TW201617314A - Carboxylic acid derivatives - Google Patents

Abstract

The present invention pertains to a compound that has an excellent retinoic acid receptor-related orphan receptor [gamma] t inhibitory effect, or a pharmaceutically acceptable salt thereof. Provided is a compound represented by general formula (I), or a pharmaceutically acceptable salt thereof. (In the formula, R1 is a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a phenyl group. R2 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, or the like. R3 is a hydrogen atom, a C2-C7 carboxyalkyl group, or a hydroxyl group. R4 is a halogen atom or a C1-C6 alkyl group. R5 is a hydrogen atom or a C1-C6 alkyl group. R6 is a hydrogen atom, a halogen atom, or a C1-C6 alkyl group. R7 is a hydrogen atom, a halogen atom, or the like. R8 is a hydroxyl group, a C1-C6 alkoxy group, a mono-C1-C6 alkylamino group, or the like. L is a single bond, a methylene group, or an oxygen atom. E is a phenylene group optionally substituted independently with one or two groups selected from halogen atoms, C1-C6 alkyl groups, and C1-C6 alkylsulfonyl groups, or the like. Q1 is a nitrogen atom or a group represented by the formula =CH-. Q2 is a nitrogen atom or a group represented by the formula =CH-. The group represented by the formula -U-T- is a group represented by the formula -CH2-CH2- or the like. Y is a methylene group or an oxygen atom. V is a nitrogen atom or a group represented by the formula =C(R9)-. R9 is a hydrogen atom, a C1-C6 alkyl group, or the like.)

Description

Carboxylic acid derivative

The present invention relates to an inhibitory effect of having an excellent retinoic acid receptor-associated orphan receptor γt (in the present specification, abbreviated as RORγt), and a compound for use as a therapeutic drug such as cognac or the like Permissible salt.

Although many autoimmune diseases are thought to be unexplained, they have long been known to be deeply involved in T cell abnormalities in many diseases. In particular, the association of high-producing IFN-γ-producing T cells (Th1 cells) has been reported since a long time ago, but the abnormality of Th1 cells also fails to fully explain the problem of the pathogenesis of the disease, but with Th1 cells. There are doubts about the conclusions. In 2006, the presence of IL-17-producing helper T cells (Th17 cells) was reported, and the promotion of autoimmune diseases was deeply related to the abnormalities of Th17 cells. Since then, studies related to Th17 cells have been vigorously carried out, and the relevance of some autoimmune diseases has become apparent, and the importance of Th17 cells has become noticeable. During the process of differentiation of Th17 cells from naive T cells and the production of IL-17 by Th17 cells, RORγt of nuclear receptors functions. In the initial T cells of RORγt knockout mice, the differentiation to Th17 cells was inhibited, IL-17 production was inhibited, and the pathology of multiple sclerosis was obtained. The result of suppression of the onset of experimental autoimmune encephalomyelitis (Non-Patent Document 1). In other pathological models, there is also a report that RORγt plays an important role in the differentiation into Th17 cells, the production of IL-17, and pathological symptoms (Non-Patent Document 2-3). From such knowledge, it is considered that a substance that inhibits the transcriptional activity of RORγt, that is, a RORγt inhibitor, may be a therapeutic drug such as an autoimmune disease.

Since the cause of the autoimmune disease has not been known so far, an immunosuppressive agent that suppresses overall immunity is used in the treatment method. However, in this treatment, the effect of the cause of the autoimmune disease itself is not expected, because it is merely a symptomatic treatment method, and it is not considered that there is sufficient therapeutic effect, or that there is more recurrence without achieving remission. Therefore, in order to achieve a sufficient therapeutic effect and to achieve remission, a treatment suitable for the cause of autoimmune diseases is necessary. Recently, as a cause of some autoimmune diseases, an abnormality in IL-17 production of hyperthyroidal Th17 cells has been confirmed. However, at present, a new method for improving the abnormality of Th17 cells has been considered as a method for treating abnormalities of Th17 cells, which is considered to be necessary.

Prior technical literature Non-patent literature

Non-Patent Document 1 Cell, 126, 1121-1133 (2006)

Non-Patent Document 2 The Journal of Clinical Investigation, 122, 2252-2256 (2012)

Non-Patent Document 3 Arthritis and Rheumatology, 66, 579-588 (2014)

[Summary of the Invention]

As a result of intensive studies on a compound having a RORγt inhibitory effect, the present inventors have found that a carboxylic acid compound having a specific chemical structure is selective and excellent in suppressing the differentiation of Th17 cells and inhibiting IL-17 production. It is useful for the prevention and treatment of diseases related to RORγt such as immune diseases. The present inventors have found that this carboxylic acid compound is useful as a dry sputum, dry arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease (Crohn's disease) or ulcerative Colitis, etc., Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type I diabetes, graft-versus-host disease (graft-versus-host disease, GvHD), alopecia areata, leukoplakia, Kawasaki disease, Behcet's disease, spheroid nephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease Medicine for the treatment and/or prevention of colorectal cancer associated with autoimmune diseases such as scleroderma, giant cell arteritis, contact dermatitis, optic neuritis, or IL-17 The active ingredient. The present invention has been completed based on the above knowledge.

The present invention is as follows.

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

Wherein R ¹ represents a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group or a phenyl group, and R ² represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkane Oxy group, R ³ represents a hydrogen atom, a C ₂ -C ₇ carboxyalkyl group or a hydroxyl group, R ⁴ represents a halogen atom or a C ₁ -C ₆ alkyl group, and R ⁵ represents a hydrogen atom or a C ₁ -C ₆ alkyl group, R ⁶ And a hydrogen atom, a halogen atom or a C ₁ -C ₆ alkyl group, and R ⁷ represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, a C ₁ -C ₆ hydroxyalkyl group, C ₁ -C ₆ cyanoalkyl, benzyloxy C ₁ -C ₆ alkyl or (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkane) group, R ⁸ represents a hydroxyl group, C ₁ -C ₆ Alkoxy, mono-C ₁ -C ₆ alkylamino or di-(C ₁ -C ₆ alkyl)amine, L represents a single bond, methylene or oxygen atom, and E represents independently 1 or 2 substituted phenyl groups selected from a halogen atom, a C ₁ -C ₆ alkyl group and a C ₁ -C ₆ alkylsulfonyl group; or may be selected from a halogen atom, a C ₁ -C ₆ alkyl group And a C ₁ -C ₆ alkylsulfonyl group-substituted pyridylene group, a thienylene group or a thiazolylene group, and Q ¹ represents a nitrogen atom or a formula represented by CH=CH- Base, Q ² represents a nitrogen atom or formula = The group represented by CH-, the group represented by the formula -UT- represents a group represented by the formula -CH ₂ -CH ₂ - or a group represented by the formula -CH=CH-, and Y represents a methylene group or an oxygen atom. V represents a nitrogen atom or a group represented by the formula = C(R ⁹ )-, and R ⁹ represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a C ₂ -C ₆ alkenyl group, C _1- C ₆ alkoxy, C ₁ -C ₆ halogenated alkoxy, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkylene) group, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkoxy), C ₂ -C ₇ alkylcarbonyl, tetrahydrofuranyl or oxetyloxy].

In the present invention, the following are exemplified as appropriate.

(2) A compound of (1), wherein R ¹ is C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, or a pharmaceutically acceptable salt thereof.

(3) (1) The compound or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl, ethyl or cyclopropyl.

(4) A compound according to any one of (1) to (3), wherein R ² is a hydrogen atom or a C ₁ -C ₆ alkyl group, or a pharmaceutically acceptable salt thereof.

(5) A compound according to any one of (1) to (3), wherein R ² is a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof.

(6) A compound according to any one of (1) to (5), wherein R ³ is a hydrogen atom, or a pharmaceutically acceptable salt thereof.

(7) A compound according to any one of (1) to (6), wherein R ⁴ is a C ₁ -C ₆ alkyl group, or a pharmaceutically acceptable salt thereof.

(8) A compound according to any one of (1) to (6), wherein R ⁴ is a methyl group, or a pharmaceutically acceptable salt thereof.

(9) A compound according to any one of (1) to (8), wherein R ⁵ is a hydrogen atom or a C ₁ -C ₆ alkyl group, or a pharmaceutically acceptable salt thereof.

(10) A compound according to any one of (1) to (8), wherein R ⁵ is a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof.

(11) A compound according to any one of (1) to (10), wherein R ⁶ is a hydrogen atom, a fluorine atom or a methyl group, or a pharmaceutically acceptable salt thereof.

(12) A compound according to any one of (1) to (10), wherein R ⁶ is a hydrogen atom, or a pharmaceutically acceptable salt thereof.

(13) A compound of any one of (1) to (12), wherein R ⁷ is a hydrogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ halogenated alkane, or a pharmaceutically acceptable salt thereof base.

(14) A compound according to any one of (1) to (12), wherein R ⁷ is a hydrogen atom or a C ₁ -C ₆ alkyl group, or a pharmaceutically acceptable salt thereof.

(15) A compound, or a pharmaceutically acceptable salt thereof, according to any one of (1) to (12), wherein R ⁷ is a hydrogen atom, a methyl group, an ethyl group, a propyl group or a 3,3,3- Trifluoropropyl.

(16) A compound according to any one of (1) to (12), wherein R ⁷ is a hydrogen atom or an ethyl group, or a pharmaceutically acceptable salt thereof.

(17) A compound according to any one of (1) to (16), wherein R ⁸ is a hydroxyl group, or a pharmaceutically acceptable salt thereof.

(18) A compound according to any one of (1) to (17), or a pharmaceutically acceptable salt thereof, wherein L is a single bond.

(19) A compound, or a pharmaceutically acceptable salt thereof, according to any one of (1) to (18), wherein E is independently 1 or 2 selected from a halogen atom, a C ₁ -C ₆ alkane And a C ₁ -C ₆ alkylsulfonyl group-substituted phenyl group, or an unsubstituted pyridine group, a thienyl group or a thiazolyl group.

(20) A compound, or a pharmaceutically acceptable salt thereof, according to any one of (1) to (18), wherein E is independently 1 or 2 selected from a halogen atom and a C ₁ -C ₆ alkane a base-substituted phenyl or unsubstituted thiazolyl group.

(21) A compound, or a pharmaceutically acceptable salt thereof, according to any one of (1) to (18), wherein E is independently one or two selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, and a methyl-substituted 1,4-phenylene group; or an unsubstituted extended pyridyl group, a thienyl group or a thiazolyl group.

(22) A compound of any one of (1) to (18) or a pharmaceutically acceptable salt thereof, wherein E is a 1,4-phenylene group, a group represented by the formula (II-I), a group represented by the formula (II-II) or a group represented by the formula (III) (wherein, C _L and C _V represent a single bond, and C _{L is} bonded to a group represented by the formula -L-, C _V and 6 members Ring combination).

(23) A compound according to any one of (1) to (22), wherein Q ¹ is a group represented by the formula: CH-, and Q ² is a nitrogen atom, or a pharmaceutically acceptable salt thereof.

(24) A compound, or a pharmaceutically acceptable salt thereof, according to any one of (1) to (22), wherein Q ¹ is a group represented by the formula: CH-, and Q ² is represented by the formula =CH- Base.

(25) A compound of any one of (1) to (24) or a pharmaceutically acceptable salt thereof, wherein the group represented by the formula -UT- is a group represented by the formula -CH ₂ -CH ₂ - .

(26) A compound according to any one of (1) to (25) or a pharmaceutically acceptable salt thereof, wherein Y is an oxygen atom.

(27) A compound according to any one of (1) to (26) or a pharmaceutically acceptable salt thereof, wherein V is a group represented by the formula: C(R ⁹ )-.

(28) A compound, or a pharmaceutically acceptable salt thereof, according to any one of (1) to (27), wherein R ⁹ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ halogenated alkoxy, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkylene) group, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkoxy) or C ₂ -C ₇ alkylcarbonyl.

(29) A compound according to any one of (1) to (27), wherein R ⁹ is a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group, or a pharmaceutically acceptable salt thereof.

(30) A compound according to any one of (1) to (27), wherein R ⁹ is a methyl group or a methoxy group, or a pharmaceutically acceptable salt thereof.

(31) A compound of (1), wherein R ¹ is C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, and R ² is a hydrogen atom or C ₁ -C ₆ , or a pharmaceutically acceptable salt thereof An alkyl group, R ³ is a hydrogen atom, R ⁴ is a C ₁ -C ₆ alkyl group, R ⁵ is a hydrogen atom or a C ₁ -C ₆ alkyl group, R ⁶ is a hydrogen atom, a fluorine atom or a methyl group, and R ⁷ is hydrogen. An atom or a C ₁ -C ₆ alkyl group, R ⁸ is a hydroxyl group, L is a single bond, and E is a phenyl group which may be independently substituted by 1 or 2 groups selected from a halogen atom and a C ₁ -C ₆ alkyl group. An unsubstituted thiazolyl group, Q ¹ is a group represented by the formula =CH-, Q ² is a nitrogen atom or a group represented by the formula =CH-, and the group represented by the formula -UT- is a formula -CH ₂ -CH ₂ a group represented by the formula, wherein Y is an oxygen atom, V is a group represented by the formula: C(R ⁹ )-, and R ⁹ is a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group.

(32) A compound of (1), wherein R ¹ is methyl, ethyl or cyclopropyl; R ² is a hydrogen atom or a methyl group; R ³ is a hydrogen atom; R ⁴ is a compound of (1) or a pharmaceutically acceptable salt thereof; Methyl; R ⁵ is a hydrogen atom or a methyl group; R ⁶ is a hydrogen atom; R ⁷ is a hydrogen atom, a methyl group, an ethyl group, a propyl group or a 3,3,3-trifluoropropyl group; and R ⁸ is a hydroxyl group; Is a single bond; E is a 1,4-phenylene group which may be independently substituted with 1 or 2 groups selected from a fluorine atom, a chlorine atom, a methyl group and a methylsulfonyl group, or an unsubstituted dipyridyl group, a thienyl group or a thiazolyl group; Q ¹ is a group represented by the formula =CH-; Q ² is a nitrogen atom or a group represented by the formula =CH-; and the group represented by the formula -UT- is a formula -CH ₂ -CH ₂ - a group represented by Y; Y is an oxygen atom; V is a group represented by the formula = C(R ⁹ )-; and R ⁹ is a methyl group or a methoxy group.

(33) A compound according to (1), wherein R ¹ is a methyl group, an ethyl group or a cyclopropyl group, R ² is a hydrogen atom or a methyl group, R ³ is a hydrogen atom, and R ⁴ is a compound or a pharmaceutically acceptable salt thereof. Methyl, R ⁵ is a hydrogen atom or a methyl group, R ⁶ is a hydrogen atom, R ⁷ is a hydrogen atom or an ethyl group, R ⁸ is a hydroxyl group, L is a single bond, E is a 1,4-phenylene group, and the formula (II) a group represented by -I), a group represented by the formula (II-II) or a group represented by the formula (III), Q ¹ is a group represented by the formula =CH-, and Q ² is a nitrogen atom or a formula =CH- The group represented by the formula -UT- represents a group represented by the formula -CH ₂ -CH ₂ -, Y is an oxygen atom, V is a group represented by the formula =C(R ⁹ )-, and R ⁹ is Methyl or methoxy.

(34) A compound or a pharmaceutically acceptable salt thereof, wherein the compound is {2'-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl) Ethyl hydrazino}-2,3-dihydro-1H-indol-5-yl)oxy]biphenyl-4-yl}acetic acid, {4'-[(1-{[2-(ethyl) Sulfhydryl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl} Acetic acid, {4'-[(1-{[2-(cyclopropylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) )oxy]-2'-methylbiphenyl-4-yl}acetic acid, {4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-) Base-2,3-dihydro-1H-indol-5-yl)oxy]-2',5'-dimethylbiphenyl-4-yl}acetic acid, {4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-2-fluoro-2'-methylbiphenyl-4-yl}acetic acid, {4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4- Methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2-fluoro-2'-methoxy-5'-methylbiphenyl-4-yl}acetic acid, { 4'-[(1-{[3-(ethylsulfonyl)pyridin-2-yl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-methylbiphenyl-4-yl}acetic acid, {4'-[(1-{[3-(ethylsulfonyl)-6-methylpyridin-2-yl]B Mercapto}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}acetic acid, {4'-[( 1-{[3-(ethylsulfonyl)pyridin-2-yl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2 ',5'-Dimethylbiphenyl-4-yl}acetic acid, {4'-[(1-{[3-(ethylsulfonyl)-6-methylpyridin-2-yl]acetamidine -4--methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2',5'-dimethylbiphenyl-4-yl}acetic acid, 2-{ 4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy] -2'-methylbiphenyl-4-yl}propionic acid, 2-{4'-[( 1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2-fluoro- 2'-methylbiphenyl-4-yl}pentanoic acid, 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-methylbiphenyl-4-yl}-5,5,5-trifluoropentanoic acid, 2-{4'-[(1-{[2-(ethylsulfonyl)) Phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2',5'-dimethylbiphenyl-4-yl} Butyric acid, 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-2'-methylbiphenyl-4-yl}butyric acid, (2R)-2-{4'-[(1-{[2-(ethylsulfonyl)phenyl) Ethyl ketone}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}butyric acid, (2S) -2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl Oxy]-2'-methylbiphenyl-4-yl}butyric acid, or (5-{4-[(1-{[2-(ethylsulfonyl)phenyl)ethenyl)} 4-Methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2-methylphenyl}-1,3-thiazol-2-yl)acetic acid.

(35) A compound of the compound of (34) or a pharmaceutically acceptable salt thereof.

(36){2'-Methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H- Indole-5-yl)oxy]biphenyl-4-yl}acetic acid, or a pharmaceutically acceptable salt thereof.

(37) {4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-methylbiphenyl-4-yl}acetic acid, or a pharmaceutically acceptable salt thereof.

(38){4'-[(1-{[2-(Cyclopropylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5- Alkyloxy]-2'-methylbiphenyl-4-yl}acetic acid, or a pharmaceutically acceptable salt thereof.

(39){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2-fluoro-2'-methylbiphenyl-4-yl}acetic acid, or a pharmaceutically acceptable salt thereof.

(40) {4'-[(1-{[3-(ethylsulfonyl)pyridin-2-yl]ethenyl}-4-methyl-2,3-dihydro-1H-indole- 5-yl)oxy]-2',5'-dimethylbiphenyl-4-yl}acetic acid, or a pharmaceutically acceptable salt thereof.

(41) {4'-[(1-{[3-(ethylsulfonyl)-6-methylpyridin-2-yl]ethenyl}-4-methyl-2,3-dihydro- 1H-Indol-5-yl)oxy]-2',5'-dimethylbiphenyl-4-yl}acetic acid, or a pharmaceutically acceptable salt thereof.

(42) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-2'-methylbiphenyl-4-yl}butyric acid, or a pharmaceutically acceptable salt thereof.

(43)(2R)-2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H- Indole-5-yl)oxy]-2'-methylbiphenyl-4-yl}butyric acid, or a pharmaceutically acceptable salt thereof.

(44) (2S)-2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H- Indole-5-yl)oxy]-2'-methylbiphenyl-4-yl}butyric acid, or a pharmaceutically acceptable salt thereof.

(45) A pharmaceutical composition comprising the compound according to any one of (1) to (44) or a pharmaceutically acceptable salt thereof as an active ingredient.

(46) The pharmaceutical composition according to (45), wherein the pharmaceutical composition has a spectroscopy-related orphan receptor γt inhibitory action.

(47) The pharmaceutical composition according to (45), wherein the pharmaceutical composition is for the treatment and/or prevention of a disease which is treated and/or prevented by the retinoic acid receptor-related orphan receptor γt inhibitory action.

(48) The pharmaceutical composition according to (45), wherein the pharmaceutical composition is used for the treatment, improvement, alleviation and/or prevention of symptoms by inhibition of Th17 cell differentiation and/or inhibition of IL-17 production. Treatment and/or prevention of diseases.

(49) The pharmaceutical composition according to (45), wherein the pharmaceutical composition is used for dryness, dryness arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, repair Lian's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type I diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Behcet's disease , spheroid nephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer treatment and / or prevention.

(50) The pharmaceutical composition according to (45), wherein the pharmaceutical composition is used for dryness, dryness arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, repair Treatment and/or prevention of schizophrenia or chronic obstructive pulmonary disease.

(51) The pharmaceutical composition according to (45), wherein the pharmaceutical composition is for the treatment and/or prevention of dryness or dryness arthritis.

(52) The pharmaceutical composition according to (49) or (50), wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

(53) A retinoid receptor-related orphan receptor γt inhibitor comprising the compound according to any one of (1) to (44) or a pharmaceutically acceptable salt thereof as an active ingredient.

(54) A use of the compound according to any one of (1) to (44), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a pharmaceutical composition.

(55) The use according to (54), wherein the pharmaceutical composition is a composition for inhibiting a reticulum receptor related orphan receptor γt.

(56) The use according to (54), wherein the pharmaceutical composition is dryness, dryness arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Shering's syndrome, Systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type I diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Behcet's disease, spheroid nephritis A composition for the treatment and/or prevention of cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer.

(57) The use according to (54), wherein the pharmaceutical composition is cognac, dryness arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, sedative syndrome or A composition for the treatment and/or prevention of chronic obstructive pulmonary disease.

(58) The use according to (54), wherein the pharmaceutical composition is a composition for the treatment and/or prevention of dryness or dryness arthritis.

(59) The use of (56) or (57), wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

(60) A compound according to any one of (1) to (44) or a pharmaceutically acceptable salt thereof, which is for use in the treatment of retinoic acid receptor-dependent orphan receptor γt inhibition And/or use in a method of treating and/or preventing a disease.

(61) A compound according to any one of (1) to (44), or a pharmaceutically acceptable salt thereof, which is used for dryness, dryness, arthritis, ankylosing spondylitis, multiple sclerosis, Rheumatoid arthritis, inflammatory bowel disease, Shering's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type I diabetes, graft-versus-host disease (GvHD) , alopecia areata, leukoplakia, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer Use in methods of treatment and/or prevention.

(62) A compound according to any one of (1) to (44), or a pharmaceutically acceptable salt thereof, which is used for dryness, dryness, arthritis, ankylosing spondylitis, multiple sclerosis, Use in methods of treatment and/or prevention of rheumatoid arthritis, inflammatory bowel disease, repair syndrome or chronic obstructive pulmonary disease.

(63) A compound according to any one of (1) to (44), or a pharmaceutically acceptable salt thereof, for use in a method of treatment and/or prevention of dryness or dryness arthritis .

(64) The compound of (61) or (62) or a pharmaceutically acceptable salt thereof, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

(65) A method for inhibiting retinoic acid receptor-related orphan receptor γt, which comprises administering a pharmacologically effective amount of a compound according to any one of (1) to (44) or a pharmaceutically acceptable salt thereof To warm-blooded animals.

(66) A method for the treatment and/or prevention of a disease, which comprises administering a pharmacologically effective amount of a compound according to any one of (1) to (44) or a pharmaceutically acceptable salt thereof to a warm blood. animal.

(67) The method according to (66), wherein the disease is dryness, dryness arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Shering's syndrome, systemic Lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type I diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Behcet's disease, spheroid nephritis, myocardium Disease, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer.

(68) The method according to (66), wherein the disease is dryness, dryness arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, sedative syndrome or chronic obstruction Sexual lung disease.

(69) The method according to (66), wherein the disease is dry or dry arthritis.

(70) The method according to (67) or (68), wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

(71) The method according to any one of (65) to (70) wherein the warm-blooded animal is a human.

In the present invention, the "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Suitable as a fluorine atom or a chlorine atom, more suitable as a fluorine atom.

In the present invention, the "C ₁ -C ₆ alkyl group" is a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-Dimethylbutyl, 1,1-dimethylbutyl or 1,2-dimethylbutyl. It is suitably a linear or branched alkyl group (C ₁ -C ₃ alkyl) having _{1 to 3} carbon atoms, more preferably a methyl group or an ethyl group (C ₁ -C ₂ alkyl group).

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

In the present invention, the "C ₁ -C ₆ halogenated alkyl group" is a group in which one or five of the above-mentioned "halogen atoms" which are the same or different are bonded to the above-mentioned "C ₁ -C ₆ alkyl group". For example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro Propyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl or 2-fluoroethyl. Suitable for the same or different 1 to 5 "halogen atom" and "C ₁ -C ₃ alkyl" group (C ₁ -C ₃ halogenated alkyl), more suitable for 3,3,3-three Fluoropropyl.

In the present invention, the "C ₂ -C ₇ carboxyalkyl group" is a group in which one of the carboxyl groups is bonded to the above-mentioned "C ₁ -C ₆ alkyl group". For example, carboxymethyl, 2-carboxyethyl, 1-carboxyethyl or 3-carboxypropyl. A group suitable for bonding one carboxyl group to "C ₁ -C ₂ alkyl group" is more preferably a carboxymethyl group.

In the present invention, "C ₁ -C ₆ hydroxyalkyl group" is a group in which one of the hydroxyl groups is bonded to the above-mentioned "C ₁ -C ₆ alkyl group". For example, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl or 3-hydroxypropyl. It is preferably a group in which one hydroxyl group is bonded to "C ₁ -C ₂ alkyl group", and more preferably a 2-hydroxyethyl group.

In the present invention, the "C ₁ -C ₆ cyanoalkyl group" is a group in which one cyano group is bonded to the above-mentioned "C ₁ -C ₆ alkyl group". For example, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl or 3-cyanopropyl. It is suitable as a group in which one cyano group is bonded to "C ₁ -C ₂ alkyl group", and is more suitably a cyanomethyl group or a 2-cyanoethyl group.

In the present invention, "benzyloxy C ₁ -C ₆ alkyl group" is a group in which one benzyloxy group is bonded to the above-mentioned "C ₁ -C ₆ alkyl group". For example, benzyloxymethyl, 2-benzyloxyethyl, 1-benzyloxyethyl or 3-benzyloxypropyl. It is preferably a group in which one benzyloxy group is bonded to "C ₁ -C ₂ alkyl group", and more preferably a 2-benzyloxyethyl group.

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

In the present invention, "(C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkane) group" is one of the above-mentioned "C ₁ -C ₆ alkoxy group" and the aforementioned "C ₁ -C ₆ alkyl group" The basis of the combination. For example, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethyl, t-butoxymethyl, 2- Methoxyethyl, 2-ethoxyethyl, 2-butoxyethyl, 1-butoxyethyl, 1-isobutoxyethyl or 3-isopropoxypropyl, suitable for a group ((C ₁ -C ₄ alkoxy)-(C ₁ -C ₃ alkane) group) in which the above-mentioned "C ₁ -C ₄ alkoxy group" is bonded to the above-mentioned "C ₁ -C ₃ alkyl group", More preferably, one of the above-mentioned "C ₁ -C ₂ alkoxy groups" is bonded to the above-mentioned "C ₁ -C ₂ alkyl group" ((C ₁ -C ₂ alkoxy)-(C ₁ -C ₂ alkane) Further, it is more suitably a methoxymethyl group or a 2-methoxyethyl group.

In the present invention, the "C ₂ -C ₆ alkenyl group" is a group having 2 to 6 carbon atoms having one double bond among the above-mentioned "C ₁ -C ₆ alkyl groups". For example, vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 1-butenyl or 5-hexenyl Suitable as an alkenyl group (C ₂ -C ₄ alkenyl group) having 2 to 4 carbon atoms, more preferably isopropenyl group.

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

In the present invention, "(C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkoxy) group" is one of the aforementioned "C ₁ -C ₆ alkoxy groups" and the aforementioned "C ₁ -C ₆ alkane" An oxy" bonded group. For example, methoxymethoxy, ethoxymethoxy, propoxymethoxy, isopropoxymethoxy, butoxymethoxy, t-butoxymethoxy, 2-methyl An oxyethoxy group, a 2-ethoxyethoxy group, a 2-butoxyethoxy group or a 3-isopropoxypropoxy group, suitably one of the aforementioned "C ₁ -C ₄ alkoxy groups" The group ((C ₁ -C ₄ alkoxy)-(C ₁ -C ₄ alkoxy) group) bonded to the above-mentioned "C ₁ -C ₄ alkoxy group" is more preferably one of the aforementioned "C ₁ -C" _{a 2 (} alkoxy group) group bonded to the above-mentioned "C ₁ -C ₂ alkoxy group" ((C ₁ -C ₂ alkoxy)-(C ₁ -C ₂ alkoxy) group), further more suitable as a methoxy group Methoxy.

In the present invention, the "C ₂ -C ₇ alkylcarbonyl group" is a group in which the above-mentioned "C ₁ -C ₆ alkyl group" is bonded to a carbonyl group. For example, ethyl, propyl, butyl, isobutyl, pentylene, trimethylethyl or valeryl. Suitable as a group in which a "C ₁ -C ₄ alkyl group" is bonded to a carbonyl group (C ₂ -C ₅ alkylcarbonyl group), more preferably an ethyl hydrazino group or a propyl fluorenyl group (C ₂ -C ₃ alkylcarbonyl group) Further suitable for ethyl ketone.

In the present invention, the "mono-C ₁ -C ₆ alkylamino group" is an amine group having one of the above-mentioned "C ₁ -C ₆ alkyl groups". For example, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group or a butylamino group. It is suitable for an amine group having a "C ₁ -C ₄ alkyl group" (mono-C ₁ -C ₄ alkylamino group), more preferably a methylamino group or an ethylamino group (mono-C ₁ -C ₂ alkylamino group), further more suitable as methylamino group.

In the present invention, the "di-(C ₁ -C ₆ alkyl)amino group" is an amine group having the same or different "C ₁ -C ₆ alkyl group" bonded thereto. For example, dimethylamino, diethylamino, dipropylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino or N-butyl-N - Methylamino group. Suitable as an amine group (di-(C ₁ -C ₄ alkyl)amino group) having the same or different "C ₁ -C ₄ alkyl group", more suitable for dimethylamino group, two Ethylamino or N-ethyl-N-methylamino (di-(C ₁ -C ₂ alkyl)amino) is further more preferably a dimethylamino group.

In the present invention, the "C ₁ -C ₆ alkylsulfonyl group" is a group in which the above-mentioned "C ₁ -C ₆ alkyl group" is bonded to a sulfonyl group. For example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl or hexylsulfonyl. Suitable for linear or branched alkylsulfonyl (C ₁ -C ₄ alkylsulfonyl) having _{1 to 4} carbon atoms, more preferably methylsulfonyl or ethylsulfonyl (C ₁ -C ₂ alkylsulfonyl), further more suitable as methylsulfonyl.

In the present invention, "tetrahydrofuranyl" is suitably a 3-tetrahydrofuranyl group.

In the present invention, "oxycarbonyloxy group" is suitably a 3-oxomethoxy group.

In the present invention, "phenylene" is a divalent group capable of removing two hydrogen atoms from benzene, and is a 1,2-phenylene group, a 1,3-phenylene group or a 1,4-phenylene group. Suitable for 1,4-phenylene.

In the present invention, the "pyridyl group" is a divalent group which can remove one hydrogen atom from each of two carbon atoms of a pyridyl group. Suitable as 2,4-extended pyridyl or 2,5-extended pyridyl.

In the present invention, the "threothiophene group" is a divalent group which can remove one hydrogen atom from each of two different carbon atoms of the thienyl group. Suitable as 2,5-thenylene.

In the present invention, the "thiazole group" is a divalent group which can remove one hydrogen atom from each of two different carbon atoms of the thiazolyl group. Suitable as 2,5-thiazole.

In the present invention, "a phenyl group which may be independently substituted with 1 or 2 groups selected from a halogen atom, a C ₁ -C ₆ alkyl group and a C ₁ -C ₆ alkylsulfonyl group" is a phenyl group or an independent group. A phenyl group substituted by 1 or 2 groups selected from a halogen atom, a C ₁ -C ₆ alkyl group and a C ₁ -C ₆ alkylsulfonyl group. Suitable as a phenyl group which may be independently substituted by 1 or 2 groups selected from a halogen atom and a C ₁ -C ₆ alkyl group, more preferably one or two independently selected from a fluorine atom, a chlorine atom, and a a group-substituted 1,4-phenylene group having a methylsulfonyl group, further more preferably a 1,4-phenylene group, a group represented by the formula (II-I) or a formula (II-II) Base.

In the present invention, "extension of pyridyl group, thienyl group or thiazolyl group which may be substituted with a group selected from a halogen atom, a C ₁ -C ₆ alkyl group and a C ₁ -C ₆ alkylsulfonyl group" a pyridyl group, a thienyl group, a thiazolyl group or a pyridyl group, a thienyl group or a group substituted with a group selected from a halogen atom, a C ₁ -C ₆ alkyl group and a C ₁ -C ₆ alkylsulfonyl group Thiazolyl. Suitable for 2,4-extended pyridyl, 2,5-extended pyridyl, 2,5-threthiophenyl or 2,5-thiazolyl, more suitable as thiazolyl, further suitable for formula (III) The base of the representation.

In the present invention, a suitable R ¹ is a C ₁ -C ₆ alkyl group or a C ₃ -C ₆ cycloalkyl group, and a more suitable R ¹ is a methyl group, an ethyl group or a cyclopropyl group.

In the present invention, a suitable R ² is a hydrogen atom or a C ₁ -C ₆ alkyl group, and more preferably R ² is a hydrogen atom or a methyl group.

In the present invention, a suitable R ³ is a hydrogen atom.

In the present invention, a suitable R ⁴ is a C ₁ -C ₆ alkyl group, and a more suitable R ⁴ is a methyl group.

In the present invention, a suitable R ⁵ is a hydrogen atom or a C ₁ - C ₆ alkyl group, and more preferably R ⁵ is a hydrogen atom or a methyl group.

In the present invention, a suitable R ⁶ is a hydrogen atom, a fluorine atom or a methyl group, and more preferably R ⁶ is a hydrogen atom.

In the present invention, a suitable R ⁷ is a hydrogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ halogenated alkyl group, and more preferably R ⁷ is a hydrogen atom or a C ₁ -C ₆ alkyl group, further suitable R ⁷ is a hydrogen atom, a methyl group, an ethyl group, a propyl group or a 3,3,3-trifluoropropyl group, and particularly preferably R ⁷ is a hydrogen atom or an ethyl group.

In the present invention, a suitable R ⁸ is a hydroxyl group.

In the present invention, a suitable L is a single bond.

In the present invention, a suitable E is a phenyl group which may be independently substituted with 1 or 2 groups selected from a halogen atom, a C ₁ -C ₆ alkyl group and a C ₁ -C ₆ alkylsulfonyl group, or an unsubstituted group. More preferably, E is a phenyl or unsubstituted extension which may be independently substituted with 1 or 2 groups selected from a halogen atom and a C ₁ -C ₆ alkyl group. Thiazolyl. Further more suitable E is a 1,4-phenylene group or an unsubstituted dipyridyl group which may be independently substituted with 1 or 2 groups selected from a fluorine atom, a chlorine atom, a methyl group and a methylsulfonyl group. Particularly preferred is E, which is a 1,4-phenylene group, a group represented by the formula (II-I), a group represented by the formula (II-II) or a formula represented by the formula (III). base.

In the present invention, a suitable Q ¹ is a group represented by the formula =CH-.

In the present invention, any one of Q ² being a nitrogen atom or a group represented by the formula =CH- is suitable.

In the present invention, a suitable group represented by the formula -UT- is a group represented by the formula -CH ₂ -CH ₂ -.

In the present invention, a suitable Y is an oxygen atom.

In the present invention, a suitable V is a group represented by the formula = C(R ⁹ )-.

In the present invention, a suitable R ⁹ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ halogenated alkoxy, (C ₁ -C ₆ Alkoxy)-(C ₁ -C ₆ alkane) group, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkoxy) group or C ₂ -C ₇ alkylcarbonyl group, more suitable R ⁹ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, still more suitable R ⁹ is methyl or methoxy.

The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof contains all the isomers (keto-enol isomer, diastereoisomer, optical isomer, rotation) Rotational isomer, etc.).

The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof has various isomers due to the presence of an asymmetric carbon atom in its molecule. With respect to the compounds of the present invention, such isomers and mixtures of such isomers are all represented in a single formula, i.e., in formula (I). Accordingly, the present invention is intended to include a mixture of such isomers and any ratios of such isomers.

As the stereoisomers described above, the compounds related to the present invention can be synthesized using optically active starting compounds, or by asymmetric synthesis or asymmetric induction, or by synthesis of compounds related to the present invention as desired. It can be obtained by performing isolation by a usual optical resolution method or separation method.

The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may contain an unnatural ratio of an atomic isotope in one or more of the atoms constituting the compound. Examples of the atomic isotope include ruthenium ( ² H), ruthenium ( ³ H), iodine-125 ( ¹²⁵ I) or carbon-14 ( ¹⁴ C). In addition, the compound is for example, may be tritium ⁽³ H), iodine -125 ⁽¹²⁵ I) or carbon -14 ⁽¹⁴ C) and other radioactive isotopes are radioactive identified. The radiolabeled compound is useful as a therapeutic or prophylactic agent, a research reagent, for example, an analytical reagent, and a diagnostic agent, for example, an in vivo imaging diagnostic agent. All isotopic variations of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

The "pharmaceutically acceptable salt" means a salt which is not highly toxic and can be used as a medicine. When the compound represented by the formula (I) of the present invention has a basic group, it can be used as a salt by reacting it with an acid, and in the case of having an acidic group, it can be formed into a salt by reacting it with a base.

Examples of the basic group-based salt include a hydrogen halide such as a hydrogen fluoride salt, a hydrochloride, a hydrogen bromide or a hydrogen iodide; a nitrate, a perchlorate, and a sulfuric acid; Inorganic acid salts of salts, phosphates, etc.; C ₁ -C ₆ alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; besylate, p-toluene Aryl sulfonates such as acid salts; acetates, malates, fumarates, succinates, citrates, ascorbates, tartrates, oxalates, maleates, etc. An organic acid salt; and an amine acid salt such as a glycinate, an amidate, a arginine, an alanate, a glutamate or an aspartate.

On the other hand, as the acid group-based salt, for example, an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; such as an aluminum salt or an iron salt; a metal salt; an inorganic salt such as an ammonium salt; such as t-butylamine salt, diisopropylamine salt, t-octylamine salt, dibenzylamine salt, a porphyrin salt, a glucosamine salt, an alkyl phenylglycine salt, an ethylenediamine salt, an N-methylglucamine salt, a phosphonium salt, a diethylamine salt, Triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine, procaine salt, diethanolamine salt, N-benzylbenzene Ethylamine salt, piperazine An amine salt of a salt, a tetramethylammonium salt, an organic salt of a hydroxymethylaminomethane salt; and an amine salt such as a glycinate, an amide salt, an arginine salt, an alanine salt, or a glutamine An acid salt of an acid salt or aspartate.

The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, which is adsorbed in the air or recrystallized, adsorbs water and adsorbs to form a hydrate. A hydrate is also included in the salt of the present invention.

The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may be a solvent if it absorbs some other solvent, and such a solvent is also included in the salt of the present invention.

The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof has selective and excellent Th17 cell differentiation inhibitory action and IL-17 production inhibitory action, and has RORγt for autoimmune diseases and the like. The relevant disease or IL-17 produces treatment and/or prevention of cancer associated with pathological conditions. For specific diseases, dryness, dry arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease (Clone's disease or ulcerative colitis, etc.), Xiagelian Syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type I diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Behcet's disease, Spherical nephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer. In the case of a preferred disease, dryness, dryness arthritis, ankylosing spondylitis, Sjogren's syndrome or chronic obstructive pulmonary disease (COPD), especially dry or dry arthritis. Further, the compound represented by the formula (I) of the present invention or The pharmaceutically acceptable salt is expected to have an effect of selectively preventing and treating the abnormality of Th17 cells, which is impossible in the existing treatment.

In the present invention, the term "prevention" refers to a situation in which the risk of developing a disease which is diagnosed as a subject by a genetic background or chronic inflammation is high, and the onset of the disease is suppressed or delayed. It is known that in the case of an autoimmune disease, it is a disease which can diagnose a risk of onset by single nucleotide polymorphism (SNPs) or gene mutation. Further, it is known that in the case of colorectal cancer, colitis is chronically sustained, and the risk of colorectal cancer is remarkably improved. The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof is expected to be diagnosed by the pair because of its selective and excellent differentiation inhibitory action against Th17 cells and inhibition of IL-17 production. Patients with a high risk of developing such diseases are administered prophylactically to inhibit or delay the onset of the disease.

[Formation for implementing the invention]

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

The solvent to be used in the reaction of each of the following steps A to P is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, it may be selected from the following solvent groups. The solvent group comprises hydrocarbons such as pentane, hexane, octane, petroleum ether, ligroin, cyclohexane; formamide, N,N-dimethylformamide, N,N- Indoleamines such as dimethylacetamide, N-methyl-2-pyrrolidone, N-methyl-2-pyrrolidone, trimethylamine hexamethylphosphate; diethyl Ether, diisopropyl ether, tetrahydrofuran, 1,4-two An ether such as an alkane, 1,2-dimethoxyethane, diethylene glycol dimethyl ether or cyclopentyl methyl ether; methanol, ethanol, n-propanol, i-propanol, n- Alcohols such as butanol, 2-butanol, 2-methyl-1-propanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol, methyl cedar Anthraquinones such as dimethyl hydrazine; hydrazines such as cyclobutyl hydrazine; nitriles such as acetonitrile, propionitrile, butyronitrile, and isobutyronitrile; ethyl formate, ethyl acetate, and acetonitrile Esters such as ester, butyl acetate, diethyl carbonate; acetone, methyl ethyl ketone, 4-methyl-2-pentanone, methyl isobutyl ketone, isophorone, ring Ketones such as ketone; nitro compounds such as nitroethane and nitrobenzene; dichloromethane, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, chloroform, carbon tetrachloride Halogenated hydrocarbons such as aromatic hydrocarbons such as benzene, toluene and xylene; carboxylic acids such as acetic acid, formic acid, propionic acid, butyric acid and trifluoroacetic acid; N-methyl Porphyrin, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 2,6-lutidine (2, 6-lutidine), 4-pyrrolidylpyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methyl Pyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-two Azabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), amines such as piperidine; water; and these Mixed solvent.

The base used in the reaction of each of the following steps A to P is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate, lithium carbonate or cesium carbonate; sodium hydrogencarbonate, potassium hydrogencarbonate or hydrogencarbonate. Alkali metal hydrogencarbonates such as lithium; alkali metal acetates such as sodium acetate, potassium acetate, lithium acetate, cesium acetate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; Alkali metal hydroxides such as sodium, potassium hydroxide, barium hydroxide, lithium hydroxide; alkali metal phosphates such as sodium phosphate and potassium phosphate; sodium L-guanidinate, potassium L-proline An alkali metal salt such as an alkali metal such as sodium fluoride or potassium fluoride; a base such as sodium methoxide, sodium ethoxide, sodium butoxide or potassium t-butoxide; a metal alkoxide; an alkali metal trialkyl sulfoxide such as sodium trimethyl siloxide, potassium trimethyl decoxide or lithium trimethyl decoxide; N-methyl Porphyrin, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 2,6-lutidine, Colin Collidine, 4-pyrrolidylpyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quin Porphyrin, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] Organic bases such as octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); lithium diisopropylamide, six An alkali metal amide such as lithium hexamethyldisilazane or sodium hexamethyldisodium sulphate; or an amino acid such as lysine.

The condensing agent used in the reaction of each of the following steps A to P is, for example, diazoalkyl azodicarboxylate-triphenylphosphine such as diethyl azodicarboxylate-triphenylphosphine. ; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide salt a carbodiimide derivative such as an acid salt, N,N'-dicyclohexylcarbodiimide; 2-halo-1-lower alkylpyridine such as 2-chloro-1-methylpyridinium iodide Bismuth halides; diarylphosphoryl azide such as diphenylphosphoryl azide; phosphonium chloride such as diethyl phosphoryl chloride; N, Imidazole derivatives such as N'-carbodiimidazole;O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetraO-(7-azabenzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate), (1H-benzotriazol-1-yloxy)tripyrrolidine a benzotriazole derivative such as hexafluorophosphate; or 4-(4,6-dimethoxy-1,3,5-trichloride) -2-yl)-4-methyl Chlorination A guanidine derivative.

The reaction temperature varies depending on the solvent, the starting material, the reagent, and the like in the respective steps from the following A to P methods, and the reaction time varies depending on the solvent, the starting material, the reagent, the reaction temperature, and the like.

After the reaction of each step of the following methods A to P, after completion of the reaction, each compound of interest is taken from the reaction mixture according to a usual method. For example, the reaction mixture is appropriately neutralized, and after being removed by filtration in the presence of insoluble matter, an organic solvent which is not mixed with water and ethyl acetate is added, and the organic layer containing the objective compound is separated and washed with water or the like. After drying, it is dried with anhydrous magnesium sulfate, anhydrous sodium sulfate or the like, filtered, and then obtained by distilling off a solvent. The obtained target compound may be appropriately combined with a usual method, for example, by recrystallization, reprecipitation, and chromatography (for example, the following suitable combination is carried out to be eluted with a suitable dissolution agent: using tannin, alumina, magnesium - Silicone Florisil, SO3H-silica (Fuji Adsorption column chromatography of a carrier such as SILYSIA; using Sephadex LH-20 (manufactured by Pharmacia), Amberlite XAD-11 (manufactured by Rohm and Haas Co., Ltd.), Diaion HP-20 (manufactured by Mitsubishi Chemical Corporation) The method of using a synthetic adsorbent for the distribution of a carrier such as column chromatography; the method using ion exchange chromatography; the phase-phase ‧ reverse phase column chromatography using tannin or alkylated tantalum (suitable for high speed) The liquid chromatography)) and the like are usually combined in a usual manner in the separation and purification of an organic compound, and can be isolated and purified. The objective compound which is insoluble in the solvent can be purified by washing the obtained crude product as a solvent. Further, the objective compound of each step can be directly used in the next reaction without purification.

A method in the following reaction step to each of the Law of ^{P, R 1, R 2, R} 3, R 4, R 5, R 6, R 7, R 8, R 9, L, E, Q 1, Q 2 And V represents the same meaning as the foregoing. R ^3a and R ^7a or lines in addition to a carboxyl group represented by R ³ and hydroxy groups R ⁷ to be included in the protected hydroxy or, also expressed by other than protected carboxy group R ³ as defined and R ⁷ of the group of For the same base. R ^8b represents a C ₁ -C ₆ alkyl group. R ^8c represents a hydrogen atom or a C ₁ -C ₆ alkyl group. R ¹⁰ represents a C ₁ -C ₆ alkyl group or a benzyl group. X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ represent a halogen atom or a trifluoromethanesulfonyl group. V is a group represented by the formula: C(R ⁹ )-, and when R ⁶ and R ^{9 are} not simultaneously a hydrogen atom, X ¹ is a bromine atom or an iodine atom, and X ² is suitably a chlorine atom or a bromine atom. X ^{3 is} suitably a bromine atom or an iodine atom, and is more suitably an iodine atom. X ^{4 is} suitably a bromine atom, an iodine atom or a trifluoromethanesulfonyl group. Tf represents a trifluoromethanesulfonyl group.

In the method of the method A, the compound represented by the formula (I), wherein R ⁸ is a C ₁ -C ₆ alkoxy group, and the group represented by the formula -UT- is a group represented by the formula -CH ₂ -CH ₂ - A method of the compound represented by the formula (Ia).

A-I step

This step is a step of producing a salt of the compound represented by the general formula (V) by reacting a compound represented by the general formula (IV) with an acid in a solvent.

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

The acid used in this step is suitable for acetic acid or protic acid, more suitable for trifluoroacetic acid or hydrochloric acid 1,4-two Alkane solution. The salt of the compound represented by the formula (V) means a case where hydrochloric acid is used.

