methylene chloride (30 mL), boron tribromide (1.0 mol / L methylene chloride solution, 35.0 mL, 35.0 mmol) was added dropwise at −78 ° C., and the mixture was stirred at room temperature for 4 hours under a nitrogen atmosphere. To this reaction solution was added a saturated aqueous ammonium chloride solution (10 mL), and the mixture was extracted with methylene chloride (20 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 5% -50%) to give the desired compound (926 mg, yield) as a white foam. 26%). ¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.20 (6H, d, J = 6.8 Hz), 3.08 (3H, s), 3.41-3.46 (1H, m), 6.79 (1H, t, J = 2.2 Hz ), 7.12 (2H, d, J = 8.8 Hz), 7.19 (1H, d, J = 1.5 Hz), 7.36 (1H, t, J = 1.7 Hz), 7.91 (2H, d, J = 8.8 Hz).
(59e) 3- (2-Methylpropanoyl) -5- [4- (methylsulfonyl) phenoxy] phenyl trifluoromethanesulfonate Compound (920 mg, 2.75 mmol) synthesized in Example (59d) was dissolved in methylene chloride (10 mL). , Pyridine (0.70 mL, 8.65 mmol) and trifluoromethanesulfonic anhydride (0.70 mL, 4.16 mmol) were added at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour and a half under a nitrogen atmosphere. The reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution (50 mL) was added, and the mixture was extracted with methylene chloride (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 5% to 40%) to give the target compound (1.17 g, yield) as a white solid. 91%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.23 (6H, d, J = 7.0 Hz), 3.10 (3H, s), 3.39-3.46 (1H, m), 7.17 (1H, t, J = 2.5 Hz ), 7.19-7.21 (2H, m), 7.65 (2H, dd, J = 3.7, 1.8 Hz), 7.97-8.00 (2H, m).
(59f) 2-Methyl-1- {3- [4- (methylsulfonyl) phenoxy] -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl} Propan-1-one Compound (1.17 g, 2.51 mmol) synthesized in Example (59e), bis (pinacolato) diboron (0.90 g, 3.54 mmol), [1,1′-bis (diphenylphosphino) ) Ferrocene] palladium (II) dichloride Dichloromethane complex (200 mg, 0.25 mmol) and potassium acetate (1.25 g, 12.7 mmol) were used in the same manner as in Example (1d) to obtain the target compound (608 mg, Yield 55%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.22 (6H, d, J = 6.6 Hz), 1.36 (12H, s), 3.07 (3H, s), 3.57-3.64 (1H, m), 7.07 (2H , d, J = 8.6 Hz), 7.68 (1H, d, J = 2.0 Hz), 7.75 (1H, dd, J = 2.3, 1.6 Hz), 7.90 (2H, d, J = 8.6 Hz), 8.20 (1H , s).

(59 g) 2-Benzyl 1-t-butyl 5- {3- (2-methylpropanoyl) -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-1,2-dicarboxylate Compound (608 mg, 1.37 mmol) synthesized in Example (59f), Compound (1.10 g, 2.89 mmol) synthesized in Example (16d), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) Dichloride Using a dichloromethane complex (115 mg, 0.14 mmol) and potassium carbonate (810 mg, 5.86 mmol), the target compound (630 mg, yield 74%) as a brown oil was obtained in the same manner as in Example (16e). Obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.22 (6H, d, J = 7.0 Hz), 1.42 (9H, s), 3.07 (3H, s), 3.45-3.53 (1H, m), 5.32 (2H , s), 6.28 (1H, d, J = 3.5 Hz), 6.96 (1H, d, J = 3.9 Hz), 7.14 (2H, d, J = 9.0 Hz), 7.32-7.44 (6H, m), 7.63 (1H, t, J = 2.0 Hz), 7.87 (1H, t, J = 1.4 Hz), 7.93 (2H, d, J = 8.6 Hz).
(59h) N-[(2R) -2-hydroxypropyl] -5- {3- (2-methylpropanoyl) -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2-carboxamide The compound (630 mg, 1.02 mmol) synthesized in Example (59 g) was dissolved in trifluoroacetic acid (5.0 mL) and stirred at room temperature for 40 minutes. After evaporating the solvent under reduced pressure, triethylamine (5 mL) was added, and the mixture was stirred for 5 minutes. A pale yellow solid was obtained by distilling off triethylamine under reduced pressure.

This was dissolved in ethyl acetate (15 mL), palladium carbon (115 mg) was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. After Celite filtration, the solvent was distilled off under reduced pressure to obtain a brown liquid compound.

This was dissolved in methylene chloride (10 mL), and (R)-(−)-1-amino-2-propanol (0.20 mL, 2.54 mmol), WSCI · HCl (400 mg, 2.09 mmol), 4-dimethyl Aminopyridine (130 mg, 1.06 mmol) was added, and the mixture was stirred at room temperature for 1 day under a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (20 mL) was added, and the mixture was extracted with methylene chloride (20 mL). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0 to 3%) to give the target compound (150 mg, yield 30) as a yellow solid. %).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.21-1.25 (9H, m), 3.08 (3H, s), 3.22-3.33 (1H, m), 3.47-3.55 (1H, m), 3.61 (1H, dd, J = 14.3, 3.7 Hz), 3.97-4.05 (1H, m), 6.45 (1H, br s), 6.59 (1H, s), 6.66 (1H, d, J = 3.5 Hz), 7.13 (2H, d, J = 8.6 Hz), 7.46 (1H, s), 7.50 (1H, s), 7.93 (2H, d, J = 8.6 Hz), 7.98 (1H, s), 10.05 (1H, br s).
(59i) 2-Methyl-1- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl}- 5- [4- (Methylsulfonyl) phenoxy] phenyl) propan-1-one The compound synthesized in Example (59h) (150 mg, 0.31 mmol), methanesulfonic anhydride (90 mg, 0.52 mmol), triethylamine ( 0.20 mL, 1.43 mmol) was used to obtain the target compound (70 mg, 48% yield) as a yellow solid in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.23 (6H, d, J = 7.0 Hz), 1.43 (3H, d, J = 5.9 Hz), 3.08 (3H, s), 3.45-3.56 (2H, m ), 4.06 (1H, dd, J = 14.1, 9.4 Hz), 4.80-4.88 (1H, m), 6.60 (1H, d, J = 3.5 Hz), 6.78 (1H, d, J = 3.5 Hz), 7.13 (2H, dd, J = 9.2, 2.5 Hz), 7.43 (1H, t, J = 2.0 Hz), 7.50 (1H, t, J = 1.8 Hz), 7.93 (2H, dd, J = 9.2, 2.5 Hz) , 7.96 (1H, t, J = 1.2 Hz).
MS (ESI) m / z: 467.16454 (M + H) ^<+> .

(Example 60)
{(4R) -2- [5- (3- [2-Fluoro-1- (fluoromethyl) ethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H- Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol

(60a) 5- {3-Bromo-5- [2-fluoro-1- (fluoromethyl) ethoxy] phenoxy} -2- (methylsulfonyl) pyridine The compound synthesized in Example (19b) (4.20 g, 12 .2 mmol) in a mixed solvent of toluene (85 mL) and tetrahydrofuran (15 mL), 1,3-difluoro-2-propanol (1.04 mL, 13.4 mmol), and triphenylphosphine (8.03 g, 30. 5 mmol), diethyl azodicarboxylate (2.2 mol / L toluene solution, 13.00 mL, 28.6 mmol) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 10 hours in a nitrogen atmosphere. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% -50%) to give the desired compound (3.51 g, 3.51 g, Yield 68%).
¹ H-NMR (CDCl ₃ , 500 MHz): δ 3.23 (3H, s), 4.58-4.74 (5H, m), 6.67 (1H, t, J = 2.0 Hz), 6.89 (1H, t, J = 2.0 Hz ), 7.04 (1H, t, J = 2.0 Hz), 7.46 (1H, dd, J = 2.9, 8.8 Hz), 8.08 (1H, d, J = 8.8 Hz), 8.46 (1H, d, J = 2.9 Hz) ).
(60b) Benzyl 5- (3- [2-fluoro-1- (fluoromethyl) ethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2- Carboxylate Compound (3.51 g, 8.31 mmol) synthesized in Example (60a), Compound (3.81 g, 11.64 mmol) synthesized in Example (19e), [1,1′-bis (diphenylphosphine) [Fino) ferrocene] palladium (II) dichloride Dichloromethane complex (0.34 g, 0.42 mmol), potassium carbonate (5.74 g, 41.56 mmol) and the same target compound as yellow oil in the same manner as in Example (16e) (3.80 g, 84% yield) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.23 (3H, s), 4.59-4.79 (5H, m), 5.33 (2H, s), 6.53 (1H, dd, J = 2.7, 3.9 Hz), 6.64 (1H, t, J = 2.3 Hz), 6.93 (1H, t, J = 2.0 Hz), 6.99 (1H, dd, J = 2.3, 3.9 Hz), 7.07 (1H, t, J = 2.0 Hz), 7.33 -7.47 (6H, m), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.38 (1H, br s).
(60c) 5- (3- [2-Fluoro-1- (fluoromethyl) ethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carvone Acid The compound (3.86 g, 7.11 mmol) synthesized in Example (60b) was dissolved in a mixed solvent of ethanol (120 mL) and ethyl acetate (30 mL), and 10% palladium carbon catalyst (0.7 g) was added. Stir for 6 hours under hydrogen atmosphere. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (3.28 g, yield ˜100%) as a yellow solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.23 (3H, s), 4.59-4.82 (5H, m), 6.56 (1H, dd, J = 2.7, 3.9 Hz), 6.68 (1H, t, J = 2.0 Hz), 6.96 (1H, t, J = 1.6 Hz), 7.06 (1H, dd, J = 2.3, 3.9 Hz), 7.11 (1H, t, J = 1.6 Hz), 7.47 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz), 9.55 (1H, br s).

(60d) Methyl N-{[5- (3- [2-fluoro-1- (fluoromethyl) ethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H- Pyrrole-2-yl] carbonyl} -L-serineate Compound (3.20 g, 7.35 mmol) synthesized in Example (60c), L-serine methyl ester hydrochloride (1.26 g, 8.08 mmol), HOBT · Similar to Example (29a) using H ₂ O (1.09 g, 8.08 mmol), N-methylmorpholine (1.62 mL, 14.69 mmol), and WSCI · HCl (1.69 g, 8.82 mmol). The target compound (2.69 g, yield 66%) was obtained as a white solid by the method.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.24 (3H, s), 3.81 (3H, s), 3.98-4.10 (2H, m), 4.59-4.80 (5H, m), 4.79-4.84 (1H, m), 6.52 (1H, dd, J = 2.7, 3.9 Hz), 6.63 (1H, t, J = 2.0 Hz), 6.73 (1H, dd, J = 2.3, 3.9 Hz), 6.87 (1H, d, J = 7.4 Hz), 6.93 (1H, t, J = 1.6 Hz), 7.07 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.74 (1H, br s).
(60e) Methyl (4S) -2- [5- (3- [2-Fluoro-1- (fluoromethyl) ethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazole-4-carboxylate Compound (2.69 g, 4.85 mmol) synthesized in Example (60d), bis (2-methoxy Ethyl) aminosulfur trifluoride (1.16 mL, 6.31 mmol) and potassium carbonate (1.01 g, 7.28 mmol) were used in the same manner as in Example (38b) to give the target compound (2.50 g, 96%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.24 (3H, s), 3.81 (3H, s), 4.55-4.80 (7H, m), 4.90 (1H, dd, J = 7.8, 10.2 Hz), 6.53 (1H, d, J = 3.9 Hz), 6.64 (1H, t, J = 2.0 Hz), 6.81 (1H, d, J = 3.9 Hz), 6.91 (1H, t, J = 1.6 Hz), 7.06 (1H , t, J = 1.6 Hz), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.59 (1H , br s).
(60f) {(4R) -2- [5- (3- [2-Fluoro-1- (fluoromethyl) ethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol Tetrahydrofuran (50 mL) was obtained from the compound (2.50 g, 4.67 mmol) synthesized in Example (60e). And lithium aluminum hydride (0.30 g, 7.94 mmol) was added at 0 ° C. After stirring for 30 minutes under a nitrogen atmosphere, water (0.30 mL), 5N aqueous sodium hydroxide solution (0.30 mL) and water (1.00 mL) were added in this order, and the mixture was stirred for 10 minutes. Ethyl acetate (150 mL) was added and stirred for 5 minutes, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the desired compound (1.04 g, 44%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.24 (3H, s), 3.62 (1H, dd, J = 2.7, 12.1 Hz), 3.98 (1H, dd, J = 2.3, 12.1 Hz), 4.12-4.17 (1H, m), 4.31-4.41 (2H, m), 4.60-4.80 (5H, m), 6.38 (1H, d, J = 3.5 Hz), 6.46 (1H, d, J = 3.5 Hz), 6.62 ( 1H, t, J = 2.0 Hz), 6.94 (1H, t, J = 1.6 Hz), 7.09 (1H, t, J = 1.6 Hz), 7.47 (1H, dd, J = 2.7, 8.6 Hz), 8.07 ( 1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 508.13445 (M + H) ^<+> .

(Example 61)
{(4R) -2- [5- (3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl) -1H-pyrrole- 2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol

(61a) 5- {3-Bromo-5-[(3S) -tetrahydrofuran-3-yloxy] phenoxy} -2- (methylsulfonyl) pyridine Compound (7.07 g, 20.5 mmol) synthesized in Example (19b) ), (R) -3-hydroxytetrahydrofuran (1.99 g, 22.6 mmol), triphenylphosphine (11.90 g, 45.2 mmol), diethyl azodicarboxylate (2.2 mol / L toluene solution, 20.0 mL, 44.0 mmol) and the target compound (6.05 g, yield 71%) as a pale yellow oil was obtained in the same manner as in Example (40b).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.09-2.16 (1H, m), 2.18-2.28 (1H, m), 3.24 (3H, s), 3.85-4.02 (4H, m), 4.87-4.91 ( 1H, m), 6.54 (1H, t, J = 2.3 Hz), 6.83 (1H, t, J = 2.0 Hz), 6.91 (1H, t, J = 2.0 Hz), 7.45 (1H, dd, J = 2.7 , 8.6 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(61b) Benzyl 5- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl) -1H-pyrrole-2-carboxylate Compound (6.05 g, 14.60 mmol) synthesized in Example (61a), Compound (7.17 g, 21.91 mmol) synthesized in Example (19e), [1,1′-bis (diphenylphosphino) Ferrocene] palladium (II) dichloride Using dichloromethane complex (0.66 g, 0.80 mmol) and potassium carbonate (10.09 g, 73.02 mmol) in the same manner as in Example (16e), the target compound (6 0.73 g, 86% yield).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.12-2.29 (2H, m), 3.23 (3H, s), 3.88-4.04 (4H, m), 4.93-4.97 (1H, m), 5.33 (2H, s), 6.51-6.53 (2H, m), 6.86 (1H, t, J = 1.6 Hz), 6.93 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.7, 3.9 Hz), 7.33-7.46 (6H, m), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.29 (1H, br s).
(61c) 5- (3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl) -1H-pyrrole-2-carboxylic acid The compound (6.73 g, 12.40 mmol) synthesized in Example (61b) was dissolved in a mixed solvent of ethanol (200 mL) and ethyl acetate (70 mL), 10% palladium carbon catalyst (1.2 g) was added, and hydrogen atmosphere was added. Stir down for 2 hours. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (5.60 g, yield˜100%) as a brown solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.11-2.30 (2H, m), 3.22 (3H, s), 3.86-4.06 (4H, m), 4.94-4.99 (1H, br m), 6.51-6.55 (2H, m), 6.91 (1H, s), 6.99-7.04 (2H, m), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 ( 1H, d, J = 2.7 Hz), 9.71 (1H, br s).

