TW201036962A - Novel 2, 5-disubstituted pyrrole derivative - Google Patents

Abstract

The present invention relates to a compound or a pharmaceutically acceptable salt thereof that has excellent ability for glucokinase activation. The provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof: [wherein R1 is the same or different C1-C6 alkyl, C1-C6 halogen-alkyl, C1-C6 alkyl substituted by one or two hydroxyl and the like; R2 is a phenyl optionally substituted by independently 1 to 5 substituets selected from A group, or a pyridyl or pyrazinyl optionally substituted by independently 1 to 3 substituets selected from A group; R3 is an alkyl optionally substituted by independently 1 to 5 substituets selected from B group and the like; U is an oxygen atom or carbonyl; n is an integral of 0 to 3; substituets A group is a halogen atom, C1-C6 alkoxy, C2-C7 alkylcarbonyl, C2-C7 halogen-alkylcarbonyl, C2-C7 alkoxycarbonyl and the like; substituets B group is a halogen atom, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, carbamoyl and the like.]

Description

[Technical Field] The present invention relates to a 2,5-disubstituted pyrrole derivative or a pharmacologically acceptable salt thereof which is excellent in glucokinase activation and which is useful as a therapeutic agent for diabetes or the like. [Prior Art]

Glucocyanase (GK in the present specification; EC2.7.1.1) is one of the four hexokinases found in mammals (hexose kinase IV). Hexokinase is an enzyme that catalyzes the conversion of glucose to glucose-6-phosphate in the initial stages of the intracellular glycolytic system, but the performance of intrinsic GK is mainly limited to the liver and pancreas. In the pancreatic β-cell, its function is a sensing mechanism for regulating the extracellular glucose concentration of glucose-stimulated insulin. In the liver, the enzyme reaction of GK becomes a rate-control stage, and the following glycolytic and hepatic-synthesis reactions are regulated. The GK of the liver and pancreatic sputum cells differs in the splicing difference and the sequence of the 15 amino acids on the N-terminal side is different, but the enzymatic properties are the same. Three hexokinases (I, II, III) other than GK are saturated with glucose activity below 1 mM, and GK has low affinity for glucose, and its Km値 is 8-15 mM, which is close to physiological blood glucose. . Therefore, in combination with changes in blood glucose from normal blood glucose (before and after 5 mM) to postprandial hyperglycemia (10-1 5 mM), GK causes an increase in intracellular glucose metabolism. It has been proposed since ancient times that the function of GK in the liver and pancreatic β cells is a hypothesis as a glucose sensor (Non-Patent Documents 1 to 3). The results of recent studies have shown that GK actually plays a major role in the maintenance of glucose constants throughout the body, so the hypothesis has been confirmed. For example, mice with glucokinase gene destruction show significant hyperglycemia symptoms and die shortly after birth. In addition, mice with GK heterogeneous deletion have poor glucose tolerance and have been dysregulated by insulin-stimulated insulin secretion (Non-Patent Literature) 4). On the other hand, in normal mice overexpressing GK, a decrease in blood glucose sputum, an increase in hepatic glucose content in the liver, and the like are observed, and this phenomenon is also the same in mice artificially causing diabetes (Non-Patent Document 5). In addition, even though the function of human GK is used as a glucose sensor, it has been known from recent years that it plays an important role in the maintenance of glucose constantity. An abnormality of the GK gene has been found in a family of early-onset diabetes called MODY2 (Maturity Onset Diabetes of the Young), and the association between the condition and the GK activity has been clarified (Non-Patent Document 6). On the other hand, a family having a mutation that increases the GK activity has been found, and in these families, symptoms of hypoglycemia accompanied by an increase in the insulin concentration in the plasma are observed (Non-Patent Document 7). From the above report, in the mammals including humans, GK functions as a glucose sensor and plays an important role in blood sugar regulation. Therefore, among the metabolic diseases of glucose including type II diabetes, substances having GK activation are considered to be useful as agents. In particular, the GK activating substance is expected to have a potent therapeutic effect on the liver, such as a sugar uptake promoting action and a sugar release inhibiting action, and an insulin secretion promoting action on the pancreatic beta cells. In recent years, it has been elucidated that the pancreatic β-cell type GK limitation is shown in the rat brain.

Venomedial hypothalamus (VMH). Neurons with a reactive glucose concentration in VMH 201036962 are known. In the rat ventricle, the amount of food intake is lowered relative to the administration of glucose, and administration of the glucose analog glucosamine inhibits glucose metabolism and hyperthyroidism (Non-Patent Document 8). It is known from experiments in electrophysiology that glucose-reactive neurons are activated by a physiological glucose concentration change (5-2 OmM), and it is clear that the function of glucokinase is similar to the peripheral tissue as a glucose sensor ( Non-patent document 9). Therefore, not only the liver and pancreatic β cells but also the glucokinase-activated substance of VMH are produced.

It is expected that not only the effect of lowering blood sugar, but also the obesity problem associated with most patients with type 2 diabetes can be corrected. From the above, a substance having a GK-activating effect is useful as a therapeutic and preventive agent for diabetes, or as a therapeutic and preventive agent for chronic complications such as retinopathy, nephropathy, neuropathy, ischemic heart disease, or arteriosclerosis. Further, many compounds having a GK activating ability have been reported so far, but are different from the structures of the compounds of the present invention. For example, Patent Document 1 describes a compound which must have a guanamine structure, but the compound of the present invention must have pyrrole instead of decylamine. Further, Patent Document 2 describes a compound having a condensed cyclopyrrole, but the compound of the present invention must be a pyrrole having no condensed ring. Further, Patent Document 3 describes a compound having a 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, there have been many reports of compounds having GK activation, which are different from the structures of the compounds of the present invention. (e.g., Patent Documents 4 to 15 and Non-Patent Documents 1 and 11). [PRIOR ART DOCUMENT] 201036962 [Patent Document] [Patent Document 1] International Publication No. 2005/0803 5 Booklet [Patent Document 2] International Publication No. 2007/03 1 73 No. 9 Booklet [Patent Document 3] International Publication Booklet No. 2007/061923 [Patent Document 4] International Publication No. 2000/05 8293 Booklet [Patent Document 5] International Publication No. 2003/0805 8 Booklet 5 [Patent Document 6] International Publication No. 2005/066 1 Book No. 45 [Patent Document 7] International Publication No. 2005/090332 Booklet [Patent Document 8] International Publication No. 2006/1 1 2549 Booklet [Patent Document 9] International Publication No. 2007/007886 Booklet [Patent Document 10] International Publication No. 2007/037534 (Patent Document Π) International Publication No. 2007/05 3 765 Booklet [Patent Document 12] International Publication No. 2007/ 1 1 73 8 No. 1 Booklet [Patent Document 13 International Publication No. 2005/04480 No. 1 Booklet [Patent Document 14] International Publication No. 2007/05 3 662 Booklet [Patent Document 15] International Publication No. 2008/ 1 3 642 No. 8 Booklet [Non-Patent Document] [ Non-Patent Document 1] Am J Physiol. 1984 Sep; 247(3 Pt 2): R527-36· [Non-Patent Document 2] Diabetes.l986Jan; 35(l): 61-7· [Non-Patent Document 3] Diabete s. 1 98 6 Oct;3 5 ( 1 0) : 1 1 63 -73.

[Non-Patent Document 4] Cell. 1 9 95 Oct 6; 83 (1): 69-7 8.

[Non-Patent Document 5] Proc Natl Acad Sci US A. 1996 Jul 9; 93(14): 7225-30· [Non-Patent Document 6] Nature.l992Apr23; 356(6371): 721-2. 201036962 [Non-Patent Literature 7] N Engl J Med. 1998 Jan 22; 338(4): 226-30. [Non-Patent Document 8] Life Sci. 1 98 5 Dec 30; 3 7(26): 2475 -82.

[Non-Patent Document 9] Diabetes. 2006 Feb; 55(2): 412-20. Erratum in : Diabetes. 2006 Mar; 55(3): 862.

[Non-Patent Document l〇]Science. 2003 Jul 18;3 0 1 (563 1 ) : 3 70-3.

[Non-Patent Document 11] J Biol Chem. 2006 Dec 8; 281(49): 37668-74. Epub 2006 Oct 6. [Disclosed] [Problem to be Solved by the Invention] The object of the present invention is to provide 2,5 - 2 A substituted pyrrole derivative and a GK activating drug using the 2,5-disubstituted pyrrole derivative, in particular, a therapeutic and preventive agent for providing diabetes and abnormal sugar tolerance. The inventors carefully studied the results of compounds having GK activation and found that 2,5-disubstituted pyrrole compounds having a specific chemical structure have excellent GK activation. Further, the compound of the present invention has excellent GK selectivity, low toxicity and few side effects. The present inventors have found that a 2,5-disubstituted pyrrole compound is useful as a candidate for diabetes mellitus, abnormal glucose tolerance, gestational diabetes, chronic diabetes mellitus (including diabetic peripheral nerve disorders, diabetic nephropathy, diabetic retinopathy, diabetes). The active ingredient of the medicine for the treatment and/or prevention of diseases in the group of the major vascular disease and the metabolic syndrome. The present invention has been completed based on the above knowledge and findings. [Means for Solving the Problem] The present invention relates to (1) a compound having the general formula (I) or a pharmacologically acceptable salt thereof, 201036962,

(I) [wherein R1 represents the same or different Cl-C6 alkyl group, Ci-Cs halogenated alkyl group, CVC6 alkyl group substituted by 1 or 2 hydroxyl groups, (Cl_C6 alkylthioalkyl) group, carboxyl group, Aminomethyl thiol, mono-Cl-C6 alkylamine carbonyl or bis-(CrQ alkyl)amine carbonyl; R 2 represents a phenyl group which may be optionally substituted from the group of substituent A, from 1 to 5 1 to 3 independently substituted pyridyl or pyridyl groups selected from the group of substituent A; R3 represents a group of 1 to 5 independently substituted CrQ alkyl, C2-C6 which may be selected from the group of substituent group B Alkenyl groups, which may be independently substituted by groups of 1 to 3 groups (Cl_c6 alkyl group, c3-C6 cycloalkyl group and ketone group) may be contained! a 3- to 6-membered saturated ring of an oxygen atom or a nitrogen atom (but bonded to a U-based carbon atom) or a group represented by the formula -NR4R5; R4 and R5 represent the same or different hydrogen atom, Ci-Cs alkyl or Cl- C6 alkoxy, or R4 and R5 together with the combined nitrogen atom form a group of 1 to 3 independently substituted by the Cl_C6 yard group and the keto group, 4 to 6 tributary saturated _ ring '4 to 6 member saturated The ring may further contain one oxygen atom or a nitrogen atom; U represents an oxygen atom or a carbonyl group (but a 2-trans group in the group represented by the formula -U-R3) _ -10- 201036962 except for a methyl ethoxy group; η represents An integer from 0 to 3;

The substituent group Α represents a halogen atom, a Ci-Ce alkoxy group, a C2-C7 alkylcarbonyl group, a C2-C7 halogenated alkylcarbonyl group, a C2-C7 alkoxycarbonyl group, a C2-C7 halogenated alkoxycarbonyl group, a Ci- Q alkylsulfonyl, C^-CU halogenated alkylsulfonyl 'C3-C6 cycloalkylsulfonyl, (Ci-Ce alkoxy HCrCi alkylsulfonyl), (G-C6 halogenated alkane) An oxyalkylsulfonyl) group and a group represented by the formula -V-NR6R7 (V represents a carbonyl group or a sulfonyl group; and R6, R7 represent the same or different hydrogen atom, C^-Ce alkyl or halogenated alkyl group, or R6 and R7 together with the combined nitrogen atom form a 4 to 6 membered saturated heterocyclic ring which may be independently substituted by 1 or 2 Ci-Q alkyl groups, and the 4 to 6 membered saturated heterocyclic ring may further contain 1 oxygen atom or nitrogen. a group of atoms; a substituent group B represents a halogen atom, a C2-C7 alkylcarbonyl group, a C2-C7 alkoxycarbonyl group, an amine carbenyl group, a mono-d-Ce alkylamine carbonyl group, a di-(C) group. a group of ^-Ce alkyl)aminocarbonyl, CrQ alkylthio, Cl-C6 alkylsulfonyl, hydroxy and 3 to 6 membered cyclic ethers. ]. Preferred in the invention are: (2) a compound of (1) or a pharmacologically acceptable salt thereof, wherein ... is a Cl_C6 alkyl group, a Ci-C6 halogenated alkyl group, a C1-C6 alkyl group substituted with 1 or 2 hydroxyl groups. Or amine mercapto. (3) The compound of (1) or (2) or a pharmacologically acceptable salt thereof, wherein the general formula (1) is a general formula (la), and R1 is an amine carbenyl group. -11- 201036962

(a) The compound of (1) or (2) or a pharmacologically acceptable salt thereof, wherein the general formula (I) is a general formula (lb), and R1 is a methyl group, a hydroxymethyl group or a 2-hydroxyethyl group. .

(5) The compound of (1) or (2) or a pharmacologically acceptable salt thereof, wherein the general formula (1) is a general formula (Ic), and R1 is a methyl group, a fluoromethyl group, a hydroxymethyl group, or a 2-hydroxy group. Ethyl or (1S)-1,2-dihydroxyethyl.

(4) A compound selected from any one of (1) to (5) or a pharmacologically acceptable salt thereof, wherein R2 is a 4- or 3-position group selected from the group of substituents. Substituted -12- 201036962 @phenyl, 2-position 5-pyridyl group substituted with a group selected from substituent group C or 5-pyridyl group substituted with 1 group selected from substituent group c . The substituent group C represents a group represented by (^-(6 alkoxy group, alkylsulfonyl group and formula -V_NR6R7 (V represents a carbonyl group or a sulfonyl group, and R6, R7 represents the same or different hydrogen atom or alkyl group). ) The group that is grouped.

(7) A compound selected from any one of (1) to (5) or a pharmacologically acceptable salt thereof, wherein R2 is 3-methoxyphenyl, 2-methylaminocarbonyl-5-pyridyl, 4- A basic base, 2-A-bulk-5-卩 ratio steep base, 2-methylamine expanded base-5-卩 steep base, 5-methylsulfonyl-2-pyridyl or 5- Methamidomethyl-2-pyrrolidine. (8) A compound selected from any one of (1) to (7) or a pharmacologically acceptable salt thereof, wherein R3 is a d-Cs alkyl group which may be independently substituted by 1 to 5 halogen atoms or may be One or two of the groups of the C3-C6 cycloalkyl group and the ketone group may be independently substituted with a 3- to 6-membered saturated ring of one oxygen atom or a nitrogen atom, and U is an oxygen atom. (9) A compound selected from any one of (1) to (7) or a pharmacologically acceptable sulfonium salt thereof, wherein R3 is a group represented by a Ci-C6 or a formula -NR4R5 (r4, R5 represent the same or different The hydrogen atom or the Ci-C^ hospital base), U is a thiol group. (10) A compound selected from any one of (1) to (7) or a pharmacologically acceptable salt thereof, wherein the group represented by the formula -U-R3 is a methoxy group, an ethoxy group, an isopropoxy group, lS)-2-fluoro-1-methylethoxy, difluoromethoxy, 1,3-difluoro-2-propoxy, cyclopentan-2-yloxy, tetrahydrofuran-3-yloxy Base, 1-cyclopropylpyrrolidin-2-one-3-yloxy, isopropylcarbonyl or dimethylaminecarbonyl. (11) The compound of (1) or a pharmacologically acceptable salt thereof, having [R1 represents -13-201036962, the same or different Ci-Ce, a halogenated compound, and substituted by 1 or 2 hydroxy groups - ( : 6 alkyl, (CrCe alkylthio hd-Ce alkyl) group, carboxyl group, amine mercapto group, mono-Ch-C6 alkyl amine carbonyl or di-(Cl_C6 alkyl) amine carbonyl; R2 means selectable From 1 to 5 independently substituted phenyl groups of substituent group A or 1 to 3 independently substituted pyridyl or pyridyl groups which may be selected from the group of substituent group A; R3 represents a self-substitutable 1 to 5 independently substituted C^C6 alkyl groups of the group B, which may be independently substituted by groups 1 to 3 of the group consisting of c2-C6 alkenyl, Ci-q alkyl and keto groups a 3- to 6-membered saturated ring of an oxygen atom or a nitrogen atom (but bonded to a U-based carbon atom) or a group represented by the formula -Nr4r5; R4 and R5 represent the same or different hydrogen atom, Ci-Ce alkyl or C^ -Ce alkoxy, or R4 and R5 together with the combined nitrogen atom form a 4 to 6 membered saturated heterocyclic ring which may be independently substituted by a group of alkyl and keto groups, 4 to 6 membered saturated heterocyclic The ring may further contain one oxygen atom or nitrogen atom U represents an oxygen atom or a carbonyl group (except for the 2-carbo-1-methylethoxy group in the group represented by the formula -U-R3); n represents an integer of 0 to 3; the substituent group a represents a halogen atom, C2-C7 alkylcarbonyl, C2-C7 halogenated alkylcarbonyl, C2_C7 alkoxycarbonyl, C2-C7 halogenated alkoxycarbonyl, Crq alkylsulfonyl, halogenated alkylsulfonyl, C3-C6 cycloalkyl a sulfonyl group, a (Cl-C6 alkoxyalkylsulfonyl) group, a halogenated alkoxy group)-(Cl_C6-heteroalkyl) group and a group represented by the formula -V-NR6R7 (V represents a parent group or a sulfonate) R6, R7 represents the same or different hydrogen atom, Ci-C6 alkyl or Cl-C6 halogenated alkyl ' or R6 and R7 together with the combined nitrogen atom can be formed by 1 or 2 Ci-Ce alkyl a group of 4 to 6-membered saturated heterocyclic rings, 4 to 6 members of the saturated-14-201036962 heterocyclic ring may further contain one oxygen atom or a nitrogen atom; the substituent group B represents a halogen atom, a C2_C7 alkane Carbonyl group, c2-c7 alkoxycarbonyl group, amine mercapto group, mono-Ci-C6 alkyl amine carbonyl group, di-(Cl_C6 alkyl) amine carbonyl group, Ci-C6 alkylthio group, Ci-Ce alkyl sulfonium sulfonate Group of hydroxyl groups, hydroxyl groups and 3 to 6 membered cyclic ethers]

(12) The compound of (1) or a pharmacologically acceptable salt thereof, wherein Ri is a C1-C6 alkyl group, a Ci-Ce halogenated alkyl group, a C^-Ce alkyl group substituted with 1 or 2 hydroxyl groups or an amine mercapto group; R2 is a 4- or 3-position phenyl substituted with one group selected from the group of substituents c, a 5-pyridyl group substituted at the 2-position via a group selected from the substituent group c, or a 5-position through one selected from a 2-substituted pyridyl group substituted with a group C, the substituent group C being a group represented by a CrC6 alkoxy group, a Ci-Ce alkylsulfonyl group and a formula -V-NR6R7 (V represents a carbonyl group or a sulfonyl group) ; r6, r7 represent the same or different hydrogen atoms or CrC6 alkyl group; group R3 is acceptable! The Ci-C6 alkyl group independently substituted with 5 halogen atoms or may be independently substituted by 1 or 2 groups consisting of (C3-C6 cycloalkyl and keto groups) may contain 1 oxygen atom or nitrogen atom a 3- to 6-membered saturated ring; U is an oxygen atom; and η is an integer from 0 to 3. (13) A compound of (1) or a pharmacologically acceptable salt thereof, wherein: is a Cl-c6 alkyl group, a C^-C:6 halogenated alkyl group, a C^-Ce alkyl group substituted with i or two hydroxyl groups or Aminomethyl thiol; R 2 is a 4- or 3-position phenyl substituted with a group selected from the group of substituents c, a 5-pyridyl group or a 5-position substituted with a group selected from the group of substituent C a 2-pyridinyl group substituted with a group selected from the group of substituent C, the substituent group c being a group represented by c^c:6 alkoxy group, Cl_C6 alkylsulfonyl group and s_v_NR6R7 (V represents a carbonyl group or Sulfhydrazyl; r6, r7 represent the same or different group of -15-201036962 hydrogen atom or Κ6 alkyl group; rule 3 is a group represented by CrG alkyl or formula -nr4r5 (R4, R5 represent the same or different A hydrogen atom or a C^-Cfi alkyl group; U is a carbonyl group; n is an integer of 0 to 3. (14) A compound of (1) or a pharmacologically acceptable salt thereof, wherein the general formula (I) is a general formula (la), R1 is an amine carbenyl group; and R2 is a 3-methoxyphenyl group or a 2-methylamine. Carbonyl-5-pyridyl, 4-methylsulfonylphenyl, 2-methylsulfonyl-5-pyridyl, 2-methylsulfonyl-5-pyridyl, 5-methylsulfonyl-2- Pyridinyl or 5-methanesulfonyl-2-pyrrolidine; the formula -U-R3 represents methoxy, ethoxy, isopropoxy, (lS)-2-fluoro-1- Methyl ethoxy, difluoromethoxy, 1,3-difluoro-2-propoxy, cyclopentan-2-yloxy, tetrahydrofuran-3-yloxy, 1-cyclopropylpyrrolidine 2-keto-3-yloxy, isopropylcarbonyl or dimethylaminecarbonyl. (15) The compound of (1) or a pharmacologically acceptable salt thereof, wherein the general formula (I) is a general formula (lb); R1 is a methyl group, a hydroxymethyl group or a 2-hydroxyethyl group; and R2 is a 3-methoxy group. Phenylphenyl, 2-methylaminocarbonyl-5-pyridyl, 4-methanesulfonylphenyl, 2-methylsulfonyl-5-pyridyl, 2-methanesulfonyl-5-pyridyl, 5 -Methanesulfonyl- 2-pyridinyl or 5-methylsulfonyl-2-pyridyl; formula -U-R3 represents methoxy, ethoxy, isopropoxy, lS)-2-fluoro-1-methylethoxy, difluoromethoxy, 1,3 -difluoro-2-propoxy, cyclopentan-2-yloxy, tetrahydrofuran-3-yloxy Base, 1-cyclopropylpyrrolidin-2-one-3-yloxy, isopropylcarbonyl or dimethylaminecarbonyl. (16) A compound of (1) or a pharmacologically acceptable salt thereof, wherein the general formula (I) is a general formula (Ic): 111 is a methyl group, a fluoromethyl group, a hydroxymethyl group, a 2-hydroxyethyl group or (1S) -1,2-dihydroxyethyl; r2 is 3-methoxyphenyl, 2-methylaminocarbonyl-5_-16- 201036962 pyridyl, 4-methylsulfonylphenyl, 2-methylsulfonyl 5-5-pyridyl, 2-methylsulfonyl-5-pyridyl, 5-methylsulfonyl-2-pyridyl or 5-methylsulfonyl-2-pyridyl; formula -U- The group represented by R3 is methoxy, ethoxy, isopropoxy, (1S)_2_fluoro-1-methylethoxy, difluoromethoxy, 1,3-difluoro-2-propoxy , cyclopentan-2-yloxy, tetrahydrofuran-3-yloxy, 1-cyclopropylpyrrolidin-2-one-3-yloxy, isopropylcarbonyl or dimethylaminecarbonyl. (17) A compound having the general formula (I) is:

{(511)-2-[5-(3-Methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-111-1] ratio-2 -yl]-4,5-dihydro-1,3-indol-5-yl}methanol, {(5R)-2-[5-(3-ethoxy-5-{[6-(formaldehyde) Indenyl) indole-3-methyl]oxy}phenyl)-111-lalyl-2-yl]-4,5-dihydro-1,3-indol-5-yl}methanol, [( 5R)-2-{5-[3-(Difluoromethoxy)-5-{[6-(methyl fluorenyl)pyran-3-yl]oxy}phenyl]-111-pyrrole-2 -yl}-4,5-dihydro-1,3-oxazol-5-yl]methanol, 5-(3-{5-[(5R)-5-(yl)methyl)-4,5- Dihydro-1,3-indol-2-yl]-1H-B ratio of alk-2-yl}-5-methoxyphenoxy)-N-methylpyridin-2-carboxamide, (J {(5R)-2-[5-(3-[(lS)-2-fluoro-1-methylethoxy]_5_{[6•(methylsulfonyl)pyrid-3-yl] Oxy}phenyl)-1Η-indole-2-yl]-4,5-dihydro-1,3-carbazole-5-yl}methanol, {(411)-2-[5-(3 -[(18)-2-fluoro-1-methylethoxy]_5_{[6-(methylsulfonyl)pyrid-3-yl]oxy}phenyl)-1Η-pyrrol-2-yl ]-4,5-dihydro-1,3-indol-4-yl}methanol, 2-{(5S)-2-[5-(3-[(lS)-2-fluoro-1-methyl) Ethoxy]·5_{[6·(methylsulfonyl)-dish-3-yl]oxy}phenyl)-1Η-卩 ratio -2-yl]-4,5-dihydro-1,3- 哗-5_ -17- 201036962 】}ethanol, (lS)-l-{(5R)-2-[5-(3-[( lS)-2-fluoro-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1Η-pyrrol-2-yl]- 4,5-dihydro-1,3-oxazol-5-yl}ethyl-1,2-diol, {(5R)-2-[5-(3-[(lS)-2-fluoro-1) -methylethoxy]_5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1 , 3-carbazole-5-yl}methanol, {(4R)-2-[5'(3-[(lS)-2-fluoro-1-methylethoxy]_5-{[5-(a Acid-expanding group) pyridin-2-yl]oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol, 5-( 3-[(lS)-2-fluoro-1-methylethoxy]-5-{5-[(4R)-4-(hydroxymethyl)-4,5-dihydro-1,3-anthracene Oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-methylpyridine-2_sulfonamide, 5-(3-[(lS)-2-fluoro-1-methyl Ethoxy]-5-{5-[(4R)-4-(hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl} Phenoxy)-N-methylpyrrol-2-sulfonamide, N,N-dimethyl-3-{5-[(5S)-5-methyl-4,5-dihydro-1, 3-Bfoxazol-2-yl]-1H-pyrrol-2-yl}-5-[4_(methylsulfonyl)phenoxy]benzamide 3-{5-[(5R)-5-(fluoromethyl)-4,5-dihydro-1,3-Bfoxazol-2-yl]-1H-pyrrol-2-yl}-mu 1 5-[{6-(methylsulfonyl)pyridin-3-yl]oxy}benzamide, N,N-methyl-3-(5-[(5S)-5-methyl) - 4,5-dihydro-1,3-D§ 哩-2-yl]-1 _ 莎-2-yl}-5-{[6-(methylsulfonyl) fluorene-steep-3- Alkyloxy}benzoic acid amine, -18- 201036962 N,N-dimethyl-3-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazole- 2-yl]-1Η-indolebi-2-yl}-5-{[6-(methylsulfonyl)pyridinium-3-methyl]oxy}benzamide, {(4R)-2 -[5-(3-{[6-(methyl aryl))disazo-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]phenyl)-1Η-pyrrole -2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol,

1-cyclopropyl-3-(3-{5-[(5S)-5-methyl-4,5-one gas-1,3-indol-2-yl]-1H-pyrrol-2-yl }-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenoxy)pyrrolidine-2-one, 2-(3-{5-[(5S)-5 - Methyl-4,5-dihydro-l,3-oxazol-2-yl]-lH-pyrrol-2-yl}-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy Benzyloxy)cyclopentanone, 1-(3-{5-[(511)-5-(hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl]- 11^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-di-Q-hydrogen-1,3-oxazol-2-yl] a compound of -1H-pyrrol-2-yl}benzamide or a pharmacologically acceptable salt thereof. (18) A compound of the compound of (17) or a pharmacologically acceptable salt thereof. (19) The compound of the general formula (I) is: {(5R)-2-[5-(3-[(lS)-2-fluoro-1-methylethoxy]-5-{[6- (Methanesulfonyl) pyridin-3-yl]oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol, -19 - 201036962 {(4R)-2-[5-(3-[(lS)-2-fluoro-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl) ]oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol, 2-{(5S)-2-[5-( 3-[(lS)-2-fluoro-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1Η-pyrrole-2 -yl]-4,5-dihydro-1,3-oxazol-5-yl}ethanol, (lS)-l-{(5R)-2-[5-(3-[(lS)-2· Fluoro-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-di Hydrogen-1,3-oxazol-5-yl}ethyl-1,2-diol, {(411)-2-[5-(3-[(13)-2-fluoro-: 1-methyl) Oxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3- Oxazol-4-yl}methanol, 5-(3-[(lS)-2-fluoro-1-methylethoxy]-5-{5-[(4R)-4-(hydroxymethyl)- 4,5-dihydro-1,3-indol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-A Pyridyl-2-sulfonamide, 3-{5-[(5R)-5-(fluoromethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrole -2-Kip N,N-dimethyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}benzamide, or 1>1-dimethyl-3- {5-[(53)-5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-111-indole-2-yl}-5-{[6-( A compound of methanesulfonyl)pyridin-3-yl]oxy}benzamide or a pharmacologically acceptable salt thereof. (20) A compound of the compound of (19) or a pharmacologically acceptable salt thereof. -20-201036962 (21) A glucokinase activator containing a compound selected from any one of (1) to (20) or a pharmacologically acceptable salt thereof as an active ingredient. (2) A pharmaceutical composition comprising the compound according to any one of (1) to (20) or a pharmacologically acceptable salt thereof as an active ingredient. (23) The pharmaceutical composition according to (22), wherein the pharmaceutical composition has a glucose kinase activation action. (24) The pharmaceutical composition according to (22), wherein the pharmaceutical composition is used for treatment

It treats and/or prevents diseases that are treated and/or prevented via glucokinase activation. (2) The pharmaceutical composition according to (22), wherein the pharmaceutical composition is used for treating and/or preventing treatment, improvement, alleviation and/or prevention by activating glucokinase to achieve glucose maintenance or blood glucose regulation. Symptoms of the disease. (26) The pharmaceutical composition according to (22), wherein the pharmaceutical composition is used for diabetes, abnormal sugar tolerance, gestational diabetes, chronic diabetes mellitus (including diabetic peripheral nerve dysfunction, diabetic nephropathy, diabetic retinopathy, Treatment and/or prevention of diabetic macroangiopathy or metabolic syndrome. (27) The pharmaceutical composition according to (22), wherein the pharmaceutical composition is used for the treatment and/or prevention of diabetes or abnormal sugar tolerance. (28) A use of the compound according to any one of (1) to (20) or a pharmaceutically acceptable salt thereof for producing a pharmaceutical composition. (29) The use of (28), wherein the pharmaceutical composition is a composition for activating glucose kinase. (30) (28), wherein the pharmaceutical composition is used for diabetes 21-201036962 disease, abnormal sugar tolerance, gestational diabetes, chronic diabetes mellitus (including diabetic peripheral nerve dysfunction, diabetic nephropathy, A composition for the treatment and/or prevention of diabetic retinopathy, diabetic macroangiopathy, or metabolic syndrome. (31) The use of (28), wherein the pharmaceutical composition is a composition for the treatment and/or prevention of diabetes or abnormal glucose tolerance. (32) A method for activating glucokinase, which is a compound according to any one of (1) to (20) or a pharmacologically acceptable salt thereof, which is administered to a warm-blooded animal in a pharmacologically effective amount. (3) A method for the treatment and/or prevention of a disease, which comprises administering to a warm-blooded animal a pharmacologically effective amount of a compound according to any one of (1) to (20) or a pharmacologically acceptable thereof. salt. (3 4) (3 3), wherein the disease is diabetes, abnormal sugar tolerance, gestational diabetes, chronic diabetes mellitus (including diabetic peripheral nerve dysfunction, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) ) or metabolic syndrome. (3) The method according to any one of (32) to (35) wherein the warm blood animal is a human. In the present invention, the "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. It is preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom. In the present invention, the "Ci-C6 alkyl group" is a linear chain of 1 to 6 carbon atoms or a branched chain alkyl group of -22 to 201036962. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1 -ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2 , 2-dimethylbutyl, 1,1-dimethylbutyl or 1,2-dimethylbutyl, preferably a linear or branched alkylalkyl group having 1 to 4 carbon atoms More preferably, it is a methyl group or an ethyl group (Ci-C2 alkyl group), and more preferably a methyl group.

In the present invention, "C^-Cs halogenated alkyl group" is the same or different one to five. The "halogen atom" is bonded to the group of the former "CrQ alkyl group". For example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, tribromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloro a group, a 2-bromoethyl group, a 2-chloroethyl group or a 2-fluoroethyl group, preferably one or five of the same or different "halogen atoms" bonded to the group of the aforementioned "Ci-Q alkyl group" (CrQ) More preferably, the same or different 1 to 5 "halogen atoms" are bonded to the alkyl group of the "alkyl group" described above, and more preferably a trifluoromethyl group or a fluoromethyl group. It is a fluoromethyl group. In the present invention, the "alkyl group substituted with 1 or 2 hydroxy groups" is a group in which one or two hydroxyl groups are bonded to the former "CrQ alkyl group". For example, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1,2-dihydroxyethyl or 2,3-dihydroxypropyl, preferably 1 or 2 hydroxy groups Further, the group of "CrQ alkyl group" is preferably a group in which one or two hydroxyl groups are bonded to a pre-alkyl group, and more preferably a hydroxymethyl group, a 2-hydroxyethyl group or a 1,2-dihydroxyethyl group. In the present invention, the "C!-C6 alkylthio group" is a linear or branched alkane sulfur having 1 to 6 carbon atoms bonded to a sulfur atom group, a "CpC^alkyl group" -23- 201036962. base. For example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, second butylthio, 1-ethylpropylthio or hexylthio, preferably a carbon atom 1 to 4 linear or branched alkylthio (C^C* alkylthio), more preferably methylthio or ethylthio (Ci-G alkylthio), more preferably methylthio base. In the present invention, "(Ci-C6 alkylthio)-(C!-C6 alkyl) group" is a group in which a "Ci-Ce alkylthio group" is bonded to the former "Ci-C^alkyl group". For example, methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl or 2-methylthioethyl, preferably one of the predecessors "CrG alkane sulfur It is bonded to the group of (Ci-C* alkyl group) ((Κ4 alkylthioalkyl) group), and more preferably one of the former "Ci-Q alkylthio groups" is bonded to the former "C^-Cz alkane". The group of the group ((Ci-Cz alkylthioalkyl) group) is more preferably a 2-methylthioethyl group. In the present invention, "mono-(^-alkylalkylaminecarbonyl) is a group which has been bonded to a carbonyl group by combining one of the aforementioned "alkyl" amine groups, for example, a methylaminecarbonyl group, an ethylaminecarbonyl group, a propylaminecarbonyl group, Isopropylaminecarbonyl or butylaminecarbonyl, preferably one of the previously described "alkyl" groups bonded to an amine group is bonded to a carbonyl group (monoalkylamine carbonyl), more preferably a methylamine carbonyl or ethylamine The carbonyl group (mono-Ci-G alkylamine carbonyl group) is more preferably a methylamine carbonyl group. In the present invention, the "di-(C^Cfi alkyl)amine carbonyl group" is a combination of the same or different two precursors. The amine group of the group is bonded to a carbonyl group, such as dimethylaminecarbonyl, diethylaminecarbonyl, dipropylaminecarbonyl, N-ethyl-N-methylaminecarbonyl, N-methyl-N-propyl Amine carbonyl or n-butyl-N-methylamine carbonyl; compared with -24 to 36,966,962, preferably an amine group of the same or different two "Ci-Q alkyl groups" bonded to a carbonyl group (di-(G-) CU alkyl)aminecarbonyl), more preferably dimethylaminecarbonyl, diethylaminecarbonyl or N-ethyl-N-methylaminecarbonyl(dialkyl)aminecarbonyl), more preferably dimethylamine Carbonyl.

In the present invention, the "C2-C6 alkenyl group" is a group having 2 to 6 carbon atoms having one double bond in the "alkyl group". For example, vinyl, 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, preferably It is an alkenyl group (C2-C4 alkenyl group) having 2 to 4 carbon atoms, more preferably a methyl group. In the present invention, "Ci-C6 Instituteoxy" is a linear or branched alkoxy group having 1 to 6 carbon atoms bonded to the oxygen atom in the above-mentioned "Ci-C6 yard group". For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, second butoxy, tert-butoxy, pentyloxy, 2-methylbutoxy , 3-ethylpropoxy, neopentyloxy, hexyloxy or 2,3-dimethylbutoxy; preferably 〇 is a linear or branched alkoxy group having from 1 to 4 carbon atoms , (C/C4 alkoxy); more preferably methoxy, ethoxy, propoxy or isopropoxy alkoxy); more preferably methoxy or ethoxyalkoxy) More preferably, it is a methoxy group. In the present invention, the "C2-C7 alkylcarbonyl group" is a group of the above-mentioned "alkyl group-bonded to a carbonyl group. For example, an ethyl group, a propyl group, a butyl group, an isobutyl group, a pentanoyl group, a trimethyl group. Ethyl group or valeryl group; preferably one "C1-C4 yard base" is bonded to the base of the ore base (C2-C5 yard curtain-25-201036962 base), more preferably acetamidine Further, the propyl group or the propyl group (c2-c3 alkylcarbonyl group) is more preferably an ethyl group. In the present invention, the "C2-C7 halogenated alkylcarbonyl group" is a group in which a "Ci-Ce halogenated alkyl group" is bonded to a carbonyl group, such as a trifluoromethylcarbonyl group, a trichloromethylcarbonyl group, a difluoromethylcarbonyl group, Dichloromethylcarbonyl, fluoromethylcarbonyl, 2,2,2-trifluoroethylcarbonyl, 2,2,2-trichloroethylcarbonyl or 2-fluoroethylcarbonyl; preferably one prescript "CrC4 The halogenated alkyl group is bonded to the carbonyl group (c2-c5-alkylcarbonyl group), more preferably one of the former halogenated alkyl groups" is bonded to the carbonyl group (c2-c3 halogenated alkylcarbonyl group), and more preferably three. Fluoromethylcarbonyl. In the present invention, the "Cz-C7 alkoxycarbonyl group" is a group in which a "Cl-c6j^oxy group" is bonded to a carbonyl group. For example, methoxycarbonyl, ethoxycarbonyl, oxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, second butoxycarbonyl or tert-butoxycarbonyl, preferably One of the former "Cl_e4 alkoxy groups" is bonded to a carbonyl group (C2_C5 alkoxycarbonyl group), more preferably a methoxycarbonyl group or an ethoxycarbonyl group (Cz-C3 alkoxycarbonyl group), and more preferably a methoxy group. Alkylcarbonyl. In the present invention, "Cl_C:6-halogenated alkoxy group" is the same or different one to five "halogen atoms" which are bonded to the group "Ci-C6 alkoxy group". For example, trifluoromethoxy 'trichloromethoxy, difluoromethoxy, dichloromethoxy, tribromomethoxy', fluoromethoxy, 2,2,2-trifluoroethoxy, 2 2,2_trichloroethoxy, 2-chloroethoxy, 2-fluoroethoxy or pentafluoroethoxy, preferably the same or different 1 to 5 pre-recorded "halogen atoms" are combined with the pre-record "Cl-(:4 alkoxy) group (CmC4 halogenated alkoxy group), more preferably the same or different i to 5 former -26-201036962 "halogen atom" is combined with the predecessor "(^-(: More preferably, the "Ci-Ce alkylsulfonyl group" is a "Ci-Cs alkane" in the present invention. a straight or branched alkylsulfonyl group having 1 to 6 carbon atoms bonded to a sulfonyl group, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropyl A sulfonyl group, a butyl sulfonyl group, an isobutyl sulfonyl group, a t-butyl sulfonyl group or a pentyl sulfonyl group, preferably a linear or branched alkane having 1 to 4 carbon atoms. Alkylsulfonyl (Crh alkylsulfonyl), more preferably methylsulfonyl or ethylsulfonyl (Ci-Cz alkyl) In the present invention, the "Cl_C6 halogenated alkylsulfonyl group" is a group in which the former "Cl_C6 halogenated alkyl group" is bonded to a sulfonyl group, and the number of carbon atoms is 1 to 6 straight or branched chain halogenated alkyl sulfonyl groups, such as trifluoromethanesulfonyl, trichloromethanesulfonyl, difluoromethanesulfonyl, chloromethanesulfonyl, fluoromethanesulfonyl , 2,2,2-trifluoroethylsulfonyl or 2-fluoroethylsulfonyl, preferably a linear or branched chain halogenated alkylsulfonyl group having 1 to 4 carbon atoms (CrQ halogenated) The alkylsulfonyl group, more preferably a linear or branched chain halogenated alkylsulfonyl halide alkylsulfonyl group having 1 or 2 carbon atoms, is more preferably a trifluoromethanesulfonyl group. In the present invention, the "c3-c6 cycloalkyl group" is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. Preferably, it is a cyclopropyl group. In the present invention, "c3-c6 cycloalkylsulfonyl group" It is a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group or a cyclohexylsulfonyl group. Preferably, it is a cyclopropyl polymer. In the present invention, "(Ci-Q alkoxy group) XCi-Ce alkylsulfonyl) is -27- 201036962 1 prescript "Ci-C 6 alkoxy group is bonded to the group of the above-mentioned "Ci-C6 alkylsulfonic acid group", for example, methoxymethyl aryl, ethoxymethanesulfonyl, propoxymethyl, isopropoxy Preferably, the one is a "C1-C4 alkoxy group", and the "Ci-Ce alkylsulfonyl group" is bonded to the former "Ci-Ce alkylsulfonyl group". The base ((C^C4 alkoxy)-((:!-C4 alkylsulfonyl))), more preferably one of the former "CrC2 alkoxy" is bonded to the former "Cl-C2 alkyl sulfonate" The base of the fluorenyl group ((Ci-C2 alkoxyalkylsulfonyl) group) is more preferably a methoxymethylsulfonyl group. In the present invention, "(Cl_C6 halogenated alkoxy)-(Cl_C6 alkylsulfonyl) group" is a pre-recorded "Ci-C6 halogenated alkoxy group" which is bonded to the former "d-Cs alkylsulfonyl group". base. For example, trifluoromethoxymethanesulfonyl, trichloromethoxymethanesulfonyl, difluoromethoxymethylsulfonyl, dichloromethoxymethanesulfonyl or fluoromethoxymethylsulfonyl Preferably, one of the former "halogenated alkoxy groups" is bonded to the group of the "CrC4 alkylsulfonyl group" ((CtC* halogenated alkoxy MCi-CU alkylsulfonyl) group), which is preferably one. The former "Cl_C2 halogenated alkoxy group" is bonded to the group of "Ci-C2 alkylsulfonyl group" ((Ci_C2 halogenated alkoxy)_(Ci_c2 sulfonyl) group) and is more preferably difluoromethyl. Oxymethanesulfonyl. In the present invention, '"selectable. From the base of the substituent group A to 5 independently substituted phenyl" is a phenyl group or a phenyl group selected from the group A of the substituent group A to 5 independently substituted phenyl groups. . Preferably, the 4-position or the 3-position is selected from the group consisting of a substituent group (d) 3-methoxyphenyl or a 4-methyl-phenylene group. In the present invention, the pyridyl group or pyridinyl group which may be substituted by the group 1 to 3 independent -28 - 201036962 of the substituent group A is a pyridyl group, and is selected from the group of the substituent group A to 1 to 3 independently. A substituted pyridyl group, a pyridyl group or a pyridyl group selected from the group of substituent A, 1 to 3 independently substituted. Preferably, it is a 5-pyridyl group substituted with 1 group selected from the group of the substituent group C or a 2-pyridyl group substituted with 1 group selected from the group of the substituent group C, more preferably 2-A Aminecarbonyl-5-pyridyl, 2-methylsulfonyl-5-pyridyl, 2-methylsulfonyl-5-pyridyl, 5-methylsulfonyl-2-pyridyl or 5-methylamine Sulfosyl-2-pyridyl.

In the present invention, "1 to 5 independently substituted alkyl groups which may be selected from the group of the substituent group B" is an alkyl group or a group of 1 to 5 independently substituted Ci-C selected from the group of the substituent group b. ^Alkyl. It is preferably a Ci-Q alkyl group which may be independently substituted by 1 to 5 halogen atoms, more preferably a methyl group, an ethyl group, an isopropyl group, a (lS)-2-fluoro-1-methylethyl group, or a second group. Fluoromethyl or 1,3-difluoro-2-propyl. In the present invention, the "3 to 6 membered cyclic ether" is ethylene oxide, oxetane, tetrahydrofuran or tetrahydropyran. Preferred is tetrahydrofuran. In the present invention, the "3 to 6 membered saturated ring which may contain one oxygen atom or a nitrogen atom" is a C3-C6 cycloalkyl group, a 3 to 6 membered cyclic ether or a 3 to 6 membered cyclic amine, a cyclopropane or a cyclohexane. Alkane, cyclopentane, cyclohexane, ethylene oxide, monotetracycline, tetrahydrofuran, tetrahydropyran, aziridine, azetidine, pyrrolidine or piperidine. Preferred is cyclopentane, tetrahydrofuran or pyrrolidine. In the present invention, "1 to 3 groups which may be substituted by (C^-Ce alkyl group, C3-C6 cycloalkyl group and keto group) may independently contain 3 oxygen atoms or nitrogen atoms. - 201036962 to 6-membered saturated ring" is a group of 3 to 6 membered saturated rings or alkyl groups, C3_C6 cycloalkyl groups and ketone groups which may contain one oxygen atom or nitrogen atom! Up to 3 independently substituted 3 to 6 membered saturated rings containing one oxygen or nitrogen atom. For example, the former "3 to 6-membered saturated ring which may contain 1 oxygen atom or nitrogen atom", cyclopentanone, cyclohexanone, tetrahydro-2-furanone, tetrahydro-2-pyranone, 2-aza Azetidinone, 2-pyrrolidone, 2-piperidone, methylcyclopentyl, methylcyclohexyl, methyltetrahydrofuran, methyltetrahydropyran, methylpyrrolidine, A Preferably, the piperidinyl, 1-methyl-2-pyrrolidone or 1-cyclopropylpyrrolidin-2-one is cyclopropane, cyclopentanone, tetrahydrofuran, tetrahydropyran, tetrahydro-2-furanone, 1-methyl-2-pyrrolidone or 1-cyclopropylpyrrolidin-2-one, more preferably cyclopentanone, tetrahydrofuran or 1-cyclopropylpyrrolidin-2-one. In the present invention, "R4 and R5 together with the combined nitrogen atom form a group which can be grouped by a C"C6 alkyl group and a ketone group! Up to 3 independently substituted 4 to 6 membered saturated heterocyclic rings, and 4 to 6 membered saturated heterocyclic rings may further contain 1 oxygen atom or nitrogen atom" which is a group which can be grouped by Ci-Ce alkyl group and ketone group. Up to 3 independently substituted 4 to 6 membered saturated heterocyclic rings (containing 4 nitrogen atoms, more preferably 1 to 6 membered fully reduced saturated heterocyclic groups of one oxygen atom or nitrogen atom), such as a nitrogen heterocycle Butane, pyrrolidine, piperidine, morphine, pipe trap, 2-azetidinone, 2-pyrrolidone, 2-piperidone, dimethylmorpholine, methylpiper or dimethylper The trap is preferably azetidine, piroidine or morpholin. In the present invention, "the base represented by the formula -V-NR6R7" is "the base of the formula -C(=0)-NR6R7" or "the base of the formula -S02-NR6R7". -30-

201036962 In the present invention, 'R6 and R7 together with a bonded nitrogen atom form a 4 to 6 membered saturated heterocyclic ring which may be substituted with 2 C^-Ce alkyl groups. The 4 to 6 membered heterocyclic ring may further contain 1 oxygen atom. Or a nitrogen atom)" is a 4- to 6-membered saturated heterocyclic ring which can be independently substituted with 1 Ci-C6 alkyl group (a full resaturated 4 to 6 members containing 1 or more oxygen atoms or nitrogen atoms) Heterocyclyl) 'for example, azetidin', pyridox, piperazine, morphine, dimethylmorpholine, methylpiper or dimethylpiperidin, preferably cyclobutane or 4 - methylpiper trap. In the present invention, the preferred R1 is a Cl_c6 alkyl group, and the Cl_c6 halogenated compound is substituted with one or two hydroxyl groups of Ci-Ce alkyl or amine mercapto group. Generally, when the general formula (la) is used, the more preferable R1 is an amine. Hyperthyroidism. When the formula (1) is - (lb), it is more preferable that R1 is a methyl group, a hydroxymethyl group or a 2-hydroxyethyl group. When (I) is a general formula (Ic), more preferably R1 is methyl, fluoromethyl, hydroxymethyl 2-hydroxyethyl or (1S)-1,2-dihydroxyethyl. In the present invention, 'preferably R2 is a phenyl group substituted at the 4-position or the 3-position via a group selected from C) Group C, and a 5-pyridyl group at the 2-position via a group selected from the substituent group C or 5 a 2-group substituted with a group selected from the group of substituents c (substituent group C is a group represented by a Ci-C6-homo-Ci-Ce-based fluorenyl-V_NR6R7 (V represents a carbonyl group or a sulfonium group) a group of R6, R7 or a different hydrogen atom or a Ci-Ce alkyl group), more preferably R2 methoxyphenyl, 2-methylaminomethyl-5-pyridyl, 4-methylsulfonate Styrene, sulfonyl-5-pyridinyl, 2-methylaminosulfonyl-5-pyrrolidyl, 5-methylpropionic acid pyridyl or 5-methylsulfonyl-2-pyrene base. The present invention is a saturated or 2-nitrogen protoplast, aza 1 group, a formula (1), a thiol group, a substituted group, a pyridyl group, and the same formula is 3-2-methyl-2 _ -31 · 201036962 When U is an oxygen atom, preferably R3 is an alkyl group which may be independently substituted by 1 to 5 halogen atoms or may be independently substituted by a group of 1 or 2 groups of (C3-C6 cycloalkyl and keto groups). It may contain 3 to 6 membered saturated rings of one oxygen atom or nitrogen atom. When U is a carbonyl group, it is preferably a Ci-Q alkyl group or a group represented by the formula -NR4R5 (R4, R5 represent the same or different hydrogen atom or alkyl group). In the present invention, a preferred group of the formula -NR4R5 is a dimethylamino group. In the present invention, the preferred formula -U-R3 represents a methoxy group, an ethoxy group, an isopropoxy group, (lS)-2-fluoro-1-methylethoxy group, a difluoromethoxy group, 1,3·Difluoro-2-propoxy, cyclopentan-2-yloxy, tetrahydrofuran-3-yloxy, 1-cyclopropylpyrrolidin-2-one-3-yloxy, different Propylcarbonyl or dimethylaminecarbonyl. In the present invention, a preferred group of the formula -NR6R7 is a methylamino group. In the present invention, preferred η is 1. In the present invention, a preferred substituent group VIII is a CrQ alkoxy group, a Cl_C6 alkylsulfonyl group and a group represented by the formula -V-NR6R7 (V represents a carbonyl group or a sulfonyl group, and R6 and R7 represent the same or different hydrogen atoms. Or a CrC6 alkyl group, more preferably the substituent group A is a methoxy group, a methylaminocarbonyl group, a methanesulfonyl group or a methylamine sulfonyl group. In the present invention, the preferred substituent group B is a halogen atom, and more preferably, the substituent group B is a fluorine atom. The compound of the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has all of the isomers (keto-enol tautomers, non-image isomers, optical isomers, rotamers ( Rotational isomer). The compound of the general formula (I) of the present invention or a pharmacologically acceptable salt of -32-201036962 has various isomers due to the presence of an asymmetric carbon atom in its molecule. In the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, general formula (I). Accordingly, the invention also includes all such isomers and mixtures of these isomers in any ratio. Ο

As the stereoisomer as described above, the compound of the present invention can be synthesized using an optically active starting material compound, or by asymmetric synthesis or asymmetric derivatization, or by conventional optical division or separation according to the desired separation. It is obtained by the compound related to the present invention. The compound of the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may contain an unnatural proportion of an isotope atom in one or more atoms constituting the compound. Examples of the isotope atom include ruthenium (2 Η), 氚 (3 Η), iodine - 1 2 5 (1 2 5 Ι), or carbon-14 (14C). Further, the prodrug compound may be radioactively labeled with a radioactive isotope such as hydrazine (3H), iodine- 1 2 5 (1 2 5 I) or carbon-14 (14C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, diagnostic agents (e.g., analytical reagents), and diagnostic agents (e.g., in vivo imaging diagnostics). All isotopic variations of the compounds of the invention, whether or not they are radioactive, are included within the scope of the invention. The "pharmaceutically acceptable salt" means a salt which can be used as a medicine as long as it has no significant toxicity. The compound of the general formula (I) of the present invention has a basic group which is reacted with an acid, and further has an acidic group to form a salt by reacting with a base. Examples of the salt of the basic group include hydrohalide salts such as hydrofluoric acid salt, hydrochloride salt, hydrobromide salt, and hydroiodide; nitrate, perchlorate, and sulfuric acid • 33-201036962 a mineral acid salt such as a salt or a phosphate; a CMC6 alkane sulfonate such as a methanesulfonate, a trifluoromethanesulfonate or an ethanesulfonate; a benzenesulfonate or a p-toluenesulfonate. Sulfonic acid salt: an acid salt of an acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc.; And an amino acid salt such as a glycinate, an aminate arginine, an alanate, a glutamate or an aspartate. On the other hand, examples of the acid group-based salt include alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and metals such as aluminum salts and iron salts. An inorganic salt such as a salt, an ammonium salt, a third octylamine salt, a dibenzylamine salt, a morpholin salt, a glucosamine salt, an alkyl phenylglycine salt, an ethylenediamine salt, N- Methyl glucosamine salt, sulfonium salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N, dibenzylethylenediamine salt, chloroprocaine salt, proca An amine salt such as an organic salt such as a procaine salt, a diethanolamine salt, an N-nodal phenethylamine salt, a piperene salt, a tetramethylammonium salt or a hydroxymethylamine amine methane salt; Amino acid salts such as glycinates, persalts, arginate, ornidamide, glutamine, aspartate. A compound having the compound of the general formula (I) of the present invention or a pharmacologically acceptable salt thereof, which is placed in the atmosphere or which absorbs water by recrystallization to adhere to water to form a hydrate, and such a hydrate is also included in the salt of the present invention. in. When a compound of the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is used as a solvate by absorbing some other solvent, these solvates are also included in the salt of the present invention. A compound having the general formula (I) of the present invention or a pharmacologically acceptable 201036962 salt thereof is preferably a compound having the general formula (I) of the present invention. In the present invention, the term "metabolic syndrome" means a condition based on insulin resistance, which significantly increases the pathological state of coronary artery disease factors through accumulation of a plurality of coronary vascular risk factors (sickness, diabetes, obesity of lifestyle-related diseases). , hypertension, etc.) (Diabetes, Obesity and Metabolism, 9, 2007, 246-258 'Journal of the American Medical Association, 285 · 2486-2497 (2001), Diabet. Med., 15: 539-553 (1998)) . [Effects of the Invention] 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 useful for use as a warm-blooded animal, preferably a mammal, including a human. Prevention of diabetes, abnormal sugar tolerance, gestational diabetes, chronic diabetes mellitus (including diabetic peripheral nerve dysfunction, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) and diseases of the group of metabolic syndrome Therapeutic medicine. Further, the novel compound represented by the general formula (I) provided by the present invention or a pharmacologically acceptable salt thereof has excellent GK activation and is useful for use as a warm-blooded animal (preferably a mammal, including a human). An active ingredient for the prevention and/or treatment of diseases. The preferred disease is diabetes or an abnormal ability to withstand sugar. It is preferably used as a therapeutic medicine for the above-mentioned diseases. [Embodiment] [Embodiment of the Invention] The compound of the general formula (I) of the present invention can be produced according to the A method to the U method described below. -35- 201036962 The solvent used in the reaction of each step from the A method to the U method is not particularly limited as long as it does not inhibit the reaction, and the starting material is dissolved to some extent, and is not particularly limited, for example, selected from the following solvent group. The solvent group is a hydrocarbon such as pentane, hexane, octane, petroleum ether, ligroin or cyclohexane; formamide, N,N-dimethylformamide, N,N- Indoleamines such as dimethylacetamide, N-methyl-2-pyrrolidone, N-methyl-2-pyrrolidone, trimethylamine hexamethylphosphate: diethyl ether, diisopropyl An ether such as ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether or cyclopentyl methyl ether; methanol 'ethanol, n-propanol, isopropanol, n-butyl Alcohol, 2-butanol, 2-methyl-1-propanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol, methyl racerus (11^11^ 1 (^11〇80 〇 〇 〇 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; Ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate or the like; acetone '2-butanone, 4-methyl-2-pentanone, methyl isobutyl ketone a ketone such as isophorone or cyclohexanone; a nitro compound such as nitroethane or nitrobenzene; Halogenated hydrocarbons such as methyl chloride, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, chloroform, carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, and xylene; acetic acid, formic acid, a carboxylic acid such as propionic acid, butyric acid or trifluoroacetic acid; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexyl Amine, N-methylpiperidine, pyridine, 2,6-lutidine, 4-pyrrolidinylpyridine, picoline, 4-dimethylaminopyridine, 2,6-di(t-butyl -4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene-36 - 201036962 (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 of these.