The reaction temperature in this step is usually -10 ° C to 50 ° C, suitably 0 ° C to 30 ° C.

The reaction time in this step is usually from 1 minute to 24 hours, and is suitably from 10 minutes to 6 hours.

A-II step

This step is carried out in the presence of a solvent, a condensing agent and a base, and the salt of the compound represented by the formula (V) is represented by the formula (VI) The step of producing a compound represented by the formula (VII) by reacting a compound or a salt thereof.

The salt of the compound represented by the formula (VI) used in this step is, for example, an alkali metal salt, an organic base salt or an ammonium salt, and is preferably a sodium salt.

The solvent used in this step is suitably a guanamine, an ether, a nitrile or a halogenated hydrocarbon, and more preferably N,N-dimethylformamide.

The condensing agent used in this step is suitably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide or chlorine. 4-(4,6-dimethoxy-1,3,5-three -2-yl)-4-methyl Porphyrin.

The base used in this step is suitable for organic bases, more suitable for N-methyl Or phenyl or diisopropylethylamine.

The reaction temperature in this step is usually from 0 ° C to 60 ° C, suitably from 10 ° C to 30 ° C.

The reaction time in this step is usually from 5 minutes to 48 hours, and is suitably from 1 hour to 24 hours.

Step A-III

This step is carried out by reacting a compound represented by the formula (VII) with a compound represented by the formula (VIII) in the presence of a solvent, a palladium catalyst and a base, and removing R ^3a and/or as desired. A step of producing a compound represented by the formula (Ia) by protecting a hydroxyl group and/or a carboxyl group in R ^7a .

The solvent used in this step is suitably an ether or an aromatic hydrocarbon, more preferably 1,2-dimethoxyethane or toluene.

The palladium catalyst used in this step is suitably palladium (triphenylphosphine) palladium (0), [1,1 ' -bis(diphenylphosphino)ferrocene]palladium (II) dichloride Chloromethane complex or XPhos-Pd-G2 (II).

The base used in this step is preferably an alkali metal carbonate or an alkali metal phosphate, and more preferably sodium carbonate, sodium carbonate aqueous solution, potassium phosphate or potassium phosphate aqueous solution.

The reaction temperature in this step is usually from room temperature to 200 ° C, suitably from 50 ° C to 120 ° C.

The reaction time in this step is usually from 5 minutes to 24 hours, and is suitably from 20 minutes to 15 hours.

This step can be carried out under microwave irradiation.

In the B method, a compound represented by the formula (I) wherein R ⁸ is a C ₁ -C ₆ alkoxy group, and a group represented by the formula -UT- is a group represented by the formula -CH ₂ -CH ₂ - A method of the compound represented by the formula (Ia).

B-I step

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

This step can be carried out in accordance with the method described in J. Org. Chem. 1995, 60, 7508.

B-II step

This step is carried out by reacting a compound represented by the formula (X) with a compound represented by the formula (XI) in the presence of a solvent, a palladium catalyst and a base, in the same manner as the A-III step of the method A. After the reaction, a compound represented by the formula (Ia) is produced by removing a protective group of a hydroxyl group and/or a carboxyl group in R ^3a and/or R ^7a as desired.

The C method produces a compound represented by the formula (I) wherein R ⁸ is a C ₁ -C ₆ alkoxy group, and the group represented by the formula -UT- is a group represented by the formula -CH ₂ -CH ₂ - A method of the compound represented by the formula (Ia).

C-I step

This step is carried out by reacting a compound represented by the formula (IV) with a compound represented by the formula (VIII) in the presence of a solvent, a palladium catalyst and a base, in the same manner as the A-III step of the method A. The step of producing the compound represented by the formula (XII) is carried out.

C-II step

This step is a step in which a compound represented by the formula (XII) is reacted with an acid in the same manner as in the A-I step of the method A to produce a salt of the compound represented by the formula (XIII). The salt of the compound represented by the formula (XIII) shows a case where hydrochloric acid is used as the acid.

C-III step

This step is carried out by reacting a salt of the compound represented by the formula (XIII) with a compound represented by the formula (VI) or a salt thereof in the presence of a base in the solvent, in the same manner as the A-II step of the method A. After the treatment, the compound represented by the formula (Ia) is produced by removing the protective group of the hydroxyl group and/or the carboxyl group in R ^3a and/or R ^7a as desired.

The compound represented by the formula (I) wherein the compound represented by the formula (I) is a compound represented by the formula (Ib) wherein R ⁸ is a hydroxyl group, and the group represented by the formula -UT- is a group represented by the formula -CH ₂ -CH ₂ - Methods.

D-I step

This step is a step of producing a compound represented by the formula (Ib) by reacting a compound represented by the formula (Ia) with a base in a solvent.

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

The base used in this step is suitably an alkali metal hydroxide, more preferably an aqueous solution of sodium hydroxide or sodium hydroxide.

The reaction temperature in this step is usually from 0 ° C to 80 ° C, suitably from 15 ° C to 45 ° C.

The reaction time in this step is usually from 5 minutes to 48 hours, and is suitably from 10 minutes to 24 hours.

Process E produces a compound represented by the formula (I) wherein R ⁸ is a mono-C ₁ -C ₆ alkylamino group or a di-(C ₁ -C ₆ alkyl)amino group, represented by the formula -UT- A method of the compound represented by the formula (Ic) wherein the group is represented by the formula -CH ₂ -CH ₂ -.

E-I step

This step is carried out in the same manner as in the A-II step of the A method, by reacting the compound represented by the formula (Ib) with the compound represented by the formula (XIV) in the presence of a solvent, a condensing agent and a base. And the step of producing the compound represented by the formula (Ic).

The F method is a method of producing a compound represented by the formula (Ie) wherein the group represented by the formula -U-T- is a group represented by the formula -CH=CH- in the compound represented by the formula (I).

F-I step

This step is a step of producing a compound represented by the formula (Ie) by reacting a compound represented by the formula (Id) with an oxidizing agent in a solvent.

The compound represented by the formula (Id) used in this step can be produced by the methods A to E.

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

The oxidizing agent used in this step is suitably 2,3-dichloro-5,6-dicyano-p-benzoquinone.

The reaction temperature in this step is room temperature to heating under reflux temperature, and the heating reflux temperature varies depending on the solvent. It is usually from 5 ° C to 150 ° C, suitably from 10 ° C to 70 ° C.

The reaction time in this step is usually from 30 minutes to 72 hours, and is suitably from 1 hour to 24 hours.

The G method is a method of producing a compound represented by the formula (XIX) wherein Y is a methylene group in the compound represented by the formula (IV) used in the A-I step of the A method and the C-I step of the C method.

G-I step

This step is a step of producing a compound represented by the formula (XVI) by reacting a compound represented by the formula (XV) with a trifluoromethanesulfonyl amide in the presence of a base in a solvent.

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

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

The trifluoromethanesulfonylation agent used in this step is suitably a trifluoromethylsulfonyl compound, more preferably trifluoromethanesulfonic anhydride.

The reaction temperature in this step is usually from -20 ° C to 50 ° C, suitably from 0 ° C to 20 ° C.

The reaction time in this step is usually from 1 minute to 24 hours, and is suitably from 10 minutes to 6 hours.

G-II step

This step is carried out in the same manner as the BI step of the B method by reacting the compound represented by the formula (XVI) with the compound (IX) in the presence of a solvent, a palladium catalyst and a base to produce a general formula ( The step of the compound represented by XVII).

The solvent used in this step is preferably a guanamine, an ether, an anthracene or a mixed solvent thereof, and is more preferably a mixed solvent of dimethoxyethane and dimethylarylene.

G-III step

This step is carried out by reacting a compound represented by the formula (XVII) with a compound represented by the formula (XVIII) in the presence of a solvent, a palladium catalyst and a base, in the same manner as the A-III step of the method A. The step of producing a compound represented by the formula (XIX) is carried out.

The H method is a method of producing a compound represented by the formula (XXI) wherein Y is an oxygen atom in the compound represented by the formula (IV) used in the A-I step of the A method and the C-I step of the C method.

H-I step

This step is carried out by reacting a compound represented by the formula (XV) with a compound represented by the formula (XX) in the presence of a solvent, a copper catalyst, a cocatalyst and a base. The step of the compound represented by the formula (XXI).

The solvent used in this step is suitable for ethers, more suitable for 1,4-two alkyl.

The copper catalyst used in this step is suitably copper (I) iodide.

The cocatalyst used in this step is suitably N,N-dimethylglycine.

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

The reaction temperature in this step is usually from 50 ° C to 150 ° C, suitably from 80 ° C to 110 ° C.

The reaction time in this step is usually from 3 hours to 72 hours, and is suitably from 12 hours to 48 hours.

The method of the present invention is a method of producing a compound represented by the formula (XXIV) wherein Y is an oxygen atom in the compound represented by the formula (XII) used in the step C-II of the C method.

I-I step

This step is carried out by reacting a compound represented by the formula (VIII) with a compound represented by the formula (XXII) in the presence of a solvent, a palladium catalyst and a base, in the same manner as the A-III step of the method A. The step of producing a compound represented by the formula (XXIII) is carried out.

I-II step

This step is carried out by reacting a compound represented by the formula (XXIII) with a compound represented by the formula (XV) in the presence of a solvent, a copper catalyst, a cocatalyst and a base, and a HI step of the H method. The procedure of the compound represented by the formula (XXIV) is carried out in the same manner.

The J method is a method of producing a compound represented by the formula (VIII) used in the A-III step of the A method, the C-I step of the C method, and the I-I step of the I method.

J-I step

This step is carried out in the same manner as the BI step of the B method by reacting the compound represented by the formula (XI) with the compound (IX) in the presence of a solvent, a palladium catalyst and a base, thereby producing a formula ( The step of the compound represented by VIII).

The K method is a method for producing a compound represented by the formula (VI) or a salt thereof used in the A-II step of the A method and the C-III step of the C method. However, when Q ¹ is a nitrogen atom, Q ² is a group represented by the formula =CH-.

K-I step

This step is carried out by reacting a compound represented by the formula (XXV) with a compound represented by the formula (XXVI) in the presence of a solvent and a base in a solvent to produce a compound represented by the formula (XXVII). The step of the compound.

The solvent used in this step is suitably a guanamine or an anthracene, more preferably N,N-dimethylformamide or dimethylammonium.

The copper catalyst used in this step is suitably copper (I) iodide.

The base used in this step is suitably an alkali metal salt of L-valine, and more preferably L-sodium citrate.

The reaction temperature in this step is usually from 50 ° C to 150 ° C, suitably from 70 ° C to 110 ° C.

The reaction time in this step is usually from 10 minutes to 48 hours, and is suitably from 0.5 hours to 12 hours.

K-II step

This step is carried out in the same manner as in the D-I step of the D method by reacting the compound represented by the formula (XXVII) with a base in a solvent to produce a compound represented by the formula (VI).

After the salt reaction of the compound represented by the formula (VI) is completed, it is taken from the basic reaction mixture. The salt to be taken varies depending on the base used in the reaction.

The L method is a compound represented by the formula (VI) used in the A-II step of the A method and the C-III step of the C method, or a salt thereof, wherein Q ¹ is a group represented by the formula =CH-, Q ² A method of a compound represented by the formula (XXXII) or a salt thereof in which a nitrogen atom is a hydrogen atom and R ^3a is a hydrogen atom.

L-I step

This step is a step of producing a compound represented by the formula (XXX) by reacting a compound represented by the formula (XXVIII) with a compound represented by the formula (XXIX) in the presence of a base in a solvent.

The solvent used in this step is suitably an guanamine or an anthracene, and is more suitably a dimethyl hydrazine.

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

The reaction temperature in this step is usually from 30 ° C to 200 ° C, suitably from 80 ° C to 120 ° C.

The reaction time in this step is usually from 1 hour to 24 hours, and is suitably from 5 hours to 10 hours.

L-II step

This step is carried out in the same manner as the KI step of the K method by reacting a compound represented by the formula (XXX) with a compound represented by the formula (XXVI) in the presence of a solvent, a copper catalyst and a base. Further, a step of producing a compound represented by the formula (XXXI) is carried out.

L-III step

This step is carried out by reacting a compound represented by the formula (XXXI) with a base in the same manner as in the D-I step of the D method to produce a compound represented by the formula (XXXII) or a salt thereof.

The salt of the compound represented by the formula (XXXII) is taken from the basic reaction mixture after completion of the reaction. The salt to be taken varies depending on the base used in the reaction.

Further, in the case where R ¹⁰ is a benzyl group, this step is carried out by reacting a compound represented by the formula (XXXI) in a hydrogen gas atmosphere in the presence of a palladium catalyst in a solvent to produce a formula (XXXII). The step of the compound indicated.

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

The palladium catalyst used in this step is suitably palladium-carbon.

The reaction temperature in this step is usually from 0 ° C to 80 ° C, and is suitably from room temperature to 50 ° C.

The reaction time in this step is usually from 10 minutes to 60 hours, and is suitably from 1 hour to 24 hours.

Further, in the case where one of R ¹⁰ is a third butyl group, this step is carried out in a solvent, and by reacting the compound represented by the formula (XXXI) with an acid, in a solvent, The reaction with a base is carried out in the same manner as in the DI step of the D method to produce a compound represented by the formula (XXXII) or a salt thereof.

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

The acid used in this step is suitably trifluoroacetic acid.

The reaction temperature in this step is usually -10 ° C to 100 ° C, and is suitably 0 ° C to 30 ° C.

The reaction time in this step is usually from 1 minute to 24 hours, and is suitably from 1 hour to 8 hours.

The M method is a method for producing a compound represented by the formula (XXXI) used in the L-III step of the L method.

M-I step

This step is carried out by reacting a compound represented by the formula (XXXIII) with a compound represented by the formula (XXIX) in the presence of a solvent, a base, a copper catalyst and a cocatalyst to produce a formula (XXXI). The step of the compound represented.

The solvent used in this step is suitable for guanamines, ethers or guanidines, and more suitable for 1,4-two. alkyl.

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

The copper catalyst used in this step is suitably copper (I) iodide or copper (I) chloride.

The cocatalyst used in this step is suitably picolinic acid.

The reaction temperature in this step is usually from 30 ° C to 200 ° C, suitably from 80 ° C to 120 ° C.

The reaction time in this step is usually from 1 hour to 24 hours, and is suitably from 5 hours to 12 hours.

In the compound represented by the general formula (VI) used in the A-II step of the A method and the C-III step of the C method, Q ¹ is a group represented by the formula =CH-, and Q ² is a formula =CH. - a method of expressing a compound represented by the formula (XXXV).

N-I step

This step is carried out in the presence of a solvent, a copper catalyst and a base, by the compound represented by the formula (XXXIV) and the formula (XXVI). The compound is reacted to produce a compound represented by the formula (XXXV).

The solvent used in this step is suitably a guanamine or an anthracene, more preferably N,N-dimethylformamide or dimethylammonium.

The copper catalyst used in this step is suitably copper (I) iodide.

The base used in this step is suitably an alkali metal hydroxide, more preferably an aqueous solution of sodium hydroxide or sodium hydroxide.

The reaction temperature in this step is usually from 50 ° C to 150 ° C, suitably from 70 ° C to 110 ° C.

The reaction time in this step is usually from 10 minutes to 48 hours, and is suitably from 0.5 hours to 12 hours.

The O method is a method for producing a compound represented by the formula (XII) used in the C-II step of the C method.

O-I step

This step is a step of producing a compound represented by the formula (XII) by reacting a compound represented by the formula (XXXVI) with a compound (XXXVII) in the presence of a base in a solvent.

This step is a compound represented by the formula (XXXVI) wherein R ^7a is a hydrogen atom in the compound represented by the formula (XII) produced by the CI step of the C method.

The solvent used in this step is suitable for guanamine or ether, and more suitable for N,N-dimethylformamide, tetrahydrofuran or 1,4-two alkyl.

The base used in this step is suitably an alkali metal hydride, an alkali metal alkoxide or an alkali metal decylamine, more preferably sodium hydride, potassium t-butoxide, lithium diisopropylamide or hexamethyl Lithium decane alkane or sodium hexamethyldiazane.

The reaction temperature in this step is usually -100 ° C to 150 ° C, and is suitably -78 ° C to 80 ° C.

The reaction time in this step is usually from 1 minute to 48 hours, and is suitably from 5 minutes to 24 hours.

The P method is a method for producing the compound represented by the formula (VIII) used in the A-III step of the A method, the C-I step of the C method, and the I-I step of the I method.

P-I step

This step is carried out in the presence of a solvent, a palladium catalyst and a base, and reacts the compound represented by the formula (XXXVIII) with the compound (IX) in the same manner as the BI step of the B method to produce a general formula ( The step of the compound represented by XXXIV).

P-II step

This step is carried out in the same manner as in the OI step of the O method by reacting a compound represented by the formula (XXXIV) with a compound represented by the formula (XXXVII) in the presence of a base in a solvent to produce a general formula. The step of the compound represented by (VIII).

General formulae (IV), (VI), (VIII), (XI), (XIV), (XV), (XVIII), (XX), (XXII), (XXV), (XXVI), (XXVIII), The compound represented by (XXIX), (XXXIII), (XXXIV), (XXXVII), and (XXXVIII) is a well-known compound; or a compound can be known as a starting material and can be easily produced according to a known method or the like.

In the above definitions of R ^7a and R ^3a in the "protected hydroxy may" and "may be protected carboxy" means the protective group by hydrogenolysis, hydrolysis, electrolysis, photolysis chemical method or the like and A cleavable protecting group means a protecting group which is generally used in organic synthetic chemistry (for example, see TW Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)).

In the above, the "protecting group" of the "protectable hydroxyl group" and the "protectable carboxyl group" in the definition of R ^3a and R ^7a may be a protecting group for a hydroxyl group used in the field of organic synthetic chemistry, and Particularly, for example, a fluorenyl group, a C ₂ -C ₇ alkylcarbonyl group, a C ₂ -C ₇ halogenated alkylcarbonyl group such as 2,2,2-trichloroethylcarbonyl, or a methoxy group. Alkoxyalkylcarbonyl such as acetamyl, propylene fluorenyl, propynyl fluorenyl, methacryl fluorenyl, crotonyl, isocrotonyl, (E)-2-methyl-2-butene An "alkylcarbonyl group" such as an unsaturated alkylcarbonyl group such as butenoyl; an arylcarbonyl group such as a benzinyl group, an α-naphthylmethyl group or a β-naphthylmethyl group, or a 2-bromobenzyl group; a halogenated arylcarbonyl group such as 4-chlorobenzylidene, a C ₁ -C ₆ alkyl group such as 2,4,6-trimethylbenzylidene or 4-toluoyl a aryl carbonyl group, a C ₁ -C ₆ alkoxylated arylcarbonyl group such as 4-anisyl fluorenyl, a nitroated aryl group such as a 4-nitrobenzyl fluorenyl group or a 2-nitrobenzyl fluorenyl group carbonyl, 2- (methoxycarbonyl) benzyl acyl such C ₂ -C ₇ alkoxycarbonyl group of the arylcarbonyl group, 4-phenylbutyl Benzyl acyl such arylated arylcarbonyl group, etc. "arylcarbonyl group"; acetyl group, ethoxycarbonyl group, butoxycarbonyl T-like C ₂ -C ₇ alkoxycarbonyl group, 2 a halogen such as 2,2-trichloroethoxycarbonyl, 2-trimethyldecyloxyethoxycarbonyl or a C ₂ -C ₇ alkane substituted with a tris-(C ₁ -C ₆ alkyl)decylalkyl group "Alkoxycarbonyl" such as oxycarbonyl; tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothio "Tetrahydrothiopyran-2-yl", 4-methoxytetrahydrothiopyran-4-yl, "tetrahydropyranyl or tetrahydrothiopyranyl"; tetrahydrofuran-2- "tetrahydrofuranyl or tetrahydrothiofuranyl" such as tetrahydrothiofuran-2-yl; trimethyldecyl, triethyldecyl, isopropyldimethylsilane Tri-(C ₁ -C ₆ alkane such as t-butyl dimethyl decyl, methyl diisopropyl decyl, methyl di-t-butyl decyl, triisopropyl decyl矽alkyl, diphenylmethyl fluorenyl, diphenylbutyl decyl, diphenyl isopropyl decyl, phenyl diisopropyl decane Like (C ₁ -C ₆ alkyl) group diaryl silicon or di - (C ₁ -C ₆ alkyl) aryl group, etc. Silicon "silicon group"; methoxymethyl, 1,1- Dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl (C ₁ -C ₆ alkoxy)methyl, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkoxy)methyl, 2-methoxyethoxymethyl, 2,2 An alkoxymethyl group such as a (C ₁ -C ₆ halogenated alkoxy)methyl group such as 2-trichloroethoxymethyl or bis(2-chloroethoxy)methyl; ethoxyethyl, 1- (isopropoxy) ethyl group or the like (C ₁ -C ₆ alkoxy) ethyl, 2,2,2-trichloroethyl and the like of the ethyl halide, "Substituted ethyl"; benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-fluorenyl C ₁ -C ₆ alkyl substituted by 1 to 3 aryl groups, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethyl Benzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4 - cyanobenzyl such aryl ring by C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, nitro, halo, cyano substituted by from 1 to 3 of the aryl group substituted with a C ₁ "Alkylene group" such as -C ₆ alkyl group; "alkenyloxycarbonyl group" such as ethylene oxycarbonyl group or allyloxycarbonyl group; benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 3, An aryl ring such as 4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl or 4-nitrobenzyloxycarbonyl may be substituted by 1 or 2 C ₁ -C ₆ alkoxy groups or Nitro "aralkyloxycarbonyl"; suitable as alkylcarbonyl, nonylalkyl or aralkyl.

Protection ‧ deprotection is a necessary step based on known methods (for example, "Protective Groups in Organic Synthesis" (Theodora W. Greene, Peter GMWuts, 1999, Wiley-Interscience Publication, etc.) get on.

The compound of the present invention or a pharmaceutically acceptable salt thereof can be administered in various forms. Examples of the administration form thereof include a tablet, a capsule, a granule, an emulsion, a pill, a powder, and a syrup (liquid). Oral administration, etc.; or by injection (intravenous, intramuscular, subcutaneous or intraperitoneal administration), drip, suppository (rectal administration), external preparation (transdermal administration), etc. Cast. Each of these preparations may be an excipient, a binder, a disintegrant, a lubricant, a flavoring agent, a dissolution aid, a suspending agent, a coating agent, a vehicle, a base, etc., depending on the usual method. Formulations can be formulated in the field of formulation technology by means of adjuvants which are usually used.

As a carrier, as a carrier, for example, an excipient such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, citric acid or the like; water, ethanol, and c can be used; Alcohol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.; dry starch , sodium alginate, agar powder, laminar powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc. Solution; disintegration inhibitor of sugar, stearin, cocoa butter, hydrogenated oil, etc.; absorption enhancer of grade 4 ammonium salt, sodium lauryl sulfate, etc.; moisturizer of glycerin, starch, etc.; starch, lactose , adsorbents such as kaolin, bentonite, colloidal citric acid, etc.; lubricants such as refined talc, stearate, boric acid powder, polyethylene glycol, and the like. Further, if necessary, a tablet which can be applied to a usual skin, such as a sugar-coated tablet, a gelatin-coated tablet, an enteric coated tablet, a film-coated tablet or a double-layer ingot, or a multilayer ingot can be prepared.

As a carrier, as a carrier, for example, glucose, lactose, cocoa butter, starch, hardened vegetable oil, kaolin can be used. Excipients such as earth, talc, etc.; agglomerates of gum arabic powder, tragacanth powder, gelatin, ethanol, etc.; disintegrants such as laminaria, agar, and the like.

When it is used as a suppository, it can be widely used as a carrier in the field, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.

As the injection, it can be used as a liquid, emulsion or suspension. Such liquids, emulsions or suspensions are sterilized and are preferably the same as blood. The solvent used for the production of such a liquid preparation, an emulsion or a suspension 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, and ethoxylated iso-hard. A fatty alcohol, a polyoxylated isostearyl alcohol, a polyoxyethylene sorbitan fatty acid ester or the like. Further, in this case, in order to prepare an isotonic solution, a sufficient amount of salt, glucose or glycerin may be contained in the preparation, or a usual dissolution aid, a buffering agent, an analgesic or the like may be contained.

When it is used as an external preparation, it can be used as an external solid preparation, a external liquid preparation (liniment, lotion), a spray, an ointment, a cream, a gel, or a patch. These external preparations can be produced according to a usual method using a solvent, a base, an additive, an excipient, or the like which is usually used in pharmaceuticals.

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

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

The amount to be used varies depending on the symptoms, age, and the like of the patient (warm-blooded animal, especially human), but it is desirable that in the case of oral administration, the lower limit per one time is 0.001 mg/kg body weight (preferably 0.01 mg/ In the case of intravenous administration, the upper limit is 500 mg/kg body weight (preferably 50 mg/kg body weight), and the lower limit is 0.005 mg/kg body weight per minute (preferably 0.05 mg/kg body weight). The upper limit is 50 mg/kg body weight (preferably 5 mg/kg body weight), and it is administered one to several times per day depending on the symptoms.

[Examples]

Hereinafter, the present invention will be described in more detail by way of examples and test examples, but the scope of the invention is not limited thereto.

In the examples, the elution in column chromatography was carried out under the observation by TLC (Thin Layer Chromatography). As for the TLC plate, a silicone resin 60F ₂₅₄ manufactured by Merck Co., Ltd. was used for the TLC plate, and a solvent used as a solvent for elution in column chromatography was used for developing the solvent, and a UV detector was used for the detection method. For the column, the silicone resin SK-85 (230-400 mesh) made by Merck, the Hi-Flash ^TM Column, INJECT COLUMN ^TM made by Yamagata, the silicone (SNAP, SNAP Ultra) made by Biotage, or Fuji Silicone (FL100B, Chromatorex-SO3H) manufactured by SILYSIA Chemical Co., Ltd. In addition to the usual column chromatography, Yamazawa's automatic chromatography apparatus (YFLC-5405-FC-GRII, W-Prep 2XY) and Biotage's automatic chromatography apparatus (Isolera, SP-1) are used suitably. Further, the abbreviations used in the examples have the following meanings.

Mg: mg, g: gram, mL: ml, MHz: megahertz, Hz: Hz

In the following examples, the nuclear magnetic resonance (hereinafter, ¹ H-NMR) spectrum uses tetramethyl decane as a standard substance, and the chemical shift value is described as a δ value (ppm). The solvent was measured using CDCl ₃ : deuterated chloroform, MeOH-d ₄ : deuterated methanol or DMSO-d ₆ : deuterated dimethyl hydrazine. The splitting pattern expresses a single peak as s, a doublet as d, a triplet as t, a quartet as q, a quartet as quint, a quartet as a sext, and a quartet as a hept. The multiple peak is denoted as m, and the broad peak is denoted as br.

Mass analysis (hereinafter, MS) is performed by APCI (Atmospheric Pressure Chemical Ionization) method, FAB (Fast Atom Bombardment) method, EI (Electron Ionization) method, or ESI (Electron Spray Ionization) method. Further, in some measurement systems, an EI and APCI were used as the measurement methods of the ionization method.

(Example 1)

{2'-Methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole- 5-yl)oxy]biphenyl-4-yl}acetic acid

(1a) 5-(4-Bromo-3-methylphenoxy)-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

5-Hydroxy-4-methyl-2,3-dihydro-1H-indole- 1-bromo-4-iodo-2-methylbenzene (12.5 g) and well-known (International Publication No. WO2007/129745) 1-1,4-dicarboxylic acid tert-butyl ester (7.00 g) Copper (I) iodide (107 mg), N,N-dimethylglycine (116 mg) and cesium carbonate (18.3 g) were added to a solution of alkane (250 mL), and stirred at 100 ° C for 5 hours and 30 minutes. After cooling to room temperature, it was allowed to stand overnight, and again stirred at 100 ° C for 9 hours, and the reaction liquid was filtered through Celite. The obtained filtrate was concentrated under reduced pressure. EtOAcjjjjjjjj

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.56 (9H, s), 2.04 (3H, s), 2.32 (3H, s), 3.03 (2H, t, J = 8.8 Hz), 3.97-4.10 (2H m), 6.55 (1H, dd, J = 8.8, 2.7 Hz), 6.69-6.83 (2H, m), 7.20-7.74 (2H, m).

(1b) 1-[5-(4-Bromo-3-methylphenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-( Methylsulfonyl)phenyl]ketone

4N hydrochloric acid was added to a solution of the compound (5.25 g) obtained in Example (1a) in dichloromethane (50 mL) Alkane solution (50 mL) was stirred at room temperature for 3 h. The reaction solution was concentrated to give crude 5-(4-bromo-3-methylphenoxy)-4-methyl-2,3-dihydro-1H-indole hydrochloride (4.54 g).

Add N-methyl to a solution of the obtained compound (4.54 g) in N,N-dimethylformamide (100 mL) The morpholine (2.07 mL) was stirred at room temperature for 10 min. Next, adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (4.51 g) and [2-(methylsulfonyl)phenyl]acetic acid (2.82 g) were stirred at room temperature for 14 hours and 30 min. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.10 (3H, s), 2.33 (3H, s), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 4.29 (2H, t , J = 8.5 Hz), 4.36 (2H, s), 6.59 - 6.55 (1H, m), 6.74 - 6.80 (2H, m), 7.34 - 7.42 (2H, m), 7.50 - 7.55 (1H, m), 7.60-7.65 (1H, m), 7.99 (1H, d, J = 8.5 Hz), 8.06-8.10 (1H, m).

MS (APCI) m/z: 514 (M+H) ⁺ .

(1c){2'-Methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H- Ethyl-5-yl)oxy]biphenyl-4-yl}ethyl acetate

Compound (600 mg) obtained in Example (1b), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl Ethyl acetate (575 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (47.6 mg) of 1,2-dimethoxy An aqueous solution (2 mL) of sodium carbonate (247 mg) was added to a solution of hexane (15 mL), and the mixture was reacted at 130 ° C for 30 minutes. The same reaction was carried out twice more. After the reaction liquids were each cooled to room temperature, they were combined and poured into water, and extracted with ethyl acetate three times. After the combined organic layers were dried over sodium sulfate, the solvent was evaporated under reduced pressure. The title compound (1.66 g) was obtained from m.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.28 (3H, t, J = 7.1 Hz), 2.16 (3H, s), 2.22 (3H, s), 3.13 (3H, s), 3.23 (2H, t , J = 8.5 Hz), 3.65 (2H, s), 4.18 (2H, q, J = 7.1 Hz), 4.30 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.72 (1H, dd , J = 8.5, 2.4 Hz), 6.77-6.80 (1H, m), 6.84 (1H, d, J = 8.5 Hz), 7.12 (1H, d, J = 7.9 Hz), 7.24 - 7.33 (4H, m) , 7.36 (1H, d, J = 7.3 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.3 Hz), 8.00 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9Hz).

MS (APCI) m/z: 598 (M+H) ⁺ .

(1d){2'-Methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-吲哚-5-yl)oxy]biphenyl-4-yl}acetic acid

The compound obtained in Example (1c) (1.66 g) was dissolved in tetrahydrofuran (45 mL) and ethanol (45 mL). After the reaction liquid was stirred at room temperature for 7 hours, the organic solvent was distilled off by concentration under reduced pressure. The precipitated solid was collected by filtration, and the filtrate was concentrated under reduced pressure. The precipitated solid was collected by filtration, combined with the solid which was originally filtered, suspended in water, acidified with 1N hydrochloric acid, and extracted with dichloromethane for 5 times. The title compound was obtained as an amorphous solid. The obtained amorphous solid was dissolved in dichloromethane (5 mL), and ethyl acetate (20 mL) was added to give a colorless solid, and the solvent was distilled off under reduced pressure to give the title compound (1.41) as a colorless solid. g).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.16 (3H, s), 2.22 (3H, s), 3.13 (3H, s), 3.23 (2H, t, J = 8.5 Hz), 3.70 (2H, s ), 4.29 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.69-6.73 (1H, m), 6.77-6.80 (1H, m), 6.84 (1H, d, J = 8.5 Hz) , 7.12 (1H, d, J = 7.9 Hz), 7.26-7.33 (4H, m), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.60-7.64 ( 1H, m), 8.00 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS (APCI) m/z: 570 (M+H) ⁺ .

(Example 2)

{4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-2'-Methylbiphenyl-4-yl}acetate sodium salt

(2a) 1-[5-(4-Bromo-3-methylphenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-( Ethylsulfonyl)phenyl]ethanone

N,N of 5-(4-bromo-3-methylphenoxy)-4-methyl-2,3-dihydro-1H-indole hydrochloride (300 mg) obtained in Example (1b) Add N-methyl to a solution of dimethylformamide (5 mL) The morpholine (0.184 mL) was stirred at room temperature for 25 min. Next, adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (348 mg) and [2-(ethylsulfonyl)phenyl]acetic acid (229 mg) were stirred at room temperature for 15 h 30 min. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.27 (3H, t, J = 7.3Hz), 2.09 (3H, s), 2.33 (3H, s), 3.17-3.25 (4H, m), 4.28 (2H , t, J = 8.5 Hz), 4.37 (2H, s), 6.56 (1H, dd, J = 8.5, 3.0 Hz), 6.74 - 6.79 (2H, m), 7.37 - 7.41 (2H, m), 7.48- 7.53 (1H, m), 7.60-7.65 (1H, m), 7.98 (1H, d, J = 9.1 Hz), 8.01-8.04 (1H, m).

MS (APCI) m/z: 528 (M+H) ⁺ .

(2b){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Ethyloxy]-2'-methylbiphenyl-4-yl}ethyl acetate

Compound (4.00 g) obtained in Example (2a), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetic acid An aqueous solution (10 mL) of potassium phosphate (4.82 g) was added to a solution of ethyl ester (2.42 g) and tetrakistriphenylphosphine palladium (0) (437 mg) in 1,2-dimethoxyethane (150 mL). And allowed to react at 100 ° C for 6 hours. After cooling the reaction liquid to room temperature, the organic layer was separated, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The title compound (4.76 g) was obtained from m.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.25-1.30 (6H, m), 2.16 (3H, s), 2.22 (3H, s), 3.19-3.25 (4H, m), 3.65 (2H, s) , 4.18 (2H, q, J = 7.3 Hz), 4.28 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.72 (1H, dd, J = 8.5, 2.4 Hz), 6.77-6.80 ( 1H, m), 6.84 (1H, d, J = 9.1 Hz), 7.12 (1H, d, J = 8.5 Hz), 7.24 - 7.34 (4H, m), 7.40 (1H, d, J = 7.9 Hz), 7.48-7.53 (1H, m), 7.60-7.65 (1H, m), 7.98-8.05 (2H, m).

MS (APCI) m/z: 612 (M+H) ⁺ .

(2c){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-methylbiphenyl-4-yl}acetic acid

The compound obtained in Example (2b) (8.52 g) was dissolved in tetrahydrofuran (150 mL) and ethanol (100 mL), and 1N aqueous sodium hydroxide (41.8 mL) was added. After the reaction mixture was stirred at room temperature for 15 hr, 1N hydrochloric acid (45 mL) was evaporated and evaporated. Water was added to the residue, and the precipitated solid was filtered and dried to give the title compound (7.43 g).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.27 (3H, t, J = 7.3Hz), 2.16 (3H, s), 2.22 (3H, s), 3.18-3.25 (4H, m), 3.70 (2H , s), 4.28 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.71 (1H, dd, J = 7.9, 2.4 Hz), 6.77-6.79 (1H, m), 6.84 (1H, d, J = 8.5 Hz), 7.12 (1H, d, J = 8.5 Hz), 7.25-7.34 (4H, m), 7.40 (1H, d, J = 7.9 Hz), 7.48-7.53 (1H, m), 7.59-7.64 (1H, m), 7.98-8.05 (2H, m).

MS (APCI) m/z: 584 (M+H) ⁺ .

(2d){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Sodium oxy]-2'-methylbiphenyl-4-yl}acetate

The compound obtained in Example (2c) (250 mg) was dissolved in methanol (7 mL), and 1N aqueous sodium hydroxide (0.428 mL) was added. After stirring for 1 hour, the solvent was evaporated under reduced pressure.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.11 (3H, t, J = 7.3Hz), 2.09 (3H, s), 2.19 (3H, s), 3.14-3.24 (4H, m), 3.26 -3.34(2H,m),4.23-4.35(4H,m),6.65-6.70(1H,m),6.76-6.79(1H,m),6.82(1H,d,J=8.5Hz),7.08-7.15 (3H, m), 7.22 (2H, d, J = 8.5 Hz), 7.49-7.53 (1H, m), 7.55-7.61 (1H, m), 7.69-7.74 (1H, m), 7.85 (1H, d , J = 8.5 Hz), 7.91 (1H, d, J = 7.9 Hz).

(Example 3)

{4'-[(1-{[2-(cyclopropylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]]-2'-methylbiphenyl-4-yl}acetic acid

(3a) [2-(cyclopropylsulfonyl)phenyl]acetic acid

To a solution of (2-iodophenyl)acetic acid (1.00 g) in dimethyl hydrazine (10 mL) was added 1N aqueous sodium hydroxide (3.82 mL) and sodium cyclopropanesulfinate (0.978 g) for 1 hour. Nitrogen bubbling. to Copper (I) iodide (1.45 g) was added to the reaction mixture, and the mixture was stirred at 100 ° C for 2 hours and 30 minutes under nitrogen bubbling. 1N hydrochloric acid, ethyl acetate, and tetrahydrofuran were added to the reaction mixture at 0 ° C, and the mixture was stirred overnight, and the salt was added thereto to be saturated, and then filtered through Celite. The filtrate was subjected to a liquid separation operation, and the aqueous layer was extracted twice with ethyl acetate. The organic layer was combined and washed with aqueous sodium sulfate and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure and dichloromethane was evaporated. The title compound (0.650 g) was obtained as a pale yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.99-1.08 (2H, m), 1.29-1.36 (2H, m), 2.67-2.77 (1H, m), 4.20 (2H, s), 7.40-7.52 ( 2H, m), 7.55-7.62 (1H, m), 7.89-7.96 (1H, m).

(3b) 5-{[4'-(2-Ethoxy-2-oxoethyl)-2-methylbiphenyl-4-yl]oxy}-4-methyl-2,3 -Dihydro-1H-indole-1-carboxylic acid tert-butyl ester

Ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (1.53 g), Example (1a ) obtained compound (2.00 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amine) Phenyl-1,1'-biphenyl)]palladium(II) (0.376 g) and potassium phosphate (3.04 g) were suspended in toluene (38 mL) and water (2 mL), and stirred at 100 ° C for 3 hours and 30 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine. The organic layer was dried with EtOAc EtOAcjjjjjjjjjjj

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.28 (3H, t, J = 7.0 Hz), 1.57 (9H, s), 2.11 (3H, s), 2.22 (3H, s), 3.01-3.08 (2H) , m), 3.65 (2H, s), 3.99-4.22 (4H, m), 6.64-6.90 (3H, m), 7.11 (1H, d, J = 8.5 Hz), 7.21 - 7.35 (4H, m), 7.62-7.75 (1H, m).

(3c){2'-Methyl-4'-[(4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]biphenyl-4-yl}ethyl acetate

Trifluoroacetic acid (3 mL) was added to a solution of the compound (2. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture to neutralize the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried with EtOAcjjjjjjjjjj

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.28 (3H, t, J = 7.0 Hz), 2.09 (3H, s), 2.22 (3H, s), 2.98-3.09 (2H, m), 3.58-3.73 (4H, m), 4.16-4.24 (2H, m), 6.47-6.81 (4H, m), 7.09 (1H, d, J = 7.9 Hz), 7.24 - 7.36 (4H, m).

(3d){4'-[(1-{[2-(Cyclopropylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indole-5- Ethyl oxy]-2'-methylbiphenyl-4-yl}ethyl acetate

To a solution of the compound obtained in Example (3c) (0.165 g) and the compound (0.120 g) (Dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (0.118 g), 3H-1,2,3-triazolo[4,5-b]pyridine-3- Alcohol (0.0280 g) was stirred at room temperature for 2 hours. Adding water to the reaction solution After extracting with a mixed solvent of ethyl acetate and dichloromethane (2:1), the organic layer was washed with saturated brine. The organic layer was dried with EtOAc EtOAcjjjjjjjjjjj

^{1 H-NMR (400MHz, CDCl} 3) δ: 0.83-0.93 (2H, m), 0.98-1.06 (2H, m), 1.28 (3H, t, J = 7.1Hz), 2.15 (3H, s), 2.22 (3H, s), 2.76-2.84 (1H, m), 3.18-3.25 (2H, m), 3.65 (2H, s), 4.18 (2H, q, J = 7.1 Hz), 4.26-4.32 (2H, m ), 4.40 (2H, s), 6.69-6.86 (3H, m), 7.12 (1H, d, J = 8.5 Hz), 7.23 - 7.34 (4H, m), 7.38-7.64 (3H, m), 7.92 8.03 (2H, m).

(3e){4'-[(1-{[2-(Cyclopropylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5- Ethyl]oxy]-2'-methylbiphenyl-4-yl}acetic acid

The compound obtained in Example (3d) (0.215 g) was dissolved in tetrahydrofuran (1 mL), ethanol (1 mL) and dichloromethane (0.2 mL). All night. 1N hydrochloric acid was added to the reaction mixture to neutralize it, and extracted with dichloromethane three times. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. ethyl acetate / hexane (1:1) solvent was added to the residue, and the precipitated solid was collected by filtration to give the title compound as a colorless solid. (0.175g).

^{1 H-NMR (400MHz, CDCl} 3 + MeOH-d 4) δ: 0.99-1.07 (2H, m), 1.28-1.35 (2H, m), 2.16 (3H, s), 2.22 (3H, s), 2.74 -2.84(1H,m), 3.17-3.27(2H,m),3.65(2H,s), 4.25-4.33(2H,m), 4.40(2H,s),6.69-6.86(3H,m),7.12 (1H, d, J = 8.5 Hz), 7.25-7.33 (4H, m), 7.39-7.66 (3H, m), 7.92-8.01 (2H, m).

MS (APCI/ESI) m/z: 596 (M+H) ⁺ .

(Example 4)

{2'-Methyl-4'-[(4-methyl-1-{[2-(phenylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole- 5-yl)oxy]biphenyl-4-yl}acetic acid

(4a) [2-(phenylsulfonyl)phenyl]acetic acid

1N aqueous sodium hydroxide solution (3.82 mL) and sodium benzenesulfinate (1.25 g) were added to a solution of (2-iodophenyl)acetic acid (1.00 g) in dimethyl hydrazine (10 mL), and nitrogen was added for 1 hour. Foaming. Copper (I) iodide (1.45 g) was added to the reaction mixture, and the mixture was stirred at 100 ° C for 2 hours and 30 minutes under nitrogen bubbling. To the reaction mixture, 1N hydrochloric acid, ethyl acetate and tetrahydrofuran were added and stirred at 0 ° C, and the salt was added thereto to be saturated, and then filtered through Celite. The filtrate was subjected to a liquid separation operation, and the organic layer was washed with an aqueous sodium sulfite solution and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure and dichloromethane was evaporated. The title compound (0.713 g) was obtained as a pale yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.96 (2H, s), 7.33-7.42 (1H, m), 7.46-7.67 (5H, m), 7.85-7.95 (2H, m), 8.15-8.24 ( 1H, m).

(4b){2'-Methyl-4'-[(4-methyl-1-{[2-(phenylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H- Ethyl-5-yl)oxy]biphenyl-4-yl}ethyl acetate

To a solution of the compound obtained in Example (3c) (0.120 g) and the compound obtained in Example (4a) (0.247 g) in dichloromethane (3 mL), triethylamine (0.0829 mL), N-[3- (Dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (0.0859 g), 3H-1,2,3-triazolo[4,5-b]pyridine-3- Alcohol (0.0203 g) was stirred at room temperature for 3 hours and 30 minutes. After adding water to the reaction mixture and extracting with a mixed solvent of ethyl acetate and dichloromethane (4:1), the organic layer was washed with saturated brine. The organic layer was dried with EtOAc EtOAcjjjjjjjjjjj

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.28 (3H, t, J = 7.6 Hz), 2.14 (3H, s), 2.22 (3H, s), 3.10-3.18 (2H, m), 3.65 (2H) , s), 4.05-4.22 (6H, m), 6.69-6.85 (3H, m), 7.12 (1H, d, J = 7.9 Hz), 7.24-7.33 (4H, m), 7.38-7.62 (6H, m ), 7.82-7.88 (3H, m), 8.14-8.19 (1H, m).

(4c){2'-Methyl-4'-[(4-methyl-1-{[2-(phenylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-吲哚-5-yl)oxy]biphenyl-4-yl}acetic acid

The compound (0.190 g) obtained in Example (4b) was dissolved in tetrahydrofuran (1 mL) and ethanol (1 mL). The title compound (0.158 g) was obtained as a colorless solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.14 (3H, s), 2.22 (3H, s), 3.09-3.18 (2H, m), 3.70 (2H, s), 4.05-4.14 (2H, m) , 4.18 (2H, s), 6.69-6.85 (3H, m), 7.09-7.14 (1H, m), 7.24-6.62 (10H, m), 7.82-7.89 (3H, m), 8.14-8.19 (1H, m).

MS (APCI) m/z: 632 (M+H) ⁺ .

(Example 5)

{2'-Methyl-4'-[(4-methyl-1-{[2-(propylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole- 5-yl)oxy]biphenyl-4-yl}acetic acid

(5a) [2-(propylsulfonyl)phenyl]acetic acid

1N aqueous sodium hydroxide solution (1.91 mL) and sodium propane sulfinate (0.584 g) were added to a solution of (2-iodophenyl)acetic acid (0.500 g) in dimethyl hydrazine (5 mL), and nitrogen for 1 hour. Foaming. Copper (I) iodide (0.727 g) was added to the reaction mixture, and the mixture was stirred at 100 ° C for 2 hours and 30 minutes under nitrogen. To the reaction mixture, 1N hydrochloric acid, ethyl acetate and tetrahydrofuran were added and stirred at 0 ° C, and the salt was added thereto to be saturated, and then filtered through Celite. The filtrate was subjected to a liquid separation operation, and the aqueous layer was extracted twice with ethyl acetate. The organic layer was combined and washed with aqueous sodium sulfate and brine. The title compound (0.124 g) was obtained.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.00 (3H, t, J = 7.3 Hz), 1.69-1.82 (2H, m), 3.12-3.20 (2H, m), 4.21 (2H, s), 7.40 -7.66 (3H, m), 7.98-8.05 (1H, m).

(5b){2'-Methyl-4'-[(4-methyl-1-{[2-(propylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H- Ethyl-5-yl)oxy]biphenyl-4-yl}ethyl acetate

To a solution of the compound obtained in Example (3c) (0.120 g) and the compound (0.0869 g) (Dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (0.0859 g), 3H-1,2,3-triazolo[4,5-b]pyridine-3- Alcohol (0.0203 g) was stirred at room temperature overnight. After adding water to the reaction mixture and extracting with a mixed solvent of ethyl acetate and dichloromethane (4:1), the organic layer was washed with saturated brine. The organic layer was dried with EtOAc EtOAcjjjjjjjjjj

¹ H-NMR (400MHz, CDCl ₃ ) δ: 0.95 (3H, t, J = 7.6 Hz), 1.28 (3H, t, J = 7.3 Hz), 1.67-1.78 (2H, m), 2.16 (3H, s ), 2.22 (3H, s), 3.11-3.26 (4H, m), 3.65 (2H, s), 4.14-4.32 (4H, m), 4.37 (2H, s), 6.69-6.87 (3H, m), 7.12 (1H, d, J = 7.9 Hz), 7.23 - 7.65 (7H, m), 7.99 - 8.05 (2H, m).