(61d) Methyl N-{[5- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl) -1H-pyrrole- 2-yl] carbonyl} -L-serineate Compound (5.55 g, 12.49 mmol) synthesized in Example (61c), L-serine methyl ester hydrochloride (2.20 g, 13.74 mmol), HOBT · H ₂ Using O (1.86 g, 13.74 mmol), N-methylmorpholine (2.75 mL, 24.97 mmol) and WSCI.HCl (2.87 g, 14.98 mmol) in the same manner as in Example (29a) The target compound (6.24 g, yield 91%) was obtained as a white solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.11-2.29 (2H, m), 3.23 (3H, s), 3.79 (3H, s), 3.86-3.95 (1H, m), 3.96-4.08 (5H, m), 4.79-4.83 (1H, m), 4.93-4.97 (1H, br m), 6.49-6.51 (2H, m), 6.74 (1H, dd, J = 2.3, 3.9 Hz), 6.89 (1H, t , J = 1.6 Hz), 6.95 (1H, d, J = 7.4 Hz), 6.97 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d , J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.97 (1H, br s).
(61e) Methyl (4S) -2- [5- (3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl) -1H -Pyrrole-2-yl] -4,5-dihydro-1,3-oxazole-4-carboxylate Compound synthesized in Example (61d) (6.24 g, 11.42 mmol), bis (2-methoxyethyl) Aminosulfur trifluoride (2.53 mL, 13.70 mmol) and potassium carbonate (2.37 g, 17.13 mmol) were used in the same manner as in Example (38b) to give the target compound (5.45 g, 91%) as a white solid. )
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.12-2.30 (2H, m), 3.24 (3H, s), 3.82 (3H, s), 3.89-3.96 (1H, m), 3.97-4.04 (3H, m), 4.58 (1H, dd, J = 9.0, 10.6 Hz), 4.67 (1H, t, J = 8.6 Hz), 4.90 (1H, dd, J = 7.8, 10.9 Hz), 4.94-4.99 (1H, br m), 6.51-6.52 (2H, m), 6.81 (1H, d, J = 3.9 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.93 (1H, t, J = 1.6 Hz), 7.45 ( 1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.55 (1H, br s).
(61f) {(4R) -2- [5- (3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol The compound synthesized in Example (61e) (5.45 g, 10.33 mmol) was dissolved in tetrahydrofuran (100 mL). Then, lithium aluminum hydride (0.78 g, 20.66 mmol) was added at 0 ° C. After stirring for 30 minutes under a nitrogen atmosphere, water (0.80 mL), 5N aqueous sodium hydroxide solution (0.80 mL) and water (2.40 mL) were added in this order, and the mixture was stirred for 10 minutes. Ethyl acetate (300 mL) was added and stirred for 5 minutes, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (2.32 g, 45%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.13-2.31 (2H, m), 3.24 (3H, s), 3.61 (1H, dd, J = 2.7, 12.1 Hz), 3.89-4.05 (5H, m) , 4.12-4.17 (1H, m), 4.32-4.41 (2H, m), 4.94-4.98 (1H, br m), 6.38 (1H, d, J = 3.9 Hz), 6.47-6.50 (2H, m), 6.88 (1H, t, J = 1.6 Hz), 6.96 (1H, t, J = 1.6 Hz), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 500.14769 (M + H) ^<+> .

(Example 62)
[(4R) -2- {5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydro-2H-pyran-4-yloxy) phenyl] -1H-pyrrole- 2-yl} -4,5-dihydro-1,3-oxazol-4-yl] methanol

(62a) 5- [3-Bromo-5- (tetrahydro-2H-pyran-4-yloxy) phenoxy] -2- (methylsulfonyl) pyridine The compound synthesized in Example (19b) (500 mg, 1.45 mmol), Tetrahydro-4-pyranol (0.17 mL, 1.74 mmol), triphenylphosphine (841 mg, 3.20 mmol), diethyl azodicarboxylate (2.2 mol / L toluene solution, 1.40 mL, 3.08 mmol) were used. The target compound (350 mg, yield 56%) was obtained as a pale yellow oil in the same manner as in Example (40b).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.74-1.83 (2H, m), 1.98-2.05 (2H, m), 3.23 (3H, s), 3.55-3.62 (2H, m), 3.93-4.00 ( 2H, m), 4.43-4.50 (1H, m), 6.58 (1H, t, J = 2.0 Hz), 6.82 (1H, t, J = 1.6 Hz), 6.96 (1H, t, J = 2.0 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(62b) Benzyl 5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydro-2H-pyran-4-yloxy) phenyl] -1H-pyrrole-2-carboxylate Compound (350 mg, 0.82 mmol) synthesized in Example (62a), compound (400 mg, 1.23 mmol) synthesized in Example (19e), [1,1′-bis (diphenylphosphino) ferrocene] palladium ( II) Dichlorochloride The target compound (360 mg, yield 80%) as a yellow oil was obtained in the same manner as in Example (16e) using dichloromethane complex (40 mg, 0.05 mmol) and potassium carbonate (565 mg, 4.09 mmol). It was.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.77-1.85 (2H, m), 2.01-2.05 (2H, m), 3.23 (3H, s), 3.58-3.63 (2H, m), 3.96-4.01 ( 2H, m), 4.50-4.55 (1H, m), 5.33 (2H, s), 6.52 (1H, dd, J = 2.4, 3.9 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.85 (1H , t, J = 1.5 Hz), 6.97 (1H, t, J = 1.5 Hz), 6.99 (1H, dd, J = 2.4, 3.9 Hz), 7.33-7.49 (6H, m), 8.06 (1H, d, J = 8.8 Hz), 8.48 (1H, d, J = 2.9 Hz), 9.24 (1H, br s).
(62c) 5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydro-2H-pyran-4-yloxy) phenyl] -1H-pyrrole-2-carboxylic acid The compound (360 mg, 0.66 mmol) synthesized in Example (62b) was dissolved in a mixed solvent of ethanol (10 mL) and ethyl acetate (5 mL), 10% palladium carbon catalyst (100 mg) was added, and the mixture was added under a hydrogen atmosphere for 2 hours. Stir. The palladium carbon catalyst was removed by celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (276 g, yield 92%) as a white solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.75-1.85 (2H, m), 2.00-2.07 (2H, m), 3.21 (3H, s), 3.56-3.63 (2H, m), 3.94-4.02 ( 2H, m), 4.50-4.57 (1H, m), 6.51 (1H, s), 6.56 (1H, s), 6.88 (1H, s), 6.96-7.03 (2H, m), 7.43 (1H, d, J = 8.6 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.47 (1H, s), 9.62 (1H, br s).

(62d) Methyl N-({5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydro-2H-pyran-4-yloxy) phenyl] -1H-pyrrole- 2-yl} carbonyl) -L-serineate Compound (276 mg, 0.60 mmol) synthesized in Example (62c), L-serine methyl ester hydrochloride (115 mg, 0.72 mmol), HOBT.H ₂ O (89 mg, 0.66 mmol), N-methylmorpholine (0.13 mL, 1.20 mmol) and WSCI.HCl (138 mg, 0.72 mmol) in the same manner as in Example (29a), the target compound (252 mg, Yield 75%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.77-1.86 (2H, m), 2.01-2.08 (2H, m), 2.53 (1H, t, J = 5.9 Hz), 3.23 (3H, s), 3.57 -3.64 (2H, m), 3.83 (3H, s), 3.95-4.09 (4H, m), 4.50-4.57 (1H, m), 4.81-4.85 (1H, m), 6.52 (1H, dd, J = 2.7, 3.9 Hz), 6.56 (1H, t, J = 2.0 Hz), 6.74 (1H, dd, J = 2.3, 3.9 Hz), 6.82 (1H, d, J = 7.4 Hz), 6.86 (1H, t, J = 1.8 Hz), 6.99 (1H, t, J = 1.8 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.58 (1H, br s).
(62e) Methyl (4S) -2- {5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydro-2H-pyran-4-yloxy) phenyl] -1H -Pyrrol-2-yl} -4,5-dihydro-1,3-oxazole-4-carboxylate Compound (252 mg, 0.45 mmol) synthesized in Example (62d), bis (2-methoxyethyl) aminosulfur The target compound (217 g, 89%) as a white solid was obtained in the same manner as in Example (38b) using trifluoride (0.10 mL, 0.54 mmol) and potassium carbonate (95 mg, 0.67 mol).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.77-1.86 (2H, m), 2.01-2.08 (2H, m), 3.24 (3H, s), 3.58-3.65 (2H, m), 3.82 (3H, s), 3.96-4.02 (2H, m), 4.51-4.61 (2H, m), 4.67 (1H, t, J = 8.2 Hz), 4.91 (1H, dd, J = 7.8, 10.6 Hz), 6.52 (1H , d, J = 3.9 Hz), 6.56 (1H, t, J = 2.0 Hz), 6.81 (1H, d, J = 3.9 Hz), 6.84 (1H, t, J = 1.6 Hz), 6.99 (1H, t , J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.55 (1H, br s).
(62f) [(4R) -2- {5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydro-2H-pyran-4-yloxy) phenyl] -1H -Pyrrole-2-yl} -4,5-dihydro-1,3-oxazol-4-yl] methanol The compound (217 mg, 0.40 mmol) synthesized in Example (62e) was dissolved in tetrahydrofuran (5 mL). Lithium aluminum hydride (30 mg, 0.80 mmol) was added at 0 ° C. After stirring for 30 minutes under a nitrogen atmosphere, water (30 μL), 5N aqueous sodium hydroxide solution (30 μL) and water (100 μL) were added in this order, and the mixture was stirred for 10 minutes. Ethyl acetate (30 mL) was added and stirred for 5 minutes, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (128 mg, 62%) as a white solid. )
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.77-1.88 (2H, m), 2.02-2.09 (2H, m), 3.24 (3H, s), 3.58-3.64 (3H, m), 3.95-4.03 ( 3H, m), 4.13-4.17 (1H, m), 4.32-4.41 (2H, m), 4.50-4.56 (1H, m), 6.38 (1H, d, J = 3.9 Hz), 6.49 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.0 Hz), 6.87 (1H, t, J = 1.6 Hz), 7.02 (1H, t, J = 1.6 Hz), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 514.16463 (M + H) ^<+> .

(Example 63)
[(4R) -2- {5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydrofuran-2-ylmethoxy) phenyl] -1H-pyrrol-2-yl} -4,5-dihydro-1,3-oxazol-4-yl] methanol

(63a) 5- [3-Bromo-5- (tetrahydrofuran-2-ylmethoxy) phenoxy] -2- (methylsulfonyl) pyridine The compound (1.50 g, 4.36 mmol) synthesized in Example (19b) was replaced with N, Dissolved in N-dimethylformamide (15 mL), tetrahydrofurfuryl bromide (1.49 mL, 13.07 mmol) and potassium carbonate (3.01 g, 21.79 mmol) were added, and the mixture was stirred at 80 ° C. for 5 hours under a nitrogen atmosphere. . The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (80 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% -60%) to give the desired compound (1.30 g, Yield 70%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.69-1.78 (1H, m), 1.89-2.00 (2H, m), 2.04-2.12 (1H, m), 3.23 (3H, s), 3.80-3.86 ( 1H, m), 3.89-3.98 (3H, m), 4.22-4.29 (1H, m), 6.60 (1H, t, J = 2.0 Hz), 6.83 (1H, t, J = 2.0 Hz), 6.98 (1H , t, J = 2.0 Hz), 7.43 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz).
(63b) Benzyl 5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydrofuran-2-ylmethoxy) phenyl] -1H-pyrrole-2-carboxylate Example (63a) ) Compound (1.30 g, 3.04 mmol), the compound synthesized in Example (19e) (1.49 g, 4.55 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium ( II) Dichlorochloride The target compound (1.60 g, yield) was obtained in the same manner as in Example (16e) using dichloromethane complex (0.15 g, 0.18 mmol) and potassium carbonate (2.10 g, 15.18 mmol). 96%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.71-1.81 (1H, m), 1.90-2.02 (2H, m), 2.05-2.14 (1H, m), 3.23 (3H, s), 3.80-3.88 ( 1H, m), 3.90-4.04 (3H, m), 4.25-4.32 (1H, m), 5.33 (2H, s), 6.52 (1H, t, J = 2.3 Hz), 6.57 (1H, s), 6.87 (1H, s), 6.98-7.01 (2H, m), 7.32-7.45 (6H, m), 8.05 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.31 ( 1H, br s).
(63c) 5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydrofuran-2-ylmethoxy) phenyl] -1H-pyrrole-2-carboxylic acid Example (63b) The compound synthesized in step (1.60 g, 2.92 mmol) was dissolved in a mixed solvent of ethanol (50 mL) and ethyl acetate (15 mL), 10% palladium carbon catalyst (0.55 g) was added, and the mixture was added under a hydrogen atmosphere for 1 hour. Stir. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (1.21 g, yield 90%) as a white solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.72-1.82 (1H, m), 1.91-2.02 (2H, m), 2.04-2.13 (1H, m), 3.20 (3H, s), 3.81-3.89 ( 1H, m), 3.90-4.09 (3H, m), 4.26-4.36 (1H, m), 6.44-6.57 (2H, m), 6.86-6.99 (2H, m), 7.13 (1H, s), 7.42 ( 1H, d, J = 8.6 Hz), 8.02 (1H, d, J = 8.6 Hz), 8.46 (1H, s), 10.06 (1H, br s).

(63d) Methyl N-({5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydrofuran-2-ylmethoxy) phenyl] -1H-pyrrol-2-yl} Carbonyl) -L-serineate Compound (1.21 g, 2.64) mmol) synthesized in Example (63c), L-serine methyl ester hydrochloride (0.50 g, 3.17 mmol), HOBT.H ₂ O ( 0.39 g, 2.90 mmol), N-methylmorpholine (0.58 mL, 5.28 mmol), WSCI.HCl (0.61 g, 3.17 mmol) and a white solid in the same manner as in Example (29a) Of the target compound (1.33 g, yield 90%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.71-1.81 (1H, m), 1.91-2.03 (2H, m), 2.05-2.14 (1H, m), 3.23 (3H, s), 3.81 (3H, s), 3.82-3.89 (1H, m), 3.91-4.08 (5H, m), 4.25-4.32 (1H, m), 4.81-4.86 (1H, m), 6.51 (1H, t, J = 2.7 Hz) , 6.54-6.56 (1H, m), 6.74 (1H, dd, J = 2.3, 3.9 Hz), 6.86-6.91 (2H, m), 7.00 (1H, d, J = 6.3 Hz), 7.43 (1H, dd , J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.94 (1H, br s).
(63e) Methyl (4S) -2- {5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydrofuran-2-ylmethoxy) phenyl] -1H-pyrrole-2 -Yl} -4,5-dihydro-1,3-oxazole-4-carboxylate Compound (1.33 g, 2.37 mmol) synthesized in Example (63d), bis (2-methoxyethyl) aminosulfur trifluoride (0.52 mL, 2.85 mmol) and potassium carbonate (0.49 g, 3.56 mmol) were used to obtain the target compound (1.14 g, 88%) as a white solid in the same manner as in Example (38b). .
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.75-1.83 (1H, m), 1.91-2.03 (2H, m), 2.05-2.15 (1H, m), 3.23 (3H, s), 3.81 (3H, s), 3.86 (1H, t, J = 7.0 Hz), 3.91-4.04 (3H, m), 4.26-4.33 (1H, m), 4.57 (1H, dd, J = 8.6, 10.6 Hz), 4.67 (1H , t, J = 8.6 Hz), 4.90 (1H, dd, J = 7.8, 10.6 Hz), 6.52 (1H, d, J = 3.9 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.81 (1H , d, J = 3.5 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.99 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H , d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.49 (1H, br s).
(63f) [(4R) -2- {5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydrofuran-2-ylmethoxy) phenyl] -1H-pyrrole-2 -Il} -4,5-dihydro-1,3-oxazol-4-yl] methanol The compound (1.14 g, 2.10 mmol) synthesized in Example (63e) was dissolved in tetrahydrofuran (20 mL) and dissolved at 0 ° C. Lithium aluminum hydride (0.16 g, 4.21 mmol) was added. After stirring for 30 minutes under a nitrogen atmosphere, water (0.16 mL), 5N aqueous sodium hydroxide solution (0.16 mL) and water (0.48 mL) were added in this order, and the mixture was stirred for 10 minutes. Ethyl acetate (80 mL) was added and stirred for 5 minutes, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the desired compound (756 mg, 71%) as a white powder. )
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.73-1.83 (1H, m), 1.92-2.02 (2H, m), 2.05-2.15 (1H, m), 3.23 (3H, s), 3.60 (1H, dd, J = 3.1, 12.1 Hz), 3.85 (1H, dd, J = 7.0, 14.9 Hz), 3.91-4.02 (4H, m), 4.09-4.15 (1H, m), 4.26-4.40 (3H, m) , 6.37 (1H, d, J = 3.9 Hz), 6.46 (1H, dd, J = 2.3, 3.9 Hz), 6.55 (1H, t, J = 2.0 Hz), 6.88 (1H, t, J = 1.6 Hz) , 7.04 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz) .
MS (ESI) m / z: 514.16351 (M + H) ^<+> .