The base used in the reaction of each step of the A method to the U method is an alkali metal carbonate such as sodium carbonate, potassium carbonate, lithium carbonate or carbonic acid planing; sodium hydrogencarbonate, potassium hydrogencarbonate or lithium hydrogencarbonate. Alkali metal hydrogencarbonates; alkali metal acetates such as sodium acetate, potassium acetate, lithium acetate, acetic acid, etc.; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; sodium hydroxide, An alkali metal hydroxide such as potassium hydroxide, cesium hydroxide or lithium hydroxide; an inorganic base such as an alkali metal fluoride such as sodium fluoride, potassium hydride; sodium methoxide or ethoxylate Alkali alkali metal such as sodium, sodium butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide or lithium methoxide; sodium trimethyl sulfoxide, trimethyl a trialkylsulfonium oxide alkali metal such as potassium oxyhydroxide or trimethylsulfonium oxide; an alkali metal thiolate such as sodium methoxide or sodium ethoxide; N-methylmorpholine, Triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 2, 6-lutidine, 4-pyrrolidinylpyridine, picoline, 4-dimethylaminopyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N, N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4_3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2 _2] octane (anthraquinone 8 (: 〇), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and other organic bases; n-butyl lithium, two An organometallic base such as lithium isopropyl amide or lithium bis(trimethyldecyl) guanamine; or an amino acid such as lysine. -37- 201036962 The following steps from the A method to the U method The condensing agent used in the reaction is, for example, 0-(7-azabenzotriazol-1-yltetramethyluronium hexafluorophosphate (HATU), 1-propanephosphonic acid cyclic anhydrate (T3P) , dicyclohexylcarbodiimide (DCCD), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCI·HC1), 1-ethyl-3- (3-Dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC), 4- (4,6-dimethoxy-1,3,5-triso-2- -4-methylmorpholine hydrochloride η hydrate (DMT-MM), isobutyl chloroformate (IBCF), 1,1'-carbonyldi-1 fluorene-imidazole (CDI), cyanophosphonic acid diethyl Ester (DEPC), diphenyl azide (DPPA), hydrazine-hydroxysuccinimide, hydrazine-hydroxy-5-norbornene-2,3-dimethylimine or dipyridyl disulfide, If necessary, it may coexist with 1-hydroxybenzotriazole (HOBt) or 1-hydroxybenzotriazole monohydrate (H0Bt, H20). The following is used in the reaction of each step of the A method to the U method. The baseing agent is, for example, sodium methoxide, sodium ethoxide, sodium phenoxide, iodine trimethyl decane, aluminum chloride, aluminum bromide, boron tribromide, boron triiodide, iodine Based on magnesium, hydrogen bromide. The palladium catalyst used in the reaction of each step from the A method to the U method is, for example, ruthenium (triphenylphosphine) palladium (0), palladium-activated carbon, palladium (II) acetate, palladium (II) trifluoroacetate, Palladium black, palladium (II) bromide, palladium (II) chloride, palladium iodide (11), palladium cyanide (11), palladium (II) nitrate, palladium (II) oxide, palladium (II) sulfate, Chloro(diacetonitrile)palladium(11), dichlorobis(benzonitrile)palladium(II), dichloro(1,5-cyclooctadiene)palladium(II), acetonitrile acetone palladium(II), sulfide Palladium (II), [1,1,-bis(diphenylphosphino)ferrocene]palladium(II) chloride, bis(dibenzylideneacetone)dipalladium(0), hydrazine (acetonitrile)palladium ( II) Tetrafluoroborate-38-201036962 A zero-valent palladium catalyst or a divalent palladium catalyst such as a salt or a chlorinated aryl palladium dimer. The oxidizing agent used in the reaction of the following steps from the oxime method to the U method is an inorganic oxidizing agent such as m-chloroperbenzoic acid, hydrogen peroxide water, oxone or dioximetry. In the reaction of each step from the A method to the U method, the reaction temperature varies depending on the solvent, the starting material, the reagent, and the like, and the reaction time varies depending on the solvent, the starting material, the reagent, the reaction temperature, and the like. 〇 In the reaction of each step from the A method to the U method, after the end of the reaction, each compound of interest is collected from the reaction mixture in accordance with a conventional method. For example, by appropriately neutralizing the reaction mixture and removing the insoluble matter, the organic solvent mixed with water and ethyl acetate is added after the removal of the insoluble matter, and the organic layer containing the objective compound is separated, washed with water or the like, and dried. Magnesium sulfate, anhydrous sodium sulfate, etc., are dried, filtered, and the solvent is distilled off to obtain. The obtained target compound may be appropriately combined with a conventional method, for example, a method conventionally used for separation and purification of a usual organic compound such as recrystallization or reprecipitation, and subjected to chromatography, elution with an appropriate dissolving agent, and separation and purification. The compound which is insoluble in the solvent can be purified by washing the obtained crude solid product with a solvent. Further, the objective compound of each step may be used as it is without further purification in the next reaction. In the reaction of each step from the A method to the U method, Me represents a methyl group, iPr represents an isopropyl group, Ac represents an ethyl group, Bn represents a benzyl group, and Boc represents a third butoxycarbonyl group. The method A is a method for producing a compound of the formula (Id) wherein U is an oxygen atom in the compound of the general formula (I). -39- 201036962 A law

In the present invention, R2 and R3 have the same meanings as the above, R8 is a Cl-C6 group (preferably methyl or ethyl), and R9, R1Q, R11 and R12 are a hydrogen atom or a radical R'. Is a halogen atom (preferably a chlorine atom, a bromine atom or an iodine atom, more preferably an immobile atom) 'γ is a halogen atom, c丨_c6 alkylsulfonyloxy, Cl_c6 ortho-oxyloxy or C6-C1Q arylsulfonyloxy (preferably halogenogen-40-201036962, more preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom), R2a, R3a, R9a 'Rl〇a, Rlla And R12a represents an amine group, a hydroxyl group and/or a carboxyl group as a substituent contained in the group of r2, R3, R9, R10, R11 and R1 2 as a protected amine group, a hydroxyl group and/or a carboxyl group, and R2; The same groups as defined by the groups of R3, R9, R1Q, R11 and R12. Step A1 This step is a step of producing a compound of the general formula (III). 0 This step is carried out by reacting a compound of 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 a known compound which can be easily produced according to a method known from the starting material or a similar method. The solvent used in this step is preferably a guanamine, more preferably N,N-dimethylformamide or N-methyl-2-pyrrolidone. The demethylating agent used in this step is preferably sodium methoxide. The reaction temperature in this step is usually from 50 ° C to 140 ° C, preferably from 80 ° C to 12 (TC °. The reaction time in this step is usually from 0.5 to 12 hours, preferably from 1 hour to 5 hours. Step A2 This step is a step of producing a compound of the general formula (V). This step is carried out by reacting a compound of the general formula (III) with a compound of the general formula (IV) in the presence of a base in a solvent. -41 - 201036962 The compound of the general formula (IV) used in this step is a known compound, or a known compound which can be easily produced according to a method known from the starting material or a similar method. The solvent used in this step is preferably ruthenium. An amine or a nitrile, more preferably N,N-dimethylformamide or acetonitrile. The base used in this step is preferably an alkali metal carbonate, more preferably potassium carbonate or carbonic acid. The reaction temperature in this step Usually -lot: to 14 (TC, preferably 0 °c to 120. (: The reaction time in this step is usually from 0.5 to 7 2 hours, preferably from 1 hour to 48 hours. Step A3' This step is to manufacture a compound having the general formula (VI) This step is carried out by reacting a compound of the general formula (V) with a demethylating agent in a solvent. The solvent used in this step is preferably a halogenated hydrocarbon, more preferably dichloromethane. The demethylating agent used in the above is preferably boron tribromide. The reaction temperature in this step is usually -100 ° C to 40 ° C. Preferably, it is -78 ° C to 2 5 〇 C. The reaction time in this step is usually It is from 1 hour to 72 hours', preferably from 12 hours to 36 hours. Step A4 - 42 - 201036962 This step is a step of producing a compound of the general formula (VII). This step is in a solvent, a palladium catalyst. And the reaction of the compound of the general formula (VI) with the bis(pinacolato) diboron in the presence of an inorganic base. The solvent used in this step is preferably an amide, more preferably ruthenium. , Ν-dimethylformamide.

The palladium catalyst used in this step is preferably a II-valent palladium catalyst, more preferably [1, bis-bis(diphenylphosphino)ferrocene]palladium(II) chloride complex. . The inorganic base used in this step is preferably an alkali metal acetate, more preferably potassium acetate. The reaction temperature in this step is usually from 50 ° C to 130 ° C, preferably from 70 ° C to 110 ° C. The reaction time in this step is usually from 1 hour to 24 hours, preferably from 2 hours to 1 hour. Step A5 ◎ This step is a step of producing a compound having the general formula (IX). This step is carried out by reacting a compound of the general formula (VII) with a compound of the formula (VIII) in the presence of triphenylphosphine and diethyldiazodicarboxylate in a solvent. The compound of the formula (VIII) used in this step is a known compound or a known compound which can be easily produced according to a method known from the starting material or a method similar thereto. The solvent used in this step is preferably an ether, an aromatic hydrocarbon or a mixed solvent of -43 to 201036962, 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 〇 t to 25. . . The reaction time in this step is usually from 0.5 to 7 hours, preferably from 1 hour to 36 hours. Step A6 This step is a step of producing a compound of the general formula (XI). This step is carried out by reacting a compound of the formula (IX) with a compound of the formula (X) in the presence of a palladium catalyst and an inorganic base in a solvent. The solvent used in this step is preferably an ether, an alcohol, an aromatic hydrocarbon or a mixed solvent of these. More preferably, it is dioxane, ethanol, toluene or a mixed solvent thereof, and more preferably dioxane. Or a mixed solvent of ethanol and toluene. The palladium catalyst used in this step is preferably a II-valent palladium catalyst, more preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (11) dichloromethane. Things. The inorganic base used in this step is preferably an alkali metal carbonate, more preferably potassium carbonate, and still more preferably an aqueous potassium carbonate solution. The reaction temperature in this step is usually from 25 ° C to 10 (TC, preferably 40. (: to 7 (TC. The reaction time in this step is usually 〇 5 hours to 12 hours, preferably 1 hour to 5 hours). Step A7 This step is a step of producing a compound of the general formula (XII). -44 - 201036962 This step is carried out in a solvent via a compound having the general formula (xi) and a reaction. The solvent is preferably a halogenated hydrocarbon, more preferably dichloromethane. The acid used in this step is a hydrogen halide such as hydrogen chloride or hydrogen bromide; an inorganic acid such as sulfuric acid, hydrobromic acid or hydrochloric acid; An organic sulfonic acid such as sulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid pyridinium salt (PPTS), camphorsulfonic acid or trifluoromethanesulfonic acid: carboxylic acid such as acetic acid, formic acid or trifluoroacetic acid ; Lewis acid, such as aluminum chloride, zinc chloride, zinc iodide, tin tetrachloride, titanium trichloride, tri-» boron fluoride, boron tribromide, or acidic ion exchange resin, It is preferably a carboxylic acid, more preferably trifluoroacetic acid. The reaction temperature in this step is usually It is -20 ° C to 60 ° C, preferably 〇 ° C to 40 ° C. The reaction time in this step is usually from 1 hour to 5 hours, preferably from 0.5 hour to 3 hours. (J A8 Step This step is a step of producing a compound of the general formula (XIII). This step is carried out 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. More preferably, the base used in this step is preferably an alkali metal hydroxide, more preferably sodium hydroxide, more preferably an aqueous sodium hydroxide solution. The reaction temperature in this step is usually 25 ° C to 100 °. c, preferably from 50 ° C to -45 to 201036962 80 ° C. The reaction time in this step is usually from 1 hour to 24 hours, preferably from 0.5 hours to 6 hours. A step of producing a compound of the general formula (XV). This step is carried out in a solvent, in the presence of a condensing agent, in the presence or absence of a base, via a compound having the general formula (XIII) and a compound having the general formula (XIV). The reaction is carried out. The compound of the general formula (XIV) used in this step is used. It is a known compound' or a known compound which can be easily produced according to a method known from the starting material or the like. The solvent used in this step is preferably an alcohol, a halogenated hydrocarbon, a guanamine or a mixed solvent thereof. Preferably, it is methanol, dichloromethane, N,N-dimethylformamide or a mixed solvent of dichloromethane and hydrazine, hydrazine-dimethylformamide. The condensing agent used in this step is preferably DMT-MM. HATU or WSCI • HC1. When using WSCI, it is also possible to coexist HOBt or HOBT when using HC1. Η 2 0 The base used in this step is preferably an organic base, more preferably Ν-methylmorpholine, hydrazine, Ν-Diisopropylethylamine or 4-dimethylaminopyridine. The reaction temperature in this step is usually -20 ° C to 60 ° C, preferably 〇 ° C to 3 〇 t. The reaction time in this step is usually from 55 hours to 72 hours, preferably from 1 hour to 24 hours. -46 - 201036962 Step A10 This step is a step of producing a compound of the general formula (Id). This step is carried out by reacting a compound of the general formula (XV) with a base and methanesulfonic anhydride or bis(2-methoxyethyl)aminosulfur trifluoride in a solvent, and removing R2a, R3a, and R9a as needed. The protecting group of the amine group, the hydroxyl group and/or the carboxyl group in R1Qa, Rlla and R12a is carried out.

When the solvent used in this step is methanesulfonic anhydride, the ether is more preferably tetrahydrofuran or dimethoxyethane. When bis(2-methoxyethyl)aminosulfur trifluoride is used, it is preferably a halogenated hydrocarbon, more preferably dichloromethane. When the base used in this step is a methanesulfonic anhydride, it is preferably an organic base, which is more preferably triethylamine. When bis(2-methoxyethyl)aminosulfur trifluoride is used, an alkali metal carbonate is preferred, and potassium carbonate is more preferred. The reaction temperature in this step is usually -100 ° C to 85. (3) When using a phthalic acid anhydride, it is preferably from 10 ° C to 60 ° C. When bis(2-methoxyethyl)aminosulfur trifluoride is used, it is preferably from -7 8 ° C to 3 0° C. The reaction time in this step is usually from 0.5 to 72 hours, preferably from hr to 24 hours. The B method is in the compound of the general formula (I), wherein the 'U is an oxygen atom has a general formula ( Method for producing a compound of Id) -47- 201036962

In the present invention, R2, R3, R8, R9 and R1. R11, R12, R2a, R3a, Rh, R1Qa, Rib, R12a, X and γ have the same meanings as the above. Step B1 This step is a step of producing a compound of the general formula (XVI) 201036962. This step is carried out in the presence of a palladium catalyst and an inorganic base in a solvent, and has a general formula (V) via the A2 step A2 of the foregoing method. The compound is reacted with pinacol borate and is carried out in the same manner as in the step A4 of the A method described above. Step B2 This step is a step of producing a compound of the general formula (XVII).

This step is carried out in the same manner as in the step A6 of the above-mentioned method A, by reacting a compound of the formula (XVI) with a compound of the formula (X) in the presence of a palladium catalyst and an inorganic base in a solvent. Step B3 This step is a step of producing a compound of the general formula (XVIII). This step is carried out in the same manner as in the A8 step of the A method described above, by reacting a compound of the formula (XVII) with a base in a solvent. Step B4 This step is a step of producing a compound of the general formula (XIX). This step is carried out in a solvent, in the presence of a condensing agent, in the presence of a base or in the absence of a hydrazine, by reacting a compound of the general formula (XVIII) with a compound of the general formula (XIV), in the same manner as in the A9 step of the former A method. Conducted. Step B5 This step is a step of producing a compound of the general formula (XX). This step is carried out by reacting a compound of the general formula (XIX) with a base and methanesulfonic anhydride or bis(2-methoxyethyl)aminosulfur trifluoride in a solvent, and the first step A 1 0 of the method of A. The same goes on. Step B 6 -49- 201036962 This step is a step of producing a compound of the general formula (XXI). This step is carried out by reacting a compound of the general formula (XX) with a demethylating agent in a solvent in the same manner as in the step A3 of the above-mentioned A method. Step B7 This step is a step of producing a compound of the general formula (Id). This step is carried out by reacting a compound of the general formula (XXI) with a compound having the general formula (VHI) in the presence of triphenylphosphine and diethyldiazodicarboxylate in a solvent, and the fifth step of the pre-recording method. In the same manner, it is carried out by removing the protective groups of the amine group, the hydroxyl group and/or the carboxyl group in R2a, R3a, R9a, R10a, Ruler 113 and R12a as needed. Step B 8 This step is a step of producing a compound of the general formula (Id). This step is carried out by reacting a compound of the general formula (XXI) with a compound of the general formula (XXII) in the presence of a base to remove the amines of R2a, R3a, R9a, R10a, 11113 and R12a* as needed. The protecting group of the group, the hydroxyl group and/or the carboxyl group is carried out. The compound of the formula (XXII) which is used in the present step is a known compound, or a known compound which can be easily produced in accordance with a method known from the starting material or a method similar thereto. The solvent used in this step is preferably a guanamine or a ketone', more preferably n, n-dimethylformamide or 2-butanone. The base used in this step is preferably an alkali metal carbonate. More preferably, it is potassium carbonate. 0-50-201036962 The reaction temperature in this step is usually from 25 ° C to 120 ° C, preferably from 40 ° C to 80 ° C. C. The reaction time in this step is usually from 1 hour to 72 hours, preferably from 6 hours to 48 hours. The C method is a method for producing a compound of the formula (Id) in which a compound of the general formula (I) and U is an oxygen atom. 201036962 C method Η0\γ/^χ Step C l, R3a-Y (XXI!)

Step C2 OH (XXIV)

OMe (III)

Step C 6 τ Cl—Si(iPr( (XXVIII)

Step C5

(XXX) Step C 8 r93 Rl〇a h2n

Step C9 R

(XXXII) R12a OH p11a', r123 (XIV) (XXXI) R12a R11a Rl0a Step C 1 0 - 12

R

Step C 1 1 - R2a-Y~ • (IV) (XXXIII) R R3

R 11 )10 In the present invention, R2, R3, R9, R10, R11, R12, R2a, R3a, R9a, -52- 201036962

RlQa, Rlla, R12a, x and y have the same meaning as the foregoing. Step ci This step is a step of producing a compound of the general formula (XXIII). This step is carried out in the same manner as in the step B8 of the above-mentioned B method, by reacting a compound of the formula (III) obtained in the first step of the first step in a solvent with a compound of the formula (XXII). Step C2 Step 0 This step is a step of producing a compound of the general formula (XXIV). This step is carried out by reacting a compound of the general formula (XXIII) with a demethylating agent in a solvent in the same manner as in the first step A1 of the method A. Step C 3 This step is a step of producing a compound of the general formula (XXV). This step is carried out by reacting a compound having the general formula (XXIV) with a pinacol borate in the presence of a palladium catalyst and an inorganic base in a solvent, in the same manner as in the step A4 of the above-mentioned A method. 〇 Step C4 This step is a step of producing a compound of the general formula (χχνπ). This step is carried out in the same manner as in the "palladium catalyst and the inorganic base" in the solvent via the reaction of the compound of the general formula (XXV) with the compound of the general formula (XXVI) in the same manner as in the sixth step of the preceding method. The compound of the formula (XXVI) used in this step is a known compound, or a known compound which can be easily produced according to a method known from the starting material or a method similar thereto. -53- 201036962 Step C5 This step is a step of producing a compound of the general formula (XX VIII). This step is carried out by reacting a compound having the general formula (XXVII) with an acid in a solvent in the same manner as in the step A7 of the above-mentioned A method. Step C6 This step is a step of producing a compound of the general formula (XXIX). This step is carried out by reacting a compound of the general formula (XXVI11) with triisopropyl decane chloride in the presence of a base in a solvent. The solvent used in this step is preferably a halogenated hydrocarbon, more preferably methylene chloride. The base used in this step is preferably an organic base, more preferably triethylamine or a mixed base of triethylamine and 4-dimethylaminopyridine. The reaction temperature in this step is usually -10 ° C to 4 (TC, preferably 〇 ° C to 30 ° C. The reaction time in this step is usually 0.1 hour to 72 hours, preferably 0.5 hour to 2 4 hours. Step C7 This step is a step of producing a compound of the general formula (XXX). This step is carried out by reacting a compound of the general formula (XXIX) in the presence of a palladium catalyst in a solvent under a hydrogen atmosphere. The solvent used in this step is preferably an ether, an alcohol, an ester or a mixed solvent of the above, more preferably tetrahydrofuran 'methanol, ethanol, ethyl acetate or a mixed solvent of ethanol and ethyl acetate. -54- 201036962 The palladium catalyst used in this step is preferably a palladium catalyst of valence, more preferably palladium-activated carbon. The reaction temperature in this step is usually -lot to 40 ° C, preferably 〇 ° c to 3 0 〇C. The reaction time in this step is usually from 0.1 to 72 hours, preferably from 0.5 to 24 hours.

This step is a step of producing a compound of the general formula (XXXI). This step is carried out by reacting a compound having the general formula (XXX) with a compound having the general formula (XIV) in the presence of a condensing agent in the presence of a condensing agent, in the presence of a base, or in the same manner as in the step A9 of the foregoing method A. get on. Step C9 This step is a step of producing a compound of the general formula (XXXII). This step is carried out by reacting a compound of the general formula (XXXI) with a base and methanesulfonic anhydride or bis(2-methoxyethyl)aminosulfur trifluoride in a solvent, and the first A 1 0 of the A method. The steps are carried out in the same manner. Step CIO This step is a step of producing a compound of the general formula (XXXIII). This step is carried out by reacting a compound of the general formula (XXXII) with tetrabutylammonium fluoride in a solvent. The solvent used in this step is preferably an ether, more preferably tetrahydrofuran. The reaction temperature in this step is usually from -10 ° C to 40 °. (:, preferably 0 °c to 30 ° C. -55- 201036962 The reaction time in this step is usually from 1 hour to 12 hours, preferably from 0.5 hours to 3 hours. The step is a step of producing a compound of the general formula (Id). This step is carried out 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, and the first method of the method A After the step A2 is carried out in the same manner, it is carried out by removing the protecting groups of the amino group 'hydroxyl group and/or the carboxyl group of 'Ri〇a' 11113 and R12a* as needed. The D method is a general formula (XIII) used in the A9 step of the former A method. a method for producing a compound.

In the present invention, 'R2a, R3a, X and Y have the same meanings as the above. Step D1 This step is a step of producing a compound of the general formula (XXXIV). This step can be carried out (0 or (ii). (i) This step is carried out in the presence of triphenylphosphine and diethyldiazodicarboxylate in a solvent, and has the general formula (VI) obtained by the A3 step of the A method described above. Compound-56-201036962 is reacted with a compound of general formula (VIII) in the same manner as step A5 of the foregoing method A. (ii) This step is carried out in a solvent in the presence of a base via the general formula (VI) The compound is reacted with a compound of the general formula (XXII) in the same manner as the step B8 of the above-mentioned method B. The step D2 is a step of producing a compound having the general formula (XXXV). ^ This step is in a solvent. a compound having the general formula (XXXIV) and 5-(4,4,5,5-tetramethyl-1,3,2·dioxacyclopentane-2-yl group in the presence of a palladium catalyst and an inorganic base The solvent used in the step is preferably an ether, more preferably dioxane. The palladium catalyst used in this step is preferably a divalent palladium. More preferably, the catalyst is [1, bis-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex. The alkali is preferably an alkali metal carbonate, more preferably potassium carbonate, more preferably an aqueous potassium carbonate solution. Q The reaction temperature in this step is usually from 25 ° C to 10 ° C, preferably from 40 ° C to 70 〇 C. The reaction time in this step is usually from 0.5 to 12 hours, preferably from 1 hour to 5 hours. Step D3 This step is a step of producing a compound having a general formula (χπι). The reaction is carried out in a solvent under a hydrogen atmosphere via a compound of the general formula (XXXV) in the presence of a fine catalyst, and is carried out in the same manner as in the procedure of C7-57-201036962 of the above-mentioned C method. The E method is used in the A9 step of the former A method. A method for producing a compound of the general formula (XIII) -58- 201036962

In the present specification, R8, R2a, R3a, X and γ have the same meaning as the foregoing. Step 1 Step This step is a step of producing a compound of the general formula (XXX VI). This step is the reaction of the compound of the general formula (XXV) with the compound of the general formula (X) obtained in the presence of a palladium catalyst and an inorganic base in a solvent, and the step 6 of the pre-report method. The same goes on. Step 2 This step is a step of producing a compound of the general formula (XXXVII). This step is carried out in the same manner as in the seventh step of the foregoing method, by reacting a compound having a general formula (??) with an acid in a solvent. Step E3 This step is a step of producing a compound having the general formula (xxxvm). -59- 201036962 This step is carried out in the same manner as in the above, in the presence of a base, by reacting a compound of the general formula (XXXVII) with a compound of the formula (IV) in the same manner as in the step A2 of the above-mentioned A method. Step E4 This step is a step of producing a compound of the general formula (XIII). This step is carried out by reacting a compound having the general formula (XXXVIII) with a base in a solvent, in the same manner as in the A8 step of the above-mentioned A method. The F method is a method for producing a compound of the general formula (XIII) used in the first step A9 of the method A.

In the present invention, R2a, R3a and Y have the same meanings as the above. Step F1 This step is a step of producing a compound of the general formula (XXXV). This step is carried out in the same manner as in the case of a base, in the presence of a base, a compound of the formula (XXVIII) obtained by the above-mentioned C method, and a compound of the formula (IV), which is reacted in the same manner as in the step A2 of the above-mentioned method A. Step F2 -60- 201036962 This step is a step of producing a compound of the general formula (XI11). This step is carried out in the presence of a catalyst in a solvent under a hydrogen atmosphere via a compound of the formula (XXXV) in the presence of a pin catalyst, in the same manner as in the above step C7 of the method C.

The G method is a method for producing a compound of the general formula (XVIII) used in the step B4 of the B method.

Step G 4 In the present invention, R2a, X and Y have the same meanings as those described above. Step G1 This step is a step of producing a compound of the general formula (XXXIX). This step is carried out in the presence of a palladium catalyst and an inorganic base in the presence of a palladium catalyst and an inorganic base, and the compound of the general formula (ΙΠ) obtained in the first step A1 is reacted with the benzoic acid pinacol ester in the same manner as in the fourth step of the pre-recording method. get on. -61 - 201036962 Step G2 This step is the step of manufacturing compound (XL). This step is carried out by reacting a compound (XXXIX) with a compound of the general formula (XXVI) in the presence of a palladium catalyst and an inorganic base in a solvent, in the same manner as in the step A6 of the above-mentioned A method. Step G3 This step is a step of producing a compound of the general formula (XLI). This step is carried out by reacting a compound (XL) with a compound of the general formula (IV) in the presence of a base in the presence of a base, in the same manner as in the step A2 of the above-mentioned A method. Step G4 This step is a step of producing a compound of the general formula (XLII). This step is carried out by reacting a compound having the general formula (XLI) with an acid in a solvent, in the same manner as in the step A7 of the above-mentioned A method. Step G5 This step is a step of producing a compound of the general formula (XVIII). This step is carried out in the presence of a palladium catalyst in a solvent under a hydrogen atmosphere in the presence of a palladium catalyst having a general formula (XLII) in the same manner as in the above step C7 of the method C. The oxime method is a method for producing a compound of the general formula (XXVIII) used in the first step C6 of the method C. -62- 201036962

This step is a step of producing a compound of the general formula (XXVIII). This step is a compound having the general formula (χχιν) and 5-(4,4,5,5-tetramethyl-1, obtained in the presence of a palladium catalyst and an inorganic base in a solvent, by the method of the C step C2. The reaction of 3,2-dioxacyclopentane-2-yl)-4-indolylpyrrole-2-carboxylic acid benzyl ester was carried out in the same manner as in the step D2 of the above-mentioned D method. The I method is a method for producing a compound of the general formula (XXIV) used in the first step C3 of the method C.

X Step I 1 R3a-〇H (IV)

X step I 2

In the present invention, 113!1 and X are in the same meaning as the above. Step 本 This step is a step of producing a compound of the general formula (XLIV). This step is carried out by reacting a compound having the general formula (XLIII) with a compound having the general formula (IV) in the presence of triphenylphosphine and diethyldiazodicarboxylate in the solvent, and the A5 step of the method of the former A method. The same goes on. The compound of the general formula (XLIII) used in this step is a known compound of -63 to 201036962, or a known compound which can be easily produced according to a method known from the starting material or the like. Step 12 This step is a step of producing a compound of the general formula (XXIV). This step is carried out by reacting a compound of the general formula (XLIV) with trimethyl borate in a solvent in the presence of a base, and further reacting with acetic acid and an oxidizing agent. The solvent used in this step is preferably an ether, more preferably diethyl ether. The base used in this step is preferably an organometallic salt group, more preferably n-butyllithium. The oxidizing agent used in this step is more preferably an inorganic oxidizing agent, more preferably 30% hydrogen peroxide water. The reaction temperature in this step is usually from -12 ° C to 40 ° C, preferably from -78 ° C to 25 °. . . The reaction time in this step is usually from 1 hour to 48 hours', preferably from 6 hours to 24 hours. The J method is a method for producing a compound of the general formula (Ie) wherein the U is a carbonyl group in the compound of the general formula (I). -64- 201036962

In the present invention, R2, R3, R8, R9, R10, R11, R12, R2a, R9a, -65-201036962 R_, Rlla, Rl2a, χ and γ have the same meanings as the above. Step J1 This step is a step of producing a compound of the general formula (XLVI). This step is carried out in the same manner as in the step A2 of the preceding method by reacting a compound of the general formula (XLV) with a compound of the general formula (IV) in the presence of a base. The compound of the general formula (XLV) used in this step is a known compound, or a known compound which can be easily produced according to a method known from the starting material or a similar method. Step J2 This step is a step of producing a compound of the general formula (XLVIII). This step is carried out by reacting a compound having the general formula (XLVI) with a compound having trifluoromethanesulfonic anhydride (XLV II) in the presence of a base in a solvent. The solvent used in this step is preferably a halogenated hydrocarbon, more preferably methylene chloride. The base used in this step is preferably an organic base, more preferably pyridine. The reaction temperature in this step is usually -20 ° C to 40 ° C, preferably 〇 ° C to 25 ° C. The reaction time in this step is usually from 0.5 to 12 hours', preferably from 1 hour to 6 hours. First Step This step is a step of producing a compound of the general formula (XLIX). -66 - 201036962 This step is carried out in the presence of a palladium catalyst and an inorganic base in the presence of a palladium catalyst and an inorganic base, via the compound of the general formula (XLVIII) and the benzoic acid pinacol ester, in the same manner as in the A4 step of the foregoing method A. Step J4 This step is a step of producing a compound of the general formula (L). This step is carried out by reacting a compound having the general formula (XLIX) with a compound having the general formula (XXVI) in the presence of a palladium catalyst and an inorganic base in a solvent, and

Step A6 of the foregoing method A is performed in the same manner. Step J5 This step is a step of producing a compound of the general formula (LI). This step is carried out by reacting a compound having the general formula (L) with an acid in a solvent in the same manner as in the step A7 of the above-mentioned A method. Step J6 This step is a step of producing a compound of the general formula (LII). This step is carried out in the presence of a palladium catalyst in a solvent under a hydrogen atmosphere in the presence of a palladium catalyst having a general formula (LI) in a solvent, in the same manner as in the above step C7 of the method C. This step is a step of producing a compound of the general formula (LIII). This step is carried out in the presence of a condensing agent, in the presence of a condensing agent, in the presence or absence of a base, by reacting a compound of the general formula (LII) with a compound of the general formula (XIV), in the same manner as in the step A9 of the foregoing method A. . Step J8 -67- 201036962 This step is a step of producing a compound of the general formula (LI V). This step is carried out by reacting a compound of the general formula (LIII) with a base and methanesulfonic anhydride or bis(2-methoxyethyl)aminosulfur trifluoride in a solvent, and the A 1 0 step of the former A method. The same goes on. Step J9 This step is a step of producing a compound of the general formula (Ie). In this step, after converting R8〇 of the compound of the general formula (LIV) into R3a (R3a is in the same sense as the above), the amine group, hydroxyl group and/or carboxyl group in R2a, R3a, R9a and R12a are removed as needed. The protection base is carried out. The postscript L method is an example of this J9 step. The K method is a method for producing a compound of the general formula (Ie) wherein u is a carbonyl group in the compound of the general formula (I). -68- 201036962

K method Ο

OH

OMe (LVII) Ο Step K2

(LVIII) Step 1, R3a-MgX (LVI) o o

OH

In the present invention, R2, R3, R9, R10, R11, R12, R2a, R3a, R9a, R1()a, Rlla, R12a, X and Y have the same meanings as those described above. -69- 201036962 Step κι This step is a step of producing a compound of the general formula (LV11). This step is carried out by reacting 3,5-dimethoxybenzaldehyde (LV) with a compound of the general formula (LVI) in a solvent. The compound of the formula (LVI) used in this step is a known compound, or a known compound which can be easily produced according to a method known from the starting material or a method similar thereto. The solvent used in this step is preferably an ether, more preferably tetrahydrofuran. The reaction temperature in this step is usually -110 ° C to 40 ° C, preferably -80 ° C to 2 5 . . . The reaction time in this step is usually from 0.5 to 12 hours, preferably from 1 hour to 6 hours. Step K2 This step is a step of producing a compound of the general formula (LVIII). This step is carried out by reacting a compound of the general formula (LV 11) with an oxidizing agent in a solvent. The solvent used in this step is preferably a halogenated hydrocarbon, more preferably methylene chloride. The oxidizing agent used in this step is preferably an inorganic oxidizing agent, more preferably manganese dioxide. The reaction temperature in this step is usually from 〇 ° C to 60 ° C, preferably from 25 ° C to 40 °. . ° The reaction time in this step is usually from 6 hours to 72 hours, preferably from 1 2 to 70 to 201036962 hours to 36 hours. Step K3 This step is a step of producing a compound having the general formula (LIX). This step is carried out by reacting a compound having the general formula (LVIII) with a demethylating agent in a solvent, in the same manner as in the step A1 of the above-mentioned A method. Step K4 This step is a step of producing a compound of the general formula (LX).

This step is carried out in the presence of a base in the presence of a base via a compound of the formula (LIX) and a compound of the formula (IV), in the same manner as in the step A2 of the above-mentioned A method. Step K5 This step is a step of producing a compound of the general formula (LXI). This step is carried out by reacting a compound having a general formula (LX) with a demethylating agent in a solvent, in the same manner as in the step A3 of the above-mentioned A method. Step K6 This step is a step of producing a compound of the general formula (LXII). This step is carried out in the same manner as in the presence of a base, by reacting a compound of the formula (LXI) with a compound having trifluoromethanesulfonic anhydride (XLVII) in the same manner as in the J2 step of the above-mentioned J method. Step K 7 This step is a step of producing a compound having the general formula (LXIII). This step is carried out in the same manner as in the presence of a palladium catalyst and an inorganic base in the presence of a palladium catalyst and an inorganic base, by reacting a compound of the general formula (LXII) with a benzoic acid pinacol ester, in the same manner as in the above-mentioned step A4 of -71 - 201036962. Step K 8 This step is a step of producing a compound of the general formula (LXIV). This step is carried out in the same manner as in the above, in the presence of a palladium catalyst and an inorganic base, by reacting a compound of the general formula (LXIII) with a compound of the general formula (XX VI) in the same manner as in the A6 step of the A method described in the foregoing. Step K9 This step is a step of producing a compound of the general formula (LXV). This step is carried out by reacting a compound having a general formula (LXIV) with an acid in a solvent, in the same manner as in the step A7 of the above-mentioned A method. Step K1 0 This step is a step of producing a compound of the general formula (LXVI). This step is carried out in the presence of a palladium catalyst in a solvent under a hydrogen atmosphere in the presence of a palladium catalyst having a general formula (LXV) in the same manner as in the above step C7 of the method C. Step K1 1 This step is a step of producing a compound of the general formula (LX VII). This step is carried out by reacting a compound having the general formula (LX VI) with a compound having the general formula (XIV) in the presence of a condensing agent, in the presence of a base, in the presence or absence of a base, in the same manner as in the step A9 of the foregoing method A. get on. Step K 1 2 This step is a step of producing a compound of the general formula (Ie). This step is carried out by reacting a compound of the general formula (LX VII) with -72-201036962 base and methanesulfonic anhydride or bis(2-methoxyethyl)aminosulfur trifluoride in a solvent. The A10 step is performed in the same manner. The L method is a method for producing a compound of the general formula (If) in which the compound of the formula (1), u is a carbonyl group, and r3 is a group represented by the formula -NR4R5. L method

In the present invention, R2, R4, R5, R8, R9, R10, R11, R12, R2a, R9a, Rl〇a, 尺118 and Rl2a have the same meaning as the above, and R4a and R5a are contained in R4 and R5. The amine group as a substituent in the group is the same group as the group defined by the groups of R4 and R5, other than the protected amine group. Step L1 This step is a step of producing a compound of the general formula (LX VIII). _ This step is carried out by reacting a compound of 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 an ether or an alcohol, more preferably tetrahydrofuran or ethanol. The base used in this step is preferably an alkali metal hydroxide ‘more preferably hydrogen-73- 201036962 sodium oxide or lithium hydroxide, more preferably an aqueous sodium hydroxide solution or a lithium hydroxide aqueous solution. The reaction temperature in this step is usually from 0 ° C to 100 ° C, preferably from 25 ° C to 70 ° C. The reaction time in this step is usually from 0.5 to 24 hours, preferably from 1 hour to 12 hours. Step L2

This step is a step of producing a compound having the general formula (If). This step is carried out by reacting a compound having the general formula (LX VIII) with a compound having the general formula (LXIX) in the presence of a condensing agent in the presence of a condensing agent, in the presence or absence of a base, and optionally removing R2a, R4a, R5a, The protecting group of the amine group, the hydroxyl group and/or the carboxyl group in R9a, R1()a, 11113 and 11128 is carried out. The compound of the general formula (LX IX) used in this step is a known compound, or a known compound which can be easily produced in accordance with a method known from the starting material or the like. The solvent used in this step is preferably a guanamine, an alcohol or a halogenated hydrocarbon, (I is more preferably n, n-dimethylformamide, methanol or dichloromethane. The condensing agent used in this step is more preferred. Preferably, it is WSCI · HC1, DMT-MM or HATU. The base used in this step is preferably an organic base, more preferably triethylamine, diisopropylethylamine or triethylamine and 4-dimethyl The reaction temperature in this step is usually -20 ° C to 40 ° C, preferably 〇 ° C to 25 ° C. -74- 201036962 The reaction time in this step is usually from 1 hour to 72 The hour is preferably from 6 hours to 36 hours. The hydrazine method is a method for producing a compound of the general formula (LI) used in the J6 step of the J method.

In the present invention, R8 is the same as the above. Step M1 This step is a step of producing a compound of the general formula (LI).

This step is a compound of the general formula (xLVIII) and 5-(4,4,5,5-tetramethyl-1,3, obtained in the presence of a palladium catalyst and an inorganic base in a solvent, by the procedure J2 of the previous method. The reaction of 2-benzylindole pentaborolan-2-yl)-1Η-pyrrole-2-carboxylic acid benzyl ester is carried out in the same manner as in the step D2 of the above-mentioned D method. The N method is a method for producing a compound of the general formula (X) used in the first step A6 of the method A, the step B2 of the method B, and the step E1 of the method of the first step E. N method

-75- 201036962 In the present invention, 'R8 and X' have the same meaning as the above. Step N1 This step is a step of producing a compound of the general formula (LXXI). This step is carried out by reacting a compound of the general formula (LXX) with a halogenating agent in a solvent. The compound of the formula (LXX) used in this step is a known compound, or a known compound which can be easily produced according to a method known from the starting material or a method similar thereto. The solvent used in this step is preferably a mixed solvent of an ether or an ether and an alcohol, more preferably tetrahydrofuran or a mixed solvent of tetrahydrofuran and methanol. The halogenating agent used in this step is an inorganic acid such as hydrochloric acid, hydrogen bromide or hydrogen iodide, a halogen molecule such as chlorine, bromine or iodine or N-chlorobutaneimine or N-bromobutane. The butadiene imine such as quinone imine or N-iodobutyl ruthenium imide is preferably dibutylimine, more preferably N-bromobutylimine. 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 from 0.5 to 48 hours, preferably from 1 hour to 24 hours. Step N2 This step is a step of producing a compound of the general formula (X). This step is carried out by reacting a compound of the general formula (LXXI) with ditributyl dicarbonate in the presence of a base in a solvent. The solvent used in this step is preferably a halogenated hydrocarbon, more preferably a dichloromethyl-76-201036962 alkane. The base used in this step is preferably an organic base, more preferably triethylamine, 4-dimethylaminopyrene or a mixed base, and more preferably triethylamine and 4-dimethyl A mixed base of aminopyridine. The reaction temperature in this step is usually -2 ° C to 40 ° C, preferably 0 ° C to 25 ° C.

The reaction time in this step is usually from 1 hour to 12 hours, preferably from 5 hours to 3 hours. The oxime method is a method for producing a compound of the general formula (XXVI) used in the first step C4 step C, the pre-g method G2 step, the pre-J method J4 step, and the pre-record κ method step K8. Law

(XXVI) 翌1 Step · Step 2 Step j X-C02Bn Less (LXX 丨V) Winter (LXX ... (LXXIIi) In the present invention, 'X is the same as the above-mentioned thing. Step 1 This step is manufacturing A step of a compound of the general formula (LXXIII). This step is carried out in the same manner as in the first step N1 of the N method described above by reacting a pyrrole-oxime-carboxylic acid tert-butyl ester (LXXII) with a halogenating agent in a solvent. The pyrrole-oxime-carboxylic acid tert-butyl ester (LXXII) used in the present invention is a known compound which can be easily produced according to a method known from the starting material or a similar method. -77- 201036962 Step 02 This step is manufactured by having a general formula ( Step of Compound of XXVI) This step is carried out by reacting a compound of the general formula (LXXIII) with a compound of the general formula (LXXIV) in the presence of a base in a solvent. The general formula (LXXIV) is used in this step. The compound is a known compound, or a known compound which can be easily produced according to a method known from the starting material or a similar method. The solvent used in this step is preferably an ether, more preferably diethyl ether. The base to be used is preferably an organometallic salt group, more preferably n-butyl lithium. The reaction temperature in this step is usually from -100 ° C to 40 ° C, preferably from -78 ° C to 25 %. The reaction time in the step is usually from 0.5 hours to 24 hours, preferably from i hours to 12 hours. The P method is the first step D2 of the D method, the first step H1 of the first method, and the first step of the first step of the M1 step. -Method for producing (4,4,5,5-tetramethyl-1,3,2,dioxacyclopentan-2-yl)-1,4-indole-2-carboxylate (LXXVIII). law

(LXXVIII) Η 0 (LXXVI) (LXXV) In the present invention, Υ is synonymous with the foregoing. Step 1 This step is a step of producing benzyl 1 -pyrrole-2-carboxylate (LXXVII). -78- 201036962 This step is carried out by reacting a pyrrole-2-carboxylic acid (LXXV) with a compound of the general formula (LXXVI) in the presence of a base in a solvent. The pyrrole-2-carboxylic acid (LXXV) used in this step is a known compound which can be easily produced in accordance with a method known from the starting material or a similar method. The compound of the general formula (LXXVI) used in this step is a known compound, or a known compound which can be easily produced in accordance with a method known from the starting material or the like.

The solvent used in this step is preferably an guanamine, more preferably ruthenium, dimethyl dimethylformamide. The base used in this step is preferably an alkali metal carbonate, more preferably potassium carbonate. The reaction temperature in this step is usually -10 ° C to 40 ° C, preferably 0 ° c to 25 ° C. The reaction time in this step is usually from 0.5 to 48 hours, preferably from 1 hour to 24 hours.

This step is to produce benzyl 5-(4,4,5,5·tetramethyl-1,3,2-dioxacyclopentan-2-yl)-1Η-pyrrole-2-carboxylate (LXXVIII). A step of. This step is carried out in the presence of a ruthenium catalyst and a 4,4'-di-t-butyl-2,2'-dipyridyl group via 1H-pyrrole-2-carboxylic acid benzyl ester (LXX VII). The boronic acid pinacol ester reaction is carried out. The solvent used in this step is preferably a hydrocarbon, more preferably hexane. The ruthenium catalyst used in this step is preferably a methoxy (cyclooctadiene) ruthenium (I)-79-201036962 dimer. The reaction temperature in this step is usually from 〇 ° C to 70 ° C, preferably from 25 t to 60. . . The reaction time in this step is usually from 0.1 to 12 hours, preferably from 5 hours to 6 hours. The Q method is a method for producing a compound of the formula (Id) wherein U is an oxygen atom in the compound of the general formula (I). Q method

(Id) In the present invention, R2, R3, R8, R9, R1G, R11, R12, R2a 'R3a' R9a, R1()a, Rlla, R12a and Y have the same meanings as the above. Step Q1 This step is a step of producing a compound of the general formula (LXXX). This step is a compound having the general formula (XIII) obtained by the first 13 A8 step in a solvent, a condensing agent and a base, and having a general formula. The compound reaction of (LXXIX) was carried out in the same manner as in the A9 step of the above-mentioned A method. -80-201036962 The compound having a formula (LXXIX) used in this step is a known compound or a known compound which can be easily produced according to a method known from the starting material or the like. Step Q2 This step is a step of producing a compound of the general formula (Id). This step is carried out by reacting a compound having the general formula (LXXX) with a base in a solvent, and removing R2a, R3a, R9a, R1Ga, Rlla and R12a as needed.

The solvent used in the step of the amine group, the hydroxyl group and/or the carboxyl group is preferably an ether, more preferably tetrahydrofuran. The base used in this step is preferably an alkali metal hydride, more preferably sodium hydride. The reaction temperature in this step is usually -20 ° C to 40 ° C, preferably 0 T: to 25. (: The reaction time in this step is usually from 5 hours to 48 hours, preferably from 1 hour to 24 hours. The rule method is a method for producing a compound of the general formula (LI) used in the J6 step of the above J method. -81 - 201036962 R method

In the present invention, R8, R2a and X have the same meanings as the above. Step R1 This step is a step of producing a compound of the general formula (LXXXII). This step is carried out in a solvent, in the presence of a palladium catalyst and an inorganic base, via a compound of the general formula (LXXXI) with 5_(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentyl boron The reaction of benzyl-2-yl)-1Η-pyrrole-2-carboxylate is carried out in the same manner as in the step D2 of the above-mentioned D method. The compound of the general formula (LXXXI) used in this step is a known compound' or a known compound which can be easily produced according to a method known from the starting material or the like. Step R2 This step is a step of producing a compound of the general formula (LI). This step is carried out by reacting a compound having the general formula (LXXXII) with a compound having the general formula (Lxxxni) in the presence of a copper catalyst 'alkali and molecular sieve 4A in a solvent. -82- 201036962 The compound of the general formula (LXXXIII) used in this step is a known compound, or a known compound which can be easily produced according to a method known from the starting material or a method similar thereto. The solvent used in this step is preferably a halogenated hydrocarbon, more preferably methylene chloride. The copper catalyst used in this step is preferably copper (II) acetate. The base used in this step is preferably an organic base, more preferably triethylamine. 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 from 12 to 360 hours, preferably from 24 to 240 hours. The S method is a method for producing a compound of the general formula (LXVI) used in the K11 step of the K method. S method

In the present invention, R2a and R3a have the same meanings as those described above. Step S1 -83- 201036962 This step is a step of producing a compound having the general formula (LXXXIV). This step is a compound of the general formula (LXII) and 5-(4,4,5,5-tetramethyl-l,3) obtained in the presence of a palladium catalyst and an inorganic base in a solvent via the K6 step of the K method. The methyl 2-mercaptocyclopentan-2-yl)-lH-pyrrole-2-carboxylate is reacted. The solvent used in this step is preferably an ether, more preferably dioxane. The palladium catalyst used in this step is preferably a palladium catalyst of valence, more preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (methylene chloride). Things. The inorganic base used in this step is preferably an alkali metal carbonate, more preferably potassium carbonate, and still more preferably an aqueous potassium carbonate solution. The reaction temperature in this step is usually from 25 ° C to 10 (TC, preferably from 4 ° C to 70 °. The reaction time in this step is usually from 〇 5 hours to 12 hours, preferably 1 hour to 5 hours. Step S2 This step is a step of producing a compound of the general formula (LX VI). This step is carried out by reacting a compound of the general formula (LXXXIV) with a base in a solvent. Preferably, it is a mixed solvent of ethers or ethers and alcohols, more preferably tetrahydrofuran or a mixed solvent of tetrahydrofuran and methanol. The base used in this step is preferably an alkali metal hydroxide, more preferably lithium hydroxide. More preferably, it is an aqueous solution of lithium hydroxide. The reaction temperature in this step is usually up to 1 ° C, preferably from 25 ° C to -84 to 70. (: . . 201036962 The reaction time in this step is usually from 0.5 to 24 The hour is preferably from 1 hour to 12 hours. The T method is a method for producing a compound of the general formula (LXXXIV) used in the first step S2 of the S method.

0

(LXXXV) A T 1 step R2a-〇H (LXXXVI)

(LXXXIV) In the present invention, R2a, 1133 and X have the same meanings as the above.