(5c){2'-Methyl-4'-[(4-methyl-1-{[2-(propylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-吲哚-5-yl)oxy]biphenyl-4-yl}acetic acid

The compound obtained in Example (5b) (0.165 g) was suspended in tetrahydrofuran (0.75 mL) and ethanol (0.75 mL), and 2N sodium hydroxide water was added under ice cooling. After the solution (1.5 mL), it was stirred at room temperature for 3 hours. The title compound (0.112 g) was obtained as a colorless solid.

¹ H-NMR (400 MHz, CDCl ₃ + MeOH-d ₄ ) δ: 0.96 (3H, t, J = 7.6 Hz), 1.67-1.79 (2H, m), 2.16 (3H, s), 2.22 (3H, s ), 3.12-3.27(4H,m), 3.66(2H,s), 4.25-4.33(2H,m), 4.37(2H,s),6.69-6.87(3H,m),7.12(1H,d,J = 8.5 Hz), 7.25-7.33 (4H, m), 7.38-7.67 (3H, m), 7.96-8.05 (2H, m).

MS (APCI) m/z: 598 (M+H) ⁺ .

(Example 6)

{4'-[(4-Chloro-1-{[2-(ethylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy] -2'-methylbiphenyl-4-yl}acetic acid

(6a) 4-chloro-5-methoxy-1H-indole

In a solution of 2-chloro-1-methoxy-4-nitrobenzene (5.00 g) and (4-chlorophenoxy)acetonitrile (5.81 g) in N,N-dimethylformamide (100 mL) Under ice cooling, potassium t-butoxide (4.22 g) was added, and the mixture was stirred at the same temperature for 3 hours and 20 minutes. Water was added to the reaction mixture, and the mixture was extracted three times with a mixed solvent of ethyl acetate / hexane (1:1), and the combined organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. (2-Chloro-3-methoxy-6-nitrophenyl)acetonitrile and (4-chloro-5-methoxy) were obtained by purifying the residue on silica gel column chromatography (dichloromethane/hexane). Mixture of benzyl-2-nitrophenyl)acetonitrile (5.06 g).

To a mixed solution of the obtained mixture (5.05 g) in ethanol (150 mL) / ethyl acetate (50 mL) was added 7.5% palladium carbon (500 mg), and stirred vigorously at room temperature under a hydrogen atmosphere. After stirring for 6 hours, it was allowed to stand overnight, and vigorously stirred for another 5 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The title compound (431 mg) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.94 (3H, s), 6.60-6.64 (1H, m), 6.95 (1H, d, J = 9.1 Hz), 7.23 - 7.28 (2H, m), 8.06 -8.22 (1H, m).

(6b) 4-chloro-5-methoxy-2,3-dihydro-1H-indole

To a solution of the compound ( 430 mg), m. Methylene chloride and a saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture, and the mixture was extracted three times with dichloromethane. The title compound (446 mg) was obtained as a colorless solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 3.08 (2H, t, J = 8.5 Hz), 3.59 (3H, t, J = 8.5 Hz), 3.82 (3H, s), 6.48 (1H, d, J = 8.5 Hz), 6.63 (1H, d, J = 8.5 Hz).

(6c) 1-(4-Chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-2-[2-(ethylsulfonyl)phenyl]ethanone

N-methyl group was added to a solution of the compound obtained in Example (6b) (210 mg) in N,N-dimethylformamide (6 mL) The morpholine (0.126 mL) was stirred at room temperature for 15 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl The ruthenium osmium (475 mg) and [2-(ethylsulfonyl)phenyl]acetic acid (339 mg) were stirred at room temperature for 14 hours and 30 minutes. The title compound (405 mg) was obtained as a colorless solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3 Hz), 3.20 (2H, q, J = 7.3 Hz), 3.28 (2H, t, J = 8.5 Hz), 3.88 ( 3H, s), 4.25 (2H, t, J = 8.5 Hz), 4.35 (2H, s), 6.74 (1H, d, J = 9.1 Hz), 7.39 (1H, d, J = 7.9 Hz), 7.48- 7.54 (1H, m), 7.59-7.65 (1H, m), 7.98-8.05 (2H, m).

MS (APCI) m/z: 394 (M+H) ⁺ .

(6d) 1-(4-Chloro-5-hydroxy-2,3-dihydro-1H-indol-1-yl)-2-[2-(ethylsulfonyl)phenyl]ethanone

A solution of the compound (400 mg) obtained from m. m. After stirring for 5 minutes, the reaction solution was warmed to room temperature and stirred for 4 hours. Water was gradually added to the reaction mixture, and the mixture was extracted with a methanol/dichloromethane (1:4) mixture for 8 times, and then the combined organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The title compound (403 mg) was obtained.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.09 (3H, t, J = 7.3Hz), 3.18 (2H, t, J = 8.5Hz), 3.24-3.32 (2H, m), 4.17-4.30 (4H,m), 6.73 (1H,d,J=8.5Hz), 7.46-7.50(1H,m),7.54-7.59(1H,m),7.67-7.76(2H,m),7.88-7.92(1H , m), 9.90 (1H, s).

MS (APCI) m/z: 380 (M+H) ⁺ .

(6e) 1-[5-(4-Bromo-3-methylphenoxy)-4-chloro-2,3-dihydro-1H-indol-1-yl]-2-[2-(B Alkylsulfonyl)phenyl]ethanone

The compound (150 mg) obtained in Example (6d) and 1,4-two of 1-bromo-4-iodo-2-methylbenzene (235 mg) To the solution of the alkane (10 mL), copper (I) iodide (7.52 mg), N,N-dimethylglycine (8.14 mg) and cesium carbonate (257 mg) were added, and the mixture was stirred at 100 ° C for 11 hours. After cooling to room temperature, it was allowed to stand overnight, and then stirred at 100 ° C for 30 minutes, and the reaction liquid was filtered through celite. The obtained filtrate was concentrated under reduced pressure. EtOAcjjjjjjjj

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.5 Hz), 2.35 (3H, s), 3.20 (2H, q, J = 7.5 Hz), 3.32 (2H, t, J = 8.5 Hz), 4.31 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.62 (1H, dd, J = 8.5, 3.0 Hz), 6.79-6.82 (1H, m), 6.87 (1H) , d, J = 8.5 Hz), 7.36-7.44 (2H, m), 7.50-7.55 (1H, m), 7.60-7.66 (1H, m), 8.00-8.05 (2H, m).

MS (APCI) m/z: 548 (M+H) ⁺ .

(6f){4'-[(4-Chloro-1-{[2-(ethylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl) Ethyloxy]-2'-methylbiphenyl-4-yl}ethyl acetate

Compound (115 mg) obtained in Example (6e), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate B Ester (60.8 mg) and To a suspension of triphenylphosphine palladium (0) (24.2 mg) in 1,2-dimethoxyethane (10 mL), an aqueous solution (1 mL) of potassium phosphate (133 mg) was added and stirred at 90 ° C for 6 hours. . After cooling to room temperature, the organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate /hexane) The title compound (75.2 mg).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.25-1.31 (6H, m), 2.23 (3H, s), 3.16-3.24 (2H, m), 3.34 (2H, t, J = 8.5 Hz), 3.65 (2H, s), 4.18 (2H, q, J = 7.1 Hz), 4.32 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.75-6.79 (1H, m), 6.82-6.85 ( 1H, m), 6.93 (1H, d, J = 8.5 Hz), 7.15 (1H, d, J = 7.9 Hz), 7.24-7.41 (5H, m), 7.49-7.55 (1H, m), 7.60-7.66 (1H, m), 8.00-8.07 (2H, m).

MS (APCI) m/z: 632 (M+H) ⁺ .

(6g){4'-[(4-Chloro-1-{[2-(ethylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-methylbiphenyl-4-yl}acetic acid

The compound obtained in Example (6f) (74.0 mg) was dissolved in tetrahydrofuran (2 mL) and ethanol (1 mL), and 1N aqueous sodium hydroxide (0.351 mL) was added. After the reaction mixture was stirred at room temperature for 14 hours, 1N hydrochloric acid (0.360 mL) was added, and the organic solvent was distilled off under reduced pressure. The title compound (56.8 mg) was obtained as a colorless solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.23 (3H, s), 3.20 (2H, q, J = 7.3 Hz), 3.34 (2H, t, J = 8.5 Hz), 3.71 (2H, s), 4.32 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.74 - 6.79 (1H, m), 6.82-6.86 (1H, m), 6.93 (1H, d, J = 8.5 Hz), 7.14 (1H, d, J = 8.5 Hz), 7.26-7.41 (5H, m), 7.48-7.55 (1H, m), 7.60-7.66 (1H, m), 8.00-8.06 (2H, m).

MS (APCI) m/z: 604 (M+H) ⁺ .

(Example 7)

{2'-Fluoro-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5 -yl)oxy]biphenyl-4-yl}acetic acid

(7a) 5-(4-Bromo-3-fluorophenoxy)-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

To 1-bromo-2-fluoro-4-iodobenzene (1.45 g) and 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester (600 mg) 1,4-two Copper (I) (22.9 mg), N,N-dimethylglycine (24.8 mg) and cesium carbonate (1.57 g) were added to the solution of the alkane (8 mL), and the reaction mixture was stirred at 100 ° C for 6 hours. . After cooling to room temperature, it was allowed to stand overnight, and again stirred at 100 ° C for 9 hours, and the reaction liquid was filtered through celite. The obtained filtrate was concentrated under reduced pressure.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.56 (9H, s), 2.03 (3H, s), 3.03 (2H, t, J = 8.8 Hz), 3.97 - 4.10 (2H, m), 6.54 - 6.63 (2H, m), 6.77-6.85 (1H, m), 7.23-7.77 (2H, br m).

(7b) 1-[5-(4-Bromo-3-fluorophenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-(A Alkylsulfonyl)phenyl]ethanone

4N hydrochloric acid was added to a solution of the compound (165 mg) obtained in Example (7a) in dichloromethane (3 mL) Alkane solution (3 mL) was stirred at room temperature for 1 hour and 30 min. The reaction solution was concentrated to give crude 5-(4-bromo-3-fluorophenoxy)-4-methyl-2,3-dihydro-1H-indole hydrochloride.

Add N-methyl to a solution of the obtained compound in N,N-dimethylformamide (4 mL) The morpholine (0.0858 mL) was stirred at room temperature for 15 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl The ruthenium hydride (162 mg) and [2-(methylsulfonyl)phenyl]acetic acid (109 mg) were stirred at room temperature for 14 hours and 30 minutes. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.08 (3H, s), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 4.30 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.56-6.65 (2H, m), 6.81 (1H, d, J = 8.5 Hz), 7.35-7.44 (2H, m), 7.50-7.56 (1H, m), 7.60-7.65 ( 1H, m), 8.02 (1H, d, J = 8.5 Hz), 8.06-8.10 (1H, m).

MS (APCI) m/z: 518 (M+H) ⁺ .

(7c){2'-Fluoro-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole Ethyl-5-yl)oxy]biphenyl-4-yl}ethyl acetate

Compound (50.0 mg) obtained in Example (7b), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetic acid Ethyl ester (42.0 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (7.88 mg) of 1,2-dimethoxy An aqueous solution (0.5 mL) of sodium carbonate (30.7 mg) was added to a suspension of hexane (2 mL), and the mixture was reacted at 130 ° C for 20 minutes in a microwave reaction apparatus. After cooling to room temperature, the reaction solution was poured into water and extracted with ethyl acetate three times. After the combined organic layer was dried over sodium sulfate, the solvent was evaporated to dryness, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a pale yellow amorphous solid title. Compound (50.0 mg).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.27 (3H, t, J = 7.3Hz), 2.13 (3H, s), 3.13 (3H, s), 3.23 (2H, t, J = 7.3Hz), 3.65 (2H, s), 4.17 (2H, q, J = 7.3 Hz), 4.31 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.61-6.67 (1H, m), 6.73 (1H , dd, J = 8.5, 1.8 Hz), 6.87 (1H, d, J = 8.5 Hz), 7.29-7.39 (4H, m), 7.44 - 7.49 (2H, m), 7.50 - 7.56 (1H, m), 7.60-7.65 (1H, m), 8.03 (1H, d, J = 9.1 Hz), 8.06-8.10 (1H, m).

MS (APCI) m/z: 602 (M+H) ⁺ .

(7d){2'-Fluoro-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole哚-5-yl)oxy]biphenyl-4-yl}acetic acid

The compound obtained in Example (7c) (49.0 mg) was dissolved in tetrahydrofuran (1 mL) and ethanol (1 mL), and 1N aqueous sodium hydroxide was added. (0.244 mL). After the reaction mixture was stirred at room temperature for 11 hr, 1N hydrochloric acid (. After adding water to the residue, it was extracted with dichloromethane three times. The title compound (45.6 mg) was obtained as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.13 (3H, s), 3.13 (3H, s), 3.23 (2H, t, J = 8.5 Hz), 3.70 (2H, s), 4.31 (2H, t , J = 8.5 Hz), 4.37 (2H, s), 6.61-6.66 (1H, m), 6.73 (1H, dd, J = 8.5, 2.4 Hz), 6.87 (1H, d, J = 8.5 Hz), 7.29 -7.39 (4H, m), 7.46-7.55 (3H, m), 7.60-7.65 (1H, m), 8.03 (1H, d, J = 8.5 Hz), 8.06-8.09 (1H, m).

MS (APCI) m/z: 574 (M+H) ⁺ .

(Example 8)

{2'-Methoxy-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole -5-yl)oxy]biphenyl-4-yl}acetic acid

(8a) 5-(4-bromo-3-methoxyphenoxy)-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

1-bromo-4-iodo-2-methoxybenzene (1.51 g) and 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester (600 mg 1,4-two Copper (I) iodide (22.9 mg), N,N-dimethylglycine (24.8 mg) and cesium carbonate (1.57 g) were added to the solution of the alkane (8 mL), and stirred at 100 ° C for 6 hours. After cooling to room temperature, it was allowed to stand overnight, and again stirred at 100 ° C for 9 hours, and the reaction liquid was filtered through celite. The obtained filtrate was concentrated under reduced pressure. EtOAcjjjjjjj

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.55 (9H, s), 2.05 (3H, s), 3.03 (2H, t, J = 8.8Hz), 3.83 (3H, s), 3.97-4.09 (2H m), 6.24 (1H, dd, J = 8.5, 2.4 Hz), 6.54 (1H, br s), 6.75-6.84 (1H, m), 7.20-7.74 (2H, m).

(8b) 1-[5-(4-Bromo-3-methoxyphenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2- (methylsulfonyl)phenyl]ethanone

4N hydrochloric acid was added to a solution of the compound (400 mg) obtained in Example (8a) in dichloromethane (4 mL) Alkane solution (4 mL) was stirred at room temperature for 2 h 30 min. The reaction solution was concentrated to give crude 5-(4-bromo-3-methoxyphenoxy)-4-methyl-2,3-dihydro-1H-indole hydrochloride (336 mg).

Add N-methyl to a solution of the obtained compound (336 mg) in N,N-dimethylformamide (10 mL) The morpholine (0.202 mL) was stirred at room temperature for 15 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (382 mg) and [2-(methylsulfonyl)phenyl]acetic acid (256 mg) were stirred at room temperature for 16 h 30 min. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.11 (3H, s), 3.12 (3H, s), 3.22 (2H, t, J = 8.5Hz), 3.84 (3H, s), 4.29 (2H, t , J = 8.5 Hz), 4.36 (2H, s), 6.25-6.29 (1H, m), 6.54 - 6.56 (1H, m), 6.80 (1H, d, J = 8.5 Hz), 7.34 - 7.39 (2H, m), 7.50-7.55 (1H, m), 7.60-7.65 (1H, m), 7.99 (1H, d, J = 9.1 Hz), 8.06-8.09 (1H, m).

MS (APCI) m/z: 530 (M+H) ⁺ .

(8c){2'-Methoxy-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H -吲哚-5-yl)oxy]biphenyl-4-yl}ethyl acetate

Compound (50.0 mg) obtained in Example (8b), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetic acid Ethyl ester (41.0 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (7.70 mg) of 1,2-dimethoxy An aqueous solution (0.5 mL) of sodium carbonate (30.0 mg) was added to a solution of hexane (2 mL), and the mixture was reacted at 130 ° C for 20 minutes in a microwave reaction apparatus. After cooling to room temperature, the reaction solution was poured into water and extracted with ethyl acetate three times. After the combined organic layer was dried over sodium sulfate (MgSO4). Mg).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.27 (3H, t, J = 7.3Hz), 2.17 (3H, s), 3.13 (3H, s), 3.23 (2H, t, J = 8.5Hz), 3.63 (2H, s), 3.76 (3H, s), 4.16 (2H, q, J = 7.3 Hz), 4.30 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.41 (1H, dd , J = 8.5, 2.4 Hz), 6.60-6.63 (1H, m), 6.86 (1H, d, J = 8.5 Hz), 7.17 (1H, d, J = 8.5 Hz), 7.31 (2H, d, J = 7.9 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.45 (2H, d, J = 7.9 Hz), 7.50-7.55 (1H, m), 7.60-7.65 (1H, m), 8.00 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).

MS (APCI) m/z: 614 (M+H) ⁺ .

(8d){2'-Methoxy-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H -吲哚-5-yl)oxy]biphenyl-4-yl}acetic acid

The compound (40.0 mg) obtained in Example (8c) was dissolved in tetrahydrofuran (1 mL) and ethanol (1 mL), and 1N aqueous sodium hydroxide (0.196 mL) was added. After the reaction mixture was stirred at room temperature for 11 hr, 1N hydrochloric acid (0.21 mL). After adding water to the residue, it was extracted three times with dichloromethane. The title compound (37.4 mg) was obtained.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.16 (3H, s), 3.13 (3H, s), 3.23 (2H, t, J = 8.5 Hz), 3.68 (2H, s), 3.75 (3H, s ), 4.30 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.41 (1H, dd, J = 7.9, 2.4 Hz), 6.60-6.62 (1H, m), 6.86 (1H, d, J = 8.5 Hz), 7.17 (1H, d, J = 8.5 Hz), 7.31 (2H, d, J = 7.9 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.46 (2H, d, J = 7.9 Hz), 7.50-7.55 (1H, m), 7.59-7.65 (1H, m), 8.01 (1H, d, J = 9.1 Hz), 8.06-8.09 (1H, m).

MS (APCI) m/z: 586 (M+H) ⁺ .

(Example 9)

{2',5'-Dimethyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H -吲哚-5-yl)oxy]biphenyl-4-yl}acetic acid

(9a) 3-(4-Bromo-2,5-dimethylphenoxy)-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

1-bromo-2,5-dimethyl-4-iodobenzene (1.50 g) and 5-butyl-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester (600mg) of 1,4-two Copper (I) iodide (22.9 mg), N,N-dimethylglycine (24.8 mg) and cesium carbonate (1.57 g) were added to the alkane (9 mL) solution, and stirred at 100 ° C for 4 hours and 30 minutes. After cooling to room temperature, it was allowed to stand overnight, and again stirred at 100 ° C for 9 hours, and the reaction liquid was filtered through celite. The obtained filtrate was concentrated under reduced pressure. EtOAcjjjjjjjj

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.56 (9H, s), 2.07 (3H, s), 2.20-2.27 (6H, m), 3.03 (2H, t, J = 8.8 Hz), 3.99-4.08 (2H, m), 6.40-6.48 (1H, m), 6.58-6.71 (1H, m), 7.19-7.70 (2H, m).

(9b) 1-[5-(4-Bromo-2,5-dimethylphenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[ 2-(methylsulfonyl)phenyl]ethanone

4N hydrochloric acid was added to a solution of the compound (300 mg) obtained in Example (9a) in dichloromethane (4 mL) A solution of the alkane (4 mL) was stirred at room temperature for 1 hour. The reaction solution was concentrated to give crude 5-(4-bromo-2,5-dimethylphenoxy)-4-methyl-2,3-dihydro-1H-indole hydrochloride (312 mg).

Add N-methyl to a solution of the obtained compound (312 mg) in N,N-dimethylformamide (4 mL) The morpholine (0.153 mL) was stirred at room temperature for 15 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl The guanidine (288 mg) and [2-(methylsulfonyl)phenyl]acetic acid (193 mg) were stirred at room temperature for 18 hours and 30 minutes. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.13 (3H, s), 2.21-2.30 (6H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.2 Hz), 4.28 (2H) , t, J = 8.5 Hz), 4.36 (2H, s), 6.49 (1H, s), 6.61 (1H, d, J = 8.5 Hz), 7.34 - 7.38 (2H, m), 7.49 - 7.55 (1H, m), 7.59-7.64 (1H, m), 7.94 (1H, d, J = 8.5 Hz), 8.05-8.10 (1H, m).

MS (APCI) m/z: 528 (M+H) ⁺ .

(9c){2',5'-Dimethyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-di Hydrogen-1H-indol-5-yl)oxybiphenyl-4-yl}ethyl acetate

Compound (50.0 mg) obtained in Example (9b), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetic acid Ethyl ester (41.2 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (7.7 mg) of 1,2-dimethoxy Add sodium carbonate to ethane (2mL) solution An aqueous solution (0.5 mL) (30.1 mg) was reacted at 130 ° C for 20 minutes in a microwave reactor. The same reaction was carried out twice more. After cooling the respective reaction liquids to room temperature, they were combined and poured into water, and extracted with ethyl acetate three times. After the combined organic layer was dried over sodium sulfate, EtOAc (EtOAc) 48.2 mg).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.28 (3H, t, J = 7.3 Hz), 2.14 (3H, s), 2.19 (3H, s), 2.28 (3H, s), 3.12 (3H, s ), 3.24 (2H, t, J = 8.5 Hz), 3.65 (2H, s), 4.18 (2H, q, J = 7.3 Hz), 4.29 (2H, t, J = 8.5 Hz), 4.37 (2H, s ), 6.54 (1H, s), 6.68 (1H, d, J = 8.5 Hz), 7.08 (1H, s), 7.25-7.33 (4H, m), 7.36 (1H, d, J = 7.3 Hz), 7.49 -7.54 (1H, m), 7.59-7.64 (1H, m), 7.96 (1H, d, J = 9.1 Hz), 8.06-8.09 (1H, m).

MS (APCI) m/z: 612 (M+H) ⁺ .

(9d){2',5'-Dimethyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-di Hydrogen-1H-indol-5-yl)oxybiphenyl-4-yl}acetic acid

The compound obtained in Example (9c) (47.0 mg) was dissolved in tetrahydrofuran (1 mL) and ethanol (1 mL), and 1N aqueous sodium hydroxide (0.230 mL) was added. After the reaction mixture was stirred at room temperature for 11 hr, 1N hydrochloric acid (. After adding water to the residue, it was extracted three times with dichloromethane. The title compound (42.8 mg) was obtained.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.14 (3H, s), 2.19 (3H, s), 2.28 (3H, s), 3.12 (3H, s), 3.24 (2H, t, J = 8.5 Hz ), 3.71 (2H, s), 4.29 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.53 (1H, s), 6.68 (1H, d, J = 8.5 Hz), 7.07 (1H) , s), 7.26-7.38 (5H, m), 7.49-7.54 (1H, m), 7.59-7.64 (1H, m), 7.96 (1H, d, J = 9.1 Hz), 8.07 (1H, d, J =7.9Hz).

MS (APCI) m/z: 584 (M+H) ⁺ .

(Embodiment 10)

{2'-Fluoro-3-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H -吲哚-5-yl)oxy]biphenyl-4-yl}acetic acid

(10a) 1-[5-(4-Bromo-3-fluoro-2-methylphenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2- [2-(methylsulfonyl)phenyl]ethanone

To a solution of 3-(4-bromo-3-fluoro-2-methylphenoxy)-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester (85.0 mg) Add 4N hydrochloric acid to dichloromethane (2mL) solution Alkane solution (2 mL) was stirred at room temperature for 3 h. The reaction solution was concentrated to give crude 5-(4-bromo-3-fluoro-2-methylphenoxy)-4-methyl-2,3-dihydro-1H-indole hydrochloride (90.0 mg). ).

Add N-methyl to a solution of the obtained compound (90.0 mg) in N,N-dimethylformamide (5 mL) The morpholine (0.032 mL) was stirred at room temperature for 15 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (80.9 mg) and [2-(methylsulfonyl)phenyl]acetic acid (83.5 mg) were stirred at room temperature for 6 hours. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.10 (3H, s), 2.28-2.30 (3H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 4.29 (2H) , t, J = 8.5 Hz), 4.36 (2H, s), 6.30 (1H, d, J = 8.5 Hz), 6.67 (1H, d, J = 8.5 Hz), 7.18-7.24 (1H, m), 7.36 (1H, d, J = 7.3 Hz), 7.50-7.55 (1H, m), 7.59-7.65 (1H, m), 7.95-7.99 (1H, m), 8.07 (1H, d, J = 7.9 Hz).

MS (APCI) m/z: 532 (M+H) ⁺ .

(10b){2'-Fluoro-3'-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3- Dihydro-1H-indol-5-yl)oxy]biphenyl-4-yl}ethyl acetate

Compound (70.0 mg) obtained in Example (10a), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetic acid Ethyl ester (57.2 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (10.7 mg) of 1,2-dimethoxy An aqueous solution (0.5 mL) of sodium carbonate (41.8 mg) was added to a solution of hexane (2 mL), and the mixture was reacted at 130 ° C for 20 minutes in a microwave reaction apparatus. After cooling to room temperature, the reaction solution was poured into water and extracted with ethyl acetate three times. After the combined organic layer was dried over sodium sulfate, the solvent was evaporated to give crystals crystals crystals (63.3 mg).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.16 (3H, s), 2.29-2.31 (3H, m), 3.12 (3H, s), 3.20-3.27 (2H,m), 3.65(2H,s), 4.17(2H,q,J=7.3Hz), 4.30(2H,t,J=8.2Hz), 4.36(2H,s),6.46(1H,d, J=8.5 Hz), 6.73 (1H, d, J=8.5 Hz), 7.05-7.12 (1H, m), 7.31-7.49 (5H, m), 7.50-7.55 (1H, m), 7.59-7.65 (1H , m), 7.98 (1H, d, J = 9.1 Hz), 8.07 (1H, d, J = 9.1 Hz).

MS (APCI) m/z: 616 (M+H) ⁺ .

(10c){2'-Fluoro-3'-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3- Dihydro-1H-indol-5-yl)oxy]biphenyl-4-yl}acetic acid

The compound (61.0 mg) obtained in Example (10b) was dissolved in tetrahydrofuran (2 mL) and ethanol (2mL), and 1N aqueous sodium hydroxide (0.297mL) was added. After the reaction mixture was stirred at room temperature for 17 hrs over 30 min, 1N hydrochloric acid (0.310 mL) After adding water to the residue, it was extracted three times with dichloromethane. The title compound (55.3 mg) was obtained.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.15 (3H, s), 2.29-2.32 (3H, m), 3.12 (3H, s), 3.23 (2H, t, J = 8.5 Hz), 3.70 (2H , s), 4.30 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.46 (1H, d, J = 8.5 Hz), 6.73 (1H, d, J = 8.5 Hz), 7.07-7.13 (1H,m),7.33-7.39(3H,m),7.46-7.55(3H,m),7.59-7.65(1H,m),7.99(1H,d,J=8.5Hz),8.06-8.09(1H , m).

MS (APCI) m/z: 588 (M+H) ⁺ .

(Example 11)

{2'-Methoxy-5'-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-di Hydrogen-1H-indol-5-yl)oxy]biphenyl-4-yl}acetic acid

(11a) 4-bromo-5-methoxy-2-methylaniline

5-methoxy-2-methylaniline (3.00 g) in chloroform solution (50 mL) was cooled to an internal temperature of 5 ° C, and N-bromosuccinimide (3.89 g) was added in 10 portions, followed by stirring at the same temperature. 5 hours. The temperature was raised to room temperature, and a 1N aqueous sodium hydroxide solution (200 mL) was added, and the mixture was extracted three times with chloroform. The obtained organic layers were combined, dried over sodium sulfate, and then evaporated. The title compound (4.51 g) was obtained from m.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.08 (3H, s), 3.63 (2H, s s), 3.82 (3H, s), 6.27 (1H, s), 7.17 (1H, s).

(11b) 1-bromo-4-iodo-2-methoxy-5-methylbenzene

The compound (1.00 g) obtained in Example (11a) was dissolved in water (30 mL) and sulfuric acid (2 mL), and the mixture was stirred at 0 ° C. Next, an aqueous solution of sodium nitrite (335 mg) (2 mL) was slowly added, and stirred at an internal temperature of 0 °C. After 5 minutes, a potassium iodide (768 mg) aqueous solution (2 mL) was added over a period of 5 minutes, and the reaction mixture was warmed to room temperature. After 1 hour, the reaction solution was warmed to 105 ° C and stirred for additional 1 hour. After the reaction solution was cooled to room temperature, it was extracted twice with dichloromethane, and the obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate. After that, it was dehydrated with sodium sulfate. The obtained solution was concentrated under reduced pressure. EtOAcjjjjjjjj

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.35 (3H, s), 3.86 (3H, s), 7.28 (1H, s), 7.39 (1H, s).

(11c) 5-(4-Bromo-5-methoxy-2-methylphenoxy)-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

The compound obtained in Example (11b) (590 mg) and 1,4-diethyl 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester (450 mg) Copper (I) iodide (17.2 mg), N,N-dimethylglycine (18.6 mg) and cesium carbonate (1.18 g) were added to the alkane (8 mL) solution, and stirred at 100 ° C for 11 hours. After cooling to room temperature, it was allowed to stand overnight, and again stirred at 100 ° C for 9 hours and 30 minutes, and the reaction liquid was filtered with celite. The obtained filtrate was concentrated under reduced pressure. EtOAcjjjjjjjj

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.56 (9H, s), 2.10 (3H, s), 2.20 (3H, s), 3.04 (2H, t, J = 8.5 Hz), 3.68 (3H, s ), 3.98-4.08 (2H, m), 6.25 (1H, br s), 6.65 (1H, br s), 7.16-7.70 (2H, m).

(11d) 1-[5-(4-Bromo-5-methoxy-2-methylphenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]- 2-[2-(methylsulfonyl)phenyl]ethanone

4N hydrochloric acid was added to a solution of the compound (174 mg) obtained in Example (11c) in dichloromethane (3 mL) Alkane solution (3 mL) was stirred at room temperature for 3 h. The reaction solution was concentrated to give crude 5-(4-bromo-5-methoxy-2-methylphenoxy)-4-methyl-2,3-dihydro-1H-indole hydrochloride.

Add N-methyl to a solution of the obtained compound in N,N-dimethylformamide (5 mL) The morpholine (0.0588 mL) was stirred at room temperature for 45 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (139 mg) and [2-(methylsulfonyl)phenyl]acetic acid (124 mg) were stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.17 (3H, s), 2.19 (3H, s), 3.12 (3H, s), 3.23 (2H, t, J = 8.5 Hz), 3.71 (3H, s ), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.29 (1H, s), 6.58 (1H, d, J = 9.1 Hz), 7.34 - 7.39 (2H, m), 7.50 -7.55 (1H, m), 7.59-7.65 (1H, m), 7.93 (1H, d, J = 8.5 Hz), 8.06-8.09 (1H, m).

MS (APCI) m/z: 544 (M+H) ⁺ .

(11e){2'-Methoxy-5'-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2, 3-dihydro-1H-indol-5-yl)oxy]biphenyl-4-yl}ethyl acetate

Compound (60.0 mg) obtained in Example (11d), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetic acid Ethyl ester (48.0 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (9.00 mg) of 1,2-dimethoxy An aqueous solution (0.5 mL) of sodium carbonate (35.0 mg) was added to a solution of hexane (2 mL), and was then subjected to a microwave reaction apparatus. The reaction was carried out at 130 ° C for 20 minutes. After cooling to room temperature, the reaction solution was poured into water and extracted with ethyl acetate three times. After the combined organic layer was dried over sodium sulfate, the solvent was evaporated to dryness, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a pale yellow amorphous solid title. Compound (53.5 mg).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.20-2.25 (6H, m), 3.12 (3H, s), 3.24 (2H, t, J = 8.2 Hz ), 3.60-3.68 (5H, m), 4.16 (2H, q, J = 7.3 Hz), 4.29 (2H, t, J = 8.2 Hz), 4.37 (2H, s), 6.37 (1H, s), 6.65 (1H,d,J=8.5Hz), 7.16(1H,s), 7.29-7.33(2H,m),7.34-7.38(1H,m),7.44-7.54(3H,m),7.58-7.64(1H , m), 7.94 (1H, d, J = 8.5 Hz), 8.05-8.09 (1H, m).

MS (APCI) m/z: 628 (M+H) ⁺ .

(11f){2'-Methoxy-5'-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2, 3-dihydro-1H-indol-5-yl)oxy]biphenyl-4-yl}acetic acid

The compound obtained in Example (11e) (52.0 mg) was dissolved in tetrahydrofuran (2 mL) and ethanol (2mL), and 1N aqueous sodium hydroxide (0.248 mL) was added. After the reaction mixture was stirred at room temperature for 18 hr, 1N hydrochloric acid (0.30 mL) The title compound (52.5 mg) was obtained as a colorless solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.22 (3H, s), 2.23 (3H, s), 3.12 (3H, s), 3.24 (2H, t, J = 8.5 Hz), 3.62 (3H, s ), 3.69 (2H, s), 4.29 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.37 (1H, s), 6.66 (1H, d, J = 8.5 Hz), 7.16 (1H) , s), 7.30-7.38 (3H, m), 7.47-7.55 (3H, m), 7.59-7.65 (1H, m), 7.95 (1H, d, J = 8.5 Hz), 8.06-8.09 (1H, m ).

MS (APCI) m/z: 600 (M+H) ⁺ .

(Embodiment 12)

{2'-(Methoxymethyl)-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-dihydro- 1H-indol-5-yl)oxy]biphenyl-4-yl}acetic acid

(12a) 1-bromo-4-iodo-2-(methoxymethyl)benzene

To a solution of (2-bromo-5-iodophenyl)methanol (1.00 g) in THF (10 mL). Methyl iodide (0.219 mL) was added and stirred at room temperature for 2 hours. After adding water to the reaction liquid, it was extracted with ethyl acetate three times. The combined organic layer was dried with EtOAc EtOAcjjjjjjjj

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.48 (3H, s), 4.46 (2H, s), 7.25 (1H, d, J = 8.5 Hz), 7.46 (1H, dd, J = 8.5, 2.1 Hz ), 7.78-7.80 (1H, m).

(12b) 5-[4-Bromo-3-(methoxymethyl)phenoxy]-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

The compound obtained in Example (12a) (800 mg) and the 1,4-dicarboxylate of 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid (610 mg) Copper (I) iodide (23.3 mg), N,N-dimethylglycine (25.2 mg) and cesium carbonate (1.59 g) were added to the alkane (10 mL) solution, and stirred at 100 ° C for 5 hours and 30 minutes. After cooling to room temperature, it was allowed to stand overnight, and again stirred at 100 ° C for 2 hours, and the reaction liquid was filtered with celite. The obtained filtrate was concentrated under reduced pressure.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.56 (9H, s), 2.04 (3H, s), 3.02 (2H, t, J = 8.5 Hz), 3.44 (3H, s), 3.99-4.08 (2H , m), 4.45 (2H, s), 6.62 (1H, dd, J = 8.5, 3.0 Hz), 6.75-6.81 (1H, br m), 7.00-7.03 (1H, m), 7.20-7.73 (2H, m).

(12c) 1-{5-[4-Bromo-3-(methoxymethyl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2 -[2-(methylsulfonyl)phenyl]ethanone

4N hydrochloric acid was added to a solution of the compound (300 mg) obtained in Example (12b) in dichloromethane (3 mL) Alkane solution (3 mL) was stirred at room temperature for 3 h and 20 min. The reaction solution was concentrated to give crude 5-[4-bromo-3-(methoxymethyl)phenoxy]-4-methyl-2,3-dihydro-1H-indole hydrochloride.

Add N-methyl to a solution of the obtained compound in N,N-dimethylformamide (5 mL) The morpholine (0.110 mL) was stirred at room temperature for 45 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (240 mg) and [2-(methylsulfonyl)phenyl]acetic acid (215 mg) were stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.10 (3H, s), 3.12 (3H, s), 3.21 (2H, t, J = 8.2Hz), 3.44 (3H, s), 4.29 (2H, t , J = 8.2 Hz), 4.37 (2H, s), 4.45 (2H, s), 6.65 (1H, dd, J = 8.5, 3.0 Hz), 6.77 (1H, d, J = 8.5 Hz), 7.01-7.04 (1H,m),7.34-7.38(1H,m), 7.40 (1H,d,J=8.5Hz), 7.50-7.55(1H,m), 7.60-7.64(1H,m),7.98(1H,d , J = 8.5 Hz), 8.05-8.09 (1H, m).

MS (APCI) m/z: 544 (M+H) ⁺ .

(12d){2'-(Methoxymethyl)-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3- Dihydro-1H-indol-5-yl)oxy]biphenyl-4-yl}ethyl acetate

Compound (60.0 mg) obtained in Example (12c), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetic acid Ethyl ester (48.0 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (9.00 mg) of 1,2-dimethoxy An aqueous solution (0.5 mL) of sodium carbonate (35.0 mg) was added to a solution of hexane (2 mL), and the mixture was reacted at 130 ° C for 20 minutes in a microwave reactor. After cooling to room temperature, the reaction solution was poured into water and extracted with ethyl acetate three times. After the combined organic layer was dried over sodium sulfate, the solvent was evaporated to dryness, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a pale yellow amorphous solid title. Compound (58.6 mg).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.28 (3H, t, J = 7.3Hz), 2.16 (3H, s), 3.13 (3H, s), 3.23 (2H, t, J = 8.5Hz), 3.31 (3H, s), 3.66 (2H, s), 4.19 (2H, q, J = 7.3 Hz), 4.26 - 4.33 (4H, m), 4.37 (2H, s), 6.80-6.86 (2H, m) , 7.07-7.09 (1H, m), 7.18 (1H, d, J = 8.5 Hz), 7.28-7.38 (5H, m), 7.50-7.55 (1H, m), 7.60-7.65 (1H, m), 8.00 (1H, d, J = 8.5 Hz), 8.06-8.09 (1H, m).

MS (APCI) m/z: 628 (M+H) ⁺ .

(12e){2'-(Methoxymethyl)-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3- Dihydro-1H-indol-5-yl)oxy]biphenyl-4-yl}acetic acid

The compound obtained in Example (12d) (56.0 mg) was dissolved in tetrahydrofuran (2 mL) and ethanol (2mL), and 1N aqueous sodium hydroxide (0.268mL) was added. After the reaction mixture was stirred at room temperature for 17 hrs over 30 min, 1N hydrochloric acid (0.30 mL) After adding water to the residue, it was extracted three times with dichloromethane. The title compound (57.3 mg) was obtained as a pale brown solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.16 (3H, s), 3.13 (3H, s), 3.23 (2H, t, J = 8.2 Hz), 3.31 (3H, s), 3.71 (2H, s ), 4.26-4.33 (4H, m), 4.37 (2H, s), 6.80-6.87 (2H, m), 7.06-7.09 (1H, m), 7.18 (1H, d, J = 7.9 Hz), 7.29- 7.39 (5H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 8.00 (1H, d, J = 9.1 Hz), 8.06-8.10 (1H, m).

MS (APCI) m/z: 600 (M+H) ⁺ .

(Example 13)

{2',3-Dimethyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-吲哚-5-yl)oxy]biphenyl-4-yl}acetic acid

(13a) 3-(4-Bromo-2,3-dimethylphenoxy)-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

To 1-bromo-4-iodo-2,3-dimethylbenzene (823 mg) and 5-butyl-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester ( 600mg) of 1,4-two To a solution of alkane (10 mL), copper (I) iodide (22.9 mg), N,N-dimethylglycine (24.8 mg) and cesium carbonate (1.57 g) were added, and the mixture was stirred at 100 ° C for 8 hours. Filter with diatomaceous earth. The obtained filtrate was concentrated under reduced pressure. EtOAcjjjjjjjj

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.55 (9H, s), 2.08 (3H, s), 2.31 (3H, s), 2.42 (3H, s), 3.02 (2H, t, J = 8.5 Hz ), 3.99-4.07 (2H, m), 6.31-6.40 (1H, m), 6.56-6.65 (1H, m), 7.18-7.68 (2H, m).

(13b) 1-[5-(4-Bromo-2,3-dimethylphenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[ 2-(methylsulfonyl)phenyl]ethanone

4N hydrochloric acid was added to a solution of the compound (435 mg) obtained in Example (13a) in dichloromethane (4 mL) Alkane solution (4 mL) was stirred at room temperature for 3 h 30 min. The reaction solution was concentrated to give crude 5-(4-bromo-2,3-dimethylphenoxy)-4-methyl-2,3-dihydro-1H-indole hydrochloride (374 mg).

Add N-methyl to a solution of the obtained compound (374 mg) in N,N-dimethylformamide (5 mL) The morpholine (0.166 mL) was stirred at room temperature for 40 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Wax (362 mg) and [2-(methylsulfonyl)phenyl]acetic acid (323 mg) were stirred at room temperature for 16 hours and 30 minutes. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.14 (3H, s), 2.28 (3H, s), 2.41 (3H, s), 3.11 (3H, s), 3.21. (2H, t, J = 8.5 Hz ), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.40 (1H, d, J = 8.5 Hz), 6.56 (1H, d, J = 8.5 Hz), 7.26-7.29 (1H , m), 7.36 (1H, d, J = 7.3 Hz), 7.49-7.54 (1H, m), 7.58-7.64 (1H, m), 7.92 (1H, d, J = 9.1 Hz), 8.05-8.08 ( 1H, m).

MS (APCI) m/z: 528 (M+H) ⁺ .

(13c){2',3'-Dimethyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-di Hydrogen-1H-indol-5-yl)oxy]biphenyl-4-yl}ethyl acetate

Compound (60.0 mg) obtained in Example (13b), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetic acid Ethyl ester (49.4mg) And [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (9.27 mg) in 1,2-dimethoxyethane (2 mL) An aqueous solution (0.5 mL) of sodium carbonate (36.1 mg) was added and reacted at 130 ° C for 20 minutes in a microwave reactor. After cooling to room temperature, the reaction solution was poured into water and extracted with ethyl acetate three times. After the combined organic layer was dried over sodium sulfate, the solvent was evaporated to dryness, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a pale yellow amorphous solid title. Compound (59.2 mg).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.28 (3H, t, J = 7.3 Hz), 2.19-2.24 (6H, m), 2.29 (3H, s), 3.11 (3H, s), 3.23 (2H) , t, J = 8.5 Hz), 3.66 (2H, s), 4.18 (2H, q, J = 7.3 Hz), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.57 (1H , d, J = 8.5 Hz), 6.64 (1H, d, J = 8.5 Hz), 6.96 (1H, d, J = 8.5 Hz), 7.23 - 7.38 (5H, m), 7.49 - 7.54 (1H, m) , 7.59-7.64 (1H, m), 7.94 (1H, d, J = 9.1 Hz), 8.06-8.09 (1H, m).

MS (APCI) m/z: 612 (M+H) ⁺ .

(13d){2',3'-Dimethyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-di Hydrogen-1H-indol-5-yl)oxy]biphenyl-4-yl}acetic acid

The compound (57.0 mg) obtained in Example (13c) was dissolved in tetrahydrofuran (2 mL) and ethanol (2 mL). After the reaction mixture was stirred at room temperature for 17 hrs over 30 min, 1N hydrochloric acid (0.300 <RTIgt; After adding water to the residue, it was extracted three times with dichloromethane. The title compound (54.2 mg) was obtained.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.19-2.23 (6H, m), 2.28 (3H, s), 3.11 (3H, s), 3.23 (2H, t, J = 8.5 Hz), 3.70 (2H) , s), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.56 (1H, d, J = 8.5 Hz), 6.64 (1H, d, J = 8.5 Hz), 6.96 (1H) , d, J = 8.5 Hz), 7.24 - 7.38 (5H, m), 7.49 - 7.54 (1H, m), 7.58 - 7.64 (1H, m), 7.94 (1H, d, J = 8.5 Hz), 8.07 ( 1H, d, J = 7.9Hz).

MS (APCI) m/z: 584 (M+H) ⁺ .

(Example 14)

{2-Fluoro-2'-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H -吲哚-5-yl)oxy]biphenyl-4-yl}acetic acid

(14a) Methyl 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate

Methyl 2-(4-bromo-3-fluorophenyl)acetate (5.33 g), bis(pinacolato) diboron (8.22 g), [1,1'-double ( Diphenylphosphino)ferrocene]dichloropalladium(II) methylene chloride complex (1.06 g) and potassium acetate (4.23 g) were suspended in N,N-dimethylformamide (100 mL). Stir at 100 ° C overnight. After adding diatomaceous earth to the reaction liquid, it was filtered, and the filtrate was diluted with ethyl acetate and water, and the insoluble matter was filtered off. The filtrate was washed with water and a brine. The title compound (6.87 g) was obtained from m.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.23-1.44 (12H, m), 3.60-3.79 (5H, m), 6.96-7.14 (2H, m), 7.66-7.79 (1H, m).

(14b) {2-Fluoro-2'-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-di Methyl-1H-indole-5-yl)oxy]biphenyl-4-yl}acetate

The compound obtained in Example (14a) (0.250 g), the compound obtained in Example (1b) (0.300 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) The methylene chloride complex (0.0476 g) and sodium carbonate (0.185 g) were suspended in 1,2-dimethoxyethane (3 mL) and water (0.75 mL), and placed in a microwave reactor at 130 ° C. Reaction for 20 minutes. After cooling to room temperature, ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine. The title compound (0.313 g) was obtained eluted eluted eluted

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.15 (3H, s), 2.15 (3H, s), 3.13 (3H, s), 3.18-3.28 (2H, m), 3.66 (2H, s), 3.74 (3H, s), 4.25-4.33 (2H, m), 4.37 (2H, s), 6.69-6.88 (3H, m), 7.03-7.22 (4H, m), 7.33-7.39 (1H, m), 7.47 -7.67 (2H, m), 7.97-8.10 (2H, m).

(14c){2-Fluoro-2'-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-di Hydrogen-1H-indol-5-yl)oxy]biphenyl-4-yl}acetic acid

The compound (0.443 g) obtained in Example (14b) was dissolved in tetrahydrofuran (2 mL) and ethanol (2 mL). 1N hydrochloric acid was added to the reaction mixture to neutralize it, and the mixture was extracted three times with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. EtOAc/EtOAc (EtOAc:EtOAc) The title compound (0.361 g).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.15 (3H, s), 2.15 (3H, s), 3.13 (3H, s), 3.19-3.26 (2H, m), 3.69 (2H, s), 4.27 -4.33(2H,m), 4.37(2H,s), 6.70-6.88(3H,m),7.06-7.39(5H,m),7.49-7.65(2H,m),7.98-8.10(2H,m) .

MS (APCI) m/z: 588 (M+H) ⁺ .

(Example 15)

{2'-Methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole- 5-yl)oxy]biphenyl-3-yl}acetic acid

(15a){2'-Methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H- Ethyl-5-yl)oxy]biphenyl-3-yl}ethyl acetate

3-Ethoxycarbonylmethylphenylboronic acid (60.7 mg), [1,1' was added to a solution of the compound (100 mg) obtained in Example (1b) (1,2-dimethoxyethane (4 mL). - bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.9 mg), sodium carbonate (61.8 mg), water (1 mL), and reacted at 130 ° C for 20 minutes in a microwave reactor. Water (1 mL) was added to the mixture. The residue obtained was purified by silica gel chromatography eluting elut elut

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 2.16 (3H, s), 2.22 (3H, s), 3.13 (3H, s), 3.23 (2H, t , J = 8.5 Hz), 3.64 (2H, s), 4.16 (2H, q, J = 7.3 Hz), 4.30 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.70-6.75 (1H , m), 6.77-6.80 (1H, m), 6.84 (1H, d, J = 8.5 Hz), 7.13 (1H, d, J = 8.5 Hz), 7.18-7.27 (3H, m), 7.32-7.40 ( 2H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 8.00 (1H, d, J = 9.1 Hz), 8.05-8.10 (1H, m).