(Example 64)
3- (3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[5- ( Methylsulfonyl) pyrazin-2-yl] oxy} phenoxy) dihydrofuran-2 (3H) -one

(64a) N-[(2R) -2-hydroxypropyl] -5- {3-methoxy-5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrole-2-carboxamide synthesized in Example (21a) The compound (2.70 g, 8.35 mmol) was dissolved in methylene chloride (20 mL), triethylamine (3.80 mL, 27.3 mmol), triisopropylsilyl chloride (3.00 mL, 14.0 mmol), 4-dimethylamino Pyridine (1.10 g, 9.00 mmol) was added and stirred for 18 hours under a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (50 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (50 mL). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 20%) to obtain a brown liquid. This was dissolved in ethyl acetate (20 mL), 10% palladium carbon catalyst (1.15 g) was added, and the mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. Celite filtration was performed, and the solvent was distilled off under reduced pressure to obtain a brown foamy compound. This compound was dissolved in methylene chloride (50 mL), and (R)-(−)-1-amino-2-propanol (1.42 mL, 18.0 mmol), WSCI • HCl (3.85 g, 20.1 mmol), 4-Dimethylaminopyridine (1.23 g, 10.1 mmol) was added, and the mixture was stirred at room temperature for 1 day under a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (60 mL) was added, and the mixture was extracted with methylene chloride (100 mL). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10-40%) to give the target compound (1.20 g, yield) as a yellow liquid. 32%).
¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.11 (18H, d, J = 7.3 Hz), 1.23 (3H, d, J = 5.9 Hz), 1.24-1.32 (3H, m), 2.84-2.97 (1H , br m), 3.25-3.31 (1H, m), 3.62 (1H, ddd, J = 14.2, 6.8, 2.9 Hz), 3.80 (3H, s), 4.01 (1H, t, J = 6.8 Hz), 6.37 (1H, t, J = 2.2 Hz), 6.43-6.48 (2H, m), 6.62-6.64 (1H, m), 6.70 (2H, s), 9.78 (1H, br s).
(64b) (5S) -2- (5- {3-methoxy-5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrol-2-yl) -5-methyl-4,5-dihydro-1 , 3-Oxazole Using the compound synthesized in Example (64a) (1.20 g, 2.69 mmol), methanesulfonic anhydride (1.30 g, 7.46 mmol), triethylamine (2.00 mL, 14.35 mmol). The target compound (627 mg, yield 54%) was obtained as a yellow liquid in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.11 (18H, d, J = 7.0 Hz), 1.22-1.31 (3H, m), 1.42 (3H, d, J = 6.3 Hz), 3.52 (1H, ddd , J = 14.1, 7.0, 3.1 Hz), 3.79 (3H, s), 4.01-4.10 (1H, m), 4.77-4.85 (1H, m), 6.36 (1H, d, J = 2.0 Hz), 6.47 ( 1H, d, J = 3.9 Hz), 6.67-6.72 (2H, m), 6.76 (1H, d, J = 3.5 Hz).
(64c) 2- (3-Methoxy-5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy ) -5- (Methylsulfonyl) pyrazine The compound (627 mg, 1.46 mmol) synthesized in Example (64b) was dissolved in tetrahydrofuran (2.0 mL), and tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution) was dissolved at 0 ° C. , 2.0 mL, 2.0 mmol) and stirred for 30 minutes under a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (30 mL) was added, and the mixture was extracted with methylene chloride (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a pale orange liquid compound. This was dissolved in acetonitrile (15 mL), the compound (310 mg, 1.61 mmol) synthesized in Example (43c) and cesium carbonate (820 mg, 2.52 mmol) were added, and the mixture was stirred at room temperature for 2.5 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 4%) to give the target compound (657 mg, yield) as a yellow solid. To 100%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.42 (3H, d, J = 5.9 Hz), 3.23 (3H, s), 3.52 (1H, dd, J = 14.1, 7.4 Hz), 3.85 (3H, s ), 4.06 (1H, dd, J = 14.1, 9.4 Hz), 4.78-4.87 (1H, m), 6.52 (1H, d, J = 3.5 Hz), 6.62 (1H, t, J = 2.2 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.94 (1H, t, J = 1.8 Hz), 7.03 (1H, t, J = 1.8 Hz), 8.49 (1H, d, J = 1.2 Hz), 8.80 (1H , d, J = 1.2 Hz).

(64d) 3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[5- ( Methylsulfonyl) pyrazin-2-yl] oxy} phenol Compound (657 mg, 1.53 mmol) synthesized in Example (64c), boron tribromide (1.0 mol / L methylene chloride solution, 3.50 mL, 3.50 mmol) ) Was used to obtain the target compound (486 mg, yield 77%) as a white solid in the same manner as in Example (40 g).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.50 (3H, d, J = 6.3 Hz), 3.23 (3H, s), 3.65 (1H, dd, J = 13.1, 7.6 Hz), 4.19 (1H, dd , J = 13.5, 9.2 Hz), 4.92-5.02 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.54 (1H, s), 6.80-6.84 (1H, m), 6.96 (1H, s), 7.44 (1H, s), 8.49 (1H, d, J = 1.2 Hz), 8.82 (1H, d, J = 1.2 Hz).
(64e) 3- (3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 5- (Methylsulfonyl) pyrazin-2-yl] oxy} phenoxy) dihydrofuran-2 (3H) -one Compound (100 mg, 0.24 mmol) synthesized in Example (64d), α-bromo-γ-butyrolactone ( 0.045 mL, 0.48 mmol) and potassium carbonate (100 mg, 0.72 mmol) were used to obtain the target compound (63 mg, 52% yield) as a white solid in the same manner as in Example (6b).
¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.42 (3H, d, J = 6.3 Hz), 2.47-2.56 (1H, m), 2.72-2.79 (1H, m), 3.24 (3H, s), 3.53 (1H, dd, J = 14.6, 7.3 Hz), 4.06 (1H, dd, J = 14.6, 8.8 Hz), 4.35-4.41 (1H, m), 4.55 (1H, td, J = 8.8, 3.9 Hz), 4.78-4.87 (1H, m), 4.99 (1H, t, J = 7.8 Hz), 6.53 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.80 (1H, t , J = 2.2 Hz), 7.02 (1H, t, J = 1.5 Hz), 7.17 (1H, t, J = 1.5 Hz), 8.50 (1H, d, J = 1.0 Hz), 8.79 (1H, d, J = 1.0 Hz).
MS (ESI) m / z: 499.12843 (M + H) ^<+> .

(Example 65)
1-methyl-3- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- { [6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) pyrrolidin-2-one

(65a) 3- (3-Bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) dihydrofuran-2 (3H) -one Compound (2) synthesized in Example (19b) 0.000 g, 5.81 mmol), α-bromo-γ-butyrolactone (1.07 mL, 11.6 mmol), potassium carbonate (2.41 g, 17.4 mmol) and white in the same manner as in Example (6b) The solid target compound (1.70 g, yield 68%) was obtained.
¹ H-NMR (CDCl ₃ , 500 MHz): δ 2.45-2.54 (1H, m), 2.70-2.78 (1H, m), 3.23 (3H, s), 4.35-4.41 (1H, m), 4.51-4.56 ( 1H, m), 4.94 (1H, t, J = 7.8 Hz), 6.75 (1H, t, J = 2.4 Hz), 6.92 (1H, t, J = 2.0 Hz), 7.11 (1H, t, J = 2.0 Hz), 7.47 (1H, dd, J = 8.8, 2.4 Hz), 8.08 (1H, d, J = 8.8 Hz), 8.47 (1H, d, J = 2.4 Hz).
(65b) Ethyl 2- (3-bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) -4-[(methylsulfonyl) oxy] butanoate Synthesized in Example (65a) The compound (1.37 g, 3.19 mmol) was dissolved in ethanol (50 mL), potassium carbonate (0.22 g, 1.60 mmol) was added at 0 ° C., the temperature was naturally raised, and the mixture was stirred at room temperature for 30 minutes. After filtering the reaction solution, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in methylene chloride (50 mL). Triethylamine (0.90 mL, 6.46 mmol) and methanesulfonyl chloride (0.27 mL, 3.49 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with methylene chloride (100 mL), 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 (elution solvent: ethyl acetate / hexane = 50% -80%) to give the desired product (673 mg, 38%) as a white solid. )
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.28 (3H, t, J = 7.0 Hz), 2.31-2.48 (2H, m), 3.01 (3H, s), 3.23 (3H, s), 4.26 (2H , q, J = 7.2 Hz), 4.38-4.48 (2H, m), 4.77 (1H, dd, J = 8.2, 4.3 Hz), 6.58 (1H, t, J = 2.2 Hz), 6.88 (1H, t, J = 1.6 Hz), 6.93 (1H, t, J = 1.6 Hz), 7.46 (1H, dd, J = 8.6, 2.7 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(65c) 3- (3-Bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) -1-methylpyrrolidin-2-one Compound (617 mg) synthesized in Example (65b) , 1.12 mmol) was dissolved in acetonitrile (2 mL), sodium iodide (308 mg, 2.01 mmol) and methylamine (2 mol / L tetrahydrofuran solution, 2.0 mL, 4.0 mmol) were added, and the mixture was stirred at 100 ° C. . On the way, methylamine (2 mol / L tetrahydrofuran solution, 1.0 mL, 2.0 mmol) was added three times every 30 minutes, and the mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature, saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then 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: ethyl acetate / hexane = 60% -100%) to give the target compound (355 mg, yield) as a white solid. 72%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.13-2.22 (1H, m), 2.51-2.60 (1H, m), 2.93 (3H, s), 3.23 (3H, s), 3.35-3.43 (1H, m), 3.47-3.54 (1H, m), 4.84 (1H, dd, J = 7.8, 6.3 Hz), 6.78 (1H, t, J = 2.3 Hz), 6.87 (1H, t, J = 2.0 Hz), 7.13 (1H, t, J = 2.0 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).

(65d) Benzyl 5- (3-[(1-methyl-2-oxopyrrolidin-3-yl) oxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H- Pyrrol-2-carboxylate Compound (355 mg, 0.80 mmol) synthesized in Example (65c), Compound (395 mg, 1.21 mmol) synthesized in Example (19e), [1,1′-bis (diphenylphosphine) [Fino) ferrocene] palladium (II) dichloride Dichloromethane complex (39 mg, 0.05 mmol) and potassium carbonate (556 mg, 4.02 mmol) were used in the same manner as in Example (16e) to give the target compound (217 mg, Yield 48%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.15-2.25 (1H, m), 2.51-2.61 (1H, m), 2.93 (3H, s), 3.22 (3H, s), 3.36-3.43 (1H, m), 3.49-3.55 (1H, m), 4.90 (1H, t, J = 7.2 Hz), 5.33 (2H, s), 6.52 (1H, t, J = 3.1 Hz), 6.75 (1H, t, J = 2.0 Hz), 6.89 (1H, t, J = 1.6 Hz), 6.98 (1H, dd, J = 3.9, 2.3 Hz), 7.15 (1H, t, J = 1.6 Hz), 7.33-7.46 (6H, m ), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.28 (1H, s).
(65e) N-[(2R) -2-hydroxypropyl] -5- (3-[(1-methyl-2-oxopyrrolidin-3-yl) oxy] -5-{[6- (methylsulfonyl) pyridine -3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide The compound (217 mg, 0.39 mmol) synthesized in Example (65d) was dissolved in a mixed solvent of ethanol (10 mL) and ethyl acetate (5 mL). 10% palladium on carbon catalyst (70 mg) was added, and the mixture was stirred for 1 hour under a hydrogen atmosphere. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure. The obtained white solid, (R)-(−)-1-amino-2-propanol (51 mg, 0.68 mmol), HOBT · H ₂ O (50 mg, 0.37 mmol), N-methylmorpholine (75 μL, 0 .68 mmol) was dissolved in N, N-dimethylformamide (5 mL), WSCI.HCl (78 mg, 0.41 mmol) was added at room temperature, and the mixture was stirred under a nitrogen atmosphere for 15 hours. To the reaction solution was added saturated brine (30 mL), and the mixture was extracted with ethyl acetate (100 mL). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 8%) to give a white solid. The target compound (148 mg, 83%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.20 (3H, d, J = 6.3 Hz), 2.09-2.21 (1H, m), 2.50-2.61 (1H, m), 2.93 (3H, s), 3.20 -3.27 (1H, m), 3.22 (3H, s), 3.36-3.43 (1H, m), 3.47-3.60 (2H, m), 3.92-4.01 (1H, m), 4.92 (1H, t, J = 7.4 Hz), 6.43-6.46 (1H, m), 6.63-6.65 (2H, m), 6.67-6.72 (1H, br m), 6.90 (1H, t, J = 1.6 Hz), 7.10 (1H, dd, J = 1.6, 0.8 Hz), 7.41 (1H, dd, J = 8.6, 2.7 Hz), 8.01 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz).
(65f) 1-methyl-3- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl}- 5-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) pyrrolidin-2-one Compound (148 mg, 0.28 mmol) synthesized in Example (65e), methanesulfonic anhydride (100 mg, 0.56 mmol) and triethylamine (0.156 mL, 1.12 mmol) were used to obtain the desired product (109 mg, yield 76%) as a white solid in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.42 (3H, d, J = 6.3 Hz), 2.14-2.23 (1H, m), 2.51-2.61 (1H, m), 2.93 (3H, s), 3.23 (3H, s), 3.35-3.43 (1H, m), 3.47-3.55 (2H, m), 4.05 (1H, dd, J = 13.7, 9.4 Hz), 4.77-4.87 (1H, m), 4.89 (1H , t, J = 7.0 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.71 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.89 (1H, t , J = 1.6 Hz), 7.15 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d , J = 2.7 Hz).
MS (ESI) m / z: 511.16648 (M + H) ^<+> .

Example 66
1-ethyl-3- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- { [6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) pyrrolidin-2-one

(66a) 3- (3-Bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) -1-ethylpyrrolidin-2-one Compound (1) synthesized in Example (65b) 0.01 g, 1.83 mmol) was dissolved in acetonitrile (10 mL), sodium iodide (0.41 g, 2.74 mmol) and ethylamine (2 mol / L tetrahydrofuran solution, 2.74 mL, 5.48 mmol) were added, and the mixture was added at 100 ° C. For 2 hours. The reaction mixture was cooled to room temperature, saturated brine (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 50% to 100%) to give the target compound (707 mg, yield) as a white solid. 85%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.17 (3H, t, J = 7.3 Hz), 2.12-2.21 (1H, m), 2.50-2.60 (1H, m), 3.23 (3H, s), 3.35 -3.44 (3H, m), 3.50 (1H, td, J = 9.4, 3.9 Hz), 4.84 (1H, dd, J = 7.8, 6.3 Hz), 6.79 (1H, t, J = 2.0 Hz), 6.87 ( 1H, t, J = 2.0 Hz), 7.13 (1H, t, J = 2.0 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.46 ( (1H, d, J = 2.7 Hz).
(66b) Benzyl 5- (3-[(1-ethyl-2-oxopyrrolidin-3-yl) oxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H- Pyrrole-2-carboxylate Compound synthesized in Example (66a) (990 mg, 2.17 mmol), Compound synthesized in Example (19e) (1.10 g, 3.26 mmol), [1,1′-bis ( Diphenylphosphino) ferrocene] palladium (II) dichloride Dichlorophosphine complex (105 mg, 0.13 mmol), potassium carbonate (1.50 g, 10.87 mmol) and the same target compound as a white solid in the same manner as in Example (16e) (890 mg, 71% yield) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.17 (3H, t, J = 7.2 Hz), 2.13-2.23 (1H, m), 2.51-2.61 (1H, m), 3.22 (3H, s), 3.35 -3.44 (3H, m), 3.51 (1H, td, J = 9.3, 3.6 Hz), 4.91 (1H, dd, J = 8.0, 6.5 Hz), 5.32 (2H, s), 6.51 (1H, dd, J = 3.9, 2.7 Hz), 6.74 (1H, t, J = 2.0 Hz), 6.90 (1H, t, J = 2.0 Hz), 6.97 (1H, dd, J = 3.9, 2.3 Hz), 7.15 (1H, t , J = 2.0 Hz), 7.32-7.45 (6H, m), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.3 Hz), 9.38 (1H, br s).

(66c) 5- (3-[(1-Ethyl-2-oxopyrrolidin-3-yl) oxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -N- [ (2R) -2-Hydroxypropyl] -1H-pyrrole-2-carboxamide Compound synthesized in Example (66b) (890 mg, 1.55 mmol), 10% palladium carbon catalyst (300 mg), (R)-(−) -1-amino-2-propanol (223 mg, 2.97 mmol), HOBT · H ₂ O (220 mg, 1.63 mmol), N-methylmorpholine (0.326 mL, 2.97 mmol), WSCI · HCl (341 mg, 1 .78 mmol) was used to obtain the target compound (588 mg, 73%) as a white solid in the same manner as in Example (65e).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.18 (3H, t, J = 7.0 Hz), 1.20 (3H, d, J = 6.3 Hz), 2.09-2.19 (1H, m), 2.49-2.61 (1H , m), 3.22-3.28 (1H, m), 3.22 (3H, s), 3.36-3.45 (3H, m), 3.46-3.60 (2H, m), 3.92-4.01 (1H, m), 4.92 (1H , t, J = 7.2 Hz), 6.43-6.46 (1H, m), 6.62-6.66 (2H, m), 6.68-6.73 (1H, br m), 6.90 (1H, t, J = 1.8 Hz), 7.10 (1H, s), 7.41 (1H, dd, J = 8.6, 2.7 Hz), 8.02 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz), 10.35 (0.5H, br s), 10.43 (0.5H, br s).
(66d) 1-ethyl-3- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl}- 5-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) pyrrolidin-2-one The compound synthesized in Example (66c) (588 mg, 1.08 mmol), methanesulfonic anhydride (389 mg, 2.16 mmol) and triethylamine (0.603 mL, 4.33 mmol) were used to obtain the desired product (472 mg, 83% yield) as a white solid in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.18 (3H, t, J = 7.4 Hz), 1.42 (3H, d, J = 6.3 Hz), 2.13-2.23 (1H, m), 2.51-2.60 (1H , m), 3.23 (3H, s), 3.35-3.44 (3H, m), 3.47-3.55 (2H, m), 4.05 (1H, dd, J = 14.1, 9.4 Hz), 4.77-4.86 (1H, m ), 4.89 (1H, t, J = 7.2 Hz), 6.51 (1H, d, J = 3.5 Hz), 6.72 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.5 Hz), 6.88 (1H, s), 7.14 (1H, s), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz) ).
MS (ESI) m / z: 525.18048 (M + H) ^<+> .