Step T1 This step is a step of producing a compound of the general formula (LXXXVII). This step is carried out 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 of the general formula (LXXXV) used in this step is a known compound, or a known compound which can be easily produced in accordance with a method known from the starting material or a method similar thereto. The compound of the general formula (LXXXVI) used in this step is a known compound, or a known compound which can be easily produced by the method known from the starting material or the like, which can be easily produced from -85 to 201036962. The solvent used in this step is preferably an guanamine, more preferably N,N-dimethylformamide. The base used in this step is preferably an alkali metal carbonate, more preferably carbonic acid. The reaction temperature in this step is usually from 60 ° C to 180 ° C, preferably 1 Torr. 〇 to 150〇C. The reaction time in this step is usually from 1 hour to 48 hours, preferably from 12 hours to 36 hours. ... Step T2 This step is a step of producing a compound of the general formula (LXXXIV). This step is carried out in a solvent, in the presence of a palladium catalyst and an inorganic base, via a compound having the general formula (1^乂乂11) and 5-(4,4,5,5-tetramethyl-1,3,2 The reaction of 2-dicyclopentaborolan-2-yl)-1Η-pyrrole-2-carboxylic acid methyl ester is carried out in the same manner as in the above S1 step of the S method. The U method is a method for producing a compound of the general formula (LXXXIV) used in the step S2 of the S method. 86 - 201036962 U Law

X U1 step Ac20 (LXXXVIII) Ο

X 0 Step U2

X o

X Step U4

(LXLIII) Step u 3 Step R3a-H (LXLI)

R (LXXXIV) In the present invention, R2a, R3a, X and Y have the same meaning as the above-mentioned matter. Step U1

This step is a step of producing a compound having the general formula (LXXXIX). This step is carried out by reacting a compound of the general formula (LXXXVIII) with acetic anhydride in the presence of an acid. The compound of the formula (LXXXVIII) used in this step is a known compound, or a known compound which can be easily produced according to a method known from the starting material or a method similar thereto. The acid used in this step is a hydrogen halide such as hydrogen chloride or hydrogen bromide; an inorganic acid such as sulfuric acid, hydrobromic acid or hydrochloric acid; a carboxylic acid such as acetic acid, formic acid or trifluoroacetic acid, preferably The inorganic acid is more preferably sulfuric acid. The reaction temperature in this step is usually -20 ° C to 40 ° C, preferably hydrazine. 〇 to -87- 201036962 2 5〇C. The reaction time in this step is usually from 0.1 to 12 hours, preferably from 0.5 to 3 hours. Step U2 This step is a step of producing a compound having the general formula (LXL). This step is carried out by reacting a compound of the general formula (LXXXIX) with a chlorinating agent. The chlorinating agent used in this step is a mineral 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 such as chlorine; sulfinic acid reagents such as sulfinium chloride; or sulfonic acid reagents such as sulfonium chloride and toluenesulfonyl chloride, preferably sulfinic acid reagents Or oxalic acid chlorides, more preferably sulphur sulphate or sulphur chloride, and more preferably sulphur sulphate. The reaction temperature in this step is usually from -20 ° C to 10 ° C, preferably to 8 〇 t:. The reaction time in this step is usually from 1 hour to 12 hours', preferably from 0.5 hours to 3 hours. Step U3 This step is a step of producing a compound of the general formula (LXLII). This step is carried out by reacting a compound having the general formula (LXL) with a compound having the general formula (LXLI) in a solvent. The compound of the general formula (LXLI) used in this step is a known compound, or a known compound produced by -88-201036962 can be easily produced according to a method known from the starting material or the like. The solvent used in this step is preferably a halogenated hydrocarbon, more preferably methylene chloride. The reaction temperature in this step is usually -20 ° C to 40 ° C, preferably 0 ° C to 25 °. (: The reaction time in this step is usually from 0.1 hour to 12 hours, preferably from 0.5 hour to 6 hours.) Step U4

This step is a step of producing a compound having the general formula (LXLIII). This step is carried out in a solvent, in the presence of a palladium catalyst and an inorganic base, via a compound of the general formula (LXLII) with 5-(4,4,5,5-tetramethyl-, 1,3,2-dioxane. The reaction of methyl pentaborane-2-yl)-1Η-pyrrole-2-carboxylate is carried out in the same manner as in the above S1 step of the S method. Step U5 This step is a step of producing a compound of the general formula (LXXXIV). This step is carried out in the presence of a base in the presence of a base via a compound of the formula (LXLIII) and a compound of the formula (IV), in the same manner as in the step A2 of the above-mentioned A method. The above-mentioned "protective amine group", "protected hydroxyl group" and "protectable carboxyl group" in the definitions of R2a, R3a, R", Rh, R9a, RlOa, 尺~ and R12a, It means a protecting group which can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis, photolysis, and a protecting group generally used in organic synthetic chemistry (for example, see TW Greene et al., Protective Groups in Organic -89-201036962)

Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)). In the definitions of R2a, R3a, R9a, R10a, R_lla, and R]2a, the "protecting group" of the "protectable hydroxyl group" is not particularly limited as long as it is a protecting group for a hydroxyl group used in the field of organic synthetic chemistry, for example,醯基,前记 "C2-C7 Institute-based carbonyl group", the former "C2-C7 halogenated compound carbonyl group", alkoxyalkylcarbonyl group such as methoxyethyl ketone group; propylene fluorenyl group, propynyl fluorenyl group, "Alkylcarbonyl" such as an unsaturated alkylcarbonyl group such as an acryloyl group, a crotonyl group or an isocyanyl group (E)-2-methyl-2-butenyl group; a benzinyl group; - an arylcarbonyl group such as a naphthylmethyl group or a β-naphthylmethyl group; a halogenated arylcarbonyl group such as a 2-bromobenzyl group or a 4-chlorobenzyl group; 2,4,6-trimethylbenzyl a G-C6 alkylated arylcarbonyl group such as a mercapto group or a 4-toluamylcarbenyl group; a Ci-Q alkoxylated arylcarbonyl group such as a 4-anisyl fluorenyl group; a 4-nitrobenzyl fluorenyl group; a nitroated arylcarbonyl group such as a 2-nitrobenzyl fluorenyl group; a C2-C7 alkoxycarbonylated arylcarbonyl group such as a 2-(methoxycarbonyl)benzylhydrazine group; a 4-phenylbenzylhydrazine group; An arylcarbonyl group such as an arylcarbonyl group; Halogen or tri-(Ci-Ce alkyl) such as "C2-C7 alkoxycarbonyl", 2,2,2-trichloroethoxycarbonyl '2-trimethyldecylalkylethoxycarbonyl "Alkoxycarbonyl" of a C2-C7 alkoxycarbonyl group substituted by a decyl group; tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran "tetrahydropyranyl or tetrahydrothiopyranyl" such as 4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; tetrahydrofuran-2 "tetrahydrofuranyl or tetrahydrothiofuranyl" such as -yl, tetrahydrothiafuran-2-yl; trimethyldecyl, triethyldecyl, isopropyldimethylalkyl, tert-butyl Tris-(C alkyl)decyl, such as dimethyl decyl, methyl diisopropyl decyl, methyl di-tert-butyl fluorenyl, triiso-90- 201036962 propyl decyl, Alkyl)diarylnonenyl or bis-(Cl-C6) such as phenylmethyl decyl, diphenylbutyl decyl, diphenyl isopropyl decyl, phenyl diisopropyl decyl "Alkyl" arylalkylalkyl or the like "decyl J: methoxymethyl, 1,1-dimethyl-1-methoxymethyl (Ci-Cs alkoxy)methyl, 2-methyl group, ethoxymethyl, propoxymethyl, butoxymethyl, butoxymethyl (Ci-C^ alkoxyalkoxy)methyl group such as oxyethoxymethyl group,

"Alkoxymethyl" such as (Ci-L halogenated alkoxy)methyl group such as 2,2,2-trichloroethoxymethyl or bis(2-chloroethoxy)methyl; - an ethoxyethyl group, a (Ci-Ce alkoxy) ethyl group such as 1-(isopropoxy)ethyl group, a halogenated ethyl group such as 2,2,2-trichloroethyl or the like Substituted ethyl"; benzyl, α-naphthylmethyl, β-naphthylmethyl, monophenylmethyl, triphenylmethyl, α-cainyldiphenylmethyl, 9-fluorenylmethyl a CrQ alkyl group substituted by 1 to 3 aryl groups; 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methyl Oxybenzyl, 4-methoxyphenyldiphenylmethyl '2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl An "aralkyl group" substituted with 1 to 3 aryl groups, such as an alkyl group, wherein the aryl ring is C^-Ce alkyl, Ci-Ce alkoxy, nitro, halogen, Cyano group substitution; "alkenyloxycarbonyl" such as vinyloxycarbonyl, allyloxycarbonyl; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethyl Oxybenzyloxycarbonyl, 2-nitrobenzyloxy An arylalkyloxycarbonyl group, preferably an alkylcarbonyl group, which may be substituted with 1 or 2 C^-Ce alkoxy groups or a nitro group, such as a carbonyl group or a 4-nitrohexyloxycarbonyl group. , 矽alkyl or aralkyl. -91- 201036962 The "protecting group" of "protectable carboxyl group" in the definition of R2a, R3a, R9a, R1Ga, Rlla & R12a2 is a carboxyl group used in the field of organic synthetic chemistry. The protecting group is not particularly limited, for example, the above-mentioned "CrC6 alkyl group"; the former "C2-C6 alkenyl group"; ethynyl group, 1-propynyl group, 2-propynyl group, fluorenyl-methyl group 2-propynyl group, a CrC6 alkynyl group such as a butynyl group; the former "Cl-c6 halogenated compound base"; a hydroxymethyl group, a C hydroxy group such as a 2-hydroxyethyl group; a 6 hydroxyalkyl group; (C2-C7 alkylcarbonyl XCrC6 alkyl); predecessor "Fangyuan $J; or the former "decylalkyl", preferably alkyl or aralkyl. R2a, R3a, R4a, R5a, R9a, R1 (U The "protecting group" of the "protectable amine group" in the definition of the ruler 11» and Rl2a is not particularly limited as long as it is a protecting group for the amine group used in the field of organic synthetic chemistry, for example, the former "protection of a hydroxyl group" "protective group" means "alkylcarbonyl"; "arylcarbonyl"; "alkoxycarbonyl"; "decylalkyl"; "aralkyl"; "alkenyloxycarbonyl"; or "aralkyloxy" The same group of carbonyl groups; or hydrazine, Ν-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, arsenyl, 5-chloro "Forming a Schiff base substituted methylene group" such as a sulfhydryl group, a diphenylmethylene group or a (5-chloro-2-hydroxyphenyl)phenylmethylene group, preferably The alkylcarbonyl group, the arylcarbonyl group or the alkoxycarbonyl group is more preferably an alkoxycarbonyl group. The steps necessary for the protection and deprotection can be carried out in accordance with a known method (for example, "Protective Groups in Organic Synthesis" (Theodora W. Greene, Peter G. M. Wuts, 1999, published by Wiley-Interscience Publication). The compound of the present invention or a pharmacologically acceptable salt thereof can be administered in various forms -92-201036962. Examples of the administration form thereof include oral administration via a tablet, a capsule, a granule, an emulsion, a nine-dose, a powder, a syrup (liquid), or the like, or an injection (intravenous, intramuscular, Non-oral administration of subcutaneous or intraperitoneal administration, drip, suppository (rectal administration). These various preparations can be generally used in the field of pharmaceutical preparations such as excipients, binders, disintegrating agents, lubricants, flavoring agents, solubilizers, suspending agents, coating agents, etc., according to the conventional method. The adjuvant is formulated. 0 When used as a tablet, excipients such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, citric acid, etc.; water, ethanol, propanol, monosaccharide syrup can be used. , glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.; dry starch, sodium alginate, agar Powder, brown algae powder (laminaran powder), sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc.; white sugar, hard a collapse inhibitor such as a fatty acid, a cocoa butter or a hydrogenated eucalyptus oil; an absorption enhancer such as a fourth-order ammonium salt or sodium lauryl sulfate; a moisturizer such as glycerin or starch; starch, lactose, kaolin, bentonite, A sorbent such as colloidal citric acid; a lubricant such as talc, stearate, boric acid powder, or polyethylene glycol is purified as a carrier. Further, a lozenge of a usual lotion such as a sugar-coated tablet, a gelatin-coated ingot, an enteric-coated ingot, a film-coated ingot or a double ingot, or a multi-layer ingot may be used as needed. When used in nine doses, excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin, talc, etc.; arabic gum powder-93-201036962, yellow gum powder, gelatin, ethanol, etc. A laminating agent such as laminaran or acacia, or the like as a carrier. When it is used as a suppository, a person known in the art can be widely used as a carrier, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides. When used as an injection, it can be used as a liquid, emulsion or suspension. Preferably, the liquid, emulsion or suspension is sterilized and isotonic with blood. The solvent for producing these liquid preparations, emulsions, or suspending agents is not particularly limited as long as it can be used as a diluent for medical use, and examples thereof include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, and poly Oxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester, and the like. Further, in this case, a sufficient amount of salt, glucose or glycerin for preparing an isotonic solution may be contained in the preparation, and a usual solubilizing agent, a buffering agent, a pain-relieving agent or the like may be contained. Further, the above-mentioned preparation may contain a coloring agent, a preservative, a flavor, a flavor, a sweetener, and the like as needed, and may further contain other pharmaceuticals. The amount of the active ingredient compound which can be contained in the above-mentioned preparation is not particularly limited and can be suitably selected from a wide range, but usually contains 0.5 to 70% by weight, preferably 1 to 30% by weight, based on the total composition. The amount of use varies depending on the symptoms, age, etc. of the patient (warm-blooded animals, especially humans). When administered orally, the upper limit for adults is 2000 mg (preferably 100 mg) per day, and the lower limit is 0. .img (preferably 1 mg, more preferably l〇mg), depending on the symptoms, 1 to 6 times per day. [Examples] -94-201036962 Hereinafter, the present invention will be described in more detail by way of Examples and Test Examples. However, the scope of the invention is not limited thereto.溶 The elution in the column chromatography analysis of the examples was carried out by TLC (Thin Layer Chromatography). The TLC observation was carried out by using a TLC plate made of Merck, 60F2 5 4 or an NH-TLC plate manufactured by Fuji Silysia Chemical Ltd. as a TLC plate, using a solvent which can be used as a solvent for elution in column chromatography, as a developing solvent, and using UV detection. The detector is used as a detection method. For the column, the silicone rubber SK-85 (230 to 400 sieve) manufactured by Merck or the silicone rubber FL100B manufactured by Fuji Silysia Chemical Ltd. was used. In addition to the usual column chromatography, Moritex Corporation's automatic chromatography analyzer (Purif-a2) and disposable column (Purif-pack SI series or NH series) are suitably used. Purification via preparative TLC was performed using a sand rubber 6OF254 manufactured by Merck, a thickness of 5 mm, and a plate of 2 〇 x 20 cm. Further, the abbreviations used in the examples have the following meanings. Mg: milligrams, g: gram 'mL: milliliters liters MHz: megahertz, HATU: 〇〇-(7-azabenzotriazol-1-yl)-Ν, Ν, Ν', Ν'-four Ketoluene hexafluorophosphate, WSCI.HC1: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, Η0ΒΤ·Η20: 1-hydroxybenzotriazole monohydrate DMT-MM: 4-(4,6-Dimethoxy-1,3,5-trit-2-yl)-4-methylmorpholine hydrochloride η hydrate. The nuclear magnetic resonance (hereinafter referred to as 1H-NMR) spectrum in the following examples is tetramethyl decane as a standard material, and the chemical shift 値 is described as δ 値 (ppm). Splitting. Expression of the formula: single peak is s' doublet is d, triplet is t, quadruple is q, -95-201036962 multiple peak is m, wide peak is br. Mass analysis (hereinafter referred to as MS) was carried out by FAB (Fast Atom Bombardment), EI (Electron Ionization) or ESI (Electron Spray Ionization). (Example 1) 2-[5-(3-{[(2S)-l-fluoropropan-2-yl]oxy}-5-[4-(methylsulfonyl)phenoxy]phenyl) -1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazole

〇., 〇 (la) 3-bromo-5-methoxyphenol 1-bromo-3,5-dimethoxybenzene (18.74 g, 86.3 mm 〇l) was dissolved in 1-methyl-2- Pyrrolidone (100 mL) was added with sodium methoxide (6.74 g, 9 6.2 mmol), and stirred at 100 ° C for 3 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, then EtOAc (EtOAc) The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted elution . 'H-NMR (CDC13, 400MHz): δ 3.77 (3Η, 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). (lb) l-Bromo-3-methoxy-5-[4-(methylsulfonyl)phenoxy]benzene-96- 201036962

The compound synthesized in Example (la) (10.45 g, 60.0 mmol) was dissolved in N,N-dimethylformamide (100 mL), and potassium carbonate (25.00 g, 18 1 mmol) was added under a nitrogen atmosphere at 100 ° C Stir for 36 hours. The reaction solution was cooled to room temperature, and then potassium carbonate was removed by Celite, and then ethyl acetate (500 mL) was added, and the mixture was extracted 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 evaporated under reduced pressure, and the obtained solid crystals crystal crystal crystal crystal crystal 'H-NMR (CDC13, 400MHz): δ 3.07 (3Η, 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). (lc) 3-bromo-5-[4-(methylsulfonate) Benzyl)phenoxy]phenol The compound synthesized in Example (lb) (18.29 g, 51.2 mmol) was dissolved in dichloromethane (4 mL), cooled to -7 8 ° C, using a dropping funnel under nitrogen atmosphere Boron tribromide (i.Omoi/L dichloromethane solution, l〇〇mL, (J lOOmmol) was added over 30 minutes. After stirring at -78 °C for 2 hours, it was naturally warmed to room temperature and stirred overnight. The mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with a mixed solvent of dichloromethane (500 mL) and methanol (50 mL). The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (16·········

iH-NMR (DMSO-D6, 400MHz): 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), -97- 201036962 7.23 (2H, d, J = 8.6 Hz), 7.94 (2H, d, J = 9.0 Hz), 10.27 (1H, s). (ld) 3-[4-(Methanesulfonyl)phenoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl Phenol The compound synthesized in Example (lc) (l〇.i〇g, 29.4 mm〇l) was dissolved in N,N-dimethylformamide (100 mL), and boranoic acid pinacol ester (11.0 9 g) was added. , 43.7 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloride complex (722 mg, 0.884 mmol), potassium acetate (14.92 g, 152 mmol) ), stirring at 90 ° C for 5 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, the reaction mixture was diluted with ethyl acetate (400 mL) and filtered to remove insolubles from Celite. Water (400 mL) was added to the filtrate to separate the layers, and the organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluting eluted eluted eluted eluted eluted eluted eluted eluted eluted ). ^-NMR (CDC13, 400MHz): δ 1.33 (12Η, s), 3.06 (3Η, 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). (1〇2-{3-[(13)-2-methoxy-:1-methylethoxy]-5-[4-(A Sulfhydryl)phenoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane borane The compound synthesized in Example (Id) (13.20 g, 33.8 Mm〇l) dissolved in tetrahydrofuran (300 mL), (R)-(-)-l-methoxy-2-propanol (3.70 mL, 37.8 mmol), triphenylphosphine (9.78 g, 37.3 mmol), cooled To (TC. Nitrogen atmosphere -98-201036962, diethyl azocarboxylate (40% toluene solution, 16.2 mL, 3 7.2 mmol) was added dropwise over 10 minutes, and stirred at 0 ° C for 30 minutes, and then naturally warmed to room. The mixture was warmed and stirred for one night. The solution was separated by adding water (30 mL) and ethyl acetate (30OmL). The organic layer was washed with saturated brine and dried over sodium sulfate. The residue was purified by column chromatography (yield: ethyl acetate / hexane = 20% to 40%) to afford the title compound (1 1.94 g, yield 76%).

*H-NMR (CDC13, 400MHz): δ 1.31 (3Η, 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), 4.5 8-4.62 ( 1 H, m), 6.76 (1H, t, J = 2.4 Hz), 7.05 -7.09 (3 H, m), 7.24 (1H, d, J = 2.4 Hz), 7.87 (2H, d, J = 9.0 Hz). (If) 5-bromo-1H-pyrrole-2-carboxylic acid ethyl ester 5-bromine 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) and cooled to EtOAc. N-bromosuccinimide (6.52 g, 30.7 mmol) was added, and the mixture was stirred at room temperature for 18 hr under nitrogen atmosphere. The solution was layered by adding water (150 mL) and ethyl acetate (200 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted eluted eluted eluted elution ). !H-NMR (CDC13, 400MHz) : δ 1.36 (3Η, 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 (ih, -99- 201036962 dd, J = 3.9, 2.7 Hz), 9.21 (1H, brs). (lg) 5-bromo-1H-pyrrole-1,2-dicarboxylic acid 1-t-butyl 2-ethyl ester

The compound synthesized in Example (If) (3.20 g, 14.7 mm 〇l) was dissolved in dichloromethane (100 mL), and di-tert-butyl dicarbonate (3.85 g, 17.6 mmol) and triethylamine (4.10) were added. mL, 19.4 mmol) and 4-dimethylaminopyridine (180 mg, 1.47 mmol) were stirred at room temperature for 1 hour under nitrogen. Water (100 mL) was added, and extracted with dichloromethane (100 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluting eluted eluted eluted eluted eluted eluted eluted eluted elution ). W-NMR (CDC13, 400MHz): δ 1.34 (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). (11〇5-{3-[(18)-2-methoxy-1-methylethoxy]-5-[4-(A Sulfhydryl)phenoxy]phenyl}-1Η-pyrrole-1,2-dicarboxylic acid 1-t-butyl 2-ethyl ester The compound synthesized in Example (le) (8.73 g, 18.9 mm〇l And Example I j (18) The synthesized compound (8.37 §, 26.13111111〇1) was dissolved in a mixed solvent of toluene (18〇1111〇 and ethanol (77mL), and [1,1'-bis(diphenylphosphine) was added. Ferrocene] palladium(II) dichloride methylene chloride complex (770 mg, 0.94 mmol), aqueous potassium carbonate solution (2 mol/L, 23.7 mL, 47.2 mmol), stirred at 100 ° C for 1 hour under nitrogen atmosphere After cooling the reaction mixture to room temperature, water (200 mL) was added, and ethyl acetate (400 mL) was evaporated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Column chromatography (solvent -100-201036962 solvent: ethyl acetate / hexane = 1% to 5 %) was used to purify the residue to give a pale yellow oil. The object compound (9.44g, 84% yield).

*H-NMR (CDCI3, 400MHz): δ 1.31 (3Η, 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). (li) 5-{3-[(lS)-2-methoxy-1-methylethoxy]- Ethyl 5-[4-(methylsulfonyl)phenoxy]phenyl}-1Η-pyrrole-2-carboxylate The compound synthesized in Example (1h) (9.44 g, 16.5 mmol) was dissolved in dichloromethane (90 mL), cooled to 0 °C. Trifluoroacetic acid (45 mL) was added dropwise while stirring under a nitrogen atmosphere, and stirred at room temperature for 1 hour. After the solvent was evaporated under reduced pressure, ethyl acetate (30 mL) was evaporated and evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted eluted eluted eluted elution ). iH-NMR (CDC13, 400MHz): δ 1.33 (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), -101- 201036962 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: 474.1 6048 (M + H)+. (1)) 5-{3-[(13)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1Η- Pyrrole-2-carboxylic acid The compound synthesized in the example (li) (4.36 g, 9.2 mmol) was dissolved in ethanol (100 mL), and 4N aqueous sodium hydroxide (23 mL, 92 mmol) was added, and the mixture was refluxed for 1 hour under nitrogen atmosphere. . The reaction solution was neutralized by adding 2N hydrochloric acid (45 mL), and the solvent was evaporated under reduced pressure. It was acidified with 1N hydrochloric acid and extracted with ethyl acetate (300 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give white crystals (yield: W-NMR (CDC13, 400MHz): δ 1.34 (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 (1 H, 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). (lk) N-(2-chloroethyl)-5-{3-[(lS)-2-methoxy-1-methyl Oxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-l H-pyrrole-2-carboxamide The compound synthesized in Example (lj) (150 mg '0.34 mmol), 2 -Chloroethylamine hydrochloride (78 mg, 0.68 mmol) and 4-dimethylaminopyridine (41 mg, 201036962 0.34 mmol) were dissolved in dichloromethane (15 mL). WSCI·HCl (71 mg, 〇 .37 mmol), stirred under a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with methylene chloride (150 mL), washed with 1N aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography (eluent solvent: ethyl acetate / hexane = 30% to 60%) to give the object as a white solid (10 mg, yield 62%) ) »

^-NMR (CDC13, 5 00MHz) : δ 1.33 (3Η, 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 (1 H, 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). C) (11) 2-(5-{3-[(13)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy Phenyl}-1Η-pyrrol-2-yl)-4,5-dihydro-1,3-oxazole The compound synthesized in Example (lk) (177 mg, 0.349 mmol) was dissolved in tetrahydrofuran (5 mL), cooled To °C. Sodium hydride (40 mg, 0.917 mm 〇l) was added, warmed to room temperature and stirred for 19 hr. After cooling the reaction mixture to 0 ° C, water (5 mL) was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the title compound (yield solvent: ethyl acetate / hexane = 50% to 100%) -103 - 201036962 Rate 7 2%). ^-NMR (CDC13, 400MHz): δ 1.33 (3Η, 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), 6.5〇 (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 : 47 1 · 1 605 0 (M + H)+. (lm)(2S)-2-{3-[5-(4,5-Dihydro-1,3-oxazol-2-yl)-1Η-pyrrol-2-yl]-5-[4-( Methanesulfonyl)phenoxy]phenoxy}propan-1-ol

The compound synthesized in Example (U) (3.17 g, 6.74 mmol) was dissolved in dichloromethane (100 mL), cooled to -78 ° C, and boron tribromide (1. , 7.07 mL, 7.07 mmol). After stirring at room temperature for 30 minutes, a saturated aqueous solution of sodium hydrogencarbonate was added to neutralize the mixture and the mixture was extracted with dichloromethane (20OmL). The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was evaporated to ethylamine (jjjjjjjjjjjjjj CDC 13, 5 00MHz) : δ 1.29 (3Η, 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 ( 1 H, m), 6.40 (1H, t, J = -104- 201036962 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: 457.1 4357 (M + H) + . (ln) 2-[5-(3-{[(2S)-l-fluoropropane- 2-yl]oxy}-5·[4-(methylsulfonyl)phenoxy]phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazole

The compound synthesized in Example (lm) (80 mg, 0.175 mmol) was dissolved in dichloromethane (10 mL), and N,N-diethylamine sulphur (0.5 mL, 0.378 mmol) was added at 0 °C. The mixture was stirred at room temperature for 2 hours and a half under a nitrogen atmosphere. A saturated aqueous solution of sodium hydrogencarbonate (20 mL) was evaporated and evaporated. The organic layer was washed with 1N aqueous sodium hydroxide (10 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was evaporated to mjjjjjlilililililililililililili ^-NMR (CDCla, 400MHz): δ 1.32 (3Η, 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: 459.1 3 825 (M + H)+. (Example 2) -105-201036962 2-(5-(3-[4-(methylsulfonyl)phenoxy]-5-(1-propen-2-yloxy)phenyl}-111- Pyrrol-2-yl)-4,5-dihydro-1,3-oxazole

0' Ό (2a)(2S)-2-{3-[5-(4,5-Dihydro-1,3-oxazol-2-yl)-1Η-pyrrol-2-yl]-5-[ 4-(Methanesulfonyl)phenoxy]phenoxy}propylmethanesulfonic acid The compound synthesized in Example (lm) (106 mg, 0.23 tnmol) was dissolved in tetrahydrofuran (5.0 mL). 65 mg, 0.37 mmol), triethylamine (〇. 〇 6 mL, 0.43 mmol), and stirred at room temperature for one and a half hours under nitrogen atmosphere. A saturated aqueous solution of ammonium chloride (20 mL) was added toEtOAc. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified to mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 'H-NMR (CDC13, 400MHz) : δ 1.40 (3Η, 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)-l-iodopropan-2-yl]oxy}-5-[4-(methylsulfonyl)benzene-106- 201036962 oxy]phenyl)-1 Η-pyrrol-2-yl]-4 ,5-dihydro-1,3-oxazole

The compound (5 04111 §, 0.94111111 〇 1) synthesized in Example (23) was dissolved in acetone (15.0 mL), sodium iodide (320 mg, 2.13 mmol) was added, and the mixture was heated to reflux under a nitrogen atmosphere and stirred for one day. Water (40 mL) was added to the mixture and the mixture was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted elution ). *H-NMR (CDC13, 400MHz): δ 1.48 (3Η, 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). (2〇2-(5 -{3-[4-(Methanesulfonyl)phenoxy]-5-(1-propen-2-yloxy)phenyl}-1H-pyrrol-2-yl)-4,5- Dihydro-1,3-oxazole The compound synthesized in Example (2b) (9 3 mg, 〇.16 mmol) was dissolved in N,N-dimethylformamide (10 mL). Sodium (5 〇〇 mg, 7.34 mmol) was stirred at 80 ° C for one day under a nitrogen atmosphere. A saturated aqueous solution of ammonium chloride (50 mL) was added and the mixture was extracted with dichloromethane (3 mL). After washing the organic layer with water, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The chromatographic analysis of the column was carried out by using a seper column (solvent solvent: methanol/dichloroform; 〇~2%) -107- 201036962 The title compound was obtained as a yellow solid (34 mg, yield: 7%): H-NMR (CDCls, 400 MHz): δ 1.99 (3 Η, 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· 1 3042 (M + H)+. (Example 3) 2-[5-(3-{[(2S)-1-(methylthio)propan-2-yl]oxybu 5-[4-(methylsulfonyl)phenoxy Phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazole

The compound (5611^, 0.11111111〇1) synthesized in Example (2 &) was dissolved in tetrahydrofuran (10 mL), sodium methoxide (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 solution of ammonium chloride (20 mL) was added and the mixture was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted elution . ^-NMR (CDCI3, 400ΜΗζ): δ 1.42 (3Η, d, J = 5.9 Hz), 2.18 (3H, s), 2.70 (1H, dd, J = 13.5, 6.1 Hz), 2.85 (1H, dd, J = -108- 201036962 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: 48 7.1 3473 (M + H)+. (Example 4) 2-[5-(3-[4-(Methylsulfonyl)phenoxy]-5-{[(2S)-l-(methylsulfonyl)propan-2-yl]oxy }}phenyl)-lH-pyrrol-2-yl]-4,5-dihydro-1,3-carbazole

0*, 0

The compound (150 mg, 0.31 mmol) synthesized in (Example 3) was dissolved in dichloromethane (5.0 mL), and m-chloroperbenzoic acid (about 65%, 170 mg, about 0.64 mmol) was added under a nitrogen atmosphere at room temperature. Stir for one hour. A saturated aqueous solution of sodium hydrogencarbonate (10 mL) was evaporated and evaporated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted eluted eluted eluted *H-NMR (CDC13, 400MHz): δ 1.45 (3Η, 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 ( 1 H, m), 6.52 (1H, d, J = 3.9 Hz), -109- 201036962 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 : 5 1 9.1 2522 ( M + H) + 〇 (Example 5) 2-(5-{3-Methoxy-5-[4-(methylsulfonyl)phenoxy]phenyl}-111-pyrrol-2-yl) -4,5-dihydro-1,3-oxazole

(5 a) 2-{3-Methoxy-5-[4-(methylsulfonyl)phenoxy]phenyl b 4,4,5,5-tetramethyl-1,3,2-di Indole cyclopentane. The compound synthesized in Example (lb) (22.8 g, 63.8 mmol), dinacol borate (24.3 g, 95.7 mmol), [1,1'-bis(diphenylphosphine) Ferrocene] palladium dichloride (Π) dichloromethane complex (1.56 g, 1.91 mmol), potassium acetate (3 1 _3 g, 319 mmol) was obtained in the same manner as in Example (1 d). The title compound was obtained as a yellow oil (24.8 g, yield: 96%). *H-NMR (CDC13, 400MHz): δ 1.33 (12Η, s), 3.05 (3H, s), 3.84 (3H, s), 6.73 (1H, t, J = 2.4Hz), 7.07 (2H, d, J = 9.0 Hz), 7.08 (1H, m), 7.20 (1H, d, J = 2.8 Hz), 7.87 (2H, d, J = 9.0 Hz). (51?) 5-{3-methoxy- 5-[4-(Methanesulfonyl)phenoxy]phenyl}-111-pyrrole-1,2-dicarboxylic acid 1-t-butyl 2-ethyl ester The compound synthesized in Example (5a) was used ( 24.8 g, 61.3 mmol), the compound (20.18, 63.2111111〇1), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, which was synthesized in 201036962 (lg) Methane complex (2.50 g, 3.06 mmol), EtOAc (EtOAc, m. %). j-NMR (CDC13, 400MHz): δ 1·35 (3H, t, J = 7.0Hz), 1·46 (9H, s), 3.05 (3Η, 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}-lH-pyrrole-2-carboxylic acid Example (5b) The compound which was synthesized (23.9 g, 46.4 mmol) was dissolved in ethanol (100 mL), and 5N aqueous sodium hydroxide (100 mL) was added, and the mixture was heated under reflux for 2 hours under a nitrogen atmosphere. 2N hydrochloric acid (26 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1 8.3 g, yield -100%). (5<1)]^-(2-hydroxyethyl)-5-{3-methoxy-5-[4-(methylsulfonyl)phenoxy]phenyl}-1Η·pyrrole-2- Formamide The compound synthesized in Example (5c) (10. The mixture was stirred at room temperature for 19 hours under a nitrogen atmosphere. The solvent was evaporated under reduced pressure, and water (200 mL) was evaporated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by chromatography (yield solvent ethyl acetate / hexane = 80% - 100%) to afford the title compound (11.6 g 〇〇%). W-NMR (CDC13, 400MHz): δ3.07 (3H, s), 3.59 (2H, dd, J = 5.1, 10.2Hz), 3.80 (2H, t, J = 5.1Hz), 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 = 9.0 Hz), 7.90 (2H, d, J = 9.0 Hz), 9.73 (1H, brs). (5e) 2-(5-{3-methoxy- 5-[4-(methylsulfonate) Benzyl)phenoxy]phenyl}-lH-pyrrol-2-yl)-4,5-dihydro-1,3-oxazole The compound synthesized in Example (5d) (11.5 g, 26.7 mm 〇l It was dissolved in tetrahydrofuran (200 mL), and methanesulfonic anhydride (7.00 g, 40.2 mmol) and triethylamine (15.0 mL, 108 mol) were added, and the mixture was stirred at room temperature for 50 hours under a nitrogen atmosphere. A saturated aqueous solution of sodium hydrogencarbonate (200 mL) was added and ethyl acetate (100 mL) The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified (jjjjjjjjjjjjj . ^-NMR (CDC13, 400MHz): 63.07 (3H, s), 3.84 (3H, s), 3.99 (2H, t, J = 9.4Hz), 4.41 (2H, t, J = 9.4Hz), 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 -112- 201036962

Hz), 7.91 (2H, d, J = 9.0 Hz). MS (ESI) m/z: 413.11712 (M + H) + 〇 (Example 6) 2-{3-[5-(4,5-II Hydrogen-1,3-1,3-oxazol-2-yl)-1Η-pyrrol-2-yl]-5-[4-(methylphenyl)phenoxy]phenoxy}propanoate

(6a) 3-[5-(4,5-Dihydro-1,3-oxazol-2-yl)-1Η-pyrrol-2-yl]methylsulfonyl)phenoxy]phenol will be the examples ( 5e) The synthesized compound (2.93 g, 7.10 mmol) was dissolved in z chloroform (7 〇mL) 'Add boron tribromide at 0 ° C (l. 〇mol / L dichlorocarbyl solution, 23.0 mL ' 23.0 Methyl), stirred at room temperature for 4 days under a nitrogen atmosphere. A saturated aqueous solution of sodium hydrogencarbonate (10 mL) was added, and extracted three times with tetrahydrofuran (100 mL).

The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified to mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ^-NMR (CDC13, 400MHz): 53.07 (3H, s), 4.07 (2H, t, J = 9.4Hz), 4.52 (2H, t, J = 9.4Hz), 6.44 (1H, t, J = 2.0 Hz), 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). 113 201036962 (6b)2-{3-[5-(4,5-Dihydro-1,3-oxazol-2- Methyl)-1Η-pyrrol-2-yl]_5-[4-(methylsulfonyl)phenoxy]phenoxy}propanoic acid methyl ester The compound synthesized in Example (6 &) (60〇11^, 1.51111111 〇 1) was dissolved in 2-butane (20 mL), and methyl 2-bromopropionate (340 μί, 3.05 mmol), potassium carbonate (625 mg, 4.52 mmol) was added, and the mixture was refluxed under nitrogen atmosphere for 19 hours. After cooling to room temperature, the insoluble matter was removed by filtration through Celite. The solvent was evaporated under reduced pressure, and the obtained residue was purified (jjjjjjjjjjjjjjj H-NMR (CDC13, 400MHz): δΐ.64 (3H,d,J = 6.7Hz), 3.07 (3H, s), 3.77 (3H, s), 3.97 (2H, t, J = 9.4Hz), 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), 7.9 1 (2H, d, J = 9.0Hz). MS (ESI) m/ z : 48 5.1 3 825 (M + H)+. (Example 7) 3-{3-[5-(4,5-Dihydro-1,3-oxazol-2-yl)-1Η-pyrrol-2-yl]-5-[4-(methylsulfonate) Mercapto)phenoxy]phenoxy}butan-2-one

The compound (200 mg, 0.502 mmol), 3-dihydro-2-butanone (110 pL, 1.05 mmol), cesium carbonate (210 mg, 1.52 mmol), using the compound of Example (6a), 201036962 was the same as Example (6b). The title compound was obtained as a white solid (3 1. Omg, yield: 13%). • H-NMR (CDC13, 400ΜΗζ): δΐ.52 (3Η, 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 = 9.0 Hz). MS (ESI) m/z: 469.1 43 3 3 (M + H)+. (Example 8) 2-(5-{3-isopropoxy-5-[4-(methylsulfonyl)phenoxy]phenyl}-1^1-pyrrol-2-yl)-4, 5-dihydro-1,3-carbazole

CJ The compound synthesized in Example (6&) (340 〇^, 0.853111111〇1) was dissolved in N,N-dimethylformamide (10 mL), and 2-bromopropane (160 μί, 1.70 mmol), potassium carbonate was added. (3 60 mg, 2.60 mmol), stirred at 80 ° C for 2 days under a nitrogen atmosphere. After cooling to room temperature, the insoluble matter was removed by filtration through Celite. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent solvent: ethyl acetate / hexane = 50% to 90%) to afford white solid (3 1 8 mg, yield 8 5%). 'H-NMR (CDCI3, 400MHz): δΐ.34 (6Η, d, J = 6.3Hz), 3.07 (3H, -115- 201036962 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), 6.8 1 (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 : 44 1 · 1 4842 (M + H)+. (Example 9) 3-{3-[5-(4,5-Dihydro-1,3-oxazol-2-yl)-1Η-pyrrol-2-yl]-5-[4-(A Sulfhydryl)phenoxy]phenoxy}dihydrofuran-2(3 fluorene)-one

Hey. 0 0 The compound (220 mg, 0.552 mmol), α-bromo-γ-butyrolactone (ΙΙΟμΙϋ, 1.19 mmol), potassium carbonate (230 mg, 1.66 mmol) was synthesized using the compound of Example (6a). 6b) The same procedure gave the title compound as a white solid ( 175 mg < ^-NMR (CDC13, 400MHz): δ2.48 (1Η, 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: 4 8 3.1 2260 (M + H) + (Example 10) -116- 201036962 2-(5- {3-[4-(Methanesulfonyl)phenoxy]-5-(tetrahydrofuran-3-yloxy)phenyl}-111-pyrrol-2-yl)-4,5-dihydro-1, 3-carbazole

Tetrahydro-3-furan (130 μί, 1.61 mmol), triphenylphosphine (410 mg, 1.56 mm 〇l) was dissolved in tetrahydrofuran (10 mL), and diethyl azocarboxylate (40% toluene solution was added dropwise at 0 °C. 720 pL, 1.58 mmol). The compound (250 mg, 0.627 mm) was dissolved in tetrahydrofuran (10 mL) and then added to the reaction mixture, and stirred at room temperature for 14 hours under nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography (eluent solvent ethyl acetate / hexane = 50% - 80%) to give the object as a white solid (277 mg, yield 94%) ). 'H-NMR (CDC13, 400MHz): 82.11-2.25 (2H, m), 3.07 (3HS s), 3.8 7-4.02 (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 = 8.6Hz). MS (ESI) m/z : 469.1 4333(M + H) +. (Example Π) 2-(5-{3-[4-(Methylsulfonyl)phenoxy]-5-[(3S)-tetrahydrofuran-3-yloxy]phenyl}-1Η-pyrrole- 2-yl)-4,5-dihydro-1,3-1,3-azole-117- 201036962

Using (3R)-tetrahydro-3-furan (76.0 μΙ^, 0.94 6 mmol), triphenylphosphine (250 mg, 0.953 mmol), azohydride diacetate (40% toluene solution, 430 pL, 0.946 mmol), The compound (15 mg, yield: 74%) was obtained as a white solid. ^-NMR (CDC13, 400MHz): 52.12-2.25 (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 : 469.1 43 3 3 ( M + H)+. (Example 12) 2-(5-{3-[2-Fluoro-1-(fluoromethyl)ethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1Η -pyrrol-2-yl)-4,5-dihydro-1,3-oxazole

Using 1,3-difluoro-2-propanol (ΙΟΟμί, 1.29 mmol), tritene (330 mg, 1.26 mmol), diethyl azocarboxylate (40% toluene solution, 5 70 μί, 1.26 mmol), Example (6a) Compound (200 mg, 0.502 mmol), -118 - 201036962 The title compound (178 mg, yield 74%) was obtained as a white solid. H-NMR (CDCI3, 4 0 0 Μ Η z) : δ 3.0 7 (3 H, s), 3 · 9 4 (2 Η, t, J = 9.4 Hz), 4.39 (2Η, t, J = 9.4Hz) ), 4.57-4.76 (5Η, m), 6.51 (1Η, 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 = 2.〇Hz), 7.12 (2H, d, J = 8.6 Hz), 7.91 (2H, d, J = 8.6Hz). MS (ESI m/z : 477· 1 295 7(M + H)+. (Example 13) (2R,3S)-3-{3-[5-(4,5-Dihydro-1,3-0-oxazol-2-yl)-1H-pyrrol-2-yl]-5- [4-(Methanesulfonyl)phenoxy]phenoxy}butan-2-ol

{Tetrahedron Letters, Vol. 38, No. 5, 773-776 (1997)} benzoic acid (lR, 2R)-2-hydroxy-1-methylpropyl ester (270 mg, 1.39 mmol), triphenylphosphine (360 mg ' 1.37 mmoI) was dissolved in tetrafluorofuran (51111^) at 0° (3 drops of diethyl azohydride (40% toluene solution, 63 (^1>, 1.39111111〇1). Example ( 6&) The synthesized compound (22〇11^, 0.552111111〇1) was dissolved in tetrahydrofuran U〇mL) and then added to the reaction mixture under a nitrogen atmosphere at room temperature for 3 hours. The solvent was distilled off under reduced pressure. The obtained residue was purified by chromatography (yield solvent: ethyl acetate / hexane = 50% to 80%). The obtained crude purified product was dissolved in methanol (10 mL), and added potassium carbonate - 119 - 201036962 (230 mg, 1.66 mmol). The mixture was refluxed for 1 hour under a nitrogen atmosphere, and the insoluble matter was removed by filtration through Celite, and the solvent was distilled off under reduced pressure, and analyzed by chromatography on a silica gel column (solvent solvent: ethyl acetate / hexane = 70%) 100%) The obtained residue was purified to purified crystals crystals crystals crystals crystals .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 _1 5 89 8 (M + H) + (Example 14) (3S)-3-{3-[5-(4,5-Dihydro-1,3-azole) -2-yl)-1Η-pyrrol-2-yl]-5-[4.(methylsulfonyl)phenoxy]phenoxy}butan-1-ol

(2R)-4-{[(l,i-Dimethylethyl)diphenylsulfanyl]oxy-2-butanol, known as {Synthesis, Vol. 9, pp. 1357-1360 (2003)} (460 mg, 1.40 mmol), triphenylphosphine (3 60 mg, 1.37 mmol) were dissolved in tetrahydrofuran (5 mL), and diethyl azocarboxylate (40% toluene, 630 pL, 1.39 mmol) was added dropwise. The compound synthesized in Example (6a) (220 mg, (K 552 mm 〇l) was dissolved in tetrahydrofuran (10 mL) and then added to the reaction mixture, and stirred at room temperature for 6 hours under a nitrogen atmosphere of 201036962. The solvent was distilled off under reduced pressure, using a silicone resin. The obtained residue was purified by column chromatography (solvent solvent: ethyl acetate / hexane = 50% to 80%).

The obtained crude purified product was dissolved in tetrahydrofuran (1 mL), and tetrabutylammonium fluoride (1M tetrahydrofuran solution, 5 60 μί, 0.560 mmol) was added, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Water (10 mL) was added and extracted with EtOAc (20 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified to mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 'H-NMR (CDC13) 400MHz): δΐ.33 (3Η, d, J = 6.3Hz), 1.85 (1H, m), 2.04 (1H, m), 3.06 (3H, s), 3.77-3.8 8 ( 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: 47 1 · 1 5 898 (M + H)+. (Example 15) 2-[5-(3-{[(lS)-3-fluoro-1-methylpropyl]oxy}-5-[4-(methylsulfonyl)phenoxy]benzene Base)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3_oxazole

The compound synthesized in (Example 14) (72.5 mg, 0.154 mmol) was dissolved in EtOAc-121 - 201036962 in dichloromethane (5 mL), and bis(2-methoxyethyl)amino group was added at 0 °C. Sulfur fluoride (7 (^L, 0.5 3 4 mmol). After stirring at room temperature for 4 hours, a saturated aqueous solution of sodium hydrogencarbonate was added and extracted with dichloromethane (1OmL). The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by chromatography (yield: ethyl acetate/hexane = 70% to 100%) , yield 6 5%) ° *H-NMR (CDC13, 400MHz): δΐ.37 (3Η, d, J = 6.3Hz), 2.00-2.13 (2H, m), 3.07 (3H, s), 3.98 ( 2H, t, J = 9.4Hz), 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 = 8.6 Hz). MS (ESI) m/z: 473 · 1 5464 (M + H) + (Example 16) {(5R)-2-[5-(3-methoxy- 5-{[ 6-(Methanesulfonyl)pyridin-3-yl]oxy}benzene ) -1Η- pyrrol-2-yl] -4,5-dihydro-1,3-5-yl} methanol fathoms

(I6a) 5-Chloro-2-(methylsulfonyl)pyridine 2,5-Dichloropyridine (1.49 g, 10 mmol) was dissolved in N,N-dimethylformamide (10 mL), nitrogen atmosphere Sodium methoxide (783 mg, 1 1.2 mmol) was added at 〇 ° C for 1 hour. Add water (100 mL) was extracted with ethyl acetate (i 〇〇 mL) -122 - 201036962. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give Compound (l. This was dissolved in dichloromethane (50 mL), and m-chloroperbenzoic acid (about 65%, 5.25 g, about 20 mmol) was slowly added at 0 ° C under a nitrogen atmosphere. (: Stirring for 2 hours. Add a saturated aqueous solution of sodium hydrogencarbonate (200 mL), and then ethyl acetate (1 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:EtOAc

*H-NMR (CDC13, 400ΜΗζ) : δ 3.24 (3 Η, s), 7 · 9 5 (1 Η, 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: 1 9 1.98 866 (M + H) + . (16b) 3-methoxy- 5-(4,4,5,5- Tetramethyl-1,3,2-dioxacyclopentan-2-yl) phenol

The compound synthesized in Example (la) (5.05 g, 24.9 mmol), dinacol borate (9-47 g, 37.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]-chlorination ί Π Π 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 634 Yield 72% p ^-NMR (CDCh, 400 MHz): δ 1. 3 4 (1 2 Η, s), 3.8 Ο (3 Η, s), 4.91 (1 Η, 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). -123- 201036962 MS (FAB) m/z : 25 1 (M + H) + . (16c) 2,5-tribromo-1H-pyrrole-1-carboxylic acid tert-butyl ester 1-pyrrolecarboxylic acid tert-butyl ester (46.68 g, 279 mmol) dissolved in tetrahydrofuran (500 mL), cooled to -7 TC N-bromosuccinimide (1 00.48 g, 5 65 mmol) was added portionwise over 1 hour. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was cooled to 0 ° C, and sodium sulfite (3 6.43) was added. g) After stirring for 30 minutes, hexane (200 mL) was added and the resulting precipitate was removed by filtration through Celite. The steam was evaporated under reduced pressure. The solvent of the filtrate was removed, and the obtained residue was purified using EtOAc EtOAc (EtOAc:EtOAc: !H-NMR (CDC 13, 500 MHz): δ 1.65 (9 Η, s), 6.25 (2 Η, s). MS (El) m/z : 3 23 (M + ) (16d) 5-bromo- 1H-pyrrole-1,2-dicarboxylic acid 2-benzyl-1-t-butyl ester The compound synthesized in Example (16c) (10.98 g, 33.8 mm hydrazine) was dissolved in diethyl ether (135 mL), 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. Benzyl chloroformate (6.25 mL, 44.0 mmol) was slowly added to the reaction solution, and stirred. 30 minutes. While stirring the reaction solution to room temperature, the mixture was stirred for 1 hour. The solution was separated into a saturated aqueous solution of ammonium chloride (200 mL) and diethyl ether (300 mL). The organic layer was washed with saturated brine. After that, it was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted %). -124- 201036962 W-NMR (CDC13, 400MHz) : 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), 7.28-7.3 9 (5H, m ). MS (FAB) m/z : 3 80 (M + H) + . (16 6) 5-(3-hydroxy-5-methoxyphenyl) -111-pyrrole-1,2-dicarboxylic acid 2-benzyl-1-t-butyl ester The compound synthesized in Example (16d) (7.78 g '20.5 mmol) and the compound synthesized in Example (16b) 4.26g, 17.0mm〇l) dissolved in a mixed solvent of 1,4_% of the hospital) (80mL) and water (20mL), adding [1,1, bis(diphenylphosphino)ferrocene] dichlorination Palladium (II) methylene chloride complex (420 mg '0.514 mmol) and potassium carbonate (5.93 g, 42.9 mmol) were stirred at 55 ° C for 6 hours under nitrogen atmosphere. After cooling the reaction mixture to room temperature, water (200 mL) was evaporated. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified (yield solvent: ethyl acetate/hexane = 5% to 30%). Rate 72%). • H-NMR (CDC13, 400MHz): δ 1.41 (9Η, 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)+. (16〇5-(3-methoxy-5-{[6-(methylsulfonate) Benzylpyridin-3-yl]oxy}phenyl)-1 Η-pyrrole-2-carboxylic acid benzyl ester-125-201036962 The compound synthesized in Example (16e) (2.96 g, 6.99 mmol) and Example (16a) The synthesized compound (1.39 g, 7.25 mmol) was dissolved in hydrazine, hydrazine-dimethylformamide (35 mL), and a mixture of carbonic acid (6.86 g, 21.1 mmol) was added, and the mixture was stirred at 100 ° C for 2 hours and a half under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water (100 mL) was added, and ethyl acetate (100 mL) was evaporated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Trifluoroacetic acid (10 mL) was added to dichloromethane (20 mL), and stirred at room temperature for 30 min. After the reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate (100 mL) was added to ethyl acetate The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the mixture was chromatographed using a gel column chromatography (solvent solvent··ethyl acetate/hexane = 2 5) %~5 0%) The obtained residue was purified to give the title compound (1. 23 g, yield: 37%) as a white solid. iH-NMR (CDC13, 400 MHz): δ 3,2 3 (3 Η, s), 3 · 8 5 (3 Η, s), 5.33 (2Η, s) 5 6.5 3 ( 1 Η, 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), 7.3 5-7.45 (6H, m), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.27 (1H, br s). (16g) 5-(3-methoxy-5-{[6-(methylsulfonyl)disorder-3-yl]oxy}phenyl)-1Η-pyrrole-2-carboxylic acid. 16f) The compound (i.22 g, 2.55 mmol) was dissolved in ethyl acetate (50 mL), and 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 of Celite, the residue was evaporated to dryness to dryness eluted elution elution *H-NMR (CDCI3, 400ΜΗζ) : δ 3.23 (3Η, 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), 8.5〇 (1H, d, J = 2.7 Hz), 9.44 (1H, br s). MS (FAB) m/z : 3 89 (M + H) + .

(1611)>^-[(28)-2,3-dihydroxypropyl]-5-(3-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy The compound synthesized by the example (16g) (946 mg, 2.44 mmol), (S)-(-)-3-amino-1,2-propanediol (by phenyl)-1 -pyrrole-2-carbamide ( 574 mg, 6.30 mmol), DMT-MM (1.98 g, 6.32 mmol). 'H-NMR (CDCh, 400MHz): δ 3.16-3.24 (2H, m), 3.23 (3H, s), 3.48-3.60 (4H, m), 3.79-3.86 (1 H, 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) + . (16丨) heart {(2 3)-2-hydroxy-3-[(triisopropyldecyl) Oxy]propyl}-5-(3-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1Η-pyrrole-2-carboxamide -127-201036962 The compound synthesized in Example (16h) (940 mg '2.04mm 〇l) was dissolved in dichloromethane (30 mL), triethylamine (〇.85 mL ' 6.13 mmol), triisopropyl chloride The house was cut (525 μί, 2.45 mmol), 4-dimethylamino-based succinimide (258 mg, 2.1 lm mmol), and stirred under a nitrogen atmosphere for 21 hours. The reaction mixture was diluted with dichloromethane (100 mL), washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified (jjjjjjjjjjjjjj ^-NMR (CDC13, 400MHz): δ 1.05-1.15 (21Η, 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)+o k. (16j)5-(3-methoxy- 5-{5-[(5R) -5-{[(Triisopropyldecyl)oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-111-pyrrol-2-yl}phenoxy 2-2-(Methanesulfonyl)pyridine The compound synthesized in Example (16i) (1.04 g, 1.68 mmol) was dissolved in tetrahydrofuran (2 mL). Amine (1.05111 [, 7.57111111〇1), 60° under nitrogen atmosphere (after stirring for 2 hours, heating under reflux for 1 hour. Add water (5 OmL) to the reaction mixture, and extract with ethyl acetate-128-201036962 (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 residue was purified by column chromatography (solvent solvent: methanol/dichloromethane = 0.5% to 3%). The title compound (9.55 mg, yield 94%) was obtained as pale yellow solid.