(15b){2'-Methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-吲哚-5-yl)oxy]biphenyl-3-yl}acetic acid

A 2 M aqueous sodium hydroxide solution (0.186 mL) was added to a solution of the compound (l. After adding 2 M hydrochloric acid to the reaction liquid to make it acidic, water (6 mL) was added, and the organic solvent was distilled off under reduced pressure. The reaction mixture was extracted with dichloromethane, dried over magnesium sulfate The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 2.08 (3H, s), 2.18 (3H, s), 3.16-3.25 (5H, m), 3.61 (2H, s), 4.24-4.36 (4H, m), 6.66-6.72 (1H, m), 6.79-6.85 (2H, m), 7.12 (1H, d, J = 8.5 Hz), 7.17-7.25 (3H, m), 7.33-7.39 (1H, m) , 7.46-7.50 (1H, m), 7.55-7.61 (1H, m), 7.67-7.73 (1H, m), 7.87 (1H, d, J = 8.5 Hz), 7.95-7.99 (1H, m), 12.34 (1H, br s).

MS (APCI) m/z: 570 (M+H) ⁺ .

(Embodiment 16)

3-{2'-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole哚-5-yl)oxy]biphenyl-4-yl}propionic acid

(16a) 3-{2'-Methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-dihydro- 1H-indol-5-yl)oxy]biphenyl-4-yl}propionic acid ethyl ester

Add [4-(2-ethoxycarbonylethyl)phenyl]boronic acid (64.7 mg) to a solution of the compound (100 mg) obtained in the compound (1 g) , [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.9 mg), sodium carbonate (61.8 mg), water (1 mL), and reacted by microwave The apparatus was allowed to react at 130 ° C for 20 minutes. Water (1 mL) was added to the mixture. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc:

¹ H-NMR (400 mHz, CDCl ₃ ) δ: 1.25 (3H, t, J = 7.0 Hz), 2.16 (3H, s), 2.22 (3H, s), 2.63-2.70 (2H, m), 2.96-3.02 (2H,m), 3.13(3H,s), 3.20-3.26(2H,m), 4.15(2H,q,J=7.0Hz), 4.26-4.33(2H,m), 4.37(2H,s), 6.70-6.74 (1H, m), 6.77-6.79 (1H, m), 6.84 (1H, d, J = 9.1 Hz), 7.11 (1H, d, J = 8.5 Hz), 7.22 (4H, s), 7.37 (1H, d, J = 7.9 Hz), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 8.00 (1H, d, J = 8.5 Hz), 8.05-8.10 (1H, m).

(16b) 3-{2'-Methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-dihydro- 1H-indol-5-yl)oxy]biphenyl-4-yl}propionic acid

A 2 M aqueous sodium hydroxide solution (0.162 mL) was added to a solution of the compound (m. After adding 2 M hydrochloric acid to the reaction liquid to make it acidic, water (6 mL) was added, and the organic solvent was distilled off under reduced pressure. The reaction mixture was extracted with dichloromethane, dried over magnesium sulfate A mixed solvent of dichloromethane/hexane (1:1) was added to the obtained solid to give a suspension, and the title compound (62.9 mg) was obtained as a white solid.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 2.08 (3H, s), 2.18 (3H, s), 2.57 (2H, t, J = 7.6Hz), 2.85 (2H, t, J = 7.6 Hz ), 3.16-3.25 (5H, m), 4.24 - 4.37 (4H, m), 6.67 (1H, dd, J = 8.5, 2.4 Hz), 6.77-6.85 (2H, m), 7.11 (1H, d, J = 8.5 Hz), 7.22 (2H, d, J = 8.5 Hz), 7.27 (2H, d, J = 8.5 Hz), 7.46-7.50 (1H, m), 7.55-7.61 (1H, m), 7.67-7.73 (1H, m), 7.87 (1H, d, J = 8.5 Hz), 7.95-7.99 (1H, m), 12.16 (1H, br s).

MS (APCI) m/z: 584 (M+H) ⁺ .

(Example 17)

{3-Fluoro-2'-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H -吲哚-5-yl)oxy]biphenyl-4-yl}acetic acid

(17a) 1-{4-Methyl-5-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenoxy]-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulphonyl)phenyl]ethanone

1,4-two of the compound (500 mg) obtained in the example (1b) A solution of bis-pinacol borate (370 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) methylene chloride complex was added to the solution of alkane (2 mL) ( 14.2 mg) and potassium acetate (286 mg) were stirred at 100 ° C for 8 hours. After cooling to room temperature, the reaction solution was filtered over Celite, and the filtrate was concentrated under reduced pressure. The title compound (443 mg) was obtained from m.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.32 (12H, s), 2.08 (3H, s), 2.48 (3H, s), 3.13 (3H, s), 3.21. (2H, t, J = 8.5 Hz ), 4.29 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.61-6.71 (2H, m), 6.77-6.83 (1H, m), 7.36 (1H, d, J = 7.9 Hz) , 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.69 (1H, d, J = 8.5 Hz), 7.96-8.00 (1H, m), 8.06-8.10 (1H, m).

(17b) (4-bromo-2-fluorophenyl)acetate

After a solution of (4-bromo-2-fluorophenyl)acetic acid (1.00 g) in ethanol (10 mL) was gradually added at room temperature (0.623 mL), the reaction mixture was refluxed for 4 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. A saturated aqueous solution of sodium hydrogencarbonate was added to the obtained residue, and extracted three times with dichloromethane. The combined organic layer was dried with EtOAc EtOAcjjjjjjjj

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.26 (3H, t, J = 7.1 Hz), 3.62 (2H, s), 4.17 (2H, q, J = 7.1 Hz), 7.13 - 7.26 (3H, m ).

(17c){3-Fluoro-2'-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-di Hydrogen-1H-indol-5-yl)oxy]biphenyl-4-yl}ethyl acetate

The compound obtained in Example (17b) (48.8 mg), the compound obtained in Example (17a) (70.0 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) ) dichloromethane complex (10.2 mg) of 1,2-dimethoxyethane An aqueous solution (0.5 mL) of sodium carbonate (39.6 mg) was added to the solution (2.5 mL), and the mixture was reacted at 130 ° C for 20 minutes in a microwave reaction apparatus. After cooling to room temperature, the reaction solution was poured into water and extracted with ethyl acetate three times. After the combined organic layer was dried over sodium sulfate, the solvent was evaporated to dryness, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title of pale brown amorphous solid. Compound (24.2 mg).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.29 (3H, t, J = 7.3Hz), 2.15 (3H, s), 2.23 (3H, s), 3.13 (3H, s), 3.23 (2H, t , J = 8.5 Hz), 3.70 (2H, s), 4.20 (2H, q, J = 7.3 Hz), 4.30 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.70-6.74 (1H , m), 6.77-6.79 (1H, m), 6.84 (1H, d, J = 8.5 Hz), 6.99-7.06 (2H, m), 7.11 (1H, d, J = 8.5 Hz), 7.27-7.31 ( 1H, m), 7.37 (1H, d, J = 7.3 Hz), 7.50-7.55 (1H, m), 7.60-7.65 (1H, m), 8.00 (1H, d, J = 8.5 Hz), 8.06-8.10 (1H,m).

MS (APCI) m/z: 616 (M+H) ⁺ .

(17d) {3-Fluoro-2'-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-di Hydrogen-1H-indol-5-yl)oxy]biphenyl-4-yl}acetic acid

The compound obtained in Example (17c) (23.0 mg) was dissolved in tetrahydrofuran (2 mL) and ethanol (2mL), and 1N aqueous sodium hydroxide (0.112 mL) was added. After the reaction mixture was stirred at room temperature for 20 hr 30 min, 1N hydrochloric acid (l.30mL) was evaporated. After adding water to the residue, it was extracted three times with dichloromethane. The title compound (22.0 mg) was obtained as a colorless crystals.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.15 (3H, s), 2.23 (3H, s), 3.13 (3H, s), 3.23 (2H, t, J = 8.2 Hz), 3.75 (2H, s ), 4.30 (2H, t, J = 8.2 Hz), 4.37 (2H, s), 6.70-6.74 (1H, m), 6.77-6.80 (1H, m), 6.83 (1H, d, J = 8.5 Hz) , 6.99-7.13 (3H, m), 7.28-7.39 (2H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 8.00 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9Hz).

MS (APCI) m/z: 588 (M+H) ⁺ .

(Embodiment 18)

{3,5-Difluoro-2'-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-di Hydrogen-1H-indol-5-yl)oxy]biphenyl-4-yl}acetic acid

(18a) (4-Bromo-2,6-difluorophenyl)acetic acid methyl ester

To a solution of (4-bromo-2,6-difluorophenyl)acetic acid (0.300 g) in ethanol (8 mL), (trimethyl decyl) diazomethane (2M hexanes, After that, it was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced EtOAc.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.67 (2H, s), 3.73 (3H, s), 7.07-7.15 (2H, m).

(18b) {3,5-Difluoro-2'-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2, Methyl 3-dihydro-1H-indol-5-yl)oxy]biphenyl-4-yl}acetate

The compound obtained in Example (18a) (0.040 g), the compound obtained in Example (17a) (0.080 g), hydrazine (triphenylphosphine) palladium (0) (0.0329 g), and potassium phosphate (0.0907 g) were suspended. Toluene (1.9 mL) and water (0.1 mL) were stirred at 100 ° C for 9 hr. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine. The organic layer was dried with EtOAc EtOAcjjjjjjjjjj

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.10-2.40 (6H, m), 3.13 (3H, s), 3.18-3.28 (2H, m), 3.68-3.79 (5H, m), 4.24 - 4.41 ( 4H, m), 6.62-6.90 (4H, m), 7.04-7.43 (3H, m), 7.46-7.67 (2H, m), 7.94-8.12 (2H, m).

(18c){3,5-Difluoro-2'-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2, 3-dihydro-1H-indol-5-yl)oxy]biphenyl-4-yl}acetic acid

The compound (0.0528 g) obtained in Example (18b) was dissolved in tetrahydrofuran (0.3 mL) and ethanol (0.3 mL). 1N hydrochloric acid was added to the reaction mixture to neutralize it, and extracted with dichloromethane three times. The title compound was obtained as a colorless amorphous solid (yield: EtOAc (EtOAc) (0.0424g).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.15 (3H, s), 2.23 (2H, s), 2.38 (1H, s), 3.12 (3H, s), 3.20-3.27 (2H, m), 3.74 -3.81(2H,m), 4.26-4.33(2H,m),4.37(2H,s),6.63-7.42(7H,m),7.49-7.65(2H,m),7.95-8.10(2H,m) .

MS (APCI) m/z: 606 (M+H) ⁺ .

(Embodiment 19)

{3-Chloro-2'-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H -吲哚-5-yl)oxy]biphenyl-4-yl}acetic acid

(19a) (4-bromo-2-chlorophenyl)acetic acid methyl ester

(4-Bromo-2-chlorophenyl)acetic acid (0.300 g) was dissolved in ethanol (8 mL), and (trimethyldecyl)diazomethane (2M hexane solution, 0.902 mL) was added at 0 ° C Stir at 0 ° C for 1 hour and at room temperature overnight. The reaction mixture was concentrated under EtOAc.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.67 - 3.79 (5H, m), 7.13 - 7.20 (1H, m), 7.34 - 7.40 (1H, m), 7.54 - 7.60 (1H, m).

(19b){3-Chloro-2'-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-di Methyl-1H-indole-5-yl)oxy]biphenyl-4-yl}acetate

The compound obtained in Example (19a) (0.035 g), the compound obtained in Example (17a) (0.070 g), hydrazine (triphenylphosphine) palladium (0) (0.0288 g), and potassium phosphate (0.0794 g) were suspended. Toluene (1.9 mL) and water (0.1 mL) were stirred at 100 ° C overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine. The organic layer was dried with EtOAc EtOAcjjjjjjjjj

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.15 (3H, s), 2.23 (3H, s), 3.13 (3H, s), 3.19-3.27 (2H, m), 3.75 (3H, s), 3.82 (2H, s), 4.25-4.39 (4H, m), 6.69-6.87 (3H, m), 7.08-7.40 (5H, m), 7.49-7.66 (2H, m), 7.98-8.10 (2H, m) .

(19c){3-Chloro-2'-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-di Hydrogen-1H-indol-5-yl)oxy]biphenyl-4-yl}acetic acid

The compound (0.0272 g) obtained in Example (19b) was dissolved in tetrahydrofuran (0.2 mL) and ethanol (0.2 mL). 1N hydrochloric acid was added to the reaction solution to neutralize, and extracted three times with dichloromethane. The organic layer was dried over sodium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexanes / ethyl alcohol / dichloromethane) and purified by fractional chromatography (ethyl acetate) The title compound (0.0153 g).

^{1 H-NMR (400MHz, CDCl} 3 + MeOH-d 4) δ: 2.15 (3H, s), 2.21 (3H, s), 3.12 (3H, s), 3.19-3.26 (2H, m), 3.84 (2H , s), 4.26-4.33 (2H, m), 4.37 (2H, s), 6.69-6.85 (3H, m), 7.07-7.20 (2H, m), 7.25-7.39 (3H, m), 7.49-7.65 (2H, m), 7.98-8.10 (2H, m).

MS (APCI) m/z: 604 (M+H) ⁺ .

(Embodiment 20)

(6-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole) -5-yl)oxy]phenyl}pyridin-3-yl)acetic acid

(20a) (6-chloropyridin-3-yl)acetic acid methyl ester

(6-Chloropyridin-3-yl)acetic acid (0.300 g) was dissolved in dichloromethane (8 mL), and (trimethyl decyl) diazomethane (2M hexane solution, 1.75 mL) was added at 0 ° C. Stir at room temperature for 1 hour and 30 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and ethyl acetate was evaporated. The organic layer was washed with saturated brine and dried over sodium sulfate. The title compound (0.114 g) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.58 - 3.91 (5H, m), 7.22 - 7.43 (1H, m), 7.56-7.76 (1H, m), 8.24 - 8.42 (1H, m).

(20b)(6-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H -吲哚-5-yl)oxy]phenyl}pyridin-3-yl)acetate

The compound obtained in Example (20a) (0.030 g), the compound obtained in Example (17a) (0.080 g), bis(triphenylphosphine)palladium (o) (0.0329 g), and cesium fluoride (0.0325 g) It was suspended in 1,2-dimethoxyethane (1 mL) and stirred at 100 ° C for 7 hours and 30 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine. The organic layer was dried with EtOAc EtOAcjjjjjjjjjjj

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.15 (3H, s), 2.39 (3H, s), 3.12 (3H, s), 3.19-3.27 (2H, m), 3.66 (2H, s), 3.73 (3H, s), 4.26-4.33 (2H, m), 4.37 (2H, s), 6.66-6.73 (2H, m), 7.29-7.71 (6H, m), 7.86-8.10 (3H, m), 8.53 -8.55 (1H, m).

(20c)(6-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H -吲哚-5-yl)oxy]phenyl}pyridin-3-yl)acetic acid

The compound (0.0121 g) obtained in Example (20b) was dissolved in tetrahydrofuran (0.2 mL) and ethanol (0.2 mL), and 2N sodium hydroxide aqueous solution (0.4 mL) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized by adding 1 N hydrochloric acid, and ethyl acetate was added thereto, followed by washing with saturated brine. The organic layer was dried with EtOAc EtOAcjjjjjjjjjjj

^{1 H-NMR (400MHz, CDCl} 3 + MeOH-d 4) δ: 2.14 (3H, s), 2.38 (3H, s), 3.12 (3H, s), 3.19-3.26 (2H, m), 3.61 (2H , s), 4.25-4.32 (2H, m), 4.36 (2H, s), 6.65-6.72 (2H, m), 7.34-7.70 (6H, m), 7.80-8.09 (3H, m), 8.49-8.53 (1H,m).

MS (APCI/ESI) m/z: 571 (M+H) ⁺ .

(Example 21)

{2'-Methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole- 5-yl)oxy]-3-(methylsulfonyl)biphenyl-4-yl}acetic acid

(21a) [4-Bromo-2-(methylsulfonyl)phenyl]acetic acid methyl ester

[4-Bromo-2-(methylsulfonyl)phenyl]acetic acid (0.0698 g) was dissolved in ethanol (3 mL), and (trimethyldecyl)diazomethane (2M) was added twice at 0 °C. After a hexane solution and 0.238 mL), the mixture was stirred at 0 ° C for 1 hour and at room temperature for 1 hour. The reaction mixture was concentrated under EtOAc.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.15 (3H, s), 3.74 (3H, s), 4.17 (2H, s), 7.23-7.28 (1H, m), 7.69-7.75 (1H, m) , 8.18-8.22 (1H, m).

(21b){2'-Methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H- Methyl-5-yl)oxy]-3-(methylsulfonyl)biphenyl-4-yl}acetate

The compound obtained in Example (21a) (0.052 g), the compound obtained in Example (17a) (0.080 g), hydrazine (triphenylphosphine) palladium (0) (0.0165 g), and potassium phosphate (0.0907 g) were suspended. Toluene (1.9 mL) and water (0.1 mL) were stirred at 100 ° C for 8 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine. The organic layer was dried with EtOAc EtOAcjjjjjjjjjjj

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.15 (3H, s), 2.23 (3H, s), 3.13 (3H, s), 3.16 (3H, s), 3.20-3.29 (2H, m), 3.77 (3H, s), 4.20-4.41 (6H, m), 6.70-6.88 (3H, m), 7.13 (1H, d, J = 7.9 Hz), 7.31-7.66 (5H, m), 7.97-8.12 (3H , m).

(21c){2'-Methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-吲哚-5-yl)oxy]-3-(methylsulfonyl)biphenyl-4-yl}acetic acid

The compound (0.0408 g) obtained in Example (21b) was dissolved in tetrahydrofuran (0.2 mL) and ethanol (0.2 mL), and 2N sodium hydroxide aqueous solution (0.4 mL) was added at 0 ° C, and then stirred at room temperature overnight. After adding 1 N hydrochloric acid, the reaction mixture was neutralized, and saturated brine was added thereto, followed by extraction three times with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. ethyl acetate /hexane (1:1) mixture was added to the residue, and the precipitated solid was filtered and dried to give a pale orange solid title. Compound (0.0344 g).

¹ H-NMR (400 MHz, CDCl ₃ + MeOH-d ₄ ) δ: 2.15 (3H, s), 2.24 (3H, s), 3.14 (3H, s), 3.18 (3H, s), 3.21-3.28 (2H , m), 4.22 (2H, s), 4.27-4.35 (2H, m), 4.37 (2H, s), 6.72-6.87 (3H, m), 7.14 (1H, d, J = 8.5 Hz), 7.36- 7.67 (5H, m), 7.98-8.09 (3H, m).

MS (APCI/ESI) m/z: 648 (M+H) ⁺ .

(Example 22)

{2',3-Dimethyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-吲哚-5-yl)oxy]biphenyl-4-yl}acetic acid

(22a) (2-methyl-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)acetate methyl ester

(4-Hydroxy-2-methylphenyl)acetic acid methyl ester (0.100 g) was dissolved in dichloromethane (4 mL), and 2,6-dimethylpyridine (0.0970 mL) and trifluoromethanesulfonate were added at 0 °C. After the anhydride (0.131 mL), it was stirred at 0 ° C for 15 minutes. After adding water to the reaction mixture and extracting with ethyl acetate, the organic layer was washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The title compound (0.155 g) was obtained.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.35 (3H, s), 3.65 (2H, s), 3.71 (3H, s), 7.04-7.12 (2H, m), 7.24-7.30 (1H, m) .

(22b){2',3-Dimethyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-dihydrol -1H-indol-5-yl)oxy]biphenyl-4-yl}acetic acid methyl ester

The compound obtained in Example (22a) (0.055 g), the compound obtained in Example (17a) (0.070 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl -1,1'-biphenyl)[2-(2'-Amino-1,1'-biphenyl)]palladium(II) (0.0098 g) and potassium phosphate (0.0794 g) were suspended in toluene (1.9) (mL) and water (0.1 mL) were stirred at 100 ° C for 8 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine. The title compound (0.0365 g) was obtained eluted eluted eluted eluted

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.16 (3H, s), 2.23 (3H, s), 2.34 (3H, s), 3.13 (3H, s), 3.19-3.27 (2H, m), 3.68 (2H, s), 3.72 (3H, s), 4.26-4.33 (2H, m), 4.37 (2H, s), 6.68-6.86 (3H, m), 7.07-7.24 (4H, m), 7.34-7.65 (3H, m), 7.97-8.10 (2H, m).

(22c){2',3-Dimethyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-dihydro -1H-indol-5-yl)oxy]biphenyl-4-yl}acetic acid

The compound obtained in Example (22b) (0.0365 g) was dissolved in tetrahydrofuran (0.2 mL) and ethanol (0.2 mL), and 2N sodium hydroxide water was added at 0 °C. After the solution (0.4 mL), it was stirred at room temperature for 50 minutes. 1N hydrochloric acid was added to the reaction mixture to neutralize it, and the mixture was extracted three times with dichloromethane. The organic layer was dried with EtOAc EtOAcjjjjjjjjj

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.16 (3H, s), 2.22 (3H, s), 2.36 (3H, s), 3.13 (3H, s), 3.19-3.27 (2H, m), 3.72 (2H, s), 4.26-4.33 (2H, m), 4.37 (2H, s), 6.68-6.86 (3H, m), 7.09-7.39 (5H, m), 7.49-7.65 (2H, m), 7.97 -8.10(2H,m).

MS (APCI) m/z: 584 (M+H) ⁺ .

(Example 23)

{4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-2',5'-dimethylbiphenyl-4-yl}acetic acid

(23a) 1-[5-(4-Bromo-2,5-dimethylphenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[ 2-(ethylsulfonyl)phenyl]ethanone

5-(4-Bromo-2,5-dimethylphenoxy)-4-methyl-2,3-dihydro-1H-indole hydrochloride (239 mg) obtained in Example (9b) Add N-methyl to a solution of N,N-dimethylformamide (5 mL) The morpholine (0.143 mL) was stirred at room temperature for 15 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (269 mg) and [2-(ethylsulfonyl)phenyl]acetic acid (178 mg) were stirred at room temperature for 3 days. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3 Hz), 2.13 (3H, s), 2.22 - 2.26 (6H, m), 3.18-3.25 (4H, m), 4.27 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.49 (1H, s), 6.61 (1H, d, J = 9.1 Hz), 7.35-7.41 (2H, m), 7.48-7.53 ( 1H, m), 7.59-7.65 (1H, m), 7.94 (1H, d, J = 9.1 Hz), 8.03 (1H, d, J = 7.9 Hz).

MS (APCI) m/z: 542 (M+H) ⁺ .

(23b){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Ethyloxy]-2',5'-dimethylbiphenyl-4-yl}ethyl acetate

Compound (210 mg) obtained in Example (23a), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate B Ester (169 mg) and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (31.6 mg) of 1,2-dimethoxyethane ( To a suspension of 10 mL), an aqueous solution (1 mL) of sodium carbonate (123 mg) was added, and the mixture was reacted at 130 ° C for 30 minutes in a microwave reaction apparatus. After cooling to room temperature, the reaction solution was poured into water and extracted with ethyl acetate three times. After the combined organic layer was dried over sodium sulfate, the solvent was evaporated to dryness, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a pale yellow amorphous solid title. Compound (148 mg).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.23-1.32 (6H, m), 2.14 (3H, s), 2.19 (3H, s), 2.28 (3H, s), 3.18-3.27 (4H, m) , 3.65 (2H, s), 4.18 (2H, q, J = 6.9 Hz), 4.28 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.53 (1H, s), 6.68 (1H, d, J = 9.1 Hz), 7.08 (1H, s), 7.25-7.33 (4H, m), 7.38-7.42 (1H, m), 7.47-7.53 (1H, m), 7.59-7.64 (1H, m) , 7.96 (1H, d, J = 9.1 Hz), 8.03 (1H, d, J = 8.5 Hz).

MS (APCI) m/z: 626 (M+H) ⁺ .

(23c){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2',5'-dimethylbiphenyl-4-yl}acetic acid

The compound (146 mg) obtained in Example (23b) was dissolved in tetrahydrofuran (3 mL) and ethanol (3mL), and 1N aqueous sodium hydroxide (0.700 mL) was added. After the reaction solution was stirred at room temperature for 17 hours and 30 minutes, 1N hydrochloric acid (0.720 mL) was added, and the organic solvent was distilled off under reduced pressure. After adding water to the residue, it was extracted three times with dichloromethane. The title compound (128 mg) was obtained as a pale yellow solid.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.26 (3H, t, J = 7.3Hz), 2.14 (3H, s), 2.19 (3H, s), 2.28 (3H, s), 3.17-3.28 (4H , m), 3.71 (2H, s), 4.28 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.53 (1H, s), 6.69 (1H, d, J = 8.5 Hz), 7.08 (1H, s), 7.27-7.34 (4H, m), 7.40 (1H, d, J = 7.3 Hz), 7.48-7.53 (1H, m), 7.60-7.65 (1H, m), 7.96 (1H, d , J = 8.5 Hz), 8.01 - 8.05 (1H, m).

MS (APCI) m/z: 598 (M+H) ⁺ .

(Example 24)

{4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-2'-methoxybiphenyl-4-yl}acetic acid

(24a) 1-[5-(4-Bromo-3-methoxyphenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2- (ethylsulfonyl)phenyl]ethanone

N-(4-bromo-3-methoxyphenoxy)-4-methyl-2,3-dihydro-1H-indole hydrochloride (110 mg) obtained in Example (8b), Add N-methyl to a solution of N-dimethylformamide (10 mL) The morpholine (0.065 mL) was stirred at room temperature for 20 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (123 mg) and [2-(ethylsulfonyl)phenyl]acetic acid (81.3 mg) were stirred at room temperature for 20 h 20 min. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.10 (3H, s), 3.16-3.26 (4H, m), 3.84 (3H, s), 4.28 (2H) , t, J = 8.5 Hz), 4.37 (2H, s), 6.26 (1H, dd, J = 8.5, 2.4 Hz), 6.55 (1H, d, J = 2.4 Hz), 6.80 (1H, d, J = 8.5 Hz), 7.35-7.42 (2H, m), 7.49-7.54 (1H, m), 7.60-7.65 (1H, m), 7.97-8.05 (2H, m).

MS (APCI) m/z: 544 (M+H) ⁺ .

(24b){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Ethyloxy]-2'-methoxybiphenyl-4-yl}ethyl acetate

Compound (150 mg) obtained in Example (24a), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate Ester (104 mg) and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (11.2 mg) of 1,2-dimethoxyethane (1,2-dimethoxyethane) An aqueous solution (2 mL) of sodium carbonate (87.6 mg) was added to the solution (10 mL), and the mixture was reacted at 130 ° C for 30 minutes in a microwave reactor. After cooling to room temperature, the reaction solution was poured into water and extracted with ethyl acetate three times. After the combined organic layer was dried over sodium sulfate, the solvent was evaporated to dryness, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a pale yellow amorphous solid title. Compound (120 mg).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.24-1.32 (6H, m), 2.16 (3H, s), 3.19-3.26 (4H, m), 3.63 (2H, s), 3.75 (3H, s) , 4.16 (2H, q, J = 7.3 Hz), 4.29 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.39-6.43 (1H, m), 6.60-6.64 (1H, m), 6.86 (1H, d, J = 8.5 Hz), 7.17 (1H, d, J = 8.5 Hz), 7.31 (2H, d, J = 7.9 Hz), 7.38-7.42 (1H, m), 7.45 (2H, d , J = 7.9 Hz), 7.48-7.53 (1H, m), 7.60-7.65 (1H, m), 7.98-8.05 (2H, m).

MS (APCI) m/z: 628 (M+H) ⁺ .

(24c){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-methoxybiphenyl-4-yl}acetic acid

The compound (119 mg) obtained in Example (24b) was dissolved in tetrahydrofuran (3 mL) and ethanol (3 mL), and 1N aqueous sodium hydroxide (0.569 mL) was added. After the reaction mixture was stirred at room temperature for 15 hours and 30 minutes, 1N hydrochloric acid (0.590 mL) was added, and the organic solvent was distilled off under reduced pressure. The title compound (106 mg) was obtained as a colorless solid.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.27 (3H, t, J = 7.6Hz), 2.16 (3H, s), 3.19-3.26 (4H, m), 3.68 (2H, s), 3.75 (3H , s), 4.28 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.41 (1H, dd, J = 8.5, 2.4 Hz), 6.60-6.63 (1H, m), 6.86 (1H, d, J = 8.5 Hz), 7.17 (1H, d, J = 8.5 Hz), 7.31 (2H, d, J = 8.5 Hz), 7.38 - 7.42 (1H, m), 7.44 - 7.53 (3H, m), 7.59-7.65 (1H, m), 7.98-8.05 (2H, m).

MS (APCI) m/z: 600 (M+H) ⁺ .

(Embodiment 25)

{4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-2'-(methoxymethyl)biphenyl-4-yl}acetic acid

(25a) 1-{5-[4-Bromo-3-(methoxymethyl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2 -[2-(ethylsulfonyl)phenyl]ethanone

5-[4-Bromo-3-(methoxymethyl)phenoxy]-4-methyl-2,3-dihydro-1H-indole hydrochloride (170 mg) obtained in Example (12c) Add N-methyl to a solution of N,N-dimethylformamide (5 mL) The morpholine (0.0699 mL) was stirred at room temperature for 20 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (152 mg) and [2-(ethylsulfonyl)phenyl]acetic acid (116 mg) were stirred at room temperature for 20 hr. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.10 (3H, s), 3.17-3.25 (4H, m), 3.44 (3H, s), 4.28 (2H) , t, J = 8.2 Hz), 4.37 (2H, s), 4.45 (2H, s), 6.63 - 6.67 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 7.01-7.04 (1H, m), 7.38-7.42 (2H, m), 7.48-7.53 (1H, m), 7.60-7.65 (1H, m), 7.98 (1H, d, J = 8.5 Hz), 8.01-8.04 (1H, m) .

MS (APCI) m/z: 558 (M+H) ⁺ .

(25b){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Ethyloxy]-2'-(methoxymethyl)biphenyl-4-yl}ethyl acetate

Compound (200 mg) obtained in Example (25a), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate B Ester (156 mg) and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (29.2 mg) of 1,2-dimethoxyethane ( An aqueous solution (2 mL) of sodium carbonate (114 mg) was added to a solution of 10 mL), and the mixture was reacted at 130 ° C for 30 minutes in a microwave reaction apparatus. After cooling to room temperature, the reaction solution was poured into water and extracted with ethyl acetate three times. After the combined organic layer was dried over sodium sulfate, the solvent was evaporated to dryness, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a pale yellow amorphous solid title. Compound (184 mg).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.22-1.32 (6H, m), 2.15 (3H, s), 3.17-3.26 (4H, m), 3.31 (3H, s), 3.66 (2H, s) , 4.19 (2H, q, J = 7.3 Hz), 4.25 - 4.32 (4H, m), 4.38 (2H, s), 6.80-6.86 (2H, m), 7.07 (1H, d, J = 3.0 Hz), 7.18 (1H, d, J = 8.5 Hz), 7.28-7.35 (4H, m), 7.40 (1H, d, J = 7.9 Hz), 7.48-7.53 (1H, m), 7.60-7.65 (1H, m) , 7.98-8.05 (2H, m).

MS (APCI) m/z: 642 (M+H) ⁺ .

(25c){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-(methoxymethyl)biphenyl-4-yl}acetic acid

The compound (183 mg) obtained in Example (25b) was dissolved in tetrahydrofuran (3 mL) and ethanol (3 mL), and 1N aqueous sodium hydroxide (0.855 mL) was added. After the reaction liquid was stirred at room temperature for 16 hours, 1N hydrochloric acid (0.900 mL) was added, and the organic solvent was distilled off under reduced pressure. After adding water to the residue, it was extracted three times with dichloromethane. By making the combined organic layer sulphur The title compound (169 mg) was obtained.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.27 (3H, t, J = 7.6Hz), 2.15 (3H, s), 3.18-3.25 (4H, m), 3.31 (3H, s), 3.71 (2H , s), 4.25-4.33 (4H, m), 4.38 (2H, s), 6.80-6.86 (2H, m), 7.07 (1H, d, J = 3.0 Hz), 7.18 (1H, d, J = 8.5 Hz), 7.30-7.35 (4H, m), 7.40 (1H, d, J = 7.9 Hz), 7.48-7.53 (1H, m), 7.60-7.65 (1H, m), 7.98-8.05 (2H, m) .

MS (APCI) m/z: 614 (M+H) ⁺ .

(Example 26)

{4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-2'-Methoxy-5'-methylbiphenyl-4-yl}acetic acid sodium salt

(26a) 1-[5-(4-Bromo-5-methoxy-2-methylphenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]- 2-[2-(ethylsulfonyl)phenyl]ethanone

5-(4-Bromo-5-methoxy-2-methylphenoxy)-4-methyl-2,3-dihydro-1H-indole hydrochloride obtained in Example (11d) ( Add N-methyl to a solution of 210 mg) of N,N-dimethylformamide (5 mL) The morpholine (0.098 mL) was stirred at room temperature for 15 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (161 mg) and [2-(ethylsulfonyl)phenyl]acetic acid (122 mg) were stirred at room temperature for 18 h 30 min. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.26 (3H, t, J = 7.6 Hz), 2.16 (3H, s), 2.18 (3H, s), 3.17-3.26 (4H, m), 3.70 (3H) , s), 4.27 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.29 (1H, s), 6.58 (1H, d, J = 9.1 Hz), 7.36-7.41 (2H, m) , 7.48-7.53 (1H, m), 7.59-7.64 (1H, m), 7.93 (1H, d, J = 8.5 Hz), 8.00-8.04 (1H, m).

MS (APCI) m/z: 558 (M+H) ⁺ .

(26b){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Ethyloxy]-2'-methoxy-5'-methylbiphenyl-4-yl}ethyl acetate

Compound (245 mg) obtained in Example (26a), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate B Ester (191 mg) and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (35.8 mg) of 1,2-dimethoxyethane ( An aqueous solution (2 mL) of sodium carbonate (139 mg) was added to the solution, and the mixture was reacted at 130 ° C for 30 minutes in a microwave reaction apparatus. After cooling to room temperature, the reaction solution was poured into water and extracted with ethyl acetate three times. After the combined organic layer was dried over sodium sulfate, the solvent was evaporated to dryness, and the obtained residue was purified by silica gel column chromatography (dichloromethane / hexane - ethyl acetate / dichloromethane). The title compound (215 mg) was obtained as a pale yellow solid.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.22-1.31 (6H, m), 2.21 (3H, s), 2.23 (3H, s), 3.18-3.27 (4H, m), 3.59-3.67 (5H, m), 4.16 (2H, q, J = 7.1 Hz), 4.28 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.37 (1H, s), 6.66 (1H, d, J = 9.1) Hz), 7.16 (1H, s), 7.31 (2H, d, J = 8.5 Hz), 7.39 (1H, d, J = 7.3 Hz), 7.45-7.53 (3H, m), 7.59-7.64 (1H, m ), 7.95 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).

MS (APCI) m/z: 642 (M+H) ⁺ .

(26c){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl Oxy]-2'-methoxy-5'-methylbiphenyl-4-yl}acetic acid

The compound (214 mg) obtained in Example (26b) was dissolved in tetrahydrofuran (3 mL) and ethanol (3 mL). After the reaction mixture was stirred at room temperature for 15 hours, 1N hydrochloric acid (1.20 mL) was added, and the organic solvent was distilled off under reduced pressure. The title compound (192 mg) was obtained as a colorless solid.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.26 (3H, t, J = 7.6Hz), 2.21 (3H, s), 2.23 (3H, s), 3.18-3.26 (4H, m), 3.62 (3H , s), 3.69 (2H, s), 4.28 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.36 (1H, s), 6.66 (1H, d, J = 8.5 Hz), 7.16 (1H, s), 7.30-7.35 (2H, m), 7.39 (1H, d, J = 7.9 Hz), 7.46-7.53 (3H, m), 7.59-7.65 (1H, m), 7.95 (1H, d , J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).

MS (APCI) m/z: 614 (M+H) ⁺ .

(26d){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Sodium oxy]-2'-methoxy-5'-methylbiphenyl-4-yl}acetate

The compound obtained in Example (26c) (73.5 mg) was dissolved in methanol (2 mL), and 1N aqueous sodium hydroxide (0.120 mL) was added. After stirring for 20 minutes, the title compound (70.8 mg) was obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.10 (3H, t, J = 7.3 Hz), 2.14-2.20 (6H, m), 3.15 (2H, s), 3.22 (2H, t, J = 8.5 Hz), 3.26-3.33 (2H, m), 3.55 (3H, s), 4.24-4.33 (4H, m), 6.39 (1H, s), 6.63 (1H, d, J = 9.1 Hz), 7.14 7.20(3H,m), 7.26(2H,d,J=8.5Hz), 7.50 (1H,d,J=7.9Hz), 7.54-7.60(1H,m), 7.68-7.73(1H,m), 7.80 (1H, d, J = 8.5 Hz), 7.91 (1H, d, J = 7.9 Hz).

(Example 27)

{4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-2'-(methoxymethyl)-5'-methylbiphenyl-4-yl}acetic acid

(27a) 5-Amino-2-bromo-4-methylbenzoic acid

Add 5-N-bromoammonium oxime to a solution of 5-amino-4-methylbenzoic acid (6.00 g) in N,N-dimethylformamide (100 mL) with ice cold The imine (7.06 g) made the internal temperature 10 ° C or less. After stirring for 1 hour and 20 minutes under ice-cooling, the title compound (6.40 g) was obtained as a pale gray solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.06 (3H, s), 5.24 (2H, s), 7.05 (1H, s), 7.21. (1H, s).

(27b) 2-bromo-5-iodo-4-methylbenzoic acid

Concentrated sulfuric acid (10 mL) was added to an aqueous solution (100 mL) of Compound (3. An aqueous solution (5 mL) of sodium nitrite (2.16 g) was added dropwise so that the internal temperature of the reaction liquid became 5 ° C or less. After 5 minutes, an aqueous solution (5 mL) of potassium iodide (2.16 g) was added dropwise, and the mixture was warmed to room temperature and stirred for 45 minutes. The reaction solution was warmed to 100 ° C and stirred for additional 1 hour. After cooling to room temperature, the reaction mixture was extracted with dichloromethane three times, and the combined organic layer was washed with saturated aqueous sodium hydrogen sulfate and dried over sodium sulfate. The residue was dissolved in methanol (50 mL) and added dropwise with stirring water (150 mL). The title compound (2.64 g) was obtained as a pale brown solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.46 (3H, s), 7.57 (1H, s), 8.42 (1H, s).

(27c) (2-bromo-5-iodo-4-methylphenyl)methanol

A solution of the compound (1.00 g) obtained in Example (27b) in THF (30 mL), EtOAc (EtOAc) The reaction solution was warmed to room temperature, and then stirred at room temperature for 19 hr, then 1N hydrochloric acid was added. After stirring for 1 hour, the reaction solution was extracted with ethyl acetate three times. After the combined organic layers were dried over sodium sulfate, the solvent was evaporated under reduced pressure. The title compound (875 mg) was obtained as a white crystal.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.93 (1H, t, J = 6.4Hz), 2.40 (3H, s), 4.66-4.69 (2H, m), 7.41 (1H, s), 7.89 (1H , s).

(27d) 1-Bromo-4-iodo-2-(methoxymethyl)-5-methylbenzene

A solution of the compound (500 mg) obtained from m. m. Methyl iodide (0.114 mL) was added and stirred for additional 3 hours. The reaction solution was poured into water, and extracted with a mixed solvent of ethyl acetate/hexane (1:1) three times. After the combined organic layer was dried over sodium sulfate (MgSO4) (512 mg).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.39 (3H, s), 3.46 (3H, s), 4.44 (2H, s), 7.40 (1H, s), 7.86 (1H, s).

(27e) 5-[4-Bromo-5-(methoxymethyl)-2-methylphenoxy]-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid Tributyl ester

The compound (500 mg) obtained in the example (27d) and the 1,4-bis 5-butyl 4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid (366 mg) Copper (I) iodide (27.9 mg), N,N-dimethylglycine (30.2 mg) and cesium carbonate (956 mg) were added to the alkane (10 mL) solution, and stirred at 100 ° C for 7 hours and 30 minutes. After cooling to room temperature, it was allowed to stand overnight, and again stirred at 100 ° C for 8 hours and 30 minutes, and the reaction liquid was filtered through celite. The obtained filtrate was concentrated under reduced pressure. EtOAcjjjjjjj

¹ H-NMR (400 HMz, CDCl ₃ ) δ: 1.56 (9H, s), 2.07 (3H, s), 2.28 (3H, s), 3.03 (2H, t, J = 8.8 Hz), 3.34 (3H, s ), 3.98-4.09 (2H, m), 4.37 (2H, s), 6.56-6.74 (2H, m), 7.19-7.67 (2H, m).

(27f) 1-{5-[4-Bromo-5-(methoxymethyl)-2-methylphenoxy]-4-methyl-2,3-dihydro-1H-indole-1 -yl}-2-[2-(ethylsulfonyl)phenyl]ethanone

4N hydrochloric acid was added to a solution of the compound (295 mg) obtained in Example (27e) in dichloromethane (4 mL) A solution of the alkane (4 mL) was stirred at room temperature. After stirring for 2 hours, the reaction mixture was concentrated to give crude 5-[4-bromo-5-(methoxymethyl)-2-methylphenoxy]-4-methyl-2,3- Dihydro-1H-indole hydrochloride (258 mg).

Add N-methyl to a solution of the obtained compound (258 mg) in N,N-dimethylformamide (8 mL) The morpholine (0.105 mL) was stirred at room temperature for 20 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (229 mg) and [2-(ethylsulfonyl)phenyl]acetic acid (175 mg) were stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3 Hz), 2.13 (3H, s), 2.26 (3H, s), 3.17-3.24 (4H, m), 3.35 (3H) , s), 4.27 (2H, t, J = 8.5 Hz), 4.34 - 4.40 (4H, m), 6.61 (1H, d, J = 8.5 Hz), 6.74 (1H, s), 7.38-7.42 (2H, m), 7.48-7.53 (1H, m), 7.60-7.65 (1H, m), 7.93 (1H, d, J = 8.5 Hz), 8.01-8.04 (1H, m).

MS (APCI) m/z: 572 (M+H) ⁺ .

(27g) {4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Ethyloxy]-2'-(methoxymethyl)-5'-methylbiphenyl-4-yl}ethyl acetate

Compound (355 mg) obtained in Example (27f), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate Ester (270 mg) and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (50.6 mg) of 1,2-dimethoxyethane ( To a solution of 16 mL), an aqueous solution (2 mL) of sodium carbonate (197 mg) was added, and the mixture was reacted at 130 ° C for 50 minutes in a microwave reaction apparatus. After cooling to room temperature, the reaction solution was poured into water and extracted with ethyl acetate three times. After the combined organic layer was dried over sodium sulfate, EtOAc (EtOAc) 285mg).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.24-1.32 (6H, m), 2.19 (3H, s), 2.31 (3H, s), 3.18-3.27 (7H, m), 3.66 (2H, s) , 4.15-4.23 (4H, m), 4.28 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.69 (1H, d, J = 8.5 Hz), 6.80 (1H, s), 7.15 ( 1H, s), 7.30-7.34 (4H, m), 7.40 (1H, d, J = 7.3 Hz), 7.47-7.53 (1H, m), 7.60-7.65 (1H, m), 7.95 (1H, d, J = 9.2 Hz), 8.01 - 8.05 (1H, m).

MS (APCI) m/z: 656 (M+H) ⁺ .

(27h){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-(methoxymethyl)-5'-methylbiphenyl-4-yl}acetic acid

The compound (285 mg) obtained in Example (27 g) was dissolved in tetrahydrofuran (5 mL) and ethanol (5mL), and 1N aqueous sodium hydroxide (1.30 mL) was added. After the reaction liquid was stirred at room temperature for 10 hours, 1N hydrochloric acid (2.00 mL) was added, and the organic solvent was distilled off under reduced pressure. The title compound (208 mg) was obtained.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.26 (3H, t, J = 7.6Hz), 2.19 (3H, s), 2.31 (3H, s), 3.18-3.28 (7H, m), 3.72 (2H , s), 4.19 (2H, s), 4.28 (2H, t, J = 8.2 Hz), 4.38 (2H, s), 6.69 (1H, d, J = 8.5 Hz), 6.80 (1H, s), 7.14 (1H, s), 7.31-7.36 (4H, m), 7.40 (1H, d, J = 8.5 Hz), 7.47-7.53 (1H, m), 7.60-7.65 (1H, m), 7.95 (1H, d , J = 8.5 Hz), 8.01 - 8.05 (1H, m).

MS (APCI) m/z: 628 (M+H) ⁺ .

(Embodiment 28)

{4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-2-fluoro-2'-methylbiphenyl-4-yl}acetic acid

(28a){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Methyl oxy]-2-fluoro-2'-methylbiphenyl-4-yl}acetate

The compound obtained in Example (14a) (0.340 g), the compound obtained in Example (2a) (0.400 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) Methylene chloride complex (II) (0.0618 g) and sodium carbonate (0.241 g) were suspended in 1,2-dimethoxyethane (3.2 mL) and water (0.8 mL), and were subjected to a microwave reaction apparatus. The reaction was carried out at 130 ° C for 20 minutes. After cooling to room temperature, ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine. The organic layer was dried with EtOAc EtOAcjjjjjjjjjjj

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.26-1.28 (3H, m), 2.15 (3H, s), 2.15 (3H, s), 3.18-3.27 (4H, m), 3.67 (2H, s) , 3.74 (3H, s), 4.25-4.32 (2H, m), 4.38 (2H, s), 6.69-6.88 (3H, m), 7.04-7.24 (4H, m), 7.37-7.65 (3H, m) , 7.98-8.05 (2H, m).

(28b){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2-fluoro-2'-methylbiphenyl-4-yl}acetic acid

The compound (0.397 g) obtained in Example (28a) was dissolved in tetrahydrofuran (1.5 mL) and ethanol (1.5 mL), and 2N sodium hydroxide aqueous solution (3 mL) was added at 0 ° C, and the mixture was stirred at room temperature for 1 hour. 1N hydrochloric acid was added to the reaction solution to neutralize it, and extracted three times with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The title compound (0.315 g) was obtained as a colorless solid.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.27 (3H, t, J = 7.3Hz), 2.15 (3H, s), 2.15 (3H, s), 3.18-3.27 (4H, m), 3.69 (2H , s), 4.24 - 4.32 (2H, m), 4.38 (2H, s), 6.69-6.88 (3H, m), 7.05-7.23 (4H, m), 7.38-7.65 (3H, m), 7.98-8.05 (2H,m).

MS (APCI) m/z: 602 (M+H) ⁺ .

(Example 29)

{4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-2-fluoro-2',5'-dimethylbiphenyl-4-yl}acetic acid

(29a){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Methyl oxy]-2-fluoro-2',5'-dimethylbiphenyl-4-yl}acetate

The compound obtained in Example (14a) (0.450 g), the compound obtained in Example (23a) (0.550 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) The methylene chloride complex (0.0828 g) and sodium carbonate (0.322 g) were suspended in 1,2-dimethoxyethane (3.6 mL) and water (0.9 mL) in a microwave reaction apparatus at 130 The reaction was carried out at ° C for 80 minutes. After cooling to room temperature, in the reaction Ethyl acetate was added to the solution and washed with water and saturated brine. The title compound (0.125 g) was obtained eluted eluted

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.26 (3H, t, J = 7.9Hz), 2.05 (3H, s), 2.18 (3H, s), 2.28 (3H, s), 3.19-3.26 (4H , m), 3.67 (2H, s), 3.74 (3H, s), 4.25-4.31 (2H, m), 4.38 (2H, s), 6.53 (1H, s), 6.71 (1H, d, J = 8.5 Hz), 7.04-7.23 (4H, m), 7.38-7.65 (3H, m), 7.94-8.05 (2H, m).