(Example 67)
1-cyclopropyl-3- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 {[6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) pyrrolidin-2-one

(67a) 3- (3-Bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) -1-cyclopropylpyrrolidin-2-one Compound synthesized in Example (65b) ( 530 mg, 0.96 mmol) was dissolved in acetonitrile (4 mL), sodium iodide (216 mg, 1.44 mmol) and cyclopropylamine (0.200 mL, 2.88 mmol) were added, and the mixture was stirred at 100 ° C. for 2 hours. The reaction mixture was cooled to room temperature, saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 60% -80%) to give the target compound (253 mg, yield) as a white solid. 57%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 0.66-0.76 (1H, m), 0.76-0.89 (3H, m), 2.07-2.17 (1H, m), 2.46-2.55 (1H, m), 2.68- 2.74 (1H, m), 3.23 (3H, s), 3.27-3.35 (1H, m), 3.39-3.46 (1H, m), 4.82 (1H, t, J = 7.2 Hz), 6.78 (1H, t, J = 2.0 Hz), 6.86 (1H, t, J = 2.0 Hz), 7.12 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(67b) Benzyl 5- (3-[(1-cyclopropyl-2-oxopyrrolidin-3-yl) oxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrole-2-carboxylate Compound (253 mg, 0.54 mmol) synthesized in Example (67a), Compound (266 mg, 0.81 mmol) synthesized in Example (19e), [1,1'-bis (diphenyl) Phosphino) ferrocene] palladium (II) dichloride Dichloromethane complex (27 mg, 0.03 mmol) and potassium carbonate (374 mg, 2.71 mmol) were used in the same manner as in Example (16e) to give the target compound (238 mg, Yield 77%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 0.66-0.75 (1H, m), 0.75-0.88 (3H, m), 2.07-2.18 (1H, m), 2.46-2.55 (1H, m), 2.67- 2.75 (1H, m), 3.22 (3H, s), 3.27-3.34 (1H, m), 3.39-3.46 (1H, m), 4.89 (1H, t, J = 7.4 Hz), 5.32 (2H, s) , 6.50 (1H, dd, J = 3.9, 2.7 Hz), 6.71 (1H, t, J = 2.0 Hz), 6.90 (1H, t, J = 1.8 Hz), 6.97 (1H, dd, J = 4.3, 2.3 Hz), 7.13 (1H, t, J = 1.8 Hz), 7.31-7.43 (6H, m), 8.03 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz), 9.47 ( 1H, br s).

(67c) 5- (3-[(1-Cyclopropyl-2-oxopyrrolidin-3-yl) oxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -N— [(2R) -2-hydroxypropyl] -1H-pyrrole-2-carboxamide Compound synthesized in Example (67b) (238 mg, 0.41 mmol), 10% palladium carbon catalyst (200 mg), (R)-(- ) -1-amino-2-propanol (62 mg, 0.82 mmol), HOBT.H ₂ O (61 mg, 0.45 mmol), N-methylmorpholine (0.090 mL, 0.82 mmol), WSCI · HCl (94 mg, 0.49 mmol) was used in the same manner as in Example (65e) to obtain the target compound (67 mg, 30%) as an orange solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 0.68-0.77 (1H, m), 0.77-0.88 (3H, m), 1.21 (3H, dd, J = 6.3, 1.2 Hz), 2.07-2.15 (1H, m), 2.46-2.57 (1H, m), 2.70-2.76 (1H, m), 3.13 (1H, br s), 3.22 (3H, s), 3.24-3.35 (2H, m), 3.38-3.46 (1H , m), 3.57 (1H, ddd, J = 13.7, 6.6, 3.1 Hz), 3.92-4.01 (1H, br m), 4.90 (1H, t, J = 7.4 Hz), 6.44-6.46 (1H, m) , 6.62-6.66 (2H, m), 6.69 (1H, dd, J = 12.1, 5.5 Hz), 6.90 (1H, t, J = 1.6 Hz), 7.10 (1H, s), 7.41 (1H, dd, J = 8.6, 2.7 Hz), 8.01 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz).
(67d) 1-cyclopropyl-3- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) pyrrolidin-2-one Compound (67 mg, 0.12 mmol) synthesized in Example (67c), methanesulfonic anhydride (45 mg) , 0.24 mmol) and triethylamine (0.070 mL, 0.48 mmol) were used to obtain the desired product (30 mg, 46% yield) as a white solid in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 0.67-0.75 (1H, m), 0.75-0.88 (3H, m), 1.42 (3H, d, J = 5.9 Hz), 2.09-2.19 (1H, m) , 2.47-2.56 (1H, m), 2.69-2.75 (1H, m), 3.23 (3H, s), 3.28-3.35 (1H, m), 3.43 (1H, td, J = 9.0, 4.3 Hz), 3.53 (1H, dd, J = 13.7, 7.4 Hz), 4.06 (1H, dd, J = 14.5, 9.0 Hz), 4.77-4.85 (1H, m), 4.87 (1H, t, J = 7.4 Hz), 6.51 ( 1H, d, J = 3.9 Hz), 6.71 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.88 (1H, t, J = 1.6 Hz), 7.15 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 537.18059 (M + H) ^<+> .

Example 68
2- (3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[6- ( Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) cyclopentanone

(68a) 2- (3-Bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) cyclopentanone Compound (1.00 g, 2.91 mmol) synthesized in Example (19b) ) Was dissolved in N, N-dimethylformamide (5 mL), 2-chlorocyclopentanone (0.88 mL, 8.72 mmol) and potassium carbonate (0.80 g, 5.81 mmol) were added, and the mixture was added at 60 ° C. under a nitrogen atmosphere. For 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with 1N aqueous sodium hydroxide solution and saturated brine. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 20% -50%) to give the object compound (721 mg, yield 58%) as a pale yellow solid.
¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.87-2.06 (2H, m), 2.12-2.20 (1H, m), 2.28-2.53 (3H, m), 3.23 (3H, s), 4.58 (1H, t, J = 8.5 Hz), 6.65 (1H, t, J = 2.0 Hz), 6.86 (6H, t, J = 2.0 Hz), 7.02 (6H, t, J = 2.0 Hz), 7.45 (6H, dd, J = 8.8, 2.9 Hz), 8.07 (1H, d, J = 8.8 Hz), 8.46 (1H, d, J = 2.9 Hz).
(68b) Benzyl 5- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5-[(2-oxocyclopentyl) oxy] phenyl) -1H-pyrrole-2-carboxylate Compound (721 mg, 1.69 mmol) synthesized in (68a), Compound (830 mg, 2.54 mmol) synthesized in Example (19e), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) Using the dichloride dichloromethane complex (83 mg, 0.10 mmol) and potassium carbonate (1.17 g, 8.46 mmol), the target compound (211 mg, 23% yield) as a pale yellow solid was prepared in the same manner as in Example (16e). Obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.87-2.06 (2H, m), 2.11-2.23 (1H, m), 2.29-2.44 (2H, m), 2.43-2.54 (1H, m), 3.23 ( 3H, s), 4.64 (1H, t, J = 9.0 Hz), 5.33 (2H, s), 6.52 (1H, dd, J = 3.9, 2.7 Hz), 6.63 (1H, t, J = 2.3 Hz), 6.90 (1H, t, J = 2.0 Hz), 6.98 (1H, dd, J = 4.3, 2.3 Hz), 7.04 (1H, t, J = 2.0 Hz), 7.33-7.47 (6H, m), 8.05 (1H , d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.25 (1H, br s).

(68c) N-[(2R) -2-hydroxypropyl] -5- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5-[(2-oxocyclopentyl) oxy] phenyl ) -1H-pyrrole-2-carboxamide Compound (210 mg, 0.38 mmol) synthesized in Example (68b), 10% palladium carbon catalyst (80 mg), (R)-(−)-1-amino-2-propanol (44 mg, 0.58 mmol), HOBT · H ₂ O (43 mg, 0.32 mmol), N-methylmorpholine (0.064 mL, 0.58 mmol), WSCI · HCl (67 mg, 0.35 mmol) The target compound (67 mg, 45%) was obtained as a pale yellow solid in the same manner as in (65e).
¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.23 (3H, d, J = 6.3 Hz), 1.91-2.06 (2H, m), 2.13-2.20 (1H, m), 2.30-2.47 (2H, m) , 2.47-2.55 (1H, m), 3.23 (3H, s), 3.24-3.29 (1H, m), 3.59 (1H, dq, J = 14.0, 3.2 Hz), 3.96-4.03 (1H, m), 4.66 (1H, t, J = 8.8 Hz), 6.40 (1H, t, J = 5.9 Hz), 6.48 (1H, t, J = 3.4 Hz), 6.59-6.62 (2H, m), 6.90 (1H, t, J = 1.5 Hz), 7.04 (1H, t, J = 1.5 Hz), 7.43 (1H, dd, J = 8.8, 2.9 Hz), 8.03 (1H, d, J = 8.8 Hz), 8.47 (1H, d, J = 2.9 Hz), 9.80 (1H, br s).
(68d) 2- (3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) cyclopentanone Compound (67 mg, 0.13 mmol) synthesized in Example (68c), methanesulfonic anhydride (47 mg, 0.26 mmol), triethylamine (0.073 mL, 0.52 mmol) was used to obtain the target product (43 mg, 67% yield) as a white solid in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.41 (3H, d, J = 6.3 Hz), 1.88-2.07 (2H, m), 2.12-2.20 (1H, m), 2.29-2.45 (2H, m) , 2.46-2.53 (1H, m), 3.23 (3H, s), 3.50 (1H, ddd, J = 14.2, 7.3, 2.0 Hz), 4.04 (1H, dd, J = 14.2, 9.3 Hz), 4.63 (1H , t, J = 8.5 Hz), 4.77-4.85 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.60 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.88 (1H, t, J = 2.0 Hz), 7.03 (1H, t, J = 2.0 Hz), 7.44 (1H, dd, J = 8.8, 2.9 Hz), 8.04 (1H, d, J = 8.8 Hz), 8.47 (1H, d, J = 2.4 Hz).
MS (ESI) m / z: 496.15353 (M + H) ^<+> .

(Example 69)
3- (3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[6- ( Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) butan-2-one

(69a) 3- (3-Bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) butan-2-one Compound (1.00 g, 2) synthesized in Example (19b) .91 mmol) was dissolved in N, N-dimethylformamide (5 mL), 3-bromo-2-butanone (0.88 mL, 5.81 mmol) and potassium carbonate (1.20 g, 8.72 mmol) were added, and nitrogen atmosphere was added. The mixture was heated at 80 ° C. for 3 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 20% -50%) to give the target compound (752 mg, yield 63%) as a yellow oil.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.52 (3H, d, J = 6.6 Hz), 2.20 (3H, s), 3.22 (3H, s), 4.60 (1H, q, J = 7.0 Hz), 6.53 (1H, t, J = 2.3 Hz), 6.85 (1H, t, J = 2.0 Hz), 6.89 (1H, dd, J = 2.3, 1.6 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz) ), 8.08 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(69b) Benzyl 5- [3- (1-methyl-2-oxopropoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrole-2-carboxylate Compound (752 mg, 1.82 mmol) synthesized in Example (69a), compound (891 mg, 2.72 mmol) synthesized in Example (19e), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II ) Dichloride Dichloromethane complex (89 mg, 0.11 mmol) and potassium carbonate (1.25 g, 9.08 mmol) were used in the same manner as in Example (16e) to give the target compound as a pale yellow solid (361 mg, 37% yield) Got.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.54 (3H, d, J = 6.6 Hz), 2.21 (3H, s), 3.23 (3H, s), 4.66 (1H, q, J = 6.9 Hz), 5.33 (2H, s), 6.49 (1H, t, J = 2.0 Hz), 6.52 (1H, dd, J = 3.9, 2.3 Hz), 6.87 (1H, t, J = 2.0 Hz), 6.93 (1H, dd , J = 2.3, 1.6 Hz), 6.99 (1H, dd, J = 3.9, 2.3 Hz), 7.34-7.46 (6H, m), 8.07 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.23 (1H, br s).

(69c) N-[(2R) -2-hydroxypropyl] -5- [3- (1-methyl-2-oxopropoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} Phenyl] -1H-pyrrole-2-carboxamide Compound (361 mg, 0.68 mmol) synthesized in Example (69b), 10% palladium carbon catalyst (120 mg), (R)-(−)-1-amino-2- Using propanol (97 mg, 1.29 mmol), HOBT.H ₂ O (96 mg, 0.71 mmol), N-methylmorpholine (0.142 mL, 1.29 mmol), WSCI · HCl (149 mg, 0.77 mmol) The target compound (110 mg, 34%) was obtained as a pale yellow solid in the same manner as in Example (65e).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.27 (3H, d, J = 7.0 Hz), 1.53 (3H, d, J = 6.6 Hz), 2.21 (3H, s), 3.24 (3H, s), 3.25-3.31 (1H, m), 3.60 (1H, dq, J = 13.9, 3.2 Hz), 3.96-4.04 (1H, m), 4.67 (1H, q, J = 6.6 Hz), 6.35-6.41 (1H, m), 6.46-6.51 (2H, m), 6.62 (1H, dd, J = 3.9, 2.7 Hz), 6.88 (1H, s), 6.94 (1H, s), 7.43 (1H, dd, J = 8.6, 2.7 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz), 9.75 (1H, br s).
(69d) 3- (3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) butan-2-one Compound synthesized in Example (69c) (110 mg, 0.22 mmol), methanesulfonic anhydride (79 mg, 0.44 mmol) , Triethylamine (0.122 mL, 0.88 mmol) was used to obtain the desired product (81 mg, yield 76%) as a pale yellow solid in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.43 (3H, d, J = 6.6 Hz), 1.53 (3H, d, J = 7.0 Hz), 2.21 (3H, s), 3.24 (3H, s), 3.54 (1H, dd, J = 14.1, 7.4 Hz), 4.08 (1H, dd, J = 14.1, 9.4 Hz), 4.67 (1H, q, J = 6.9 Hz), 4.79-4.88 (1H, m), 6.47 (1H, t, J = 2.2 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.86 (1H, t, J = 1.6 Hz), 6.93 (1H , s), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 484.15307 (M + H) ^<+> .

(Example 70)
(1R) -1-{(4S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] Oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} ethanol

(70a) Benzyl 5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H-pyrrole-2 -Carboxylate Compound (986 mg, 2.59 mmol) synthesized in Example (34 g) and compound (523 mg, 2.71 mmol) synthesized in Example (43c) were dissolved in acetonitrile (25 mL), and cesium carbonate (1 .68 g, 5.17 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and then 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: ethyl acetate / hexane = 20% -50%) to give the target compound (1.38 g) as a pale yellow solid. Yield 100%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.38 (3H, dd, J = 6.6, 1.6 Hz), 3.23 (3H, s), 4.45-4.73 (3H, m), 5.33 (2H, s), 6.53 (1H, dd, J = 3.9, 2.7 Hz), 6.69 (1H, t, J = 2.2 Hz), 6.96 (1H, t, J = 1.8 Hz), 6.99 (1H, dd, J = 3.9, 2.3 Hz) , 7.05 (1H, t, J = 1.8 Hz), 7.32-7.46 (5H, m), 8.50 (1H, d, J = 1.2 Hz), 8.81 (1H, d, J = 1.2 Hz), 9.21 (1H, br s).
(70b) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H-pyrrole-2- Carboxylic acid The compound (1.34 g, 2.49 mmol) synthesized in Example (70a) was dissolved in a mixed solvent of ethyl acetate (5 mL) and ethanol (20 mL), 10% palladium carbon catalyst (250 mg) was added, and hydrogen was added. Stir for 2 hours under atmosphere. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (719 mg, yield 65%) as a white solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.37 (3H, d, J = 6.3 Hz), 3.23 (3H, s), 4.44-4.74 (3H, m), 6.53 (1H, s), 6.70 (1H , s), 6.96-7.05 (2H, m), 7.08 (1H, s), 8.49 (1H, s), 8.80 (1H, s), 9.47 (1H, br s).