*H-NMR (CDC13, 400MHz): 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)-111-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5- The compound synthesized in Example (16_]) (943111 §, 1.57111111〇1) was dissolved in tetrahydrofuran (10 mL), tetrabutylammonium fluoride (1.0 mol/L tetrahydrofuran solution, 1.70 mL) was added. , 1.70 mmol), stirred at room temperature for 30 minutes under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution (5 mL) was added to the mixture, and ethyl acetate (100 mL) was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified (jjjjjjjd • H-NMR (CDCls, 400MHz): δ 3.00 (1Η, 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 -129- 201036962

Hz), 4.75-4.82 ( 1 H, 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: 444.1 20 1 2 (M + H) + 〇 (Example 17) {(5R)-2-[5-(3-ethoxy -5 {[6-(Methanesulfonyl)U is later than _3_yl]oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-anthracene Azol-5-yl}methanol

(17a) l - oxa-3-ethoxy-5-methoxybenzene The compound synthesized in Example (1 a) (4.1 0 g, 20.2 mmol) was dissolved in N,N - _ Methyl ugly fei ( lOOmL), add acetamidine (2.43mL, 30.4mmol), potassium carbonate (7.00 § '50.6111〇1〇1)' under nitrogen atmosphere at 60 ° (: stirring for 25 hours. Cool the reaction solution to room temperature, through the game After the potassium carbonate was removed by filtration, the residue was extracted with ethyl acetate (100 mL), and the mixture was evaporated to ethyl ether (1 mL). The solvent was distilled off under reduced pressure, and the obtained residue was purified (jjjjjjjjj ^-NMR (CDC13, 400MHz) : δΐ.40 (3Η, 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 201036962 (1H, m). (17b) 3-bromo-5-ethoxyphenol The compound synthesized in Example (17a) (4.75 g, 20.6 mmol), methoxy sulphur Sodium (1.56 g, 22.3 mmol) was obtained in the same manner as in Example (1) Colored solid of the desired compound (4.1 9g, 94% yield).

^-NMR (CDC13, 400MHz): δΐ.40 (3Η, t, J = 7.0Hz), 3.98 (1H, q, J = 7.0Hz), 6.32 (1H, t, J = 2.0Hz), 6.60 (1H , brs), 6.64 (1H, t, J = 2.0Hz). (17c)3-Ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-diindole Borane-2-yl)phenol The compound synthesized in Example (17b) (4.19 g, 19.3 mmol), dinacol borate (7.35 g, 28.9 mmol), [1, K-bis(diphenylphosphine) a ferrocene]palladium dichloride (methylene chloride) methylene chloride complex (790 mg, 0.967 mmol) of potassium acetate (9.47 g, 96.5 mmol), which was obtained in the same manner as in Example (Id). Compound (3.22 g, yield 63%). CJ ^-NMR (CDCh, 400MHz) : δΐ.33 (12Η, s), 1.39 (3H, t, J = 7.0Hz), 4.04 (2H, q, J = 7.0Hz), 6.52 (1H, t, J = 2.4Hz), 6.83 (1H, t, J = 2.4Hz), 6.92 (1H, t, J = 2.0Hz) ° (17d) 5-(3 -ethoxy-5-hydroxyphenyl)-lH - Ethyl pyrrole-2-carboxylate The compound synthesized in Example (17c) (3.22 g, 12.2 mmol) and the compound synthesized in Example (lg) (4.66 g, 14.6 mm 〇1) were dissolved in 1,4-dioxane. Mixed solvent of alkane (45mL) and water (15mL) 'Addition of bis(diphenylphosphino)ferrocene]-chlorinated (II)-chloromethyl compound (300mg, 0.367mmol), -131- 201036962 Potassium carbonate (3.4 g, 24-6 mmol) was stirred at 50 ° C for 19 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, water (50 mL) was added, and the mixture was extracted with diethyl ether (50 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The obtained residue was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (3OmL) was dropped. After stirring at room temperature for 1 hour under a nitrogen atmosphere, the solvent was evaporated under reduced pressure. Diluted with dichloromethane (5 OmL) and the mixture was partitioned with saturated aqueous sodium hydrogen carbonate (5OmL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluting eluted eluted eluted eluted eluted eluted eluted eluted elution %). iH-NMR (CDC13, 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 = 2.7 Hz), 9.73 (1H, brs). (17〇5-(3-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1Η- Ethyl pyrrole-2-carboxylate The compound synthesized in Example (17d) (3.18 g '1 1.6 mmol) was dissolved in N,N-dimethylformamide (80 mL). The compound synthesized in Example (16a) was added. (2.43g, 12.7mmol), carbonic acid (11.3g, 34.7mmol), stirred at 100 ° C for 17 hours under nitrogen atmosphere. After cooling the reaction solution to room temperature, 'add water (100 mL) to diethyl ether (100 mL) After extracting the organic layer, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The chromatographic analysis of the column was carried out using -132-201036962 (solvent solvent: ethyl acetate / hexane = 30% to 60%) The residue was purified to give the title compound (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj .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 = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.24 (1H, brs). (17〇>1-[(23)-2,3-dihydroxypropyl -5-(3-Ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1Η-pyrrole-2-carboxamide The example (17e The synthesized compound (3.18 g, 7.39 mm 〇l) was dissolved in ethanol (50 mL), and 5N aqueous sodium hydroxide solution (20 mL) was added, and the mixture was heated under reflux for 2 hours under nitrogen atmosphere. 2N hydrochloric acid (5 OmL) was added to the reaction mixture. 'The extract was extracted with ethyl acetate (5 mL), and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in methanol (1 mL). (S)-(-)-3-Amino-1,2-propanediol (1.7 〇g GSJmmol), DMT-MM (5.20 g '28.8 mmol)' was obtained as a white solid in the same manner as in Example (5d). Target (972 mg 'yield 2 8 %). !H-NMR (CDCb, 400 MHz): δ ΐ.44 (3 Η, t, J = 7.〇Hz), 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), 7.4 4 (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)° -133- 201036962 ( 17 £) 5-(3-Ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-&{(2 3)-2-hydroxy-3 -[(Triisopropyldecyl)oxy]propyl}-111-pyrrole-2-carboxamide The compound synthesized in Example (17f) (972 mg, 2.05 mmol) was dissolved in dichloromethane (40 mL) , adding triisopropyl decane chloride (483 μί, 2.26 mmol), triethylamine (860 μί, 6.17 mol), 4-dimethylaminopyridine (25 mg, 2.0 5 mmol) under nitrogen atmosphere It was stirred for 50 hours at room temperature, and water (40 mL) was added, and extracted twice with dichloromethane (30 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified (jjjjjjjjjjjj . W-NMR (CDC13, 400MHz): δΐ.01-1.14 (21H, m), 1.44 (3H, t, J = 7.0Hz), 3.23 (3H, s), 3.38 (1H, m), 3.60-3.7 8 (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 = 2.7 Hz), 9.90 (1H, brs). (1711) 5-(3-ethoxy-5-{5-[(5 ft)-5-{[(triisopropyldecyl) Oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-1^1-pyrrol-2-yl}phenoxy)-2-(methylsulfonyl) Pyridine was synthesized using the compound (975 mg, 1.55 mmol), carbaryl anhydride (540 mg, 3.10 mmol), triethylamine (1.08 mL, 7.75 mol) in the same manner as in Example (5e). The title compound was obtained as a white solid (85 6 mg, yield: 90% of 201036962).

^-NMR (CDCh, 400MHz) : δ0.95-1.12 (2 1 H, m), 1.42 (3Η, t, J = 7.0Hz), 3.23 (3H, s), 3.80-3.8 8 (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 (ih, 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-(methyl aryl))u~deep-3_yl]oxy}phenyl)-1Η-pyrrole 2-yl]-4,5-dihydro-i,3-oxazol-5-yl}methanol The compound synthesized in Example (17h) (856 mg, 1.39 mmol), tetrabutyl fluoride (1M tetrahydrofuran) The title compound (5 3 8 mg > yield 84%) was obtained as a white solid. 'H-NMR (CDC13, 400MHz): δΐ.43 (3Η, t, J = 7.0Hz), 3.22 (3H, s), 3.67 (1H, dd, J = 5.1, 12.5Hz), 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 = 2.7 Hz). MS (ESI) m/z: 45 8.1 3 85 8 (M + H)+. (Example 18) [(511)-2-{5-[3-{[6-(Methanesulfonyl)pyridin-3-yl]oxy}-5-(2,2,2-trifluoroethyl) Oxy)phenyl]-1H-pyrrol-2-yl}-4,5-dihydro-1,3-oxazol-5-yl]methyl-135- 201036962 alcohol

(18 a) 1-bromo-3-methoxy-5-(2,2,2-trifluoroethoxy)benzene The compound synthesized in Example (la) (4.10 g, 20.2 mmol) was dissolved in N. N-dimethylformamide (100 mL), 1,1,1-trifluoro-2-iodoethane (2,99 mL, 30.3 mmol), potassium carbonate (7.00 g, 50.6 mmol), nitrogen atmosphere % r Stir at 60 ° C for 25 hours. Further, 1,1,1-trifluoro-2-iodoethane (2.99 mL, 30.3 mmol) was added, and the mixture was stirred at 100 °C. Cool the reaction solution to room temperature,

After removing potassium carbonate by filtration through Celite, 1N hydrochloric acid (100 mL) was added, and extracted twice with diethyl ether (100 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified (jjjjjjjjjjj Rate ~1 0 0%). ^-NMR (CDC13, 400MHz): 53.79 (3H, s), 4.31 (2H, q, UJ = 8.2Hz), 6.44 (1H, t, J = 2.4Hz), 6.69 (1H, t, J = 2.0Hz , 6.76 (1H, t, J = 2.0 Hz). (18b) 3-bromo-5-(2,2,2-trifluoroethoxy)phenol. The compound synthesized in Example (18a) (5.76 g, 20.2 mmol), sodium methoxide (1 · 5 6 g ' 2 2.3 mmo 1) 'The title compound was obtained as a white solid (3. %). 'H-NMR (CDC13, 400MHz): 54.31 (2H, q, J = 8.2Hz), 6.40 (1H, -136- 201036962 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-dioxacyclopentan-2-yl)-5- (2,2,2-Trifluoroethoxy)phenol The compound synthesized in Example (18b) (3.57 g, 13.2 mm ο 1), benzoic acid pinacol ester (5.02 g, 19.8 mmol), [ 1,1,-bis(diphenylphosphino)ferrocene]--chlorination (II) _ chloroformine complex (540 mg, 0.661 mmol), potassium acetate (6.48 g '66.0 mmol) The title compound (4.1 g, yield 98%) was obtained. • H-NMR (CDC13, 400MHz): δΐ.34 (12Η, s), 4.35 (2Η, q, J = 8.2Hz), 6.59 (1H, t, J = 2.4Hz), 6.90 (1H, d, J = 2.4Hz), 6.94 (1 H,d,J = 2.4Hz). (18d) 5-[3-Hydroxy-5-(2,2,2-trifluoroethoxy)phenyl]-1H-pyrrol-2-carboxylic acid ethyl ester The compound synthesized in Example (18c) 4.11g, 12.9mmol), the compound synthesized in the example (lg) (4_93g, 15.5mmol), [1,K-bis(diphenyl(J phosphine)ferrocene]palladium(II) chloride dichloride The title compound (3.38 g, yield 80) was obtained as a pale yellow solid (yield %). 'H-NMR (CDC13, 400MHz): δΐ.40 (3H, t, J = 7,0Hz), 4.3 8 (2H, q, J = 7.0Hz), 4.38 (2H, q, J = 7.8 Hz), 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, 3.9 Hz), 9.84 (1H, brs). -137- 201036962 (18e) 5-[3-{[6-(methylsulfonyl)pyridin-3-yl]oxy} Ethyl 5-(2,2,2-trifluoroethoxy)phenyl]-1H-pyrrole-2-carboxylate The compound synthesized in Example (18d) (3.38 g, 10.3 mmol) was dissolved in N , N-dimethylformamide (80 mL). The compound synthesized in Example (16a) was added (2.16 g, 11.3 Methyl), carbonic acid planer (l〇.〇g, 30_7mmol), stirred at 100 ° C for 17 hours under nitrogen atmosphere. After cooling the reaction solution to room temperature, add water (100 mL) to diethyl ether (l〇〇mL) After extracting the organic layer, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and analyzed by chromatography using a gel column chromatography (solvent solvent: ethyl acetate / hexane = 30% - 60) %) The residue was purified to give the title compound (3························ 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 = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.31 (1H, brs). (18〇>1-[(23)-2,3-dihydroxypropyl]- 5-[3-{[6-(Methanesulfonyl)pyridin-3-yl]oxy}-5-(2,2,2-trifluoroethoxy)phenyl]-1H-pyrrole-2- The compound synthesized in Example (18e) (3.53 g, 7.29 mmol) was dissolved in ethanol (50 mL). Add 5 N aqueous sodium hydroxide (20mL), under a nitrogen atmosphere was heated at reflux for 2 hours. 2N hydrochloric acid (5 OmL) was added to the reaction mixture, and extracted with ethyl acetate (5 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. -138- 201036962 The obtained residue was dissolved in methanol (100 mL) using (S)-(-)-3-amino-1,2-propanediol (1.70 笆, 18.71111111 〇1), 〇]^7'-? 4]\/1 (5.2 (^, 28.8111111〇1)' The object obtained as a white solid (yield: 729 mg, yield: 9%) was obtained in the same manner as in Example (5d).

^-NMR (CDC13j 400MHz): 53.17 (3H, s), 3.29 (1H, m), 3.3 4-3.5 0 (3 H, m), 3.37 (1H, m), 4.40 (2H, q, J = 8.2 Hz), 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). (18g) N-{(2S)-2-hydroxy-3-[(triisopropyldecyl)oxy]propyl}-5-[3-{[6-(methylsulfonyl)pyridine-3 -Alkyloxy-5-(2,2,2-trifluoroethoxy)phenyl]-1H-pyrrole-2-carboxamide The compound synthesized in Example (18f) (729 mg, 1.38 mm 〇 l) Dissolved in dichloromethane (30 mL), adding triisopropyl decane chloride (3 25 μΙ>, 1.52 mmol), triethylamine (578 μί, 4.15 mol), 4-dimethylaminopyridine (170 mg) , 1.39 mmol), stirred at room temperature for 50 hours under a nitrogen atmosphere. Water (30 mL) was added and extracted with dichloromethane (30 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified (jjjjjjjjjjj ). 1H-NMR (CDC13, 400MHz): 51.00-1.14 (21H, m), 3.23 (3H, s), 3.34 (1Η, m), 3.60-3.76 (3 H, 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 -139- 201036962 (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- (Methanesulfonyl)-5-[3-(2,2,2-trifluoroethoxy)-5-{5-[(511)-5-{[(triisopropyldecyl)oxy Methyl}_4,5-dihydro-1,3-oxazol-2-yl]-111-pyrrol-2-yl}phenoxy]pyridine The compound synthesized in Example (18g) (583 mg, O. 85 1 mmol), methanesulfonic acid anhydride (300 mg, 1.72 mmol), triethylamine (600 μί, 4.3 0 mol), the title compound (53 1 mg, f yield 9 3 %). ^-NMR (CDC13, 400MHz): δ0.98-1.12 (21Η, 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 = 2.0 Hz), 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 = 2.7 Hz). (18i)[(5R)-2-{5-[3{[6-(Methanesulfonyl)pyridin-3-yl]oxy)}-5-(2,2,2-trifluoro Methoxy)phenyl]-1Η-pyrrol-2-yl}-4,5-dihydro-1,3-oxazol-5-yl]methanol The compound synthesized in Example (18h) (531 mg, 0.795) Mm 〇l), tetrabutylammonium fluoride (1M THF, 1.60 mL, 1.60 mmol)yield h-NMR (CDC13, 400MHz): 53.24 (3H, s), 3.71 (1H, dd, J = 5.1, 201036962 12·5Ηζ), 3.76 (1H, dd, J = 7.4, 14.1 Hz), 3.84 (1H, Dd, J = 3.1, 12.5 Hz), 4.04 (1H, dd, J = 9.4, 14.1 Hz), 4.41 (2H, q, J = 8.2 Hz), 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: 5 12.11031 (M + H) + 〇 (Example 19) [(5R)-2-{5-[3-(Difluoromethoxy)- 5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl]-111-pyrrol-2-yl}-4,5-dihydro-1,3-oxadazole-5- Methanol

(19a) 5-(3-Bromo-5-methoxyphenoxy)-2-(methylsulfonyl)pyridine

The compound synthesized in Example (la) (10.sup.., 53.2 mmol) was dissolved in hydrazine, dimethyl-dimethylformamide (300 mL). The compound (11.2 g, 58.4 mmol) synthesized in the Example (1 6a), and a carbonic acid (52.5 g, 161 mmol) were added, and the mixture was stirred at 1 ° C for 3 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, water (300 mL) was added and extracted with diethyl ether (20OmL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted eluted eluted eluted elution . 'H-NMR (CDC13, 400MHz): 53.23 (3H, s), 3.81 (3H, s), 6.58 (1H, t, J = 2.4Hz), 6.83 (1H, t, J = 2.4Hz), 6.96 ( 1H, t, -141- 201036962 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) (I7.9 g, 50.0 mmol), Boron bromide (1. 〇mol/L dichlorocarbyl solution, 100 mL, 100 mmol) was obtained as a white solid (17.2 g, yield -100%). ^-NMR (CDC13, 400MHz): 63.24 (3H, s), 6.53 (1H, t, J = 2.0Hz), 6.81 (1H, t, J = 2.0Hz), 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-[3t bromine - 5 -(Difluoromethoxy)phenoxy]-2-(methylsulfonyl)pyridine The compound synthesized in Example (19b) (3.77 g, 11 mmol) was dissolved in N,N-dimethylformamidine. Amine (100 mL) was added with chloro (difluoro)acetic acid methyl ester (1.74 mL, 16.5 mmol), EtOAc (. The reaction solution was cooled to room temperature, and the potassium carbonate was removed by filtration through Celite, and then 1N hydrochloric acid (1 mL) was added and extracted twice with diethyl ether (1 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted . ^-NMR (CDC13s 400MHz): δ3.24 (3Η, s), 6.54 (1H, t, J = 72.3Hz), 6.84 (1H, t, J = 2.0Hz), 7.09 (1H, t, J = 2.0 Hz), 7.21 201036962 (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 = 2.7 Hz) 〇(19d) 1H-pyrrole-2-carboxylic acid benzyl ester Benzyl bromide (2 〇 mL, 168 mmol) was dissolved in N,N-dimethylformamide (200 mL), and potassium carbonate (37.32 g) was added. , 27 0mmol). Pyrrole-2-carboxylic acid (5.03 g, 45.3 mm 〇l) was added portionwise with stirring at room temperature under a nitrogen atmosphere, and further stirred for 16 hours. Ethyl acetate (150 mL) was added and diluted. The insoluble matter was removed by filtration. The solution was separated by adding water (400 mL) and diethyl ether (200 mL), and 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 evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjj ) : δ 6.28 (1Η, q, J = 3.0 Hz), 6.95 -6.99 (2H, m), 7.3 2-7.44 (5H, m), 9.14 (1H, br s). (196)5-(4, The compound synthesized in the example (19d) (4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)-:^-pyrrole O -2-carboxylic acid benzyl ester ( 25.0 g, 124 mmol) was suspended in hexane (3 70 mL), and benzoic acid pinacol ester (16.0 g, 63.0 mm 〇l), 4,4'-di-t-butyl-2,2,dipyridyl group was added. (500 mg, 1.86 mmol), methoxy (cyclooctadiene) ruthenium (I) dimer (617 mg, 0.931 mmol), and stirred at 50 ° C for 1 hour. Ethyl acetate (300 mL) was added to the reaction mixture, and the mixture was washed twice with water (150 mL). The solvent was evaporated under reduced pressure, and the residue was evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj H-NMR (CDC13, 400MHz): δ 1 · 3 2 (1 2 H, s), 5 · 3 2 (2 H, 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 (IH, br s). MS (El) m/z : 327 (M + ). (19f)5-[3 -(Difluoromethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl]-1H-pyrrole-2-carboxylic acid benzyl ester using Example (19c) Synthetic compound (2.32g, 5.8 9mmol), real

Example (19e) Compound (2.50 g, 7.64 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride complex (145 mg, 0.178) Methyl acetate (2.44 g, 17.7 mmol). W-NMR (CDC13, 400MHz): δ3·24 (3H, s), 5.34 (2H, s), 6.56 (1Η, dd, J = 2.7, 3.9Hz), 6.58 (1H, t, J = 72.7Hz) , 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), 7.3 5-7.45 (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) =>(19 8)5-[3-(Difluoromethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl]->1-[ (2 3)-2,3-Dihydroxypropyl]-111-pyrrole-2-carboxamide The compound synthesized in Example (19f) (2.37 g, 4.61 mmol) was dissolved in tetrahydrofuran (5〇1111〇, A 10% palladium carbon catalyst (1. 〇〇§) was added, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The palladium carbon catalyst was removed by filtration through Celite, and washed with ethyl acetate at -144 - 201036962. The solvent was distilled off under reduced pressure. The obtained residue was dissolved in methanol (5 mL) using (S)-(-)-3-amino-1,2-propanediol (840 mg, 9.22 mmol), DMT-MM (3.20) g, 11.6 mmol), m.p. (m. • H-NMR (CDC13, 400MHz): 53.25 (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 = 72.7 Hz), 6.65 (1H, t, J = 3.1 Hz), 6.81 (1H, t, J = 2.4 Hz), 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-[(triisopropyl) The compound synthesized in the example (19g) (1.93 g, 3.8 8 mmol) was dissolved in dichloromethane (40 mL) and hydrazine, Ν·············· a mixed solvent of methylformamide (2 mL), added triisopropylsulfonium chloride (1.08 mL, 5.05 mmol), triethylamine (1.62 mL, 11.6111〇1), 4-dimethylamino group Pyridine (4 8 〇 111 §, 3.93111111 〇 1) was stirred at room temperature for 21 hours under a nitrogen atmosphere. Water (40 mL) was added and extracted with dichloromethane (40 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluting with EtOAc EtOAc EtOAc (EtOAc: EtOAc . 'H-NMR (CDCb, 400MHz): δΐ.04-1.16 (21Η, m), 3.07 (1H, t, -145- 201036962 J = 3.9Hz), 3.39 (1H, m), 3.67 (1H, dd, J = 6.3, 9.8 Hz), 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), 8.5 0 (1 H,d,J = 2 · 7 H z),9 · 7 6 (1 H , brs). (19)) 5-[3-(Difluoromethoxy)-5-{5-[(511)-5-{[(triisopropyldecyl)oxy]methyl}-4,5- Dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy]-2-(methylsulfonyl)pyridine The compound synthesized in Example (19h) (2.08 g, 3.18 mmol), a castanic anhydride (1.17 g, 6.72 mmol), triethylamine (2.22 mL, 1.5.9 m〇l). The title compound was obtained as a white solid in the same manner as in Example (16j). .45g 'yield 72%. ^-NMR (CDC13, 400ΜΗζ): δΐ.03-1.12 (21Η, m), 3.24 (3Η, s) 3.81-3.91 (3H,m), 4.00 (1H,dd,J = 9.4, 14.5Hz), 4.76 (1 shirt, 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 (1 H 5 brs), 7.48 (1H, dd, J = 2.7, 8.6Hz), 8.08 (1H,d, J = 8.6HZ), 8.50 (1H, d, J = 2.7 Hz). (19))[(511)-2-{5-[3-(Difluoromethoxy)-5-{[6-(methylsulfonyl)pyridine-3' [oxy}phenyl]-1H-pyrrol-2-yl}-4,5-dihydro-i,3-oxazol-5-yl]methyl leaver. The compound synthesized in Example (19i) (i.45g) , 2.28 mm (1), tetrabutylammonium fluoride (1 mol/L tetrahydrofuran solution ' 2.74 mL, 2.74 mmol), -146-201036962 , yield 91%). • H-NMR (CDC13, 400MHz): 53.24 (3 H, 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 : 480.1 0409(M + H)+. (Example 20) [(5R)-2-{5-[3-(Cyclopropyloxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl] -111-pyrrol-2-yl}-4,5-dihydro-1,3-oxazol-5-yl]methanol

(20a) 1,3-tribromo-5-(2-chloroethoxy)benzene

3,5-Tribromophenol (7.00 g, 27.8 mm 〇l) was dissolved in toluene (200 mL), and 2-chloroethanol (2.23 mL, 33.4 mmol) and triphenylphosphine (8.02 g, 30.6 mmol) were added. Diethyl azocarboxylate (40% toluene solution, 15.2 mL, 33.4 mmol) was added dropwise at 〇 ° C, and stirred at room temperature for 1 hour under nitrogen atmosphere. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the resulting insoluble matter was removed by filtration. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted elution -147- 201036962 *H-NMR (CDCI3, 400MHz): δ3.8〇(2H, t, J = 5.9Hz), 4.20 (2H; t, J = 5.9Hz), 7.02 (2H, d, J = 2 .〇Hz), 7.29 (1H, t, J = 2.0Hz)·(20b) 1,3-tribromo-5-(vinyloxy)benzene The compound synthesized in the example (20&) (87/^ , 2 7.8111111 〇 1) Dissolved in tetrahydrofuran (200 mL) 'Addition of potassium t-butoxide (4.10 g '36.5 mmol) at 0 °C. After stirring at room temperature for 1 hour under a nitrogen atmosphere, water (200 mL) was evaporated and evaporated. The solvent was distilled off under reduced pressure. The resulting insoluble material was removed by filtration and washed with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography (eluent solvent hexane) to give the object (yield: s. *H-NMR (CDC13, 400MHz): 54.57 (1 H, dd, J = 2.0, 5.9 Hz), 4.86 (1H, dd, J = 2.0, 13.7 Hz), 6.55 (1H, dd, J = 5.9. 13.7 Hz), 7.10 (2H, d, J = 2.0 Hz), 7.38 (1H, t, J = 2.0 Hz). (20c) l,3-tribromo-5-(cyclopropyloxy)benzene. (20b) The synthesized compound (9.72 g, 33.3 mmol) was dissolved in 1,2-dichloroethane (300 mL), and chloro(iodo)methane (14.8 mL, 203 mmol) was added at -78 °C. 1.09 M hexane solution, 100 mL, 109 mmol), trifluoroacetic acid (8 〇〇μΙ>, 10.4 mm 〇l). The mixture was stirred for 1 hour while gradually raising the temperature to room temperature under a nitrogen atmosphere, and further stirred at 70 ° C for 17 hours. After cooling the reaction mixture to room temperature, 1N hydrochloric acid (20 mL) was added and extracted twice with diethyl ether (200 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified (jjjjjjjjjjjjjj H-NMR (CDC13, 400MHz): δ 0.75-0.83 (4 Η, 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 synthesized in Example (20 c) (5.62 g, 19.2 mmol) was dissolved in diethyl ether (150 mL), and butyl lithium (1.65 mol/L hexane solution, 12-8 mL, 21.1 mmol) was added at -78 °C. ). 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 solution was cooled to 〇 ° C, and acetic acid (3.63 mL, 63.4111111 〇 1) and 30% hydrogen peroxide water (7, 401111 >, 65.3111111 〇 1) were sequentially added dropwise. After stirring at room temperature for 21 hours, water (100 mL) was added to separate the layers. The organic layer was washed with a saturated aqueous solution of sodium thiosulfate and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified to crystals crystals eluted eluted eluted eluted eluted eluted eluted eluted 〇%). *H-NMR (CDCh, 400MHz): 50.74-0.80 (4Η, 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). (2(^)5-[3-Bromo-5-(cyclopropyloxy)phenoxy]-2-(methylsulfonate) The compound synthesized in the example (20d) (4.41 g, 19.2 mmol) was dissolved in N,N-dimethylformamide (20 mL). The compound synthesized in Example (16a) was added (4.00 g). , 20.9 mmol), potassium carbonate (8.00 g, 57.9 mmol), stirred under nitrogen atmosphere -149-201036962 at 1 ° C for 20 hours. After cooling the reaction mixture to room temperature, water (200 mL) was added to diethyl Ether (200 mL) was extracted twice. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the mixture was chromatographed using a gel column chromatography (solvent solvent: ethyl acetate / hexane = 30) The residue was purified to give the title compound (yield (yield: EtOAc) (yield: EtOAc, EtOAc (EtOAc) s), 3.72 (1H, m), 6.70 (1H, t, J = 2.4Hz), 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). (2 0〇5-[3-(cyclopropyloxy)-5-{[6-(A Benzylsulfonyl)pyridin-3-yl]oxy}phenyl]-1H-pyrrole-2-carboxylic acid benzyl ester The compound synthesized in Example (2〇e) (6.00 g, 15.6 mmol), Example (19e) Synthetic compound (6.64 g, 20.3 mmol), [1, K-bis(diphenylphosphino)ferrocene]palladium(II) chloride complex (390 mg, 0.478 mmol), potassium carbonate (6-47 g, 46.8 mmol), m. Compound Compound Compound Compound Compound Compound Compound Compound Compound 4Η, m), 3.23 (3H, s), 3.77 (1H, m), 5.33 (2H, s), 6.53 (1H, dd5 5 = 2.1, 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) 5 8.49 ( 1 H, brs), 9.35 (1H, brs). -150- 201036962 (20g) 5-[3-(Cyclopropoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl]-N-[(2S) -2,3-Dihydroxypropyl]-1H-pyrrole-2-carboxamide The compound synthesized in Example (20f) (2.62 g, 5.19 mm) was dissolved in tetrahydrofuran (50 mL), and 10% palladium carbon was added. The catalyst (1.50 g) was stirred at room temperature for 4.5 hours under a hydrogen atmosphere. The palladium carbon catalyst was removed by filtration through Celite, and washed with ethyl acetate. The solvent was distilled off under reduced pressure.

The obtained residue was dissolved in methanol (50 mL), using (S)-(-)-3-amino-1,2-propanediol (710 mg, 7.79 mmol), DMT-MM (3.59 g > The object of the white solid (2.14 g, yield: 85%) was obtained. 'H-NMR (CDC13, 400ΜΗζ): δΟ.78-0.82 (4Η, 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 (1 H,d,J = 8 · 6 Hz) , 8.45 (1H, d, J = 2.7 Hz), 10.20 (1H, brs). (201〇5-[3-(cyclopropyloxy)-5-{[6-(methylsulfonyl)pyridine- 3-yl]oxy}phenyl]-N-{(2S)-2-hydroxy-3-[(triisopropyldecyl)oxy]propyl}-lH-pyrrole-2-carboxamide Example (2 g) of the compound (2.14 g, 4.39 mmol) was dissolved in dichloromethane (50 mL), triisopropyl hexane (1.22 mL, 5.70 mmol), triethylamine (1.84 mL, 13.2mol), 4-dimethylaminopyrrolidine (5 40mg, 4.42mm 〇l), stirred at room temperature for 18 hours under nitrogen atmosphere. Add-151- 201036962 Add water (50 mL) to dichloromethane (50 mL) The extract was washed twice, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The layer was analyzed (eluent solvent: ethyl acetate / hexane = 40% - 60%). The obtained residue was purified to afford white crystals (yield: 207 g, yield: 71%). H-NMR (CDC13, 400 MHz) : 50.80-0.85 (4Η, 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 = 2.4 Hz), 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). (20丨) 5-[3-(Cyclopropyloxy)-5-{5-[(511)-5-{[(triisopropyldecyl)oxy]methyl}-4,5- Dihydro-1,3-0-oxazol-2-yl]_1H-pyrrol-2-yl}phenoxy]-2-(methylsulfonyl)pyridine

The compound synthesized in Example (2 Oh) (2.00 g, 3 · 1 1 mmol), methanesulfonic anhydride (1.14 g, 6.54 mmol), triethylamine (2.17 mL, 15.6 mol), and the example (16j) The same procedure gave the title compound as a white solid (y-79 g, yield 92%). ^-NMR (CDC13, 400MHz): δ0.80-0.84 (4Η, 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, 1 = 2.1, 8.6Hz), -152- 201036962 8.05 (1H,d,J=8.6Hz), 8.49 (1H,d,J = 2.7Hz). (2 0j)[(5R)-2-{5-[3-(cyclopropyloxy)- 5-{[6-(methylsulfonyl)pyridine-3-yl]oxy}phenyl]-1Η-pyrrol-2-yl}-4,5-dihydro-1,3-oxazol-5-yl Methanol The compound (1.79 g, 2.86 mmol) synthesized in Example (2〇i), tetrabutylammonium fluoride (1 mol/L tetrahydrofuran solution, 3,43 mL ' 3.43 mm 〇l) was used in the same manner as in Example (1). 6k) The title compound (1.26g, yield: 94%), mp (yield: 94%): NMR (CDC13, 400MHz): 60.79-0.84 (4H, m), 3.23 (3H, s),

O 3.68-3.79 (3H, m), 3.85 (1H, dd, J = 3.1, 12.5Hz), 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 =1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz). MS (ESI) m/z : 470.1 3 85 8(M + H)+ 〇 (Example 21) 〇5-(3-{5-[(5R)-5-(hydroxymethyl)-4,5-dihydro-1,3- Methyl oxazol-2-yl]-1H-pyrrol-2-yl}-5-methoxyphenoxy)pyridine-2-carboxylate

(21a) 5-(3-Pentyl-5-methoxyphenyl)-1Η-pyrrole-2- decanoic acid sulfonate The compound synthesized in Example (la) (5. g, 24.6 mmol), Example (19e) synthesized compound (8.46g '25.9mm〇l), [1,1'-bis(diphenylphosphino)-153-201036962 ferrocene]palladium(II) dichloride methylene chloride The title compound (5.83 g, yield: 73%) was obtained as a brown solid (yield: EtOAc, m. ^-NMR (CDCb, 400MHz): δ 3 . 8 3 (3 Η, s), 5.16 (1 Η, s), 5.34 (2Η, 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 -7.3 5 (5H, m) , 9.32 (1H, s).

(2 lb) 5-(3-hydroxy-5-methoxyphenyl)-lH-pyrrole-2-carboxylic acid The compound synthesized in Example (21a) (2.00 g, 6.19 mmol) was dissolved in ethyl acetate. 40 mL), 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 filtration through Celite, and washed with tetrahydrofuran. The solvent was evaporated under reduced pressure to give the title compound Compound Compound Compound Compound Compound Compound Compound Compound Compound Compound Compound Compound

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)-1Η-pyrrole-2-carboxamide The examples ( 21b) The synthesized compound (500 mg ' 2.14 mmol), N-methylmorpholine (〇.47 mL, 4.29 mmol) was dissolved in N,N-dimethylformamide (10 mL), and WSCI.HCl was added at room temperature. (493 mg, 2.57 mmol), (S)-(-)-3-amino-1,2-propanediol (215 kL, 2.36 mm 〇1), and stirred for 14 hours under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (60 mL), washed with saturated sodium hydrogen carbonate aqueous------ The solvent was evaporated under reduced pressure, and the residue was purified eluted eluted elut elut elut elut elut elut elut elut elut elut 'H-NMR (CDC13, 400MHz): δ 3.39 (2Η, 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-[(triisopropyldecyl)oxy]propyl}-5-{3-methoxy-5-[(triisopropyl)矽alkyl)oxy]phenyl}-1Η-pyrrole-2-carboxamide The compound synthesized in Example (2lc) (4〇〇mg, 1.3lmmol) was dissolved in N,N-dimethylformamide (l〇mL), adding triethylamine (〇.91mL, 6.53mmol), triisopropyl decane chloride (〇.84mL ' 3.92mmol), 4-dimethylaminopyridyl (239mg' 1.96mmol) ), stirring for 15 hours under a nitrogen atmosphere. CJ was diluted with ethyl acetate (5 mL) and washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified using silica gel column chromatography (eluent solvent: ethyl acetate / hexane = 0% to 50%) to afford white crystals (yield: 619mg, 77%).

'H-NMR (CDC13, 400MHz): δ 1.07- 1.1 3 (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 -155- 201036962 =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- [(Triisopropyldecyl)oxy]phenyl}-1Η-pyrrol-2-yl)-5-{[(triisopropyldecyl)oxy]methyl}-4,5-dihydro -1,3-carbazole. The compound (619 mg, 1.0 mmol) synthesized from the compound (21d), and the anhydride (348 mg, 2.00 mmol) of 'triethylamine (0.42 mL, 3_0 mmol)' was used in the examples. (1 6j) The title compound (298 mg, yield 50%) *H-NMR (CDC13, 400MHz): δ 1.05 (18Η, 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-i,3_ oxazol-2-yl]-1H-pyrrol-2-yl}-5-methoxyphenol The compound synthesized in Example (21e) (297 mg, 0.50 mmol) The title compound (102 mg, yield 72%) was obtained as a white solid (yield: EtOAc, m. • H-NMR (CD3OD, 400MHz): δ 3.78 (i H, dd, J = 1 2.3 , 5 . 3 Ηz) 5 3 . 8 2 (3 H, s), 3 · 9 3 - 3 · 9 9 ( 2 H,m),4.1 7 (1 H,dd,J = 1 3 . 7,9.8 -156- 201036962

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). (21g) 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 (5 mL), and acetic acid IE (484 mg, 2.16 mmol), 1 , P-bis(diphenylphosphino)ferrocene (2.39 g, 4.32 mmol), triethylamine (6.0 mL, 43.2 mmol), stirred at room temperature for 3 days under a carbon monoxide atmosphere, and insoluble in the filtered reaction solution Things. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted eluted eluted 6%). iH-NMR (CDC13, 400MHz): 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 Methyl-1H-pyrrol-2-yl}-5-methoxyphenoxy)pyridine-2-carboxylate The compound synthesized in Example (2 If) (420 mg, 1.4 5 mmol) and Example (21 g) The compound (224 mg, 1.44 mmol) was dissolved in N,N-dimethylformamide (5 mL). The reaction solution was cooled to room temperature, and water (3 mL) was evaporated. After washing the organic layer with saturated brine, • 157-201036962 was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was evaporated to mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ^-NMR (CDCI3, 400MHz): δ 3.73 (1Η, 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), 4.8 5 -4.79 ( 1 H, 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 = gg, 2.9 Hz), 8.13 (1H, d, J = 8.3 Hz), 8.54 (1H, d, J = 2.4 Hz). MS (ESI) m/z : 424.1 5078 (M + H)+ . (Example 22) 5-(3-{5-[(5R)-5-(hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrole-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, 〇.71 mmol) synthesized in Example (21h) was dissolved in tetrahydrofuran (1 mL), and methanol (1 mL) was added. After water (4 mL) and lithium hydroxide monohydrate (89 mg, 2.13 mmol), the mixture was stirred at 60 ° C for 1.5 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and 2N hydrochloric acid was added to be acidic. The solvent was evaporated under reduced pressure - EtOAc (EtOAc) (yield: 100%).

!H-NMR (CD3〇D, 400MHz) : δ 3 · 8 1 (1 H, dd, J = 1 3.2, 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). (221>) 5-(3-{5-[(511)-5-(hydroxymethyl)-4,5-dihydro -1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-methoxyphenoxy)-N-methylpyridine-2-carboxamide The examples (22 &) The synthesized compound (7〇11^, 〇.17111111〇1) was dissolved in N,N-dimethylformamide (1 mL), and HOBt·H20 (29 mg, 0.19 mmol), methylamine hydrochloride (23111) was added. §, 0.34111111〇1), 18 (:1· HCl (39 mg '0.21 mmol)' was stirred under a nitrogen atmosphere for 14 hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water and brine, and evaporated. Drying over magnesium sulfate, distilling off the solvent under reduced pressure, using a silica gel column chromatography (solvent solvent··methanol/dichloromethane=3 %~1 〇%) pure The residue was obtained to give the title compound (mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjJ 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 (1 H, m), 6.47 (1H, d, J = 3.4 Hz), 6.51 (1H, t, J = -159- 201036962 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 · 1 6652 (M + H)+. (Example 23) l-[5-(3-{5-[(5R)-5-(Hydroxymethyl)-4,5--hydro-1,3-propanol-2-yl]- 1H_pyrrol-2-yl}-5-methoxyphenoxy)pyridin-2-yl]ethanone

(23&) 5-Fluoro-1methoxy-~methylpyridine-2-carboxamide A 5-fluoro-2-pyridyl D-dicarboxylic acid (200 mg, 1.42 mmol) was dissolved in dichloromethane (1 mL) > Add HOBt, H2 〇 (239 mg, 1.56 mmol), hydrazine, hydrazine-dimethylhydroxylamine hydrochloride (277 mg, 2.83 mmol), WSCI · HCl (543 mg, 2.83 mmol), triethylamine (0.98) (mL, 7.09 mmol), stirred under a nitrogen atmosphere for 15 hours. The reaction mixture was diluted with ethyl acetate (20 mL), and evaporated. The solvent was distilled off under reduced pressure. The residue was purified using EtOAc EtOAc EtOAc (EtOAc:EtOAc .). • H-NMR (CDC13, 400MHz): 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). -160- 201036962 (23b) 1-(5-fluoropyridin-2-yl)ethanone The compound synthesized in Example (23a) (2i3 mg, 1.16 mmol) was dissolved in tetrahydrofuran (5 mL) ), cooled to -78 t. Methyl iodide (3.0 mol/L tetrahydrofuran solution, 〇. 58 mL, 1.74 mmol) was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (3 mL), washed with saturated aqueous sodium chloride and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluted eluted eluted eluted eluted 44%) ° *H-NMR (CDC13, 400MHz): δ 2.74 (3 Η, s), 7 5 4 (1 Η, 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) l-[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 the example (23b) and the compound (125 mg, 〇.43 mmol) synthesized in the compound (21f) were dissolved in N,N-dimethylacetamide (2 mL), and added. Potassium carbonate (120 mg, 0.87 mmol) was stirred at 80 ° C for 3 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, then water (3 mL) was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluting eluted eluted eluted eluted elut elut elut elut elut elut lH-NMR (CDC13, 400MHz): δ 2.7Ο (3 Η, s), 3 _ 72 (1 Η, dd, J -161- 201036962 = 12.1, 5.5 Hz), 3.82 (4H, td, J = 8.4, 5.3 Hz), 3.89 (ih dd J = 12.1, 3.1 Hz), 4.05 (1H, dd, J = 14.5, 9.8 Hz), 4.79-4.85 (IH, m), 6.49 (IH, d, J = 3.9 Hz) , 6.53 (1H, s), 6.76 (ih, 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 : 40 8.1 5 504 (M + H)+. (Example 24)

5-(3-{5-[(5R)-5-(hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl μ1Η_[^ -2-yl}-5- Methoxyphenoxy)-indole-methylpyridine-2-sulfonamide

(24a) 5-Chloropyridine-2-thiol 2,5-Dichloropyridine (5.00 g, 33 • 8 mmol) was dissolved in dimethyl hydrazine (35 mL) under nitrogen atmosphere, and sodium disulfide nonahydrate (9.00) was added. After g, 37.2 mm 〇 l), the mixture was stirred at 120 ° C for 2 hours. The reaction solution was cooled to room temperature, and water (50 mL) was added and then neutralized with 5 N hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and hexane, and then purified using a silica gel column chromatography (solvent solvent: methanol/dichloromethane = 〇% to 10%) to give the title compound as a yellow solid. 2.2 8g, yield 4 6%) ° ^-NMR (CDC13, 400MHz) δ 2.63 (1Η, s), 7.34 (lH, 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-162- 201036962

The compound (1. g, 6.87 mm) which was synthesized in Example (24a) was dissolved in dichloromethane (30 mL) / 1 N hydrochloric acid (30 mL) and cooled to -5 1 . While maintaining the reaction solution below 〇 ° C, an ice-cold 5% sodium persulfate aqueous solution (3 OmL) was added thereto, and the mixture was stirred for 15 minutes. The organic layer was extracted with a pre-cooled seperate funnel, cooled to -78 ° C, and then a commercial 40% methylamine/methanol solution (1.33 mL ' 17.2 mmol) in dichloromethane (1 mL) Stir for 2 hours at 〇 °c. Water (5 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (3OmL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluting eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted ). ^-NMR (CDC13, 400MHz): δ 2 · 7 7 (3 Η, d, J = 4 · 9 Η z), 4.8 1 (1Η, 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-Sulcoguanamine The compound synthesized in Example (24b) (889 mg, 4.30 mmol) was dissolved in hydrazine, dimethyl-dimethylcarbamide (15 mL), and sodium hydride (172 mg, 4.30 mmol) was added. After ice-cooling, p-methoxybenzyl chlorohydrazine. 7 〇 mL, 5.16 mmol) was added, and the mixture was warmed to room temperature and stirred for 3 hours. Water (2OmL) was added to the mixture, and the mixture was extracted twice with ethyl acetate (2OmL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted elution ). -163- 201036962 ^-NMR (CDC13, 400MHz) : 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

The compound (i 〇 5 mg, 0.32 mmol) synthesized in Example (24c) and the compound (I 39 mg, 0.48 mmol) synthesized in Example (21f) were dissolved in N,N-dimethylformamide (1.5 mL). The carbonic acid planing (314 mg, 0.96 mmol) was added, and the mixture was stirred at 1 ° C for 1.5 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, then water (3 mL) The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluting with EtOAc EtOAc EtOAc . • H-NMR (CDC13, 400MHz): δ 2 · 7 9 (3 Η, s), 3.7 4 (2 Η, td, JQ = 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), 4.7 8 -4.84 ( 1 H, 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), 6.8 6-6.8 8 (3 H, 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--164- 201036962

The compound synthesized in the example (24d) (81 mg, 0.14 mmol) under a nitrogen atmosphere under a nitrogen atmosphere of -1H-pyrrol-2-yl}-5-methoxyphenoxy)-N-methylpyridine-2-sulfonamide. Dissolved in trifluoroacetic acid (0.5 rnL) and dichloromethane (5 mL) and stirred for 16 hours. A saturated aqueous solution of sodium hydrogencarbonate (2 mL) was added and the mixture was extracted twice with dichloromethane (20 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was evaporated to mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

!H-NMR (CDC13s 400MHz) : δ 2 · 7 6 (3 Η, d, J = 3 · 4 Hz), 3 · 7 2 (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, d5 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). u MS (ESI) m/z : 459.1 3442 (M + H) +. (Example 25) {(5R)-2-[5-(3-{[6-(azetidin-1-ylsulfonyl)pyridin-3-yl]oxy}-5-methoxy Phenyl)-111-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl} Methanol

-165 201036962 (2 5 &) 2-(azetidin-1-ylsulfonyl)-5-chloropyridine The compound synthesized in Example (24 a) (1. g, 6, 87 mmol) Dissolved in dichloromethane (30 mL) / 1 N hydrochloric acid (30 mL), cooled to - 5 °C. While maintaining the reaction solution below 〇 ° C, the ice-cold 7 % aqueous sodium perchlorate solution (3 OmL) was dripped and stirred for 15 minutes. The organic layer was extracted with a pre-ice-cold separatory funnel'cooled to -78 ° C and a commercially available azetidine hydrochloride (2-24 mg ' 17.2 mmol) of methylene chloride suspension (10 mL) was added. Wet to sputum.搅拌 Stir for 30 minutes. Water (30 mL) was added to the reaction mixture, and ethyl acetate (30 mL) was evaporated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The obtained residue was purified (yield: ethyl acetate / hexane = 5% to 60%) to afford the title compound ( 735 mg, yield 46%). NMR (CDC13j 400 MHz): δ 2.19-2.25 ( 2Η, 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). (2 5b){(5R)-2-[5-(3-{[6-(azetidin-1-ylsulfonyl)pyridin-3-yl](oxy} -5-Methoxyphenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol The compound synthesized in Example (25&) (10011 ^, 0.43111111〇1) and the examples (2 1〇 synthesized compound (16111^, 0.56«1111〇1) dissolved in >1, :^-dimethylformamide (3mL), added carbonic acid planing (280mg) The mixture was stirred for 2 hours at 10 ° C under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water (2OmL) was then evaporated. After washing the organic layer with saturated brine, the mixture was dried over anhydrous magnesium sulfate - 166 - 201036962. The solvent was evaporated under reduced pressure and purified by chromatography on silica gel column (solvent solvent: methanol / dichloromethane = 1% to 5%) The residue was obtained to give the title compound (lll,

!H-NMR (CDC13j 400MHz) : δ 2.18-2.24 (2Η, m), 3.72 (1Η, 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 : 4 8 5.1 4698 (M + H)+. (Example 26) [(511)-2-{5-[3-Methoxy-5-({6-[(methoxymethyl)sulfonyl]pyridin-3-yl}oxy)benzene Base]-111-pyrrol-2-yl}-4,5-dihydro-1,3-oxazol-5-yl]methanol

(2 6a) 5-Chloro-2·[(methoxymethyl)thio]pyridine The compound synthesized in Example (24a) (200 mg, 1.37 mmol) was dissolved in methanol (51111 〇 '添力卩28%甲甲Sodium oxyhydroxide/methanol solution (0.3〇1111^'1.55111111〇1), methoxymethyl chloride (0.23 mL, 3.01 mmol), and stirred at 50 ° C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and then added. Water (20 mL) was extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate - 167 - 201036962. The solvent was distilled off under reduced pressure. The obtained residue was purified (yield: ethyl acetate / hexane = 0% to 20%) to afford the desired compound (188 mg, yield: 74%). NMR (CDC13, 400 MHz) δ 1.51 ( 3Η, 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). (2 6 b) 5-Chloro-2-[(methoxymethyl)sulfonyl]pyridine

The compound (187 mg, 0.99 mmol) which was obtained from the compound (26a) was dissolved in dichloromethane (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 (3 mL) was added to the reaction mixture, and the mixture was extracted twice with dichloromethane (3OmL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluting eluted eluted eluted eluted eluted 8 5 %). ^-NMR (CDCI3, 400MHz): δ 3 · 66 (3 Η, s), 4 · 8 8 (2Η, s), 7.98 (1Η, dd, J = 8.3, 2.4 Hz), 8.12 (1H, d, J = 8.3 Hz), 8.75 I | (1H, d, J = 2.0 Hz). (26c)[(5R)-2-{5-[3 -methoxy- 5-({6-[(methoxy) Methyl)sulfonyl]pyridin-3-yl}oxy)phenyl]-1H-pyrrol-2-yl}-4,5-dihydro-1,3-oxazole-5-yl] Methanol The compound (185rng, 〇.83mmol) synthesized in Example (26b) and the compound (360mg, 1.25mmol) synthesized in Example (21f) were dissolved in N,N-dimethylformamide (3mL). 23 1mg, i.67mrn〇l), under nitrogen atmosphere -168- 201036962

Stir at 100 ° C for 2 hours. The reaction solution was cooled to room temperature, water (30 mL) was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was evaporated to mjjjjjlililililililililililili ^-NMR (CDC13, 400MHz): δ 3.6 7 (3 Η, s), 3.7 5 (1 Η, 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: 474.1 3 3 1 2 (M + H)+. (Example 27) {(511)-2-[5-(3-{[6-(Cyclopropylsulfonyl)pyridin-3-yl]oxy}-5-methoxyphenyl-1H- Pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol

(27&) 5-Chloro-2-[(3-chloropropyl)thio]pyridine The compound synthesized in Example (24a) (600 mg, 4.12 mmol) was dissolved in methanol (15 mL) Sodium/methanol solution (〇.95 mL, 4.94 mmol), 1-Methyl-3-chloropropene (〇.61 mL, 6.18 mmol), at 6 〇. Harmful -169- 201036962 Mix for 1.5 hours. The reaction solution was cooled to room temperature, water (40 mL) was evaporated, The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. ^-NMR (CDC13, 400MHz): δ 2.21-2.14 (2Η, 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). i (2 71>)5-chloro-2-[(3 -Chloropropyl)sulfonyl]pyridine The compound synthesized in Example (27 &) (8461^, 3.8〇111111〇1) was dissolved in dichloromethane (20 mL), and then, after cooling, m-chloroperbenzoic acid (2.02 g) , 7.62 mmol), stir for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate (40 mL) was added to the mixture, and the mixture was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (solvent solvent: ethyl acetate / hexane = 0% to 20%) to afford the title compound (73 3 mg, yield 7 6%). 'H-NMR (CDCI3, 400MHz): δ 2.26-2.3 1 (2Η, 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)-(27〇5-chloro-2-(cyclopropylsulfonyl)pyridine will be implemented The compound (274 mg, 3.05 mmol) synthesized in Example (27b) was dissolved in tetrahydrofuran (10 mL), and then cooled to -30 ° C, then potassium butoxide-170-201036962 (5 8 2 mg, 5.1 8 mmol) was added thereto. After stirring for 30 minutes, a saturated aqueous solution of ammonium chloride (4 mL) was added to the mixture, and the mixture was extracted twice with dichloromethane (4OmL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified using EtOAc EtOAc (EtOAc: EtOAc EtOAc EtOAc -NMR (CDC13, 400MHz) : δ 1.07-1.12 (2Η, m), 1.37-1.41

(2H, m), 2.76-2.83 (1 H, 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-methoxybenzene The compound synthesized in Example (27c) (266 mg, 1.22 mmol) and the example (21f), s-lH-pyrrol-2-yl]-4,5-dihydro-1,3-Bfazol-5-yl}methanol The compound which was synthesized (440 mg, 1.53 mmol) was dissolved in N,N-dimethylformamide (3 mL), and potassium carbonate (338 mg, 2.44 mmol) was added, and the mixture was stirred at 3 ° C for 3 hours under a nitrogen atmosphere. The reaction mixture was poured to room temperature, and water (30 mL) was added, and ethyl acetate (30 mL) was evaporated, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Chromatography (solvent solvent: methanol / methylene chloride = 〇% to 5%) to give the title compound (9 6 mg, yield: 17 %) of white solid. 'H-NMR (CDCI3, 400 MHz) : δ 1.06-1 . 1 1 (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 (1 H, m), 6.51 (1H, d, J = 3.5 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.76 (1H, d, J - 3.5 -171- 201036962

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: 470.1 3790 (M + H)+. (Example 28) {(5R)-2-[5-(3-Isopropoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1Η- Pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol

(28 a) 1-Bromo-3-isopropoxy-5-methoxybenzene The compound synthesized in Example (la) (31.62 g, 155.74 mm) was dissolved in hydrazine, hydrazine-dimethylformamide. Amine (200 mL) was added 2-bromopropane (29.25 mL, 311.48 mmol), EtOAc (EtOAc) 1 equivalent of hydrochloric acid (200 mL) was added, and diethyl ether (1.0 L) was added for extraction. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluting eluted eluted eluted eluted eluted eluted eluted eluted %). ^-NMR (CDC13, 400MHz): δ 1.29 (6Η, 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 201036962 The compound synthesized in Example (28a) (33.95 g, 138.51 mmol), sodium methoxide (10.68 g' The title compound (31.52 g, yield 98%) was obtained. • H-NMR (CDC13, 400MHz): δ 1.32 (6Η, 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).