(29b){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2-fluoro-2',5'-dimethylbiphenyl-4-yl}acetic acid

The compound (0.549 g) obtained in Example (29a) was dissolved in tetrahydrofuran (2 mL), ethanol (2 mL) and dichloromethane (0.5 mL). Stir for 1 hour and 30 minutes. The reaction solution was neutralized by adding 1N hydrochloric acid, and extracted three times with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. hexane/ethyl acetate (7:3). The title compound (0.377 g) was obtained as a colorless solid.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.26 (3H, t, J = 7.6Hz), 2.05 (3H, s), 2.18 (3H, s), 2.28 (3H, s), 3.17-3.26 (4H , m), 3.69 (2H, s), 4.24 - 4.32 (2H, m), 4.38 (2H, s), 6.52 (1H, s), 6.71 (1H, d, J = 8.5 Hz), 7.03-7.24 ( 4H, m), 7.37-7.65 (3H, m), 7.94-8.05 (2H, m).

MS (APCI) m/z: 616 (M+H) ⁺ .

(Embodiment 30)

{2'-Ethyl-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole- 5-yl)oxy]biphenyl-4-yl}acetic acid

(30a) 2-bromo-5-iodobenzaldehyde

Pyridinium dichromate (9.62 g) was added to a solution of (2-bromo-5-iodophenyl)methanol (4.00 g) in dichloromethane (100 mL). After the reaction mixture was filtered over EtOAc EtOAc (EtOAc)

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.39 (1H, d, J = 8.5 Hz), 7.75 (1H, dd, J = 8.5, 2.4 Hz), 8.20 (1H, d, J = 2.4 Hz), 10.25 (1H, s).

(30b) 1-bromo-2-vinyl-4-iodobenzene

A solution of methyltriphenylphosphonium bromide (8.04 g) in tetrahydrofuran (100 mL) was stirred at -78 ° C, and lithium bis(trimethylsilyl)amide (lithium bis(trimethylsilyl)amide) was added dropwise over a period of 20 minutes. 1.09 mol/L tetrahydrofuran solution, 20.7 mL). After 10 minutes, a solution of the compound (3.50 g) obtained in Example (30a) in tetrahydrofuran (10 mL) was added dropwise. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated. The title compound (2.40 g) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 5.40 (1H, d, J = 10.9 Hz), 5.70 (1H, d, J = 17.0 Hz), 6.89-6.97 (1H, m), 7.27 (1H, d , J = 8.5 Hz), 7.41 (1H, dd, J = 8.5, 2.4 Hz), 7.84 (1H, d, J = 2.4 Hz).

(30c) 5-(4-Bromo-3-vinylphenoxy)-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

Compound (2.40 g) obtained in Example (30b) and 1, 4-dihydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester (1.94 g) -two Copper (I) iodide (148 mg), N,N-dimethylglycine (160 mg) and cesium carbonate (5.06 g) were added to a solution of alkane (150 mL), and stirred at 100 ° C for 9 hours. After cooling to room temperature, it was allowed to stand overnight, and again stirred at 100 ° C for 4 hours and 30 minutes, and the reaction liquid was filtered through celite. The obtained filtrate was concentrated under reduced pressure, and the residue was purified mjjjjjjj

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.56 (9H, s), 2.06 (3H, s), 3.03 (2H, t, J = 8.5 Hz), 3.98 - 4.09 (2H, m), 5.34 (1H) , d, J = 10.9 Hz), 5.60 (1H, d, J = 17.0 Hz), 6.61 (1H, dd, J = 9.1, 3.0 Hz), 6.75 - 6.83 (1H, m), 6.94 - 7.04 (1H, m), 7.08 (1H, s), 7.23-7.73 (2H, m).

(30d) 1-[5-(4-Bromo-3-vinylphenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-( Ethylsulfonyl)phenyl]ethanone

4N hydrochloric acid was added to a solution of the compound (930 mg) obtained in Example (30c) in dichloromethane (10 mL) A solution of the alkane (10 mL) was stirred at room temperature. After stirring for 1 hour, the reaction mixture was concentrated to give crude 5-(4-bromo-3-ethylphenoxy)-4-methyl-2,3-dihydro-1H-indole hydrochloride. (788mg).

Add N-methyl to a solution of the obtained compound (788 mg) in N,N-dimethylformamide (50 mL) The morpholine (0.473 mL) was stirred at room temperature for 25 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl The ruthenium hydride (892 mg) and [2-(ethylsulfonyl)phenyl]acetic acid (736 mg) were stirred at room temperature for 13 hr. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.11 (3H, s), 3.17-3.26 (4H, m), 4.28 (2H, t, J = 8.5 Hz ), 4.37 (2H, s), 5.35 (1H, d, J = 11.0 Hz), 5.61 (1H, d, J = 17.7 Hz), 6.63 (1H, dd, J = 8.5, 3.1 Hz), 6.79 (1H) , d, J = 9.2 Hz), 6.99 (1H, dd, J = 17.1, 11.0 Hz), 7.09 (1H, d, J = 3.1 Hz), 7.37-7.45 (2H, m), 7.48-7.54 (1H, m), 7.60-7.66 (1H, m), 7.96-8.06 (2H, m).

MS (APCI) m/z: 540 (M+H) ⁺ .

(30e){2'-Vinyl-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H- Ethyl-5-yl)oxy]biphenyl-4-yl}ethyl acetate

Compound (300 mg) obtained in Example (30d), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate B An aqueous solution (1 mL) of potassium phosphate (353 mg) was added to a solution of the ester (209 mg) and triphenylphosphine palladium (0) (64.1 mg) in 1,2-dimethoxyethane (10 mL). Stir at °C for 4 hours and 30 minutes. After cooling to room temperature, the organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a pale yellow amorphous solid. The title compound (308 mg).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.23-1.31 (6H, m), 2.17 (3H, s), 3.18-3.26 (4H, m), 3.66 (2H, s), 4.18 (2H, q, J = 7.3 Hz), 4.29 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 5.17 (1H, d, J = 10.9 Hz), 5.60 (1H, d, J = 17.6 Hz), 6.67 (1H, dd, J = 17.6, 10.9 Hz), 6.80 (1H, dd, J = 8.5, 2.7 Hz), 6.85 (1H, d, J = 8.5 Hz), 7.15-7.20 (2H, m), 7.27- 7.34(4H,m), 7.40 (1H,d,J=7.9Hz), 7.48-7.54(1H,m), 7.59-7.65(1H,m),7.97-8.06(2H,m).

MS (APCI) m/z: 624 (M+H) ⁺ .

(30f){2'-Ethyl-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H- Ethyl-5-yl)oxy]biphenyl-4-yl}ethyl acetate

A suspension of the compound obtained in Example (30e) (305 mg) and 7.5% palladium carbon (50 mg) in ethanol (4 mL) / tetrahydrofuran (4 mL) was vigorously stirred under a hydrogen atmosphere. After stirring for 10 hours, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The title compound (272 mg) was obtained from m.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.06 (3H, t, J = 7.9 Hz), 1.24-1.32 (6H, m), 2.17 (3H, s), 2.55 (2H, q, J = 7.9 Hz ), 3.18-3.27(4H,m), 3.66(2H,s), 4.19(2H,q,J=7.3Hz), 4.29(2H,t,J=8.2Hz), 4.38(2H,s),6.66 -6.70(1H,m),6.83-6.88(2H,m),7.08(1H,d,J=8.5Hz),7.23-7.26(2H,m),7.29-7.33(2H,m),7.40(1H , d, J = 7.9 Hz), 7.48-7.54 (1H, m), 7.60-7.65 (1H, m), 7.97-8.05 (2H, m).

MS (APCI) m/z: 626 (M+H) ⁺ .

(30g){2'-Ethyl-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-吲哚-5-yl)oxy]biphenyl-4-yl}acetic acid

The compound (272 mg) obtained in Example (30f) was dissolved in tetrahydrofuran (2 mL) and ethanol (2 mL), and 1N aqueous sodium hydroxide (1.30 mL) was added. After the reaction mixture was stirred at room temperature for 20 hr, 1N hydrochloric acid (l. The title compound (251 mg) was obtained as a colorless solid.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.06 (3H, t, J = 7.6Hz), 1.27 (3H, t, J = 7.6Hz), 2.17 (3H, s), 2.54 (2H, q, J = 7.6 Hz), 3.18-3.25 (4H, m), 3.71 (2H, s), 4.28 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.68 (1H, dd, J = 8.5, 2.4 Hz), 6.83-6.87 (2H, m), 7.08 (1H, d, J = 8.5 Hz), 7.24-7.27 (2H, m), 7.30-7.34 (2H, m), 7.38-7.42 (1H, m ), 7.48-7.53 (1H, m), 7.60-7.65 (1H, m), 7.98-8.05 (2H, m).

MS (APCI) m/z: 598 (M+H) ⁺ .

(Example 31)

{4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-2-fluoro-2'-methoxy-5'-methylbiphenyl-4-yl}acetic acid sodium salt

(31a){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Methyl oxy]-2-fluoro-2'-methoxy-5'-methylbiphenyl-4-yl}acetate

Compound (250 mg) obtained in Example (26a), [3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene An aqueous solution (4 mL) of potassium phosphate (285 mg) was added to a solution of methyl acetate (197 mg) and triphenylphosphine palladium (0) (51.7 mg) in 1,2-dimethoxyethane (20 mL). It was allowed to react at 100 ° C for 9 hours and 30 minutes. After cooling the reaction liquid to room temperature, the organic layer was separated, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The title compound (252 mg) was obtained from m.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3 Hz), 2.21 (3H, s), 2.24 (3H, s), 3.18-3.28 (4H, m), 3.61 (3H) , s), 3.65 (2H, s), 3.73 (3H, s), 4.28 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.35 (1H, s), 6.69 (1H, d, J=8.5 Hz), 7.04-7.11 (3H, m), 7.27-7.32 (1H, m), 7.38-7.41 (1H, m), 7.48-7.53 (1H, m), 7.60-7.65 (1H, m) , 7.96 (1H, d, J = 8.5 Hz), 8.01 - 8.05 (1H, m).

MS (APCI) m/z: 646 (M+H) ⁺ .

(31b){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2-fluoro-2'-methoxy-5'-methylbiphenyl-4-yl}acetic acid

The compound (251 mg) obtained in Example (31a) was dissolved in tetrahydrofuran (8 mL) and ethanol (4 mL), and 1N aqueous sodium hydroxide (1. After the reaction mixture was stirred at room temperature for 17 hours, 1N hydrochloric acid (1.20 mL) was added, and the organic solvent was distilled off under reduced pressure. The title compound (236 mg) was obtained as a colorless solid.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.26 (3H, t, J = 7.3Hz), 2.21 (3H, s), 2.24 (3H, s), 3.19-3.26 (4H, m), 3.61 (3H , s), 3.69 (2H, s), 4.28 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.35 (1H, s), 6.69 (1H, d, J = 8.5 Hz), 7.06 -7.14(3H,m), 7.28-7.34(1H,m),7.39(1H,d,J=7.9Hz),7.48-7.54(1H,m),7.59-7.65(1H,m),7.96(1H , d, J = 9.1 Hz), 8.01 - 8.05 (1H, m).

MS (APCI) m/z: 632 (M+H) ⁺ .

(31c){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Sodium oxy]-2-fluoro-2'-methoxy-5'-methylbiphenyl-4-yl}acetate

The compound (120 mg) obtained in Example (31b) was dissolved in methanol (3 mL), and 1N aqueous sodium hydroxide (0.190 mL) was added. After stirring for 1 hour, the title compound (120 mg) was obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.10 (3H, t, J = 7.6 Hz), 2.19-2.14 (6H, m), 3.17 (2H, s), 3.22 (2H, t, J = 8.5 Hz), 3.26-3.33 (2H, m), 3.53 (3H, s), 4.24-4.34 (4H, m), 6.37 (1H, s), 6.66 (1H, d, J = 8.5 Hz), 6.96- 7.04(2H,m),7.07-7.14(2H,m), 7.50 (1H,d,J=7.9Hz), 7.54-7.60(1H,m), 7.67-7.74(1H,m),7.82(1H, d, J = 8.5 Hz), 7.89 - 7.93 (1H, m).

(Example 32)

{4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-2-fluoro-2'-methoxybiphenyl-4-yl}acetate sodium salt

(32a){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Methyl oxy]-2-fluoro-2'-methoxybiphenyl-4-yl}acetate

Compound (250 mg) obtained in Example (24a), [3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene Acetone An aqueous solution (2 mL) of potassium phosphate (292 mg) was added to a solution of the ester (203 mg) and triphenylphosphine palladium (0) (53.1 mg) in 1,2-dimethoxyethane (15 mL). The reaction was allowed to proceed for 9 hours and 30 minutes at °C. After cooling the reaction liquid to room temperature, the organic layer was separated, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The title compound (230 mg) was obtained as a pale brown solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.17 (3H, s), 3.18-3.26 (4H, m), 3.65 (2H, s), 3.73 (3H) , s), 3.75 (3H, s), 4.29 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.39-6.43 (1H, m), 6.60-6.62 (1H, m), 6.88 ( 1H, d, J = 8.5 Hz), 7.04-7.14 (3H, m), 7.28-7.31 (1H, m), 7.40 (1H, d, J = 7.3 Hz), 7.48-7.54 (1H, m), 7.60 -7.65 (1H, m), 7.99-8.05 (2H, m).

MS (APCI) m/z: 632 (M+H) ⁺ .

(32b){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2-fluoro-2'-methoxybiphenyl-4-yl}acetic acid

The compound (230 mg) obtained in Example (32a) was dissolved in tetrahydrofuran (8 mL) and ethanol (4 mL), and 1N aqueous sodium hydroxide (1. After the reaction mixture was stirred at room temperature for 18 hours and 30 minutes, 1N hydrochloric acid (1.10 mL) was added, and the organic solvent was evaporated. By Water was added to the residue, and the precipitated solid was filtered.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.6 Hz), 2.16 (3H, s), 3.19-3.25 (4H, m), 3.69 (2H, s), 3.74 (3H) , s), 4.29 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.38-6.43 (1H, m), 6.60-6.62 (1H, m), 6.88 (1H, d, J = 8.5 Hz), 7.05-7.14 (3H, m), 7.27-7.31 (1H, m), 7.40 (1H, d, J = 7.9 Hz), 7.48-7.54 (1H, m), 7.59-7.65 (1H, m) , 7.99-8.05 (2H, m).

MS (APCI) m/z: 618 (M+H) ⁺ .

(32c){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Sodium oxy]-2-fluoro-2'-methoxybiphenyl-4-yl}acetate

The compound (120 mg) obtained in Example (32b) was dissolved in methanol (3 mL), and 1N aqueous sodium hydroxide (0.194 mL) was added. After stirring for 1 hour, the title compound (124 mg) was obtained.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.11 (3H, t, J = 7.3Hz), 2.10 (3H, s), 3.16 (2H, s), 3.21 (2H, t, J = 8.5Hz ), 3.26-3.32 (2H, m), 3.70 (3H, s), 4.26-4.35 (4H, m), 6.28-6.33 (1H, m), 6.70-6.74 (1H, m), 6.87 (1H, d , J = 8.5 Hz), 6.95-7.03 (2H, m), 7.05-7.11 (2H, m), 7.51 (1H, d, J = 7.3 Hz), 7.55-7.60 (1H, m), 7.69-7.74 ( 1H, m), 7.87 (1H, d, J = 9.1 Hz), 7.92 (1H, d, J = 7.3 Hz).

(Example 33)

{2'-Ethyl-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole- Sodium 5-yl)oxy]-5'-methylbiphenyl-4-yl}acetate

(33a) 2-bromo-5-iodo-4-methylbenzaldehyde

Pyridine pyridinium dichromate (2.01 g) was added to a solution of the compound (br. The reaction mixture was concentrated under reduced vacuo.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.47 (3H, s), 7.52 (1H, s), 8.30 (1H, s), 10.21 (1H, s).

(33b) 1-bromo-2-vinyl-4-iodo-5-methylbenzene

A solution of methyltriphenylphosphonium bromide (1.01 g) in tetrahydrofuran (15 mL) was stirred at -78 ° C, and bis(trimethyldecyl)amine lithium (1.09 mol/L tetrahydrofuran solution, 2.60) was added dropwise over 10 minutes. mL). After 10 minutes, a solution of the compound (613 mg) obtained in THF (6 mL) After warming to room temperature and stirring for 29 hours, water was added to the reaction liquid, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and the solvent was evaporated. The title compound (259 mg) was obtained eluted eluted eluting

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.39 (3H, s), 5.35 (1H, d, J = 10.9 Hz), 5.66 (1H, d, J = 17.6 Hz), 6.91 (1H, dd, J = 17.6, 10.9 Hz), 7.41 (1H, s), 7.95 (1H, s).

(33c) 5-(4-Bromo-5-vinyl-2-methylphenoxy)-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

The compound (250 mg) obtained in the example (33b) and the 1,4-bis 5-butyl 4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid (193 mg) Copper (I) iodide (14.7 mg), N,N-dimethylglycine (16.0 mg) and cesium carbonate (504 mg) were added to the alkane (10 mL) solution, and stirred at 100 ° C for 9 hours. After cooling to room temperature, it was allowed to stand overnight, and again stirred at 100 ° C for 5 hours, and the reaction liquid was filtered through celite. The obtained filtrate was concentrated under reduced vacuum.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.56 (9H, s), 2.09 (3H, s), 2.28 (3H, s), 3.04 (2H, t, J = 8.8 Hz), 3.98-4.08 (2H , m), 5.22 (1H, d, J = 10.9 Hz), 5.36-5.46 (1H, m), 6.56-6.83 (2H, m), 6.92 (1H, dd, J = 17.0, 10.9 Hz), 7.17- 7.70 (2H, m).

(33d) 1-[5-(4-Bromo-5-vinyl-2-methylphenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2 -[2-(ethylsulfonyl)phenyl]ethanone

4N hydrochloric acid was added to a solution of the compound (90.0 mg) obtained in Example (33c) in dichloromethane (2 mL) A solution of the alkane (2 mL) was stirred at room temperature. After stirring for 2 hours, the reaction mixture was concentrated to give crude 5-(4-bromo-5-vinyl-2-methylphenoxy)-4-methyl-2,3-dihydro-1H- Guanidine hydrochloride (110 mg).

Add N-methyl to a solution of the obtained compound (110 mg) in N,N-dimethylformamide (5 mL) The morpholine (0.0445 mL) was stirred at room temperature for 60 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (84.1 mg) and [2-(ethylsulfonyl)phenyl]acetic acid (69.3 mg) were stirred at room temperature for 18 hours and 20 min. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.26 (3H, t, J = 7.3Hz), 2.15 (3H, s), 2.26 (3H, s), 3.18-3.26 (4H, m), 4.28 (2H , t, J = 8.5 Hz), 4.37 (2H, s), 5.24 (1H, d, J = 10.9 Hz), 5.43 (1H, d, J = 17.0 Hz), 6.62 (1H, d, J = 8.5 Hz) ), 6.83 (1H, s), 6.93 (1H, dd, J = 17.0, 10.9 Hz), 7.36-7.43 (2H, m), 7.47-7.53 (1H, m), 7.59-7.65 (1H, m), 7.94 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).

MS (APCI) m/z: 554 (M+H) ⁺ .

(33e){2'-Vinyl-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H- Ethyl-5-yl)oxy]-5'-methylbiphenyl-4-yl}ethyl acetate

Compound (104 mg) obtained in Example (33d), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate Ester (81.6 mg) and decyltriphenylphosphine palladium (0) (21.7 mg) of 1,2-dimethoxyethane (8 mL) An aqueous solution (1 mL) of potassium phosphate (119 mg) was added to the solution, and stirred at 100 ° C for 8 hours. After cooling to room temperature, the organic layer was dried over sodium sulfate, and the solvent was evaporated to dryness, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a colorless solid. The title compound (106 mg).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.22-1.29 (6H, m), 2.21 (3H, s), 2.30 (3H, s), 3.17-3.28 (4H, m), 3.66 (2H, s) , 4.18 (2H, q, J = 7.1 Hz), 4.28 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 5.06 (1H, d, J = 10.9 Hz), 5.43 (1H, d, J = 17.6 Hz), 6.62 (1H, dd, J = 17.6, 10.9 Hz), 6.69 (1H, d, J = 9.1 Hz), 6.93 (1H, s), 7.14 (1H, s), 7.26-7.33 ( 4H, m), 7.38-7.42 (1H, m), 7.47-7.53 (1H, m), 7.60-7.65 (1H, m), 7.96 (1H, d, J = 8.5 Hz), 8.01-8.05 (1H, m).

MS (APCI) m/z: 638 (M+H) ⁺ .

(33f){2'-Ethyl-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H- Ethyl-5-yl)oxy]-5'-methylbiphenyl-4-yl}ethyl acetate

A solution of the compound (105 mg) obtained in Example (33e) and 7.5% palladium carbon (20.0 mg) in ethanol (5 mL) was vigorously stirred under a hydrogen atmosphere. After stirring for 8 hours and 30 minutes, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The title compound (87.5 mg) was obtained.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 0.97 (3H, t, J = 7.5 Hz), 1.24-1.31 (6H, m), 2.21 (3H, s), 2.26 (3H, s), 2.47 (2H) , q, J = 7.5 Hz), 3.19-3.25 (4H, m), 3.66 (2H, s), 4.19 (2H, q, J = 7.3 Hz), 4.28 (2H, t, J = 8.2 Hz), 4.38 (2H, s), 6.60 (1H, s), 6.65-6.69 (1H, m), 7.05 (1H, s), 7.24-7.33 (4H, m), 7.40 (1H, d, J = 7.9 Hz), 7.48-7.54 (1H, m), 7.60-7.65 (1H, m), 7.95 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).

MS (APCI) m/z: 640 (M+H) ⁺ .

(33g) {2'-Ethyl-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-吲哚-5-yl)oxy]-5'-methylbiphenyl-4-yl}acetic acid

The compound obtained in Example (33f) (86.0 mg) was dissolved in THF (2 mL) and ethanol (2mL), and 1N aqueous sodium hydroxide (0.403mL) was added. After the reaction mixture was stirred at room temperature for 23 hours, 1N hydrochloric acid (0.42 mL) was added, and the organic solvent was evaporated. The title compound (74.7 mg) was obtained as a colorless solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 0.98 (3H, t, J = 7.3 Hz), 1.23-1.30 (4H, m), 2.20 (3H, s), 2.26 (3H, s), 2.47 (2H) , q, J = 7.3 Hz), 3.18-3.27 (4H, m), 3.71 (2H, s), 4.28 (2H, t, J = 8.2 Hz), 4.38 (2H, s), 6.60 (1H, s) , 6.67 (1H, d, J = 8.5 Hz), 7.05 (1H, s), 7.26-7.35 (4H, m), 7.38-7.42 (1H, m), 7.48-7.53 (1H, m), 7.59-7.65 (1H, m), 7.95 (1H, d, J = 8.5 Hz), 8.01 - 8.05 (1H, m).

MS (APCI) m/z: 612 (M+H) ⁺ .

(33h){2'-Ethyl-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H- Sodium-5-yl)oxy]-5'-methylbiphenyl-4-yl}acetate

The compound (63.5 mg) obtained in Example (33 g) was dissolved in methanol (5 mL), and 1N aqueous sodium hydroxide (0.104 mL) was added. After stirring for 30 minutes, the title compound (67.0 mg) was obtained.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 0.90 (3H, t, J = 7.6Hz), 1.11 (3H, t, J = 7.3Hz), 2.13 (3H, s), 2.21 (3H, s ), 2.42 (2H, q, J = 7.7 Hz), 3.17 (2H, s), 3.27-3.34 (2H, m), 3.22 (2H, t, J = 8.5 Hz), 4.24 - 4.35 (4H, m) , 6.51 (1H, s), 6.64 (1H, d, J = 9.1 Hz), 7.03 (1H, s), 7.10 (2H, d, J = 7.9 Hz), 7.22 (2H, d, J = 7.9 Hz) , 7.48-7.52 (1H, m), 7.54-7.60 (1H, m), 7.68-7.74 (1H, m), 7.81 (1H, d, J = 8.5 Hz), 7.89-7.93 (1H, m).

(Example 34)

{2'-Cyclopropyl-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole -5-yl)oxy]biphenyl-4-yl}acetate

(34a) 1-[5-(4-Bromo-3-cyclopropylphenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2- (ethylsulfonyl)phenyl]ethanone

Diethylzinc (0.9 mmol/L toluene solution, 0.370 mL) was added to toluene (6 mL), and the mixture was stirred under ice-cooling, and dichloromethane (0.0372 mL) was added. After the reaction mixture was stirred for 1 hour under ice-cooling, a toluene solution (3 mL) of the compound (100 mg) obtained in Example (30d) was added, and the mixture was stirred again under ice cooling. After 3 hours, the reaction solution was warmed to room temperature and stirred for additional 19 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times, and the combined organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The title compound (22.6 mg) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.58-0.65 (2H, m), 0.96-1.03 (2H, m), 1.26 (3H, t, J = 7.6 Hz), 2.06-2.16 (4H, m) , 3.16-3.26(4H,m), 4.27(2H,t,J=8.5Hz), 4.37(2H,s), 6.45-6.53(2H,m),6.73(1H,d,J=8.5Hz), 7.39 (2H, d, J = 8.5 Hz), 7.48-7.53 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 9.1 Hz), 8.03 (1H, d, J = 7.9Hz).

MS (APCI) m/z: 554 (M+H) ⁺ .

(34b){2'-Cyclopropyl-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H -吲哚-5-yl)oxy]biphenyl-4-yl}ethyl acetate

Compound (22.0 mg) obtained in Example (34a), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetic acid An aqueous solution (0.5 mL) of potassium phosphate (24.1 mg) was added to a solution of ethyl acetate (17.3 mg) and triphenylphosphine palladium (0) (4.58 mg) in 1,2-dimethoxyethane (3 mL). And stirred at 100 ° C for 7 hours. After cooling to room temperature, the organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate /hexane) The title compound (23.0 mg).

MS (APCI) m/z: 638 (M+H) ⁺ .

(34c){2'-Cyclopropyl-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H -吲哚-5-yl)oxy]biphenyl-4-yl}acetate

The compound obtained in Example (34b) (21.0 mg) was dissolved in tetrahydrofuran (2 mL) and ethanol (2mL), and 1N aqueous sodium hydroxide (0.1000 mL) was added. After the reaction mixture was stirred at room temperature for 18 hours, 1N hydrochloric acid (0.105 mL) was added, and the organic solvent was distilled off under reduced pressure. The precipitated solid was collected by filtration and dried to give the title compound (15.5 mg) as a colorless solid. The obtained solid was dissolved in methanol (1 mL), and 1N aqueous sodium hydroxide (0.0254 mL) was added. After stirring for 30 minutes, the title compound (16.1 mg)

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 0.57-0.66 (2H, m), 0.80-0.87 (2H, m), 1.11 (3H, t, J = 7.6Hz), 1.82-1.91 (1H, m), 2.07 (3H, s), 3.14-3.24 (4H, m), 3.27-3.33 (4H, m), 4.24-4.35 (2H, m), 6.45-6.48 (1H, m), 6.52-6.56 ( 1H,m), 6.79(1H,d,J=8.5Hz),7.07(1H,d,J=8.5Hz),7.18-7.26(4H,m),7.48-7.52(1H,m),7.55-7.60 (1H, m), 7.69-7.74 (1H, m), 7.84 (1H, d, J = 9.1 Hz), 7.89-7.93 (1H, m).

MS (APCI) m/z: 610 (M-Na+2H) ⁺ .

(Example 35)

{2'-Ethyl-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole -5-yl)oxy]biphenyl-4-yl}acetic acid

(35a){2'-Ethyl-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H -吲哚-5-yl)oxy]biphenyl-4-yl}ethyl acetate

The compound obtained in Example (30e) (100 mg), copper (I) chloride (15.9 mg), and palladium(II) chloride (5.69 mg) of N,N-dimethylformamide (8 mL) / water (1 mL) The suspension was stirred at room temperature under an oxygen atmosphere. After 40 minutes, the reaction solution was warmed to 60 ° C and stirred at the same temperature for 4 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted three times with a mixed solvent of ethyl acetate/hexane (2:1). After the combined organic layer was dried over sodium sulfate, EtOAc (EtOAc) Mg).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.24-1.29 (6H, m), 1.98 (3H, s), 2.13 (3H, s), 3.18-3.25 (4H, m), 3.66 (2H, s) , 4.17 (2H, q, J = 7.3 Hz), 4.29 (2H, t, J = 8.5 Hz), 4.39 (2H, s), 6.85 (1H, d, J = 8.5 Hz), 6.98-7.03 (2H, m), 7.27-7.36 (4H, m), 7.36-7.43 (2H, m), 7.48-7.54 (1H, m), 7.60-7.66 (1H, m), 7.99-8.06 (2H, m).

MS (APCI) m/z: 640 (M+H) ⁺ .

(35b){2'-Ethyl-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H -吲哚-5-yl)oxy]biphenyl-4-yl}acetic acid

The compound (10.6 mg) obtained in Example (35a) was dissolved in tetrahydrofuran (0.5 mL) and ethanol (0.5 mL), and 1N aqueous sodium hydroxide (0.100 mL) was added. After the reaction mixture was stirred at room temperature for 14 hours and 20 minutes, 1N hydrochloric acid (0.105 mL) was added, and the organic solvent was distilled off under reduced pressure. The title compound (6.3 mg) was obtained as a colorless solid.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.27 (3H, t, J = 7.3Hz), 2.00 (3H, s), 2.13 (3H, s), 3.19-3.26 (4H, m), 3.72 (2H , s), 4.29 (2H, t, J = 8.2 Hz), 4.39 (2H, s), 6.85 (1H, d, J = 8.5 Hz), 6.99-7.02 (2H, m), 7.27-7.31 (3H, m), 7.32-7.37 (2H, m), 7.41 (1H, d, J = 7.3 Hz), 7.48-7.54 (1H, m), 7.60-7.66 (1H, m), 7.99-8.06 (2H, m) .

MS (APCI) m/z: 612 (M+H) ⁺ .

(Example 36)

{4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy Biphenyl-4-yl}acetic acid

(36a) 3-(4-Bromophenoxy)-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

1,4,5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid (10.0 g) and 1-bromo-4-iodobenzene (13.6 g) -two To the solution of the alkane (150 mL), copper (I) iodide (1.53 g), N,N-dimethylglycine (1.66 g), and cesium carbonate (26.1 g) were added, and the mixture was stirred at 100 ° C for 24 hours. Saturated aqueous ammonium chloride solution (60 mL) and a saturated aqueous sodium hydrogen carbonate solution (30 mL) were added to the mixture. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was washed with EtOAc (mjjjjjjd

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.55 (9H, s), 2.04 (3H, s), 2.95-3.09 (2H, m), 3.93-4.07 (2H, br m), 6.68-6.81 (3H , m), 7.30-7.39 (2H, m), 7.62-7.75 (1H, br m).

(36b) 1-[5-(4-Bromophenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-(ethylsulfonyl) Phenyl]ethanone

4N hydrochloric acid was added to a solution of the compound (200 mg) obtained in Example (36a) in dichloromethane (2 mL) A solution of the alkane (2 mL) was stirred at room temperature. After stirring for 1 hour and 30 minutes, the reaction mixture was concentrated to give crude 5-(4-bromophenoxy)-4-methyl-2,3-dihydro-1H-indole hydrochloride.

Add N-methyl to a solution of the obtained compound in N,N-dimethylformamide (5 mL) The morpholine (0.109 mL) was stirred at room temperature for 20 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (206 mg) and [2-(ethylsulfonyl)phenyl]acetic acid (170 mg) were stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.26 (3H, t, J = 7.3Hz), 2.09 (3H, s), 3.17-3.25 (4H, m), 4.28 (2H, t, J = 8.5Hz ), 4.37 (2H, s), 6.72-6.80 (3H, m), 7.34-7.41 (3H, m), 7.48-7.54 (1H, m), 7.60-7.65 (1H, m), 7.99 (1H, d , J = 8.5 Hz), 8.01 - 8.05 (1H, m).

MS (APCI) m/z: 514 (M+H) ⁺ .

(36c){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Ethyl]biphenyl-4-yl}ethyl acetate

Compound (115 mg) obtained in Example (36b), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate An aqueous solution (1 mL) of potassium phosphate (142 mg) was added to a solution of the ester (97.3 mg) and decyltriphenylphosphine palladium (0) (25.8 mg) in 1,2-dimethoxyethane (6 mL). It was reacted at 90 ° C for 7 hours. After cooling the reaction liquid to room temperature, the organic layer was separated, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The title compound (82.5 mg) was obtained.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.22-1.31 (6H, m), 2.15 (3H, s), 3.18-3.26 (4H, m), 3.64 (2H, s), 4.17 (2H, q, J = 7.1 Hz), 4.29 (2H, t, J = 8.2 Hz), 4.38 (2H, s), 6.82-6.86 (1H, m), 6.90-6.95 (2H, m), 7.31-7.36 (2H, m ), 7.38-7.42 (1H, m), 7.47-7.54 (5H, m), 7.60-7.66 (1H, m), 7.98-8.05 (2H, m).

MS (APCI) m/z: 598 (M+H) ⁺ .

(36d){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl Oxy]biphenyl-4-yl}acetic acid

The compound obtained in Example (36c) (85.0 mg) was dissolved in tetrahydrofuran (2 mL) and ethanol (1mL), and 1N aqueous sodium hydroxide (0.427mL) was added. After the reaction mixture was stirred at room temperature for 14 hours, 1N hydrochloric acid (0.450 mL) was added, and the organic solvent was evaporated. The title compound (77.0 mg) was obtained as a colorless solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.6 Hz), 2.15 (3H, s), 3.19-3.26 (4H, m), 3.71 (2H, s), 4.29 (2H) ,t,J=8.5Hz), 4.38(2H,s), 6.84(1H,d,J=8.5Hz),6.91-6.95(2H,m),7.33-7.37(2H,m),7.38-7.42( 1H, m), 7.47-7.54 (5H, m), 7.60-7.65 (1H, m), 7.98-8.05 (2H, m).

MS (APCI) m/z: 570 (M+H) ⁺ .

(Example 37)

{4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy -2-fluorobiphenyl-4-yl}acetic acid

(37a){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Methyl oxy]-2-fluorobiphenyl-4-yl}acetate

Compound (115 mg) obtained in Example (36b), [3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene A solution of potassium acetate (142 mg) (1 mL) was added to a solution of methyl acetate (263 mg) and triphenylphosphine palladium (0) (25.8 mg) in 1,2-dimethoxyethane (6 mL). And allowed to react at 90 ° C for 7 hours. After cooling the reaction liquid to room temperature, the organic layer was separated, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The title compound (129 mg) was obtained from m.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.27 (3H, t, J = 7.3Hz), 2.14 (3H, s), 3.19-3.27 (4H, m), 3.65 (2H, s), 3.73 (3H , s), 4.29 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.86 (1H, d, J = 9.1 Hz), 6.93 (2H, d, J = 9.1 Hz), 7.06-7.13 (2H, m), 7.33-7.47 (4H, m), 7.48-7.54 (1H, m), 7.60-7.66 (1H, m), 7.99-8.06 (2H, m).

MS (APCI) m/z: 602 (M+H) ⁺ .

(37b){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2-fluorobiphenyl-4-yl}acetic acid

The compound (128 mg) obtained in Example (37a) was dissolved in tetrahydrofuran (2 mL) and ethanol (1 mL), and 1N aqueous sodium hydroxide (0.638 mL). After the reaction mixture was stirred at room temperature for 14 hours, 1N hydrochloric acid (0.650 mL) was added, and the organic solvent was evaporated. The title compound (107 mg) was obtained as a colorless solid.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.27 (3H, t, J = 7.6Hz), 2.14 (3H, s), 3.17-3.26 (4H, m), 3.70 (2H, s), 4.29 (2H ,t,J=8.5Hz), 4.38(2H,s), 6.86(1H,d,J=8.5Hz),6.91-6.95(2H,m),7.08-7.14(2H,m),7.35-7.54( 5H, m), 7.60-7.65 (1H, m), 7.99-8.05 (2H, m).

MS (APCI) m/z: 588 (M+H) ⁺ .

(Example 38)

{2'-(Difluoromethoxy)-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro- 1H-indol-5-yl)oxy]biphenyl-4-yl}acetic acid

(38a) 1-[5-(4-Bromo-3-hydroxyphenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-(B Alkylsulfonyl)phenyl]ethanone

To a solution of the compound (m.sub.2) (MeOH) (EtOAc, m. After cooling the reaction mixture to 0 ° C, the reaction solution was poured into water and extracted with dichloromethane for 8 times. Will merge The title compound (768 mg) was obtained.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.11 (3H, t, J = 7.6Hz), 2.02 (3H, s), 3.19 (2H, t, J = 8.5Hz), 3.27-3.36 (3H , m), 4.23-4.34 (4H, m), 6.25-6.31 (1H, m), 6.39-6.42 (1H, m), 6.83 (1H, d, J = 9.1 Hz), 7.37 (1H, d, J = 9.1 Hz), 7.50 (1H, d, J = 7.9 Hz), 7.56-7.60 (1H, m), 7.69-7.74 (1H, m), 7.85 (1H, d, J = 8.5 Hz), 7.89-7.93 (1H,m).

MS (APCI) m/z: 530 (M+H) ⁺ .

(38b) 1-{5-[4-Bromo-3-(difluoromethoxy)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2 -[2-(ethylsulfonyl)phenyl]ethanone

To a solution of the compound (130 mg) obtained in Example (38a) in N,N-dimethylformamide (5 mL), sodium chlorodifluoroacetate (74.7 mg) and cesium carbonate (160 mg), and Stir at °C for 3 hours. After cooling to room temperature, the reaction mixture was filtered through EtOAc (EtOAc)EtOAc. The title compound (76.5 mg).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.08 (3H, s), 3.17-3.26 (4H, m), 4.29 (2H, t, J = 8.5 Hz ), 4.38 (2H, s), 6.30-6.69 (2H, m), 6.77-6.82 (2H, m), 7.40 (1H, d, J = 7.3 Hz), 7.46 (1H, d, J = 8.5 Hz) , 7.49-7.54 (1H, m), 7.61-7.66 (1H, m), 7.99-8.05 (2H, m).

MS (APCI) m/z: 580 (M+H) ⁺ .

(38c){2'-(Difluoromethoxy)-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3- Dihydro-1H-indol-5-yl)oxy]biphenyl-4-yl}ethyl acetate

Compound (75.0 mg) obtained in Example (38b), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetic acid An aqueous solution (0.5 mL) of potassium phosphate (82.3 mg) was added to a solution of ethyl ester (56.2 mg) and triphenylphosphine palladium (0) (14.9 mg) in 1,2-dimethoxyethane (6 mL). And stirred at 90 ° C for 4 hours. After cooling to room temperature, after standing overnight, it was stirred again at 90 ° C for 50 minutes. After cooling to room temperature, the organic layer was dried over sodium sulfate and evaporated. The title compound (49.6 mg) was obtained from m.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.23-1.32 (6H, m), 2.14 (3H, s), 3.18-3.26 (4H, m), 3.65 (2H, s), 4.18 (2H, q, J = 7.1 Hz), 4.30 (2H, t, J = 8.5 Hz), 4.39 (2H, s), 6.30 (1H, t, J = 74.1 Hz), 6.73 (1H, dd, J = 9.1, 2.4 Hz) , 6.78-6.81 (1H, m), 6.86 (1H, d, J = 8.5 Hz), 7.27-7.36 (3H, m), 7.38-7.44 (3H, m), 7.48-7.54 (1H, m), 7.60 -7.66 (1H, m), 8.00-8.06 (2H, m).

MS (APCI) m/z: 664 (M+H) ⁺ .

(38d){2'-(Difluoromethoxy)-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3- Dihydro-1H-indol-5-yl)oxy]biphenyl-4-yl}acetic acid

The compound obtained in Example (38c) (48.0 mg) was dissolved in tetrahydrofuran (3 mL) and ethanol (2 mL), and 1N aqueous sodium hydroxide was added. (0.217 mL). After the reaction solution was stirred at room temperature for 18 hours, 1N hydrochloric acid (0.225 mL) was added, and the organic solvent was distilled off under reduced pressure. The title compound (40.4 mg) was obtained as a colorless solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.14 (3H, s), 3.19-3.25 (4H, m), 3.71 (2H, s), 4.30 (2H) , t, J = 8.5 Hz), 4.38 (2H, s), 6.31 (1H, t, J = 73.8 Hz), 6.73 (1H, dd, J = 8.5, 2.4 Hz), 6.79 (1H, d, J = 1.8 Hz), 6.86 (1H, d, J = 8.5 Hz), 7.26-7.37 (3H, m), 7.39-7.45 (3H, m), 7.49-7.53 (1H, m), 7.60-7.66 (1H, m ), 8.00-8.05 (2H, m).

MS (APCI) m/z: 636 (M+H) ⁺ .

(Example 39)

{4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-2'-(oxetane-3-yloxy)biphenyl-4-yl}acetic acid

(39a){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Ethyloxy]-2'-hydroxybiphenyl-4-yl}ethyl acetate

Compound (380 mg) obtained in Example (38a), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate An aqueous solution (1 mL) of potassium phosphate (456 mg) was added to a solution of the ester (270 mg) and decyltriphenylphosphine palladium (0) (82.8 mg) in 1,2-dimethoxyethane (10 mL). °C Stir for 10 hours. After cooling to room temperature, the organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The title compound (44.4 mg) was obtained from m.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.24-1.32 (6H, m), 2.14 (3H, s), 3.17-3.26 (4H, m), 3.66 (2H, s), 4.18 (2H, q, J = 7.3 Hz), 4.28 (2H, t, J = 8.2 Hz), 4.38 (2H, s), 5.22 (1H, s), 6.47 (1H, d, J = 2.4 Hz), 6.52 (1H, dd, J = 8.5, 2.4 Hz), 6.87 (1H, d, J = 8.5 Hz), 7.12 (1H, d, J = 8.5 Hz), 7.37-7.44 (5H, m), 7.48-7.54 (1H, m), 7.60-7.66 (1H, m), 7.98-8.06 (2H, m).

(39b){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Ethyloxy]-2'-(oxycyclobutane-3-yloxy)biphenyl-4-yl}ethyl acetate

3-oxetanyl tosylate (52.8 mg) was added to a solution of the compound obtained in Example (39a) (71.0 mg) in N,N-dimethylformamide (4 mL). And cesium carbonate (113 mg), and stirred at 100 ° C for 6 hours and 30 minutes. After cooling, the reaction solution was filtered, and the filtrate was evaporated. The title compound (15.9 mg) was obtained as a colorless crystals.

MS (APCI) m/z: 670 (M+H) ⁺ .

(39c){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-(oxycyclobutane-3-yloxy)biphenyl-4-yl}acetic acid

The compound (15.9 mg) obtained in Example (39b) was dissolved in tetrahydrofuran (2 mL) and ethanol (1 mL), and 1N aqueous sodium hydroxide (0.100 mL) was added. After the reaction liquid was stirred at room temperature for 9 hours, 1N hydrochloric acid (0.100 mL) was added, and the organic solvent was distilled off under reduced pressure. The title compound (15.2 mg) was obtained as a colorless solid.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.27 (3H, t, J = 7.3Hz), 2.13 (3H, s), 3.18-3.26 (4H, m), 3.71 (2H, s), 4.29 (2H ,t,J=8.2Hz), 4.38(2H,s),4.69-4.75(2H,m),4.83-4.90(2H,m),5.08-5.18(1H,m),6.09-6.11(1H,m ), 6.41-6.47 (1H, m), 6.84 (1H, d, J = 8.5 Hz), 7.20-7.24 (1H, m), 7.31-7.43 (3H, m), 7.49-7.54 (3H, m), 7.60-7.66 (1H, m), 7.99-8.06 (2H, m).

MS (APCI) m/z: 642 (M+H) ⁺ .

(Embodiment 40)

{4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-2'-(propan-2-yl)biphenyl-4-yl}acetic acid

(40a)(4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Ethyloxy]-2'-{[(trifluoromethyl)sulfonyl]oxy}biphenyl-4-yl)acetate

To a solution of the compound obtained in Example (39a) (285 mg) in THF (12 mL),1,1,1-trifluoro-N-phenyl-N-[(trifluoromethylsulfonyl)methane Sulfonamide (332 mg) and sodium hydride (35.4 mg) were stirred at room temperature for 3 hours and 30 minutes. Water was added to the reaction mixture and extracted with dichloromethane three times. The title compound (245 mg) was obtained from m.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.22-1.31 (6H, m), 2.13 (3H, s), 3.19-3.27 (4H, m), 3.66 (2H, s), 4.17 (2H, q, J=7.1 Hz), 4.30 (2H, t, J=8.5 Hz), 4.39 (2H, s), 6.86-6.90 (2H, m), 6.90-6.94 (1H, m), 7.33-7.42 (6H, m ), 7.49-7.54 (1H, m), 7.60-7.66 (1H, m), 8.02-8.06 (2H, m).

(40b){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Ethyloxy]-2'-(prop-1-en-2-yl)biphenyl-4-yl}ethyl acetate

Compound (240 mg) obtained in Example (40a), [4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaboron a solution of the ring (108 mg) and triphenylphosphine palladium (0) (37.2 mg) in 1,2-dimethoxyethane (12 mL). An aqueous solution (1 mL) of potassium phosphate (205 mg) was added and stirred at 85 ° C for 5 hours. After cooling to room temperature, the organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The title compound (216 mg) was obtained from m.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.22-1.30 (6H, m), 1.63 (3H, s), 2.17 (3H, s), 3.17-3.27 (4H, m), 3.63 (2H, s) , 4.17 (2H, q, J = 7.3 Hz), 4.28 (2H, t, J = 8.2 Hz), 4.38 (2H, s), 4.95 (1H, s), 5.03 (1H, s), 6.76-6.81 ( 1H, m), 6.82-6.88 (2H, m), 7.17 (1H, d, J = 8.5 Hz), 7.24-7.42 (5H, m), 7.48-7.53 (1H, m), 7.60-7.65 (1H, m), 7.98-8.05 (2H, m).

MS (APCI) m/z: 638 (M+H) ⁺ .

(40c){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Ethyloxy]-2'-(propan-2-yl)biphenyl-4-yl}ethyl acetate

To a solution of the compound (140 mg) obtained in EtOAc (EtOAc) (MeOH) (EtOAc) After stirring for 6 hours and 30 minutes, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The title compound (121 mg) was obtained from m.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.12 (6H, d, J = 6.7Hz), 1.23-1.33 (6H, m), 2.18 (3H, s), 2.99-3.08 (1H, m), 3.19 - 3.27 (4H, m), 3.66 (2H, s), 4.19 (2H, q, J = 7.1 Hz), 4.29 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.61-6.65 ( 1H, m), 6.84 (1H, d, J = 8.5 Hz), 6.96-6.98 (1H, m), 7.05 (1H, d, J = 8.5 Hz), 7.21-7.25 (2H, m), 7.29-7.33 (2H, m), 7.40 (1H, d, J = 7.9 Hz), 7.48-7.53 (1H, m), 7.60-7.65 (1H, m), 7.99 (1H, d, J = 8.5 Hz), 8.02 8.05 (1H, m).