(70c) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -N-[(1S, 2R) -2-Hydroxy-1- (hydroxymethyl) propyl] -1H-pyrrole-2-carboxamide Compound (300 mg, 0.69 mmol) synthesized in Example (70b), D-allo-threoninol (109 mg, 1. 03 mmol), HOBT.H ₂ O (102 mg, 0.76 mmol), N-methylmorpholine (0.152 mL, 1.38 mmol), WSCI · HCl (159 mg, 0.83 mmol) and the same as in Example (29a) The target compound (312 mg, 87%) as a white solid was obtained by the method described above.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.33 (3H, d, J = 6.3 Hz), 1.37 (3H, dd, J = 6.3, 1.6 Hz), 2.75-2.80 (2H, m), 3.24 (3H , s), 3.79-3.86 (1H, m), 3.91-3.97 (1H, m), 4.06-4.13 (2H, m), 4.45-4.72 (3H, m), 6.50 (1H, dd, J = 3.9, 2.7 Hz), 6.65-6.68 (2H, m), 6.78 (1H, d, J = 7.8 Hz), 6.97 (1H, t, J = 1.6 Hz), 7.06 (1H, t, J = 1.6 Hz), 8.49 (1H, d, J = 1.2 Hz), 8.79 (1H, d, J = 1.2 Hz), 9.76 (1H, br s).
(70d) (1R) -1-{(4S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazine-2 -Il] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} ethanol Compound synthesized in Example (70c) (312 mg, 0.60 mmol) , Methanesulfonic anhydride (160 mg, 0.90 mmol) and triethylamine (0.250 mL, 1.79 mmol) were used in the same manner as in Example (16j) to give the target compound as a white solid (121 mg, yield 40%) Got.
¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.15 (3H, d, J = 6.8 Hz), 1.39 (3H, dd, J = 6.6, 1.7 Hz), 3.24 (3H, s), 4.19-4.31 (4H , m), 4.46-4.72 (3H, m), 6.36 (1H, d, J = 3.9 Hz), 6.41 (1H, d, J = 3.9 Hz), 6.66 (1H, t, J = 2.2 Hz), 6.99 (1H, t, J = 1.5 Hz), 7.11 (1H, t, J = 1.5 Hz), 8.50 (1H, d, J = 1.5 Hz), 8.81 (1H, d, J = 1.5 Hz), 10.14 (1H , br s).
MS (ESI) m / z: 505.15571 (M + H) ^<+> .

(Example 71)
1- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (Methylsulfonyl) pyridin-3-yl] oxy} phenyl) -2-methylpropan-1-one

(71a) 1- (3-Hydroxy-5-methoxyphenyl) -2-methylpropan-1-one The compound synthesized in Example (59b) (6.40 g, 30.73 mmol), sodium thiomethoxide (2. The target compound (6.00 g, yield 100%) as a yellow oil was obtained in the same manner as in Example (1a) using 66 g, 36.88 mmol).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.21 (6H, d, J = 6.6 Hz), 3.41-3.52 (1H, m), 3.83 (3H, s), 5.17 (1H, br s), 6.61 ( 1H, t, J = 2.3 Hz), 7.04 (1H, dd, J = 2.3, 1.2 Hz), 7.08 (1H, dd, J = 2.3, 1.2 Hz).
(71b) 1- (3-Methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -2-methylpropan-1-one Compound (980 mg) synthesized in Example (71a) , 5.05 mmol) and the compound synthesized in Example (16a) (1.45 g, 7.57 mmol) were dissolved in N, N-dimethylformamide (15 mL), and cesium carbonate (4.93 g, 15.14 mmol) was dissolved. In addition, the mixture was stirred at 100 ° C. for 1.5 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature, saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then 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: ethyl acetate / hexane = 20% -40%) to give the desired compound as a colorless oil (975 mg, yield). 55%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.21 (6H, d, J = 6.6 Hz), 3.23 (3H, s), 3.38-3.50 (1H, m), 3.87 (3H, s), 6.83 (1H , t, J = 2.3 Hz), 7.23 (1H, dd, J = 2.3, 1.2 Hz), 7.38 (1H, dd, J = 2.3, 1.2 Hz), 7.43 (1H, dd, J = 8.6, 2.7 Hz) , 8.06 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
(71c) 1- (3-hydroxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -2-methylpropan-1-one Compound (975 mg) synthesized in Example (71b) , 2.79 mmol), 1.0 mol / L boron tribromide dichloromethane solution (11.2 mL, 11.2 mmol) and the same method as in Example (40 g), and the target compound (643 mg, 69%) as a white solid was obtained. Got.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.21 (6H, d, J = 7.0 Hz), 3.24 (3H, s), 3.37-3.48 (1H, m), 6.14 (1H, br s), 6.80 ( 1H, t, J = 2.2 Hz), 7.21 (1H, dd, J = 2.3, 1.2 Hz), 7.35 (1H, dd, J = 2.3, 1.2 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz ), 8.06 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).

(71d) 3-Isobutyryl-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl trifluoromethanesulfonate Compound (643 mg, 1.92 mmol) synthesized in Example (71c) was dissolved in methylene chloride (10 mL). In a nitrogen atmosphere, pyridine (0.46 mL, 5.75 mmol) and trifluoromethanesulfonic anhydride (0.48 mL, 2.88 mmol) were added and stirred for 1 hour. Saturated aqueous ammonium chloride solution (10 mL) was added, and the mixture was extracted with methylene chloride (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 40%) to give the target compound (735 mg, 82%) as a white solid. )
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.24 (6H, d, J = 6.6 Hz), 3.26 (3H, s), 3.37-3.48 (1H, m), 7.24 (1H, t, J = 2.0 Hz ), 7.51 (1H, dd, J = 8.6, 2.7 Hz), 7.67 (2H, dd, J = 2.3, 1.6 Hz), 7.70 (1H, t, J = 2.0 Hz), 8.14 (1H, d, J = 8.6 Hz), 8.51 (1H, d, J = 2.7 Hz).
(71e) Methyl 5- (3-isobutyryl-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxylate Compound synthesized in Example (71d) ( 626 mg, 1.34 mmol), known (Adv. Synth. Cat., 345, 2003, 1103) methyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate (504 mg, 2.01 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (66 mg, 0.08 mmol), potassium carbonate (925 mg , 6.70 mmol) using a method similar to Example (16e) to obtain a light yellow oil. The compound (521 mg, yield 88%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.25 (6H, d, J = 6.6 Hz), 3.25 (3H, s), 3.47-3.56 (1H, m), 3.90 (3H, s), 6.62 (1H , dd, J = 3.9, 2.7 Hz), 6.97 (1H, dd, J = 3.9, 2.3 Hz), 7.44-7.48 (2H, m), 7.54 (1H, dd, J = 2.3, 1.6 Hz), 7.99 ( 1H, t, J = 1.6 Hz), 8.09 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz), 9.42 (1H, br s).
(71f) 5- (3-Isobutyryl-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxylic acid Compound (521 mg) synthesized in Example (71e) , 1.18 mmol) is dissolved in a mixed solvent of methanol (12 mL), tetrahydrofuran (4 mL) and water (4 mL), lithium hydroxide monohydrate (250 mg, 5.89 mmol) is added, and the mixture is heated at 50 ° C. for 2 hours. did. 1N Hydrochloric acid (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product (510 mg, yield 88%) as a pale yellow solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.27 (6H, d, J = 6.6 Hz), 3.25 (3H, s), 3.49-3.58 (1H, m), 6.64 (1H, dd, J = 4.3, 2.7 Hz), 7.09 (1H, dd, J = 3.9, 2.3 Hz), 7.47 (1H, dd, J = 8.6, 2.7 Hz), 7.54 (1H, t, J = 1.6 Hz), 7.62 (1H, t, J = 1.6 Hz), 8.10 (1H, d, J = 8.6 Hz), 8.53 (1H, d, J = 2.7 Hz), 8.96 (1H, s), 11.57 (1H, br s).

(71 g) N-[(2S) -2,3-dihydroxypropyl] -5- (3-isobutyryl-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole- 2-carboxamide Compound (261 mg, 0.61 mmol) synthesized in Example (71f), (S)-(−)-3-amino-1,2-propanediol (85 mg, 0.91 mmol), HOBT · H ₂ Using O (91 mg, 0.67 mmol), N-methylmorpholine (0.135 mL, 1.22 mmol) and WSCI.HCl (140 mg, 0.73 mmol) in the same manner as in Example (29a), The compound (174 mg, 55%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.24 (6H, d, J = 6.6 Hz), 3.24 (3H, s), 3.47-3.64 (5H, m), 3.81-3.88 (1H, m), 6.48 (1H, t, J = 6.5 Hz), 6.60 (1H, dd, J = 3.9, 2.7 Hz), 6.67 (1H, dd, J = 3.9, 2.3 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 7.47 (1H, t, J = 1.6 Hz), 7.52 (1H, dd, J = 2.3, 1.6 Hz), 8.01 (1H, t, J = 1.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 10.04 (1H, br s).
(71h) N-{(2S) -2-hydroxy-3-[(triisopropylsilyl) oxy] propyl} -5- (3-isobutyryl-5-{[6- (methylsulfonyl) pyridin-3-yl] Oxy} phenyl) -1H-pyrrole-2-carboxamide The compound (174 mg, 0.34 mmol) synthesized in Example (71 g) was dissolved in methylene chloride (5 mL), and triisopropylsilyl chloride (0.108 mL, 0.50 mmol) was dissolved. ), Triethylamine (0.234 mL, 1.68 mmol) and 4-dimethylaminopyridine (62 mg, 0.50 mmol) were added, and the mixture was stirred at room temperature for 8 hours under a nitrogen atmosphere. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and 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: ethyl acetate / hexane = 20% -50%) to give the desired product (110 mg, yield) as a white solid. 49%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.04-1.16 (21H, m), 1.24 (6H, d, J = 6.6 Hz), 3.09 (1H, d, J = 4.7 Hz), 3.24 (3H, s ), 3.35-3.43 (1H, m), 3.47-3.56 (1H, m), 3.67 (1H, dd, J = 10.0, 6.1 Hz), 3.70-3.80 (2H, m), 3.84-3.91 (1H, m ), 6.41 (1H, t, J = 5.7 Hz), 6.60 (1H, dd, J = 4.3, 2.7 Hz), 6.64 (1H, dd, J = 3.9, 2.7 Hz), 7.43-7.47 (2H, m) , 7.52 (1H, t, J = 1.8 Hz), 7.99 (1H, t, J = 1.6 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz), 9.81 (1H, br s).

(71i) 2-Methyl-1- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] Methyl} -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenyl) propan-1-one Compound (110 mg, 0.16 mmol) synthesized in Example (71h) ), Methanesulfonic anhydride (59 mg, 0.33 mmol), triethylamine (0.091 mL, 0.65 mmol), and a yellow solid target product (100 mg, 93% yield) in the same manner as in Example (16j). )
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.01-1.12 (21H, m), 1.24 (6H, d, J = 6.6 Hz), 3.24 (3H, s), 3.47-3.55 (1H, m), 3.83 -3.93 (3H, m), 4.01 (1H, dd, J = 14.3, 9.6 Hz), 4.73-4.81 (1H, m), 6.60 (1H, d, J = 3.9 Hz), 6.76 (1H, d, J = 3.9 Hz), 7.42-7.47 (2H, m), 7.50 (1H, s), 7.97 (1H, s), 8.08 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz ).
(71j) 1- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -{[6- (Methylsulfonyl) pyridin-3-yl] oxy} phenyl) -2-methylpropan-1-one Compound (100 mg, 0.15 mmol) synthesized in Example (71i), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 0.183 mL, 0.18 mmol) was used to give the target compound (57 mg, yield 75%) as a white solid in the same manner as in Example (16k).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.24 (6H, d, J = 6.6 Hz), 3.24 (3H, s), 3.47-3.57 (1H, m), 3.69-3.80 (2H, m), 3.86 (1H, dd, J = 12.5, 3.1 Hz), 4.04 (1H, dd, J = 14.3, 10.0 Hz), 4.76-4.83 (1H, m), 6.48 (1H, d, J = 3.9 Hz), 6.61 ( 1H, d, J = 3.9 Hz), 7.42 (1H, t, J = 2.0 Hz), 7.46 (1H, dd, J = 8.6, 2.7 Hz), 7.50 (1H, t, J = 2.0 Hz), 7.98 ( 1H, t, J = 1.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 484.15384 (M + H) ^<+> .

(Example 72)
N, N-dimethyl-3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4 -(Methylsulfonyl) phenoxy] benzamide

(72a) Methyl 3- (5-{[(1R) -2-hydroxy-1-methylethyl] carbamoyl} -1H-pyrrol-2-yl) -5- [4- (methylsulfonyl) phenoxy] benzoate Examples Compound (600 mg, 1.44 mmol) synthesized in (48d), D-alaninol (0.168 mL, 2.17 mmol), HOBT.H ₂ O (215 mg, 1.59 mmol), N-methylmorpholine (0.318 mL, 2.89 mmol) and WSCI.HCl (332 mg, 1.73 mmol) were used to obtain the target compound (617 mg, 90%) as a white solid in the same manner as in Example (29a).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.27 (3H, d, J = 6.6 Hz), 3.08 (3H, s), 3.62 (1H, dd, J = 11.1, 6.1 Hz), 3.77 (1H, dd , J = 10.9, 3.5 Hz), 3.94 (3H, s), 4.21-4.31 (1H, m), 6.14 (1H, d, J = 7.8 Hz), 6.58 (1H, dd, J = 3.9, 2.7 Hz) , 6.64 (1H, dd, J = 3.9, 2.7 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.46 (1H, t, J = 2.0 Hz), 7.58 (1H, dd, J = 2.3, 1.2 Hz), 7.92 (2H, d, J = 9.0 Hz), 8.09 (1H, t, J = 1.6 Hz), 9.96 (1H, br s).
(72b) Methyl 3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4- ( Methylsulfonyl) phenoxy] benzoate Using the compound synthesized in Example (72a) (617 mg, 1.31 mmol), methanesulfonic anhydride (470 mg, 2.61 mmol), triethylamine (0.910 mL, 6.53 mmol) The target product (534 mg, yield 90%) as a white solid was obtained in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.34 (3H, d, J = 6.8 Hz), 3.08 (3H, s), 3.93-3.97 (1H, m), 3.95 (3H, s), 4.30-4.39 (1H, m), 4.52 (1H, t, J = 8.3 Hz), 6.61 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.13 (2H, d, J = 8.8 Hz), 7.46 (1H, s), 7.59 (1H, s), 7.93 (2H, d, J = 8.8 Hz), 8.08 (1H, s).

(72c) 3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4- (methyl [Sulfonyl) phenoxy] benzoic acid The compound (534 mg, 1.17 mmol) synthesized in Example (72b) was dissolved in a mixed solvent of tetrahydrofuran (9 mL) and water (3 mL), and lithium hydroxide monohydrate (148 mg, 3.52 mmol) was added and stirred at room temperature for 4 hours. 2N hydrochloric acid (2 mL) and methylene chloride (10 mL) were added, and the precipitate was collected by filtration. This was washed with water and dichloromethane and dried to give the desired product (557 mg, yield ˜100%) as a white solid.
¹ H-NMR (DMSO-D6, 400 MHz): δ 1.32 (3H, d, J = 6.6 Hz), 3.22 (3H, s), 3.73-3.85 (1H, m), 4.37-4.49 (1H, m), 4.64-4.80 (1H, m), 6.86-7.02 (2H, m), 7.27 (2H, d, J = 8.6 Hz), 7.47 (1H, s), 7.95 (2H, d, J = 8.6 Hz), 8.05 (1H, t, J = 2.0 Hz), 8.32 (1H, s).
(72d) N, N-dimethyl-3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -[4- (Methylsulfonyl) phenoxy] benzamide The compound (518 mg, 1.18 mmol) synthesized in Example (72c) was dissolved in N, N-dimethylformamide (15 mL) and dimethylamine hydrochloride (287 mg) was dissolved at room temperature. , 3.53 mmol), 4-dimethylaminopyridine (431 mg, 3.53 mmol), triethylamine (800 μL, 5.74 mmol) and WSCI · HCl (451 mg, 2.35 mmol) were added, and the mixture was stirred for 22 hours under a nitrogen atmosphere. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 5%) to give a white solid. The target compound (195 mg, 35%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.33 (3H, d, J = 6.6 Hz), 3.02 (3H, br s), 3.08 (3H, s), 3.12 (3H, br s), 3.94 (1H , t, J = 7.8 Hz), 4.28-4.39 (1H, m), 4.51 (1H, t, J = 8.6 Hz), 6.56 (1H, d, J = 3.9 Hz), 6.77 (1H, d, J = 3.9 Hz), 6.99 (1H, t, J = 1.6 Hz), 7.15 (2H, d, J = 8.6 Hz), 7.29 (1H, t, J = 1.6 Hz), 7.46 (1H, s), 7.92 (2H , d, J = 8.6 Hz).
MS (ESI) m / z: 468.16002 (M + H) ^<+> .