Use of hydrazine (28c) 3-isopropoxy- 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane-2-yl)phenol Example (28b) Synthetic compound (31.52g, 136.4mmol), pinacol borate (51.96g, 204.6mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride The chloromethane complex (3.34 g, 4.09 mmol), EtOAc (m.) W-NMR (CDC13, 400MHz): 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) 〇(2 8 d) 5-(3-hydroxy-5-isopropoxybenzene -1H-pyrrole-1,2-dicarboxylic acid 2-benzyl-1-t-butyl ester was synthesized using the compound (20.17 g, 72.51 mmol) synthesized in Example (28c), and (16d). Compound (28.95 g, 76.14 mmol), [1, plant-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloride complex (2.96 g, 3.63 mmol), potassium carbonate (49.11) The title compound (27.5 3 g, yield 84%) was obtained from m. -173- 201036962 *H-NMR (CDC13, 400MHz) : δ 1.31 (6H, d, J = 5.9 Hz), 1.40 (9H, s), 4.46-4.55 (1 H, 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) 5-(3-hydroxy-5-isopropoxyphenyl)-lH-pyridyl Benzyl-2-carboxylate The compound synthesized in Example (28d) (9.97 g, 22.0 8 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (40 mL) was added dropwise while stirring at room temperature under a nitrogen atmosphere. After stirring for 30 minutes, the solvent was distilled off under reduced pressure. The solution was diluted with ethyl acetate (400 mL) and a saturated aqueous sodium hydrogen carbonate solution (200 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluting eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted %). *H-NMR (CDCI3, 400MHz): δ 1.34 (6Η, 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). (281〇5-(3-isopropoxy-5-{[6-(methylsulfonyl)pyridin-3-yl] Benzyloxy]phenyl)-1 -pyrrole-2-carboxylic acid benzyl ester The compound synthesized in Example (28e) (6.20 g, 17.64 mmol), and the compound synthesized in Example (16a) (3.48 g, 18.17 mmol) Dissolved in n,N-dimethyl 201036962

Formamidine (10 OmL) was added with cesium carbonate (17.25 g, 5 2.9 3 mmol) and stirred at 1 ° C for 2 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, water (100 mL) was then evaporated and evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted eluted elution !H-NMR (CDC13, 400MHz): δ 1.36 (6Η, 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) (2 8 §) 5-(3-isopropoxy-5 -{[6-(Methanesulfonyl)pyridin-3-yl]oxy}phenyl)-1Η-pyrrole-2-carboxylic acid The compound synthesized in Example (28f) (6.21 g, 12.26 mmol) was dissolved. A mixed solvent of ethyl acetate (70 mL) and ethanol (20 mL) was added with 10% palladium carbon catalyst (1.17 g), and stirred under a hydrogen atmosphere for 2 hours. The palladium carbon catalyst was removed by filtration through Celite. The solvent was removed by distillation to give the title compound (yield: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; ), 4.54 -4.63 (1 H, 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). -175- 201036962 (2 81〇] ^-[(2 3)-2,3-Dihydroxypropyl]-5-(3-isopropoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}benzene -1H-pyrrole-2-carboxamide A compound (1.83 g, 4.39 mmol), (S)-(-)-3-amino-1,2-propanediol' (1. 〇〇g '1099 mmol), DMT-MM (2.09 g, 6.59 mmol), m. 'H-NMR (CDC13, 400ΜΗζ) : δ 1.36 (6Η, d, J = 5.9 Hz), 3.23 (3H, s), 3.55 -3.63 (4H, m), 3.82-3.86 ( 1 H, m), 4.54 -4.60 (1H, m), 6.3 9-6.43 ( 1 H, 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). (2 81)^{(2 3)-2-hydroxy-3- [(Triisopropyldecyl)oxy]propyl}-5-(3-isopropoxy- 5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl) -1 Η-pyrrole-2-carbamide The example (281 § synthesized compound (0.79 §, 1.6 1111111 〇 1) was dissolved in dichloromethane (20 mL), and triisopropyl decane chloride (0.52 mL, 2.42) was added. Methyl acetate (1.12 mL, 8.07 mol), 4-dimethylaminopyridinium (0.30 g, 2.42 mmol), stirred at room temperature for 22 hours under nitrogen atmosphere. The residue was purified by chromatography on silica gel column eluting solvent (ethyl acetate /hexane = 30% to 60%) to afford white crystals (yield: 773 mg, yield: 75%). H-NMR (CDC13, 400 MHz ) : δ 1.04-1.16 (21Η, m), 1.37 (6H, d, J = 5.9 Hz), 3.1 2 (1H, d, J = 4.3 Hz), 3.23 (3H, s), 201036962

3.36-3.44 (1 H, m), 3.65-3.79 (3H, m), 3.84-3.90 (1 H, 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) » (2 8))5 -(3-isopropoxy-5-{5-[(5 ft)-5-{[(triisopropyldecyl)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 acid ( 420 mg, 2.41 mmol), triethylamine (yield: 67 mL, 4.82 mmol),yield (yield: 927 mg &gt; yield 92%) (CDCh, 5 00MHz) : δ 1.03-1.12 (21Η, m), 1.36 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 3.83-3.91 (4H, m), 4.54-4.59 ( 1 H, m), 4.73 -4.78 ( 1 H, 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). (2 8k){ (5 R)-2-[5-(3-isopropyloxy 5-[{6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazole- The compound synthesized by the example (28j) (921 mg, 1.47 mmol), tetrabutylammonium fluoride (1 mol/L tetrahydrofuran solution, 1.61 mL, 1 Jlmmol) was used in the same manner as in Example (16k). Method The title compound was obtained as a white solid - 177 - 201036962 (53 8. mg' yield 78%). • H-NMR (CDC13, 5 00MHz): 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 : 472.1 5594 (M + H)+ (Example 29) 5-(3-Isopropoxy-5-{5-[(4R)-4-methyl-4,5-dihydro-1,3-Bfoxazol-2-yl]- 1H-pyrrol-2-yl}phenoxy)-2-(methylsulfonyl)pyridine

(29&amp;)1^-[(111)-2-hydroxy-1-methylethyl]-5-(3-isopropoxy-5-{[6-(methylsulfonyl)pyridine-3- The compound synthesized by the example (28g) (530 mg, 1.27 mmol), D-aminopropanol (〇.15 mL, 1.91 mmol), HOBT, hydroxy) phenyl)-1 Η-pyrrole-2-carboxamide , H2O (206 mg, 1.53 mmol), N-methylmorpholine (0.28 mL, 2.5 5 mmol) was dissolved in N,N-dimethylformamide (12 mL), and WSCI-HCl (268 mg, 1.40) was added at room temperature. Methyl), stirred under nitrogen for 20 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (yield: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 89%) 〇*H-NMR (CDC13, 400ΜΗζ): δ 1.27 (3Η, d, J = 6.3 Hz), 1.36 (6H, d, J = 6.3 Hz), 2.83-2.87 (1 H, m), 3.23 (3H, s),

3.59-3.65 ( 1 H, m), 3.73 -3.78 (1 H, m), 4.21-4.28 (1H, br m), 4.52-4.60 (1 H, m)5 6.09 ( 1 H, 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- Df oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulfonyl) pyridine The compound synthesized in Example (29a) (538 mg, 1.14 mmol), a. (408 mg, 2.2 7 mmol), triethylamine (EtOAc: EtOAc (EtOAc) ^-NMR (CDCI3, 400MHz): δ 1.32 (3Η, 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 -179- 201036962

Hz). MS (El) m/z : 45 5 · 1 5 1 7 (M + ). (Example 30) {2-[5-(3-Isopropoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1Η-pyrrole-2- 4,5-dihydro-1,3-oxazol-4-yl}methanol

(30a) N-{[5-(3-Isopropoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1Η-pyrrol-2-yl] Methyl carbonyl}Methyl methinate The compound synthesized in Example (28g) (2.00 g, 4.80 mmol), DL-methyl-methyl sulphate hydrochloride (0.82 g, 5.28 mm 〇1), ΗΟΒΤ·Η20 (0.7) Lg, 5.2 8 mmol), N-methylmorpholine (1. 〇6 mL, 9.60 mmol), WSCI · HCl (1·10 g '5·76 mmol), obtained as a white solid in the same manner as in Example (29a) The compound of interest (2.36 g, 95%). !H-NMR (CDC13, 400MHz) : 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 ( 1 H, 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)2-[5-(3-isopropoxy- 5- {[6-(methylsulfonyl) Pyridin-3-yl]oxy}benzene-180- 201036962 base)-1 Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazole-4-carboxylic acid methyl ester Example (3〇a) synthesized compound (2.36g, 4.41mm〇l), methanesulfonic anhydride (1-588, 8.81111111〇1), triethylamine (2.46111]^, 17.63111111〇1), and examples The title compound (1.52 g, yield 69%) was obtained as white solid. ^-NMR (CDC13, 400MHz) : δ 1.37 (6Η, 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-(A) Sulfhydryl)pyridin-3-yl]oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol Example (30b The synthesized compound (498 mg, 1.0 mmol) was dissolved in tetrahydrofuran (1 mL), and lithium aluminum hydride (114 mg, 2.99 mm) was added at 0 °C. After stirring for 30 minutes under a nitrogen atmosphere, water (0.1 2 mL), a 5 N aqueous sodium hydroxide solution (.12 mL) and water (0.36 mL) were sequentially added and stirred for 10 minutes. After adding ethyl acetate (40 mL) and stirring for 5 minutes, it was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluted eluted eluted elut elut elut elut elut elut elut elut elut j-NMR (CDC13, 400MHz): 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, 201036962 11.7 Hz), 4.13 (1H, t, J = 7.0 Hz), 4.3 3 -4.3 9 ( 1 H, m), 4.39-4.43 ( 1 H, 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: 472.1 5279 (M + H)+. (Example 31) 2-[5-(3-Isopropoxy-5-{[6-(methylsulfonyl)[I-B-but-3-yl]oxy}phenyl)-1Η-pyrrole -2-yl]-4,5-dihydro-1,3-oxazole-4-carboxylic acid

The compound (620 mg, 1.24 mmol) synthesized in Example (30b) was dissolved in ethanol (12 mL), and 2N aqueous sodium hydroxide (6.21 mL) was added, and the mixture was heated under reflux for 1 hour under a nitrogen atmosphere. The reaction liquid was neutralized with 2 equivalents of hydrochloric acid, and the solvent was evaporated under reduced pressure. Water (50 ml) was added, and ethyl acetate (200 mL) was evaporated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound Compound Compound Compound Compound *H-NMR (CDC13, 400MHz): δ 1.36 (6Η, 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), -182- 201036962 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, brs). MS (ESI) m/ z : 48 6.1 3 5 1 1 (M + H)+. (Example 32) 2-[5-(3-Isopropoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1Η-pyrrol-2-yl ]-Ν,Ν-dimethyl-4,5-dihydro-1,3-oxazole-4-carboxamide

The compound synthesized (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) The title compound (11 l mg, yield 67%) was obtained as white solid.

'H-NMR (CDC13, 400MHz): δ 1.36 (6Η, d, J = 5.9 Hz), 2.97 (3H, s), 3.23 (3H, s), 3.25 (3H, s), 4.40-4.47 (1 H , 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: 5 1 3 · 1 83 00 (M + H)+. (Example 33) -183- 201036962 2-[5-(3-Isopropoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1Η-pyrrole -2-yl]-4,5-dihydro-1,3-oxazol-4-carboxamide

7. b The compound (200 mg, 0.41 mmol) of (Example 31) was dissolved in dichloromethane (10 mL), aqueous ammonia (28%, 0.13 mL, 2.06 mmol), WSCI.HCl (95 mg, 0.49 mmol) , HOBT-H2〇 (61mg, 0.45mmol),

C J was stirred at room temperature for 5 hours under a nitrogen atmosphere. The reaction mixture was diluted with methylene chloride (3 mL) and washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen sulfate and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted 'H-NMR (CDC13, 500MHz): δ 1.37 (6H, d, J = 5.9 Hz), 3_23 (3H, s), 4.5 5 -4.66 (3 H, 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), 6.8 3 -6.8 5 (2H, CJ 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 : 48 5.1 4 8 8 1 (M + H)+. (Example 3 4) 2-(3-[(18)-2-Fluoro-1-methylethoxy]-5-{5-[(58)-5-methyl-4,5-dihydro -1,3-oxazol-2-yl]-111-pyrrol-2-yl}phenoxy)-5-[(4-methylpiperazin-1-yl)carbonyl]pyrazine-184- 201036962

(3 4a) 2-Chloro-5-[(4-methylpiped_;!-yl)carbonyl]pyridine 5-hydroxypyridin-2-carboxylic acid (5.00 g, 39.0 mmol) dissolved in sulfite Chloro(6 mL) was added, and a few drops of N,N-dimethylformamide were added, and the mixture was heated to reflux under nitrogen atmosphere for 5 hours. The solvent was evaporated under reduced pressure, and the obtained residue was diluted with dichloromethane (50 mL). On the ice bath, diisopropylethylamine (18.7 mL, 107 mmol) and 1-methylpiped (4.37 mL, 39.2 mmol) were added, and the mixture was stirred at room temperature for 3 days under nitrogen atmosphere. Water (100 mL) was added to the mixture and the mixture was evaporated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluted eluted eluted eluted elut elut elut elut elut elut elut ^-NMR (CDC13, 400MHz): δ 2.34 (3Η, s), 2.44 (2H, t, J = 〇5.1 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)-l-{ [T-butyl(dimethyl)decyl]oxy}propan-2-ol (R)-(-)-l,2-propanediol (21.23 g, 279.01 mmol) was dissolved in dichloromethane (300 ml) Add triethylamine (58.33 mL, 418.52 mmol), 4-dimethylaminopyridine (3.41 g, 27.90 mmol), tert-butyldimethylchloromethane (42.05, 279.01 mmol), stir at room temperature All night. It was diluted with dichloromethane (200 mL) -185 - 201036962 and washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified (yield solvent: ethyl acetate/hexane = 〇% to 20%). 43.75g, 82%). ^-NMR (CDC13, 400MHz): δ 0.08 (6Η, s), 0.91 (9Η, 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), 3.7 8-3.86 ( 1 H, m). (34c){[(2S)-2-(3-bromo-5 -Methoxyphenoxy)propyl]oxy}(t-butyl)oxime Dimethyldecane % The compound synthesized in Example (la) (33.47 g &gt; 164.9 mmol), and (34b) Compound (37.7 g, l 97.82 mmol), triphenylphosphine (47.74 L, 181.3〇1111〇1), diethyl azocarboxylate (40% toluene solution, 7 9.0 〇!^, 181.341»111〇1), The title compound (57.19 g, yield: 92%) was obtained in the crude crystals of the compound (2). </ s </ s </ s </ s </ s> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; , s), 0.88 (9H, s), 1.27 (3H, d, J = 6.3 Hz), 3.63 (1 H, dd, J = 5 .1, i 0.6 \

Hz), 3.74-3.78 ( 1 H,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-[(lS)-2-{[t-butyl(dimethyl)decyl]oxyindole-methylethoxy]phenol was synthesized using the compound (34c) Compound (57 19 g, 1 52 mm 〇 1), sodium methoxide sulphate (1 1.56 g, 160 mmol) The title compound (45.50 g, m. , yield 83%). JH-NMR (CDC13, 400MHz): δ 0.04 (3Η, 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), 4.40-4.3 3 ( 1 H, m), 6.34 (1H, t, J = 2.0 Hz), 6.58 (1H, s) , 6.66 (1H, s). (3") 5-{3-[(13)-2-{[T-butyl(dimethyl)decyl]oxy}-1_methylethoxy] -5-Hydroxyphenylindole-indole-pyrrole-2-carboxylic acid benzyl ester

The compound (45.50 g &gt; l26 mmol) synthesized in Example (34d), the compound synthesized in Example (19e) (43.26 g, 132 mmol), [U-bis(diphenylphosphino)ferrocene]palladium dichloride ( II) Methylene chloride complex (5-l4g' 6.3 0 mmol), potassium carbonate (87.01 g, 630 mmol),yield of the title compound (5 6.70 g, yield 93%) . 'H-NMR (CDC13&gt; 400MHz): δ 0.05 (3Η, 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 ( 1 H, 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)5-{3-hydroxy-5-[(lS)-2-hydroxy-1- Methyl ethoxy]phenyl}-lH-pyrrole-2-carboxylic acid benzyl ester The compound synthesized in Example (34e) (34.12 g, 7 〇.84 mmol), tetrabutylammonium fluoride (1 mol/L tetrahydrofuran) The title compound (22.00 g, yield: 85%) was obtained as a pale yellow oil (yield:::::::::::::::::::::::::::: 'H-NMR (CDC13, 400MHz) : δ 1.27 (3H, d, J = 6.3 Hz),

3.70-3.79 (2H, m), 4.47-4.54 (1 H, 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), 7.3 2 -7.46 (5H, m), 9.83 (1H, br s) = (34g) 5-{3-[(lS)-2-fluoro-1-methylethoxy]-5-hydroxyphenyl}-111 - benzyl pyrrole-2-carboxylate The compound synthesized in Example (34f) (4.81 g, 13.09 mmol) was dissolved in 1,2-dimethoxyethane (10 mL) and dropped at -78 °C. Bis(2-methoxyethyl)aminosulfur trifluoride (3.14 mL ' 17.02 mmol). After stirring for 30 minutes under a nitrogen atmosphere, bis(2-methoxyethyl)aminosulfur trifluoride (3.00 mL, 16.27 mmol) was further added and stirred for 30 minutes. After the natural temperature was stirred at room temperature for 2 hours, bis(2-methoxyethyl)aminosulfur trifluoride (4.80 mL, 26.03 mmol) was further added and stirred overnight. After adding ethanol (10 mL) and stirring for 10 minutes, water (4 mL) was added. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified (jjjjjjjjjjjjjjj lH-NMR (CDC13, 400MHz): 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, -188- 201036962 J = 2.0 Hz), 6.49 (1H, dd, J = 2.1, 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), 7.3 3 -7.46 (5H, m), 9.81 (1H, s). (34h)5-{3-[(lS)-2-Fluoro- 1-methylethoxy]-5-({5-[(4-methylpipet-l-yl)carbonyl]pyridin-2-yl}oxy)phenyl}-1Η-pyrrole-2- Benzyl carboxylate

The compound synthesized in Example (34 g) (1.50 g '4_06 mmol), (34a) Compound ( 〇.96 g, 3.98 mmol) was dissolved in acetonitrile (40 mL), and potassium carbonate (1.68 g, 12.18 mmol) was added. Stir at 80 ° C for 18 hours. After cooling the reaction mixture to room temperature, water (30 mL) was evaporated and evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluting eluted eluted eluted eluted elution W-NMR (CDC13, 400MHz): 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) , 3.6 9 - 3.7 3 (2 H,brm),3 . 8 1 - 3 . 8 5 (2 H,brm ),4 · 4 3 - 4,7 2 (3 H, 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 (ih, br s). (34i) 5-{3-[(lS)-2-fluoro-1-methylethoxy]-5-((5_[(4_methylpiped-br))] 2-(yl)oxy)phenyl}-lH-lalyl-2-nonanoic acid The compound synthesized in Example (34h) (2.20 g, 384 mm〇i) was dissolved in -189-201036962

Methanol (35 mL) was added with a 10% pin carbon catalyst (2.4 g) and stirred under a hydrogen atmosphere for 6 hours. The palladium-carbon catalyst was removed by filtration through Celite, and the solvent was evaporated to give the title compound (l. 4 g, yield: 83%). 'H-NMR (CDC13, 400MHz): δ 1.30 (3Η, s), 2.38 (3H, s), 2.53-2.67 (4H, br m), 3.68-3.8 8 (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). (34)) 2-(3-[(18)-2-Fluoro-1-methylethoxy]-5-{5-[(58)-5-methyl-4 ,5-dihydro-1,3-oxazol-2-yl]-111-pyrrol-2-yl}phenoxy)-5-[(4-methylpiperidin-1-yl)carbonyl]pyridinium The compound (50 0 mg, 1.03 mmol), (R)-b-amino-2-propanol (194 mg, 2.59 mmol), 4-dimethylaminopyridine (505 mg, 4.14 mmol). Dissolved in dichloromethane (20 mL), WSCI· HCl (496 mg &gt; 2.59 mmol) was added at room temperature and the mixture was stirred for 15 hours under nitrogen atmosphere. The reaction mixture was diluted with methylene chloride (60 mL), and evaporated. The solvent was distilled off under reduced pressure, and the obtained residue was purified using chrome column chromatography (solvent solvent: methanol / dichloromethane = 5%). The obtained white solid compound (360 mg), methanesulfonic acid anhydride (1 8 5 mg: 1.02 mmol), triethylamine (285 μM, 2.03 mmol) was used to obtain a white solid in the same manner as in Example (16j). Compound (24 2 mg, yield 49%) - 'H-NMR (CDC13, 400 MHz): δ 1.37 (3 Η, dd, J = 1.6, 6.3 Hz), -190- 201036962 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 = ΊΑ, 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 ( 1 H, 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) {(511)-2-[5-(3-[(18)-2-Fluoro-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridine- 3-yl]oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-Bfazole-5-yl}methanol

(3 5a) 5-(3-[(lS)-2-fluoro-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl -1 Η-pyrrole-2-carboxylic acid benzyl ester The compound synthesized in Example (34g) (924 mg, 2.50 mmol) and the compound synthesized in Example (16 &amp;) (50311^, 2.63111111〇1) were dissolved in :^-Dimethylformamide (20 mL), and then added (2.54 g, 7.50 mmol) of carbonic acid, and stirred at 1 ° C for 2 hours under nitrogen atmosphere. After cooling the reaction mixture to room temperature, water (5 mL) was evaporated and evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue (yield: ethyl acetate/hexane = 10% to 50%) Yield 62%) 〇'H-NMR (CDC13, 400MHz): δ 1.36 (3Η, dd, J = 1.6, 6.3 Hz), 3.23 (3H, s), 4.45-4.70 (3 H, m), 5.33 ( (2H, s, J = 3.1, 3.9 Hz) = 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-[(lS)-2-Fluoro-1-methylethoxy]-5-{[6-(methylsulfonyl) Pyridine-3-yl]oxy}phenyl)-1Η-pyrrole-2-carboxylic acid The compound synthesized in Example (35 &amp;) (1.67 §, 3.181111111〇1) was dissolved in ethyl acetate (30 mL) and ethanol ( A mixed solvent of 5 mL) was added with a palladium carbon catalyst (820 mg), and stirred under a hydrogen atmosphere for 5 hours. The compound (1 · 3 1 g, yield 95%) was obtained by removing the palladium carbon catalyst and distilling off the solvent under reduced pressure to give a white solid. lH-NMR (CDC13j 400MHz): δ 1.35 (3Η, d, J = 6.3 Hz), 3.21 \ i (3H, s), 4.43 -4.74 (3 H, m), 6.51 (1H, s), 6.60 (1H , s), 6.91 S), 7.01 (1H, s), 7.05 (1H, s), 7.44 (1H, d, J = B.6 Hz), 8-〇4 (1H, d, J = 8.6 Hz) , 8.47 (1H, s), 9.67 (1H, br s). (35c) N-[(2S)-2,3-Dihydroxypropyl]-5-(3-[(lS)-2-fluoro- 1-Methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1Η-pyrrole-2-carboxamide was synthesized using Example (35b) Compound (1.31 g, 3.02 mmol), -192-201036962 (S)-(-)_3-amino-1,2·propanediol (〇_69g, 7.54mmol), DMT-MM (2.39g' 7.54mmol) The title compound (1.27 g, 83%) was obtained as a white solid. 1Η - NMR ( CD C13,4 0 0 Μ Η z ) : δ 1.3 5 (3 Η, dd, J = 1 · 6,6 · 3 Η z), 3.23 (3Η, s), 3.47-3.60 (4Η, m), 3.79-3.83 (1 Η, 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-[(lS)-2-Fluoro-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl) -1^-{(2 3)-2-hydroxy-3-[(triisopropyldecyl)oxy]propyl}-1Η-pyrrole-2-carboxamide The compound synthesized in Example (35c) (1.27g, 2,50mmol) dissolved in dichloromethane (25mL) 'Addition of triisopropyl decane chloride (〇.8〇mL, O 3.75mmol), triethylamine (1.74mL, 12.51mol), 4 Dimethylaminopyridine (0.46 g, 3.75 mmol) was stirred at room temperature for 22 hours under nitrogen. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted elution . ^-NMR (CDCh, 400MHz): δ 1.04-1.13 (21Η, m), 1.36 (3H, dd, J = 6.3, 1.6 Hz), 3.13 (1H, d, J = 4.7 Hz), 3.23 (3H, s ), 3.3 4-3.42 ( 1 H, m), 3.64-3.78 (3H, m), 3.83 -3.90 (1 H, br m), -193- 201036962 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-[(lS)-2-fluoro-1-methylethoxy]-5-{5-[( 5R)-5-{[(triisopropyldecyl)oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}benzene Oxy)-2-(methylsulfonyl)pyridine

The compound (1.46 g, 2.20 mmol), methanesulfonic anhydride (790 mg, 4.40 mmol), triethylamine (i.23 mL, 8.80 mmol) synthesized in Example (35d) was used in the same manner as in Example (1 6 j). The desired product was obtained as a pale-yellow solid (1.25 g, yield: 8%) °H-NMR (CDC13, 4 00 MHz): δ 1.03-1.14 (21 Η, 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 ( 1 H, 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), I) 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- [(lS)-2-fluoro-1-methylethoxy]methanesulfonyl)pyridin-3-yl]oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro -1,3-Dfoxazol-5-yl}methanol The compound (i.25 g, 1.94 mmol) synthesized using Example (35e), tetrabutylammonium fluoride (1 mol/L tetrahydrofuran solution ' 2.32 mL, 2.32 mmol) The same procedure as in the Example (1 6k) was used to give a pale-yellow solid (yield: 830 mg, yield 88%).'H-NMR (CDC13, 5 00MHz) : δΐ.36 (3H, dd, J = 16,6 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 : 490.1 4446 (M + H)+. (Example 36) 5-(3-[(18)-2-Fluoro-1-methylethoxy]-5-{5-[(411)-4-methyl-4,5-dihydro_ 1,3 -oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulfonyl) valine

〇

(36a) 5-(3-[(lS)-2-fluoro-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl) -N-[(lR)-2-Hydroxy-1-methylethyl]-1H-pyrrole-2-carbamide The compound synthesized in Example (3 5 b) (15 Omg, 0.35 mmol), D- Aminopropanol (8 〇μΙν, 〇4 mmol), DMT-MM (273 mg, 0.86 mmol),yield of the title compound (124 mg, 7.3%) 195- 201036962 *H-NMR (CDC13, 400MHz) : 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), 3.5 7-3.63 ( 1 H, m), 3.72-3.78 ( 1 H, m), 4.20-4.27 (1 H, br m), 4.45 -4.72 (3 H, 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-[(lS)-2-Fluoro-1-methylethoxy]-5-{ 5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-( Sulfhydryl)pyridine The compound (124 mg, 0.25 mmol), methanesulfonic anhydride (91 mg, 0.50 mmol), triethylamine (0.14 inL '1.Olmmol) was synthesized using the compound of Example (36a). 6 j) The title compound (84 mg, 70%) *H-NMR (CDCh, 400 ΜΗζ): δ 1.33 (3Η, 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), 4.2 8-4.3 7 ( 1 H, 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: 474.1 4763 (M + H)+. (Example 37) -196- 201036962 5-{3-[(lS)-2-fluoro-1-methylethoxy]-5-(5-{[(4R)-4-[2-(A) Thio)ethyl]-4,5-dihydro-1,3-oxazol-2-yl}-1Η-pyrrol-2-yl)phenoxy}-2-(methylsulfonyl)pyridine

(3 7&amp;) 5-(3-[(13)-2-fluoro-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridinium-3-yl]oxy} Phenyl)-N-[(lR)-l-(hydroxymethyl)-3-(methylthio)propyl]-1 H-pyrrole-2-carboxamide using the compound synthesized in Example (35b) ( 150 mg, 0.35 mmol), D-methionine (51 mg, O.38 mmol), HOBT-H2 oxime (51 mg '0.38 mmol), N-methylmorpholine (76 μί, 0.69 mmol), WSCI. HCl (79 mg) The title compound (1, 4 4 mg, 91%) was obtained.

• H-NMR (CDC13, 400MHz): 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- 3.8 2 (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). (3 71〇5-{3-[(18)-2-fluoro-1-methylethoxy]-5-(5-{[(411)-4- [2-(A-197-201036962 thio)ethyl]-4,5-dihydro-1,3-oxazol-2-yl}-1Η-pyrrol-2-yl)phenoxypurine-2- (Methanesulfonyl)pyridine The compound (178 mg, 0.32 mmol), methanesulfonic anhydride (116 mg, 0.65 mmol), triethylamine (〇.22 mL, 1.61 mmol) synthesized using the compound (37a), The title compound (88 mg, 51%) was obtained as a white solid. mp NMR (CDC13, 400 MHz): δ 1.34 (3H, dd, J = 1·6, 6.3 Hz), 1.7 5 - 1.90 (2Η, m), 2.03 (3H, s), 2.49-2.63 (2H, m)s 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 = g.6 Hz), 8.47 (1H, d, J = 2.7 Hz). MS (FAB + ) m/z : 5 3 4 1 5 3 4 (M + H)+. (Example 38) {(411)-2-[5-(3-[(13)-2-fluoro-1-methylethoxy]-5_{[6-(methyl fluorenyl)) -3-yl]oxy}phenyl-l-yl]-4,5·dihydro-I,3·isophilic 4-yl}methanol

(3 8a) N-U5-(3-[(lS)-2-fluoro-1-methylethoxy]_5_{[6•(())pyridin-3-yl]oxy}phenyl -1 Η -pyrrole 2 -yl]carbonyl b L-serine methyl vinegar-198- 201036962 The compound synthesized in Example (35b) (1.10 g, 2.53 mmol), methyl L-serinate hydrochloride Salt (〇.43g, 2.7 9mmol), HOBT-H2O (0.38g, 2.79mmol), N-methylmorpholine (0.56mL, 5.06mmol) dissolved in dichloromethane (20mL) and N,N-dimethyl A mixed solvent of carbamide (8 mL) was added, and WSCI.HCl (0-58 g, 3.04 mmol) was added at room temperature, and the mixture was stirred under nitrogen atmosphere for 20 hours. The reaction mixture was diluted with methylene chloride (200 mL), and washed with 1% aqueous hydrochloric acid and saturated aqueous sodium hydrogen carbonate aqueous sodium sulfate, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified (jjjjjjjjjjj ). !H-NMR (CDC13s 400MHz) : δ 1.36 (3Η, 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). (381?)(48)-2-[5-(3-[ (13)-2-fluoro-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1 H-pyrrol-2-yl Methyl-4,5-dihydro-1,3-oxazole-4-carboxylate The compound synthesized in Example (38 &amp;) (91〇11^, 1.7〇111111〇1) was dissolved in methyl chloride ( 20 mL), bis(2-methoxyethyl)aminosulfur trifluoride (〇.39 mL, 2-12 mmol) was added dropwise at -78 °C. After stirring for 30 minutes under a nitrogen atmosphere, &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&& A saturated aqueous solution of sodium hydrogencarbonate (1 mL) was added, and the mixture was evaporated. The solvent was evaporated under reduced pressure, and the residue was purified to mjjjjjlilililililililililililili 'H-NMR (CDC13, 400MHz) : δ 1.37 (3Η, 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-[(lS)-2-fluoro-1-methylethoxy]-5-{[6-(methylsulfonyl) Pyridin-3-yl]oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol. The synthesis of Example (38b) The compound (950 mg, 1.84 mmol) was dissolved in tetrahydrofuran (2 mL), and EtOAc (140 mg, 3.. After stirring under a nitrogen atmosphere for 30 minutes, water (〇.14 mL), 5N aqueous sodium hydroxide (0.14 mL), and water (0.45 mL) were sequentially added and stirred for 10 minutes. After adding ethyl acetate (70 mL) and stirring for 5 minutes, it was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluting - 201036962 'H-NMR (CDCh, 400MHz) : 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 : 490.1 43 5 6 ( M + H)+. (Example 39) 2-{(5S)-2-[5-(3-[(lS)-2-fluoro-1-methylethoxy]-5-{[6-(meth) Pyridin-3-yl]oxy}phenyl)·1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}ethanol

〇(3 9a) N-{(2R)-2-(benzyloxy)-4-[(triisopropyldecyl)oxy]butyl}-5-(3-[(lS)-2 -Fluoro-l-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1 -pyrrole-2-carboxamide using the examples ( 35b) Synthetic compound (2.50 g, 5.75 mmol), known as {J_Org. Chem. 60, No. 12, 3910-3915 (1995)} (2R)-2-(benzyloxy)-4 -[(Triisopropyldecyl)oxy]butan-1-amine (2.04 g, 5.80 mm 〇l), DMT-MM (3.98 g, 14.4 rnmol), obtained in the same manner as in Example (5d) The object of the white solid (4.23 g, yield 96%). -201- 201036962 • H-NMR (CDC13, 400MHz): δΐ.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), 7.28-7.3 7 (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). (391&gt;)5-( 3-[(13)-2-fluoro-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-N-{(2R -2-hydroxy-4-[(triisopropyldecyl)oxy]butyl}-1 Η-pyrrole-2-carboxamide The compound synthesized in Example (39 &amp;) (4.23 §, 5.51111111〇1) It was dissolved in acetic acid (80 mL), and 10% palladium carbon catalyst (1.70 g) was added thereto, and the mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere. The palladium carbon catalyst was removed by filtration through Celite, and washed with ethyl acetate. The solvent was evaporated under reduced pressure, and the residue obtained was purified (jjjjjjjjjjjj . *H-NMR (CDCI3, 400MHz): δΐ.04-1.17 (21Η, 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, 14.1 Hz), 3.93 -4.09 (3 H, m), 4.46 (1H, d, =4.7Hz), 4.58 (1H, d , J = 4.7Hz), 4.68 (1H, m), -202- 201036962 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-[(lS)-2-fluoro-1-methylethoxy]-5-{5-[(5S)-5-{2-[(triisopropyldecyl)) Oxy]ethyl}-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulfonyl)pyridine

The compound (2.28 g, 3.36 mmol) synthesized in the example (39b), decylsulfonic anhydride (1.46 g, 8.38 mmol), and triethylamine (2.81 mL, 20.2 mol) were used in the same manner as in Example (16j). The title compound was obtained as a white solid (2.l, g, yield: 5%). 'H-NMR (CDC13j 400MHz) : δΐ.02-1.15 (21Η, m), 1.37 (3Η, 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 = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz). (39d) 2-{(5S)-2-[5-(3-[(lS)-2-fluoro-1-methylethoxy) ]·5-{[6-(Methanesulfonyl)pyridin-3-yl]oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazole- 5-Base}ethanol The compound synthesized in Example (39c) (2.10 g, 3.18 mmol), tetra-203-201036962 butyl ammonium fluoride (1 mol/L tetra-furfuran solution, 3.82 mL, 3.82 mmol), The title compound (1.15 g, yield 72%) was obtained. 'H-NMR (CDCh, 400MHz): δΐ.34 (3Η, d, J = 6.3Hz), 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), 6.9.0 (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 = 2.7 Hz). MS (ESI) m/z: 5 04.1 6046 (M + H)+. (Example 40) 2-{(4R)-2-[5-(3-[(lS)-2-fluoro-1-methylethoxy]-5-{[6-(methylsulfonyl)) Pyridin-3-yl]oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-Dfazole-4-yl}ethanol

(40 a) (2S)-4-(nodaloxy)-1-[(diisopropyltrimoxy)oxy]butan-2-ol (2S)-4-(nodaloxy) Butyl-1,2-one alcohol (3. 〇〇g, l5.3niinol) was dissolved in dichloromethane (1 50 mL) 'Addition of triisopropyl decane chloride (3.6 〇 mL, 16.8 mmol), triethyl Amine (6.40 mL, 45.9 mmol), 4-dimethylaminopyrrolidine (1 _8: 7 g '1 5.3 mmol) was stirred at room temperature for 24 hours under nitrogen atmosphere. Tim -204- 201036962

Water (1 50 mL) was added for 2 times with dichloromethane (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 residue was purified using silica gel column chromatography (eluent solvent: ethyl acetate / hexane = 10% to 30%) to give the title compound (5.6 g). Rate ~1 0 0 %). ^-NMR (CDC13, 400ΜΗζ): δΐ.02-1.12 (21Η, m), 1.72-1.84 (2H, m), 2.86 (1H, d, J = 3.1Hz), 3.58 (1H, dd, J = 6.7 , 9.8 Hz), 3.62-3.72 (3 H, m), 3.86 (1H, m), 4.52 (2H, s), 7.28-7.35 (5H, m). (4013)2-[(1 ft)-3 -(benzyloxy)-1-{[(triisopropyldecyl)oxy]methyl}propyl]-1H-isoindole-1,3(2H)-dione Example (4 The compound (5. Diethyl azocarboxylate (40% toluene solution, 8.00 mL, 17.6 mmol) was added dropwise at 0 ° C, and stirred at room temperature for 3 hr under nitrogen atmosphere. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted %). !H-NMR (CDCh, 400MHz) : δΟ.92- 1.08 (2 1 Η, m), 2.06 (lH, m), 2.37 (1H, m), 3.46-3.58 (2H, m), 3.94 (1H, Dd, J = 6.3, 9.8 Hz), 4.14 (1H, t, J = 9.8 Hz), 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-[(triisopropyldecyl)oxy]butan-2-amine will be carried out The compound (4.87 g, 10.1 mmol) synthesized in Example (40b) was dissolved in -205 - 201036962 ethanol (100 mL). The hydrazine monohydrate (4.90 mL, 10 mmol) was added and heated under reflux for 3 hours under a nitrogen atmosphere. After insoluble material was removed by filtration, a saturated aqueous solution of sodium hydrogencarbonate (100 mL) was added, and extracted twice with diethyl ether (100 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals crystals crystals crystals crystals j-NMR (CDC13, 400MHz): δΐ.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). (40(1)1^{(111)-3-(benzyloxy)-1-{[(triisopropyldecyl)oxy]methyl}propyl]-5-(3-[( lS)-2-fluoro-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1Η-pyrrole-2-carboxamide The compound (1.90 g, 4.37 mmol) synthesized in Example (35b) was synthesized as a compound (1,5 g, 4.98 mmol), DMT-MM (3.63 g, 13-1 mmol), and Example (5d) The title compound was obtained as a white solid (2.33 g, yield: 69%). NMR (CDC13, 400 MHz): δ ΐ.03-1.13 (21 Η, 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), -206- 201036962 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.54 (1H, brs). (40e) N-{(lR)-3-(Benzyloxy)-1-(hydroxyl) Methyl)propyl]-5-(3-[(lS)-2-fluoro-1-methylethoxy]-5-{[6·(methylsulfonyl)pyridin-3-yl]oxy }phenyl)-1Η-pyrrole-2-carboxamide

The compound (2.32 g, 3.02 mmol) synthesized in Example (40d), tetrabutyl fluoride (1 mol/L tetrahydrofuran solution, 6.35 mL, 6.35 mmol) was used in the same manner as in Example (16k). The title compound was obtained as a white solid (1.43 g, yield 7 7 %) 〇H-NMR (CDC13, 400 MHz) : δ ΐ.37 (3 Η, 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 = 6.7) Hz), 7.3 2-7.40 (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-S}- lH-pyrrol-2-yl)-5-[(lS)-2-fluoro-1-methylethoxy]phenoxy}-2-(methylsulfonyl)pyridine was synthesized using Example (40e) The compound (1.43 g, 2.34 mmol), a formic acid anhydride (1. 〇 2 g, 5.86 mmol), and triethylamine (1.96 mL, 14-1 mol) were obtained in the same manner as in Example (16j). -207- 201036962 (1.29 g, yield 9 3%). iH-NMR (CDC13, 400MHz): δΐ.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), 4.3 8-4.49 (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 = 2.7 Hz). (40 g) 2-{(4R)-2-[5-(3-[(lS)-2-fluoro-1-methylethoxy]methylsulfonyl)pyridin-3-yl] Oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-Bfoxazol-4-yl}ethanol The compound (40 〇 synthesized compound (1.298, 2.17111111〇1) Dissolved in dichloromethane (30 mL), adding boron tribromide (1.〇m〇l/L dichloromethane solution, 2.61 mL, 2.61 mm 〇.1) at -78 ° C under nitrogen atmosphere at room temperature After stirring for 1.5 hours, a saturated aqueous solution of sodium hydrogencarbonate (3 mL) was added, and the mixture was extracted twice with dichloromethane (3 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Solvent The obtained residue was purified using a silica gel column chromatography (solvent solvent: methanol / methylene chloride 5%) to give a white solid object (984 mg, yield: 90%). H-NMR (CDC13, 400 MHz): δ ΐ. 38 (3H, dd, J=1.6, 6.3 Ηζ), 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), 4.5 8 (1H, d, J = 5.1Hz), 4.70 (1H, m), 6.52 ( 1H, d, -208- 201036962 J = 3.9Hz), 6.57 (1HS 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 : 504.1 6046 ( M + H)+. (Example 41) (lS)-l-{(5R)-2-[5-(3-[(lS)-2-fluoro-1-methylethoxy]-5-{[6-(A Sulfomethyl)pyridin-3-yl]oxy}phenyl)-1Η·pyrrol-2-yl]-4,5·dihydro-1,3-oxazol-5-yl}ethyl-1,2- Glycol

(41&amp;)]^-{(28)-2-[(4 8)-2,2-dimethyl-1,3-dioxocyclopentan-4-yl]-2-hydroxyethyl}- 5-(3-[(18)-2-fluoro-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1Η- Pyrrole-2-carboxamide

The compound synthesized in Example (35b) (1.54 g, 3.54 mmol), well-known {Chem. Res. Toxicol., Vol. 14, No. 4, pp. 379-388 (2001)} (lS)-2-amino group- 1-[(4S)-2,2-Dimethyl-1,3-dioxocyclopentan-4-yl]ethanol (690 mg, 4.28 mmol), DMT-MM (2.45 g, 8.85 mmol), Example (5d) The title compound (m.p. (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, d, J = 12.1Hz) (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 = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.65 (1H, brs). (41b)(lS)-l-{(5R)-2-[5-(3-[(lS )-2-fluoro-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl )-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}ethyl-1,2-diol The compound synthesized in Example (41 &amp;) (1.64 § 2.84111111〇1) was dissolved in tetrahydrofuran (40 mL), methanesulfonic anhydride (1.24 g, 7.12 mmol), triethylamine (2.38 mL, 17.1 mol) was added, and the mixture was stirred at 50 ° C for 22 hours under a nitrogen atmosphere. Water (40 mL) was added, and extracted with EtOAc (40 mL). The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. 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. EtOAc (EtOAc m. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified (jjjjjjjd ^-NMR (CDC13, 400MHz): 51.36 (3Η, dd, J=1.6, 6.7Hz), 3.13 (1H, brd, J = 1.2Hz), 3.23 (3H, s), 3.69 (1H, dd, J = 5.9, -210- 201036962 1 1 .3Hz), 3.8 1 (1H, dd, J = 3.5, 1 1 .3Hz), 3.88 (ih, m) 3.93-4.01 (2H, m), 4.46 (1H, d, J = 4.7 Hz), 4.58 (iH, d, J = 4.7 Hz), 4 _ 6 7 (1 H, m), 4 · 6 8 (1 H, d, J = 5 · 5 Hz), 6 · 4 9 ( ihd J = 3.9Hz), 6.57 (1H, t, J = 2.4Hz), 6.73 (1H, d, J = 3.9Hz), 6.88 (1 H,t,J = 2 · 0 H z),7.0 4 (1 H,t,J = 2.0 H z), 7.4 5 (1 H, dd, J = 2 7 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7Hz). MS (ESI) m/z : 520.1 5537(M + H)+ 〇

(Example 42) (lR)-l-{(4S)-2-[5-(3-[(lS)-2-fluoro-1-methylethoxy b 5_{[6_(methylsulfonyl) Pyridin-3-yl]oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-diamino-1,3-oxazol-4-ylindole-1,2-diol

(42a) (lS)-2-{[T-butyl(diphenyl)decyl]oxy}-l-[(4S)_2,2-dimethyl-1,3-dioxocyclopentane- 4-yl]ethanol will be known as {18.-1-.[[48]-2,2-two of {J.Am.Chem.Soc. 123, No. 24, 5 695-5 702 (2001)} Methyl-1,3-dioxocyclopentan-4-yl]ethyl-1,2-diol (7.34 g, 45.3 mmol) was dissolved in dichloromethane (300 mL) and tert-butyldiphenyl decane was added. The base chlorine (14.2 mL, 54.6 mmol), triethylamine (15.8 mL, 113 mmol), and 4-dimethylamino group B were steep (560 mg, 4.58 mmol), and stirred at room temperature for 23 hours under nitrogen atmosphere. Water (300 mL) was added and extracted twice with dichloromethane (200 mL). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate s. The solvent was evaporated under reduced pressure, and the residue was purified (jjjjjjjjjjjjj 95%). ^-NMR (CDC13) 400MHz) : 61.06 (9Η, s), 1.37 (3Η, s), 1.41 (3H, s), 2.43 (1H, d, J = 5.5Hz), 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) 4-nitrobenzoic acid (lR)-2-{[t-butyl(diphenyl)decyl]oxy}-1-[(4 3)-2,2-di Methyl-1,3-dioxocyclopentan-4-yl]ethyl ester The compound synthesized in Example (42a) (8.65 g, 21.6 mmol), 4-nitrobenzoic acid (5.42 g, 32.4 mmol), Triphenylphosphine (7.93 g, 30.2 mmol), diethyl azocarboxylate (40% toluene solution, 14.71111, 32.3111111 〇1) gave the title compound as a pale yellow oil (m. 10.7 g, yield 90%). • H-NMR (CDC13, 400MHz): δΐ.02 (9Η, s), 1.31 (3H, s), 1.36 (3H, s), 3.97 (2H, d, J = 3.5Hz), 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), 8.3 1 (2H, d5 J = 8.2Hz). (42c)(1R)-2-{[T-butyl(diphenyl)decyl]oxy l-[(4S)-2,2-dimethyl-1,3-dioxocyclopentane_4_yl]ethanol

The compound (1. 212-201036962 Toluene solution, 48. 〇 1111 &lt;, 50. 〇 111111 〇 1). After -20 (3 泮 泮 泮 泮 泮 泮 泮 泮 泮 泮 泮 泮 泮 泮 泮 泮 泮 泮 泮 泮 萃取 萃取 萃取 萃取 萃取 萃取 萃取 萃取 萃取 萃取 萃取 萃取 萃取 泮The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure, and the residue was purified by chromatography (yield: ethyl acetate/hexane = 10% to 30%) , yield 88%).

!H-NMR (CDC13) 400MHz) : δΐ.07 (9Η, s), 1.33 (3Η, s), 1.34 (3H, s), 2.50 (1H, d, J = 4.7Hz), 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-{(lS)-2-{[t-butyl(diphenyl)decyl]oxy}-l-[(4R)-2,2-dimethyl-1,3-di Oxycyclopentan-4-yl]ethyl}-1Η-isoindole-1,3(2H)-dione The use of the compound (4 2〇 synthesized compound (6.87 §, 17.2111111〇1), 酞醯亚Amine (2.78 g, 18.9 mmol), triphenylphosphine (4.96 g, 18.9 mmol), diethyl azocarboxylate (40% toluene solution, 8.6 〇 111 [, 18_9111111 〇 1), and examples (2 0 a) The title compound (8.65 g, yield: 5%) was obtained as a pale yellow oil. W-NMR (CDCh, 400 MHz): δ ΐ.03 (9H, s), 1.13 (3H, s), 1.14 (3H, s), 3.67-3.81 (3H, m), 3.94 (1H, dd, 1 = 6.3, 8.6Hz), 4.08 (1H, m), 4.24 (1H, m), 7.27-7.44 (6H, m ), 7.5 9-7.78 (8H, m). (42e)(lS)-2-{[T-butyl(diphenyl)decyl]oxy}-l-[(4R)_2,2_dimethyl Base-1,3-dioxocyclopentan-4-yl]ethaneamine-213-201036962 The compound synthesized in Example (42d) (8-65 g, 16.3 mmol) was dissolved in ethanol (150 mL). (7.92 mL, 163 mmol), heated under reflux in a nitrogen atmosphere for 1.5 hours. Insoluble materials were removed by filtration. A saturated aqueous solution of sodium hydrogencarbonate (150 mL) was added, and the mixture was extracted with diethyl ether (150 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Chromatography (solvent: ethyl acetate / hexane = 20% to 50%) eluted eluted to afford the desired compound (5. NMR (CDC13, 400MHz) : δΐ.06 (9Η, 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-{(lS)-2-{[T-butyl(diphenyl)decyl]oxy}-l-[(4R)-2,2-dimethyl-1 ,3-dioxocyclopentan-4-yl]ethyl}-5-(3-[(13)-2-fluoro-1-methylethoxy]-5-{[6-(methylsulfonate) The compound synthesized by the compound of Example (35b) (1.55 g, 3.57 mmol), the compound synthesized by the example (42e), (pyridin-3-yl]oxy}phenyl)-1 -pyrrole-2-carboxamide 1.71 g, 4.28 mmol), DMT-MM (2.47 g, 8.9 3 mmol), in the same manner as in Example (5 d) The method to the procedure of white solid (2.67g, 92% yield). 'H-NMR (CDC13, 400MHz) : δΐ.06 (9Η, s), 1.33 (6H, s), 1.37 (3H, dd5 J=1.6, 6.3Hz), 3.24 (3H, s), 3.46 (1H, Td, 3 = 5.9, 14.1 Hz), 3.65 (1H, m), 3.71-3.81 (2H, m), 4.01 (1H, dd, -214- 201036962 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) 〇

(428) 1^-{(18)-1-[(41〇-2,2-dimethyl-1,3-dioxocyclopentan-4-yl]_2. hydroxyethyl}-5-( 3-[(18)-2-fluoro-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1Η-pyrrole-2 -Metformamide The compound (2.67 g, 3-27 mmol) synthesized in Example (42f), tetrabutylammonium fluoride (1 mol/L tetrahydrofuran solution 4.43 mL, 4.43 mmol) was used in the same manner as in Example (1 6k). The title compound was obtained as a white solid (1. 56 g, yield: 83%). ???H-NMR (CDC13, 400 MHz): δ ΐ.36 (3 Η, s), 1.37 (3H, dd, J = 1.7, 6.3 Hz) , 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)(lR)-l-{(4S)-2-[5-(3-[(lS)-2-fluoro-1-methyl ethoxy--21 5-201036962 base]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro·1,3 - oxazol-4-yl}ethyl-1,2-diol The compound synthesized in Example (42 g) (1.56 g, 2.70 mmol) was dissolved in tetrahydrofuran (40 mL), methanesulfonic anhydride (1.18 g, 6.77) Methyl acetate (2.26 mL, 16.2 mol) was stirred at 50 ° C for 16 hours under nitrogen atmosphere. Water (40 mL) was then evaporated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was dissolved in 8% of a mixture 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. EtOAc (EtOAc) The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified to mjjjjjlililililililililililililili ^-NMR (CDC13, 400MHz): δΐ.35 (3Η, dd, J = 1.6, 6.3Hz), 3.22 (3H, s), 3.68-3.71 (3H, m), 3.80 (1H, dd, J = 7.4 , 14.1Hz), { j 3.98 (1H, dd, J=10.2, 14.1Hz), 4.45 (1 Hs d, J = 4.7Hz), 4.57 (1H, d, J = 4.7Hz), 4.62-4.70 (2H , m), 6.38 (1 H, d, J = 3.9Hz), 6.54 (1H, t, J = 2.4Hz), 6.61 (1H, d, J-3.9Hz), 6.86 (1H, t, J = 2.0 Hz), 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 = 2.7 MS (ESI) m/z: 520.1 5 5 3 7 (M + H)+. (Example 43) -216- 201036962 {(511)-2-[5-(3-[(13)-2-fluoro-1-methylethoxy]-5-{[5-(methylsulfonate) Base) pyridin-2-yl]oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol

(43a) 5-(methylthio)pyridin-2-amine

2-Aminopyridin (50.8 g, 〇.53 mmol) was dissolved in dichloromethane (1.0 L), and N-bromobutaneimine (97.9 g, 0.55 mol) was added at 0 ° C for 30 minutes, nitrogen Stir at 0 ° C for 2 hours and a half under an atmosphere. The reaction solution was warmed to room temperature, and the precipitate was filtered. The precipitate was filtered off with ethyl acetate. The mother liquor was collected, and the solvent was distilled off under reduced pressure. This operation was repeated twice to obtain a mother liquid which was distilled under reduced pressure to give a compound as a yellow oil. This was dissolved in hydrazine, hydrazine-dimethylformamide (300 mL), sodium methoxide (75.0 g, 1.07 mol) was added, and the mixture was stirred at 100 ° C for 3 hours under a nitrogen atmosphere. The reaction solution was warmed to room temperature, water (1. 5L) was added, and ethyl acetate (1.0L). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluting eluted eluted eluted eluted eluted eluted eluted %). W-HMR (CDC13, 400MHz): 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). 431〇2-Chloro-5-(methylthio)pyrazine-217- 201036962 Sodium nitrite (50.9 g, 0.74 mol) was dissolved in water (150 mL), and dropped to 5N hydrochloric acid at 〇 °c for 1 hour. The compound synthesized in Example (43a) (40.4 g, 0.28 mol) was stirred at 0 ° C for 40 minutes at 0 ° C. The reaction solution was warmed to room temperature and water was added ( 5 OOmL), which was extracted with ethyl acetate (1.0 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Ethyl acetate / hexane = 10% to 20%) EtOAc (EtOAc: EtOAc) , 8.24 (1H, d, J = 1.2 Hz), 8.39 (1H, d, J = 1.2 Hz). (43c) 2-Chloro-5-(methylsulfonyl)pyridinium. Synthesis of Example (43b) Compound (10.82 §, 67.4111111〇1) was dissolved in dichloromethane (200 mL), and m-chloroperbenzoic acid was slowly added at 0 °C. (Approximately 65%, 37.4 g, ca. 140 mmol), and stirred for 1 hour and a half at 〇 ° C under N.sub.2 C. After the layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified using silica gel column chromatography (solvent solvent: ethyl acetate / hexane = 30% to 50%). The title compound was obtained as a white solid (10. lg &gt; yield 7 8%). 'H-NMR (CDCh, 400 MHz): δ 3.27 (3 Η, s), 8.70 (1 Η, d, J = 1.2 Hz), 9.09 ( 1H, d, J = 1.2 Hz) (43d) 5-{3-[(lS)-2-fluoro-1-methylethoxy][(triisopropyldecyl)oxy]phenyl} -1 Η-pyrrole-2-carboxylic acid benzyl ester-218- 201036962 The compound synthesized in Example (34 g) (9.72 g, 26.31 mmol), triethylamine (ll.OOmL, 78.94 mmol), 4-dimethyl Aminopyridine (4.82 g, 3 9.471!1111〇1) was dissolved in dichloromethane (25 〇 1111 〇, triisopropyl sulfonium chloride (8.45 mL, 3 9.47 mmol) was added at room temperature, and stirred under nitrogen atmosphere 5 hour. The reaction mixture was diluted with methylene chloride (300 mL), washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluting eluted eluted eluted eluted eluted elution = iH-NMR (CDC13, 400MHz): 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).