MS (APCI) m/z: 640 (M+H) ⁺ .

(40d){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-(propan-2-yl)biphenyl-4-yl}acetic acid

The compound obtained in Example (40c) (120 mg) was dissolved in THF (2 mL) and ethanol (1mL), and 1N aqueous sodium hydroxide (0.563mL). After the reaction mixture was stirred at room temperature for 17 hours, 1N hydrochloric acid (0.575 mL) was added, and the organic solvent was evaporated. The title compound (110 mg) was obtained as a colorless solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.11 (6H, d, J = 7.3 Hz), 1.26 (3H, t, J = 7.6 Hz), 2.17 (3H, s), 2.97-3.08 (1H, m ), 3.18-3.27 (4H, m), 3.72 (2H, s), 4.28 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.63 (1H, dd, J = 8.5, 2.4 Hz) , 6.84 (1H, d, J = 8.5 Hz), 6.96-6.98 (1H, m), 7.05 (1H, d, J = 7.9 Hz), 7.23 - 7.35 (4H, m), 7.40 (1H, d, J = 7.9 Hz), 7.47-7.53 (1H, m), 7.59-7.65 (1H, m), 7.99 (1H, d, J = 8.5 Hz), 8.01-8.05 (1H, m).

MS (APCI) m/z: 612 (M+H) ⁺ .

(Example 41)

{4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-2'-(tetrahydrofuran-3-yl)biphenyl-4-yl}acetic acid

(41a){2'-(4,5-Dihydrofuran-3-yl)-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-A Ethyl 2,3-dihydro-1H-indol-5-yl)oxy]biphenyl-4-yl}ethyl acetate

Compound (100 mg) obtained in Example (40a), 2-(4,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaboron An aqueous solution (1 mL) of potassium phosphate (85.4 mg) was added to a solution of pentacyclopentyl (78.9 mg) and triphenylphosphine palladium (0) (15.5 mg) in 1,2-dimethoxyethane (7 mL). It was stirred at 90 ° C for 3 hours and 30 minutes. After cooling to room temperature, the organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The title compound (96.0 mg) was obtained from m.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.22-1.29 (6H, m), 2.17 (3H, s), 2.54-2.61 (2H, m), 3.18-3.26 (4H, m), 3.64 (2H, s), 4.17 (2H, q, J = 7.3 Hz), 4.23-4.31 (4H, m), 4.38 (2H, s), 5.96 (1H, s), 6.66 (1H, dd, J = 8.5, 2.4 Hz) ), 6.79-6.87 (2H, m), 7.08 (1H, d, J = 8.5 Hz), 7.27-7.31 (4H, m), 7.40 (1H, d, J = 7.9 Hz), 7.47-7.54 (1H, m), 7.59-7.65 (1H, m), 7.97-8.05 (2H, m).

MS (APCI) m/z: 666 (M+H) ⁺ .

(41b){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Ethyloxy]-2'-(tetrahydrofuran-3-yl)biphenyl-4-yl}ethyl acetate

To a solution of the compound (89.3 mg) obtained in Example (41a) (3 mL) / dichloromethane (3mL), 7.5% palladium carbon (50.0 mg) was added and stirred vigorously under a hydrogen atmosphere. After stirring for 4 hours, the title compound (81.1 mg) was obtained.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.23-1.32 (6H, m), 1.89-2.01 (1H, m), 2.13-2.25 (4H, m), 3.18-3.27 (4H, m), 3.40- 3.50 (1H, m), 3.62-3.68 (3H, m), 3.72-3.80 (1H, m), 3.94 (1H, t, J = 7.9 Hz), 3.98-4.06 (1H, m), 4.19 (2H, q, J = 7.1 Hz), 4.29 (2H, t, J = 8.5 Hz), 4.34 - 4.44 (2H, m), 6.66 - 6.70 (1H, m), 6.82 (1H, d, J = 8.5 Hz), 7.01-7.04(1H,m),7.09(1H,d,J=8.5Hz), 7.20-7.24(2H,m),7.31-7.35(2H,m), 7.40(1H,d,J=7.3Hz) , 7.48-7.54 (1H, m), 7.60-7.65 (1H, m), 7.99 (1H, d, J = 8.5 Hz), 8.02-8.05 (1H, m).

MS (APCI) m/z: 668 (M+H) ⁺ .

(41c){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-(tetrahydrofuran-3-yl)biphenyl-4-yl}acetic acid

The compound (80.0 mg) obtained in Example (41b) was dissolved in tetrahydrofuran (2 mL) and ethanol (1 mL), and 1N aqueous sodium hydroxide (0.359 mL). After the reaction mixture was stirred at room temperature for 17 hours, 1N hydrochloric acid (0.370 mL) was added, and the organic solvent was evaporated. The title compound (65.0 mg) was obtained as a colorless amorphous solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.9 Hz), 1.89-2.00 (1H, m), 2.14 - 2.26 (4H, m), 3.18-3.26 (4H, m) , 3.39-3.49 (1H, m), 3.62-3.80 (4H, m), 3.94 (1H, t, J = 7.9 Hz), 3.99-4.07 (1H, m), 4.29 (2H, t, J = 8.2 Hz ), 4.33-4.44 (2H, m), 6.65-6.70 (1H, m), 6.82 (1H, d, J = 8.5 Hz), 7.01-7.04 (1H, m), 7.09 (1H, d, J = 8.5 Hz), 7.21-7.25 (2H, m), 7.31-7.36 (2H, m), 7.40 (1H, d, J = 7.9 Hz), 7.48-7.53 (1H, m), 7.59-7.65 (1H, m) , 7.97-8.05 (2H, m).

MS (APCI) m/z: 640 (M+H) ⁺ .

(Example 42)

{4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-3'-methylbiphenyl-4-yl}acetic acid

(42a) (4'-Bromo-3'-methylbiphenyl-4-yl)acetate

1-Bromo-4-iodo-2-methylbenzene (767 mg), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) A solution of potassium phenyl phosphate (1.10 g) (1 mL) was added to a solution of phenyl]ethyl acetate (500 mg) and yttriumtriphenylphosphine palladium (0) (199 mg) in 1,2-dimethoxyethane (8 mL). The mixture was stirred at 80 ° C for 2 hours and 20 minutes, and then at 90 ° C for 4 hours. After cooling to room temperature, the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then evaporated, m.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.27 (3H, t, J = 7.3Hz), 2.46 (3H, s), 3.65 (2H, s), 4.17 (2H, q, J = 7.3Hz), 7.23-7.25(1H,m), 7.35(2H,d,J=7.9Hz), 7.42-7.45(1H,m),7.51(2H,d,J=7.9Hz),7.57(1H,d,J= 7.9Hz).

MS (APCI) m/z: 333 (M+H) ⁺ .

(42b) 5-{[4'-(2-Ethoxy-2-oxoethyl)-3-methylbiphenyl-4-yl]oxy}-4-methyl-2,3 -Dihydro-1H-indole-1-carboxylic acid tert-butyl ester

The compound obtained in Example (42a) (410 mg) and 1,4-diethyl 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester (460 mg) Copper (I) iodide (11.7 mg), N,N-dimethylglycine (12.7 mg) and cesium carbonate (802 mg) were added to the alkane (10 mL) solution, and stirred at 100 ° C for 7 hours. After cooling to room temperature, it was allowed to stand overnight, and stirred again at 100 ° C for 12 hours. After standing at room temperature for one night, it was stirred again at 100 ° C for 13 hours. After cooling to room temperature, the reaction solution was filtered over Celite. The obtained filtrate was concentrated under reduced pressure. EtOAcjjjjjjjj

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.27 (3H, t, J = 7.3Hz), 1.56 (9H, s), 2.11 (3H, s), 2.39 (3H, s), 3.04 (2H, t , J = 8.8 Hz), 3.64 (2H, s), 3.98-4.10 (2H, m), 4.17 (2H, q, J = 7.3 Hz), 6.59-6.77 (2H, m), 7.23-7.70 (7H, m).

(42c){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Ethyloxy]-3'-methylbiphenyl-4-yl}ethyl acetate

4N hydrochloric acid was added to a solution of the compound (130 mg) obtained in Example (42b) in dichloromethane (2 mL) A solution of the alkane (2 mL) was stirred at room temperature. After stirring for 1 hour, the reaction solution was concentrated to give crude {3'-methyl-4'-[(4-methyl-2,3-dihydro-1H-indol-5-yl)oxy. Biphenyl-4-yl}ethyl acetate hydrochloride (117 mg).

Add N-methyl to a solution of the obtained compound (117 mg) in N,N-dimethylformamide (6 mL) The morpholine (0.0859 mL) was stirred at room temperature for 15 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (108 mg) and [2-(ethylsulfonyl)phenyl]acetic acid (77.2 mg) were stirred at room temperature for 15 h. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.23-1.30 (6H, m), 2.17 (3H, s), 2.37 (3H, s), 3.17-3.26 (4H, m), 3.64 (2H, s) , 4.17 (2H, q, J = 7.3 Hz), 4.28 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.66-6.72 (2H, m), 7.28-7.36 (3H, m), 7.37-7.46(2H,m), 7.47-7.54(3H,m), 7.59-7.65(1H,m), 7.96(1H,d,J=8.5Hz),8.01-8.05(1H,m).

MS (APCI) m/z: 612 (M+H) ⁺ .

(42d){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-3'-methylbiphenyl-4-yl}acetic acid

The compound obtained in Example (42c) (150 mg) was dissolved in THF (3 mL) and ethanol (2mL), and 1N aqueous sodium hydroxide (0.736mL). After the reaction mixture was stirred at room temperature for 4 hours, 1N hydrochloric acid (0.750 mL) was added, and the organic solvent was distilled off under reduced pressure. The title compound (140 mg) was obtained as a colorless solid.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.26 (3H, t, J = 7.3Hz), 2.17 (3H, s), 2.37 (3H, s), 3.21 (4H, q, J = 7.3Hz), 3.70 (2H, s), 4.28 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.65-6.71 (2H, m), 7.27-7.36 (3H, m), 7.38-7.45 (2H, m), 7.47-7.55 (3H, m), 7.59-7.65 (1H, m), 7.96 (1H, d, J = 8.5 Hz), 8.01-8.05 (1H, m).

MS (APCI) m/z: 584 (M+H) ⁺ .

(Example 43)

{4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-2'-(methoxymethoxy)biphenyl-4-yl}acetic acid

(43a) 1-{5-[4-Bromo-3-(methoxymethoxy)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}- 2-[2-(ethylsulfonyl)phenyl]ethanone

To a solution of the compound (430 mg) obtained from m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m Stir at room temperature for 1 hour. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane three times. The combined organic layers were dried over sodium sulfate and evaporated. The title compound (394 mg) was obtained from m.

¹ H-NMR (400 HMz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.10 (3H, s), 3.17-3.26 (4H, m), 3.51 (3H, s), 4.28 (2H) , t, J = 8.5 Hz), 4.37 (2H, s), 5.20 (2H, s), 6.30-6.35 (1H, m), 6.77-6.83 (2H, m), 7.36-7.42 (2H, m), 7.49-7.54 (1H, m), 7.60-7.66 (1H, m), 7.98 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).

MS (APCI) m/z: 574 (M+H) ⁺ .

(43b){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Ethyloxy]-2'-(methoxymethoxy)biphenyl-4-yl}ethyl acetate

Compound (390 mg) obtained in Example (43a), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate B An aqueous solution (2 mL) of potassium phosphate (432 mg) was added to a solution of the ester (256 mg) and triphenylphosphine palladium (0) (78.4 mg) in 1,2-dimethoxyethane (20 mL) at 90 ° C Stir for 4 hours. After standing at room temperature for one night, it was stirred again at 90 ° C for 3 hours and 30 minutes. The reaction liquid was cooled to room temperature, and the organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The title compound (354 mg) was obtained from m.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.22-1.32 (6H, m), 2.16 (3H, s), 3.18-3.26 (4H, m), 3.38 (3H, s), 3.64 (2H, s) , 4.17 (2H, q, J = 7.1 Hz), 4.28 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 5.08 (2H, s), 6.46-6.50 (1H, m), 6.83 6.88(2H,m), 7.19(1H,d,J=8.5Hz), 7.31(2H,d,J=7.9Hz),7.38-7.42(1H,m),7.45(2H,d,J=7.9Hz ), 7.48-7.54 (1H, m), 7.60-7.65 (1H, m), 7.99 (1H, d, J = 8.5 Hz), 8.02-8.05 (1H, m).

MS (APCI) m/z: 658 (M+H) ⁺ .

(43c){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-(methoxymethoxy)biphenyl-4-yl}acetic acid

The compound (60.0 mg) obtained in Example (43b) was dissolved in tetrahydrofuran (3 mL) and ethanol (2mL), and 1N aqueous sodium hydroxide (0.274 mL) was added. After the reaction mixture was stirred at room temperature for 15 hr, 1N hydrochloric acid (0.274 mL) was added, and the organic solvent was evaporated. Borrow Water was added to the residue, and the precipitated solid was filtered and dried to give the title compound (47.7 mg).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.27 (3H, t, J = 7.6Hz), 2.16 (3H, s), 3.17-3.25 (4H, m), 3.38 (3H, s), 3.70 (2H , s), 4.28 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 5.08 (2H, s), 6.48 (1H, dd, J = 8.5, 2.4 Hz), 6.83-6.88 (2H, m), 7.18 (1H, d, J = 8.5 Hz), 7.29-7.34 (2H, m), 7.38-7.42 (1H, m), 7.43-7.53 (3H, m), 7.59-7.65 (1H, m) , 7.99 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).

MS (APCI) m/z: 630 (M+H) ⁺ .

(Example 44)

{4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-2'-(prop-1-en-2-yl)biphenyl-4-yl}acetic acid

(44a){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-(prop-1-en-2-yl)biphenyl-4-yl}acetic acid

The compound (70.0 mg) obtained in Example (40b) was dissolved in tetrahydrofuran (2 mL) and ethanol (1 mL), and 1N aqueous sodium hydroxide (0.329 mL) was added. After the reaction mixture was stirred at room temperature for 20 hours, 1N hydrochloric acid (0.335 mL) was added, and the organic solvent was evaporated. The title compound (58.8 mg) was obtained as a colorless solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 1.64 (3H, s), 2.17 (3H, s), 3.18-3.26 (4H, m), 3.69 (2H) , s), 4.28 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 4.95 (1H, s), 5.03 (1H, s), 6.76-6.80 (1H, m), 6.82-6.84 ( 1H,m), 6.86 (1H,d,J=8.5Hz), 7.17(1H,d,J=8.5Hz), 7.25-7.30(2H,m),7.33-7.42(3H,m),7.47-7.54 (1H, m), 7.59-7.65 (1H, m), 7.98-8.06 (2H, m).

MS (APCI) m/z: 610 (M+H) ⁺ .

(Example 45)

{2'-(Difluoromethoxy)-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro- 1H-indol-5-yl)oxy]-2-fluorobiphenyl-4-yl}acetic acid

(45a){2'-(Difluoromethoxy)-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3- Methyl dihydro-1H-indol-5-yl)oxy]-2-fluorobiphenyl-4-yl}acetate

Compound (75.0 mg) obtained in Example (38b), [3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) To a solution of methyl phenyl]acetate (405 mg) and decyltriphenylphosphine palladium (0) (39.8 mg) in 1,2-dimethoxyethane (8 mL), an aqueous solution of potassium phosphate (219 mg) (1 mL) ), The mixture was stirred at 85 ° C for 5 hours and 30 minutes. After cooling to room temperature, the organic layer was dried over sodium sulfate and evaporated. The title compound (207 mg) was obtained from m.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.27 (3H, t, J = 7.3Hz), 2.14 (3H, s), 3.18-3.28 (4H, m), 3.66 (2H, s), 3.73 (3H , s), 4.30 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.37 (1H, t, J = 73.8 Hz), 6.70-6.75 (1H, m), 6.80-6.83 (1H, m), 6.87 (1H, d, J = 8.5 Hz), 7.06-7.14 (2H, m), 7.21-7.28 (2H, m), 7.40 (1H, d, J = 7.3 Hz), 7.48-7.54 (1H , m), 7.60-7.66 (1H, m), 8.00-8.05 (2H, m).

MS (APCI) m/z: 668 (M+H) ⁺ .

(45b){2'-(Difluoromethoxy)-4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3- Dihydro-1H-indol-5-yl)oxy]-2-fluorobiphenyl-4-yl}acetic acid

The compound (205 mg) obtained in Example (45a) was dissolved in tetrahydrofuran (3 mL) and ethanol (1.5 mL), and 1N aqueous sodium hydroxide (0.921 mL) was added. After the reaction liquid was stirred at room temperature for 6 hours, 1N hydrochloric acid (0.935 mL) was added, and the organic solvent was distilled off under reduced pressure. The title compound (175 mg) was obtained as a colorless solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.6 Hz), 2.14 (3H, s), 3.18-3.26 (4H, m), 3.70 (2H, s), 4.30 (2H) , t, J = 8.5 Hz), 4.38 (2H, s), 6.37 (1H, t, J = 73.8 Hz), 6.72 (1H, dd, J = 8.5, 2.4 Hz), 6.81-6.84 (1H, m) , 6.87 (1H, d, J = 8.5 Hz), 7.08-7.15 (2H, m), 7.21-7.31 (2H, m), 7.38-7.42 (1H, m), 7.48-7.54 (1H, m), 7.60 -7.66 (1H, m), 8.00-8.06 (2H, m).

MS (APCI) m/z: 654 (M+H) ⁺ .

(Example 46)

{4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-2'-methoxy-6'-methylbiphenyl-4-yl}acetic acid

(46a) 5-(4-iodo-3-methoxy-5-methylphenoxy)-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

5-bromo-2-iodo-1-methoxy-3-methylbenzene (500 mg) and 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid Butyl ester (381mg) of 1,4-two Copper (I) (14.6 mg), N,N-dimethylglycine (15.8 mg) and cesium carbonate (997 mg) were added to a solution of alkane (10 mL), and stirred at 100 ° C for 10 hours and 30 minutes. After cooling to room temperature, it was allowed to stand overnight, and again stirred at 100 ° C for 6 hours and 30 minutes, and the reaction liquid was filtered through celite. The obtained filtrate was concentrated under reduced pressure. EtOAcjjjjjjj

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.56 (9H, s), 2.06 (3H, s), 2.37 (3H, s), 3.04 (2H, t, J = 8.5Hz), 3.81 (3H, s ), 3.97-4.10 (2H, m), 6.28-6.35 (2H, m), 6.74-6.85 (1H, m), 7.22-7.75 (1H, m).

(46b) 2-[2-(ethylsulfonyl)phenyl]-1-[5-(4-iodo-3-methoxy-5-methylphenoxy)-4-methyl-2 ,3-dihydro-1H-indol-1-yl]ethanone

4N hydrochloric acid was added to a solution of the compound (205 mg) obtained in Example (46a) in dichloromethane (2 mL) A solution of the alkane (2 mL) was stirred at room temperature. After stirring for 2 hours, the reaction mixture was concentrated to give crude 5-(4-iodo-3-methoxy-5-methylphenoxy)-4-methyl-2,3-dihydro-1H. - hydrazine hydrochloride.

Add N-methyl to a solution of the obtained compound in N,N-dimethylformamide (5 mL) The morpholine (0.0912 mL) was stirred at room temperature for 10 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl The ruthenium hydride (172 mg) and [2-(ethylsulfonyl)phenyl]acetic acid (142 mg) were stirred at room temperature for 15 hours. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal

MS (APCI) m/z: 606 (M+H) ⁺ .

(46c){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Ethyloxy]-2'-methoxy-6'-methylbiphenyl-4-yl}ethyl acetate

Compound (54.0 mg) obtained in Example (46b), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetic acid Ethyl ester (38.8 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (7.28 mg) of 1,2-dimethoxy Adding carbonic acid to ethane (2mL) solution An aqueous solution (0.5 mL) of sodium (28.4 mg) was reacted at 130 ° C for 20 minutes in a microwave reactor. After cooling the reaction mixture to room temperature, water was poured and extracted with ethyl acetate three times. After the combined organic layer was dried over sodium sulfate, the solvent was evaporated to give crystals crystals crystals (26.7 mg).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.23-1.30 (6H, m), 1.94-2.20 (6H, m), 3.06-3.27 (4H, m), 3.59-3.75 (5H, m), 4.09- 4.31(4H,m),4.33-4.40(2H,m),6.12-6.31(1H,m),6.42-6.55(1H,m),6.65-6.89(1H,m),7.14-7.42(5H,m ), 7.47-7.54 (1H, m), 7.58-7.66 (1H, m), 7.87-8.05 (2H, m).

MS (APCI) m/z: 642 (M+H) ⁺ .

(46d){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-methoxy-6'-methylbiphenyl-4-yl}acetic acid

The compound obtained in Example (46c) (26.0 mg) was dissolved in tetrahydrofuran (3 mL) and ethanol (3mL), and 1N aqueous sodium hydroxide (0.150mL) was added. After the reaction mixture was stirred at room temperature for 18 hours, 1N hydrochloric acid (0.170 mL) was added, and the organic solvent was evaporated. Water was added to the residue, and the mixture was combined with methylene chloride.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.22-1.30 (3H, m), 1.93-2.01 (3H, m), 2.09-2.19 (3H, m), 3.02-3.27 (4H, m), 3. 3.78(5H,m), 4.15-4.31(2H,m),4.31-4.41(2H,m), 6.19-6.32(1H,m),6.42-6.56(1H,m),6.58-6.89(1H,m ), 7.16-7.42 (5H, m), 7.47-7.54 (1H, m), 7.58-7.65 (1H, m), 7.82-8.05 (2H, m).

MS (APCI) m/z: 614 (M+H) ⁺ .

(Example 47)

{2'-Methyl-4'-[(4-methyl-1-{[3-(methylsulfonyl)pyridin-2-yl]ethenyl}-2,3-dihydro-1H-吲哚-5-yl)oxy]biphenyl-4-yl}acetic acid

(47a) [3-(Methylsulfonyl)pyridin-2-yl]propanedioic acid diethyl ester

2-Chloro-3-(methylsulfonyl)pyridine (0.300 g), copper (I) iodide (0.149 g), diethyl malonate (0.476 mL), cesium carbonate (1.53 g) and pyridine Formic acid (0.193g) is suspended in 1,4-two The alkane (7.5 mL) was stirred at 100 ° C for 7 hours. The reaction solution was allowed to stand at room temperature overnight, and then stirred at 100 ° C for 4 hours. After adding a saturated aqueous solution of ammonium chloride to the reaction mixture and extracting with ethyl acetate, the organic layer was washed with saturated brine. The organic layer was dried with EtOAc EtOAcjjjjjjjjjjj

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.30 (6H, t, J = 7.3 Hz), 3.12 (3H, s), 4.30 (4H, q, J = 7.3 Hz), 5.85 (1H, s), 7.50-7.54 (1H, m), 8.32-8.36 (1H, m), 8.83-8.85 (1H, m).

(47b) [3-(Methylsulfonyl)pyridin-2-yl]acetic acid

The compound (0.0533 g) obtained in Example (47a) was dissolved in methanol (1.5 mL), and 2N sodium hydroxide aqueous solution (0.75 mL) was added, and the mixture was stirred at 50 ° C for 2 hours and 30 minutes. After the reaction solution was allowed to stand at room temperature overnight, 1N hydrochloric acid was added to neutralize. The reaction solution was extracted three times with a dichloromethane/ethanol (19:1) mixture, and the organic layer was dried over sodium sulfate. The title compound (0.0322 g) was obtained.

^{1 H-NMR (400MHz, CDCl} 3) δ: 3.20 (3H, s), 4.45 (2H, s), 7.47-7.53 (1H, m), 8.36-8.39 (1H, m), 8.79-8.82 (1H, m).

(47c){2'-Methyl-4'-[(4-methyl-1-{[3-(methylsulfonyl)pyridin-2-yl]ethenyl}-2,3-dihydro -1H-indol-5-yl)oxy]biphenyl-4-yl}ethyl acetate

To a solution of the compound obtained in Example (3c) (0.050 g) and the compound (0.032 g) (Dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (0.0358 g), 3H-1,2,3-triazolo[4,5-b]pyridine-3- Alcohol (0.0085 g) was stirred at room temperature for 4 hours. After adding water to the reaction mixture and extracting with a mixed solvent of ethyl acetate and dichloromethane (4:1), the organic layer was washed with saturated brine. The organic layer was dried with EtOAc EtOAcjjjjjjjjjjj

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.28 (3H, t, J = 7.3Hz), 2.17 (3H, s), 2.22 (3H, s), 3.21-3.299 (5H, m), 3.65 (2H , s), 4.18 (2H, q, J = 7.3 Hz), 4.32-4.40 (2H, m), 4.62 (2H, s), 6.69-6.86 (3H, m), 7.12 (1H, d, J = 8.5 Hz), 7.23-7.34 (4H, m), 7.45-7.51 (1H, m), 7.94-7.99 (1H, m), 8.34-8.39 (1H, m), 8.78-8.82 (1H, m).

(47d){2'-Methyl-4'-[(4-methyl-1-{[3-(methylsulfonyl)pyridin-2-yl]ethenyl}-2,3-dihydro -1H-indol-5-yl)oxy]biphenyl-4-yl}acetic acid

The compound (0.0116 g) obtained in Example (47c) was dissolved in tetrahydrofuran (0.2 mL) and ethanol (0.2 mL), and 2N sodium hydroxide aqueous solution (0.4 mL) was added at 0 ° C, and then stirred at room temperature for 30 minutes. 1N hydrochloric acid was added to the reaction solution to neutralize it, and the mixture was extracted three times with a dichloromethane/methanol (19:1) mixed solution. The organic layer was dried with EtOAc EtOAcjjjjjjjjjjj

¹ H-NMR (400 MHz, CDCl ₃ + MeOH-d ₄ ) δ: 2.17 (3H, s), 2.22 (3H, s), 3.21-3.30 (5H, m), 3.65 (2H, s), 4.32-4.40 (2H, m), 4.62 (2H, s), 6.69-6.86 (3H, m), 7.09-7.54 (6H, m), 7.93-7.98 (1H, m), 8.35-8.40 (1H, m), 8.77 -8.82 (1H, m).

MS (APCI) m/z: 571 (M+H) ⁺ .

(Example 48)

{4'-[(1-{[3-(ethylsulfonyl)pyridin-2-yl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-methylbiphenyl-4-yl}acetic acid

(48a) [3-(ethylsulfonyl)pyridin-2-yl]propanedioic acid diethyl ester

2-Chloro-3-(ethylsulfonyl)pyridine (0.500 g), copper (I) iodide (0.695 g), diethyl malonate (0.740 mL), cesium carbonate (2.38 g) and pyridine Formic acid (0.299g) is suspended in 1,4-two The alkane (12 mL) was stirred at 100 ° C for 10 hours. After adding a saturated aqueous ammonium chloride solution to the reaction mixture and extracting with ethyl acetate, the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate and evaporated. The title compound (0.195 g) was obtained from m.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.22-1.35 (9H, m), 3.20 (2H, q, J = 7.3 Hz), 4.29 (4H, q, J = 7.1 Hz), 5.85 (1H, s ), 7.46-7.54 (1H, m), 8.25-8.33 (1H, m), 8.80-8.88 (1H, m).

(48b) [3-(ethylsulfonyl)pyridin-2-yl]acetic acid

The compound (0.040 g) obtained in Example (48a) was dissolved in ethanol (0.75 mL), and 2N sodium hydroxide aqueous solution (0.75 mL) was added, and the mixture was stirred at 80 ° C for 2 hours. 1N Hydrochloric acid was added to the reaction mixture to neutralize it, and the mixture was concentrated under reduced pressure. A methylene chloride/ethanol (9:1) mixed solvent was added to the obtained residue, and the title compound (0.0298 g) was obtained as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 7.6 Hz), 3.30-3.42 (2H, m), 4.19 (2H, s), 7.36-7.47 (1H, m), 8.23 -8.34 (1H, m), 8.66-8.78 (1H, m).

(48c){4'-[(1-{[3-(ethylsulfonyl)pyridin-2-yl]ethenyl}-4-methyl-2,3-dihydro-1H-indole- 5-ethyl)oxy]-2'-methylbiphenyl-4-yl}ethyl acetate

To a solution of the compound obtained in Example (3c) (0.065 g) and the compound obtained in Example (48b) (0.040 g) in dichloromethane (2 mL), triethylamine (0.0449 mL), N-[3- (Dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (0.0466 g), 3H-1,2,3-triazolo[4,5-b]pyridine-3- Alcohol (0.0110 g) was stirred at room temperature overnight. After adding water to the reaction mixture and extracting with a mixed solvent of ethyl acetate and dichloromethane (4:1), the organic layer was washed with saturated brine. The organic layer was dried with EtOAc EtOAcjjjjjjjjjj

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.23-1.35 (6H, m), 2.16 (3H, s), 2.22 (3H, s), 3.18-3.43 (4H, m), 3.65 (2H, s) , 4.18 (2H, q, J = 7.1 Hz), 4.32-4.39 (2H, m), 4.61 (2H, s), 6.69-6.86 (3H, m), 7.12 (1H, d, J = 8.5 Hz), 7.24-7.34 (4H, m), 7.43-7.48 (1H, m), 7.94-7.99 (1H, m), 8.30-8.34 (1H, m), 8.78-8.82 (1H, m).

(48d){4'-[(1-{[3-(ethylsulfonyl)pyridin-2-yl]ethenyl}-4-methyl-2,3-dihydro-1H-indole- 5-yl)oxy]-2'-methylbiphenyl-4-yl}acetic acid

The compound obtained in Example (48c) (0.0882 g) was dissolved in tetrahydrofuran (0.4 mL) and ethanol (0.4 mL), and 2N sodium hydroxide aqueous solution (0.8 mL) was added at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. 1N Hydrochloric acid was added to the reaction mixture to neutralize it, and the mixture was concentrated under reduced pressure. A mixed solvent of dichloromethane/ethanol (4:1) was added to the residue, and the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The title compound (0.0593 g) was obtained eluted elute

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.31 (3H, t, J = 7.6Hz), 2.16 (3H, s), 2.22 (3H, s), 3.18-3.43 (4H, m), 3.66 (2H , s), 4.31-4.39 (2H, m), 4.61 (2H, s), 6.68-6.86 (3H, m), 7.12 (1H, d, J = 8.5 Hz), 7.23 - 7.36 (4H, m), 7.46-7.51 (1H, m), 7.93-7.98 (1H, m), 8.30-8.35 (1H, m), 8.77-8.82 (1H, m).

MS (APCI) m/z: 585 (M+H) ⁺ .

(Example 49)

{2-Fluoro-2'-methyl-4'-[(4-methyl-1-{[3-(methylsulfonyl)pyridin-2-yl]ethenyl}-2,3-di Hydrogen-1H-indol-5-yl)oxy]biphenyl-4-yl}acetic acid

(49a) 5-{[2'-Fluoro-4'-(2-methoxy-2-oxoethyl)-2-methylbiphenyl-4-yl]oxy}-4-A Base 2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

The compound obtained in Example (14a) (0.365 g), the compound obtained in Example (1a) (0.400 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl -1,1'-biphenyl)[2-(2'-Amino-1,1'-biphenyl)]palladium(II) (0.0752 g) and potassium phosphate (0.609 g) suspended in toluene (7.6 (mL) and water (0.4 mL) were stirred at 100 ° C for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried with EtOAc EtOAcjjjjjjjjjjj

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.56 (9H, s), 2.10 (3H, s), 2.14 (3H, s), 3.00-3.08 (2H, m), 3.66 (2H, s), 3.74 (3H, s), 3.98-4.08 (2H, m), 6.68-6.90 (3H, m), 7.04-7.21 (4H, m), 7.65-7.75 (1H, m).

(49b) {2-Fluoro-2'-methyl-4'-[(4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]biphenyl-4-yl }methyl acetate

Trifluoroacetic acid (1 mL) was added to a solution of the compound (m. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture to neutralize the mixture, and the mixture was extracted with ethyl acetate, and then the organic layer was washed with brine. The title compound (0.229 g) was obtained.

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.09 (3H, s), 2.14 (3H, s), 2.98-3.05 (2H, m), 3.59-3.68 (4H, m), 3.74 (3H, s) , 6.48-6.51 (1H, m), 6.67-6.79 (3H, m), 7.04-7.21 (4H, m).

(49c){2-Fluoro-2'-methyl-4'-[(4-methyl-1-{[3-(methylsulfonyl)pyridin-2-yl]ethenyl}-2, Methyl 3-dihydro-1H-indol-5-yl)oxy]biphenyl-4-yl}acetate

To a solution of the compound obtained in Example (49b) (0.230 g) and the compound obtained in the compound (47b) (0.0999 g) in dichloromethane (3mL), triethylamine (0.129mL), N-[3- (Dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (0.133 g), 3H-1,2,3-triazolo[4,5-b]pyridine-3- Alcohol (0.0316 g) was stirred at room temperature overnight. After adding water to the reaction liquid and extracting with ethyl acetate, the organic layer was washed with saturated brine. The title compound (0.146 g) was obtained eluted eluted

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.15 (3H, s), 2.16 (3H, s), 3.21-3.28 (5H, m), 3.66 (2H, s), 3.74 (3H, s), 4.32 -4.39 (2H, m), 4.62 (2H, s), 6.70-6.87 (3H, m), 7.04-7.21 (4H, m), 7.45-7.50 (1H, m), 7.95-8.00 (1H, m) , 8.34 - 8.38 (1H, m), 8.78 - 8.81 (1H, m).

(49d) {2-Fluoro-2'-methyl-4'-[(4-methyl-1-{[3-(methylsulfonyl)pyridin-2-yl]ethenyl}-2, 3-dihydro-1H-indol-5-yl)oxy]biphenyl-4-yl}acetic acid

The compound obtained in Example (49c) (0.146 g) was dissolved in tetrahydrofuran (0.6 mL) and ethanol (0.6 mL). After (1.2 mL), it was stirred at room temperature for 20 minutes. 1N Hydrochloric acid was added to the reaction mixture to neutralize it, and the mixture was concentrated under reduced pressure. A mixed solution of dichloromethane/ethanol (4:1) was added to the residue, and the insoluble material was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (methanol / dichloromethane). The title compound (0.0981 g) was obtained as a colorless solid (yield: EtOAc).

^{1 H-NMR (400MHz, CDCl} 3 + MeOH-d 4) δ: 2.14 (3H, s), 2.16 (3H, s), 3.21-3.28 (5H, m), 3.65 (2H, s), 4.31-4.39 (2H, m), 4.62 (2H, s), 6.69-6.88 (3H, m), 7.06-7.22 (4H, m), 7.47-7.52 (1H, m), 7.93-7.99 (1H, m), 8.35 -8.40 (1H, m), 8.78-8.81 (1H, m).

MS (APCI) m/z: 589 (M+H) ⁺ .

(Example 50)

{4'-[(1-{[3-(ethylsulfonyl)-6-methylpyridin-2-yl]ethenyl}-4-methyl-2,3-dihydro-1H-indole哚-5-yl)oxy]-2'-methylbiphenyl-4-yl}acetic acid

(50a) (3-iodo-6-methylpyridin-2-yl)propane diacid dibenzyl ester

2-Fluoro-3-iodo-6-methylpyridine (1.00 g), dibenzyl malonate (4.10 mL), and cesium carbonate (5.50 g) were suspended in dimethyl hydrazine (10 mL), and Stir at 100 ° C for 7 hours. After adding water to the reaction liquid and extracting with ethyl acetate, the organic layer was washed with saturated brine. Making the organic layer sulphur The title compound (1.41 g) was obtained eluted eluted eluted

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.41 (3H, s), 5.16-5.35 (5H, m), 6.81 (1H, d, J = 8.5 Hz), 7.28-7.40 (10H, m), 7.92 (1H, d, J = 8.5 Hz).

(50b) [3-(ethylsulfonyl)-6-methylpyridin-2-yl]propanedioate dibenzyl ester

The compound obtained in Example (50a) (1.41 g), sodium ethanesulfinate (0.392 g), sodium L-guanidine salt (0.0771 g), and copper (I) iodide (0.0536 g) were suspended in Dimethylhydrazine (10 mL) was bubbled with nitrogen for 15 minutes and then stirred at 95 ° C for 4 hours and 30 minutes. After adding water to the reaction liquid and extracting with ethyl acetate, the organic layer was washed with saturated brine. The organic layer was dried with EtOAc EtOAcjjjjjjjjjjj

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.17 (3H, t, J = 7.3 Hz), 2.52 (3H, s), 3.01 (2H, q, J = 7.3 Hz), 5.21. (2H, d, J =12.8 Hz), 5.28 (2H, d, J = 12.8 Hz), 5.94 (1H, s), 7.22-7.43 (11H, m), 8.10 (1H, d, J = 7.9 Hz).

(50c) [3-(ethylsulfonyl)-6-methylpyridin-2-yl]acetic acid

The compound (0.157 g) obtained in Example (50b) was dissolved in ethyl acetate (2 mL) and ethanol (2 mL), and 20% of palladium carbonate (0.0628 g) was added, and the mixture was stirred under a hydrogen atmosphere for 40 minutes. The title compound (0.0667 g) was obtained.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.29 (3H, t, J = 7.3Hz), 2.65 (3H, s), 3.25 (2H, q, J = 7.3Hz), 4.35 (2H, s), 7.31 (1H, d, J = 8.5 Hz), 8.19 (1H, d, J = 8.5 Hz).

(50d){4'-[(1-{[3-(ethylsulfonyl)-6-methylpyridin-2-yl]ethenyl}-4-methyl-2,3-dihydro- 1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}ethyl acetate

To a solution of the compound obtained in Example (3c) (0.100 g) and the compound obtained in Example (50c) (0.200 g) in dichloromethane (4 mL), triethylamine (0.0691 mL), N-[3- (Dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (0.143 g), 3H-1,2,3-triazolo[4,5-b]pyridine-3- Alcohol (0.0170 g) was stirred at room temperature for 1 hour. After adding water to the reaction liquid and extracting with ethyl acetate, the organic layer was washed with saturated brine. The organic layer was dried with EtOAc EtOAcjjjjjjjjjjj

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.24-1.33 (6H, m), 2.16 (3H, s), 2.22 (3H, s), 2.63 (3H, s), 3.20-3.40 (4H, m) , 3.65 (2H, s), 4.18 (2H, q, J = 7.1 Hz), 4.32-4.38 (2H, m), 4.56 (2H, s), 6.69-6.85 (3H, m), 7.10-7.33 (6H , m), 7.94 - 7.98 (1H, m), 8.17 (1H, d, J = 7.9 Hz).

(50e){4'-[(1-{[3-(ethylsulfonyl)-6-methylpyridin-2-yl]ethenyl}-4-methyl-2,3-dihydro- 1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}acetic acid

The compound (0.184 g) obtained in Example (50d) was dissolved in tetrahydrofuran (0.8 mL) and ethanol (0.8 mL), and 2N sodium hydroxide aqueous solution (1.6 mL) was added at 0 ° C, and the mixture was stirred at room temperature for 40 minutes. 1N Hydrochloric acid was added to the reaction mixture to neutralize it, and the mixture was concentrated under reduced pressure. Methylene chloride/ethanol (4:1) was added to the residue, and the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The title compound (0.124 g) was obtained from m.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 2.16 (3H, s), 2.22 (3H, s), 2.63 (3H, s), 3.19-3.40 (4H , m), 3.70 (2H, s), 4.30-4.38 (2H, m), 4.56 (2H, s), 6.69-6.85 (3H, m), 7.11 (1H, d, J = 8.5 Hz), 7.23 7.34(5H,m), 7.94-7.98(1H,m), 8.15-8.19(1H,m).

MS (APCI) m/z: 599 (M+H) ⁺ .

(Example 51)

{4'-[(1-{[3-(ethylsulfonyl)pyridin-2-yl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2',5'-dimethylbiphenyl-4-yl}acetic acid

(51a) 5-{[4'-(2-Ethoxy-2-oxoethyl)-2,5-dimethylbiphenyl-4-yl]oxy}-4-methyl- 2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

Ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (0.864 g), Example (9a ) obtained compound (1.17 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amine) Phenyl-1,1'-biphenyl)]palladium(II) (0.213 g) and potassium phosphate (1.72 g) were suspended in toluene (19 mL) and water (1 mL), and stirred at 100 ° C for 7 hours and 30 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine. The title compound (1.32 g) was obtained eluted eluted eluted

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.28 (3H, t, J = 7.0 Hz), 1.56 (9H, s), 2.08-2.17 (6H, m), 2.30 (3H, s), 3.01-3.09 (2H,m), 3.65(2H,s),3.99-4.22(4H,m),6.42-6.79(2H,m),7.05-7.09(1H,m),7.23-7.34(4H,m),7.61 -7.72 (1H, m).

(51b){2',5'-Dimethyl-4'-[(4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]biphenyl-4-yl }ethyl acetate

Trifluoroacetic acid (3 mL) was added to a solution of the compound (l. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture to neutralize the mixture, and the mixture was extracted with ethyl acetate, and then the organic layer was washed with brine. The title compound (1.02 g) was obtained.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.28 (3H, t, J = 7.0Hz), 2.11 (3H, s), 2.12 (3H, s), 2.33 (3H, s), 2.98-3.07 (2H , m), 3.58-3.67 (4H, m), 4.18 (2H, q, J = 7.0 Hz), 6.41-6.53 (2H, m), 6.61-6.69 (1H, m), 7.03-7.09 (1H, m ), 7.18-7.36 (4H, m).

(51c){4'-[(1-{[3-(ethylsulfonyl)pyridin-2-yl]ethenyl}-4-methyl-2,3-dihydro-1H-indole- 5-ethyl)oxy]-2',5'-dimethylbiphenyl-4-yl}ethyl acetate

To a solution of the compound (0.100 g) obtained in Example (51b) and the compound (0.261 g) obtained from the compound (48b) in dichloromethane (4mL), triethylamine (0.0667mL), N-[3- (Dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (0.0692 g), 3H-1,2,3-triazolo[4,5-b]pyridine-3- Alcohol (0.0164 g) was stirred at room temperature for 3 hours. After adding water to the reaction liquid and extracting with ethyl acetate, the organic layer was washed with saturated brine. The organic layer was dried with EtOAc EtOAcjjjjjjjjjjj

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.25-1.36 (6H, m), 2.14 (3H, s), 2.20 (3H, s), 2.28 (3H, s), 3.15-3.43 (4H, m) , 3.65 (2H, s), 4.18 (2H, q, J = 7.1 Hz), 4.32-4.38 (2H, m), 4.61 (2H, s), 6.52-6.71 (2H, m), 7.06-7.09 (1H , m), 7.25-7.40 (4H, m), 7.43-7.48 (1H, m), 7.91-7.95 (1H, m), 8.29-8.33 (1H, m), 8.78-8.82 (1H, m).

(51d){4'-[(1-{[3-(ethylsulfonyl)pyridin-2-yl]ethenyl}-4-methyl-2,3-dihydro-1H-indole- 5-yl)oxy]-2',5'-dimethylbiphenyl-4-yl}acetic acid

The compound (0.0656 g) obtained in Example (51c) was dissolved in tetrahydrofuran (0.3 mL) and ethanol (0.3 mL), and 2N sodium hydroxide aqueous solution (0.6 mL) was added at 0 ° C, and then stirred at room temperature for 30 minutes. 1N Hydrochloric acid was added to the reaction mixture to neutralize it, and the mixture was concentrated under reduced pressure. Methylene chloride/ethanol (4:1) mixed solvent was added to the residue, and the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The title compound (0.0177 g) was obtained from m.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 2.12 (3H, s), 2.18 (3H, s), 2.26 (3H, s), 3.19-3.42 (4H , m), 3.68 (2H, s), 4.30-4.38 (2H, m), 4.61 (2H, s), 6.51 (1H, s), 6.68 (1H, d, J = 8.5 Hz), 7.03-7.49 ( 6H, m), 7.90-7.95 (1H, m), 8.29-8.34 (1H, m), 8.77-8.82 (1H, m).

MS (APCI) m/z: 599 (M+H) ⁺ .

(Example 52)

{4'-[(1-{[3-(ethylsulfonyl)-6-methylpyridin-2-yl]ethenyl}-4-methyl-2,3-dihydro-1H-indole哚-5-yl)oxy]-2',5'-dimethylbiphenyl-4-yl}acetic acid

(52a) (3-iodo-6-methylpyridin-2-yl)propane diacid tert-butyl methyl ester

2-Fluoro-3-iodo-6-methylpyridine (1.00 g), third butyl methyl malonate (1.47 g), and cesium carbonate (5.50 g) were suspended in dimethyl hydrazine. (10 mL) and stirred at 100 ° C overnight. After adding water to the reaction liquid and extracting with ethyl acetate, the organic layer was washed with water and saturated brine. The title compound (0.238 g) was obtained eluted eluted

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.51 (9H, s), 2.47 (3H, s), 3.81 (3H, s), 5.07 (1H, s), 6.81 (1H, d, J = 8.5Hz ), 7.94 (1H, d, J = 8.5 Hz).

(52b) [3-(ethylsulfonyl)-6-methylpyridin-2-yl]propanedioic acid tert-butyl methyl ester

The compound obtained in Example (52a) (0.238 g), sodium ethanesulfinate (0.0848 g), sodium L-guanamine salt (0.0167 g), and copper (I) iodide (0.0116 g) were suspended in Dimethylhydrazine (6 mL) was bubbled with nitrogen for 15 minutes and then stirred at 95 ° C for 4 hours and 30 minutes. After adding water to the reaction liquid and extracting with ethyl acetate, the organic layer was washed with saturated brine. The organic layer was dried with EtOAc EtOAcjjjjjjjjj

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.30 (3H, t, J = 7.3Hz), 1.49 (9H, s), 2.62 (3H, s), 3.16 (2H, q, J = 7.3Hz), 3.81 (3H, s), 5.70 (1H, s), 7.31 (1H, d, J = 8.5 Hz), 8.12 (1H, d, J = 8.5 Hz).

(52c) [3-(ethylsulfonyl)-6-methylpyridin-2-yl]acetate methyl ester

The compound obtained in Example (52b) (0.0902 g) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) Time. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture to neutralize the mixture, and the mixture was extracted with ethyl acetate, and then the organic layer was washed with brine. The organic layer was dried with EtOAc EtOAcjjjjjjjjjj

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.30 (3H, t, J = 7.3Hz), 2.63 (3H, s), 3.24 (2H, q, J = 7.3Hz), 3.74 (3H, s), 4.39 (2H, s), 7.28 (1H, d, J = 8.5 Hz), 8.16 (1H, d, J = 8.5 Hz).

(52d){4'-[(1-{[3-(ethylsulfonyl)-6-methylpyridin-2-yl]ethenyl}-4-methyl-2,3-dihydro- 1H-indol-5-yl)oxy]-2',5'-dimethylbiphenyl-4-yl}ethyl acetate

The compound (0.157 g) obtained in Example (52c) was dissolved in tetrahydrofuran (1 mL) and ethanol (1 mL), and 2N sodium hydroxide aqueous solution (0.107 mL) was added, and the mixture was stirred at room temperature for 1 hour. Sodium [3-(ethylsulfonyl)-6-methylpyridin-2-yl]acetate (0.0490 g) was obtained as a yellow amorphous solid.

Triethylamine (0.0467 mL), N-[3-(dimethylamine) was added to a solution of the obtained compound (0.049 g) and the compound (0.070 g) Propyl]-N'-ethylcarbodiimide hydrochloride (0.0646 g), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (0.0115 g) And stirred at room temperature for 1 hour. After adding water to the reaction liquid and extracting with ethyl acetate, the organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The title compound (0.108 g) was obtained.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.21-1.34 (6H, m), 2.14 (3H, s), 2.20 (3H, s), 2.28 (3H, s), 2.63 (3H, s), 3.21. -3.28(2H,m), 3.36(2H,q,J=7.4Hz), 3.66(2H,s), 4.19(2H,q,J=7.0Hz),4.32-4.38(2H,m),4.56( 2H, s), 6.53-6.71 (2H, m), 7.08-7.10 (1H, m), 7.26-7.35 (5H, m), 7.91-7.96 (1H, m), 8.16-8.20 (1H, m).