(Example 73)
N, N-dimethyl-3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [3 -(Methylsulfonyl) phenoxy] benzamide

(73a) Benzyl 5- [3-hydroxy-5- (methoxycarbonyl) phenyl] -1H-pyrrole-2-carboxylate methyl 3-bromo-5-hydroxybenzoate (10.13 g, 43.8 mmol), Example ( 19e) (19.0 g, 58.1 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (1.56 g, 1.91 mmol), potassium carbonate ( 12.5 g, 90.4 mmol) was used, and the target compound (13.4 g, yield 87%) was obtained as a white solid in the same manner as in Example (16e).
¹ H-NMR (CD ₃ OD, 500 MHz): δ 3.90 (3H, s), 5.32 (2H, s), 6.55 (1H, d, J = 3.9 Hz), 6.95 (1H, d, J = 3.9 Hz) , 7.32-7.34 (3H, m), 7.35-7.38 (2H, m), 7.45 (2H, d, J = 6.8 Hz), 7.82-7.84 (1H, m).
(73b) Benzyl 5- {3- (methoxycarbonyl) -5- [3- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2-carboxylate Compound (2.00 g, synthesized in Example (73a)) 5.69 mmol) was dissolved in methylene chloride (60 mL), [3- (methylsulfonyl) phenyl] boric acid (3.05 g, 15.25 mmol), copper (II) acetate (1.80 g, 9.94 mmol), Triethylamine (4.60 mL, 33.0 mmol) and molecular sieves 4A (1.00 g) were added, and the mixture was stirred at room temperature for 4 days under a nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and the precipitate was filtered through celite. The filtrate was extracted with methylene chloride (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% -60%) to give the target compound (1.19 g, Yield 41%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.07 (3H, s), 3.94 (3H, s), 5.35 (2H, s), 6.59-6.61 (1H, m), 6.99-7.01 (1H, m) , 7.29 (1H, dd, J = 7.8, 2.4 Hz), 7.33-7.47 (6H, m), 7.55-7.58 (3H, m), 7.72 (1H, dd, J = 6.8, 1.0 Hz), 8.03 (1H , s), 9.34 (1H, br s).
(73c) Methyl 3- (5-{[(2R) -1-hydroxypropan-2-yl] carbamoyl} -1H-pyrrol-2-yl) -5- [3- (methylsulfonyl) phenoxy] benzoate Examples Compound (1.38 g, 2.73 mmol) synthesized in (73b) was dissolved in a mixed solvent of ethyl acetate (40 mL) and methanol (15 mL), palladium carbon (0.55 g) was added, and the mixture was added at room temperature under a hydrogen atmosphere at room temperature. Stir for half an hour. After filtration through celite, the solvent was distilled off under reduced pressure to obtain a white solid. The obtained compound was dissolved in a mixed solvent of methylene chloride (20 mL) and tetrahydrofuran (10 mL), and D-alaninol (0.30 mL, 3.83 mmol), WSCI · HCl (0.71 g, 3.70 mmol), HOBT · H ₂ O (0.62 g, 4.05 mmol) and N-methylmorpholine (0.70 mL, 6.37 mmol) were added at room temperature, and the mixture was stirred overnight under a nitrogen atmosphere. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 1% to 4%) to give the target compound (1.06 g, Yield 82%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.28 (3H, d, J = 7.0 Hz), 2.79 (1H, br s), 3.08 (3H, s), 3.59-3.66 (1H, m), 3.74- 3.80 (1H, m), 3.94 (3H, s), 4.23-4.30 (1H, m), 6.09 (1H, s), 6.56-6.58 (1H, m), 6.61-6.64 (1H, m), 7.29 ( 1H, dd, J = 8.2, 2.3 Hz), 7.41-7.43 (1H, m), 7.53-7.60 (3H, m), 7.71 (1H, d, J = 7.8 Hz), 8.03-8.05 (1H, m) , 9.80 (1H, s).

(73d) Methyl 3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [3- ( Methylsulfonyl) phenoxy] benzoate Using the compound (1.06 g, 2.24 mmol) synthesized in Example (73c), methanesulfonic anhydride (800 mg, 4.59 mmol), triethylamine (1.25 mL, 8.97 mmol). In the same manner as in Example (16j), the target compound (873 mg, yield 86%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H, d, J = 6.6 Hz), 3.08 (3H, s), 3.92-4.00 (1H, m), 3.94 (3H, s), 4.33-4.39 (1H, m), 4.51-4.57 (1H, m), 6.61 (1H, d, J = 3.9 Hz), 6.80 (1H, d, J = 3.5 Hz), 7.29 (1H, dd, J = 8.2, 1.2 Hz), 7.46 (1H, s), 7.55-7.57 (2H, m), 7.58-7.60 (1H, m), 7.70-7.73 (1H, m), 8.05-8.07 (1H, m).
(73e) N, N-dimethyl-3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -[3- (Methylsulfonyl) phenoxy] benzamide The compound (858 mg, 1.89 mmol) synthesized in Example (73d) was dissolved in a mixed solvent of tetrahydrofuran (12 mL) and water (5 mL), and lithium hydroxide monohydrate (250 mg, 5.96 mmol) was added at room temperature, and the mixture was stirred at 40 ° C. for 2 hours and a half under a nitrogen atmosphere. 2N hydrochloric acid was added to the reaction solution until the pH reached about 3, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a white solid. The obtained compound was dissolved in methylene chloride (20 mL), dimethylamine (2.0 mol / L tetrahydrofuran solution, 2.00 mL, 4.00 mmol), HATU (1.45 g, 3.81 mmol), N, N-diisopropyl. Ethylamine (1.00 mL, 5.74 mmol) was added, and the mixture was stirred at room temperature for 3 hours and a half under a nitrogen atmosphere. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% to 70%) to give the target compound (745 mg, yield) as a white solid. 84%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.35 (3H, d, J = 6.6 Hz), 3.00-3.13 (6H, br m), 3.08 (3H, s), 3.97 (1H, t, J = 8.0 Hz), 4.32-4.40 (1H, m), 4.53 (1H, t, J = 8.6 Hz), 6.56 (1H, d, J = 3.9 Hz), 6.79 (1H, d, J = 3.9 Hz), 6.94- 6.96 (1H, m), 7.28-7.33 (2H, m), 7.44 (1H, s), 7.56 (1H, dd, J = 8.2, 7.8 Hz), 7.62 (1H, dd, J = 2.3, 1.6 Hz) , 7.71 (1H, ddd, J = 7.8, 1.6, 0.8 Hz).
MS (ESI) m / z: 468.15880 (M + H) ^<+> .

(Example 74)
3- (3-methoxyphenoxy) -N, N-dimethyl-5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrole- 2-Il} benzamide

(74a) Benzyl 5- [3- (methoxycarbonyl) -5- (3-methoxyphenoxy) phenyl] -1H-pyrrole-2-carboxylate Compound (2.00 g, 5.69 mmol) synthesized in Example (73a) ) In methylene chloride (60 mL), (3-methoxyphenyl) boric acid (2.20 g, 14.48 mmol), copper (II) acetate (1.78 g, 9.83 mmol), triethylamine (4.60 mL, 33.0 mmol) and molecular sieves 4A (1.00 g) were added, and the mixture was stirred at room temperature for 5 days under a nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and the precipitate was filtered through celite. The filtrate was extracted with methylene chloride (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% to 40%) to give the target compound (1.43 g, Yield 55%).
¹ H-NMR (CDCl ₃ , 500 MHz): δ 3.79 (3H, s), 3.91 (3H, s), 5.33 (2H, s), 6.57-6.61 (3H, m), 6.71 (1H, d, J = 8.8 Hz), 6.98-7.01 (1H, m), 7.23-7.29 (1H, m), 7.30-7.45 (6H, m), 7.56 (1H, s), 7.96 (1H, s), 9.44 (1H, br s).
(74b) Methyl 3- (5-{[(2R) -1-hydroxypropan-2-yl] carbamoyl} -1H-pyrrol-2-yl) -5- (3-methoxyphenoxy) benzoate Example (74a) (1.43 g, 3.13 mmol), palladium carbon (0.60 g), D-alaninol (0.35 mL, 4.47 mmol), WSCI · HCl (0.85 g, 4.43 mmol), HOBT · Using H ₂ O (0.73 g, 4.77 mmol) and N-methylmorpholine (0.80 mL, 7.28 mmol), the target compound (1.05 g, yield) was obtained in the same manner as in Example (73c). 85%).
¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.28 (3H, d, J = 6.8 Hz), 2.74 (1H, br s), 3.61-3.66 (1H, m), 3.75-3.80 (1H, m), 3.80 (3H, s), 3.92 (3H, s), 4.21-4.31 (1H, m), 6.03 (1H, s), 6.54-6.56 (1H, m), 6.58-6.63 (3H, m), 6.71 ( 1H, dd, J = 8.3, 1.5 Hz), 7.24-7.28 (1H, m), 7.38 (1H, s), 7.54 (1H, d, J = 1.5 Hz), 7.94-7.97 (1H, m), 9.67 (1H, br s).

(74c) Methyl 3- (3-methoxyphenoxy) -5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrole-2- Il} benzoate Using the compound synthesized in Example (74b) (1.05 g, 2.47 mmol), methanesulfonic anhydride (880 mg, 5.05 mmol), triethylamine (1.50 mL, 10.76 mmol), Example The target compound (938 mg, yield 93%) was obtained as a pale yellow solid in the same manner as (16j).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.34 (3H, d, J = 6.6 Hz), 3.80 (3H, s), 3.91-3.98 (1H, m), 3.92 (3H, s), 4.29-4.39 (1H, m), 4.51 (1H, dd, J = 9.0, 8.2 Hz), 6.57 (1H, d, J = 3.5 Hz), 6.59-6.62 (2H, m), 6.71 (1H, ddd, J = 8.2 , 2.2, 1.0 Hz), 6.77 (1H, d, J = 3.9 Hz), 7.24-7.28 (1H, m), 7.39-7.41 (1H, m), 7.53-7.55 (1H, m), 7.96-7.97 ( 1H, m).
(74d) 3- (3-Methoxyphenoxy) -N, N-dimethyl-5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H -Pyrrole-2-yl} benzamide The compound synthesized in Example (74c) (938 mg, 2.31 mmol) was dissolved in a mixed solvent of tetrahydrofuran (15 mL) and water (5 mL), and lithium hydroxide monohydrate (375 mg). , 8.94 mmol) at room temperature and stirred at 40 ° C. for 5 hours under a nitrogen atmosphere. When 2N hydrochloric acid was added to the reaction solution until the pH reached about 3, a precipitate was obtained. This was collected by filtration to obtain a white solid. The obtained compound was dissolved in methylene chloride (15 mL), dimethylamine (2.0 mol / L tetrahydrofuran solution, 2.20 mL, 4.40 mmol), HATU (1.75 g, 4.60 mmol), N, N-diisopropyl. Ethylamine (1.25 mL, 7.18 mmol) was added, and the mixture was stirred at room temperature for 5 hours under a nitrogen atmosphere. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% to 100%) to give the target compound (900 mg, yield) as a white solid. 93%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.34 (3H, d, J = 6.3 Hz), 2.95-3.12 (6H, br m), 3.79 (3H, s), 3.90-3.96 (1H, m), 4.30-4.37 (1H, m), 4.46-4.54 (1H, m), 6.52 (1H, dd, J = 3.9, 1.2 Hz), 6.60-6.64 (2H, m), 6.71 (1H, dd, J = 8.6 , 2.0 Hz), 6.76 (1H, d, J = 3.1 Hz), 6.91 (1H, s), 7.22 (1H, s), 7.25-7.27 (1H, m), 7.33 (1H, s).
MS (ESI) m / z: 420.19167 (M + H) ^<+> .

(Example 75)
3- (4-Methoxyphenoxy) -N, N-dimethyl-5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrole- 2-Il} benzamide

(75a) Benzyl 5- [3- (methoxycarbonyl) -5- (4-methoxyphenoxy) phenyl] -1H-pyrrole-2-carboxylate Compound (2.00 g, 5.69 mmol) synthesized in Example (73a) ) In methylene chloride (60 mL), (4-methoxyphenyl) boric acid (2.20 g, 14.48 mmol), copper (II) acetate (1.75 g, 9.67 mmol), triethylamine (4.60 mL, 33.0 mmol) and molecular sieves 4A (1.00 g) were added, and the mixture was stirred at room temperature for 7 days under a nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and the precipitate was filtered through celite. The filtrate was extracted with methylene chloride (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% to 40%) to give the target compound (0.93 g, 0.93 g, Yield 36%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.83 (3H, s), 3.91 (3H, s), 5.34 (2H, s), 6.56 (1H, dd, J = 3.9, 2.7 Hz), 6.92 (2H , dt, J = 9.4, 2.9 Hz), 6.98-7.02 (3H, m), 7.30-7.32 (1H, m), 7.32-7.48 (6H, m), 7.88-7.89 (1H, m), 9.31 (1H , br s).
(75b) Methyl 3- (5-{[(2R) -1-hydroxypropan-2-yl] carbamoyl} -1H-pyrrol-2-yl) -5- (4-methoxyphenoxy) benzoate Example (75a) (930 mg, 2.03 mmol), palladium-carbon (400 mg), D-alaninol (0.25 mL, 3.20 mmol), WSCI · HCl (550 mg, 2.87 mmol), HOBT · H ₂ O (465 mg, 3.04 mmol) and N-methylmorpholine (0.60 mL, 5.46 mmol) were used to obtain the target compound (725 mg, 84% yield) as a white solid in the same manner as in Example (73c).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.25 (3H, d, J = 7.0 Hz), 3.60 (1H, dd, J = 10.9, 5.9 Hz), 3.74 (1H, dd, J = 10.9, 3.5 Hz) ), 3.80 (3H, s), 3.88 (3H, s), 4.19-4.26 (1H, m), 5.98 (1H, d, J = 7.0 Hz), 6.50 (1H, dd, J = 3.9, 2.7 Hz) , 6.57 (1H, dd, J = 3.9, 2.7 Hz), 6.88 (2H, dt, J = 6.3, 3.8 Hz), 6.97 (2H, dt, J = 6.4, 3.9 Hz), 7.26 (1H, dd, J = 2.0, 2.0 Hz), 7.42 (1H, dd, J = 2.3, 1.2 Hz), 7.86 (1H, dd, J = 1.6, 1.6 Hz), 9.55 (1H, br s).

(75c) Methyl 3- (4-methoxyphenoxy) -5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrole-2- Il} benzoate Using the compound synthesized in Example (75b) (725 mg, 1.71 mmol), methanesulfonic anhydride (620 mg, 3.56 mmol), triethylamine (1.00 mL, 7.17 mmol), Example (16j) ) To give the target compound (680 mg, yield 98%) as a pale yellow solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.39 (3H, d, J = 6.6 Hz), 3.83 (3H, s), 3.91 (3H, s), 4.01 (1H, br s), 4.38 (1H, br s), 4.57 (1H, br s), 6.58 (1H, d, J = 3.5 Hz), 6.80-6.85 (1H, m), 6.92 (2H, dt, J = 6.5, 3.8 Hz), 7.01 (2H , dt, J = 6.3, 3.8 Hz), 7.39 (1H, s), 7.45-7.47 (1H, m), 7.94 (1H, s).
(75d) 3- (4-Methoxyphenoxy) -N, N-dimethyl-5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H -Pyrrole-2-yl} benzamide Compound (680 mg, 1.67 mmol) synthesized in Example (75c), lithium hydroxide monohydrate (220 mg, 5.24 mmol), dimethylamine (2.0 mol / L tetrahydrofuran solution) , 1.30 mL, 2.60 mmol), HATU (1.05 g, 2.76 mmol), N, N-diisopropylethylamine (0.80 mL, 4.59 mmol) and white in the same manner as in Example (74d) The solid target compound (562 mg, yield 80%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.33 (3H, d, J = 6.6 Hz), 2.93-3.12 (6H, br m), 3.82 (3H, s), 3.93 (1H, t, J = 7.8 Hz), 4.28-4.38 (1H, m), 4.50 (1H, t, J = 8.4 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.82 ( 1H, dd, J = 2.0, 1.2 Hz), 6.90 (2H, dt, J = 6.5, 3.9 Hz), 7.01 (2H, dt, J = 6.4, 3.9 Hz), 7.15 (1H, dd, J = 2.2, 1.8 Hz), 7.25-7.27 (1H, m).
MS (ESI) m / z: 420.19272 (M + H) ^<+> .

(Example 76)
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-phenoxybenzamide

(76a) Benzyl 5- [3- (methoxycarbonyl) -5-phenoxyphenyl] -1H-pyrrole-2-carboxylate The compound synthesized in Example (73a) (2.00 g, 5.69 mmol) was converted to methylene chloride ( 20 mL), phenylboric acid (1.90 g, 15.58 mmol), copper (II) acetate (1.90 g, 10.49 mmol), triethylamine (4.70 mL, 33.7 mmol), molecular sieve 4A (1. 00 g) and stirred at room temperature for 7 days under a nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and the precipitate was filtered through celite. The filtrate was extracted with methylene chloride (60 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% to 40%) to give the target compound (1.75 g, Yield 72%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 3.91 (3H, s), 5.34 (2H, s), 6.57 (1H, dd, J = 3.9, 2.7 Hz), 6.99 (1H, dd, J = 3.9, 2.3 Hz), 7.02-7.04 (1H, m), 7.04-7.06 (1H, m), 7.14-7.19 (1H, m), 7.30-7.45 (8H, m), 7.55 (1H, dd, J = 2.3, 1.2 Hz), 7.95 (1H, dd, J = 1.6, 1.6 Hz), 9.43 (1H, br s).
(76b) Methyl 3- (5-{[(2R) -2-hydroxypropyl] carbamoyl} -1H-pyrrol-2-yl) -5-phenoxybenzoate Compound synthesized in Example (76a) (1.75 g, 4.09 mmol), palladium on carbon (0.55 g), (R)-(−)-1-amino-2-propanol (0.55 mL, 6.99 mmol), WSCI · HCl (1.10 g, 5.74 mmol) , HOBT.H ₂ O (1.05 g, 6.86 mmol) and N-methylmorpholine (1.30 mL, 11.82 mmol) were used in the same manner as in Example (73c) to obtain the target compound (1. 19 g, yield 74%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.25 (3H, d, J = 6.3 Hz), 2.51 (1H, d, J = 3.9 Hz), 3.30 (1H, ddd, J = 14.0, 7.7, 5.4 Hz) ), 3.62 (1H, ddd, J = 14.1, 6.6, 3.1 Hz), 3.92 (3H, s), 4.03 (1H, br s), 6.34 (1H, t, J = 5.9 Hz), 6.55 (1H, dd , J = 3.7, 2.9 Hz), 6.63 (1H, dd, J = 3.9, 2.3 Hz), 7.02-7.04 (1H, m), 7.05-7.06 (1H, m), 7.15-7.19 (1H, m), 7.35-7.41 (3H, m), 7.53 (1H, dd, J = 2.3, 1.6 Hz), 7.95 (1H, dd, J = 1.8, 1.4 Hz), 9.65 (1H, br s).