(43〇5-{3-[(13)-2-fluoro-1-methylethoxy]-5-[(triisopropyldecyl)oxy]phenyl}-1Η-pyrrole-2- The carboxylic acid The compound (13.65 g, 25.96 mmol) synthesized in Example (43d) was dissolved in ethanol (4001111 〇, and 10% palladium carbon catalyst (2.0 (^) was added, and stirred under a hydrogen atmosphere for 40 minutes. The palladium-carbon catalyst was removed by filtration with celite, and the solvent was evaporated under reduced pressure to give the title compound (1·························· , m), 1.23-1.31 -219- 201036962 (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). (43 〇1^-[(23)-2,3-Dihydroxypropyl]-5-{3-[(13)-2-fluoro-1-methylethoxy]-5-[(triisopropyl)矽alkyl)oxy]phenyl}-lH-pyrrole-2-carboxamide The compound synthesized in Example (43e) (3_52 g, 8.08 mmol), (S)-(-)-3-amino-1, 2-propanediol (1.84 g, 20.20 mmol), DMT-MM (6.40 g, 20.20 mmol), obtained in the same manner as in Example (5d) The title compound (3.83 g, 94%) mp. = 1.6, 6.3 Hz), 3,51-3.66 (4H, m), 3.84-3.89 ( 1 H, 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 (lH, 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), 9.8 1 (1H, br s). (43g) 5-{3-[(lS)-2-fluoro-1-methylethoxy]_5-[(triisopropyldecyl)oxy]phenyl]N-{(2S)-2 -Hydroxy-3-[(triisopropyldecyl)oxy]propyl}-1Η-pyrrole-2-carboxamide The compound synthesized in Example (43f) (3.83 g, 7.53 mmol) was dissolved in two Chloroform (70 mL), adding triisopropyl decane chloride (2.42 mL, 11.29 mmol), triethylamine (5.25 mL, 37-64 mol), 4-dimethylaminopyridine (1.38 g, 1 1.29 mmol) 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 carbonate - 220 - 201036962, and aqueous sodium chloride and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted elution %). 'H-NMR (CDC13, 400MHz): δ 1.05- 1.1 4 (42H, m), 1.35 (3H, dd, J = 1.2, 6.3 Hz), 3.3 8-3.45 ( 1 H, m), 3.66-3.79 ( 3H, m), 3.85-3.91 (1H, br m), 4.42-4.66 (3H, m), 6.3 0-6.3 5 ( 1 H, br m), 6.40 (1H, t, J = 2.0 Hz), 6.46 (1H, t, J = 2.7 Hz), 6.60 u (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). (4311)(5 ft)-2-(5-{3-[(13)-2-fluoro-b-methylethoxy]_5_[(triisopropyldecyl)oxy Examples of the use of phenyl]phenyl}-1Η-pyrrol-2-yl)-5-{[(triisopropyldecyl)oxy]methyl}-4,5-dihydro-1,3-indazole (43 g) of the synthesized compound (5.01 g, 7.52 mmol), methanesulfonic acid anhydride (2.70 g, 15.04 mmol), triethylamine (4.19 mL, 〇3 0 · 0 7 mmol) was the same as in the Example (1 6j) The title compound was obtained as an orange oil (4.15 g, yield: 85%). W-NMR (CDC13, 400MHz): δ 1.03 - 1.1 5 (3 9H, 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-[(lS)-2-fluoro-1-methylethoxy]-5-{5-[(5R)-5-(hydroxymethyl-221 - 201036962)-4,5-di Hydrogen-1,3-oxazol-2-yl]-1 Η-pyrrol-2-yl}phenol The compound synthesized in Example (43h) (4.15 g, 6.41 mmol), tetrabutyl vaporized (lmol/ The title compound (2.02 g,yield: 94%) Compound Compound Compound Compound Compound Compound Compound Compound Compound ^-NMR (CDC13, 400MHz): δ 1.35 (3Η, 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). (4 3j ){(5R)-2-[5-(3-[(lS)-2-fluoro-1-methylethoxy]-5-{[5-(methylsulfonyl)pyrylene-2-yl) ]]oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol The compound synthesized in Example (43i) (120 mg, 0.36 mmol The compound (69 mg, 0.36 mmol), which was obtained from the compound (43c), was dissolved in acetonitrile (3 mL), and potassium carbonate (99 mg, 0.72 mmol) was added, and the mixture was stirred at room temperature for 3 hours under nitrogen atmosphere. Water (1 mL) was added, and ethyl acetate (3 mL) was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted ^-NMR (CDCI3, 400MHz): δ 1.34 (3Η, dd, J = 1.2, 6.3 Hz), -222- 201036962 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 : 49 1.1 3 903 (M + H) + 〇 (Example 4 4)

{(411)-2-[5-(3-[(13)-2-fluoro, 1-methylethoxy]-5-{[5-(methylsulfonyl)pyrid-2-yl] Oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol

(4 4&amp;)&gt;1-[(5-{3-[(18)-2-fluoro-1-methylethoxy]-5-[(triisopropyldecyl)oxy]phenyl }-1Η-pyrrol-2-yl)carbonyl]-L·serine methyl ester

The compound (7.01 g, 16.09 mmol), methyl L-serinate hydrochloride (2.75 g, 17.70 mmol), H0BT.H20 (2.39 g, 17.70 mmol), N-methyl The desired compound of the white solid was obtained in the same manner as in the Example (29 &amp;) (M.sub.sup.) (3.541^, 32.19111111〇1), 胥8 (:1·11 (:1 (3.7〇8,19.31111111〇1)) 7.88g, yield 91%). *H-NMR (CDC13, 5 00MHz): δΐ.12 (18Η, 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)5 4.82-4.86 ( 1 H, m), 223- 201036962 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)(4S)-2-(5-{3-[(lS)-2 -Fluoro-1-methylethoxy]-5-[(two Ethyl decylalkyl)oxy]phenyl}-1Η-pyrrol-2-yl-4,5-dihydro-1,3-oxazole-4-carboxylic acid methyl ester was synthesized using Example (4 4 a) Compound (7.77 g, 14.48 mmol), bis(2-methoxyethyl)aminosulfur trifluoride (3.47 mL, 18.8 mmol), potassium carbonate (3.00 §, 21.7) The title compound (7.21 g, 96%) was obtained as a white solid. (H.sup.. Hz), 1.23-1.31 (3H, m), 1,35 (3H, dd, J = 1.5, 6.3 Hz), 3.82 (3H, s), 4.42-4.6 8 (5 H, 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-[(lS)-2-Fluoro-1-methylethoxy]-5-[(triisopropyldecyl) Oxy]phenyl}-1Η-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol-4-yl}methanol The compound synthesized in Example (44b) (7.21 g, 13.90 mmol It was dissolved in tetrahydrofuran (150 mL), and lithium aluminum hydride (1.06 g, 27.80 mmol) was added at 0 °C. After stirring for 30 minutes under a nitrogen atmosphere, water (1.OmL), 5N aqueous sodium hydroxide (1 mL), and water (3.0 mL) were sequentially added and 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 evaporated under reduced pressure------------------------- Yield 55%).

!H-NMR (CDCh, 400MHz) : δ 1.13 (18Η, d, J = 7.4 Hz), 1.23 - 1.32 (3 H, 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).罄(44d)3-[(lS)-2-fluoro-1-methylethoxy]-5-{5-[(4R)-4-(hydroxymethyl)-4,5-dihydro-1 , 3-Dfoxazol-2-yl]-1H-pyrrole-2-indole benzene, using the example (44 〇 synthesized compound (3.73 g, 7-60 mmo1), four 8. 6 mmol), with butyl ammonium fluoride (1 mol /L tetrahydrofuran solution, 8.361^ In the same manner as in the Example (1 6k), pale orange _S@$% (2.05 g, yield 81%) was obtained. *H-NMR (CDC13, 400 ΜΗζ): δ 1.35 (3Η, J = 1-6, 6-3 Ηζ^ 3.80 (1Η, dd, J = 3.9, 11.3 Ηζ), 3.99 (lH, dd' J = 3·1, η.3 Ηζ), 4.31-4.67 (6Η, m ), 6.47-6.50 (2Η, bait), 6 73 (1 Η, UJ = I. 6 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.07 (lH, X, J = 1,6 Hz) , II. 03 (1H, br s). (44e){(4R)-2-[5-(3-[(lS)-2 -Fluoro-1-methylethane]]methyl)pyryl Till-2-yl]oxy}phenyl)-1Η-pyrrole-2-indole]_4,5-dihydro-1,3-oxazole-4-yl}methanol-225-201036962. Example (44d) The compound which was synthesized (250 mg, 0.75 mmol), and the compound (144 mg, 0.75 mmol) of the compound (43c) was dissolved in acetonitrile (8 mL), and potassium carbonate (207 mg, 1.50 mmol) was added. After stirring for 8 hours at room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (40 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Chromatography (solvent: methanol / methylene chloride = 0% to 5%) to give the title compound (3 20 mg, 8 7%) as a white solid. [H-NMR (CDC13, 400 MHz): δ 1.39 (3Η, 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: 49 1.1 3 903 (M + H)+. (Example 45) 5-(3-[(lS)-2-fluoro-1-methylethoxy]-5-{5-[(4R)-4-(hydroxymethyl)-4,5- Dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-methylpyrrol-2-carboxamide

-226- 201036962 (45a) 5-Chloro-N-methylpyrrol-2-carboxamide

5-chloroindole was dissolved in n,N-dimethylformamide (10 mL) than hydrazine-2-decanoic acid (1.99 g, 12.6 mmol), H0Bt, H20 (2.11 g, 13.8 mmol), WSCI • HCl was added. (2.89 g, 15.1 mmol), N-methylphenofin (2.76 mL, 25.1 mmol), 40% methylamine/methanol (2_92 mL, 37.6 mmol). Water (50 mL) was added to the mixture. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluting with EtOAc EtOAc EtOAc EtOAc ° /.). ^-NMR (CDC13, 400MHz): δ 3 . Ο 3 (3 Η, 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-[(lS)-2-fluoro-1-methylethoxy]-5-{5-[(4R)-4-(hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-methylpyridin-2-carboxamide makes the examples ( 45&) synthesized compound (17〇1^, 0.99111111〇1) and the compound synthesized in Example (44d) (331 mg, 0.99 mmol) dissolved in N,N-dimethylformamide (3 mL), potassium carbonate (274 mg, 1.88 mmol), stirred at 90 ° C for 2 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, then water (30 mL) was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified to mjjjjjjlililililililililililili -227 - 201036962 • H-NMR (CDC13, 400MHz): δΐ .39 (3H, dd, J = 6.3, 1.5 Hz), 3.05 (3H, d9 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), 4.3 2-4.3 9 (2H, m), 4.46-4.51 (1H, m) , 4.55-4.61 (1H, m), 4.63 -4.70 (1 H, 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: 470.1 83 68 (M + H)+. (Example 46) 5-(3-[(lS)-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

(46a) 5-(3-[(lS)-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)·Ν-methylpyridine-2-sulfonamide The compound (24 mg, 1.0 mmol) synthesized in Example (24c) and the compound (368 mg, 1.0 mmol) synthesized in Example (44d) were dissolved in N,N-dimethylcarnitamine (5 mL), and cesium carbonate was added thereto. (718 mg, 2.20 mmol), stirred at 90 ° C for 3 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, then water (30 mL) was evaporated and evaporated, The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified to mjjjjjlililililililililililili • H-NMR (CDC13, 400MHz): δ 1.38 (3Η, 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), 4.3 5-4.43 (4H, m), 4.47 (1H, d, J = 5.1 Hz), 4.59 (1H, d, J = 4.7 Hz), 4.63 -4.72 ( 1 HS 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-[(lS)-2-Fluoro-1-methylethoxy]-5-{5- [(4R)-4-(hydroxymethyl)-4,5-dihydro-1,3-oxoxazol-2-yl]·1Η-pyrrol-2-yl}phenoxy)-N-methyl The compound synthesized in Example (46a) (540 mg '0.86 mmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at 45 ° C for 5 hours under nitrogen atmosphere. The solvent was distilled off under reduced pressure, and dichloromethane and triethylamine were added in small portions, and the solvent was evaporated under reduced pressure. Purification of the residue by using a seper chromatographic layer chromatography (solvent solvent: methanol / hexanes = 0% to 4%) to give the title compound as a white solid (257 mg, yield: 59%, s, H, NMR (CDCI3, 400 MHz) ): δ 1 . 3 9 (3 Η, 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 -229- 201036962 (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 ( 1 H, m), 4.66-4.74 (l jj 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: 505.1 53 74 (M + H) + 〇 (Example 47) 5-(3-[(lS)-2-fluoro-1-methyl Oxy]-5-{5-[(4R)-4-(hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}benzene Oxy)-N-methylpyridin-2-sulfonamide

(47a) 5-bromopyrrol-2-thiol 2,5-tribromopyridinium (30〇11^'1.26111111〇1) was dissolved in dimethyl hydrazine (3 mL) under nitrogen atmosphere, and sodium disulfide was added. After hydrate (454 mg, 1.89 mm 〇l), it was stirred at 1 0 ° C for 1 · 5 hours. The reaction solution was cooled to room temperature and water (30 mL) was added and neutralized with 5 N hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and then the obtained solid was dissolved in diethyl ether/tetrahydrofuran. The solvent was evaporated under reduced pressure and evaporated to dryness crystals crystals crystals crystalssssssssssssssssssssssssssssssssss d, J = l 〇-230- 201036962

Hz), 8.34 (1H, d, J = 1.0 Hz). (47b) 5-bromo-N-methylpyrazine-2-sulfonamide The compound synthesized in Example (47a) (988 mg, 5.17 mmol) was dissolved. Methylene chloride (15 mL) / 1 N hydrochloric acid (15 mL), cooled to -1 (TC). While maintaining the reaction mixture below -5 °C, the ice-cold 7% aqueous sodium perchlorate solution (15 mL) was added and stirred for 1 hour. The organic layer was separated into a chilled separatory funnel, and then cooled to 〇 ° C, and then a commercially available 40% methylamine/methanol solution (1.00 mL, 12.9 mmol) was warmed to room temperature and stirred for 17 hours. A saturated aqueous solution of ammonium chloride (30 mL) was added to the mixture, and the mixture was applied to dichloromethane (30 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by column chromatography (solvent: ethyl acetate / hexanes: 30%) to afford the title compound (147 mg, yield: 11%). NMR (CDC13, 400 MHz): δ 2.83 ( 3Η, 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). O (4 7c)5-(3 -[(lS)-2-fluoro-1-methylethoxy]-5-{5-[(4 R)-4-(hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-methylpyrrolin- 2-sulfonamide The compound synthesized in Example (47b) (103 mg, 0.41 mmol) and the example (44-synthesis compound (13〇11^, 0.39111111〇1) were dissolved in]^, dimethyl dimethyl The amine (2 mL) was added with EtOAc (EtOAc (EtOAc)EtOAc. After washing the organic layer with water, it was dried with anhydrous sulfuric acid-231-201036962 magnesium. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (solvent solvent: methanol/dichloromethane = 0% to 3.5%). The title compound (131 mg, yield 66%) was obtained as white solid.

*H-NMR (CDC13, 400ΜΗζ): δ 1.39 (3Η, 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, s 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 = l 〇Hz) MS (ESI) m/z: 506.1 4859 (M + H)+. (Example 48) 1:^-Dimethyl-3-{5-[(53)-5-methyl-4,5,dihydro-1,3-oxazol-2-yl]-1^pyrrole -2-yl}-5-[4-(methylsulfonyl)phenoxy]benzamide

0., 0

(4 8&amp;) 3-[4-(Methanesulfonyl)phenoxy]-5-{[(trifluoromethyl)sulfonyl]oxy)benzoic acid methyl ester 3,5-dihydroxybenzene Methyl formate (9.1 〇 8, 54.1111111 〇 1) and 4-fluorophenylformamidine (7.10 g, 40.8 mmol) were dissolved in hydrazine, hydrazine-dimethylformamide (80 mL), and a carbonate chain was added (30. g' 217mmo1) 'Stirring at 100 ° C for 15 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature &lt;RTI ID=0.0&gt;&gt;&gt; The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent solvent: ethyl acetate / hexane = 30 / / - 70%) to give a white solid. This was dissolved in dichloromethane (100 mL), and pyridine (7.50 mL, 92.7 mmol) and trifluoromethanesulfonic anhydride (7.80 mL, 4 6.4 mm 〇l) were added at 0 ° C, and stirred at 0 ° C under a nitrogen atmosphere. 3 hours and a half. The reaction mixture was warmed to room temperature and brine (EtOAc) The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted . !H-NMR (CDCh, 400MHz) : δ 3.10 (3Η, 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). (4 81?) 3-[4-(Methanesulfonyl)phenoxy]-5-(4,4,5,5-four Methyl-1,3,2-diindolecyclopentan-2-yl)benzoic acid The compound synthesized in Example (48a) (9.58 g, 21.1 mmol), boranoic acid pinacol ester (7.45) g, 29.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloride (11) dichloromethyl compound complex (850 mg, 1.04 mmol), potassium acetate (10.6 g ' The title compound (6.83 g, yield: 75%) was obtained as a pale red solid. -233 - 201036962 !H-NMR (CDC13j 400MHz) : 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 , 〇.8 Hz). (4 8(〇5-{3-(methoxycarbonyl)-5-[4-(methylsulfonyl)phenoxy]phenyl}, 11_1_pyrrole-1,2- 2-Benzyl 1-t-butyl dicarboxylate The compound (9.40 g, 24.7 mmol) synthesized in Example (16d) and the compound (6.58 g, 15.2 mmol), [1,1] 'Bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloride complex (1.1 g, 1.35 mmol), potassium carbonate (8.70 g, 63.0 mmol), and the example (I6e) The same procedure gave the title compound ( 7.79 g, yield: 85%). ???H-NMR (CDCI3, 400 MHz): δ 1.24 (9 Η, 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)5 7.31-7.44 (5H,m), 7.71-7.72 (1H,m), 7.92 (2H, d,J = 9 0 Hz), 7.95-7.96 ( 1 H,m (4 8(1)5-{3-(methoxycarbonyl)-5-[4-(methylsulfonyl)phenoxy]phenyl}-111-pyrrole-2-carboxylic acid (48c) The synthesized compound (7.79 g '1. 9 mmol) was dissolved in trifluoroacetic acid (10.0 mL) and stirred at room temperature for 45 min. The solvent was evaporated under reduced pressure, and then triethylamine (5 mL) was added and stirred for 5 min. The triethylamine was distilled off under reduced pressure to give a pale-yellow solid. This was dissolved in ethyl acetate (100 mL), palladium carbon (1.5 g) was added, and hydrogen gas was stirred at room temperature for 1 day under the atmosphere of 234-201036962. After filtration of the celite, the solvent was evaporated under reduced pressure to give the title compound (yield: 66). ). ^-NMR (CD3OD, 5 00MHz): δ 3.13 (3Η, 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: 41 5 (M + ). (48e) 3-(5-{[(2R)-2.hydroxypropyl]aminecarbamoyl}-lH-pyrrole-2·yl)- Methyl 5-[4-(methylsulfonyl)phenoxy]benzoate The compound (2.86 g, 6-88 mmol) synthesized in Example (48d) was dissolved in dichloromethane (7 mL) and N, N- a mixed solvent of methylformamide (45 mL), (R)-(-)-l-amino-2-propanol (1.20 g, 15.98 mmol), WSCI · HCl (2.80 g, 14.61 mmol), 4 Dimethylaminopyridine (900 mg, 7.3 7 mmol) was stirred at room temperature for 3 days under a nitrogen atmosphere. The solvent was evaporated under reduced pressure, and brine (5 mL) was evaporated. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was evaporated to mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ^-NMR (CDCI3, 400MHz): δ 1.26 (3Η, d, J = 6.3 Hz), 2.41 (1H, s s), 3.09 (3H, s), 3.27-3.34 ( 1 H, 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), -235 - 201036962 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-carbazole -2 -yl]-1H-pyridyl-2-yl}-5-[4-(methylsulfonyl)phenoxy]benzoic acid methyl ester The compound synthesized in Example (48e) (2.24 g, 4.74mniol , methanesulfonic anhydride (1.25 g, 7.17 mmol), triethylamine (2. 〇〇mL, 14.3 mmol), m. Yield 92%) « 'H-NMR (CDCh, 400MHz) : δ 1.43 (3Η, d, J = 6.3 Hz), 3.〇g (3H, s), 3.53 (1H, dd, J = 13.5, 6.8 Hz), 3.94 (3H, s), 4.〇6 (1H, dd, J = 14.9, 10.2 Hz), 4.8 0-4.8 8 ( 1 H, 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: 45 5.1 3005 (M + H) + 〇 (48g) 3-{5-[(5S)-5-methyl-4,5-dihydro-1,3- Df oxazol-2-yl]-1H-pyrrol-2-yl}-5-[4-(methylsulfonyl)phenoxy]benzoic acid The compound synthesized in Example (48f) (820 mg, 1.80 mmol) It was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (2 mL), and lithium hydroxide monohydrate (200 mg, 4.77 mmol) was added at room temperature, and the mixture was stirred at 50 ° C for 5 hours. Five equivalents of hydrochloric acid (3 mL) were added, and the resulting precipitate was collected by filtration. The obtained solid was washed with diethyl ether (2 mL). -236- 201036962 MS (FAB) m/z : 441 (M + H) + . (4 81〇]^,;^-dimethyl-3-{5-[(53)-5-methyl-4 ,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[4-(methylsulfonyl)phenoxy]benzamide. Examples ( 4 8 g) The synthesized compound (78 mg, 0.18 mmol) was dissolved in dichloromethane (10 mL), dimethylamine hydrochloride (170 mg, 2.08 mmol), WSCI, HCl (140 mg, 0.73 mmol), triethyl Amine (0.40 mL,

2.8 7 mmol), stirred at room temperature for one night under a nitrogen atmosphere. A saturated aqueous solution of ammonium chloride (30 mL) was added to the mixture and the mixture was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluted eluted elut elut elut elut elut elut elut elut elut !H-NMR (CDC13j 5 00MHz) : δ 1.41 (3Η, 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 (1 H, 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: 468.1 5943 (M + H)+. (Example 49) N-ethyl-N-methyl-3-{5-[(5S)-5-methyl-4,5-diamino.i,3-indol-2-yl]-1H -pyrrol-2-yl}-5-[4-(methylsulfonyl)phenoxy]benzamide-237- 201036962

The compound synthesized in Example (48 g) (97 mg, 0.22 mmol) was dissolved in chloroform (lO.OmL), N-ethylmethylamine (〇.i〇mL, 1.16 mmol), HATU (250 mg, 0.66 mmol), hydrazine, hydrazine-diisopropylethylamine (〇2〇mL, 1.15 mmol) was stirred at room temperature overnight under nitrogen. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluting eluted eluted eluted eluted elution . W-NMR (CDC13, 400MHz): δ 1.11-1:27 (3H,m), 1.43 (3H,d, J = 6.3 Hz), 2.97 (3H, s 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: 482.1 7604 (M + H)+. (Example 50) (3-{5-[(5S)-5-methyl-4,5-diindole-1,3-Df 哩-2 -yl]-1H-D ratio: alk-2-yl} -5-[4-(methylsulfonyl)phenoxy]phenyl)(pyrrolidinyl)-methanone

-238- 201036962

The compound (10 mg, 0.23 mmol), pyridine (0.15 mL, 2.16 mmol), HATU (250 mg, 0.66 mmol), N,N-diisopropylethylamine (〇. The title compound (61 mg, yield 53%) was obtained. H-NMR (CDC13, 500MHz): 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 (1 H, 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: 494.1 7477 (M + H)+. (Example 51) (3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-Bfoxazol-2-yl]-1H-pyrrolyl}-5-[4 -(Methanesulfonyl)phenoxy]phenyl)(morpholine-4-yl)methanone

The compound (102 mg, 0.23 mmol), moffolin (0.15 mL, 1.72 mmol), H ATU (2 5 Omg, 0.66 mmol), N,N-diisopropylethylamine ( The title compound (121 mg, yield -100%) was obtained as a white solid. 'H-NMR (CDCls, 500MHz) : δ 1.43 (3Η, d, J = 5.9 Hz), 3.08 -239- 201036962 (3 Η, s), 3 · 1 8 (2 Η, q, J = 7.3 Η z ), 3 · 4 4 - 3 . 8 8 (6 Η,m),3 . 5 5 (1 Η, 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, dts J = 9.4, 2.4 Hz). MS (ESI) m/z: 5 1 0.1 686 1 (M + H)+. (Example 52) N-Methoxy-N-methyl-3-{5-[(5S)-5-methyl-4,5-dihydro-l,3-Dfoxa-2-yl]- 1H-pyrrol-2-yl}-5-[4-(methylsulfonyl)phenoxy]benzamide

The compound (I52 mg, 〇.35 mmol), N,0-methyl-methyl-amine hydrochloride (170 mg, 1.74 mm ο 1) 'HATU (325 mg' 0.86 mmol), N,N-Diisopropylethylamine (3 mL, 1.7 2 mm, EtOAc). 'H-NMR (CDC13, 400MHz) : δ 1.43 (3Η, d, J = 6.3 Hz), 3.08 (3H, s), 3.38 (3H, s), 3.47- 3.57 ( 1 H, m), 3.58 (3H , s), 4.10 (1H, dd, J = 14.3, 9.2 Hz), 4.82-4.89 (1 H, 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) -240- 201036962 MS (ESI) m/z : 484· 1 5489 (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

0 The compound (80 mg, 0.18 mmol), azetidine hydrochloride (120 mg, 1.28 mmol), WSCI.HCl (100 mg, 0.52 mmol), triethylamine (0.1 mL) The title compound (1 2 mg, yield: 14%) was obtained as white solid. ^-NMR (CDC13, 400MHz): δ 1.43 (3Η, d, J = 6.3 Hz), 2.3 3 -2.40 (2H, m), 3.08 (3H, s), 3.56 (1H, dd, J = 14.1, 7.4 Hz), 3.73-3.78 ( 1 H, m), 4.20-4.28 (2H, m), 4.28-4.3 5 (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: 480.1 5 870 (M + H), (Example 54) 3-{5-[(5R)-5-(hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-ylindole-indole, fluorenyl-dimethyl-5-[4-(methylsulfonyl)phenoxy Benzoylamine-241 - 201036962

(54&amp;) 3-(5-{[(2 8)-2,3-dihydroxypropyl]amine-carbamoyl}-111-pyrrol-2-yl)-5-[4-(methylsulfonyl) Methyl phenoxy]benzoate The compound synthesized in Example (48d) (1.58 g, 3.80 mmol) was suspended in a mixed solvent of methanol (30 mL) and tetrahydrofuran (30 mL), and (S)-(-)-3 was added. -Amino-1,2-propanediol (5 4 4 mg, 5.9 7 mm ο 1), D Μ Τ-Μ Μ (2 _ 5 6 g, 8.18 mmol), and stirred under a nitrogen atmosphere for 6 hours. After concentrating the reaction mixture, water was added and extracted with ethyl acetate. After washing with saturated brine, it was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified (jjjjjjjd 'H-NMR (CDC13, 400MHz) : δ 3.08 (3Η, 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 ( 1 H, 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)3-[ 5-({(2S)-2-hydroxy-3-[(triisopropyldecyl)oxy)propyl]aminecarbamyl)-1Η-pyrrol-2-yl]-5-[4·( Methanesulfonyl)phenoxy]benzoic acid methyl ester-242- 201036962 The compound synthesized in Example (54 &amp;) (1.258, 2.56111111〇1) was dissolved in dichloromethane (25 mL), and triethylamine (l 〇 5 mL, 7.57 mmol), triisopropyl decane chloride (610 μί, 2.85 mmol), 4-dimethylaminopyridine (314 mg 2.5 7 mmol), and stirred under nitrogen atmosphere for 5 hours. The reaction mixture was diluted with ethyl acetate (1 mL), washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography (solvent solvent: ethyl acetate/hexane = 40% to 60%) to afford white solid.

(1.16g, 70%). W-NMR (CDC13, 400MHz): 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), 3.8 5 -3.90 ( 1 H, 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) 3-[4-(methylsulfonyl)phenoxy]-5-{5 -[(5R)-5-{[(triisopropyldecyl)oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrole-2- Methyl benzoate was synthesized using the compound (1.i6g&gt; 1.80 mmol), methanesulfonic anhydride (633 mg, 3.63 mmol), triethylamine (〇.99 mL, 7.14 mmol) synthesized in Example (54b). The title compound (1.11 g,yield 98%) was obtained as a pale yellow solid. -243- 201036962 *H-NMR (CDC13, 400MHz) : δ 1.02-1.14 (21H, m), 3.08 (3H, s), 3.83 -3.92 (3 H, 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 (lH, 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-(Methanesulfonyl)phenoxy]-5-{5-[(5R)-5-{[(triisopropyldecyl)oxy]methyl}-4, 5-Dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}benzoic acid The compound synthesized in Example (54c) (1. 〇lg, 1.75 mmol) was dissolved in ethanol (1) 5 mL), 2N aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at 70 ° C for 1 hour. Water (10 ml) was added to the reaction mixture, and the mixture was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystal crystal crystal crystal crystal crystal crystal crystal MS (FAB) m/z : 613 (M + H) + . (54〇3-{5-[(511)-5-(hydroxymethyl)-4,5-dihydro-1,3-oxazole -2-yl]-11 pyrrole-2-ylindole-indole, fluorene-dimethyl-5-[4-(methylsulfonyl)phenoxy]benzamide. Synthesis of Example (54d) Compound (944 mg, 1.54 mmol) was dissolved in N,N-dimethylformamide (15 mL), dimethylamine hydrochloride (289 mg, 3.54 mmol), HATU (1.21 g, 3-18 mmol), N, N- Diisopropylethylamine (1.08 mL, 6.18 mmol) was stirred at room temperature for 15 hours under nitrogen. Water (50 mL), 1N hydrochloric acid (15 mL) After extracting with 100 mL), the mixture was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (solvent solvent: methanol/dichloromethane = 〇. 5 to 5 %). 'A compound of orange oil (1.20 g) was obtained.

This was dissolved in tetrahydrofuran (15 mL), and tetrabutylammonium fluoride (1.0 mol/L tetrahydrofuran solution, 1.60 mL, 1.60 mmol) was added, and the mixture was stirred for 1 hour under a nitrogen atmosphere. A saturated aqueous solution of sodium hydrogencarbonate (5 mL) was added toEtOAc. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluting eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted . ^-NMR (CDC13, 400MHz): δ 2 · 9 9 (3 Η, brs), 3 _ 0 7 (3 Η, 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-u-oxazol-2-yl]·1Η-pyrrol-2-yl}-^1 Dimethyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}benzole-245 - 201036962 guanamine

(55a) 3-Hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}benzoic acid methyl ester The compound synthesized in Example (16a) (17.4 g '90.8 mmol) was dissolved. N,N-dimethylformamide (500 mL). Methyl 3,5-dihydroxybenzoate (30.5 g, 181 mmol) and potassium carbonate (37.7 g, 273 mmol) were added, and stirred at 100 ° C for 5.5 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, water (500 mL) was added and extracted with diethyl ether (400 mL) three times. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted elution . H-NMR (CDC13, 400MHz): δ3.24 (3H, s), 3.91 (3H, s), 6.36 (1Η, brs), 6.82 (1Η, t, J = 2.4Hz), 7.28 (1Η, brs ), 7.43 (1Η, 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) Synthesis of methyl 3-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-5-{[(trifluoromethyl)sulfonyl]oxy}benzoate Example (55a) The compound (18.9 g, 58.5 mmol) was dissolved in dichloromethane (500 mL). Trifluoromethanesulfonic anhydride (13.8 mL, 82.0 mmol) and pyridin (14.2 mL, 176 mmol) were added at 0 ° C, and stirred at room temperature for 2 hours under nitrogen atmosphere. Water (400 m L) was added and extracted twice with dichloromethane (40 mL). -246-201036962 After washing the organic layer with saturated brine, it was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified to crystals crystals eluted eluted elution ). 'H-NMR (CDC13, 400MHz): 53.26 (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 = 2.7 Hz) · (55c) 5-[3-(Methoxycarbonyl)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl]-1H-pyrrole- Benzyl 2-carboxylate The compound synthesized in Example (55b) (20.9 g, 45.9 mmol), the compound synthesized in Example (19e) (18-0 g, 55.0 mmol), [1,1'-bis(diphenylphosphine) a ferrocene]palladium(II) chloride dichloride complex (1.13 g, 1.38 mmol) and potassium carbonate (12.7 g, 91.9 mmol) were obtained as a white solid. The compound of interest (1 9.3 g, yield 83%). 'H-NMR (CDC13, 400MHz): 63.24 (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), 7.3 5-7.47 (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 = 2.9 Hz), 9.49 (1 H, brs) 〇(55d)3-[5-({(2S)-2-hydroxy-3-[(triisopropyldecyl) Oxy]propyl}aminocarbazino)-1Η-pyrrol-2-yl]-5_{[6-(methylsulfonyl)pyridin-3-yl]oxy} methyl benzoate-247- 201036962 The compound (55 〇 synthesized compound (19.3 g, 38.1 mmol) was dissolved in a mixed solvent of ethyl acetate (200 mL) and tetrahydrofuran (200 mL), and a 10% palladium carbon catalyst (7.8 Og) was added thereto in a hydrogen atmosphere. The mixture was stirred for 3.5 hours, and the palladium-carbon catalyst was removed by filtration through Celite, washed with ethyl acetate, and the solvent was evaporated 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 · 9 5.4 mm 〇l), stirred at room temperature for 19 hours under nitrogen atmosphere. Solvent, add water (200 mL), Ethyl acetate (100 mL) was extracted for 10 times. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. Triisopropyl decane (12, 2 mL, 57.0 mmol), triethylamine (16.0 mL, 115 mol), 4-dimethylaminopyridine (4.66 g, 3 8.1 mmol), stirred at room temperature under nitrogen 17 hours. Water (200 mL) was added and the mixture was extracted with dichloromethane (200 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. (Isolation solvent: ethyl acetate / hexane = 40% to 70%). The obtained residue was purified to give white crystals (yield: 79%) (yield: 79%). &quot;H-NMR (CDCla, 400 ΜΗζ): δ ΐ. 03-1.16 (21Η, m), 3.12 (1H, d, J = 4.7Hz), 3.24 (3H, s), 3.39 (1H, ddd, J = 4.7, 7.0, 14.1Hz), 3.67 (1H, dd, J = 6.3, 9.8 Hz), 3.74 (1H, ddd, J = 3.1, 7.0, 14.1 Hz), 3.78 (1H, dd, J = 4.7, 10.2 Hz), 3.87 (1H, m), 3.95 -248 - 201036962 (1H, s), 6.44 (1H, brt, J = 6.3Hz), 6.61 (1H, dd, J = 2.7, 3.9 Hz), 6.64 (1H, dd, J = 2.4, 3.9 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 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 (1 H, Brs ).

(55e) 3-{[6-(Methanesulfonyl)pyridin-3-yl]oxy}-5-{5-[(5R)-5-{[(triisopropyldecyl)oxy] Methyl}-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}benzoic acid methyl ester The compound synthesized in Example (55d) (19.4 g, 30.0 mmol ), methanesulfonic anhydride (11.Og, 63.1 mmol), triethylamine (21.0 mL, 151 mol),yield of the title compound (15.6 g, yield: ). 'H-NMR (CDC13, 400ΜΗζ): δΐ.03-1.13 (21Η, m), 3.25 (3H, s), 3.83-3.93 (3H, m), 3.95 (3H, s), 4.02 (1H, dd, J = 9.8, 14.5 Hz), 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, 8.6 Hz), 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-[(511)-5-{[(三异Propyl decyl)oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-111-pyrrol-2-yl}benzamide The synthesis of Example (55e) The compound (4.02 g, 6.40 mmol) was dissolved in ethanol (100 mL), and 2N aqueous sodium hydroxide (50 mL) was added, and the mixture was heated to reflux for 1 hour under nitrogen atmosphere -249-201036962. 2N hydrochloric acid (55 mL) was added to the reaction mixture, and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was dissolved in methanol (7 mL), using dimethylamine (2.0 mol/L methanol solution, 8.00 mL, 16.0 mmol), DMT-MM (4 43 g, 16.0 mmol), and Example (5d) The title compound (1.84 g, yield 45%) was obtained as white solid. ^-NMR (CDC13, 400MHz): δΐ.02-1.13 (21Η, 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). (5 5g)3-{5-[ (5R)-5-(hydroxymethyl)-4,5-dihydro-1,3-Bfoxazol-2-yl]-1H-pyrrol-2-yl}-N,N-dimethyl-5- {[6-(Methanesulfonyl)pyridin-3-yl]oxy}benzamide The compound synthesized in Example (55f) (i.84 g, 2.87 mmol), tetrabutylammonium fluoride (1 mol/ The title compound (1.27 g, yield: 191 g) (CDCI3, 400 MHz) was obtained as a white solid. 62.98 (3 H, 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, -250- 201036962 J = 3.9Hz), 6.97 (1H, brs), 7.29 (1H, br s), 7.40 (1H, brs), 7.44 (1H, dd, J = 2.4, 9.0 Hz), 8.05 (1H, d, J = 9.0 Hz), 8.48 (1H, d, J = 2.4 Hz). MS ( ESI) m/z: 485.1 4948 (M + H) + (Example 56) 3-{5-[(51〇-5-(fluoromethyl)-4,5-dihydro-1,3-anthracene Zin-2-yl]-111-pyrrol-2-yl}-N,N-dimethyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}benzamide

The compound (5 63 g, l_16 mmol) synthesized in Example (5 5 g) was dissolved in 1,2-dimethoxyethane (15 mL), and bis(2-methoxyethyl) was dropped at 〇 ° C under a nitrogen atmosphere. Aminosulfur trifluoride (〇.32 mL, 1.7 mmol). The temperature was raised to room temperature, and bis(2-methoxyethyl)aminosulfur trifluoride (0.3 2 mL, 1.7 mm 〇l) was added in the middle, and stirred for 7 hours. After adding methanol (2 mL) and stirring for 10 minutes, aq. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was evaporated to mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj • H-NMR (CDC13, 500MHz): δ 3.02 (3Η, 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 -251- 201036962 =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 : 487.1 4624 (M + H)+. (Example 57) N,N-monomethyl-3-{5-[(5S)-5-methyl-4,5-dichloro-1,3-indole-2-yl]-1H- Pyrrol-2-yl}-5-{[6-(methylsulfonyl)pyridine·3_yl]oxy}benzamide

(57 3) 5-[3-(Methoxycarbonyl)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl]-1Η-pyrrole-2-carboxylic acid The compound (2,9 g, 4.52 mmol) of the compound (55c) was dissolved in tetrahydrofuran (150 mL), and a 10% palladium carbon catalyst (2.53 g) was added thereto, and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. The palladium carbon catalyst was removed by filtration through Celite, and washed with ethyl acetate. The solvent was evaporated under reduced pressure to give crystal crystal crystal crystal crystal crystal crystal crystals W-NMR (DMSO-D6, 400MHz) δ : 3 · 2 8 (3 Η, s), 3 · 8 9 (3 Η, 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) 3-(5-{[(2R)-2-Hydroxypropyl]aminecarbamyl} -lH-pyrrole-2--252- 201036962 base)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}benzoic acid methyl ester The compound synthesized using the compound (5 7 &amp; (1.528, 3.65111111〇1), (R)-(-)-l-amino-2-propanol (450 μΕ, 5.69 mmol), DMT-MM (2.80 g, 8.94 mmol), and Example (5d) The same procedure gave the title compound as a white solid (1·2 8 g, 7 4%) ° 'H-NMR (CDC13, 400 MHz): δ 1.25 (3 Η, d, J = 6.3 Hz), 3.24 (3H, s) , 3.26-3.32 ( 1 H, m), 3.59-3.65 ( 1 H, m), 3.95 (3H, s), () 4.00-4.04 ( 1 H, 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, d5 J = 2.7 Hz), 9.96 (1H, br s). MS (FAB) m/z : 474 (M + H)+. (57c) 3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]_1H_pyrrol-2-yl}-5-{[6-( Methanesulfonyl)pyridin-3-yl]oxy}benzoic acid methyl acetonate U The compound synthesized in Example (57b) (1.26 g, 2 67 mm 〇1), methanesulfonic anhydride (93 6 mg, 5.37 mmol), The title compound (0.92 g,yield: 76%) ofyield (yield: 76%). *H-NMR (CDC13, 400MHz): δ 1.43 (3Η, 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 (1 H, 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 -253 - 201036962 (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: 456.1 2 143 (M + H)+. (57d)N,N-dimethyl- 3-{5-[(5S) -5-methyl-4,5-dihydro-i,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulfonyl)pyridine-3- The compound synthesized in Example (57c) (9 2 0 mg, 2. 2 mmol) was dissolved in ethanol (15 mL), and 2N aqueous sodium hydroxide (5 mL) was added at 70 ° C Stir for 1 hour. After adding water (10 mL) to the reaction mixture, ice-cooled, and 1N hydrochloric acid (10 mL) was added, and the precipitated white solid (73 0 mg) was collected by filtration. This was suspended in hydrazine, hydrazine-dimethylformamide (8 mL), dimethylamine hydrochloride (2 83 mg, 3.47 mmol), HATU (1.25 g, 3.28 mmol), N,N-diisopropyl The ethyl ethylamine (1.15 mL, 6.58 mmol) was stirred at room temperature for 6 hours under a nitrogen atmosphere. Water (50 mL) was added to the mixture, and the mixture was evaporated. The solvent was evaporated under reduced pressure, and the residue was purified to mjjjjjjjjjjjj ^-NMR (CDC13, 400MHz): δ 1.4 2 (3 Η, d, J = 6.3 Hz), 3.02 (3H, br s), 3.12 (3H, s 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 (1 H, 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 -254- 201036962 (2H, m), 8.07 ( 1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz). MS (ESI) m/z: 469.1 5449 (M + H) + ° (Example 58) N,N-dimethyl -3_{5-[(4R)-4_methyl-4,5-dihydro-i,3_carbazole-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulfonate) Pyridin-3-yl]oxy}benzamide

(58a) 3-(5-{[(lR)-2-Hydroxy-1-methylethyl]aminemethanyl}-1Η-pyrrole-2-yl)-5-{[6-(methylsulfonate) Methyl pyridin-3-yl]oxy}benzoate The compound synthesized in Example (57a) (1.53 g, 3.67 mmol), D-aminopropanol (570 pL, 7.36 mmol), DMT-MM (2.89) g, 9.23 mmol), mp (m.)

!H-NMR (CDC13, 500MHz) : δ 1.28 (3Η, d, J = 6.8 Hz), 2.75 (1H, br s), 3.24 (3H, s), 3.60-3.66 ( 1 H, m), 3.74- 3.8 0 ( 1 H, m), 3.95 (3H, s), 4.22-4.30 ( 1 H, 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) + . -255- 201036962 (58b) 3-{5-[(4R)-4 -methyl-4,5-dihydro- l,3 -carbazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}benzoic acid methyl ester was synthesized using Example (58a) The compound (990 mg, 2.09 mmol), methanesulfonic acid anhydride (730 mg, 4-19 mmol), triethylamine (i.2mL, 8-7 mn ol) was obtained in the same manner as in Example (1 6j). Yield 94%) ° *H-NMR (CDC13, 400MHz) : δ 1.34 (3Η, d, J = 6.3 Hz), 3.25 (3H, s), 3.92-3.97 ( 1 H, m), 3.95 (3H , s), 4.3 0-4.3 9 ( 1 H, 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 The compound synthesized in Example (58b) (899 mg, 1.97 mmol), 2 N aqueous sodium hydroxide (5 mL), dimethylamine hydrochloride (20 8 mg, 2.55 mmol), HATU (927 mg, 2.44 mmol), N,N-diisopropylethylamine ( EtOAc, EtOAc (EtOAc) 'H-NMR (CDCh, 400MHz): δ 1.32 (3Η, 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 -256- 201036962

Hz), 4.28-4.37 ( 1 H, 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: 469.1 5449 (M + H)+. (Example 59) 2-methyl-1-(3-{5-[(58)-5-methyl, 4,5-dihydro-1,3-oxazol-2-yl]-1^1 -pyrrol-2-yl}-5-[4-(methylsulfonyl)phenoxy]phenyl)propan-1-one

〇·.,,〇 (59a) 1-(3,5-Dimethoxyphenyl)-2-methylpropan-1-ol

3,5-Dimethoxybenzaldehyde (6.67g' 40.1mmol) was dissolved in tetrahydrofuran (40mL), and isopropylmagnesium bromide (〇.72mol/L tetrahydrofuran solution, 90mL, 64.8 mmol) was added dropwise at -78 °C. The mixture was stirred at room temperature for 4 hours and a half under a nitrogen atmosphere. A saturated aqueous solution of ammonium chloride (2 mL) was added and ethyl acetate (200 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluting eluted eluted eluted elution . · ^-NMR (CDC13, 400MHz): δ 0.82 (3Η, 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 ( 1 H, m), 3.80 (6H, s), 4.29 (1H, dd, J = 7.0, 3.1 Hz), 6.37 (1H, t, -257- 201036962 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, 18.2mm) Dissolved in dichloromethane (200 mL), and added manganese dioxide (15.0 g, 173 mmol) at room temperature under reflux in a nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was filtered through Celite. The mother liquid was evaporated under reduced pressure to give the title compound (m. !H-NMR (CDC13, 400MHz) : δ 1.21 (6Η, d, J = 7.0 Hz), 3.46-3.53 (1 H, m), 3.84 (6H, s), 6.65 (1H, t, J = 2.2 Hz ), 7.09 (2H, d, J = 2.0 Hz). (59e) l-{3-Methoxy-5-[4-(methylsulfonyl)phenoxy]phenylmethylpropan-1-one The compound synthesized in Example (59b) (2.55 g, 12.2 mm 〇l) was dissolved in 1-methyl-2-pyrrolidone (30 mL), and sodium methoxide (1.75 g ' 2 5.0 mmol) was added at room temperature. The mixture was stirred at 100 ° C for 3 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, 2N aqueous hydrochloric acid (150 mL) was added, and ethyl ether (300 mL) was applied. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was dissolved in N,N-dimethylformamide (30 mL), and 4-fluorophenylformamidine (4.40 g, 25.3 mmol) and potassium carbonate (7.05 g, 5 l.Ommol) were added at room temperature. Stir at 1 ° C for one night under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (150 mL) was added and extracted with diethyl ether (300 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Distillation under reduced pressure -258-201036962 Remove solvent. The title compound (3.98 g, yield 94%) was obtained from EtOAc EtOAc EtOAc EtOAc : δ 1.21 (6Η, d, J = 6.8 Hz), 3.07 (3H, s), 3.42-3.47 (1 H, in), 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)l-{3-hydroxy-5-[4-(methylsulfonyl)phenoxy]phenyl}-2-methylpropan-1_

I ketone The compound synthesized in Example (59c) (3.78g ' 10.9mmol) was dissolved in dichloromethane (30mL), and boron tribromide U. 〇mol/L dichloromethane solution was dropped at -78 ° C, 35.0 m L, 35. Ommol) was stirred at room temperature for 4 hours under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution (10 mL) was added to dichloromethane (20 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:EtOAc %). iH-NMR (CDCh, 400MHz): δ 1.20 (6Η, 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-methylpropenyl)-5-[4-(methylsulfonyl)phenoxy]phenyl trifluoromethanesulfonate-259-201036962 Compound synthesized in Example (59d) (920 mg, 2.75 mmol) was dissolved in dichloromethane (10 mL), and pyridine (..sup.70mL, 8.65mmol) and trifluoromethyl anhydride (0.70mL, 4.16mm) were added at 〇 ° C. Stir at 0 ° C for 1 hour and a half. The reaction mixture was warmed to room temperature and brine (50 mL) The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluting eluted eluted eluted eluted eluted eluted eluted eluted eluted 1 %). ^-NMR (CDCh, 400MHz): δ 1.23 (6Η, d, J = 7.0 Hz), 3.10 (3H, s), 3.3 9-3.46 ( 1 H, 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- l-{3-[4- (Methanesulfonyl)phenoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)phenyl}propan-1- The ketone was synthesized using the compound (1", 7 g, 2.51 mmol), boranoic acid pinacol ester (〇.90 g, 3.54 mmol), [1, Γ-bis(diphenylphosphino)ferrocene]. Palladium dichloride (methylene chloride) methylene chloride complex (200 mg, 0.25 mmol), potassium acetate (1.25 g, 12.7 mmol),yield Rate 55%). ^-NMR (CDCla, 400MHz): δ 1.22 (6Η, d, J - 6.6 Hz), 1.36 (12H, s), 3.07 (3H, s), 3.5 7-3.64 ( 1 H, m), 7.07 (2H , d, J = 8.6 Hz), 7.68 (1H, d5 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). -260- 201036962 (5 9g) 5-{3-(2-methylpropenyl)-5-[4-(methylsulfonyl)phenoxy]phenyl}-111-pyrrole-1,2- 2-benzyl-1-t-butyl ester of dicarboxylic acid

The compound synthesized in Example (59f) (608 mg, 1.37 mmol), the compound synthesized in Example (16d) (1.10 g, 2 - 89 mmol), [1, 1, bis(diphenylphosphino)ferrocene] dichloride Palladium (II) methylene chloride complex (115 mg, 0.14 mmol), EtOAc (EtOAc: EtOAc (EtOAc) %). *H-NMR (CDCls, 400MHz): δ 1.22 (6Η, d, J = 7.0 Hz), 1.42 (9H, s), 3.07 (3H, s), 3.45-3.53 ( 1 H, 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-methylpropenyl)-5-[4-(methylsulfonyl)phenoxy]phenyl}-1Η-pyrrole-2-carboxamide Example (59g The compound (630 mg '1.02 mmol) was dissolved in trifluoroacetic acid (5.0 mL) and stirred at room temperature for 40 min. After distilling off the solvent under reduced pressure, triethylamine (5 mL) was added and stirred for 5 min. Diethylamine was distilled off under reduced pressure to give a pale yellow solid. This was dissolved in ethyl acetate (15 mL). palladium carbon (ll5 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. After filtration through Celite, the solvent was distilled off under reduced pressure to give a brown liquid compound. This was dissolved in dichloromethane (1 OmL) 'Add (R)_(-)-1-amino-2-propanol (0.20 mL, 2.54 mmol), WSCI.HCl (400 mg ' 2.09 mmol)' 4- -261-201036962 Dimethylaminopyridine (130 mg, 1.06 mmol), stirred at room temperature for 1 day under a nitrogen atmosphere. A saturated aqueous solution of ammonium chloride (20 mL) was added and dichloromethane was evaporated. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the title compound (150 mg, yield 30%) was obtained as a yellow solid (yield: solv. .