(52e){4'-[(1-{[3-(ethylsulfonyl)-6-methylpyridin-2-yl]ethenyl}-4-methyl-2,3-dihydro- 1H-indol-5-yl)oxy]-2',5'-dimethylbiphenyl-4-yl}acetic acid

The compound obtained in Example (52d) (0.108 g) was suspended in tetrahydrofuran (1 mL), ethanol (1 mL) and dichloromethane (0.6 mL), and 2N aqueous sodium hydroxide (1 mL) Stir for 1 hour. 1N Hydrochloric acid was added to the reaction mixture to neutralize it, and the mixture was concentrated under reduced pressure. Methylene chloride/ethanol = 4/1 was added to the residue, and the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The title compound (0.0280 g), m.

¹ H-NMR (400 MHz, CDCl ₃ + MeOH-d ₄ ) δ: 1.29 (3H, t, J = 7.3 Hz), 2.13 (3H, s), 2.20 (3H, s), 2.27 (3H, s), 2.64 (3H, s), 3.20-3.39 (4H, m), 3.65 (2H, s), 4.31-4.39 (2H, m), 4.56 (2H, s), 6.53 (1H, s), 6.67 (1H, d, J = 8.5 Hz), 7.07 (1H, s), 7.24 - 7.35 (5H, m), 7.89 - 7.93 (1H, m), 8.15-8.20 (1H, m).

MS (APCI) m/z: 613 (M+H) ⁺ .

(Example 53)

4-(Benzyloxy)-2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H -吲哚-5-yl)oxy]-2'-methylbiphenyl-4-yl}butyric acid

(53a) 5-({4'-[4-(Benzyloxy)-1-ethoxy-1-oxobutan-2-yl]-2-methylbiphenyl-4-yl} Oxy)-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

Potassium tert-butoxide (67.1 mg) and benzyl 2-bromoethyl ether were added sequentially to a solution of the compound obtained in Example (3b) (250 mg) in N,N-dimethylformamide (2 mL). 0.0828 mL) and stirred at room temperature for 48 hours. Ice water (10 mL) was added to the mixture. The residue obtained was purified by silica gel chromatography eluting elut elut

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.21 (3H, t, J = 7.3 Hz), 1.50-1.64 (9H, m), 2.00-2.13 (4H, m), 2.21 (3H, s), 2.39 -2.50 (1H, m), 3.04 (2H, t, J = 8.9 Hz), 3.36-3.44 (1H, m), 3.46-3.53 (1H, m), 3.85 (1H, t, J = 7.6 Hz), 3.99-4.20(2H,m), 4.45(2H,d,J=12.2Hz), 4.49(2H,d,J=12.2Hz), 6.70(1H,dd,J=8.2,2.7Hz),6.75-6.78 (1H, m), 6.81-6.89 (1H, m), 7.10 (1H, d, J = 7.9 Hz), 7.20-7.38 (10H, m).

MS (APCI) m/z: 636 (M + H) ⁺ , 580 (M-tBu) ⁺ .

(53b) 4-(Benzyloxy)-2-{2'-methyl-4'-[(4-methyl-2,3-dihydro-1H-indol-5-yl)oxy] Phenyl-4-yl}butyrate ethyl ester hydrochloride

4N hydrochloric acid was added to a dichloromethane solution (5 mL) of the compound (194 mg) obtained in Example (53a) A solution of the alkane (1 mL) was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced vacuo to give title crystal.

(53c) 4-(Benzyloxy)-2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-di Ethyl hydrogen-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}butanoate

N-methyl group was added to the N,N-dimethylformamide solution (2 mL) of the compound (163 mg) obtained in Example (53b) The porphyrin (0.0369 mL) was stirred at room temperature for 10 minutes, then [2-(ethylsulfonyl)phenyl]acetic acid (76.6 mg) and DMT-MM (110 mg). Ice water (15 mL) was added to the reaction mixture, and the precipitated insoluble material was filtered, washed with water and evaporated to dryness.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.21 (3H, t, J = 7.3 Hz), 1.27 (3H, t, J = 7.6 Hz), 2.01-2.12 (1H, m), 2.16 (3H, s ), 2.21 (3H, s), 2.39-2.50 (1H, m), 3.18-3.26 (4H, m), 3.36-3.45 (1H, m), 3.46-3.54 (1H, m), 3.85 (1H, t , J=7.6Hz), 4.03-4.19(2H,m), 4.28(2H,t,J=8.5Hz), 4.38(1H, s), 4.45(1H,d,J=11.6Hz),4.49(2H , d, J = 11.6 Hz), 6.71 (1H, dd, J = 8.5, 2.4 Hz), 6.76-6.80 (1H, m), 6.84 (1H, d, J = 9.2 Hz), 7.11 (1H, d, J=8.5 Hz), 7.20-7.42 (10H, m), 7.47-7.54 (1H, m), 7.59-7.66 (1H, m), 7.98-8.06 (2H, m).

MS (APCI) m/z: 746 (M+H) ⁺ .

(53d) 4-(Benzyloxy)-2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-di Hydrogen-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}butyric acid

A 2 M aqueous sodium hydroxide solution (0.820 mL) was added to a mixture of the compound (m. After the solvent was concentrated under reduced pressure, water (6 mL) was added to the residue, and 2M hydrochloric acid (0.820 mL) was added. The precipitated insoluble material was filtered, and the title compound (189 mg) was obtained.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.11 (3H, t, J = 7.3Hz), 1.88-1.98 (1H, m), 2.08 (3H, s), 2.18 (3H, s), 2.24 -2.35 (1H, m), 3.21 (2H, t, J = 7.9 Hz), 3.26-3.45 (5H, m), 3.71 (1H, t, J = 7.6 Hz), 4.24 - 4.34 (4H, m), 4.40 (1H, d, J = 12.2 Hz), 4.45 (1H, d, J = 12.2 Hz), 6.67 (1H, dd, J = 8.5, 2.4 Hz), 6.78-6.86 (2H, m), 7.13 (1H) , d, J = 7.9 Hz), 7.24 - 7.37 (9H, m), 7.50 (1H, d, J = 7.9 Hz), 7.58 (1H, t, J = 7.6 Hz), 7.86 (1H, d, J = 8.5 Hz), 7.91 (1H, d, J = 7.9 Hz), 12.42 (1H, br s).

MS (APCI) m/z: 718 (M+H) ⁺ .

(Example 54)

2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-methylbiphenyl-4-yl}-4-hydroxybutyric acid

(54a) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-2'-methylbiphenyl-4-yl}-4-hydroxybutyric acid

To a mixed solution of the compound (179 mg) obtained in Example (53d) in ethanol / tetrahydrofuran (2:1) (6 mL) was added 7.5% palladium carbon (Kawaken Fine Chemicals PH PH) (71.6 mg) and stirred under a hydrogen atmosphere. 10 hours. Further, 10% palladium carbon (Kawaken Fine Chemicals PH AD) (71.6 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 4.5 hours. After the insoluble material was filtered, the filtrate was evaporated to ethylamine.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.11 (3H, t, J = 7.3Hz), 1.73-1.85 (1H, m), 2.05-2.22 (7H, m), 3.16-3.25 (2H, m), 3.26-3.38 (4H, m), 3.70 (1H, t, J = 7.3 Hz), 4.24 - 4.35 (4H, m), 4.56 (1H, br s), 6.67 (1H, dd, J = 8.2) , 2.7 Hz), 6.78-6.85 (2H, m), 7.13 (1H, d, J = 7.9 Hz), 7.27 (2H, d, J = 8.5 Hz), 7.32 (2H, d, J = 8.5 Hz), 7.50 (1H, d, J = 7.3 Hz), 7.54 - 7.62 (1H, m), 7.68-7.75 (1H, m), 7.86 (1H, d, J = 8.5 Hz), 7.89-7.94 (1H, m) , 12.35 (1H, br s).

MS (APCI) m/z: 628 (M+H) ⁺ .

(Example 55)

4-cyano-2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole -5-yl)oxy]-2'-methylbiphenyl-4-yl}butyric acid

(55a) 5-{[4'-(4-Cyano-1-ethoxy-1-oxobutan-2-yl)-2-methylbiphenyl-4-yl]oxy} -4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

Potassium tert-butoxide (53.7 mg) and 3-bromopropionitrile (0.0347 mL) were sequentially added to a solution of the compound obtained in Example (3b) (200 mg) in N,N-dimethylformamide (2 mL). It was stirred at room temperature for 29 hours. Water (8 mL) was added to the reaction mixture, and the mixture was evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.24 (3H, t, J = 7.0 Hz), 1.49-1.65 (9H, m), 2.08-2.23 (7H, m), 2.23 - 2.34 (1H, m) , 2.35-2.48 (2H, m), 3.05 (2H, t, J = 8.9 Hz), 3.72-3.78 (1H, m), 3.98-4.27 (4H, m), 6.71 (1H, dd, J = 8.5, 2.4 Hz), 6.75-6.79 (1H, m), 6.80-6.89 (1H, m), 7.10 (1H, d, J = 8.5 Hz), 7.24-7.33 (4H, m), 7.65-7.75 (1H, m ).

MS (APCI) m/z: 555 (M+H) ⁺ , 540 (M-Me) ⁺ , 499 (M-tBu) ⁺ , 455 (M-Boc) ⁺ .

(55b) 4-cyano-2-{2'-methyl-4'-[(4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]biphenyl- 4-yl}ethyl butyrate hydrochloride

4N hydrochloric acid was added to a dichloromethane solution (2 mL) of the compound (86.0 mg) obtained in Example (55a) Alkane solution (0.4 mL), stirred at room temperature for 7.5 hours, then added 4N hydrochloric acid The alkane solution (0.1 mL) was stirred for an additional 15.5 hours. The reaction mixture was concentrated under reduced vacuo to give title crystal.

(55c) 4-cyano-2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H -吲哚-5-yl)oxy]-2'-methylbiphenyl-4-yl}butyric acid ethyl ester

N-methyl group was added to the N,N-dimethylformamide solution (1.5 mL) of the compound obtained in Example (55b) (76.1 mg) After the mixture was stirred at room temperature for 5 minutes, [2-(ethylsulfonyl)phenyl]acetic acid (38.9 mg) and DMT-MM (55.8 mg). Water (5 mL) was added to the reaction mixture, and the precipitated insoluble material was filtered.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.24 (3H, t, J = 7.0 Hz), 1.27 (3H, t, J = 7.3 Hz), 2.11-2.34 (8H, m), 2.35-2.47 (2H) , m), 3.18-3.26 (4H, m), 3.69-3.78 (1H, m), 4.08-4.32 (4H, m), 4.38 (2H, s), 6.72 (1H, dd, J = 8.2, 2.7 Hz ), 6.77-6.80 (1H, m), 6.84 (1H, d, J = 9.2 Hz), 7.11 (1H, d, J = 7.9 Hz), 7.24-7.34 (4H, m), 7.38-7.42 (1H, m), 7.47-7.54 (1H, m), 7.59-7.66 (1H, m), 7.97-8.06 (2H, m).

(55d) 4-cyano-2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H -吲哚-5-yl)oxy]-2'-methylbiphenyl-4-yl}butyric acid

A 2 M aqueous sodium hydroxide solution (0.292 mL) was added to a mixture (3 mL) of EtOAc. After the solvent was concentrated under reduced pressure, water (6 mL) was added to the residue, and 2M hydrochloric acid (0.300 mL) was added. The title compound (88.7 mg) was obtained as a white solid.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.11 (3H, t, J = 7.3Hz), 1.94-2.05 (1H, m), 2.08 (3H, s), 2.19 (3H, s), 2.22 -2.35(1H,m), 2.37-2.48(2H,m),3.16-3.25(2H,m),3.25-3.38(2H,m),3.64(1H,t,J=7.6Hz),4.24-4.34 (4H,m), 6.67 (1H, dd, J=8.5, 2.4 Hz), 6.78-6.86 (2H, m), 7.14 (1H, d, J = 8.5 Hz), 7.28-7.35 (4H, m), 7.48-7.53 (1H, m), 7.55-7.61 (1H, m), 7.68-7.74 (1H, m), 7.86 (1H, d, J = 8.5 Hz), 7.89-7.94 (1H, m), 12.67 ( 1H, br s).

MS (APCI) m/z: 637 (M+H) ⁺ .

(Example 56)

2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-methylbiphenyl-4-yl}pentanoic acid

(56a) 2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pentanoate

To a solution of 4-(ethoxycarbonylmethyl)phenylboronic acid pinacol ester (200 mg) in tetrahydrofuran (4 mL), lithium diisopropylamine (1.09 M hexane-tetrahydrofuran solution, 1.26 mL) and stirred for 20 minutes. 1-Bromopropane (0.125 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 17 hr. A saturated aqueous solution of ammonium chloride (2 mL) was added to the mixture, and the mixture was evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

^{1 H-NMR (400MHz, CDCl} 3) δ: 0.90 (3H, t, J = 7.3Hz), 1.19 (3H, t, J = 7.0Hz), 1.21-1.38 (14H, m), 1.68-1.80 (1H , m), 1.97-2.11 (1H, m), 3.55 (1H, t, J = 7.6 Hz), 4.01-4.19 (2H, m), 7.32 (2H, d, J = 7.9 Hz), 7.76 (2H, d, J = 7.9 Hz).

(56b) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -ethyl)oxy]-2'-methylbiphenyl-4-yl}pentanoic acid ethyl ester

The compound obtained in Example (56a) (566 mg), [1,1'-bis (two) was added to a solution of the compound (m. Phenylphosphino)ferrocene]dichloropalladium(II) (92.7 mg), sodium carbonate (361 mg), and water (3.5 mL) were reacted at 130 ° C for 1 hour in a microwave reactor. Saturated brine (2 mL) and water (2 mL) were added to the mixture, and the mixture was extracted with ethyl acetate. The residue obtained was purified by EtOAc EtOAc (EtOAc)

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.94 (3H, t, J = 7.3 Hz), 1.18-1.36 (8H, m), 1.72-1.83 (1H, m), 2.03-2.14 (1H, m) , 2.16 (3H, s), 2.22 (3H, s), 3.17-3.26 (4H, m), 3.58 (1H, t, J = 7.6 Hz), 4.06-4.23 (2H, m), 4.28 (2H, t , J = 8.5 Hz), 4.38 (2H, s), 6.71 (1H, dd, J = 8.5, 2.4 Hz), 6.76-6.79 (1H, m), 6.84 (1H, d, J = 9.2 Hz), 7.12 (1H,d,J=7.9Hz), 7.24(2H,d,J=7.9Hz), 7.33(2H,d,J=7.9Hz), 7.40(1H,d,J=7.3Hz),7.47-7.54 (1H, m), 7.59-7.66 (1H, m), 7.97-8.05 (2H, m).

MS (APCI) m/z: 654 (M+H) ⁺ .

(56c) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-2'-methylbiphenyl-4-yl}pentanoic acid

A 2M aqueous sodium hydroxide solution (1.38 mL) was added to a mixture of EtOAc (EtOAc) (EtOAc) After concentrating the reaction solution under reduced pressure, add Water (15 mL) and 2M hydrochloric acid (1.45 mL) were added and stirred. The precipitated insoluble material was filtered, washed with water and evaporated to dryness.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 0.88 (3H, t, J = 7.3Hz), 1.11 (3H, t, J = 7.3Hz), 1.14-1.33 (2H, m), 1.59-1.71 (1H, m), 1.88-2.02 (1H, m), 2.08 (3H, s), 2.18 (3H, s), 3.17-3.25 (2H, m), 3.26-3.36 (2H, m), 3.55 (1H) , t, J = 7.3 Hz), 4.24 - 4.35 (4H, m), 6.67 (1H, dd, J = 8.5, 2.4 Hz), 6.77 - 6.85 (2H, m), 7.13 (1H, d, J = 8.5 Hz), 7.27 (2H, d, J = 7.9 Hz), 7.33 (2H, d, J = 7.9 Hz), 7.50 (1H, d, J = 7.3 Hz), 7.54 - 7.61 (1H, m), 7.68- 7.75 (1H, m), 7.86 (1H, d, J = 8.5 Hz), 7.89-7.94 (1H, m), 12.35 (1H, s).

MS (APCI) m/z: 626 (M+H) ⁺ .

(Example 57)

2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-methylbiphenyl-4-yl}propionic acid

(57a) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -ethyl)oxy]-2'-methylbiphenyl-4-yl}propionic acid ethyl ester

2-[4-(4,4,5,5-tetramethyl-1,3) was added to a solution of the compound obtained in Example (2a) (380 mg) in 1,2-dimethoxyethane (12 mL) Ethyl 2-(2-dioxaborolan-2-yl)phenyl]propanoate (328 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (58.7 Mg), sodium carbonate (229 mg), and water (2.5 mL) were reacted at 130 ° C for 1 hour in a microwave reactor. Saturated brine (2 mL) and water (2 mL) were added to the mixture, and the mixture was extracted with ethyl acetate. The residue obtained was purified by EtOAc EtOAc (EtOAc)

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.21-1.30 (6H, m), 1.53 (3H, d, J = 7.1 Hz), 2.16 (3H, s), 2.22 (3H, s), 3.18-3.26 (4H, m), 3.75 (1H, q, J = 7.1 Hz), 4.08-4.23 (2H, m), 4.28 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.71 (1H, Dd, J = 8.2, 2.7 Hz), 6.77-6.80 (1H, m), 6.84 (1H, d, J = 8.5 Hz), 7.12 (1H, d, J = 8.5 Hz), 7.22-7.27 (2H, m ), 7.32 (2H, t, J = 6.4 Hz), 7.38-7.42 (1H, m), 7.48-7.53 (1H, m), 7.59-7.65 (1H, m), 7.98-8.05 (2H, m).

MS (APCI) m/z: 626 (M+H) ⁺ .

(57b) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-2'-methylbiphenyl-4-yl}propionic acid

A 2 M aqueous sodium hydroxide solution (1.64 mL) was added to a mixed solution (10 mL) of the compound (342 mg) obtained from the compound (57m), and the mixture was stirred at 45 ° C for 4 hours. After standing to cool to room temperature, water (12 mL) and 2M hydrochloric acid (1.70 mL) were added to the reaction mixture and stirred. The insoluble material was filtered, washed with water and evaporated to dryness.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.11 (3H, t, J = 7.3Hz), 1.36 (3H, d, J = 6.7Hz), 2.08 (3H, s), 2.18 (3H, s ), 3.12-3.43 (4H, m), 3.64 (1H, q, J = 6.7 Hz), 4.24 - 4.34 (4H, m), 6.67 (1H, dd, J = 8.2, 2.7 Hz), 6.77-6.85 ( 2H, m), 7.12 (1H, d, J = 8.5 Hz), 7.24 (2H, d, J = 7.9 Hz), 7.32 (2H, d, J = 7.9 Hz), 7.50 (1H, d, J = 6.7) Hz), 7.55-7.61 (1H, m), 7.68-7.74 (1H, m), 7.86 (1H, d, J = 8.5 Hz), 7.89-7.94 (1H, m), 12.72 (1H, br s).

MS (APCI) m/z: 598 (M+H) ⁺ .

(Example 58)

2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2-fluoro-2'-methylbiphenyl-4-yl}pentanoic acid

(58a) 2-[3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pentanoate

_n -Butyllithium (1.6 M hexane solution, 1.91 mL) was gradually added at -78 ° C in diisopropylamine (0.430 mL), and stirred for 0.5 hr. After adding tetrahydrofuran (4 mL) at -78 ° C and stirring for 15 minutes, a solution of the compound obtained in Example (14a) (600 mg) in tetrahydrofuran (2 mL) was added in cannulation, and Stir at 78 ° C for 0.5 hours. Next, 1-iodopropane (0.399 mL) was added, and the mixture was stirred under ice cooling for 2 hours. After a saturated aqueous solution of ammonium chloride (4 mL) was added to the mixture, the mixture was evaporated and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

^{1 H-NMR (400MHz, CDCl} 3) δ: 0.90 (3H, t, J = 7.3Hz), 1.18-1.32 (2H, m), 1.35 (12H, s), 1.68-1.80 (1H, m), 1.96 -2.09 (1H, m), 3.56 (1H, t, J = 7.6 Hz), 3.65 (3H, s), 6.98-7.03 (1H, m), 7.06-7.10 (1H, m), 7.66-7.71 (1H , m).

(58b) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 Methyl-oxy]-2-fluoro-2'-methylbiphenyl-4-yl}pentanoate

To a solution of the compound (440 mg) obtained in Example (2a) (1,2-dimethoxyethane (15 mL), the boronic acid ester (420 mg) obtained in Example (58a), [1,1'- (Diphenylphosphino)ferrocene]dichloropalladium(II) (68.0 mg), sodium carbonate (265 mg), and water (3 mL) were reacted at 130 ° C for 1 hour in a microwave reactor. Saturated brine (2 mL) and water (2 mL) were added to the mixture, and the mixture was extracted with ethyl acetate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.94 (3H, t, J = 7.3 Hz), 1.22-1.36 (5H, m), 1.71-1.84 (1H, m), 1.99-2.20 (7H, m) , 3.17-3.26 (4H, m), 3.59 (1H, t, J = 7.6 Hz), 3.70 (3H, s), 4.28 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.72 ( 1H, dd, J = 7.9, 2.4 Hz), 6.77-6.80 (1H, m), 6.85 (1H, d, J = 9.2 Hz), 7.05-7.19 (4H, m), 7.40 (1H, d, J = 7.9 Hz), 7.51 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97-8.06 (2H, m).

MS (APCI) m/z: 658 (M+H) ⁺ .

(58c) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-2-fluoro-2'-methylbiphenyl-4-yl}pentanoic acid

A 2 M aqueous sodium hydroxide solution (2.50 mL) was added to a mixture of EtOAc (m. After concentrating the reaction mixture under reduced pressure, water (15 mL) and 2M hydrochloric acid (2.70 mL) were added and stirred. The precipitated insoluble material was filtered, washed with water and evaporated to dryness.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7.3 Hz), 1.11 (3H, t, J = 7.3 Hz), 1.15-1.33 (2H, m), 1.61-1.73 (1H, m), 1.88-2.01 (1H, m), 2.03-2.11 (6H, m), 3.16-3.25 (2H, m), 3.25-3.35 (2H, m), 3.61 (1H, t, J = 7.6 Hz), 4.24 - 4.36 (4H, m), 6.68 (1H, dd, J = 8.2, 2.7 Hz), 6.80-6.87 (2H, m), 7.13 (1H, d, J = 7.9 Hz), 7.16- 7.29 (3H, m), 7.47-7.53 (1H, m), 7.55-7.61 (1H, m), 7.68-7.75 (1H, m), 7.86 (1H, d, J = 8.5 Hz), 7.89-7.94 ( 1H, m), 12.50 (1H, s).

MS (APCI) m/z: 644 (M+H) ⁺ .

(Example 59)

{4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-2'-methylbiphenyl-4-yl}(fluoro)acetic acid

(59a) Ethyl fluoride [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate

n-Butyllithium (1.6 M hexane solution, 1.88 mL) was slowly added at -78 ° C in diisopropylamine (0.422 mL), and stirred for 0.5 hr. After adding tetrahydrofuran (4 mL) at -78 ° C and stirring for 1 hour, a solution of 4-(ethoxycarbonylmethyl)phenylboronic acid pinacol ester (581 mg) in tetrahydrofuran (2 mL) was added to the mixture. And stirred at -78 ° C for 0.5 hours. Next, a solution of N-fluorobenzenesulfonimide (1.26 g) in tetrahydrofuran (5 mL) was added, and the mixture was stirred at -78 ° C for 2.5 hours, and then stirred under ice cooling for 1.5 hours. After adding a saturated aqueous solution of ammonium chloride (10 mL), the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine. The organic layer was filtered using an ISOLUTE phase separator, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAcjjjjjjj

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.24 (3H, t, J = 7.3 Hz), 1.35 (12H, s), 4.14 - 4.31 (2H, m), 5.79 (1H, d, J = 48.2 Hz ), 7.47 (2H, d, J = 7.9 Hz), 7.85 (2H, d, J = 7.9 Hz).

(59b){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-methylbiphenyl-4-yl}(fluoro)acetic acid

The compound obtained in Example (59a) (350 mg), [1,1'-bis (two) was added to a solution of the compound (400 mg) obtained in the compound (2). Phenylphosphino)ferrocene]dichloropalladium(II) (61.8 mg), sodium carbonate (241 mg), and water (3 mL) were reacted at 130 ° C for 1 hour in a microwave reactor. Saturated brine (2 mL) and water (2 mL) were added to the mixture, and the mixture was washed with ethyl acetate. After 2 M hydrochloric acid was added until the obtained aqueous layer became acidic, it was extracted with ethyl acetate using an ISOLUTE phase separator, and the solvent was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc)

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.11 (3H, t, J = 7.3Hz), 2.08 (3H, s), 2.19 (3H, s), 3.16-3.25 (2H, m), 3.30 (2H, q, J = 7.3 Hz), 4.24 - 4.35 (4H, m), 6.04 (1H, d, J = 47.0 Hz), 6.69 (1H, dd, J = 8.5, 2.4 Hz), 6.80-6.86 ( 2H,m),7.16(1H,d,J=8.5Hz), 7.40(2H,d,J=7.9Hz), 7.46-7.53(3H,m),7.54-7.61(1H,m),7.68-7.75 (1H, m), 7.86 (1H, d, J = 8.5 Hz), 7.89-7.94 (1H, m), 13.57 (1H, br s).

MS (APCI) m/z: 602 (M+H) ⁺ .

(Embodiment 60)

2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-methylbiphenyl-4-yl}-5,5,5-trifluoropentanoic acid

(60a) 5,5,5-trifluoro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]penta Ethyl acetate

Add lithium diisopropylamide (1.09 M hexane-tetrahydrofuran solution, 1.83 mL) to a solution of 4-(ethoxycarbonylmethyl)phenylboronic acid pinacol ester (290 mg) in tetrahydrofuran (6 mL). Stir for 0.5 hours. 1,1,1-Trifluoro-3-iodopropane (0.234 mL) was added to the reaction mixture, and the mixture was stirred at -78 °C for 2 hours, and stirred for 2 hours under ice cooling. Saturated aqueous ammonium chloride (4 mL) was added to the mixture, and the mixture was evaporated. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc)

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.19 (3H, t, J = 7.0Hz), 1.34 (12H, s), 1.91-2.12 (3H, m), 2.23-2.36 (1H, m), 3.53 -3.64 (1H, m), 4.03-4.21 (2H, m), 7.29 (2H, d, J = 8.2 Hz), 7.79 (2H, d, J = 8.2 Hz).

(60b) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-2'-methylbiphenyl-4-yl}-5,5,5-trifluoropentanoic acid ethyl ester

The compound obtained in Example (60a) (197 mg), [1,1'-bis (two) was added to a solution of the compound (180 mg) obtained in Example (2a) (1,2-dimethoxyethane (6 mL). Phenylphosphino)ferrocene]dichloropalladium(II) (27.8 mg), sodium carbonate (108 mg), and water (1.5 mL) were reacted at 130 ° C for 45 minutes in a microwave reactor. Saturated brine (2 mL) and water (2 mL) were added to the mixture, and the mixture was extracted with ethyl acetate. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc)

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.21-1.30 (6H, m), 2.00-2.18 (6H, m), 2.22 (3H, s), 2.25-2.39 (1H, m), 3.18-3. 4H, m), 3.58-3.65 (1H, m), 4.08-4.25 (2H, m), 4.25-4.33 (2H, m), 4.38 (2H, s), 6.72 (1H, dd, J = 8.5, 2.4 Hz), 6.77-6.80 (1H, m), 6.84 (1H, d, J = 8.5 Hz), 7.12 (1H, d, J = 8.5 Hz), 7.23 - 7.34 (4H, m), 7.40 (1H, d , J = 7.3 Hz), 7.48-7.54 (1H, m), 7.59-7.66 (1H, m), 7.97-8.06 (2H, m).

MS (APCI) m/z: 708 (M+H) ⁺ .

(60c) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-2'-methylbiphenyl-4-yl}-5,5,5-trifluoropentanoic acid

A 2 M aqueous sodium hydroxide solution (0.920 mL) was added to a mixture of EtOAc (EtOAc, EtOAc) After concentrating the reaction mixture under reduced pressure, water (12 mL) and 2M hydrochloric acid (0.950 mL) were added and stirred. The precipitated insoluble material was filtered, washed with water and evaporated to dryness.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.11 (3H, t, J = 7.3Hz), 1.81-1.94 (1H, m), 2.04-2.36 (9H, m), 3.16-3.25 (2H, m), 3.26-3.39 (2H, m), 3.64-3.71 (1H, m), 4.24-4.36 (4H, m), 6.67 (1H, dd, J = 8.5, 2.4 Hz), 6.78-6.85 (2H, m), 7.14 (1H, d, J = 8.5 Hz), 7.27-7.37 (4H, m), 7.47-7.53 (1H, m), 7.54-7.61 (1H, m), 7.68-7.75 (1H, m) , 7.86 (1H, d, J = 8.5 Hz), 7.91 (1H, d, J = 7.9 Hz), 12.64 (1H, s).

MS (APCI) m/z: 680 (M+H) ⁺ .

(Example 61)

2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-methylbiphenyl-4-yl}-4-methoxybutyric acid

(61a) 4-methoxy-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanoate

Add lithium diisopropylamide (1.09 M hexane-tetrahydrofuran solution, 3.67 mL) to a solution of 4-(ethoxycarbonylmethyl)phenylboronic acid pinacol ester (580 mg) in tetrahydrofuran (12 mL) at -78 °C. Stir for 0.5 hours. 2-Bromoethyl methyl ether (0.376 mL) was added to the reaction mixture, and the mixture was stirred for 2 hr. Saturated aqueous ammonium chloride (6 mL) was added to the mixture and the mixture was evaporated. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc)

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.18 (3H, t, J = 7.0 Hz), 1.34 (12H, s), 1.90-2.04 (1H, m), 2.30-2.44 (1H, m), 3.18 -3.30 (4H, m), 3.30-3.38 (1H, m), 3.77 (1H, t, J = 7.6 Hz), 4.01-4.19 (2H, m), 7.31 (2H, d, J = 7.9 Hz), 7.77 (2H, d, J = 7.9 Hz).

(61b) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -ethyl)oxy]-2'-methylbiphenyl-4-yl}-4-methoxybutanoic acid ethyl ester

The compound obtained in Example (61a) (356 mg), [1,1'-bis (two) was added to a solution of the compound (3. Phenylphosphino)ferrocene]dichloropalladium(II) (55.6 mg), sodium carbonate (217 mg), and water (3 mL) were reacted at 130 ° C for 45 minutes in a microwave reactor. Saturated brine (2 mL) and water (2 mL) were added to the mixture, and the mixture was extracted with ethyl acetate. The residue obtained was purified by EtOAc EtOAc EtOAc EtOAc

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.23 (3H, t, J = 7.0 Hz), 1.27 (3H, t, J = 8.5 Hz), 1.96-2.08 (1H, m), 2.16 (3H, s ), 2.22 (3H, s), 2.34-2.46 (1H, m), 3.17-3.26 (4H, m), 3.27-3.44 (5H, m), 3.79 (1H, t, J = 7.6 Hz), 4.06- 4.25 (2H, m), 4.28 (2H, t, J = 8.2 Hz), 4.38 (2H, s), 6.71 (1H, dd, J = 8.5, 2.4 Hz), 6.76-6.80 (1H, m), 6.84 (1H, d, J = 9.2 Hz), 7.12 (1H, d, J = 8.5 Hz), 7.22-7.28 (2H, m), 7.29-7.36 (2H, m), 7.38-7.42 (1H, m), 7.47-7.54 (1H, m), 7.59-7.66 (1H, m), 7.97-8.06 (2H, m).

(61c) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-2'-methylbiphenyl-4-yl}-4-methoxybutyric acid

A solution of the compound (371 mg) obtained in EtOAc (EtOAc m. After concentrating the reaction mixture under reduced pressure, water (12 mL) and 2M hydrochloric acid (1. The precipitated insoluble material was filtered, washed with water and dried, then evaporated to dryness

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 1.11 (3H, t, J = 7.3 Hz), 1.81-1.93 (1H, m), 2.08 (3H, s), 2.15-2.30 (4H, m) , 3.16-3.43 (9H, m), 3.66 (1H, t, J = 7.3 Hz), 4.24 - 4.35 (4H, m), 6.67 (1H, dd, J = 8.5, 2.4 Hz), 6.78-6.86 (2H , m), 7.14 (1H, d, J = 7.9 Hz), 7.28 (2H, d, J = 8.5 Hz), 7.32 (2H, d, J = 8.5 Hz), 7.48-7.52 (1H, m), 7.55 -7.61 (1H, m), 7.68-7.74 (1H, m), 7.86 (1H, d, J = 9.2 Hz), 7.89-7.94 (1H, m), 12.41 (1H, s).

MS (APCI) m/z: 642 (M+H) ⁺ .

(Example 62)

3-cyano-2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole -5-yl)oxy]-2'-methylbiphenyl-4-yl}propionic acid

(62a) ethyl 3-cyano-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate

To a solution of 4-(ethoxycarbonylmethyl)phenylboronic acid pinacol ester (580 mg) in tetrahydrofuran (12 mL) was added lithium diisopropylamine (1.09 M hexane-tetrahydrofuran solution, 3.67 mL) at -78 ° C and Stir for 0.5 hours. Next, iodoacetonitrile (0.289 mL) was added to the reaction mixture, and the mixture was further stirred at the same temperature for 2.5 hours. Saturated aqueous ammonium chloride (6 mL) was added to the mixture and the mixture was evaporated. The residue obtained was purified by EtOAc EtOAc EtOAc EtOAc

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.20 (3H, t, J = 7.0 Hz), 1.34 (12H, s), 2.79 (1H, dd, J = 16.8, 7.3 Hz), 3.04 (1H, dd , J = 16.8, 7.6 Hz), 3.93 (1H, t, J = 7.6 Hz), 4.09-4.27 (2H, m), 7.28 (2H, d, J = 7.9 Hz), 7.82 (2H, d, J = 7.9Hz).

MS (APCI) m/z: 330 (M+H) ⁺ .

(62b) 3-cyano-2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H -吲哚-5-yl)oxy]-2'-methylbiphenyl-4-yl}propionic acid ethyl ester

The compound obtained in Example (62a) (346 mg), [1,1'-bis (two) was added to a solution of the compound (370 mg) obtained in Example (2a) (1,2-dimethoxyethane (12 mL). Phenylphosphino)ferrocene]dichloropalladium(II) (57.2 mg), sodium carbonate (223 mg), and water (3 mL) were reacted at 130 ° C for 45 minutes in a microwave reactor. Saturated brine (2 mL) and water (2 mL) were added to the mixture, and the mixture was extracted with ethyl acetate. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc)

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.22-1.31 (6H, m), 2.15 (3H, s), 2.21 (3H, s), 2.84 (1H, dd, J = 16.8, 7.6 Hz), 3.07 (1H, dd, J = 16.8, 7.6 Hz), 3.17-3.26 (4H, m), 3.97 (1H, t, J = 7.6 Hz), 4.08-4.32 (4H, m), 4.38 (2H, s), 6.72 (1H, dd, J = 8.5, 2.4 Hz), 6.77-6.80 (1H, m), 6.84 (1H, d, J = 8.5 Hz), 7.11 (1H, d, J = 7.9 Hz), 7.30 (4H) , s), 7.38-7.42 (1H, m), 7.48-7.53 (1H, m), 7.60-7.66 (1H, m), 7.98-8.05 (2H, m).

(62c) 3-cyano-2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H -吲哚-5-yl)oxy]-2'-methylbiphenyl-4-yl}propionic acid

A 2 M aqueous sodium hydroxide solution (1.07 mL) was added to a mixture of EtOAc (EtOAc) (EtOAc) After concentrating the reaction mixture under reduced pressure, water (12 mL) and 2M hydrochloric acid (1.10 mL) were added and stirred. The precipitated insoluble material was filtered, washed with water, dried, evaporated, evaporated,

¹ H-NMR (DMSO-d ₆ ) δ: 1.11 (3H, t, J = 7.3 Hz), 2.08 (3H, s), 2.19 (3H, s), 3.00 (1H, dd, J = 16.8, 7.6 Hz ), 3.11 (1H, dd, J = 16.8, 7.3 Hz), 3.17-3.25 (2H, m), 3.26-3.37 (2H, m), 4.06 (1H, t, J = 7.3 Hz), 4.24 - 4.34 ( 4H, m), 6.68 (1H, dd, J = 8.5, 2.4 Hz), 6.78-6.85 (2H, m), 7.14 (1H, d, J = 8.5 Hz), 7.33 (2H, d, J = 7.9 Hz) ), 7.38 (2H, d, J = 8.5 Hz), 7.48-7.52 (1H, m), 7.55-7.61 (1H, m), 7.68-7.74 (1H, m), 7.86 (1H, d, J = 8.5) Hz), 7.89-7.94 (1H, m), 12.99 (1H, br s).

MS (APCI) m/z: 623 (M+H) ⁺ .

(Example 63)

2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2',5'-dimethylbiphenyl-4-yl}butyric acid

(63a) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 Ethyl-oxy]-2',5'-dimethylbiphenyl-4-yl}butyric acid ethyl ester

2-[4-(4,4,5,5-tetramethyl-1,3) was added to a solution of the compound (300 mg) obtained in Example (23a) in 1,2-dimethoxyethane (12 mL) , 2-two Ethyl boroborolan-2-yl)phenyl]butanoate (264 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (45.2 mg), carbonic acid Sodium (176 mg) and water (2.5 mL) were reacted at 130 ° C for 45 minutes in a microwave reactor. Saturated brine (2 mL) and water (2 mL) were added to the mixture, and the mixture was extracted with ethyl acetate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.93 (3H, t, J = 7.3 Hz), 1.21-1.30 (6H, m), 1.76-1.89 (1H, m), 2.07-2.24 (7H, m) , 2.27 (3H, s), 3.17-3.27 (4H, m), 3.48 (1H, t, J = 7.6 Hz), 4.06-4.24 (2H, m), 4.28 (2H, t, J = 8.2 Hz), 4.38(2H,s), 6.53(1H,s), 6.68(1H,d,J=8.5Hz),7.08(1H,s),7.22-7.28(2H,m),7.33(2H,d,J= 7.9 Hz), 7.40 (1H, d, J = 7.9 Hz), 7.50 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.96 (1H, d, J = 8.5 Hz) ), 8.03 (1H, d, J = 7.9 Hz).

(63b) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-2',5'-dimethylbiphenyl-4-yl}butyric acid

A 2 M aqueous sodium hydroxide solution (1.29 mL) was added to a mixture of EtOAc (EtOAc) (EtOAc) (EtOAc) After the reaction mixture was concentrated under reduced pressure, water (15 mL) and 2M hydrochloric acid (1. The precipitated insoluble material was filtered, washed with water and evaporated to dryness.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.85 (3H, t, J = 7.3 Hz), 1.11 (3H, t, J = 7.3 Hz), 1.60-1.72 (1H, m), 1.91-2.04 (1H, m), 2.08 (3H, s), 2.11 (3H, s), 2.23 (3H, s), 3.16-3.25 (2H, m), 3.25-3.38 (2H, m), 3.38-3.45 (1H , m), 4.23-4.35 (4H, m), 6.47 (1H, s), 6.67 (1H, d, J = 8.5 Hz), 7.10 (1H, s), 7.26 (2H, d, J = 8.5 Hz) , 7.32 (2H, d, J = 8.5 Hz), 7.47-7.52 (1H, m), 7.54-7.60 (1H, m), 7.68-7.74 (1H, m), 7.82 (1H, d, J = 8.5 Hz ), 7.88-7.93 (1H, m), 12.63 (1H, br s).

MS (APCI) m/z: 626 (M+H) ⁺ .

(Example 64)

(2R)-2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole- 5-yl)oxy]-2'-methylbiphenyl-4-yl}butyric acid

And (2S)-2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole -5-yl)oxy]-2'-methylbiphenyl-4-yl}butyric acid

(64a) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 Ethyl-oxy]-2'-methylbiphenyl-4-yl}butanoic acid ethyl ester

2-[4-(4,4,5,5-tetramethyl-1,3) was added to a solution of the compound obtained in Example (2a) (380 mg) in 1,2-dimethoxyethane (12 mL) Ethyl 2-(2-dioxaborolan-2-yl)phenyl]butanoate (343 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (58.7 Mg), sodium carbonate (229 mg), water (2.5 mL), and allowed to react at 130 ° C for 1 hour in a microwave reactor. Saturated brine (2 mL) and water (2 mL) were added to the mixture, and the mixture was extracted with ethyl acetate. The residue was purified by EtOAc EtOAc EtOAc EtOAc

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.93 (3H, t, J = 7.3 Hz), 1.24 (3H, t, J = 7.3 Hz), 1.27 (3H, t, J = 7.3 Hz), 1.77- 1.88 (1H, m), 2.06-2.18 (4H, m), 2.22 (3H, s), 3.17-3.26 (4H, m), 3.48 (1H, t, J = 7.6 Hz), 4.07-4.24 (2H, m), 4.28 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.71 (1H, dd, J = 8.5, 2.4 Hz), 6.76-6.80 (1H, m), 6.84 (1H, d , J = 9.2 Hz), 7.12 (1H, d, J = 8.5 Hz), 7.21-7.28 (2H, m), 7.29-7.35 (2H, m), 7.37-7.42 (1H, m), 7.48-7.53 ( 1H, m), 7.59-7.66 (1H, m), 7.97-8.05 (2H, m).

MS (APCI) m/z: 640 (M+H) ⁺ .

(64b) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-2'-methylbiphenyl-4-yl}butyric acid

A 2 M aqueous sodium hydroxide solution (1.43 mL) was added to a mixture (10 mL) of EtOAc. After allowing to cool to room temperature, water (12 mL) and 2M hydrochloric acid (1.50 mL) were added to the mixture and stirred. The insoluble material was filtered, washed with water, dried, evaporated, evaporated.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 0.86 (3H, t, J = 7.3Hz), 1.11 (3H, t, J = 7.3Hz), 1.61-1.74 (1H, m), 1.93-2.05 (1H, m), 2.08 (3H, s), 2.18 (3H, s), 3.17-3.24 (2H, m), 3.25-3.36 (2H, m), 3.42-3.48 (1H, m), 4.24-4.35 (4H, m), 6.67 (1H, dd, J = 8.5, 2.4 Hz), 6.78-6.85 (2H, m), 7.13 (1H, d, J = 7.9 Hz), 7.27 (2H, d, J = 8.5 Hz), 7.33 (2H, d, J = 7.9 Hz), 7.48-7.52 (1H, m), 7.55-7.61 (1H, m), 7.68-7.74 (1H, m), 7.86 (1H, d, J = 8.5 Hz), 7.89-7.93 (1H, m), 12.38 (1H, br s).

MS (APCI) m/z: 612 (M+H) ⁺ .

(64c)(4S)-4-benzyl-3-[(2R)-2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4- Methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}butanyl]-1,3- Azolidin-2-one and (4S)-4-benzyl-3-[(2S)-2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl) }-4-Methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}butanyl]-1,3- Azolidin-2-one

To a solution of the compound (600 mg), hexane (8 mL), m. After cooling to room temperature, the reaction liquid was concentrated under reduced pressure to give a crude 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl] acetonitrile as an amorphous solid. }-methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}butanyl chloride.

(4S)-4-benzyl-1,3- A solution of the oxazolidine-2-one (226 mg) in tetrahydrofuran (10 mL) was stirred at -78 ° C, and n-butyl lithium (1.6 mol/L hexane solution, 0.797 mL) was slowly added. After stirring at -78 ° C for 30 minutes, the above 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2 was slowly added dropwise. A solution of 3-dihydro-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}butanyl chloride in tetrahydrofuran (1.5 mL). After stirring at -78 ° C for 2 hours, a saturated aqueous solution of ammonium chloride was added, and the mixture was warmed to room temperature and then extracted three times with dichloromethane. After the combined organic layer was dried over sodium sulfate, the solvent was evaporated, evaporated, mjjjjjj Two kinds (low polarity compound: 302 mg, highly polar compound: 358 mg).

Low polarity compound

^{1 H-NMR (400MHz, CDCl} 3) δ: 0.96 (3H, t, J = 7.3Hz), 1.27 (3H, t, J = 7.3Hz), 1.84-1.96 (1H, m), 2.15 (3H, s ), 2.18-2.26 (4H, m), 2.80 (1H, dd, J = 13.4, 9.7 Hz), 3.17-3.25 (4H, m), 3.35-3.42 (1H, m), 4.04-4.17 (2H, m ), 4.28 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 4.60-4.69 (1H, m), 5.00 (1H, t, J = 7.6 Hz), 6.68-6.73 (1H, m) , 6.76-6.79 (1H, m), 6.84 (1H, d, J = 9.1 Hz), 7.11 (1H, d, J = 7.9 Hz), 7.21-7.42 (10H, m), 7.47-7.53 (1H, m ), 7.59-7.65 (1H, m), 7.97-8.05 (2H, m).

MS (APCI) m/z: 771 (M+H) ⁺ .

Highly polar compound

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.93 (3H, t, J = 7.3 Hz), 1.27 (3H, t, J = 7.3 Hz), 1.84-1.96 (1H, m), 2.13-2.28 (7H) , m), 2.67 (1H, dd, J = 14.0, 8.5 Hz), 3.01-3.10 (1H, m), 3.17-3.27 (4H, m), 4.07-4.15 (1H, m), 4.19-4.32 (3H , m), 4.38 (2H, s), 4.75-4.82 (1H, m), 4.95 (1H, t, J = 7.6 Hz), 6.69-6.74 (1H, m), 6.77-6.80 (1H, m), 6.85 (1H, d, J = 9.1 Hz), 6.92-6.97 (2H, m), 7.12-7.31 (6H, m), 7.38-7.42 (1H, m), 7.43-7.53 (3H, m), 7.60- 7.65 (1H, m), 7.98-8.05 (2H, m).

MS (APCI) m/z: 771 (M+H) ⁺ .

(64d)(2R)-2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-吲哚-5-yl)oxy]-2'-methylbiphenyl-4-yl}butyric acid and (2S)-2-{4'-[(1-{[2-(ethylsulfonate) Phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}butyric acid

Hydrogen peroxide water (0.0780 mL) and lithium hydroxide (32.7 mg) were added to a solution of the low-polarity compound (300 mg) in tetrahydrofuran (10 mL) and water (4 mL) obtained in Example (64c). Stir for 5 hours. 1N Hydrochloric acid (0.800 mL) was added, and the organic solvent was distilled off by concentration under reduced pressure. The residue was dissolved in ethanol and water, and concentrated under reduced pressure until a solid precipitated. The titled compound 64-1 (219 mg) was obtained as a colorless solid.

Example 64-1:

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.96 (3H, t, J = 7.3 Hz), 1.27 (3H, t, J = 7.6 Hz), 1.80-1.93 (1H, m), 2.08-2.26 (7H , m), 3.16-3.27 (4H, m), 3.53 (1H, t, J = 7.9 Hz), 4.28 (2H, t, J = 8.2 Hz), 4.38 (2H, s), 6.69-6.73 (1H, m), 6.77-6.79 (1H, m), 6.84 (1H, d, J = 8.5 Hz), 7.11 (1H, d, J = 8.5 Hz), 7.23 - 7.42 (5H, m), 7.47 - 7.53 (1H , m), 7.59-7.65 (1H, m), 7.97-8.05 (2H, m).