(76c) Methyl 3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-phenoxybenzoate Examples Using the compound synthesized in (76b) (1.19 g, 3.02 mmol), methanesulfonic anhydride (1.08 g, 6.20 mmol), triethylamine (1.70 mL, 12.20 mmol), Example (16j) In the same manner as above, the target compound (1.12 g, yield 99%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.44 (3H, d, J = 6.3 Hz), 3.56 (1H, dd, J = 13.7, 7.4 Hz), 3.92 (3H, s), 4.10 (1H, dd , J = 13.9, 9.2 Hz), 4.80-4.92 (1H, m), 6.57 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.04 (1H, s), 7.04 -7.07 (1H, m), 7.16 (1H, t, J = 7.4 Hz), 7.35-7.41 (3H, m), 7.52-7.53 (1H, m), 7.96 (1H, s).
(76d) N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -Phenoxybenzamide Compound (1.12 g, 2.98 mmol) synthesized in Example (76c), lithium hydroxide monohydrate (350 mg, 8.34 mmol), dimethylamine (2.0 mol / L tetrahydrofuran solution, 1. 80 mL, 3.60 mmol), HATU (1.40 g, 3.68 mmol) and N, N-diisopropylethylamine (0.85 mL, 4.88 mmol) were used to obtain a white solid in the same manner as in Example (74d). The compound (823 mg, yield 71%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.42 (3H, d, J = 6.3 Hz), 2.98-3.09 (6H, br m), 3.53 (1H, dd, J = 14.1, 7.4 Hz), 4.06 ( 1H, dd, J = 14.1, 9.4 Hz), 4.76-4.87 (1H, m), 6.51 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.89 (1H, dd , J = 2.2, 1.4 Hz), 7.04 (1H, s), 7.06 (1H, d, J = 1.2 Hz), 7.15 (1H, t, J = 7.4 Hz), 7.21 (1H, t, J = 2.0 Hz ), 7.31 (1H, t, J = 1.6 Hz), 7.33-7.39 (2H, m).
MS (ESI) m / z: 390.18166 (M + H) ^<+> .

(Example 77)
3- (4-Fluorophenoxy) -N, N-dimethyl-5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrole- 2-Il} benzamide

(77a) 3-Bromo-5-fluoro-N, N-dimethylbenzamide 3-Bromo-5-fluorobenzoic acid (10.1 g, 46.1 mmol) was dissolved in methylene chloride (150 mL) and dimethylamine (2. 0 mol / L tetrahydrofuran solution, 46.0 mL, 92.0 mmol), HATU (25.0 g, 65.7 mmol), N, N-diisopropylethylamine (16.0 mL, 91.9 mmol) were added, and 4 at room temperature under a nitrogen atmosphere. Stir for hours. Saturated aqueous sodium hydrogen carbonate solution (200 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (300 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% to 60%) to give the desired compound (11.3 g, Yield 100%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ2.98-3.10 (6H, br m), 7.08 (1H, ddd, J = 8.6, 2.3, 1.6 Hz), 7.30 (1H, ddd, J = 8.2, 2.3 , 1.6 Hz), 7.35 (1H, dd, J = 1.6, 1.2 Hz).
(77b) 3-Bromo-5- (4-fluorophenoxy) -N, N-dimethylbenzamide The compound synthesized in Example (77a) (2.02 g, 8.21 mmol) and 4-fluorophenol (1.63 g) , 14.5 mmol) was dissolved in N, N-dimethylformamide (20 mL), cesium carbonate (5.55 g, 17.0 mmol) was added, and the mixture was stirred at 80 ° C. for 3 days and at 130 ° C. for 1 day under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted 3 times with ethyl acetate (100 mL). The organic layer was washed twice with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% -60%) to give the target compound (2.49 g, 2.49 g, Yield 90%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.93-3.10 (6H, br m), 6.91 (1H, dd, J = 2.3, 1.2 Hz), 6.99-7.03 (2H, m), 7.05-7.10 (2H , m), 7.11 (1H, dd, J = 2.3, 1.6 Hz), 7.24 (1H, t, J = 1.6 Hz).
(77c) Methyl 5- [3- (dimethylcarbamoyl) -5- (4-fluorophenoxy) phenyl] -1H-pyrrole-2-carboxylate Compound synthesized in Example (77b) (2.49 g, 7.36 mmol) ), Methyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate (2.75 g, 11.0 mmol), [1 , 1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride Dichloromethane complex (380 mg, 0.47 mmol), potassium carbonate (4.05 g, 29.3 mmol) and the same method as in Example (16e) To obtain the target compound (2.64 g, yield 94%) as a yellow foam.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.96-3.13 (6H, br m), 3.88 (3H, s), 6.52 (1H, dd, J = 3.7, 2.9 Hz), 6.87 (1H, dd, J = 2.3, 1.6 Hz), 6.93 (1H, dd, J = 3.9, 2.3 Hz), 7.00-7.10 (4H, m), 7.17 (1H, t, J = 2.0 Hz), 7.31 (1H, t, J = 1.4 Hz), 9.33 (1H, br s).

(77d) 5- [3- (Dimethylcarbamoyl) -5- (4-fluorophenoxy) phenyl] -N-[(2R) -2-hydroxypropyl] -1H-pyrrole-2-carboxamide In Example (77c) The synthesized compound (2.64 g, 6.90 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5.0 mL), methanol (15.0 mL) and water (5.0 mL), and lithium hydroxide monohydrate (1. 10 g, 26.2 mmol) was added at room temperature, and the mixture was stirred at 50 ° C. for 3.5 hours under a nitrogen atmosphere. 2N hydrochloric acid was added to the reaction solution until the pH reached about 3, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a white solid. This solid was dissolved in methylene chloride (30 mL), and (R)-(−)-1-amino-2-propanol (0.90 mL, 11.4 mmol), WSCI • HCl (1.90 g, 9.91 mmol), HOBT.H ₂ O (1.72 g, 11.2 mmol) and N-methylmorpholine (2.20 mL, 20.0 mmol) were added at room temperature, and the mixture was stirred under a nitrogen atmosphere for 3 hours. Water (40 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (60 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 1% to 6%) to give the target compound (1.44 g, Yield 49%) was obtained.
¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.18-1.21 (3H, m), 2.91-3.12 (6H, br m), 3.18-3.24 (1H, m), 3.58 (1H, dd, J = 6.3, 2.9 Hz), 3.61 (1H, d, J = 13.7 Hz), 3.61 (1H, dd, J = 6.3, 2.9 Hz), 3.91-3.96 (1H, m), 6.46 (1H, dd, J = 6.1, 3.2 Hz), 6.55 (1H, br s), 6.64 (1H, dd, J = 3.9, 2.4 Hz), 6.81 (1H, s), 6.97-7.02 (2H, m), 7.02-7.08 (2H, m), 7.19 (1H, s), 7.23 (1H, s), 10.32 (1H, br s).
(77e) 3- (4-Fluorophenoxy) -N, N-dimethyl-5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H -Pyrrole-2-yl} benzamide Compound (1.44 g, 3.38 mmol) synthesized in Example (77d), methanesulfonic anhydride (865 mg, 4.97 mmol), triethylamine (1.50 mL, 10.8 mmol) Was used to give the target compound (788 mg, yield 57%) as a white solid in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.41 (3H, d, J = 6.3 Hz), 2.94-3.10 (6H, br m), 3.51 (1H, dd, J = 14.1, 7.4 Hz), 4.03 ( 1H, dd, J = 13.9, 9.2 Hz), 4.76-4.86 (1H, m), 6.51 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.5 Hz), 6.84 (1H, dd , J = 2.2, 1.4 Hz), 6.98-7.08 (4H, m), 7.19 (1H, t, J = 1.8 Hz), 7.30 (1H, t, J = 1.4 Hz).
MS (ESI) m / z: 408.17252 (M + H) ^<+> .

(Example 78)
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- (pyridine -3-yloxy) benzamide

(78a) 3-Bromo-5- (pyridin-3-yloxy) -N, N-dimethylbenzamide The compound synthesized in Example (77a) (2.01 g, 8.17 mmol) and pyridin-3-ol (1. 40 g, 14.7 mmol) was dissolved in N, N-dimethylformamide (20 mL), cesium carbonate (5.73 g, 17.6 mmol) was added, and the mixture was stirred at 130 ° C. for one day under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted 3 times with ethyl acetate (100 mL). The organic layer was washed twice with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% -60%) to give the target compound (2.28 g, Yield 87%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.96-3.09 (6H, m), 6.97 (1H, dd, J = 2.3, 1.6 Hz), 7.19 (1H, dd, J = 2.2, 1.8 Hz), 7.31 -7.32 (1H, m), 7.33-7.37 (2H, m), 8.43-8.47 (2H, m).
(78b) Methyl 5- [3- (dimethylcarbamoyl) -5- (pyridin-3-yloxy) phenyl] -1H-pyrrole-2-carboxylate The compound synthesized in Example (78a) (2.28 g, 7. 10 mmol), methyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate (2.71 g, 10.8 mmol), [ 1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride Dichloromethane complex (355 mg, 0.43 mmol), potassium carbonate (4.15 g, 30.0 mmol), and similar to Example (16e) The target compound (2.41 g, yield 93%) as a white foam was obtained by the method.
¹ H-NMR (CDCl ₃ , 500 MHz): δ 2.99-3.13 (6H, br m), 3.88 (3H, s), 6.54 (1H, dd, J = 3.9, 2.9 Hz), 6.93-6.95 (2H, m ), 7.24 (1H, t, J = 2.0 Hz), 7.33 (1H, dd, J = 8.5, 4.6 Hz), 7.36-7.37 (1H, m), 7.38 (1H, s), 8.44 (1H, dd, J = 4.4, 1.5 Hz), 8.46 (1H, d, J = 2.9 Hz), 9.41 (1H, br s).

(78c) 5- [3- (Dimethylcarbamoyl) -5- (pyridin-3-yloxy) phenyl] -N-[(2R) -2-hydroxypropyl] -1H-pyrrole-2-carboxamide Example (78b) The compound synthesized in (1) (2.41 g, 6.60 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5.0 mL), methanol (10.0 mL) and water (5.0 mL), and lithium hydroxide monohydrate (1 .05 g, 25.0 mmol) was added at room temperature, and the mixture was stirred at 50 ° C. for 3 hours and a half under a nitrogen atmosphere. 2N hydrochloric acid was added to the reaction solution until the pH reached about 2, and the resulting precipitate was filtered off. A saturated aqueous sodium bicarbonate solution was added to the filtrate until the pH reached about 5, and the mixture was extracted with methylene chloride (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a pink solid (1.14 g). This solid was dissolved in methylene chloride (25 mL), and (R)-(−)-1-amino-2-propanol (0.53 mL, 6.73 mmol), WSCI • HCl (1.07 g, 5.58 mmol), HOBT.H ₂ O (950 mg, 6.20 mmol) and N-methylmorpholine (1.20 mL, 10.9 mmol) were added at room temperature, and the mixture was stirred for 7 hours and a half under a nitrogen atmosphere. Water (40 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (60 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 1% to 8%) to give the target compound (1.02 g, Yield 37%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.22 (3H, d, J = 6.3 Hz), 2.87 (1H, br s), 2.94-3.12 (6H, br m), 3.19-3.28 (1H, m) , 3.62 (1H, ddd, J = 13.7, 6.5, 2.9 Hz), 3.96 (1H, br s), 6.45 (1H, br s), 6.50 (1H, dd, J = 3.7, 2.9 Hz), 6.63 (1H , dd, J = 3.7, 2.5 Hz), 6.89 (1H, dd, J = 2.2, 1.4 Hz), 7.23-7.25 (1H, m), 7.27-7.36 (3H, m), 8.42 (1H, dd, J = 4.7, 1.6 Hz), 8.44 (1H, dd, J = 2.7, 0.8 Hz), 10.08 (1H, br s).
(78d) N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -(Pyridin-3-yloxy) benzamide Compound (1.09 g, 2.67 mmol) synthesized in Example (78c), methanesulfonic anhydride (925 mg, 5.31 mmol), triethylamine (1.50 mL, 10.8 mmol) ) Was used to give the target compound (853 mg, yield 82%) as a white solid in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.41 (3H, d, J = 6.3 Hz), 2.88-3.14 (6H, m), 3.45-3.52 (1H, m), 3.96-4.03 (1H, m) , 4.76-4.85 (1H, m), 6.53 (1H, d, J = 3.5 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.89 (1H, t, J = 1.2 Hz), 7.24-7.36 ( 4H, m), 8.40 (1H, d, J = 4.7 Hz), 8.44 (1H, dd, J = 2.0, 0.8 Hz).
MS (ESI) m / z: 391.17744 (M + H) ⁺ .

(Example 79)
3-[(3-Bromopyridin-2-yl) oxy] -N, N-dimethyl-5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazole-2- Yl] -1H-pyrrol-2-yl} benzamide

(79a) 3-Bromo-5- (dimethylcarbamoyl) phenyl acetate 3-Bromo-5-hydroxybenzoic acid (10.0 g, 46.1 mmol) was dissolved in acetic anhydride (70 mL) and concentrated sulfuric acid (0.10 mL, 1.88 mmol) was added and stirred at room temperature for 30 minutes under a nitrogen atmosphere. 1N Hydrochloric acid (50 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (100 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Thionyl chloride (30 mL) was added to the obtained crude product, and the mixture was heated to reflux for 1 hour. Thionyl chloride was distilled off under reduced pressure. The obtained crude product was dissolved in methylene chloride (50 mL), dimethylamine (2M tetrafuran solution, 50.0 mL, 100 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 50% to 70%) to give the target compound (11.7 g) as a pale yellow solid. Yield 89%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.30 (3H, s), 3.00 (3H, s), 3.10 (3H, s), 7.12 (1H, m), 7.34 (1H, m), 7.44 (1H , m).
(79b) Methyl 5- [3- (dimethylcarbamoyl) -5-hydroxyphenyl] -1H-pyrrole-2-carboxylate Compound (11.7 g, 40.9 mmol) synthesized in Example (79a), methyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate (14.4 g, 57.3 mmol), [1,1′-bis (Diphenylphosphino) ferrocene] palladium (II) dichloride Dichloromethane complex (1.00 g, 1.22 mmol) and potassium carbonate (17.0 g, 123 mmol) were used to obtain a white solid in the same manner as in Example (16e). The compound (10.3 g, yield 87%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz): δ2.93 (3H, s), 2.98 (3H, s), 3.78 (3H, s), 6.62 (1H, dd, J = 3.9, 2.4Hz), 6.65 ( 1H, m), 6.85 (1H, dd, J = 3.9, 2.4Hz), 7.25 (1H, t, J = 1.6Hz), 7.35 (1H, t, J = 1.6z), 9.73 (1H, s).
(79c) Methyl 5- {3-[(3-bromopyridin-2-yl) oxy] -5- (dimethylcarbamoyl) phenyl} -1H-pyrrole-2-carboxylate Compound synthesized in Example (79b) ( (640 mg, 2.22 mmol) was dissolved in dimethylacetamide (30 mL). 3-Bromo-2-chloropyridine (860 mg, 4.47 mmol) and cesium carbonate (2.20 g, 6.75 mmol) were added, and the mixture was stirred at 100 ° C. for 22 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 1N hydrochloric acid (50 mL) was added, and the mixture was extracted twice with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 40% -70%) to give the target compound (488 mg, yield) as a white solid. 49%).
¹ H-NMR (CDCl ₃ , 400 MHz): δ3.06 (3H, brs), 3.12 (3H, brs), 3.87 (3H, s), 6.56 (1H, dd, J = 3.9, 2.7Hz), 6.93- 6.97 (2H, m), 7.13 (1H, t, J = 1.6Hz), 7.41 (1H, t, J = 1.9Hz), 7.49 (1H, t, J = 1.6Hz), 7.97 (1H, dd, J = 7.4, 2.0Hz), 8.07 (1H, dd, J = 4.7, 1.6Hz), 9.44 (1H, brs).