W-NMR (CDC13, 400MHz): δ 1.21-1.25 (9H, m), 3.08 (3H, s) 3.22-3.3 3 ( 1 Η, m), 3.47-3.5 5 ( 1 Η, m), 3.61 (1Η , dd, J = 14 3 3.7 Hz), 3.97-4.05 (1 H, 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), i〇.〇5 (1H, br s). (59i) 2-Methyl-l-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrole -2-yl}-5-[4-(methylsulfonyl)phenoxy]phenyl)propane - a compound synthesized using the compound (59h) (15 mg, 0.31 mm), methanesulfonic anhydride ( The title compound (70 mg,yield: 48%) (yield:yield:yield::::::::::::::::::::::::::::::::::::::::::::::::::::: ^-NMR (CDC13, 400MHz): δ 1.23 (6Η, d, J = 7.0 Hz), i 43 (3H, d, J = 5.9 Hz), 3.08 (3H, s), 3.45-3.56 (2H, m) , 4.06 (iH 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). -262- 201036962 MS (ESI) m/z : 467.1 6454 (M + H)+. (Example 60) {(4R)-2-[5-(3-[2-Fluoro-1-(fluoromethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridine-3 -yl]oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl} methanol

(60&amp;) 5-{3-bromo-5-[2-fluoro-1-(fluoromethyl)ethoxy]phenoxy}-2-(methylsulfonyl)pyridine

The compound synthesized in Example (19b) (4.20 g ' 12.2 mm 〇l) was dissolved in a mixed solvent of toluene (85 mL) and tetrahydrofuran (15 mL), and 1,3-difluoro-2-propanol (1.04 mL, 13.4) was added. Methyl) and triphenylphosphine (8.03 g, 30.5 mmol), diethyl azocarboxylate (2.2 mol/L in toluene, 13.00 mL, 28.6 mmol) was added dropwise at 〇 ° C, and stirred at room temperature under nitrogen atmosphere. . The solvent was distilled off under reduced pressure, and the obtained residue was purified by chromatography (yield solvent: ethyl acetate / hexane = 10% to 50%). 68%). ^-NMR (CDC 13) 5 00ΜΗζ): δ 3.23 (3Η, s), 4.58-4.74 (5Η, 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) 5-(2-[2-fluoro-1-(fluoromethyl)ethoxy]-5-{[6-(methylsulfonic acid) n ratio steep-263- 201036962 -3 -based Alkyl phenyl)-1 Η-pyridol-2-residual acid vinegar The compound synthesized in Example (60a) (3.51 g, 8.31 mmol), and the compound synthesized in Example (19e) (3.81 g, 11.64 mmol) ), [1,1,-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloride complex (〇.34g' 0.42mmol), potassium carbonate (5.74g, 41.56mmol) The title compound (3. 80 g, yield 84%) was obtained as a yellow oil. 'H-NMR (CDC13, 400ΜΗζ): δ 3.23 (3Η, 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), 7.3 3 - 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)-1Η-pyrrole-2-carboxylic acid The compound synthesized in Example (60b) (3.86 g, 7.11 mmol) 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 thereto, and the mixture was stirred under a hydrogen atmosphere. hour. The palladium-carbon catalyst was removed by filtration through Celite, and the solvent was evaporated under reduced pressure to give the title compound (yield: </RTI> 'H-NMR (CDC13, 400MHz): δ 3.23 (3Η, 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) 〇-264- 201036962

(60d) N-{ [5-(3-[2-Fluoro-1-(fluoromethyl)ethoxy]_5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}benzene Methyl)-1Η-pyrrol-2-yl]carbonyl}-L-serine methyl ester The compound synthesized in Example (60c) (3.20 g, 7.35 mmol), Methyl L-methyl sulphate hydrochloride (1.26) g, 8.08 mmol), HOBT.H2O (1.09 g, 8.08 mmol), N-methylphenofin (1.62 mL, 14-69 mmol), WSCI. HCl (1.69 g, 8.82 mmol), in the same manner as in Example (29a) The title compound (2.69 g, yield 66%). lH-NMR (CDC13, 400MHz): δ 3.24 (3H, s), 3.81 (3H, s), 3.98-4.10 (2Η, m), 4.5 9-4.80 (5H, m), 4.79-4.84 ( 1 H, 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). (6〇6)(4 8)-2-[5-(3-[2-Fluor-1- (fluoromethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1 H-pyrrol-2-yl]-4,5-di Hydrogen-1,3-indazole-4-carboxylic acid methyl ester The compound synthesized in Example (6〇d) (2,69 g, 4.85 mmol), bis(2-methoxyethyl)amine trifluoride Sulfur (1.16 mL, 6.31 mmol), m.p. (yield:::::::::::::::::::::::::::::::::::::: 'H-NMR (CDC13, 400MHz): δ 3.24 (3Η, s), 3.81 (3H, s)&gt; 4.5 5 -4.80 (7H, m), 4.90 (1H, dd, J = 7.8, 10.2 Hz), 6.53 (lH, -265- 201036962 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-(methyl-)-pyridin-3-yl]oxy}phenyl)-1 Η-pyrrol-2-yl]-4,5-dihydro·1, 3-oxazole-4-yl}methanol The compound synthesized in Example (60e) (2.50 g, 4.67 mmol) was dissolved in tetrahydrofuran (5 〇mL), and lithium hydride (0.30 g, 7.94 mmol) was added at 0 °C. . After stirring for 30 minutes under a nitrogen atmosphere, water (0.3 OmL), 5N aqueous sodium hydroxide (30 mL), and water (1.00 mL) were sequentially added and stirred for 10 minutes. Ethyl acetate (150 mL) was added and stirred for 5 min and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by chromatography (yield solvent: methanol/Z1 chloromethane = 5% to 5%) to give a white solid. 4 4%) ° 'H-NMR (CDC13) 400MHz) : δ 3.24 (3Η, s), 3.62 (lH, dd&gt; J = 2.7, 12.1 Hz), 3.98 (1H, dd, J = 2.3, 12.1 Hz) , 4.12-4-17 (1H&gt; m), 4.31-4.41 (2H, m), 4.60-4.80 (5H, m), 6.38 (lH,d,J = 3.5 Hz), 6.46 (1H, d, J = 3.5 Hz), 6.62 (1H, t, J = 2 〇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 : 5 0 8.1 3445 (M + H)+. -266-201036962 (Example 61) {(4R)-2-[5-(3-{[6-(Methanesulfonyl)pyridine-3-yl]oxy}-5-[(3S)-tetrahydrofuran -3-yloxy]phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol

(Ί (61a) 5-{3-bromo-5-[(3S)-tetrahydrofuran-3-yloxy]phenoxy}-2-(methylsulfonyl)pyridine using the compound synthesized in Example (19b) (7·7 g, 20.5 mmol), (R)-3-hydroxytetrahydrofuran (1.99 g, 22.6 mmol), triphenylphosphine (11.90 g, 45.2 mmol), diethyl azocarboxylate (2.2 mol/L toluene) A solution of the title compound (6.05 g,yield: 71%) (yield: 71%). : δ 2.09-2.16 (1Η, m), 2.18-2.28 Ο (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 (1HS dd, J = 2.7, 8.6 Hz), 8.08 (1H, d , J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz). (61b) 5-(3-{[6-(Methanesulfonyl)pyridin-3-yl]oxy}_5_[(3s _tetrahydrofuran-3-yloxy]phenyl)-1 fluorene-pyrrole-2-carboxylic acid carboxylic acid ester. The compound synthesized in Example (61a) (6. 5 g, 14.60 mmol), and (19e) Compound (7.17g, 21.91mmol), [1,1'-bis(diphenyl-267-201036962 phosphine) ferrocene Iron] palladium(II) chloride dichloride complex (0.66 g, 〇. 80 mmol), potassium carbonate (1 〇. 〇 9 g, 73.02 mmol) was obtained in the same manner as in Example (16e). Compound (6.73 g, yield 86%). <H-NMR (CDCh, 400 MHz): 6 2.1 2-2.29 (2H, m), 3.23 (3H, s), 3.8 8-4.04 (4H, m ), 4.93 -4.97 ( 1 H, 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), 7.3 3 -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-(Methanesulfonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy ]Phenyl)-1 Η-pyrrole-2-carboxylic acid The compound synthesized in Example (61b) (6.73 g, 12.40 mmol) was dissolved in a mixed solvent of ethanol (200 mL) and ethyl acetate (70 mL), and 10% was added. Palladium carbon catalyst (1.2 g) was stirred under a hydrogen atmosphere for 2 hours. The palladium-carbon catalyst was removed by filtration through Celite. The solvent was evaporated under reduced pressure to give a brown solid. Compound (5.60 g, yield -100%). lH-NMR (CDC13, 400MHz): δ 2.11-2.30 (2H, m), 3.22 (3H, s), 3.86-4.06 (4Η, m), 4.94-4.99 (1 Η, br m), 6.51-6.55 ( 2Η,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 (1 H, br s). (61d) N-{[5-(3-{[6-(methylsulfonyl)pyridine-3-yl]oxybu 5 [(3S)tetrahydrofuran-3-yloxy]phenyl)-1 Η- Pyrrole-2-yl]carbonyl bromide L-serine methyl ester 268 - 201036962 The compound synthesized according to the embodiment (61c) (5.55 g, 12.49 mmol), methyl L-serinate hydrochloride (2.20 g, 13.74) Ment), HOBT.H2 〇 (1.86 g, 13.74 mmol), N-methylmorpholine (2.75 mL, 24.97 mmol), WSCI. HC1 (2·87 g, 14.98 mmol), and the examples (2 9 a) The title compound (6.24 g, yield 91%) was obtained. ^-NMR (CDC13, 400MHz): δ 2.11-2.29 (2Η, m), 3.23 (3H, s), 3.79 (3H, s), 3.8 6- 3.95 ( 1 H, m), 3.96-4.08 (5H, m),

4.79-4.8 3 ( 1 H, m), 4.93 -4.97 (1 H, 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)(4S)-2-[5-(3-{[6-(Methanesulfonate) Pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3 Methyl carbazole-4-carboxylate The compound synthesized in Example (61d) (6.24 g, 11.42 mmol), bis(2-methoxyethyl)aminosulfur trifluoride (2.53 mL, 13.70 mmol) Potassium carbonate (2.37 g, 17.13 mmol), m. *H-NMR (CDCI3, 400ΜΗζ): δ 2.12-2.30 (2Η, m), 3.24 (3Η, s), 3.82 (3H, s), 3.8 9-3.96 ( 1 H,m), 3.9 7-4.04 ( 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 (1 H, br m), 6.51-6.52 (2H, m), -269- 201036962 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-(Methanesulfonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy) The compound synthesized in the example (61e) (5.45 g, 10.33 mmol) was obtained from the compound of the formula (61e): phenyl)-iH-pyrrole-2-yl]-4,5-dihydro-1,3-Doxazol-4-yl}methanol It was dissolved in tetrahydrofuran (100 mL), and lithium aluminum hydride (〇78 g, 20-66 mmol) was added at 〇 °C. After stirring for 30 minutes under a nitrogen atmosphere, water (0.8 OmL), 5N aqueous sodium hydroxide (0.80 mL), and water (2.40 mL) were sequentially added and stirred for 10 minutes. Ethyl acetate (300 mL) was added and stirred for 5 minutes, then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified to mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 'H-NMR (CDC13, 400MHz): δ 2.13-2.31 (2Η, 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: 500.1 4769 (M + H)+. (Example 62) [(4R)-2-{5-[3-{[6-(Methanesulfonyl)pyridin-3-yl]oxy}-5-(tetrahydro-2H--270- 201036962 Piperazin-4-yloxy)phenyl]-1H-pyrrol-2-yl}-4,5-dihydro-1,3-oxazol-4-yl]methanol

(62 a) 5-[3-Bromo-5-(tetrahydro-2H-pyran-4-yloxy)phenoxy]-2-(methylsulfonyl)pyridine 〇

The compound (500 mg, 1.45 mmol), tetrahydro-4-pyran (0.17 mL, 1.74 mmol), triphenylphosphine (841 mg, 3-20 mmol), diethyl azocarboxylate (2.2 mol) was used. The title compound (3 50 mg, yield 56%) was obtained as a pale-yellow oil (yield: 50%, yield: 56%). 1.74-1.8 3 (2H, m), 1.98-2.05 (2Η, m), 3.23 (3H, s), 3.55-3.62 (2H, m), 3.93 -4.00 (2H, m), 4.43-4.50 (1 H , 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)5-[3-{[6-(Methanesulfonyl)pyridine-3- Benzyl]oxy}-5-(tetrahydro-2H-pyran-4-yloxy)phenyl]-1H-pyrrole-2-carboxylic acid benzyl ester. The compound synthesized in Example (62a) (3 50 mg, 82.82 mmol), the compound synthesized in Example (19e) (400 mg, 1.23 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride complex (40mg, 0.05mmol), potassium carbonate (565mg, 4.09mmol), Example (16e) -271 - 201 036 962 in the same manner to give the desired compound as a yellow oil (360mg '80% yield). 'H-NMR (CDCI3, 400MHz) : δ 1.77- 1.8 5 (2Η, m), 2.01-2.05 (2H, m), 3.23 (3H, s), 3.5 8-3.63 (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-(Methanesulfonyl)pyridine-3 -yl]oxy}-5-(tetrahydro-2H-pyran-4-yloxy)phenyl]-1H-pyrrole-2-carboxylic acid The compound synthesized in Example (62b) (360 mg ' 〇. 66 mmol The solvent was dissolved in a mixed solvent of ethanol (10 mL) and ethyl acetate (5 mL), and a 1% by weight palladium carbon catalyst (100 mg) was added thereto, and the mixture was stirred under a hydrogen atmosphere for 2 hours. The palladium-carbon catalyst was removed by filtration through Celite, and the solvent was evaporated to give the title compound ( 276 g, yield: 92%) ???H-NMR (CDCh, 400 MHz): δ 1.75- 1.85 ( 2Η, 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 (1 H, m), 6.51 (1H, s), 6.56 (1H, s) 5 6.8 8 ( 1 H, 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) N-({5-[3-{[6-(Methanesulfonyl)pyridin-3-yl]oxy}-5-(tetrahydro-2H-pyran-4-yloxy)benzene Methyl]·1Η-pyrrol-2-yl}carbonyl)-L-serine methyl ester The compound synthesized in Example (62c) (276 mg, 〇. 60 mmol), L--272-201036962 methyl amide hydrochloride Salt (115 mg, 0.72 mmol), H0BT.H20 (89 mg, 0.66 mmol), N-methylmorpholine (〇_13 mL, 1.20 mmol), WSCI. 11 (:1 (13811^'0.72111111〇1), The title compound (252 mg, yield: 75%) was obtained as white solid.

!H-NMR (CDC13s 400MHz) : δ 1.77- 1.8 6 (2Η, m), 2.01-2.08 (2Η, m), 2.53 (1H, t, J = 5.9 Hz), 3.23 (3H, s), 3.5 7 -3.64 (2H, m), 3.83 (3H, s), 3.95-4.09 (4H, m), 4.5 0-4.5 7 ( 1 H, 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). (62〇(4 8)-2-{5-[3-{[6-(methylsulfonyl)pyridin-3-yl]oxy }-5-(tetrahydro-2H-piperidin-4-yloxy)phenyl]-1H-pyrrol-2-yl}-4,5-dihydro-1,3-oxazol-4-carboxylate The acid methyl ester was synthesized using the compound (252 mg, 0.45 mniol), bis(2-methoxyethyl)aminosulfur trifluoride (〇.i〇mL, 0.54 mmol), potassium carbonate (9511). ^, 〇.67111〇1), the title compound (21 7 g, 89%) was obtained as a white solid in the same manner as in Example (38 &quot; lH-NMR (CDCh, 400 MHz): δ 1.77-1.86 (2 Η, m ), 2.01-2.08 (2H, m), 3.24 (3H, s), 3.5 8-3.6 5 (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), -273- 201036962 6.56 (1H, t, J = 2.0 Hz), 6.81 (1H, d, J = 3.9 Hz), 6.84 ( Ih 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). (62〇[(4 ft)-2-{5-[3-{[6-(methylsulfonyl)pyridin-3-yl] Oxy}-5-(tetrahydro-2H-piperidin-4-yloxy)phenyl]-1H-pyrrol-2-yl}-4,5-dihydro-1,3·曙口坐-4 -Methyl-methanol The compound (217 mg, 0.40 mmol) which was obtained from the compound (62e) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum hydride (30 mg, 0.80 mmol) was added at 0 °C. After stirring for 30 minutes under a nitrogen atmosphere, water (30 μM, 5 N aqueous sodium hydroxide solution (30 μM, water (100 μM, stirring for 10 minutes) was added, and ethyl acetate (3 OmL) was added and stirred for 5 minutes to dry. The residue was evaporated to dryness crystals crystals crystals crystalsssssssssssssssssssssss 〇•H-NMR (CDC13, 400MHz): δ 1.77- 1.8 8 (2H, m), 2.02-2.09 (2H, m), 3.24 (3H, s), 3.5 8-3.64 (3H, m), 3.95 - 4.03 (3 H, m), 4.13-4.17 (1H, m), 4.32-4.41 (2H, m), 4.50-4.56 ( 1 H, 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 : 5 1 4.1 6463 (M + H)+. -274-201036962 (Example 63) [(41〇-2-{5-[3-{[6-(Methanesulfonyl)pyridin-3-yl]oxy}-5-(tetrahydrofuran-2-yl) Methoxy)phenyl]-1Η-indolebi-2-yl}-4,5-dihydro-1,3-indol-4-yl]methanol

C) (63a) 5-[3-Bromo-5-(tetrahydrofuran-2-ylmethoxy)phenoxy]-2.(methylsulfonyl)pyridine The compound synthesized in Example (19b) (1.50 g , 4.36 mmol) dissolved in N,N-dimethylformamide (15 mL), tetrahydrofurfuryl bromide (1.49 mL, 13.0 7 «1111〇1) and potassium carbonate (3.01 §, 21.79111 «1〇1) It was stirred at 80 for 5 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, water (3 mL) was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and analyzed by chromatography on a silica gel column (dissolution)

The residue was purified to give the title compound (yield: <RTIgt; </RTI> <RTIgt; H-NMR (CDC13, 400MHz): δ 1.69- 1.78 ( 1 H,m), 1.89-2_〇〇(2H, m), 2.04-2.12 (1H, m), 3.23 (3H, s)5 3.8 0 - 3.8 6 ( 1 H, 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). -275 - 201036962 (63b) 5-[3-{[6-(Methylamino)pyridin-3-yl]oxy}_5_(tetrahydrofuran-2-ylmethoxy)phenyl]-1H -Pyrrolidine-2-carboxylic acid benzyl ester The compound (i, 3 〇g, 3.04 mmol) synthesized in Example (63a), the compound synthesized in Example (19e) (1.49 g, 4.55 mmol), [1,1, _bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloride complex (0.15 g, 0.18 mm 〇l), potassium carbonate (2.10 g '15.18 mmol), and the examples ( I6e) The title compound (1. 60 g, yield: 6%) was obtained. 'H-NMR (CDC13, 400MHz): δ 1.71-1.81 (1Η, m), 1.90-2.02 (2H, m), 2.05-2.14 (1H, m), 3.23 (3H, s), 3.80-3.88 ( 1 H, m), 3.90- 4.04 (3H, m), 4.25-4.32 ( 1 H, 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-(Methanesulfonyl)pyridin-3-yl]oxy}-5-(tetrahydrofuran-2-ylmethoxy)phenyl]- 1H-pyrrole-2·carboxylic acid The compound synthesized in Example (63b) (1.60 g, 2.92 mmol) was dissolved in a mixed solvent of ethanol (5 OtnL) and ethyl acetate (15 mL). The medium (0.55 g) was stirred under a hydrogen atmosphere for 1 hour. The palladium-carbon catalyst was removed by filtration through celite, and the solvent was evaporated under reduced pressure to give the title compound (1,1 g, yield: 90%). ^-NMR (CDCI3, 400MHz): δ 1.72-1.82 (1 Η, m), 1.91-2.02 (2H, m), 2.04-2.13 (1H, m), 3.20 (3H, s), 3.81-3.89 (1H , 3.90- 4.09 (3H,m), 4.26-4.36 (1H,m),6.44-6.57 (2H,m), -276- 201036962 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). (63(1)&gt;1-({5- [3-{[6-(Methanesulfonyl)pyridin-3-yl]oxy}-5-(tetrahydrofuran-2-ylmethoxy)phenyl]-1H-pyrrol-2-yl}carbonyl)- Methyl L-serinate

The compound (1.21 g, 2.64) mm_ol), methyl L-serinate hydrochloride (〇.50 g, 3.17 mmol), HOBT.H2O (0.39 g, 2.90 mmol), N- Methylmorpholine (〇.58111):, 5.28111111〇1), ^3 (:1· HCl (0.61 g, 3.17 mmol), the title compound (1.33) g, yield 90%). W-NMR (CDC13, 400MHz): δ 1.71-1.81 (1H, m), 1.91-2.03 (2Η, m), 2.05-2.14 (1H, m), 3.23 (3H, s ), 3.81 (3H, s), 3.82-3.89 ( 1 H, m), 3.91-4.08 (5H, m), 4.25-4.32 (1 H, m), 4.81-4.86 (1H, m), 6.51 (1H , t, J = 2.7 Hz), 6.54-6.5 6 ( 1 H, 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)(4S)-2-{5-[3-{[6-(Methanesulfonyl)pyridin-3-yl]oxy}-5-(tetrahydrofuran-2-ylmethoxy)phenyl Methyl-1H-pyrrol-2-yl}-4,5-dihydro-1,3-oxazole-4-carboxylate The compound synthesized in Example (63d) (1.33 g, 2.37 mmol), double (2-methoxyethyl) The title compound (1.14 g, 88%) was obtained as a white solid. m. m. - 201036962 • H-NMR (CDC13, 400MHz): δ 1.75- 1.83 ( 1 H, m), 1.91-2.03 (2H, m), 2.05-2.15 (1H, m)5 3.2 3 (3 H, s), 3.81 (3H, s), 3.86 (1H, t, J = 7.0 Hz), 3.91-4.04 (3H, m), 4.26-4.3 3 ( 1 H, m), 4.57 (1H, dd, J = 8.6, 10.6 Hz), 4.67 (1H, t, J = 8.6 Hz), 4.9 〇 (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 = i.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, brs). (63f)[(4R)-2-{5-[ 3-{[6-(methylsulfonyl)H-threo-3-yl]oxy}-5-(tetrahydrofuran-2-ylmethoxy)phenyl]-1H-pyrrol-2-yl}-4, 5-Dihydro-1,3-indol-4-yl]methanol The compound synthesized in Example (63e) (1.14 g, 2.10 mmol) was dissolved in tetrahydrofuran (20 mL), and lithium hydride was added at 0 ° C. 〇.16g, 4.21mm〇l). After stirring for 30 minutes under a nitrogen atmosphere, water (0.16 mL), 5N aqueous sodium hydroxide (1. 16 mL), and water (0.48 mL) were sequentially added and stirred for 10 minutes. Ethyl acetate (80 mL) was added and stirred for 5 min and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was evaporated to mjjjjjlililililililililililili *H-NMR (CDCh, 400MHz): δ 1.73 - 1.83 ( 1 Η, 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, -278- 201036962 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: 5 1 4.1 63 5 1 (M + H) + 〇 (Example 64) 3-(3-{5-[(5S)-5 -methyl-4 ,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulfonyl)pyridin-2-yl]oxyindole Oxy)dihydrofuran-2(3H)-one

(64a) N-[(2R)-2-Hydroxypropyl]-5-{3-methoxy-5-[(triisopropyldecyl)oxy]phenyl}-1Η-pyrrole-2· Formamide

The compound synthesized in Example (21a) (2.70 g, 8,35 mmol) was dissolved in dichloromethane (20 mL), triethylamine (3.80 mL, 27.3 mmol), triisopropyl chloride (3.00) mL, 14.0 mmol), 4-dimethylamino hydrazine was steep (1.10 g, 9.00 mmol), and stirred under a nitrogen atmosphere for 18 hours. A saturated aqueous solution of ammonium chloride (5 mL) was added toEtOAc. After washing with saturated brine, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography (solvent solvent: ethyl acetate/hexane = 〇% to 20%) to give a brown liquid. This was dissolved in ethyl acetate (2 mL), and then added - 279 - 201036962 10% palladium carbon catalyst (1.15 g), and stirred at room temperature for 4 hours under a hydrogen atmosphere. The mixture was filtered through Celite, and the solvent was evaporated under reduced pressure to give a brown powdery compound. This compound was dissolved in dichloromethane (50 mL), (R)-(-)-l-amino-2-propanol (1.42 mL, 18.0 mmol), WSCI.HCl (3.85 g, 20.1 mmol), 4-Dimethylamine-based shame (1.23 g, 10 mmol) was stirred at room temperature for 1 day under a nitrogen atmosphere. Saturated aqueous ammonium chloride (60 mL) was added and extracted with dichloromethane (100 mL). The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted eluted eluted eluted 3 2 %). 'H-NMR (CDC13, 5 00MHz) : 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 (1 H, m), 6.70 (2H, s), 9.78 (1H, br s). (6 41?) (58)-2-(5-{3-Methoxy-5-[(triisopropyldecyl)oxy]phenyl}-11pyrrol-2-yl)-5-methyl-4,5 -Dihydro-1,3-oxazole The compound synthesized in Example (64a) (1.20 g, 2.69 mmol), sulfonate (1.30 g, 7.46 mmol), triethylamine (2.00 mL, 14.35 mmol) The title compound (627 mg &gt; yield: 54%) was obtained as a yellow liquid. ^-NMR (CDC13, 400MHz): δ 1.11 (18Η, d, J = 7.0 Hz), -280- 201036962 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), 4.77-4.8 5 ( 1 H, 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). (64&lt;〇2-(3-methoxy-5-) {5-[(58)-5-Methyl-4,5-dihydro-1,3-oxazol-2.yl]-1H-pyrrol-2-yl}phenoxy)-5-(methane The compound synthesized in the example (64b) (627 mg, 1.46 mmol) was dissolved in tetrahydrofuran (2.0 mL), and tetrabutylammonium fluoride (lm?l/L tetrahydrofuran solution, 2.0 mL) was added at 〇 ° C The mixture was stirred for 30 minutes under a nitrogen atmosphere, and a saturated aqueous solution of ammonium chloride (3 mL) was added, and the mixture was extracted with dichloromethane (3OmL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by distillation to give a pale-yellow liquid. Compound was obtained from acetonitrile (15 mL), and the compound (310 mg, 1.61 mmol) Stirring 2 Half. The reaction was added to water (3 OmL), ethyl acetate (5 OmL) and extracted. After washing with water and saturated brine the organic C) layer, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted eluted eluted elution %) ° • H-NMR (CDC13, 400MHz): δ 1.42 (3Η, 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 ( 1 H, 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, -281 - 201036962 J = 1.2 Hz), 8.80 (1H, d, J = 1.2 Hz). (64(1)3-{5-[(58)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-111-pyrrol-2-yl}-5- {[5-(Methanesulfonyl)pyrylene-2-yl]oxy}phenol The compound synthesized in Example (64c) (657 mg, 1.53 mmol), boron tribromide (l. 〇mol/L dichloride) The title compound (486 mg, yield: 7%) was obtained as a white solid. m.p. , 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 ( 1 H , m), 6.50 (1H, d, J = 3.9 Hz), 6.54 (1H, s), 6.80-6.84 (1 H, 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). (646)3-(3-{5-[(53)-5-methyl-4,5-dihydro-1 , 3-oxazol-2-yl]-1^1-pyryl-2-yl}-5-{[5-(methylsulfonic acid) fluoren-2-yl]oxy}phenoxy) Hydrogenfuran-2(3H)-one The compound synthesized by the example (64d) (i〇〇mg, 〇.24mmol), α-bromo-γ-butyrolactone (〇_〇45mL, 0.48mmol), carbonic acid Potassium (100 mg, O.72 mmol) in the same manner as in Example (6b) The title compound (63 mg, yield 52%) was obtained as a white solid. *H-NMR (CDCI3, 500 ΜΗζ): δ 1.42 (3 Η, d, J = 6.3 Hz), 2.47-2.56 (1 H, m), 2.72- 2.79 ( 1 H, 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 -282- 201036962 (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 .〇Hz). MS (ESI) m/z: 499.1 2843 (M + H) + 〇 (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)pyrrole D-but-2-indole

(65&amp;) 3-(3-Bromo-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenoxy)dihydrofuran-2(3H)-one

The compound synthesized in Example (19b) (2.00 g, 5.8 1 mmol), α-bromo-γ-butyric acid vinegar (1.07 mL, 11.6 mmol), potassium carbonate (2.41 g, 17.4 mmol), and the 6b) The title compound (1.7 〇g 'yield 68%) was obtained as a white solid. 'H-NMR (CDC13, 500MHz) : δ 2.45-2.54 (1 Η, 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), 8.〇8 d, J = 8.8 Hz), 8.47 (1H, d, J = 2.4 Hz). -283 - 201036962 (65b)2- (3-Bromo-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenoxy)-4-[(methylsulfonyl)oxy]butyric acid ethyl ester Example (65a) The compound (1.37 g, 3.19 mmol) was dissolved in ethanol (50 mL), and potassium carbonate (0.22 g, 1.60 mmol) was added at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. After filtering the reaction mixture, the solvent was evaporated under reduced pressure, and the obtained residue was dissolved in dichloromethane (5OmL). Triethylamine (0-90 mL, 6.46 mmol) and methanesulfonium chloride (〇.27 mL, 3.49 mmol) were added at 0 ° C, and stirred at room temperature for 2 hr under nitrogen atmosphere. The reaction mixture was diluted with methylene chloride (1 mL), washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography (eluent solvent: ethyl acetate / hexane = 50% to 80%) to afford white solid (6 7 3 mg, 3 8%). 'H-NMR (CDC13, 400MHz): δ 1.28 (3Η, 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), 4.3 8-4.48 (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), S.46 (1H, d, J = 2.7 Hz). (65 c) 3-(3-bromo-5-methylsulfonyl)pyridin-3-yl]oxy}phenoxy)4 _methylpyrene is slightly steeper _2_嗣The compound synthesized in Example (65b) (617 mg, 1.12 mm 〇l) was dissolved in acetonitrile (2 mL). Addition of sodium (308 mg, 2.01 mmol), methylamine (2m〇i/L tetrahydrofuran solution, 2_〇) 1^, 4. 〇1!1111〇1) At 1〇〇. (: Stirring. Methylamine (2 mol/L tetrahydrofuran solution, K〇mL, 2.0 mmol) was added every 3 〇-284-201036962 minutes for 3 times, and stirred for 2 hours. After cooling the reaction solution to room temperature, saturated salt was added. Water (10 mL) was extracted with ethyl acetate (30 mL), and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and chromatographic column chromatography (solvent solvent: acetic acid) Ethyl acetate / hexane = 60% - 100%) The obtained residue was purified to crystals crystals crystals crystals crystalsssssssssssssssssssssssss ), 2.51-2.60

(1H, m), 2.93 (3H, s), 3.23 (3H, s), 3.3 5 -3.43 ( 1 H, m), 3.47-3.54 (1 H, 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) 5-(3-[(l-Methyl-2-ketopyryrrolidin-3-yl)oxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy Benzyl)-1 Η-pyrrole-2-carboxylic acid benzyl ester The compound synthesized in Example (65c) (355 mg, 0.80 mmol), and the compound synthesized in Example (19e) (3 95 mg, 1.21 mmol), [1 , 1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride complex (39 mg, 0.05 mmol), potassium carbonate (556 mg, 4.02 mmol), and the example (16e) The title compound (21 7 mg, yield: 8%) was obtained from the title compound: NMR (CDC13, 400 MHz): δ 2.15-2.25 (1H, m), 2.51-2.61 (1 Η, m) , 2.93 (3H, s), 3.22 (3H, s), 3.3 6-3.43 ( 1 H, m), 3.49-3.5 5 (1 H, m), 4.90 (1H, t, J = 7.2 Hz) # 5.33 (2H, s), 6.52 -285 - 201036962 (1 H, 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), 7.3 3 -7.46 (6H, m), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d , J = 2.7 Hz), 9.28 (1H, s). (65 6)1^-[(211)-2-Hydroxypropyl]-5-(3-[(1-methyl-2-ketopyridyl) Azetidin-3-yl)oxy]- 5-{[6-(Methanesulfonyl)pyridin-3-yl]oxy}phenyl)-1Η-pyrrole-2-carboxamide The compound synthesized in Example (65d) (217 mg, 0.39 mmol) was dissolved. A mixed solvent of ethanol (10 mL) and ethyl acetate (5 mL) was added to a 10% palladium carbon catalyst (70 mg), and the mixture was stirred for 1 hour under a hydrogen atmosphere. The palladium carbon catalyst was removed by filtration through Celite, and the solvent was distilled off under reduced pressure. The white solid obtained, (R)-(-)-l-amino-2-propanol (51 mg, 0.68 mmol), HOBT.H2O (50 mg, 〇.37 mmol), N-methyl phenoline (75 μί, 0.68 mmol) was dissolved in N,N-dimethylformamide (5 mL), and WSCI. HCl (78 mg, 0.41 mmol) was stirred at room temperature for 15 hours under nitrogen atmosphere. Saturated brine (30 mL) was added to the mixture, and ethyl acetate (l? After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. 83%). h-NMR (CDC13, 400MHz): δ 1.20 (3H,d,J = 6.3 Hz), 2.09- 2, .2 1 (1H, m), 2.50 -2.6 1 (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. 〇l (1H , m), 4.92 (1H, t, J = 7.4 -286- 201036962

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)l- 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

Using the compound synthesized in Example (65e), 〇48 mg, 0.28 mmol), methanesulfonic acid anhydride (10 mg, 0.56 mmol), and triethylamine (〇.156 mL '1.12 mmol)' were the same as in Example (i6j) The method gave a white solid of the desired product U 〇 9 mg 'yield 76%. ^-NMR (CDC13j 400MHz): δ 1.42 (3Η, 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), 3.3 5-3.43 (1 H, m), 3.47-3. 13.7, 9.4 Hz), 4.77-4.87 (1 H, 6.51 (1H, d, J = 3.9 Hz), 6.71 d, J = 3.9 Hz ), 6.89 (1H, t, J Hz), 7.44 (1H, dd, J = 8.6, 2.7 55 (2H, m), 4.05 (1H, dd, J = m), 4.89 (1H, t, J = 7 〇Hz), (1H, t, J = 2.0 Hz), 6.74 (1H, =1.6 Hz), 7.15 (1H, t, J = 1.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 ( 1H, d, J = 2.7 Hz). MS (ESI) m/z: 5 1 1 . 1 6648 (M + H) + (Example 66) 1-ethyl-3-(3-{5-[ (58)-5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1s-pyrrol-2-yl}-5-{[6-(methylsulfonyl)pyridine -3-yl]oxy}phenoxyl-287 - 201036962 pyridine-2-one

(6 6&amp;) 3-(3-bromo-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenoxy)-1-ethylpyrrolidin-2-one

The compound (1. Olg, 1.83 mmol) synthesized in Example (65b) was dissolved in acetonitrile (10 mL), sodium iodide (0.41 g, 2.74 mmol), ethylamine (2 mol/L)

I I tetrahydrofuran solution, 2.74 mL, 5.48 mmol) was stirred at 100 ° C for 2 h. After the reaction mixture was cooled to room temperature, brine (20 mL) was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified eluting eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted ). !H-NMR (CDC13, 400MHz) : δ 1.17 (3Η, t, J = 7.3 Hz), .... a. 2.12-2.21 (1H, m), 2.50-2.60 ( 1 H, m), 3.23 ( (3H, s) J = 2.0 Hz), 6.87 (1H, t, J = 2.0 Hz), 7.13 (1H, t, J = 2.0 Hz), 7.45 (1H, dds J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz). (6 61&gt;) 5-(3-[(2-ethyl-2-ketopyrrolidin-3-yl)oxy]-5 -{[6-(Methanesulfonyl)pyridin-3-yl]oxy}phenyl)-1Η-pyrrole-2-carboxylic acid benzyl ester. The compound synthesized in Example (66a) (990 mg &gt; 2.17 mmol),实-288 - 201036962 Example (19e) Synthesis of compound (1.10g, 3.26mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloride The title compound (8 90 mg, yield 71%) (yield: ield: ield:::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: ^-NMR (CDC13, 400MHz): δ 1.17 (3Η, t, J = 7.2 Hz), 2.13-2.23 (1H, m), 2.51-2.61 (1H, m), 3.22 (3H, s),

3.3 5-3.44 (3 H, 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-[(l-Ethyl-2-ketopyrrolidin-3-yl)oxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy Phenyl)-N-[(2R)-2-hydroxypropyl]-1H-pyrrole-2-carboxamide The compound synthesized in Example (66b) (890 mg, 1.55 mmol), 10% palladium carbon catalyst (300 mg), (R)-(-)-l-amino-2-propanol (223 mg, 2.97 mmol), HOBT.H2O (220 mg, 1.63 mmol), N-methylmorpholine (0.326 mL, 2.97) The title compound (5 8 8 mg, 73%) was obtained as a white solid. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 1.18 (3Η, 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), -289- 201036962 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 ( 1 H, m), 6.62-6.66 (2H, m), 6.6 8 -6.73 ( 1 H, 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) l-Ethyl-3-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazole-2 -yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenoxy)pyrrolidin-2-one Example (66c) The compound (588 mg, 1.08 mmol), methanesulfonic acid anhydride (389 mg, 2.16 mmol), triethylamine (0.603 mL, 4.33 mmol) was obtained as a white solid. (4 7 2 mg, yield 83%). ^-NMR (CDC13, 400MHz): δ 1.18 (3Η, 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), 3.3 5-3.44 (3 H, m), 3.47-3.5 5 (2H, m), 4.05 (1H, dd, J = 14.1, 9.4 Hz), 4.77-4.86 ( 1 H , 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 : 52 5.1 8048 (M + H)+. (Example 67) -290- 201036962 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 (65b) The synthesized compound (530 mg, 0.96 mm 〇1) was dissolved in acetonitrile (4 mL), sodium iodide (216 mg, 1.44 mmol), cyclopropylamine (0.200 mL, 2.88 mmol), and stirred at 100 ° C 2 hour. After the reaction mixture was cooled to room temperature, brine (1 mL) was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted eluted eluted eluted 5 7%). !H-NMR (CDC13, 400MHz) : δ 0.66-0.76 (1 Η, m), 0.76-0.89 (3H, m), 2.07-2.17 (1H, m), 2.46-2.55 (1 H, m), 2.68 -2.74 (1H, m), 3.23 (3H, s), 3.27-3.3 5 (1 H, m), 3.3 9-3.46 ( 1 H, 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) 5-(3-[(l-cyclopropyl-2-ketopyrrolidin-3-yl) Oxy]-5-{[6-(A-291 - 201036962 sulfonyl) ros-3-yl]oxy}phenyl)-1 Η-pyrrol-2-yl decanoate using the example (67a a compound synthesized (25 3 mg, 0.54 mmol), a compound synthesized in Example (19e) (266 mg, 〇.81 mmol), [1,1,-bis(diphenylphosphino)ferrocene]palladium dichloride ( II) Dichloromethane complex (27 mg, 0.03 mmol), potassium carbonate (374 mg, 2.71 mmol),yield 7 %). !H-NMR (CDC13j 400MHz) : δ 0.66-0.75 ( 1 Η, 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), 3.27-3.3 4 ( 1 H, m), 3.3 9-3.46 ( 1 H, 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-ketopyrrolidin-3-yl)oxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy The compound synthesized by the example (67b) (23 8 mg, 0.41 mmol), 10% palladium carbon was used for the phenyl)-N-[(2R)-2-hydroxypropyl]-1H-pyrrole-2-carboxamide. Catalyst (200 mg), (R)-(-)-l-amino-2-propanol (62 mg, 0.82 mmol), H0BT.H20 (61 mg, 0.45 mmol), N-methylmorpholine (0.090 mL) The title compound (67 mg, 30%) (yield: EtOAc, EtOAc) -292- 201036962 •H-NMR (CDC13, 400MHz) : 6 0.68-0.77 (1 H, 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), 3.24-3.3 5 (2H, m), 3.3 8-3.46 ( 1 H, 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 ( 1 H, 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) l-Cyclopropyl-3-(3-{5-[(5S)-5-methyl-4,5-dihydro-1 , 3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulfonyl)pyridine-3-yl]oxy}phenoxy)pyrrolidine-2 - The ketone was synthesized using the compound (67 mg, 0.12 mmol), toluenesulfonic acid anhydride (45 mg, 0.24 mmol), triethylamine (0.070 mL, 0.48 mmol) in the same manner as in Example (16j). The title compound was obtained as a white solid (3 mg, yield 46%). !H-NMR (CDCI3, 400MHz) : δ 0.67-0.75 ( 1 Η, 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 ( 1 H, m), 3.23 (3H, s), 3.28-3.3 5 ( 1 H, 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 (1 H, 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 (1HS d, J = 3.9 Hz), -293- 201036962 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: 5 3 7.1 8 059 (M + H)+. (Example 68) 2-(3-{5-[(5S)-5-methyl-4,5-monohydro-1,3-indol-2-yl]-1Η-Πbide-2- }}-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenoxy)cyclopentanone

(6 8&amp;) 2-(3-bromo-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenoxy)cyclopentanone The compound synthesized in Example (19b) L.OOg, 2.91 mmol) was dissolved in hydrazine, hydrazine-dimethylformamide (5 mL), 2-chlorocyclopentanone (0.88 mL, 8.72 mmol), potassium carbonate (0.80 g, 5.81 mmol), nitrogen atmosphere Heat at 60 ° C for 2 hours. After cooling the reaction mixture to room temperature, it was diluted with ethyl acetate (5 mL) and washed with 1N aqueous sodium hydroxide and brine. It was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:EtOAc • H-NMR (CDC13, 500 MHz): δ 1.87-2.06 (2Η, m), 2.12-2.20 (1H, m), 2.28-2.5 3 (3 H, 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 -294- 201036962 (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)5-(3-{[6 -(Methanesulfonyl)pyridin-3-yl]oxy}-5-[(2-ketocyclopentyl)oxy]phenyl)-1Η-pyrrole-2-carboxylic acid benzyl ester

The compound synthesized in Example (68a) (721 mg, 1.69 mmol), the compound synthesized in Example (19e) (830 mg, 2.54 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride The title compound (2 11 ) was obtained as a pale yellow solid (yield: (II) Mg, yield 23%). ^-NMR (CDC13, 400MHz): δ 1.87-2.06 (2Η, m), 2.11-2.23 (1H, m), 2.29-2.44 (2H, m), 2.43-2.54 (1 H, m), 3.23 (3H , s), 4.64 (1H5 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-keto) Cyclopentyloxy]phenyl)-lH-pyrrole-2-carboxamide The following examples (681 〇 synthesized compound (21011^, 0.38111111〇1), 10% palladium carbon catalyst (80 mg), (R) )-(-)-l-Amino-2-propanol (44 mg, 0.58 mmol), H〇BT.H20 (43 mg '0.32 mmol), N-methylmorpholine (〇.〇 64 mL, 〇 '58 mmol , WSCI*HCl (67 mg, 0.35 mmol), m. : 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), 2.47-2.5 5 (1 H, m ), 3.23 (3H, s), 3.24-3.29 ( 1 H, m), 3.59 (1H, dq, J = 14.0, 3.2 Hz), 3.96-4.03 (1 H, m), 4.66 (1H, t, J = 8.8 Hz), 6.40 (1H, t, J = 5.9 Hz), 6.48 (1H, ts 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 (1HS d, J = 8.8 Hz), 8.47 (1H, d, J = 2.9 Hz), 9.80 ( 1H, br s). (68(1)2-(3-{5-[ (53)-5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-111-pyrrol-2-yl}-5-{[6-(methylsulfonyl)pyridine- 3-Amino]oxy}phenoxy)cyclopentanone The compound (67 mg, 0.13 mmol), methanesulfonic anhydride (47 mg, 0.26 mmol), triethylamine (〇.〇73 mL ' The title compound was obtained as a white solid (43 mg &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&& Hz), 1.8 8 -2.07 (2H, m), 2.12-2.20 (1H, m), 2.29-2.45 (2H, m), 2.46-2.5 3 ( 1 H, 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 (1 H, 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 : 496.1 5 3 5 3 (M + H)+. -296-201036962 (Example 69) 3-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrole- 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 of (19b) l. 〇〇g, 2.9 1 mmol) dissolved in hydrazine, hydrazine-dimethylformamide (5 mL), 3-bromo-2-butanone (0.88 mL, 5.81 mmol), potassium carbonate (1.20 g, 8.72) Methyl), heated at 80 ° C for 3 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, a saturated aqueous sodium hydrogen sulfate solution (30 mL) was evaporated. It was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:EtOAc 'H-NMR (CDC13s 400MHz) : δ 1.52 (3Η, 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, t3 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) 5-[3-(l-Methyl-2-ketopropoxy)-5-{[ 6-(Methanesulfonyl)pyridin-3-yl]oxy}phenyl]-1H-pyrrole-2-carboxylic acid benzyl ester-297 - 201036962 The compound synthesized using Example (69a) (752 mg, 1.82 mmol) The compound synthesized in Example (19e) (891 mg, 2.72 mmol), [1, bis-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (89 mg, O. The title compound (3 6 1 mg, yield: 7%) was obtained as a pale yellow solid (yield: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; iH-NMR (CDC13, 400MHz): 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), 7.3 4-7.46 (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-(l-methyl-2-ketopropoxy)-5-{[6-(methylsulfonyl)pyridine -3-yl]oxy}phenyl]-1 oxime-pyrrole-2-carboxamide The compound synthesized in Example (69b) (361 mg, 0.68 mmol), 10% carbon catalyst (120 mg), (R) )-(-)-l-Amino-2-propanol (97 mg, 1.29 mmol), H0BT.H20 (96 mg, 0.71 mmol), N-methyl-f-follow (咐 · 1 4 2 m L, 1 · 2 9 mm ο 1), WS CI. H C1 (1 4 9 mg, Ο. 7 7 mm ο 1), m.p. 〇'H-NMR (CDCb, 400MHz): 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 ( 1 H, m), 4.67 •298- 201036962 (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-l,3-oxazol-2-yl]_1H_pyrrol-2-yl}-5-{ [6-(Methanesulfonyl)pyridin-3-yl]oxy}phenoxy)butan-2-one The compound synthesized in Example (69c) (ll 〇mg, 0.22 mmol), methanesulfonic anhydride (79 mg) The title compound (81 mg,yield: 76%) ofyield (yield: 76%). 'H-NMR (CDC13, 400MHz) : δ 1.43 (3Η, 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), 4.79-4.8 8 ( 1 H, 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 : 484.1 5307 (M + H)+. (Example 7〇) (lR)-l-{(4S)-2-[5-(3-[(lS)-2-fluoro-1-methylethoxy]-5-{[5-(( Methanesulfonyl)pyrylene-2-yl]oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol-299- 201036962

(70 a) 5-(3-[(IS)-2-Fluoro-1-methylethoxy]-5-{[5-(methylsulfonyl)pyrylene-2-yl]oxy}benzene Benzyl-pyridole-2-carboxylic acid benzyl ester The compound synthesized in Example (34g) (9 86 mg, 2.59 mmol) and the compound synthesized in Example (43c) (523 mg, 2.71 mmol) were dissolved in acetonitrile (2) 5 mL), a carbonic acid planer (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 mixture, and ethyl acetate (10 mL) was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified to mjjjjjjjjjjjjjjjj ). 'H-NMR (CDC13, 400MHz): δ 1.38 (3Η, dd, J = 6.6, 1.6 Hz), 3.23 (3H, s), 4.45 -4.73 (3 H, 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), 9.2 1 (1H, br s). (70b) 5-(3-[(lS)-2-Fluoro-1-methylethoxy]-5-{ [5-(Methanesulfonyl)pyrylene-2-yl]oxy}phenyl)-1Η-pyrrole-2-carboxylic acid The compound synthesized in Example (70a) (1.34 g ' 2.49 mmol) was dissolved in acetic acid A mixed solvent of ethyl ester (5 mL) and ethanol (20 mL) was added with 10% palladium on carbon-300-201036962 (2 5 Omg), and stirred under a hydrogen atmosphere for 2 hours. The palladium-carbon catalyst was removed by filtration through Celite, and the solvent was evaporated to give the title compound (yield: yield: 65%). 'H-NMR (CDC13, 400ΜΗζ): δ 1.37 (3Η, 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).

(70〇5-(3-[(18)-2-fluoro-1-methylethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}phenyl) -^[(13,211)-2-hydroxy-1-(hydroxymethyl)propyl]-1Η-pyrrole-2-carboxamide A compound (300 mg, 0.69 mmol), which was synthesized using Example (7〇b), DL- lysine (109 mg, l. 〇 3 mmol), HOBT. H20 (1 〇 2 mg, 0.76 mmol), N-methylmorpholine (〇.152 mL, 1.38 mmol), WSCI. HCl (15 9 mg, O The title compound (312 mg, 87%) was obtained as a white solid. (H,H,HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 1.37 (3H, dd, J = 6.3, 1.6 Hz), 2.75 -2.80 (2H, m), 3.24 (3H, s), 3.79-3.8 6 ( 1 H, 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 = 15 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) , (76d)(lR)-l-{(4S)-2-[5-(3-[(lS)-2-fluoro-1-methylethoxy-301 - 201036962 ]]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}phenyl)_1H_ The compound synthesized by the example (7〇c) (3l2mg, 0.60mmol), methanesulfonic anhydride (160mg, the compound of the formula (7〇c)) The title compound (1 2 1 mg, yield 40%) was obtained as a white solid in the same manner as the compound (16j).