(79d) 5- {3-[(3-Bromopyridin-2-yl) oxy] -5- (dimethylcarbamoyl) phenyl} -N-[(2R) -2-hydroxypropyl] -1H-pyrrole-2- Carboxamide Compound (448 mg, 1.10 mmol) synthesized in Example (79c) was dissolved in methanol (20 mL), 5N aqueous sodium hydroxide solution (1.1 mL, 5.50 mmol) was added, and the mixture was stirred at 65 ° C. for 3 hours. did. 2N Hydrochloric acid (3.0 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
The obtained residue was dissolved in methanol (20 mL), and (R)-(−)-1-amino-2-propanol (0.220 mL, 2.79 mmol) and DMT-MM (920 mg, 3.32 mmol) were used. In the same manner as in Example (5d), the target compound (237 mg, yield 44%) was obtained as a pale yellow oil.
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.12 (3H, d, J = 6.3 Hz), 2.95 (3H, s), 3.07 (3H, s), 3.12 (1H, m), 3.52 (1H, m), 3.86 (1H, brs), 4.01 (1H, brs), 6.42 (1H, dd, J = 3.9, 2.4Hz), 6.67 (1H, dd, J = 3.9, 2.4Hz), 6.91 (1H, dd , J = 7.8, 4.7Hz), 7.02 (1H, m), 7.05 (1H, m), 7.38 (1H, brs), 7.41 (1H, m), 7.92 (1H, dd, J = 7.8, 1.6Hz) , 8.01 (1H, dd, J = 4.7, 1.6Hz), 10.92 (1H, brs).
(79e) 3-[(3-Bromopyridin-2-yl) oxy] -N, N-dimethyl-5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazole -2-yl] -1H-pyrrol-2-yl} benzamide Compound (237 mg, 0.486 mmol) synthesized in Example (79d), methanesulfonic anhydride (215 mg, 1.23 mmol), triethylamine (0.41 mL) , 2.94 mmol) and the white solid target compound (161 mg, 71% yield) was obtained in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 400MHz): δ 1.42 (3H, d, J = 6.3Hz), 3.03 (3H, brs), 3.10 (3H, brs), 3.51 (1H, dd, J = 14.1, 7.4Hz ), 4.04 (1H, dd, J = 14.1, 9.0Hz), 4.81 (1H, m), 6.54 (1H, d, J = 3.5Hz), 6.75 (1H, d, J = 3.9Hz), 6.92 (1H , dd, J = 7.8, 4.7Hz), 7.10 (1H, dd, J = 1.8, 1.6Hz), 7.39 (1H, t, J = 1.6Hz), 7.46 (1H, t, J = 1.6Hz), 7.95 (1H, dd, J = 7.8, 1.6Hz), 8.05 (1H, dd, J = 4.7, 1.8Hz).
MS (ESI) m / z: 469.08753 (M + H) ^<+> .

(Example 80)
3- (2,4-Difluorophenoxy) -N, N-dimethyl-5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H- Pyrrol-2-yl} benzamide

(80a) Methyl 5- [3- (2,4-difluorophenoxy) -5- (dimethylcarbamoyl) phenyl] -1H-pyrrole-2-carboxylate The compound (520 mg, 1.80 mmol) synthesized in Example 79b Dissolved in dimethylacetamide (30 mL). 1,2,4-trifluorobenzene (720 mg, 5.45 mmol, cesium carbonate (1.76 g, 5.40 mmol) was added and stirred for 24 hours under a nitrogen atmosphere at 100 ° C. After cooling the reaction solution to room temperature, 1 Normal hydrochloric acid (50 mL) was added, and the mixture was extracted twice with ethyl acetate (50 mL) The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified on silica gel. Purification by column chromatography (elution solvent: ethyl acetate / hexane = 40% to 70%) gave the target compound (408 mg, yield 57%) as a white solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ3.00 (3H, s), 3.11 (3H, s), 3.88 (3H, s), 6.54 (1H, dd, J = 3.9, 2.7Hz), 6.81- 6.91 (3H, m), 6.94 (1H, dd, J = 3.9, 2.4Hz), 7.17 (1H, m), 7.22 (1H, m), 7.36 (1H, brs), 9.34 (1H, brs).
(80b) 5- [3- (2,4-Difluorophenoxy) -5- (dimethylcarbamoyl) phenyl] -N-[(2R) -2-hydroxypropyl] -1H-pyrrole-2-carboxamide Example (80a ) (405 mg, 1.10 mmol) synthesized in a mixed solvent of methanol (6 mL), tetrahydrofuran (1 mL) and water (2 mL), lithium hydroxide monohydrate (130 mg, 3.10 mmol) was added. , And stirred at 70 ° C. for 3 hours. 2N Hydrochloric acid (2.0 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
The obtained residue was dissolved in methanol (20 mL), and (R)-(−)-1-amino-2-propanol (0.160 mL, 2.03 mmol) and DMT-MM (840 mg, 3.04 mmol) were used. In the same manner as in Example (5d), the target compound (279 mg, yield 62%) was obtained as a pale yellow oil.
¹ H-NMR (CDCl ₃ , 400 MHz): δ1.15 (3H, d, J = 6.3 Hz), 2.92 (3H, s), 3.08 (3H, s), 3.16 (1H, m), 3.57 (1H, m), 3.88 (1H, m), 6.44 (1H, m), 6.68 (1H, dd, J = 3.9, 2.4Hz), 6.75-6.88 (4H, m), 7.13 (1H, m), 7.27-7.29 (2H, m), 10.91 (1H, brs).
(80c) 3- (2,4-Difluorophenoxy) -N, N-dimethyl-5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} benzamide Compound (279 mg, 0.629 mmol) synthesized in Example (80b), methanesulfonic anhydride (280 mg, 1.61 mmol), triethylamine (0.53 mL, 3.80 mmol) Was used to give the target compound (188 mg, yield 70%) as a white solid in the same manner as in Example (16j).
¹ H-NMR (CDCl ₃ , 400MHz): δ 1.41 (3H, d, J = 6.3Hz), 2.95 (3H, brs), 3.09 (3H, brs), 3.48 (1H, dd, J = 14.2, 7.3Hz ), 3.99 (1H, dd, J = 14.2, 9.3Hz), 4.81 (1H, m), 6.53 (1H, d, J = 3.4Hz), 6.75 (1H, d, J = 3.4Hz), 6.79-6.85 (2H, m), 6.87 (1H, brs), 7.13 (1H, m), 7.23 (1H, brs), 7.35 (1H, brs).
MS (ESI) m / z: 426.16292 (M + H) ^<+> .

(Test Example 1)
(1) Preparation of GK A cDNA encoding human pancreatic GK polypeptide (GenBank Accssion No. NM_000162 human glucokinase, variant1) is cloned from a human cDNA library by polymerase chain reaction (hereinafter referred to as “PCR”). Then, it was introduced into a glutathione S transferase (hereinafter referred to as GST) fusion protein expression vector (GEX4T, GE Healthcare Bioscience). A vector was introduced into Escherichia coli (BL21, Invitrogen), and the transformed Escherichia coli was cultured overnight at 37 ° C. to recover the cells. The collected cells were frozen and thawed, suspended in phosphate buffer added with Triton-X at a final concentration of 1%, and crushed with an ultrasonic crusher. The supernatant obtained by subjecting the homogenate to low-speed centrifugation (10,000 × g, 30 minutes) is further subjected to high-speed centrifugation (100,000 × g, 10 minutes) to recover the supernatant, and the GST fusion protein purification system (Bulk GST purification module, GE Health) The fusion protein was purified using Care Bioscience. GK fusion protein was divided into small volumes and stored at -80 ° C.
(2) GK activity test GK activity was measured using the GK purified in (1). Specifically, GK purified in (1) and glucose-6-phosphate dehydrogenase (Sigma) were added to solution 1 of the glucose measurement kit (D-glucose UV method, Roche Diagnostics) and the enzyme solution It was. The enzyme solution, test compound dilution, and glucose (final concentration 5 mM) were mixed on a 96-well plate for ELISA, and reacted at room temperature for 30 minutes. After completion of the reaction, absorbance at a wavelength of 340 nm was measured using Spectramax Plus (Molecular Probe). The absorbance of unreacted (when glucose was not added) was used as the background.

The GK activation rate was represented by a numerical value represented by a formula (absorbance after reaction for 30 minutes when test compound was added) / (absorbance after reaction for 30 minutes without addition of test compound). The results of the GK activation rate obtained at a test compound concentration of 1 μM are shown in Table 1.
(Table 1)
―――――――――――――
Example GK activation rate ―――――――――――――
16 2.3
17 2.3
19 2.3
22 2.4
28 2.4
29 2.4
33 2.2
35 2.6
36 2.5
38 2.5
39 2.7
40 2.7
41 2.3
43 2.1
44 2.4
46 2.4
47 2.2
48 2.5
56 2.5
57 2.6
58 2.3
60 2.2
61 2.2
67 2.3
68 2.5
71 2.4
74 2.1
―――――――――――――.

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

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

The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent GK activation action, and is used for warm-blooded animals (particularly, humans) for diabetes, impaired glucose tolerance, Treatment or prevention of gestational diabetes, diabetic chronic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome (especially diabetes or impaired glucose tolerance) It is useful as a (especially therapeutic agent).

Claims

Formula (I)

[Where:
R 1 is the same or different and is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted by 1 or 2 hydroxy groups, (C 1 -C 6 alkylthio)-(C 1 -C 6 alkyl) group, carboxyl group, carbamoyl group, mono-C 1 -C 6 alkylaminocarbonyl group or di- (C 1 -C 6 alkyl) aminocarbonyl group,
R 2 may be independently substituted with 1 to 5 groups independently selected from a group selected from Substituent Group A or 1 to 3 independently substituted with a group selected from Substituent Group A A good pyridyl or pyrazinyl group,
R 3 is a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a (C 1 -C 6 alkyl group) which may be independently substituted with 1 to 5 groups independently selected from the substituent group B , A C 3 -C 6 cycloalkyl group and an oxo group) which may be independently substituted by 1 to 3 and may contain one oxygen atom or one nitrogen atom; And a group represented by the formula —NR 4 R 5 .
R 4 and R 5 are the same or different and each represents a hydrogen atom, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group, or together with the nitrogen atom to which R 4 and R 5 are bonded, It forms a 4- to 6-membered heterosaturated ring which may be independently substituted by 1 to 3 groups independently of the group consisting of a C 1 -C 6 alkyl group and an oxo group. The 4- to 6-membered heterosaturated ring may further contain one oxygen atom or nitrogen atom.
U represents an oxygen atom or a carbonyl group;
(However, the 2-hydroxy-1-methylethoxy group is excluded from the group represented by the formula -UR 3. )
n represents an integer of 0 to 3,
Substituent group A includes a halogen atom, C 1 -C 6 alkoxy group, C 2 -C 7 alkylcarbonyl group, C 2 -C 7 halogenated alkylcarbonyl group, C 2 -C 7 alkoxycarbonyl group, C 2 -C 7 halogenated alkoxycarbonyl group, C 1 -C 6 alkylsulfonyl group, C 1 -C 6 halogenated alkylsulfonyl group, C 3 -C 6 cycloalkylsulfonyl group, (C 1 -C 6 alkoxy)-(C 1- C 6 alkylsulfonyl) group, (C 1 -C 6 halogenated alkoxy)-(C 1 -C 6 alkylsulfonyl) group and group represented by the formula —V—NR 6 R 7 (V is a carbonyl group or a sulfonyl group) are shown, R 6, R 7 are the same or different, a hydrogen atom, or a C 1 -C 6 alkyl group or a C 1 -C 6 halogenated alkyl group, 6 and a together with the nitrogen atom to which R 7 is bonded, C 1 -C 6 alkyl independently one or two substituted or .4 to form a 4 to 6-membered heterocyclic saturated ring or may have 6 membered group The heterosaturated ring may further comprise one oxygen or nitrogen atom)),
Substituent group B includes halogen atom, C 2 -C 7 alkylcarbonyl group, C 2 -C 7 alkoxycarbonyl group, carbamoyl group, mono-C 1 -C 6 alkylaminocarbonyl group, di- (C 1 -C 6 An alkyl) aminocarbonyl group, a C 1 -C 6 alkylthio group, a C 1 -C 6 alkylsulfonyl group, a hydroxy group, and a 3- to 6-membered ring ether. Or a pharmacologically acceptable salt thereof.
In claim 1, R 1 is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted with one or two hydroxy groups, or a carbamoyl group. A compound or a pharmacologically acceptable salt thereof.
The compound or pharmacologically acceptable salt thereof according to claim 1 or 2, wherein the general formula (I) is the general formula (Ia) and R 1 is a carbamoyl group.
The compound or pharmacologically acceptable salt thereof according to claim 1 or 2, wherein the general formula (I) is the general formula (Ib) and R 1 is a methyl group, a hydroxymethyl group or a 2-hydroxyethyl group.
The general formula (I) is the general formula (Ic) in claim 1 or 2, and R 1 is a methyl group, a fluoromethyl group, a hydroxymethyl group, a 2-hydroxyethyl group, or (1S) -1,2 A compound which is a dihydroxyethyl group or a pharmacologically acceptable salt thereof.
6. The group according to claim 1, wherein R 2 is a group selected from Substituent Group C, a phenyl group substituted at the 4- or 3-position with one selected from Substituent Group C, and Substituent Group C Or a pharmacologically acceptable compound thereof, which is a 5-pyridyl group substituted at the 2-position with a group selected from the above, or a 2-pyrazinyl group substituted at the 5-position with a group selected from Substituent Group C Salt.
Substituent group C includes a C 1 -C 6 alkoxy group, a C 1 -C 6 alkylsulfonyl group and a group represented by the formula —V—NR 6 R 7 (V represents a carbonyl group or a sulfonyl group, R 6 , R 7 is the same or different and represents a hydrogen atom or a C 1 -C 6 alkyl group.
6. The compound according to claim 1, wherein R 2 is a 3-methoxyphenyl group, a 2-methylaminocarbonyl-5-pyridyl group, a 4-methylsulfonylphenyl group, or 2-methylsulfonyl-5-. A compound or a pharmaceutically acceptable salt thereof which is a pyridyl group, 2-methylaminosulfonyl-5-pyridyl group, 5-methylsulfonyl-2-pyrazinyl group or 5-methylaminosulfonyl-2-pyrazinyl group.
The C 1 -C 6 alkyl group or (C 3 -C 6 cycloalkyl) according to any one of claims 1 to 7, wherein R 3 may be independently substituted with 1 to 5 halogen atoms independently. A compound having a 3- to 6-membered saturated ring which may be independently substituted by 1 or 2 groups and may contain one oxygen atom or nitrogen atom, and U is an oxygen atom, Its pharmacologically acceptable salt.
In any one selected from claims 1 to 7, R 3 is, C 1 -C 6 alkyl or a group of the formula -NR 4 R 5 (R 4, R 5 are the same or different, A hydrogen atom or a C 1 -C 6 alkyl group), wherein U is a carbonyl group, or a pharmacologically acceptable salt thereof.
The group represented by the formula -UR 3 is selected from the group consisting of methoxy group, ethoxy group, isopropoxy group, and (1S) -2-fluoro-1-methylethoxy group. , Difluoromethoxy group, 1,3-difluoro-2-propoxy group, cyclopentanone-2-yloxy group, tetrahydrofuran-3-yloxy group, 1-cyclopropylpyrrolidin-2-one-3-yloxy group, isopropylcarbonyl group Or a dimethylaminocarbonyl group or a pharmacologically acceptable salt thereof.
A compound having the general formula (I)
{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol,
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol,
2-{(5S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethanol,
(1S) -1-{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] Oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethane-1,2-diol,
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol,
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyrazine-2-sulfonamide,
3- {5-[(5R) -5- (fluoromethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N-dimethyl-5 -{[6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide, or
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ A compound which is 6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide or a pharmacologically acceptable salt thereof.
A glucokinase activator comprising a compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof as an active ingredient.
A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof as an active ingredient.
The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition has a glucokinase activating action.
The pharmaceutical composition according to claim 13, for treating and / or preventing a disease which is treated and / or prevented by a glucokinase activating action.
The pharmaceutical composition activates glucokinase, maintains glucose homeostasis or regulates blood glucose, and thereby treats and / or prevents diseases that are treated, ameliorated, reduced and / or prevented. A pharmaceutical composition according to claim 13 for.
The pharmaceutical composition is used to treat diabetes, impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome and / or Or the pharmaceutical composition according to claim 13 for prevention.
14. The pharmaceutical composition according to claim 13, for the treatment and / or prevention of diabetes or impaired glucose tolerance.
Use of the compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition.
The use according to claim 19, wherein the pharmaceutical composition is a composition for activating glucokinase.
Treatment and / or treatment of diabetes, impaired glucose tolerance, gestational diabetes, chronic diabetes complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) and / or metabolic syndrome 20. Use according to claim 19 which is a composition for prevention.
20. Use according to claim 19, wherein the pharmaceutical composition is a composition for the treatment and / or prevention of diabetes or impaired glucose tolerance.
A method for activating glucokinase, comprising administering to a warm-blooded animal a pharmacologically effective amount of a compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof.
A method for treating and / or preventing a disease, comprising administering to a warm-blooded animal a pharmacologically effective amount of the compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof.
25. The disease according to claim 24, wherein the disease is diabetes, glucose intolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome. the method of.
25. The method according to claim 24, wherein the disease is diabetes or impaired glucose tolerance.
The method according to any one of claims 23 to 26, wherein the warm-blooded animal is a human.