Ή-NMR (CDC13! 5 00ΜΗζ) : δ 1.15 (3Η, 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: 5 0 5.1 5 5 7 1 (M + H)+. (Example 71)

L-(3-{5-[(5R)-5-(Hydroxymethyl)-4,5-dihydro·ι,3•oxazol-2-yl]-1H-pyrrol-2-yl}-5 -{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)_2-methylpropan-1-one

(71 a) 1-(3-Hydroxy-5-methoxyphenyl)-2-methylpropan-1-one The compound synthesized in Example (59b) (6.40 g, 30.73 mmol), methoxy The title compound (6 〇〇g, yield 100%) was obtained as a yellow oil (yield: EtOAc, EtOAc)丨H-NMR (CDC13,400MHz): 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). (711&gt;) 1-(3-methoxy- 5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-2-methylpropan-1-one

The compound synthesized in Example (71a) (980 mg, 5.05 mmol) and the compound synthesized in Example (16a) (1.45 g, 7.57 mmol) were dissolved in hydrazine, dimethyl-dimethylformamide (15 mL), and cesium carbonate was added thereto. (4.93 g, 15.14 mmol), stirred at 1 ° C for 1.5 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, brine (10 mL) The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the title compound (yield: 975 mg, yield: 55%). lH-NMR (CDC13, 400MHz): δ 1.21 (6H,d, J = 6.6 Hz), 3.23 (3H, s), 3.3 8-3.5 0 ( 1 H, 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) l-(3-Hydroxy-5-{[6-(methylsulfonyl)pyridine- The compound synthesized by the example (71b) (975 mg, 2.79 mmol), - 303 - 201036962 l.Omol/L boron tribromide II was used for the 3-amino]oxy}phenyl)-2-methylpropan-1 -anthracene. The title compound (643 mg, 6 9%) was obtained as a white solid, m.p. (H, NMR (CDC 13 &gt; 400 MHz): δ 1.21 (6 Η) , d, J = 7.0 Hz), 3.24 (3H, s), 3.3 7-3.48 ( 1 H, 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). ί (71d) trifluoromethanesulfonic acid 3-isobutyl decyl- 5-{[6-(methylsulfonyl)pyridin-3-yl]% oxy}phenyl ester The compound synthesized in Example (71c) (643 mg, 1.92 mmol) was dissolved in dichloromethane (10 mL), cooled to EtOAc, pyridine (0.46 mL &lt;RTI ID=0.0&gt;&gt; A saturated aqueous solution of ammonium chloride (1 mL) was added and extracted with dichloromethane (5OmL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified eluted eluted eluted eluted eluted eluted eluted eluted %). H-NMR (CDCh, 400MHz): 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). -304- 201036962 (7 1e) 5-(3-isobutyl)- 5-{[6-(methylsulfonyl)pyridin-3-yl]oxy The compound synthesized by the compound (71d) (626 mg, 1.34 mmol), which is known (Adv. Synth. Cat., 345, 2003, l 103) 5-- Methyl (4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)-1Η-pyrrole-2-carboxylate (504 mg, 2.01 mmol), [1 , bis(diphenylphosphino)ferrocene]palladium dichloride (Π) dichloromethane complex (66 mg, 0.08 mmol), cesium carbonate (925 mg, 6.70 mmol), - and examples ( 16e) The title compound (5 21 mg, yield: 8%) was obtained as a pale yellow oil. !H-NMR (CDC13, 400MHz) : δ 1.25 (6Η, d, J = 6.6 Hz), 3.25 (3H, s), 3.47-3.56 (1 H, 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). (71〇5-( 3-isobutyl indolyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}benzene Q-yl)-ih-pyrrole-2-carboxylic acid The compound synthesized by the example (71 e) 521 mg, 1.18 mmol) was dissolved in a mixed solvent of methanol (12 mL), tetrahydrofuran (4 mL) and water (4 mL), and then, then,,,,,,,,,,,,,,,,,,,, Hydrochloric acid (1 mL) was extracted with EtOAc. EtOAc was evaporated. %). NMR (CDCI3, 400MHz): δ 1.27 (6Η, d, J = 6.6 Hz), 3.25 -305 - 201036962 (3H, s), 3.49-3.5 8 ( 1 H, m), 6_64 (1H ,dd,J = 4,3,2.7 Hz) 7.09 (1H,d d, 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), il 57 (1H br s) 0 (71§)^1-[(2 3)-2,3-dihydroxypropyl]_5_(3_isobutylindenyl_5_{[6_(甲醯醯基) Pyridin-3-yl]oxy}phenyl)-lH-pyrrole-2-carboxamide The use of the compound (71 〇, 61111111. 1), (S)-(-)- 3-Amino-1,2-propanediol (85 mg, 0.91 mm 〇l), hobt. 112 〇 (9111^'0.67111111〇1), &gt;}-methylmorpholine (0.1351111^, 1,221^11.1 ;), WSCI.HCl (140 mg, 0.73 mmol), m. , d, J = 6.6 Hz), 3.24 (3H, s)5 3.47-3.64 (5 H, 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 (1 H, br s). (71h) N-{(2S)-2-hydroxy-3-[(triisopropyldecyl)oxy]propyl}-5-(3-isobutyl)- 5- {[ 6-(Methanesulfonyl)pyridine-3-yl]oxyindole phenyl)-1H-pyrrole-2-carboxamide The compound synthesized in Example (71 g) (174 mg, 0.34 mmol) was dissolved in -306- 201036962

Dichloromethane (5 mL), triisopropylsulfonium chloride (O.lOSmL '0.50 mmol), triethylamine (0.234 mL, 1.68 mmol), 4-dimethylaminopyridine (62 mg, 0.50 mmol) The mixture was stirred at room temperature for 8 hours under a nitrogen atmosphere. 1N hydrochloric acid was added to the reaction mixture, and extracted with dichloromethane (5 mL). The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and 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 solvent: ethyl acetate / hexane = 20% to 50%) to give the object as a white solid (ll 〇mg, yield 49%) ). JH-NMR (CDC13, 400MHz): 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-l-(3-{[6-(methylsulfonic acid) oxime ratio _3_yl]oxy}-5-{5-[(5 ft)-5-{ [(Triisopropyldecyl)oxy]methyl}_4,5-diazo-1,3-oxazol-2-yl]-111-pyrrol-2-yl}phenyl)propan-1-one The compound (11 mg, methanesulfonic anhydride (59 mg '0.33 mmol), triethylamine (〇〇91 mL, 0.65 mmol)) of the compound (71h) was obtained in the same manner as in Example (16j). The object of the solid (100 mg, yield 93%). -307-201036962^-NMR (CDC13, 400MHz): 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)l-(3-{5-[(5R)-5-(hydroxymethyl)-4,5-dihydro- 1,3-P oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-2-methyl The compound synthesized by the example (7H) (l〇〇mg, 0.15 mm〇l), four Ammonium butyl fluoride (1 mol/L tetrahydrofuran solution '0.183 mL ' 0.18 mmol). The title compound (yield: 75%) was obtained as a white solid. , 400ΜΗζ) : δ 1.24 (6Η, d, J = 6.6 Hz), 3.24 (3H, s), 3.47-3.5 7 ( 1 H, 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 : 484.1 5 3 84 (M + H)+. (Example 72) N,N-Dimethyl-3-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2--308 - 201036962 base] -1 Η-pyrrol-2-yl}-5-[4-(methylsulfonyl)phenoxy]benzamide

(72&amp;) 3-(5-{[(111)-2-hydroxy-1-methylethyl]aminemethanyl}-1^pyrrol-2-yl)-5-[4-(methylsulfonate) Methyl phenoxy]benzoic acid The compound synthesized in Example (48d) (600 mg, 1.44 m mol)., D-(I-aminopropanol (0 · 1 6 8 m L, 2 · 1 7 mm) ο 1), Η BT BT · Η 2 〇 (2 1 5 mg, 1.59 mmol), Ν-methylmorpholine (〇.318 mL, 2.89 mmol), WSCI. ^^1 (3 3 2«^, 1.73111111 The title compound (617 mg, 90%) was obtained as a white solid. </RTI> NMR (CDC13, 400 MHz): δ 1.27 (3 Η, 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 =

(II 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) 3-{5-[(4R)-4-methyl- Methyl 4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[4-(methylsulfonyl)phenoxy]benzoate (72a) Compound (617 mg, 1.31 mmol), carbamic acid anhydride (470 mg '2.61 mmol), triethylamine (. 910 mL, 6.53 mmol), as a white solid. The target (534 mg, -309-201036962, yield 90%). 'H-NMR (CDC13, 500MHz) : δ 1.34 (3Η, d, J = 6.8 Hz), 3.08 (3H, s), 3.93 -3.97 (1 H, m), 3.95 (3H, s), 4.30-4.39 ( 1 H, 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 -(Methanesulfonyl)phenoxy]benzoic acid f 1 The compound synthesized in Example (72b) (5 3 4 mg, 1.17 mm 〇l) was dissolved in a mixed solvent of tetrahydrofuran (9 mL) and water (3 mL). Lithium hydroxide monohydrate (148 mg, 3, 52 mmol) was added and stirred at room temperature for 4 hours. 2 equivalents of hydrochloric acid (2 mL) and dichloromethane (10 mL) were added, and the precipitate was collected by filtration. After washing with water and methylene chloride, the title compound (5 5 7 mg, yield ~ 100%) was obtained. ^-NMR (DMS0-D6, 400ΜΗζ): δ 1.32 (3Η, d, J = 6.6 Hz), 3.22 (3H, s), 3.7 3 - 3.8 5 ( 1 H, m), 4.3 7-4.49 ( 1 H , m), ^ 4.64-4.80 ( 1 H, 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). (7 2(1)1^,:^-dimethyl-3-{5-[(411)- 4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[4-(methylsulfonyl)phenoxy]benzene The compound synthesized in Example (72c) (518 mg, 1.18 mmol) was dissolved in N,N-dimethylformamide (i5 mL), and dimethylamine hydrochloride-310-201036962 (287 mg) was added at room temperature. , 3.53 mmol), 4-dimethylamino group P was steep (431 mg, 3.53 mmol), triethylamine (800 μί, 5.74 mmol), WSCI. HCl (451 mg, 2.35 mmol), and stirred under nitrogen atmosphere for 22 hours. After adding water (30 mL) to the reaction mixture, the mixture was extracted with ethyl acetate (1 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure, and chromatographic analysis using a gel column chromatography (solvent solvent: methanol/dichloro Methane = 2% to 5%) Purification of the residue to give a white solid (1 9 5 mg, 35%) ° 1H-NMR (CDC13, 400MHz): δ 1.33 (3H, d, J = 6.6 Hz), 3.02 o (3H, br s), 3.08 (3H, s) , 3 · 1 2 (3 H, br s), 3.9 4 (1 H, t, J = 7.8 Hz), 4.28-4.39 ( 1 H, m), 4.5 1 (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: 468.1 6002 (M + H)+. (Example 73) QN,N-Dimethyl-3-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]_1H-pyrrole- 2-yl}-5-[3-(methylsulfonyl)phenoxy]benzamide

(7 3 a) 5-[3-Hydroxy-5-(methoxycarbonyl)phenyl]-1H-pyrrole-2-carboxylic acid benzyl ester using methyl 3-bromo-5-hydroxybenzoate (10.13 g, 43.8 mmol), the compound synthesized in the example (19e) (19. (^, 58.1111111〇1), [1,1'-bis(diphenylphosphino)-311 - 201036962 ferrocene]-palladium chloride (11) Methylene chloride complex (1568, 191111111 〇 1), potassium carbonate (12.5 g, 90.4 mmol),yield of the title compound (13.4 g, yield 87%). Η-ΝΜΚ_ (CD3OD, 500ΜΗζ): δ 3.90 (3H, s), 5.32 (2H, s), 6.55 (1Η, d, J = 3.9 Ηζ), 6.95 (1Η, d, J = 3.9 Ηζ), 7.3 2-7.3 4 (3Η, m), 7.3 5-7.3 8 (2H, m), 7.45 (2H, d, J = 6.8 Hz), 7.82-7.84 (1H, m). (73b)5-{3- (Methoxycarbonyl)-5-[3-(methylsulfonyl)phenoxy]phenyl}_ih-pyrrole-2-carboxylic acid benzyl ester The compound synthesized in Example (73 &amp;) (2.0 (^, 5.69111111〇1) Dissolved in dichloromethane (60 mL), [3-(methylsulfonyl)phenyl]boronic acid (3.05 g, 15.25 mmol), copper acetate (11) (1.80 g, 9.94 mmol), triethyl Base amine (4.60mL, 33.0m Mol), molecular sieve 4A (1.00 g), stirred at room temperature for 4 days under a nitrogen atmosphere. Water (2 OmL) was added to the reaction mixture, and the precipitate was filtered through Celite (dichloromethane). The filtrate was extracted, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and analyzed by chromatography on a gel column (solvent solvent: ethyl acetate / hexane = 10% - 60) The resulting residue was purified to give the title compound (1·························· 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), 7.3 3 -7.47 (6H, m), 7.5 5 -7.5 8 (3H, m), 7.72 (1H, dd, J = 6.8, 1.0 Hz), 8.03 (1H, s), 9.34 (1H, br s). -312- 201036962 (73c)3-(5 -{[(2R)-l-Hydroxypropan-2-yl]amine-carbamoyl}-1Η-pyrrol-2-yl)-5-[3-(methylsulfonyl)phenoxy]benzoic acid methyl ester

The compound synthesized in the example (73 b) (1.38 g, 2.7 3 mmol) was dissolved in a solvent mixture of ethyl acetate (40 mL) and methanol (15 mL), and added, palladium carbon (0.55 g), under a hydrogen atmosphere at room temperature Stir for 3 hours and a half. After filtration through Celite, the solvent was evaporated under reduced pressure to give a white solid. The obtained compound was dissolved in a mixed solvent of dichloromethane (20 mL) and tetrahydrofuran (10 mL), and D-aminopropanol (0.30 mL, 3.83 mmol), WSCI.HCl (0.71 g ' 3.70 mmol), HOBT was added at room temperature. .H 2 O (0.62 g, 4.05 mmol), N-methyl-propofoline (0.70 mL, 6.37 mmol), and stirred overnight under nitrogen atmosphere. Water (20 mL) was added to the mixture. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue obtained was purified using EtOAc EtOAc (EtOAc:MeOHMeOH ). ^-NMR (CDC13, 400MHz): δ 1.28 (3Η, d, J = 7.0 Hz), 2.79 (1H, br s), 3.08 (3H, s), 3.59-3.66 ( 1 H, m), 3.74-3.80 ( 1 H, m), 3.94 (3H, s), 4.23-4.30 (1 H, 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), 7.5 3 -7.60 (3 H, m), 7.71 (1H, d, J = 7.8 Hz), 8.03 -8.05 ( 1 H, m), 9_80 (1H, s). (73 &lt;1) 3-{5-[(411)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1-pyrrol-2-yl}-5 -[3-(Methanesulfonyl)phenoxy]benzoic acid methyl ester The compound synthesized in Example (73c) (1.06 g, 2.24 mmol), A-313-201036962 Institute of extended anhydride (800 mg, 4 · 5 9 mmo) 1), triethylamine (1.25 mL, 8.9 7 mmol),yield (yield: 86%). *H-NMR (CDC13, 400MHz): δ 1.36 (3Η, d, J = 6.6 Hz), 3.08 (3H, s), 3.92-4.00 (1 H, m), 3.94 (3H, s), 4.3 3 - 4.3 9 ( 1 H, m), 4.51-4.57 (1H, m), 6.61 (1H, d, J = 3.9 Hz), 6.80 (1H, d5 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 ( 1 H, m), 7.70-7.73 ( 1 H, m), 8.05-8.07 ( 1 H, m) (73e) N,N-Dimethyl-3-{5-[(4R)-4-methyl-4,5-dihydro-1,3-Dfoxazol-2-yl]-1H-pyrrole- 2-Base}-5-[3-(methylsulfonyl)phenoxy]benzamide The compound synthesized in Example (73d) (858 mg, 1.89 mmol) was dissolved in tetrahydrofuran (1 2 mL) and water ( 5 mL) of a mixed solvent, lithium hydroxide monohydrate (250 mg, 5.96 mmol) was added at room temperature, and stirred at 40 ° C for 2 hours and a half under a nitrogen atmosphere. 2N hydrochloric acid was added to the reaction solution to a pH of about 3, and extracted with ethyl acetate (2OmL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The obtained compound was dissolved in dichloromethane (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 The amine (1.0 mL, 5.74 mmol) was stirred at room temperature for three and a half hours under a nitrogen atmosphere. A saturated aqueous solution of sodium hydrogencarbonate (2 mL) was evaporated and evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted eluted elution Rate 84%).

• H-NMR (CDCI3, 400MHz): δ 1.35 (3Η, 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 (1 H, 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), 7.28-7.3 3 (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: 468.1 5 880 (M + H)+. (Example 74) 3-(3-Methoxyphenoxy)-1^,&gt;4-dimethyl-5-{5-[(41〇-4-methyl-4,5-dihydro) -1,3-oxazol-2-yl]-1H-pyrrol-2-yl}benzamide

(7 4&amp;) 5-[3-(Methoxycarbonyl)-5-(3-methoxyphenoxy)phenyl]-11--pyrrole-2-carboxylic acid benzyl ester Example (73 &amp; The synthesized compound (2.0 (^, 5.69111111〇1) was dissolved in dichloromethane (6 mL), (3-methoxyphenyl)boronic acid (2.2 〇g, 14.48 mmol), copper (II) acetate (1.78) g, 9.83 mmol), triethylamine (4.60 mL, 33.0 mmol), molecular sieve 4A (1.00 g), and stirred at room temperature for 5 days under nitrogen atmosphere. Water (20 mL) was added to the reaction mixture. Soil filtration; -315-201036962 Precipitate. The filtrate was extracted with dichloromethane (100 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Analysis (Isolation solvent: ethyl acetate / hexane = 10% - 40%) The obtained residue was purified to give the title compound (yield: 5.3 g, yield: 5%) (+) NMR (CDC13, 5 00 MHz): δ 3.79 (3Η, s), 3.91 (3Η, 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 ( 1 H, m), 7.3 0-7.45 (6H, m), 7.56 (1H, s), 7.96 (1H, s), 9.44 (1H , s s). (741)) 3-(5-{[(211)-1-Hydroxypropan-2-yl]aminemethanyl}-;^-pyrrol-2-yl)-5-(3 - Methyl methoxyphenoxy)benzoate The compound synthesized in Example (74a) (1.43 g, m mmol), palladium carbon (0.60 g), D-amine HCl (0.85 g, 4.43 mmol), HOBT.H2 The title compound (1.05 g,yield: 85%) was obtained as a yellow solid (yield:::::::::::::::::::::::::::::::::::::::::::::::::: 'H-NMR (CDC13, 5 00MHz) : δ 1.28 (3Η, d, J = 6.8 Hz), 2.74 (1H, br s), 3.61-3.66 (1H, m), 3.75-3.80 ( 1 H, 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), 6.5 8-6.63 (3H, m), 6.71 (1H, dd, J = 8.3, 1.5 Hz), 7.24-7.28 (1 H, m), 7.38 (1H, s), 7.54 (1H, d, J = 1.5 Hz), 7.94-7.97 (1 H, m), 9.67 (1H, br s). (74c) 3-(3-Methoxyphenoxy)-5-{5-[(4R)-4-methyl-4,5-dihydro-316- 201036962 -1,3-oxazole-2 Methyl--111-pyrrol-2-yl}benzoic acid The compound synthesized in Example (74b) (1.05 g, 2.47 mmol), methanesulfonic acid anhydride (880 mg, 5.05 mmol), triethylamine (1.50 mL) The title compound (93 8 mg &gt; yield 93%) was obtained as a pale yellow solid.

• H-NMR (CDC13, 40〇MHz): δ 1.34 (3Η, d, J = 6.6 Hz), 3.80 (3H, s), 3.91-3.98 (1H, m), 3.92 (3H, s), 4.29- 4.39 ( 1 H, m), 4.51 (1H, dd, J = 9.0, 8.2 Hz), 6.57 (1H, d, J = 3.5 Hz), 6.5 9-6.62 (2H, m), 6.71 (1H, ddd, J = 8.2, 2.2, 1.0 Hz), 6.77 (1HS d, J = 3.9 Hz), 7.24-7.28 (1 H, m), 7.39-7.41 (1H, m), 7.5 3 -7.5 5 ( 1 H, m ), 7.96-7.97 ( 1 H, m). (74d) 3-(3-Methoxyphenoxy)-N,N-dimethyl-5-{5-[(4R)-4-methyl -4,5-Dihydro-1,3-oxazol-2-yl]-111-pyrrol-2-yl}benzamide The compound synthesized in Example (74 c) (93 8 mg, 2.3 1 mmol) A mixed solvent of tetrahydrofuran (15 mL) and water (5 mL) was added, and lithium hydroxide monohydrate (3 75 mg, 8.94 mmol) was added at room temperature, and the mixture was stirred at 40 ° C for 5 hours under a nitrogen atmosphere. 2 equivalent of hydrochloric acid was added to the reaction solution to a pH of about 3 to obtain a precipitate. This was filtered to give a white solid. The obtained compound was dissolved in dichloromethane (15 mL), dimethylamine (2.0 mol/L tetrahydrofuran solution, 2.20 mL, 4.40 mmol), HATU (1.75 g, 4.60 mmol), hydrazine, hydrazine-diisopropyl The amine (1.25 mL, 7.18 mmol) was stirred at room temperature for 5 hours under nitrogen. A saturated aqueous solution of sodium hydrogencarbonate (20 mL) was evaporated and evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate.减-317-201036962 The solvent was removed by distillation, and the residue was purified using EtOAc EtOAc (EtOAc:EtOAc:EtOAc , yield 93%). ^-NMR (CDCh, 400MHz): δ 1.34 (3Η, d, J = 6.3 Hz), 2.95-3.12 (6H, br m), 3.79 (3H, s), 3.90-3.96 ( 1 H, m), 4.30 -4.3 7 (1 H, m), 4.46-4.54 (1 H, 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: 420.1 91 67 (M + H)+. (Example 75) 3-(4-Methoxyphenoxy)-1&gt;^-dimethyl-5-{5-[(411)-4-methyl-4,5-dihydro-1, 3-oxazol-2-yl]-1H-pyrrol-2-yl}benzamide

(7 5 &amp;) 5-[3-(Methoxycarbonyl)-5-(4-methoxyphenoxy)phenyl]-111-pyrrole-2-carboxylic acid benzyl ester Example (73 a) The compound which was synthesized (2.00 g, 5.69 mmol) was dissolved in dichloromethane (60 mL), (4-methoxyphenyl)boronic acid (2.20 g ' 14.48 mmol), copper (II) acetate (1.75 g, 9.67 mmol) Diethyl virgin (4.60 mL, 33.0 mmol) and molecular sieve 4A (1.00 g) were stirred at room temperature for 7 days under a nitrogen atmosphere. Water (2 OmL) was added to the reaction mixture, and the precipitate was filtered through Celite. The filtrate was extracted with dichloromethane (100 mL). After washing the organic layer with a saturated aqueous solution of -318 - 201036962, it was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted ° 'H-NMR (CDCb, 400MHz) : δ 3.83 (3Η, 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 (1 H, m), 7.32-7.48 (6H, m), 7.8 8-7.89 ( 1 H, m), 9.31 (1H, br s) (7 51&gt;) 3-(5-{[(2 ft)-1-hydroxypropan-2-yl]aminecarbamyl}-111-pyrrol-2-yl)-5-(4-methoxy Methyl phenoxy)benzoate The compound (930 mg, 2.03 mmol), palladium carbon (400 mg), D-aminopropanol (〇.25 mL, 3.20 mmol) of the compound synthesized in Example (75a) WSCI. HCl (5) 50 mg, 2.8 7 mm ο 1), Η BT BT · Η 2 Ο (4 6 5 mg, 3 · 0 4mm ο 1), heart methylmorpholine (0.6〇!1^,5.46111111〇1), The title compound was obtained as a white solid ( 725 mg, yield: 84%). ???H-NMR (CDCIs, 400 MHz): δ 1.25 (3 Η, 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), 9.5 5 (1 H, br s) (75c) 3-(4-methoxyphenoxy)-5-{5-[(4R)-4-methyl-4, 5-Dihydro-319-201036962 - 1,3-oxazol-2-yl]-111-pyrrol-2-yl}benzoic acid methyl ester The compound (725 mg, 1.71 mmol) synthesized using Example (75b) The title compound (680 mg, yield 98) was obtained as a pale yellow solid (yield: 98%). %).

^-NMR (CDC13, 400MHz): δ 1.39 (3Η, 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), 6.8 0-6.8 5 ( 1 H, 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 (1 H, 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]-115-pyrrole-2- The compound synthesized by the example (75c) (680 mg, 1.67 mm )l), lithium hydroxide monohydrate (220 mg, 5.24 mmol), dimethylamine (2.0 mol/L tetrahydrofuran solution, 1.30) </ RTI> </ RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Compound (5 6 2 mg, yield 80%). !H-NMR (CDCh, 400MHz) : δ 1.33 (3Η, d, J = 6.6 Hz), 2.93-3.12 (6H, br m), 3.82 (3H, s), 3.93 (1H, t, J = 7.8 Hz ), 4.28-4.3 8 ( 1 H, 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 (2HS 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), 7.2 5 -7.27 ( 1 H, m). -320- 201036962 MS (ESI) m/z : 420.1 9272 (M + H)+. (Real Example 76) N,N-Dimethyl- 3-{5-[(5S)-5-methyl-4,5-dihydro-l,3-Doxazol-2-yl] 1Ηpyrrol-2-yl}-5-phenoxybenzamide

σ(76a)5-[3_(Methoxycarbonyl)-5-phenoxyphenyl]-1H-pyrrole-2-carboxylic acid. The compound synthesized in Example (73 a) (2.00 g, 5.69 mmol Dissolved in dichloromethane (20 mL), adding phenylboronic acid (1.90 g, 15.58 mmo 1), copper (II) acetate (1.90 g, 10.49 mmol), triethylamine (4.70 mL, 33.7 mmol), molecular sieve 4A (1.00 g) was stirred at room temperature for 7 days under a nitrogen atmosphere. Water (20 mL) was added to the reaction mixture, and the precipitate was filtered through Celite. The filtrate was extracted with dichloromethane (60 mL). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was evaporated to mjjjjjjjjjjj . 'H-NMR (CDC13, 400MHz): δ 3.91 (3H, s), 5_34 (2H, s), 6.57 (1Η, dd, J = 3.9, 2.7 Hz), 6.99 (1H, dd, J = 3.9, 2.3 Hz), 7.02-7.04 ( 1 H,m), 7.04-7.06 ( 1 H,m), 7.14-7.19 (1H,m), 7.3 0-7.45 (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). -321- 201036962 (76b) 3-(5-{[(2R)-2-hydroxypropane Methylaminocarbazide}-1Η-pyrrol-2-yl)-5-phenoxybenzoate

The compound synthesized in Example (76a) (1.75 g, 4.09 mmol), palladium carbon (0.55 g), (R)-(-)-l-amino-2-propanol (0.55 mL '6-99 mmol), WSCI HCl (1.10 g, 5.74 mmol), HOBT-H2O (1_05 g, 6.86 mmol), N-methyl-formoline (1.30 mL, 11.82 mmol). (1.99 g, yield 74%). • H-NMR (CDC13, 400MHz): δ 1.25 (3Η, 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) 0 (76c)3-{ 5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]_ 1H-pyrrole (|

Methyl-2-methyl}-5-phenoxybenzoate The compound (119 g, 3〇2ηιιηη1) 'methanesulfonic anhydride (1. 〇8g '6.20 mmol), triethyl b. The title compound (1.12 g, yield 99%) was obtained as a pale yellow solid. 'H-NMR (CDC13, 400ΜΗζ) : δ 1.44 (3Η, d, J = 6.3 Hz), 3.56 (1H, dd, J = 13.7, 7.4 Hz), 3.92 (3H, s), 4.10 (1H, dd, J = -322- 201036962 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), 7.52-7.5 3 (1 H, m), 7.96 (in, s). (76 sentences &gt;1,&gt; 1-dimethyl-3_{5_[(58)_5.methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrole· 2_yl}_5-phenoxybenzamide

The compound synthesized in Example (76c) (1.12 g, 2.98 mmol), 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), N,N-diisopropylethylamine (0.85 mL, 4.88 mmol),yield 71%). !H-NMR (CDC13, 400MHz) : δ 1.42 (3Η, 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 (1 H, 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), 7.3 3 -7.3 9 (2H, m). MS (ESI) m/z: 3 90 _ 1 8 1 66 (M + H)+. (Example 77) 3-(4-Fluorophenoxy)-N,N-dimethyl-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3- Oxazol-2-yl]-111-pyrrol-2-yl}benzamide-323 - 201036962

(77a) 3-bromo-5-fluoro-N,N-dimethylbenzamide A solution of 3-bromo-5-fluorobenzoic acid (10 g, 46.1 mmol) in dichloromethane (150 mL). Add 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), nitrogen atmosphere Stir at room temperature for 4 hours. In the opposite direction,

I. A saturated aqueous solution of sodium hydrogencarbonate (200 mL) was evaporated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluting eluted eluted eluted eluted eluted eluted eluted eluted eluted %). *H-NMR (CDC13, 400MHz): 52.98-3.1 0 (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) were dissolved in N,N-dimethylformamide (20 mL), and cesium carbonate (5.55 g, 17.0 mmol) was stirred at 80 ° C for 3 Torr under a nitrogen atmosphere and stirred at 130 ° C for one day. The reaction solution was cooled to room temperature, and water (1 mL) was added, and ethyl acetate (1 mL) was extracted three times. The organic layer was washed twice with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted elution elution , yield 90%). *H-NMR (CDC13, 400MHz): δ 2.93-3.10 (6Η, 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)5-[3-(dimethylaminemethanyl)-5-(4 -fluorophenoxy)phenyl]-1H-pyrrole-2-carboxylate

The compound synthesized in Example (77b) (2.49 g, 7.36 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane-2-yl)- 1 Η-pyrrole-2-carboxylic acid methyl ester (2.75g, ll.Ommol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride complex (3, 80 mg, 〇. 47 mmol), potassium carbonate (4.05 g, 29.3 mmol),yield of the title compound (2, 64 g, yield 94%). -NMR (CDC13, 400MHz): 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). (77(1)5-[3-(dimethylamine-mercapto)-5-(4-fluorophenoxy)phenyl]-1^-[(211)-2-hydroxypropyl]-1H· Pyrrole-2-carboxamide The compound synthesized in Example (77c) (2.64 g, 6.90 mmol) was dissolved in a mixture solvent of tetrahydrofuran (5.0 mL), methanol (15-mL) and water (5.0 mL), and hydrogen was added at room temperature. Lithium oxide monohydrate (1.10g, 26.2mmol), stirred at 50 ° C for 3 hours and a half under nitrogen atmosphere. Add 2 equivalents of hydrochloric acid to the reaction solution to pH ~ -325 - 201036962 3 ' with ethyl acetate (5 OmL) The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a white solid. The solid was dissolved in dichloromethane (30mL). 2-propanol (0.90 mL, 11.4 mmol), WSCI, HCl (1.90 g, 9.91 mmol), H0BT.H20 (1.72 g, 11.2 mmol), N-methylmorpholine (2.20 mL, 20.0 mm 〇l) The mixture was stirred for 3 hours under a nitrogen atmosphere, and water (40 mL) was added to the mixture, and the mixture was extracted with dichloromethane (6 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Using a silicone tube color layer The residue was purified (yield solvent: methanol / methylene chloride = 1% to 6%) to give the title compound (1.44 g, yield: 49%) of white solid. iH-NMR (CDC13, 5 00 MHz): δ 1.18-1.21 (3H, m), 2.91-3.12 (6Η, 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 (1HS 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 f (1 H, br s). (776) 3-(4-Vephenoxy)-1^,]^-monomethyl-5_{5_[(58)-5-methyl-4, 5-Dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}benzamide The compound synthesized in Example (77d) (1.44 g, 3.3 8 mm ο 1), methane The title compound (788 mg, yield: 57%) of the title compound ( 788 mg, yield: 57%) of the title compound ( </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> - 201036962 • H-NMR (CDC13s 400MHz): 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 (1 H, 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: 408·1 7252 (M + H)+. (Example 78) N,N-Dimethyl-3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-Dfoxazol-2-yl]-1H-pyrrole -2-yl}-5-(pyridin-3-yloxy)benzamide

(78a) 3-bromo-5-(pyridin-3-yloxy)-N,N-dimethylbenzamide

The compound synthesized in Example (77 &amp;) (2.〇4, 8.17111111〇1) and pyridin-3-ol (1.40§, 14.71111111〇1) were dissolved in 1^,:^-dimethylformamide (2 〇1111〇, a carbonic acid planer (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, and water (100 mL) was added, and ethyl acetate (100 mL) was extracted three times. The organic layer was washed twice with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the mixture was chromatographed using a gel column chromatography (solvent solvent ethyl acetate/hexane = 10% to 60%) The obtained residue was purified to give the title compound (yield (yield: 87%) (yield: 87%): H-NMR (CDCI3, 400 MHz): δ 2.96-3.09 (6 Η, m), 6.97 (1H, dd - 327- 201036962 J = 2.3, 1.6 Hz), 7.19 (1H, dd, J = 2.2, 1.8 Hz), 7.31-7.32 (1H, m), 7.3 3 -7.3 7 (2H, m), 8.43 -8.47 (2H, m (78b) 5-[3-(Dimethylaminomethane)-5-(pyridin-3-yloxy)phenyl]-1H-pyrrole-2-carboxylic acid methyl ester using Example (78a) Synthetic compound (2.28 g, 7.10 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)-1 Methyl Η-pyrrole-2-carboxylate (2.71 g, 10 mmol. 8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Π) dichloromethane complex (3 5 5 mg '0.43 mmol), potassium carbonate (4.15 g, 30.0 mmol), m.p. (CDC13, 500MHz) : δ 2.99-3.13 (6Η, 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-(Dimethylaminomethane)-5-(pyridin-3-yloxy)phenyl]-N-[(2R)-2-hydroxypropyl]-1H-pyrrole- 2-Prodecylamine The compound (2.41 g, 6.60 mmol) synthesized in Example (78b) was dissolved in tetrahydrofuran (5. 〇mL), methanol (10 mL) and water (5.0 mL). Lithium hydroxide monohydrate (1. 5 g, 25.0 mmol) was added, and the mixture was stirred at 50 ° C for 3 hours and a half under a nitrogen atmosphere. 2 equivalent of hydrochloric acid was added to the reaction solution to a pH of about 2, and the resulting precipitate was filtered off. A saturated aqueous solution of sodium hydrogencarbonate was added to the filtrate to a pH of about 5, and extracted with dichloromethane (1 mL). Saturated saline solution - 328 - 201036962

After washing the organic layer, it was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a white solid (l. This solid was dissolved in dichloromethane (25 mL), and (R)-(-)-l-amino-2-propanol (〇.531^, 6.73111111〇1), slip 8 (: 1· HCl (1.07g, 5.58mmol), HOBT.H2〇 (950mg, 6.20mmol), N-methylmorpholine (1.2〇mL, 10.9mmol), stirred under nitrogen for 7 hours. Add water to the reaction solution. (4 〇 mL), and extracted with dichloromethane (60 mL), and the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and analyzed by column chromatography (solvent solvent: methanol) / methylene chloride = 1% to 8%) The obtained residue was purified to crystals crystals crystals crystals crystalssssssssssssssssssssss = 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 ( 1 H, 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-pyrrole- 2-Base}-5-(pyridin-3-yloxy)benzamide The compound synthesized in Example (78c) (1. 〇9 g, 2.67 mmol), decylsulfonic anhydride (925 mg, 5.31 mmol), The title compound (8 5 3 mg &gt; yield 82%) was obtained as a white solid in the same manner as the compound (1 6j). (CDC13,400MHz) : 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 ( 1 H, 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: 391.1 7744 (M + H) + » (Example 79) 3-[(3-Bromopyridin-2-yl)oxy]-N,N-dimethyl-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3 -oxazol-2-yl]-11^pyrrol-2-yl}benzamide

α(79a)acetic acid 3-bromo-5-(dimethylaminomethyl decyl) phenyl ester 3 -Bromo-5-hydroxybenzoic acid (10.Og' 46.1 mmol) was dissolved in acetic anhydride (70 mL), and concentrated sulfuric acid was added. (0.1 mL, 1.88 mmol) was stirred at room temperature for 30 min under nitrogen atmosphere. 1N hydrochloric acid (5 OmL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (100 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. To the obtained crude purified material, sulfinium chloride (30 mL) was added, and the mixture was refluxed for 1 hour. The sulfinium chloride is distilled off under reduced pressure. The obtained crude purified product was dissolved in dichloromethane (5 mL), dimethylamine (2M THF, 50.0 mL, 100 mmol). A saturated aqueous solution of sodium hydrogencarbonate (5 mL) was obtained and evaporated. The organic layer was washed with saturated brine -330-201036962 and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted elution %). 'H-NMR (CDC13s 4〇αΜΗζ) : δ 2.30 (3Η, s), 3.00 (3H, s), 3.10 (3H, s), 7.12 (1H, m), 7.34 (1H, m), 7.44 (1H , m). (79b) 5-[3-(Dimethylcarbamoyl)-5-hydroxyphenyl]_1H-pyrrole-2 -carboxylic acid methyl ester

The compound synthesized in Example (79a) (ii.7 g, 40.9 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl) Methyl 1-111-pyrrole-2-carboxylate (14.4 g '57_3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride complex (l OOg, 1.22 mmol), potassium carbonate (17.0 g, 123 mmol). The title compound (l. • H-NMR (CDCb, 400MHz): 52.93 (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-(dimethylaminocarbamimidyl)phenyl}-111-pyrrole-2-carboxylate was synthesized in Example (79b) The compound (64 mg, 2.22 mmol) was dissolved in dimethylacetamide (30 mL). The 3-bromo-2-chloroindole ratio was steep (860 mg, 4.47 mmol) and the carbonic acid planer (2.20 g' 6.75 mmol) was stirred at i00 ° C for 22 hours under a nitrogen atmosphere. After cooling the reaction solution to room temperature, add 1 equivalent of hydrochloric acid -331- 201036962

(5 OmL), extracted twice with ethyl acetate (5 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified eluting eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted ). ^-NMR (CDC13, 400MHz): 53.06 (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-(dimethylaminomethane)phenyl}-N-[(2R)-2-hydroxypropyl] -1H-pyrrole-2-carboxamide The compound synthesized in Example (79c) (448 mg '1 mmol) was dissolved in methanol (20 mL), and 5N aqueous sodium hydroxide (1.lmL, 5.50 mmol) was added. Stir at 65 ° C for 3 hours. 2N hydrochloric acid (3.0 mL) was added to the reaction mixture, and extracted with ethyl acetate (3 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The obtained residue was dissolved in methanol (20 mL), using (R)-(-)-1-amino-2-propanol (0.220mL, 2.79mmol), DMT-MM (920mg ' 3.32mmol) (5d) The title compound was obtained (yield: 44%) (yield: 44%). ^-NMR (CDCI3, 400ΜΗζ): δΐ.12 (3Η, d, J = 6.3Hz), 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, dd5 -332- 201036962 J = 3.9, 2.4Hz), 6.91 (1H, Dd, J = 7.8, 4.7 Hz), 7.02 (1H, m), 7.05 (1H, m), 7.38 (1H, brs), 7.41 (iH, m)j 7&gt;92 (1Η&gt; dd? J = 7.8, 1.6Hz), 8.01 (1H, dd, 1 = 4.7, 1.6H2), 1〇92 (1H, brs). (79e)3-[(3-Bromo-U-steep-2-yl)oxy]-N , N-dimethyl_5_{5_[(58)_5_methyl-4,5-monoamino-1,3-indol-2-yl]-1H-H ratio slightly-2 -yl}benzamide The compound synthesized by the example (79d) (237 mg, 0.486 mmol), methanesulfonic acid anhydride (215 mg, 1.23 mmol), triethylamine (〇.41 mL,

The title compound (1 6 1 mg, yield 71%) was obtained as white solid. • H-NMR (CDC13, 400MHz): δ 1.42 (3Η, 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, 4.7 Hz), 7.10 (1H, dd, J = 1.8, 1.6 Hz), 7.39 (1H, t, J = 1.6 Hz), 7.46 (1H, t, J = 1.6 Hz), 7.95 (1H, dd, J = 7.8, 1.6 Hz), 8.05 (1H' dd, J = 4.7, 1,8 Hz). MS (ESI) m/z: 469.08753 (M + H)+. (Example 80) 3-(2,4-Difluorophenoxy)-1&gt;1-dimethyl-5-{5-[(5 8)-5-methyl-4,5-hydro-1, 3-Bfoxazol-2-yl]-1H-indol-2-yl}benzamide

-333- 201036962 (80a) 5-[3-(2,4-Difluorophenoxy)-5-(dimethylcarbamoyl)phenyl]-1H-pyrrole-2-carboxylic acid methyl ester will be implemented The compound synthesized in Example 79b (520 mg, 1.80 mmol) was dissolved in dimethylacetamide (30 mL). 1,2,4-Trifluorobenzene (720 mg, 5.45 mmol), cesium carbonate (1.76 g, 5.40 mmol) were added, and the mixture was stirred at 1 ° C for 24 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, 1N aqueous hydrochloric acid (5 mL) was added, and the mixture was extracted twice with ethyl acetate (5OmL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified eluting eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted ). 'H-NMR (CDC 13, 400MHz): 53.00 (3 H, 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-(dimethylamine-mercapto)phenyl]-N-[(2R)-2-hydroxypropyl]-1H-pyrrole- 2-Prodecylamine The compound (4 0511^, 1.10111111〇1) synthesized in the example (80 &amp;) was dissolved in a mixed solvent of methanol (6 mL), tetrahydrofuran (1 mL) and water (2 mL), and lithium hydroxide monohydrate was added. (130 mg, 3.10 mmol) was stirred at 70 ° C for 3 h. 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 brine and dried over anhydrous magnesium sulfate. The obtained residue was dissolved in methanol (20 mL), using (R)-(-)-1-amine- 2--334-201036962 propanol (0.160mL, 2.03mmoi), DMT-MM (840mg, 3.04mmol), The title compound (279 mg &gt; yield 62%: H-NMR (CDCb, 400 MHz): δ ΐ.15 (3 Η, d, J = 6.3 Hz) was obtained in the same manner as Example (5d). ), 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), 6.7 5 -6.8 8 (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}benzimidamide Example (80b) The compound (yield: 279 mg, 0.629 mmol), EtOAc (280 mg, EtOAc, EtOAc, EtOAc, 188 mg, yield 70%). ^-NMR (CDCh, 400MHz): δ 1.4 1 (3Η, 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: 426.1 6292 (M + H)+. (Test Example 1) (1) Preparation of GK The cDNA encoding human pancreas type GK multi-201036962 peptide was cloned from a human cDNA library via a polymerase chain reaction (hereinafter referred to as "PCR") (GenBank registration) No. NM_000 1 62 human glucokinase, variantl), introduced into a glutathione transferase (hereinafter referred to as GST) fusion protein expression vector (GEX4T, GE Healthcare Bio-Sciences). The vector was introduced into Escherichia coli (BL21, Invitrogen), and the transformed Escherichia coli was cultured at 37 ° C overnight to recover the cells. After the freeze-thawed cells were frozen-thawed, they were suspended in a phosphate buffer solution to which a final concentration of 1% Triton-X was added, and were disrupted by an ultrasonic breaker. Homogenization by low-speed centrifugation (l〇, 〇〇〇xg, 30 minutes), further high-speed centrifugation (l〇〇, 〇〇〇xg, 10 minutes) supernatant, recovery of supernatant, using GST fusion protein purification system (Bulk GST purification module, GE Healthcare Bio-Sciences) Purified fusion protein. The GK fusion protein was dispensed into a small volume and stored at -80 °C. (2) GK activity test GK activity was measured using (1) purified GK. Specifically, the solution 1 of the glucose assay kit (D-glucose UV method, R 〇che D iag η 〇stics) is added (1) purified GK, and glucose-6-phosphate dehydrogenase (Sigma). As an enzyme solution. The enzyme solution, the 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 the end of the reaction, the absorbance at a wavelength of 34 0 nm was measured using SpectraMax. Plus (Molecular Probes). Further, the absorbance of unreacted (when glucose was not added) was used as a background 値. The GK activation rate is a mathematical expression expressed by the mathematical formula of (absorbance after 30 minutes of reaction when the test compound is added) / (absorbance after 30 minutes of reaction of the test compound is not added). The test compound concentration of 1 μΜ obtained GK activation rate - 336 - 201036962 The results are not shown in Table 1. (Table 实施 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 201036962 Formulation Example 1: Capsules Compound of Example 1 5 Omg Lactose 1 28 mg Corn starch 7 Omg Magnesium stearate 2 mg 2 5 Om g Mixed on the prescription The powder was passed through a 60-mesh sieve, and 250 mg of the powder was poured into a gelatin capsule to prepare a capsule. Formulation Example 2: Tablets Example 1 Compound 5 Omg Lactose 1 26 mg Corn starch 23 mg Magnesium stearate 1 mg 200 mg Mix The powder of the above-mentioned prescription is granulated with corn starch paste. After drying, it is made into a sugar-coated garment by tableting. [Industrial Applicability] 1 tablet of 200 mg of tablet. The tablet can be given to the present invention as needed. The compound represented by the general formula (I) or a pharmacologically acceptable salt thereof has excellent GK activation, and is useful for use as a blood-stained animal (especially a human) for diabetes, an abnormal sugar tolerance, and pregnancy Pregnancy diabetes, chronic diabetes mellitus (including diabetic peripheral nerve dysfunction, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome (especially diabetes - 338 - 201036962 or abnormal glucose tolerance) or Prophylactic agent (especially therapeutic agent) [Simple description of the diagram] Μ [Description of main component symbols] 値.

Claims (1)

201036962 VII. Scope of application for patents · 1. A compound of general formula (I) or a pharmacologically acceptable salt thereof (I) Ο [wherein R1 represents the same or different Cl-C6 alkyl group, Cl_c6 halogenated alkyl group, c丨-C6 alkyl group substituted by 1 or 2 hydroxy groups, (C丨-C6 alkylthioalkyl group) a carboxy group, a carboxy group, an amine carbhydryl group, a mono-Ci_C6 alkylamine carbonyl group or a bis(Cl-C6 alkyl)amine carbonyl group; R2 represents a substituent which may be independently substituted from the group 1 to 5 of the substituent group A; Phenyl or pyridyl or pyridyl group which may be optionally substituted from the group of substituent group A; O R3 represents a group of 1 to 5 independently substituted CrCe which may be selected from the group of substituent group B An alkyl group, a C2-C6 alkenyl group, which may be independently substituted by a group of 1 to 3 groups (Cl-C6 alkyl group, c3-C6 cycloalkyl group and ketone group) may contain 1 oxygen atom or a nitrogen atom. 3 to the guest saturated ring (but bonded to the u system as a carbon atom) or the formula -NR4R5; R4, R5 represent the same or different hydrogen atom, Cl-C6 alkyl or (^-(:6 alkoxy) , or R4 and R5 together with the combined nitrogen atom form a group of 1 to 3 independently substituted by the Cl-C6 alkyl group and the keto group, 4 to 6 members of the saturated hetero-340-201036962 ring, 4 to 6 members The saturated heterocyclic ring may further contain one oxygen atom or A nitrogen atom; U represents an oxygen atom or a carbonyl group (except for 2-hydroxy-1-methylethoxy group in the group represented by the formula -U-R3); η represents an integer of 〇 to 3; and a substituent group Α represents a halogen atom , Ci-Ce alkoxy, C2-C7 alkylcarbonyl, C2-C7 halogenated alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 halogenated alkoxycarbonyl, CrQ alkylsulfonyl, halogenated alkyl Sulfhydryl, I ^•(^cycloalkylsulfonyl, (Ci-Ce alkoxy hCCi-Cs alkylsulfonyl), (Mountain-(:6-haloalkoxyalkylsulfonyl)) And a group represented by the formula -V-NR6R7 (V represents a carbonyl group or a sulfonyl group; R6, R7 represent the same or different hydrogen atom, a CrQ alkyl group or a CrQ halogenated alkyl group, or R6 and R7 together with a combined nitrogen atom; a group of 4 to 6 membered saturated heterocyclic rings which may be independently substituted by 1 or 2 CrQ alkyl groups, and 4 to 6 membered saturated heterocyclic rings may further contain 1 oxygen atom or a nitrogen atom; B represents a halogen atom, a C2-C7 alkylcarbonyl group, a C2-C7 alkoxy group (carbonyl group, an aminecarbamyl group, a mono-C^-G alkylamine carbonyl group, a bis(Cl-C6 alkyl) amine carbonyl group, Ci-C6 alkylthio, Ci-Q alkylsulfonyl, hydroxyl And a group of 3 to 6 members of the cyclic ether group. 2) The compound of claim 1 or a pharmacologically acceptable salt thereof, wherein 1 is a Ci-C6 alkyl group, a CrC6 halogenated alkyl group, a 1 or A hydroxy-substituted Ci-Cfi alkyl group or an amine carbaryl group. The compound of claim 1 or 2 or a pharmacologically acceptable salt of -341 - 201036962, wherein the general formula (I) is a general formula ( La), R1 is an amine carbenyl group; (la) 4. The compound of claim 1 or 2, or a pharmacologically acceptable salt thereof, wherein the general formula (I) is a general formula (lb). Is methyl, hydroxymethyl or 2-hydroxyethyl; (lb) 5. The compound of claim 1 or 2, or a pharmacologically acceptable salt thereof, wherein the general formula (I) is a general formula (Ic), and R1 is a methyl group, a fluoromethyl group or a hydroxymethyl group. , 2-hydroxyethyl or (1S)-1,2-dihydroxyethyl; The compound of any one of claims 1 to 5, or a pharmacologically acceptable salt thereof, wherein R2 is 4 or 3 is substituted by a group selected from the group of substituents C. a phenyl group, a 5-pyridyl group substituted at the 2-position by a group selected from the substituent group C, or a 2-pyridyl group substituted at the 5-position via a group selected from the substituent group C; the substituent group C represents A group consisting of an alkoxy group, an alkylsulfonyl group and a group represented by the formula -V-NR6R7 (V represents a carbonyl group or a sulfonyl group, and R6 and R7 represent the same or different hydrogen atoms or a Ci-Cfi alkyl group). 7. A compound or a pharmacologically acceptable salt thereof, according to any one of claims 1 to 5, wherein R2 is 3-methoxyphenyl, 2-methylaminocarbonyl-5-pyridyl, 4-methyl Sulfophenyl, 2-methylsulfonyl-5-pyridyl, 2-methylamine-5-pyridyl, 5-methanesulfonyl-2-pyridinyl or 5-methylsulfonamide Base-2-la cultivating base. 8. The compound of any one of claims 1 to 7 or a pharmacologically acceptable salt thereof, wherein R3 is a CrC6 alkyl group which may be independently substituted by 1 to 5 halogen atoms or may be passed through (CrC6 naphthenic) One or two of the groups of the group and the ketone group may be independently substituted with a 3- to 6-membered saturated ring of one oxygen atom or nitrogen atom, and U is an oxygen atom. 9. The compound of any one of claims 1 to 7 or a pharmacologically acceptable salt thereof, wherein R3 is a Ci-Ce alkyl group or a group represented by the formula _NR4R5 (R4, R5 represent the same or different hydrogens) Atom or C^c: 6 alkyl), u is a few groups. 10. A compound according to any one of claims 1 to 7 or a pharmacologically acceptable salt thereof, wherein the group represented by the formula -U-R3 is a methoxy group, an ethoxy group, an isopropoxy group, (lS) )-2-fluoro-1-methylethoxy, difluoromethoxy, 1~, '~ wind- 343 - 201036962 -2 -propoxy, cyclopentan-2-yloxy, tetrahydrofuran-3 - yloxy, 1-cyclopropylpyrrolidin-2-one-3-yloxy, isopropylcarbonyl or dimethylaminecarbonyl. A compound of the general formula (I) which is: {(5 ft)-2-[5-(3-[(13)-2-fluoro-1-methylethoxy]-5-{ [6-(Methanesulfonyl)pyridin-3-yl]oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol {(4R)-2-[5-(3-[(lS)-2-fluoro-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl] Oxy}phenyl)-1Η-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol, 2-{(5S)-2-[5-(3 -[(lS)-2-fluoro-1.methylethoxy]·5_{[6_(methylsulfonyl)pyrene-thromoxy-3-yl]oxy}phenyl)-1Η -卩比略- 2-based]-4,5-dihydro-1,3-oxazol-5-yl}ethanol' (lS)-l-{(5R)-2-[5-(3-[(lS)-2 -Fluoro-b methylethoxy]_5·{[6 (methyl fluorenyl) fluorene-threspect-3-yl] oxy] benzyl) _1 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Hydrogen-1,3-oxazol-5-yl}ethyl-1,2-diol, 0 {(4R)-2-[5_(3-[(1S)-2-a small methyl ethoxy]] -5-{[5-(methylsulfonyl) fluoren-2-yl]oxy}phenyl)-1H, slightly _2-yl]_4,5-diamino-indole, 3曙哩-4- Methyl methoxide, 5-(3-[(lS)-2-fluoro-1-methylethoxyl%]-5-{5-[(4R)-4-(hydroxymethyl)-4,5 -dihydro-1,3-oxazol-2-yl]_lfT nLL ^ J 1H_pyrrol-2-yl}phenoxy)-N-methylpyridin-2-sulfonamide, 3-{5-[(5R)-5-(fluoromethyl)-4,5-di ,, t ~ m -1,3-oxazol-2-yl]-1H-pyrrole-2.yl}-N,N_-·methyl-5- {[6_(String pseudo-) pyridine- 3-amino]oxy}benzene-344 - 201036962 formamide, or 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 or a pharmacologically acceptable compound thereof Salt. A glucokinase activator comprising a compound selected from any one of claims 1 to 11 or a pharmacologically acceptable salt thereof as an active ingredient. A pharmaceutical composition comprising a compound selected from any one of claims 1 to 10 or a pharmacologically acceptable salt thereof as an active ingredient. 14. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition has glucokinase activation. A pharmaceutical composition according to claim 13 wherein the pharmaceutical composition is for treating and/or preventing a disease which is treated and/or prevented via glucokinase activation. 16. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition is for treating and/or preventing treatment, amelioration, amelioration and/or prevention of glucose maintenance by activating glucokinase to achieve constant maintenance or glucose regulation of glucose. A disease that prevents symptoms. 17. The pharmaceutical composition according to claim 13 of the patent application, wherein the pharmaceutical composition is used for diabetes, abnormal sugar tolerance, gestational diabetes, chronic diabetes mellitus (including diabetic peripheral nerve dysfunction, diabetic nephropathy, diabetic retinopathy) , diabetes mellitus) or treatment and/or prevention of metabolic syndrome. 1 8. The pharmaceutical composition according to claim 13 of the patent scope, wherein the pharmaceutical composition -345 - 201036962 is used for the treatment and/or prevention of diabetes or sugar tolerance. 19. The use of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition. 20. The use of claim 19, wherein the pharmaceutical composition is a composition for activating glucokinase. 2 1. The use of claim 19, wherein the pharmaceutical composition is for diabetes, abnormal sugar tolerance, gestational diabetes, chronic diabetes mellitus (including diabetic peripheral nerve dysfunction, diabetic nephropathy, diabetic retina) Composition for the treatment and/or prevention of metabolic syndrome or diabetic macroangiopathy) or metabolic syndrome. 2 2. The use of claim 19, wherein the pharmaceutical composition is a composition for the treatment and/or prevention of diabetes or an abnormal glucose tolerance. A method of activating a glucokinase, which comprises administering to a warm-blooded animal a pharmacologically effective amount of a compound selected from any one of claims 1 to 11 or a pharmacologically acceptable salt thereof. A method for the treatment and/or prevention of a disease, which comprises administering to a warm-blooded animal a pharmacologically effective amount of a compound selected from any one of claims 1 to 11 or a pharmacologically acceptable salt thereof. 25. The method of claim 24, wherein the disease is diabetes, abnormal glucose tolerance, gestational diabetes, chronic diabetes mellitus (including diabetic peripheral nerve dysfunction, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) ) or metabolic syndrome. 26. The method of claim 24, wherein the disease is diabetes or is resistant to sugar -346-201036962. The method of any of the items 2, wherein the warm blood is 27. The animal of the 23rd patent is a human. -347 - 201036962 IV. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the representative figure: Μ 〇 /INN 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: (I)