MS (APCI) m/z: 612 (M+H) ⁺ .

Hydrogen peroxide water (0.0910 mL) and lithium hydroxide (38.1 mg) were added to a solution of the highly polar compound (350 mg) in tetrahydrofuran (10 mL) and water (4 mL) obtained in Example (64c). Stir for 5 hours and 30 minutes. 1N hydrochloric acid (1.00 mL) was added, and the organic solvent was distilled off by concentration under reduced pressure. The residue was dissolved in ethanol and water, and concentrated under reduced pressure until a solid precipitated. The title compound 64-2 (210 mg) was obtained as a colorless solid.

Example 64-2:

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.96 (3H, t, J = 7.3 Hz), 1.27 (3H, t, J = 7.3 Hz), 1.80-1.92 (1H, m), 2.09-2.26 (7H) , m), 3.18-3.26 (4H, m), 3.52 (1H, t, J = 7.9 Hz), 4.28 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.69-6.73 (1H, m), 6.77-6.79 (1H, m), 6.84 (1H, d, J = 8.5 Hz), 7.11 (1H, d, J = 8.5 Hz), 7.23 - 7.42 (5H, m), 7.48 - 7.54 (1H , m), 7.60-7.65 (1H, m), 7.98-8.05 (2H, m).

MS (APCI) m/z: 612 (M+H) ⁺ .

(Example 65)

2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-3-fluoro-2'-methylbiphenyl-4-yl}butyric acid

(65a) methyl (4-bromo-2-fluorophenyl)acetate

In a solution of 4-bromo-2-fluorophenylacetic acid (10 g) in ethanol (100 mL), (trimethyldecyl) diazomethane (2M hexanes, 43 mL) After that, it was stirred for another 30 minutes at room temperature. After concentrating the reaction mixture, EtOAc m.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.64 (2H, s), 3.71 (3H, s), 7.11-7.18 (1H, m), 7.23 - 7.31 (2H, m).

(65b) Methyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate

To the dimethyl hydrazine solution (15 mL) of the compound (1.00 g) obtained in Example (65a), bis-pinacol borate (1.34 g), [1,1'-bis(diphenylphosphine) was added. Base ferrocene]dichloropalladium(II) (0.198 g), potassium acetate (1.19 g), and stirred at 80 ° C for 6.5 hours. The reaction solution is allowed to cool to After room temperature, water (60 mL) was added and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc)

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.34 (12H, s), 3.67-3.71 (5H, m), 7.22-7.30 (1H, m), 7.48 (1H, d, J = 10.4 Hz), 7.51 -7.56 (1H, m).

(65c)2-[2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanoate

To a solution (17 mL) of the compound (m. Iodoethane (1.36 mL) was added to the reaction mixture, and the mixture was stirred at -78 ° C for 3.5 hr, and stirred for 2 hr. Saturated aqueous ammonium chloride (5 mL) and water (5 mL) were added to the mixture, and ethyl acetate was evaporated. The organic layer was washed with brine, dried over magnesium sulfate The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc)

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.88 (3H, t, J = 7.6 Hz), 1.33 (12H, s), 1.73-1.86 (1H, m), 2.04-2.18 (1H, m), 3.66 (3H, s), 3.85 (1H, t, J = 7.6 Hz), 7.33 (1H, t, J = 7.3 Hz), 7.47 (1H, d, J = 10.4 Hz), 7.52-7.57 (1H, m) .

(65d) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 Methyl-oxy]-3-fluoro-2'-methylbiphenyl-4-yl}butanoate

The compound obtained in Example (65c) (366 mg), chloro (2-dicyclohexylphosphino-2', 4', 6' was added to a solution of the compound (500 mg) in toluene (10 mL). -triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (74.4 mg), potassium phosphate (603 mg), Water (1 mL) was stirred at 100 ° C for 7.5 hours. After cooling to room temperature, water (1 mL) and saturated brine (1 mL) were added to the mixture, and the mixture was extracted with ethyl acetate using an ISOLUTE phase separator, and the solvent was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

¹ H-NMR (400MHz, CDCl ₃ ) δ: 0.94 (3H, t, J = 7.3 Hz), 1.27 (3H, t, J = 7.6 Hz), 1.76-1.90 (1H, m), 2.07-2.21 (4H , m), 2.23 (3H, s), 3.17-3.27 (4H, m), 3.71 (3H, s), 3.88 (1H, t, J = 7.6 Hz), 4.29 (2H, t, J = 8.2 Hz) , 4.38 (2H, s), 6.69-6.74 (1H, m), 6.76-6.80 (1H, m), 6.84 (1H, d, J = 8.5 Hz), 6.99 (1H, d, J = 11.6 Hz), 7.05 (1H, d, J = 7.9 Hz), 7.11 (1H, d, J = 8.5 Hz), 7.32 - 7.43 (2H, m), 7.51 (1H, t, J = 7.6 Hz), 7.63 (1H, t , J = 7.6 Hz), 7.98-8.06 (2H, m).

(65e) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-3-fluoro-2'-methylbiphenyl-4-yl}butyric acid

A 2 M aqueous sodium hydroxide solution was added to a methanol (tetrahydrofuran (1:1) mixed solution (12 mL) of the compound (556 mg) obtained in Example (65d). (2.59 mL), stirred at room temperature for 24 hours and stirred at 40 ° C for 2.5 hours. 2M hydrochloric acid (2.70 mL) was added to the reaction liquid, and the reaction liquid was concentrated under reduced pressure. Then, methanol and water were added to the obtained residue and stirred, and the liquid portion was decanted and removed. Methanol was added to the obtained residue, and the precipitated solid was collected by filtration. The solid was washed with a mixture of methanol/water (1:1).

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 0.86 (3H, t, J = 7.3Hz), 1.11 (3H, t, J = 7.3Hz), 1.65-1.78 (1H, m), 1.96-2.11 (4H,m), 2.20(3H,s), 3.17-3.25(2H,m), 3.25-3.39(2H,m),3.72(1H,t,J=7.6Hz),4.24-4.35(4H,m ), 6.67 (1H, dd, J = 8.5, 2.4 Hz), 6.79-6.86 (2H, m), 7.12-7.19 (3H, m), 7.38 (1H, t, J = 7.9 Hz), 7.48-7.52 ( 1H, m), 7.55-7.61 (1H, m), 7.68-7.74 (1H, m), 7.86 (1H, d, J = 9.2 Hz), 7.89-7.94 (1H, m), 12.51 (1H, s) .

MS (APCI) m/z: 630 (M+H) ⁺ .

(Example 66)

2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-3-fluoro-2'-methylbiphenyl-4-yl}propionic acid

(66a) 2-[2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate

To a solution of the compound (2.50 g) obtained in m. m. m. Methyl iodide (1.06 mL) was added to the reaction mixture, and stirred at -78 ° C for 3 hours. Saturated aqueous ammonium chloride solution (5 mL) and water (5 mL) were added to the mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine. The organic layer was dried with MgSO.sub. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.33 (12H, s), 1.50 (3H, d, J = 6.7 Hz), 3.67 (3H, s), 4.03 (1H, q, J = 6.7 Hz), 7.25-7.32 (1H, m), 7.47 (1H, d, J = 10.4 Hz), 7.55 (1H, d, J = 7.3 Hz).

(66b) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 Methyl-oxy]-3-fluoro-2'-methylbiphenyl-4-yl}propionic acid methyl ester

The compound obtained in Example (66a) (350 mg), chloro(2-dicyclohexylphosphino-2', 4', 6' was added to a solution of the compound (500 mg) in toluene (10 mL). -triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (74.4 mg), potassium phosphate (603 mg), Water (1 mL) was stirred at 100 ° C for 7.5 hours. After cooling to room temperature, water (1 mL) and saturated brine (1 mL) were added to the reaction mixture, and ISOLUTE was used. The phase separator was extracted with ethyl acetate, and the solvent was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.6 Hz), 1.54 (3H, d, J = 7.3 Hz), 2.15 (3H, s), 2.23 (3H, s), 3.18-3.27(4H,m), 3.72(3H,s), 4.06(1H,q,J=7.3Hz), 4.29(2H,t,J=8.5Hz), 4.38(2H,s),6.71(1H , dd, J = 8.2, 2.7 Hz), 6.76-6.79 (1H, m), 6.84 (1H, d, J = 8.5 Hz), 6.97-7.02 (1H, m), 7.03-7.08 (1H, m), 7.11 (1H, d, J = 8.5 Hz), 7.30 (1H, t, J = 7.9 Hz), 7.38-7.42 (1H, m), 7.48-7.54 (1H, m), 7.60-7.65 (1H, m) , 7.98-8.05 (2H, m).

(66c) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-3-fluoro-2'-methylbiphenyl-4-yl}propionic acid

A solution of the compound (572 mg) (m. 2M hydrochloric acid (2.80 mL) was added to the reaction liquid, and the reaction liquid was concentrated under reduced pressure. Then, methanol and water were added to the obtained residue and stirred, and the liquid portion was decanted and removed. Methanol was added to the obtained residue, and the precipitated solid was collected by filtration, washed with methanol/water (1:1), and then evaporated to dryness 482 mg).

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.11 (3H, t, J = 7.3Hz), 1.41 (3H, d, J = 7.3Hz), 2.08 (3H, s), 2.21 (3H, s ), 3.16-3.24(2H,m), 3.26-3.39(2H,m), 3.92 (1H,q,J=7.3 Hz), 4.25-4.34(4H,m),6.68(1H,dd,J=8.5 , 2.4 Hz), 6.79-6.85 (2H, m), 7.11-7.19 (3H, m), 7.37 (1H, t, J = 8.2 Hz), 7.48-7.52 (1H, m), 7.55-7.61 (1H, m), 7.68-7.74 (1H, m), 7.86 (1H, d, J = 8.5 Hz), 7.89-7.93 (1H, m), 12.50 (1H, s).

MS (APCI) m/z: 616 (M+H) ⁺ .

(Example 67)

2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2-fluoro-2'-methylbiphenyl-4-yl}butyric acid

(67a) 2-[3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanoate

Methyl 2-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (861.9 mg) In a tetrahydrofuran (6 mL) solution, lithium diisopropylamide (1.09 mol/Ln-hexane-tetrahydrofuran solution, 4.11 mL) was added at -78 ° C under a nitrogen atmosphere, and stirred for 30 minutes. Iodoethane (358 μL) was added, and after stirring for 40 minutes, it was stirred at 0 ° C for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. After drying over anhydrous sodium sulfate and filtration, hexane was added to the residue which was concentrated under reduced pressure, and insoluble matter was filtered out. The filtrate was purified by EtOAc EtOAc EtOAc elutcd

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.88 (3H, t, J = 7.3 Hz), 1.35 (12H, s), 1.70-1.86 (1H, m), 2.00-2.15 (1H, m), 3.41 - 3.50 (1H, m), 3.66 (3H, s), 7.00 (1H, d, J = 10.4 Hz), 7.08 (1H, d, J = 7.9 Hz), 7.65 - 7.72 (1H, m).

(67b) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 Methyl-oxy]-2-fluoro-2'-methylbiphenyl-4-yl}butanoate

The compound obtained in Example (2a) (261.3 mg), the compound obtained in Example (67a) (256.7 mg), and potassium phosphate (314.9 mg) of 1,2-dimethoxyethane (5 mL) / water ( 0.4 mL) of the suspension was replaced with nitrogen, and hydrazine (triphenylphosphine)palladium(0) (28.6 mg) was added, and the mixture was stirred at 90 ° C for 7 hours under a nitrogen atmosphere. Ethyl acetate and water were added to the reaction mixture, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the title compound was obtained from mjjjjjjjj

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.93 (3H, t, J = 7.3 Hz), 1.27 (3H, t, J = 7.3 Hz), 1.77-1.90 (1H, m), 2.07-2.22 (7H , m), 3.16-3.28 (4H, m), 3.50 (1H, t, J = 7.9 Hz), 3.71 (3H, s), 4.23-4.32 (2H, m), 4.37 (2H, s), 6.69- 6.75 (1H, m), 6.78-6.81 (1H, m), 6.85 (1H, d, J = 8.5 Hz), 7.05-7.13 (3H, m), 7.14-7.20 (1H, m), 7.40 (1H, d, J = 7.3 Hz), 7.50 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.98-8.06 (2H, m).

MS (APCI) m/z: 644 (M+H) ⁺ .

(67c) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-2-fluoro-2'-methylbiphenyl-4-yl}butyric acid

A solution of the compound (228.0 mg) in EtOAc (EtOAc m. Under ice cooling, 1N hydrochloric acid (2.3 mL) was added and neutralized, and extracted with dichloromethane. The title compound (194.9) was obtained as a colorless solid (yield). Mg).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 0.95 (3H, t, J = 7.3 Hz), 1.27 (3H, t, J = 7.3 Hz), 1.78-1.91 (1H, m), 2.07-2.22 (7H , m), 3.16-3.27 (4H, m), 3.47-3.55 (1H, m), 4.24-4.32 (2H, m), 4.38 (2H, s), 6.69-6.74 (1H, m), 6.77-6.80 (1H, m), 6.85 (1H, d, J = 8.5 Hz), 7.05-7.21 (4H, m), 7.37-7.43 (1H, m), 7.47-7.54 (1H, m), 7.58-7.66 (, H, m), 7.97-8.07 (2H, m).

MS (APCI) m/z: 630 (M+H) ⁺ .

(Example 68)

2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2-fluoro-2'-methylbiphenyl-4-yl}propionic acid

(68a) 2-[3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate

To a solution of the compound (1.05 g) obtained in Example (14a) in tetrahydrofuran (7 mL), lithium diisopropylamine (1.09 mol/Ln-hexane-tetrahydrofuran solution, 5.0 mL) was added dropwise at -78 ° C under a nitrogen atmosphere. ) and stir for 30 minutes. Methyl iodide (0.34 mL) was added at the same temperature, stirred for 30 minutes, and then stirred at 0 ° C for 1 hour. A saturated aqueous ammonium chloride solution was added at 0 ° C, extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtration, the residue was evaporated. mjjjjjjjjj

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.35 (12H, s), 1.49 (3H, d, J = 7.3Hz), 3.66 (3H, s), 3.72 (1H, q, J = 7.3Hz), 6.96-7.02 (1H, m), 7.04-7.10 (1H, m), 7.66-7.73 (1H, m).

(68b) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 Methyl-oxy]-2-fluoro-2'-methylbiphenyl-4-yl}propionic acid methyl ester

The compound obtained in Example (2a) (255 mg), the compound obtained in Example (68a) (234 mg), and potassium phosphate (308 mg) of 1,2-dimethoxyethane (5 mL) / water (0.4 mL) The suspension is replaced by nitrogen, and ruthenium (triphenylphosphine) is added. Palladium (0) (27.9 mg) was stirred at 90 ° C for 6 hours under a nitrogen atmosphere. Ethyl acetate was added to the reaction mixture, washed with water and dried over anhydrous sodium sulfate. The residue was purified with EtOAc EtOAcjjjjjjj It was used in the next reaction with a purity of 93.9%.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 1.54 (3H, d, J = 7.3 Hz), 2.09-2.21 (6H, m), 3.17-3.28 (4H , m), 3.71 (3H, s), 3.76 (1H, q, J = 7.3 Hz), 4.24 - 4.32 (2H, m), 4.38 (2H, s), 6.69-6.75 (1H, m), 6.78- 6.81 (1H, m), 6.85 (1H, d, J = 8.5 Hz), 7.05-7.14 (3H, m), 7.18 (1H, t, J = 7.6 Hz), 7.37-7.42 (1H, m), 7.47 -7.54 (1H, m), 7.59-7.65 (1H, m), 7.98-8.06 (2H, m).

MS (APCI) m/z: 630 (M+H) ⁺ .

(68c) 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-2-fluoro-2'-methylbiphenyl-4-yl}propionic acid

A solution of the compound (324 mg) in EtOAc (EtOAc m. 1N hydrochloric acid (3 mL) was added to the reaction mixture, and the mixture was neutralized, and dichloromethane was added thereto for extraction. The organic layer was dried over anhydrous sodium sulfate.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.6 Hz), 1.56 (3H, d, J = 7.1 Hz), 2.10-2.19 (6H, m), 3.15-3.31 (4H , m), 3.80 (1H, q, J = 7.1 Hz), 4.24 - 4.33 (2H, m), 4.38 (2H, s), 6.69-6.75 (1H, m), 6.77-6.81 (1H, m), 6.86 (1H, d, J = 8.5 Hz), 7.06-7.23 (4H, m), 7.40 (1H, d, J = 7.9 Hz), 7.51 (1H, t, J = 7.3 Hz), 7.62 (1H, t , J = 7.3 Hz), 7.96-8.07 (2H, m).

MS (APCI) m/z: 616 (M+H) ⁺ .

(Example 69)

(5-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2-methylphenyl}thiophen-2-yl)acetic acid

(69a) [5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl]acetate

Ethyl 5-(bromothiophen-2-yl)acetate (521 mg), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.451 mL) and triethylamine (0.874mL) of 1,4-two The alkane (5 mL) solution was degassed under a nitrogen atmosphere for 1 minute. Dichlorobis(triphenylphosphine)palladium(II) (73.4 mg) was added and stirred at 95 ° C for 2.5 hours. After cooling the reaction mixture to room temperature, water was added to the reaction mixture, and the mixture was extracted with methylene chloride using an ISOLUTE phase separator, and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc elut elut elut

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.0 Hz), 1.33 (12H, s), 3.86 (2H, br s), 4.18 (2H, q, J = 7.0 Hz) , 7.02 (1H, d, J = 3.6 Hz), 7.49 (1H, d, J = 3.6 Hz).

(69b)(5-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-2-methylphenyl}thiophen-2-yl)acetate

The compound obtained in Example (69a) (135 mg), [1,1'-bis (two) was added to a solution of the compound (160 mg) obtained in Example (2). Phenylphosphino)ferrocene]dichloropalladium(II) (24.7 mg), sodium carbonate (96.3 mg), and water (1 mL) were reacted at 130 ° C for 30 minutes in a microwave reactor. The reaction mixture was diluted with ethyl acetate (15 mL). Water was evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.26-1.33 (6H, m), 2.13 (3H, s), 2.36 (3H, s), 3.18-3.27 (4H, m), 3.83 (2H, s) , 4.21 (2H, q, J = 7.1 Hz), 4.29 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.66-6.71 (1H, m), 6.75-6.78 (1H, m), 6.81-6.86 (2H, m), 6.88-6.91 (1H, m), 7.24-7.31 (1H, m), 7.40 (1H, d, J = 7.3 Hz), 7.48-7.54 (1H, m), 7.60- 7.66 (1H, m), 7.98-8.06 (2H, m).

(69c)(5-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-2-methylphenyl}thiophen-2-yl)acetic acid

A solution of the compound ( 148 mg), EtOAc (EtOAc m. After concentrating the reaction mixture under reduced pressure, water (8 mL) was added to the residue, and 2M hydrochloric acid (0.490 mL) was added and stirred. The precipitated insoluble material was filtered, washed with water and evaporated to dryness

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 1.11 (3H, t, J = 7.3 Hz), 2.06 (3H, s), 2.33 (3H, s), 3.20 (2H, t, J = 8.2 Hz ), 3.27-3.36 (2H, m), 3.82 (2H, s), 4.24 - 4.34 (4H, m), 6.66 (1H, dd, J = 8.2, 2.7 Hz), 6.80-6.85 (2H, m), 6.91-6.97(2H,m), 7.29 (1H,d,J=8.5Hz), 7.48-7.52(1H,m), 7.55-7.61(1H,m), 7.68-7.74(1H,m),7.86( 1H, d, J = 8.5 Hz), 7.89-7.93 (1H, m), 12.59 (1H, br s).

MS (APCI) m/z: 590 (M+H) ⁺ .

(Embodiment 70)

(5-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2-methylphenyl}-1,3-thiazol-2-yl)acetic acid

(70a)(5-{4-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-2-methylphenyl}-1,3-thiazol-2-yl)acetate

2-[2-(ethylsulfonyl)phenyl]-1-{4-methyl-5-[3-methyl] synthesized from the compound obtained in Example (2a) according to Example (17a) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2,3-dihydro-1H-indole-1 (5-Bromo-1,3-thiazol-2-yl)acetate (66.6 mg), chlorine (2-di) in a solution of ethyl ketone (purity: 28%, 454 mg) in toluene (1.9 mL) Cyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium ( II) (21.0 mg), potassium phosphate (170 mg), and water (0.1 mL) were stirred at 100 ° C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (6 mL), and extracted with EtOAc EtOAc. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc)

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.23-1.34 (6H, m), 2.13 (3H, s), 2.34 (3H, s), 3.18-3.26 (4H, m), 4.07 (2H, s) , 4.21-4.33(4H,m), 4.38(2H,s), 6.70(1H,dd,J=8.5,2.4Hz),6.77-6.80(1H,m),6.83(1H,d,J=8.5Hz ), 7.22-7.28 (1H, m), 7.38-7.42 (1H, m), 7.48-7.54 (1H, m), 7.57-7.66 (2H, m), 7.98-8.05 (2H, m).

(70b)(5-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-2-methylphenyl}-1,3-thiazol-2-yl)acetic acid

A solution of the compound (46.0 mg) in EtOAc (EtOAc m. After concentrating the reaction mixture under reduced pressure, water (3 mL) was added to the residue, and 2M hydrochloric acid (0.223 mL) was added and stirred. The precipitated insoluble material was filtered, and the title compound (36.0 mg) was obtained as a brown solid.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.11 (3H, t, J = 7.3Hz), 2.06 (3H, s), 2.30 (3H, s), 3.20 (2H, t, J = 8.2Hz ), 3.25-3.44 (2H, m), 3.64 (2H, s), 4.24 - 4.35 (4H, m), 6.67 (1H, dd, J = 8.5, 2.4 Hz), 6.80-6.86 (2H, m), 7.29 (1H, d, J = 8.5 Hz), 7.48-7.60 (3H, m), 7.68-7.74 (1H, m), 7.86 (1H, d, J = 8.5 Hz), 7.89-7.94 (1H, m) .

MS (ESI) m / z: 591 (M+H) ⁺ .

(Example 71)

(4-{5-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Ethyl]pyridin-2-yl}phenyl)acetate

(71a) 5-[(6-Bromopyridin-3-yl)oxy]-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

N,N-di in 2-bromo-5-fluoropyridine (776 mg) and 5-butyl-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester (250 mg) To a solution of methylformamide (20 mL), cesium carbonate (980 mg) was added, and the mixture was reacted at 150 ° C for 70 minutes using a microwave apparatus. After cooling to room temperature, the title compound ( 580 mg).

MS (APCI) m/z: 405 (M+H) ⁺ .

(71b) 1-{5-[(6-Bromopyridin-3-yl)oxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2- (ethylsulfonyl)phenyl]ethanone

4N hydrochloric acid was added to a solution of the compound (400 mg) obtained in Example (71a) in dichloromethane (10 mL) A solution of the alkane (4 mL) was stirred at room temperature. After stirring for 4 hours, the reaction mixture was concentrated to give crude 5-[(6-bromopyridin-3-yl)oxy]-4-methyl-2,3-dihydro-1H-indole hydrochloride. Salt (335 mg).

Add N-methyl to a solution of the obtained compound (335 mg) in N,N-dimethylformamide (8 mL) The morpholine (0.198 mL) was stirred at room temperature for 20 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (353 mg) and [2-(ethylsulfonyl)phenyl]acetic acid (269 mg) were stirred at room temperature for 3 hr. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.10 (3H, s), 3.17-3.25 (4H, m), 4.29 (2H, t, J = 8.5 Hz ), 4.37 (2H, s), 6.79 (1H, d, J = 9.1 Hz), 7.03 (1H, dd, J = 8.5, 3.0 Hz), 7.34 - 7.41 (2H, m), 7.49 - 7.54 (1H, m), 7.60-7.65 (1H, m), 7.99-8.07 (3H, m).

MS (APCI) m/z: 515 (M+H) ⁺ .

(71c)(4-{5-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]pyridin-2-yl}phenyl)acetate

Compound (100 mg) obtained in Example (71b), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate An aqueous solution (10 mL) of potassium phosphate (124 mg) was added to a solution of the ester (84.5 mg) and triphenylphosphine palladium (0) (44.8 mg) in 1,2-dimethoxyethane (3 mL) using microwave The apparatus was allowed to react at 120 ° C for 50 minutes. After cooling the reaction liquid to room temperature, the solvent was distilled off under reduced pressure. The title compound (95 mg) was obtained from m.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.21-1.31 (6H, m), 2.15 (3H, s), 3.18-3.25 (4H, m), 3.66 (2H, s), 4.16 (2H, q, J = 7.3 Hz), 4.30 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.84 (1H, d, J = 8.5 Hz), 7.18 (1H, dd, J = 8.5, 2.4 Hz) , 7.34-7.42 (3H, m), 7.51 (1H, t, J = 1732.8 Hz), 7.59-7.66 (2H, m), 7.89 (2H, d, J = 8.5 Hz), 8.02 (2H, t, J =8.5Hz), 8.39 (1H, d, J = 2.4Hz).

MS (APCI) m/z: 599 (M+H) ⁺ .

(Example 72)

(4-{5-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]pyridin-2-yl}phenyl)acetic acid

(72a)(4-{5-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]pyridin-2-yl}phenyl)acetic acid

The compound obtained in Example (71c) (55 mg) was dissolved in THF (4 mL) and ethanol (2mL), and 1N aqueous sodium hydroxide (0.250mL) was added. After the reaction mixture was stirred at room temperature for 2 hours, 1N hydrochloric acid (0.250 mL) was added, and the organic solvent was distilled off under reduced pressure. The title compound (50.0 mg) was obtained as a colorless solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.14 (3H, s), 3.17-3.26 (4H, m), 3.68 (2H, s), 4.29 (2H) ,t,J=8.5Hz), 4.38(2H,s), 6.84(1H,d,J=8.5Hz), 7.22(1H,dd,J=8.5,2.4Hz),7.34-7.42(3H,m) , 7.51 (1H, t, J = 7.3 Hz), 7.57-7.65 (2H, m), 7.81 (2H, d, J = 8.5 Hz), 7.99-8.05 (2H, m), 8.39 (1H, d, J =2.4Hz).

MS (APCI) m/z: 571 (M+H) ⁺ .

(Example 73)

({4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy) ]]-2'-methylbiphenyl-4-yl}oxy)acetic acid

(73a)({4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indole-5- Ethyl)oxy]-2'-methylbiphenyl-4-yl}oxy)ethyl acetate

4-(2-ethoxy-2-oxoethoxyethoxy)phenylboronic acid was added to a solution of the compound (150 mg) obtained in Example (2a) (1,2-dimethoxyethane (4 mL). 95.4 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (23.2 mg), sodium carbonate (90.2 mg), water (1 mL), made by microwave reaction apparatus It was reacted at 130 ° C for 20 minutes. Water (1 mL) was added to the reaction mixture, and ethyl acetate was evaporated. After concentrating the organic layer under reduced pressure, ethyl acetate /hexane (3:1) was added as a suspension, and the insolubles were filtered out, and the filtrate was concentrated under reduced pressure. The title compound (98.2 mg) was obtained.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.27 (3H, t, J = 7.6Hz), 1.32 (3H, t, J = 7.0Hz), 2.16 (3H, s), 2.21 (3H, s), 3.17-3.26(4H,m),4.23-4.34(4H,m), 4.38(2H,s),4.66(2H,s),6.67-6.87(3H,m),6.93(2H,d,J=8.5 Hz), 7.10 (1H, d, J = 7.9 Hz), 7.19-7.25 (2H, m), 7.40 (1H, d, J = 7.3 Hz), 7.51 (1H, t, J = 7.3 Hz), 7.62 ( 1H, t, J = 7.0 Hz), 7.97-8.06 (2H, m).

(73b)({4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indole-5- Alkyloxy]-2'-methylbiphenyl-4-yl}oxy)acetic acid

A 2 M aqueous sodium hydroxide solution (0.309 mL) was added to a solution of the compound (yield: EtOAc) The reaction liquid was concentrated under reduced pressure, and water (10 mL) was added to the obtained residue, and then 2M hydrochloric acid (0.310 mL) was added to acid. The precipitated insoluble material was filtered, washed with water, and evaporated to dryness.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.11 (3H, t, J = 7.3Hz), 2.08 (3H, s), 2.18 (3H, s), 3.16-3.25 (2H, m), 3.25 -3.41(2H,m),4.23-4.35(4H,m),4.69(2H,s),6.66(1H,dd,J=8.2,2.7Hz),6.76-6.79(1H,m),6.81(1H ,d,J=9.2Hz), 6.93(2H,d,J=8.5Hz), 7.10(1H,d,J=8.5Hz), 7.23(2H,d,J=8.5Hz),7.50(1H,d , J = 7.9 Hz), 7.55-7.61 (1H, m), 7.68-7.74 (1H, m), 7.85 (1H, d, J = 8.5 Hz), 7.89-7.94 (1H, m), 13.06 (1H, Br s).

MS (APCI) m/z: 600 (M+H) ⁺ .

(Example 74)

3-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2-fluoro-2'-methylbiphenyl-4-yl}propionic acid

(74a) {4-[(1E)-3-Ethoxy-3-epoxypropan-1-en-1-yl]-2-fluorophenyl}boronic acid

Add (ethyl (triphenylphosphoranylidene) acetate) (622 mg) to a solution of 2-fluoro-4-methylphenylphenylboronic acid (200 mg) in dichloromethane (6 mL). Stir at room temperature for one night. After the reaction mixture was concentrated under reduced pressure to EtOAc (EtOAc) (EtOAc) 137 mg).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.25 (3H x 1/6, t, J = 7.0 Hz), 1.35 (3H x 5/6, t, J = 7.3 Hz), 4.19 (2H x 1/) 6, q, J = 7.0 Hz), 4.28 (2H x 5/6, q, J = 7.3 Hz), 5.02-5.07 (2H, m), 6.04 (1H x 1/6, d, J = 12.1 Hz) , 6.49 (1H x 5/6, d, J = 15.8 Hz), 6.92 (1H x 1/6, d, J = 12.1 Hz), 7.18-7.22 (1H, m), 7.28-7.39 (1H, m) , 7.64 (1H x 5/6, d, J = 15.8 Hz), 7.78-7.88 (1H, m).

(74b)(2E)-3-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H- Ethyl-5-yl)oxy]-2-fluoro-2'-methylbiphenyl-4-yl}prop-2-enoate

The compound obtained in Example (74a) (169 mg), [1,1'-bis (two) was added to a solution of the compound (250 mg) obtained in the compound (2). Phenylphosphino)ferrocene]dichloropalladium(II) (38.6 mg), sodium carbonate (150 mg), and water (1.5 mL) were reacted at 130 ° C for 20 minutes in a microwave reactor. Saturated brine (3 mL) was added to the mixture and the mixture was evaporated. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc)

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.23-1.39 (6H, m), 2.12-2.19 (6H, m), 3.18-3.27 (4H, m), 4.18-4.33 (4H, m), 4.38 ( 2H, s), 6.00 (1H x 1/5, d, J = 12.8 Hz), 6.46 (1H x 4/5, d, J = 15.8 Hz), 6.71-6.76 (1H, m), 6.78-6.82 ( 1H, m), 6.84-6.88 (1H, m), 6.91 (1H x 1/5, d, J = 12.8 Hz), 7.09-7.13 (1H, m), 7.19-7.36 (3H, m), 7.37- 7.42 (1H, m), 7.48-7.54 (1H, m), 7.60-7.64 (1H, m), 7.67 (1H x 4/5, d, J = 15.8 Hz), 7.98-8.05 (2H, m).

MS (APCI) m/z: 642 (M+H) ⁺ .

(74c)3-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -ethyl)oxy]-2-fluoro-2'-methylbiphenyl-4-yl}propionic acid ethyl ester

To a solution of the compound (158 mg) obtained in EtOAc (EtOAc, m. The reaction mixture was filtered, EtOAcjjjjjjjjjj

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.21-1.33 (6H, m), 2.14 (3H, s), 2.15 (3H, s), 2.66 (2H, t, J = 7.6 Hz), 2.99 (2H) , t, J = 7.6 Hz), 3.18-3.26 (4H, m), 4.15 (2H, q, J = 7.1 Hz), 4.28 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.69 -6.74(1H,m), 6.77-6.81(1H,m), 6.85(1H,d,J=8.5Hz),6.94-7.04(2H, m),7.07-7.17(2H,m),7.40(1H , d, J = 7.3 Hz), 7.47-7.54 (1H, m), 7.58-7.66 (1H, m), 7.98-8.06 (2H, m).

(74d) 3-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-2-fluoro-2'-methylbiphenyl-4-yl}propionic acid

A solution of the compound (154 mg), EtOAc (EtOAc m. The reaction liquid was concentrated under reduced pressure, and water (10 mL) was added to the residue, and 2M hydrochloric acid (0.490 mL) was added to acid. The precipitated insoluble material was collected by filtration.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.11 (3H, t, J = 7.3Hz), 2.07 (3H, s), 2.08 (3H, s), 2.60 (2H, t, J = 7.6Hz ), 2.87 (2H, t, J = 7.6 Hz), 3.17-3.25 (2H, m), 3.26-3.37 (2H, m), 4.25-4.35 (4H, m), 6.65-6.70 (1H, m), 6.80-6.87 (2H, m), 7.08-7.23 (4H, m), 7.50 (1H, d, J = 7.3 Hz), 7.55-7.61 (1H, m), 7.69-7.75 (1H, m), 7.86 ( 1H, d, J = 9.2 Hz), 7.89-7.94 (1H, m), 12.21 (1H, br s).

MS (APCI) m/z: 616 (M+H) ⁺ .

(Example 75)

(2R)-2-({4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indole) -5-yl)oxy]-2'-methylbiphenyl-4-yl}oxy)propionic acid

And (2S)-2-({4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indole) Indole-5-yloxy]-2'-methylbiphenyl-4-yl}oxy)propionic acid

(75a) 2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propionic acid ethyl ester

N,N-dimethylformamide solution (7 mL) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (660 mg) Ethyl 2-bromopropionate (0.584 mL) and cesium carbonate (1.47 g) were added and stirred at room temperature for 6 hours. Ethyl acetate (60 mL) and water (15 mL) were added to the mixture, and the mixture was partitioned. The combined organic layers were washed twice with water, washed once with saturated brine and dried over magnesium sulfate. After concentrating under reduced pressure, EtOAc m.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.24 (3H, t, J = 7.0 Hz), 1.33 (12H, s), 1.62 (3H, d, J = 6.7 Hz), 4.15 - 4.25 (2H, m ), 4.79 (1H, q, J = 7.0 Hz), 6.86 (2H, d, J = 8.5 Hz), 7.73 (2H, d, J = 8.5 Hz).

(75b) 2-({4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indole- Ethyl 5-yl)oxy]-2'-methylbiphenyl-4-yl}oxy)propionate

The compound obtained in Example (75a) (194 mg), [1,1'-bis (two) was added to a solution of the compound (2. Phenylphosphino)ferrocene]dichloropalladium(II) (61.8 mg), sodium carbonate (120 mg), and water (1.5 mL) were reacted at 130 ° C for 1 hour in a microwave reactor. Saturated brine (5 mL) was added to the reaction mixture, and the mixture was applied to ethyl acetate. The obtained residue was purified by silica gel column chromatography (ethyl acetate /hexane) to give the crude product 2-({4'-[(1-{[2-(ethylsulfonyl)phenyl)] Ethyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}oxy)propionic acid. 2-({4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2) obtained using CHIRALPAK IA (2-propanol/acetonitrile) , 3-dihydro-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}oxy)propanoic acid for optical resolution, each of the optical isomers obtained is Pre-peak (54.6 mg, >99% ee), post-peak (61.6 mg, 92% ee).

(75c)(2R)-2-({4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H) -吲哚-5-yl)oxy]-2'-methylbiphenyl-4-yl}oxy)propionic acid and (2S)-2-({4'-[(1-{[2- (Ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4 -yl}oxy)propionic acid

To a solution of the compound (54.6 mg) obtained in m.p. After the reaction mixture was concentrated under reduced pressure, water (6 mL) and 2M hydrochloric acid (0.27 mL) were added and stirred. The precipitated insoluble material was filtered, washed with water and evaporated to dryness.

Example 75-1:

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.11 (3H, t, J = 7.3Hz), 1.52 (3H, d, J = 6.7Hz), 2.08 (3H, s), 2.17 (3H, s ), 3.16-3.24(2H,m), 3.26-3.40(2H,m),4.24-4.35(4H,m),4.84(1H,q,J=6.7Hz),6.66(1H,dd,J=8.5 , 2.4 Hz), 6.76-6.84 (2H, m), 6.86-6.92 (2H, m), 7.10 (1H, d, J = 7.9 Hz), 7.19-7.25 (2H, m), 7.48-7.52 (1H, m), 7.55-7.61 (1H, m), 7.68-7.74 (1H, m), 7.85 (1H, d, J = 9.2 Hz), 7.89-7.94 (1H, m), 13.08 (1H, br s).

MS (APCI) m/z: 614 (M+H) ⁺ .

A 2M aqueous sodium hydroxide solution (0.288 mL) was added to a solution of the compound (m. After the reaction mixture was concentrated under reduced pressure, water (6 mL) and 2M hydrochloric acid (0.27 mL) were added and stirred. The precipitated insoluble material was filtered, washed with water and evaporated to dryness.

Example 75-2:

¹ H-NMR (DMSO-d ₆ ) δ: 1.11 (3H, t, J = 7.3 Hz), 1.52 (3H, d, J = 6.7 Hz), 2.08 (3H, s), 2.17 (3H, s), 3.17-3.24(2H,m), 3.26-3.37(2H,m),4.24-4.34(4H,m),4.84(1H,q,J=6.7Hz),6.66(1H,dd,J=8.2,2.4 Hz), 6.76-6.83 (2H, m), 6.86-6.91 (2H, m), 7.10 (1H, d, J = 7.9 Hz), 7.20-7.25 (2H, m), 7.48-7.52 (1H, m) , 7.55-7.61 (1H, m), 7.68-7.74 (1H, m), 7.85 (1H, d, J = 9.2 Hz), 7.89-7.93 (1H, m), 13.09 (1H, br s).

MS (APCI) m/z: 614 (M+H) ⁺ .

(Example 76)

{2'-Methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-1H-indol-5-yl)oxy] Biphenyl-4-yl}acetic acid

(76a){2'-Methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-1H-indol-5-yl) Oxy]biphenyl-4-yl}acetic acid

The compound obtained in Example (1d) (0.300 g) was dissolved in dichloromethane (5 mL), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.239) was added in three portions. g) Heating under reflux for 6 hours. Ethyl acetate, dichloromethane and ethanol were added to the reaction mixture, and the mixture was washed with water five times and washed with saturated brine. The organic layer was dried (Na2SO4). The obtained solid (0.172 g) was evaporated.

^{1 H-NMR (400MHz, CDCl} 3 + MeOH-d 4) δ: 2.22 (3H, s), 2.43 (3H, s), 3.16 (3H, s), 3.65 (2H, s), 4.90 (2H, s ), 6.68-6.82 (3H, m), 7.00-7.14 (2H, m), 7.23-7.46 (5H, m), 7.56-7.72 (3H, m), 8.07-8.26 (2H, m).

MS (APCI/ESI) m/z: 568 (M+H) ⁺ .

(Example 77)

{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-1H-indol-5-yl)oxy]-2'-methyl Biphenyl-4-yl}acetic acid

(77a){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-1H-indol-5-yl)oxy]-2' -methylbiphenyl-4-yl}acetic acid

The compound obtained in Example (2c) (0.275 g) was dissolved in dichloromethane (5 mL), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.214) was added in three portions. g), heating under reflux for 6 hours. After cooling the reaction mixture to room temperature, the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate and dichloromethane were added to the residue, and the mixture was washed with water five times and washed with saturated brine. The organic layer was dried over sodium sulfate and evaporated. The obtained solid (0.303 g) was obtained eluted eluted elut elut elut elut elut elut

^{1 H-NMR (400MHz, CDCl} 3 + MeOH-d 4) δ: 1.29 (3H, t, J = 7.3Hz), 2.22 (3H, s), 2.42 (3H, s), 3.22 (2H, q, J =7.3 Hz), 3.65 (2H, s), 4.89 (2H, s), 6.69-6.81 (3H, m), 7.02-7.14 (2H, m), 7.24-7.35 (4H, m), 7.42-7.71 ( 4H, m), 8.04-8.26 (2H, m).

MS (APCI) m/z: 582 (M+H) ⁺ .

(Example 78)

{4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)methyl ]-2'-methylbiphenyl-4-yl}acetic acid

(78a) 4-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole哚-1-carboxylic acid tert-butyl ester

Adding double to 4-methyl-5-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester (1.03 g) Bispinol borate (1.71g) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) methylene chloride complex (221mg), potassium acetate (795mg) , 1,2-dimethoxyethane (10 mL), dimethyl hydrazine (4 mL), and stirred at 100 ° C for 10 hours. After cooling to room temperature, it was filtered through celite. The filtrate was concentrated under reduced pressure. EtOAcjjjjjjjj

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.33 (12H, s), 1.55 (9H, s), 2.41 (3H, s), 2.95-3.02 (2H, m), 3.92-4.02 (2H, m) , 7.58-7.76 (2H, m).

(78b) 5-(4-bromo-3-methylbenzyl)-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

Add 1-bromo-4-(chloromethyl)-2-methyl to a mixture of the compound (640 mg) obtained in Example (78a) and 1,2-dimethoxyethane (8 mL), water (4 mL) Base benzene (469 mg), hydrazine (triphenylphosphine) palladium (0) (103 mg), sodium carbonate (472 mg) were stirred at 100 ° C for 10 hours. After cooling to room temperature, it was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over sodium sulfate. The title compound (684 mg) was obtained as white crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50-1.62 (9H, m), 2.05 (3H, s), 2.33 (3H, s), 2.95-3.03 (2H, m), 3.85 (2H, s) , 3.92-4.05 (2H, m), 6.78 (1H, d, J = 8.2 Hz), 6.89-7.01 (2H, m), 7.39 (1H, d, J = 8.2 Hz), 7.58-7.72 (1H, m ).

(78c) 5-{[4'-(2-Ethoxy-2-oxoethyl)-2-methylbiphenyl-4-yl]methyl}-4-methyl-2,3 -Dihydro-1H-indole-1-carboxylic acid tert-butyl ester

Add [4-(4,4,5,5-tetramethyl) to a mixture of the compound obtained in Example (78b) (684 mg) and 1,2-dimethoxyethane (8 mL), water (4 mL) -1,3,2-dioxaborolan-2-yl)phenyl]acetate (572 mg), [1,1'-bis(biphenylphosphino)ferrocene]dichloropalladium (II A dichloromethane complex (103 mg) and sodium carbonate (472 mg) were stirred at 120 ° C for 30 minutes in a microwave reactor. After cooling to room temperature, it was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over sodium sulfate. After filtration and concentrating under reduced pressure, the title compound (yield: 570 mg)

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.28 (3H, t, J = 7.2 Hz), 1.50-1.61 (9H, m), 2.12 (3H, s), 2.22 (3H, s), 2.97-3.05 (2H,m), 3.65 (2H, s), 3.91-4.06 (4H, m), 4.18 (2H, q, J = 7.2 Hz), 6.93-7.08 (2H, m), 7.09-7.15 (1H, m ), 7.25-7.36 (5H, m), 7.62-7.77 (1H, m).

(78d){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) )ethyl]-2'-methylbiphenyl-4-yl}ethyl acetate

4N Hydrochloric acid was added to a solution of the compound (158 mg) obtained in Example (78c) in dichloromethane (1 mL) The alkane solution (2 mL) was stirred at room temperature for 3 hours. After concentration under reduced pressure, crude [2'-methyl-4'-[(4-methyl-2,3-dihydro-1H-indol-5-yl)methyl]biphenyl-4- Base ethyl acetate hydrochloride.

Add [2-(ethylsulfonyl)phenyl]acetic acid (90 mg), 1-ethyl-3-(3-dimethylaminopropyl)carboxy fluorene to the obtained compound in dichloromethane. Amine hydrochloride (94 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (45 mg), N,N-diisopropylethylamine (0.17 mL) Stir at room temperature for 12 hours. The title compound (132 mg) was obtained as white crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.22-1.30 (6H, m), 2.17 (3H, s), 2.22 (3H, s), 3.15-3.25 (4H, m), 3.65 (2H, s) , 3.97 (2H, s), 4.15-4.27 (4H, m), 4.37 (2H, s), 6.94-6.99 (1H, m), 7.00-7.08 (2H, m), 7.09-7.14 (1H, m) , 7.24-7.34 (4H, m), 7.37-7.42 (1H, m), 7.47-7.53 (1H, m), 7.58-7.65 (1H, m), 7.95-8.00 (1H, m), 8.00-8.05 ( 1H, m).

(78e){4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl )methyl]-2'-methylbiphenyl-4-yl}acetic acid

1,4-two of the compound (117 mg) obtained in Example (78d) 1N sodium hydroxide (0.96 mL) was added to a solution of hexane (2 mL) and stirred at room temperature for 5 hr. After the reaction liquid was neutralized with 1 N hydrochloric acid, water was added thereto, and the precipitated solid was filtered. The title compound (89 mg) was obtained as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.25 (3H, t, J = 7.6 Hz), 2.17 (3H, s), 2.22 (3H, s), 3.15-3.24 (4H, m), 3.70 (2H , s), 3.97 (2H, s), 4.20-4.26 (2H, m), 4.37 (2H, s), 6.95-6.99 (1H, m), 7.00-7.07 (2H, m), 7.09-7.13 (1H , m), 7.25-7.35 (4H, m), 7.37-7.41 (1H, m), 7.47-7.52 (1H, m), 7.59-7.64 (1H, m), 7.95-8.00 (1H, m), 8.01 -8.06(1H,m).

MS (APCI) m/z: 582 (M+H) ⁺ .

(Example 79)

2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2'-methylbiphenyl-4-yl}-N-methylacetamide

Methylamine hydrochloride (109 mg), 1-ethyl-3-(3-di) was added to a solution of the compound (188 mg) of N,N-dimethylformamide (8 mL). Methylaminopropyl)carboxy quinone imine hydrochloride (93 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (48 mg), N,N-di Isopropylethylamine (0.22 mL) was stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction mixture for liquid separation. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and evaporated. Ethyl acetate (5 mL) was added to the residue, and the mixture was stirred for 1 hr.

¹ H-NMR (DMSO-d ₆ ) δ: 1.11 (3H, t, J = 7.3 Hz), 2.08 (3H, s), 2.18 (3H, s), 2.59 (3H, d, J = 4.9 Hz), 3.21 (2H, t, J = 8.2 Hz), 3.26-3.34 (2H, m), 3.42 (2H, s), 4.25-4.35 (4H, m), 6.68 (1H, dd, J = 7.9, 2.4 Hz) , 6.78-6.84 (2H, m), 7.11 (1H, d, J = 8.5 Hz), 7.23 (2H, d, J = 8.5 Hz), 7.29 (2H, d, J = 8.5 Hz), 7.50 (1H, d, J = 7.9 Hz), 7.55-7.60 (1H, m), 7.68-7.74 (1H, m), 7.86 (1H, d, J = 8.5 Hz), 7.89-7.93 (1H, m), 7.97-8.03 (1H,m).

MS (APCI) m/z: 597 (M+H) ⁺ .

(Test Example 1)

Inhibitory effect of IL-17 production by RORγt gene introduction into cells

(1) Production of RORγt gene into cells

Based on the base sequence of the mRNA encoding the full length amino acid sequence of the mouse (Mus musculus) RORgamma t protein (GenBank Accession No. AF163668: http://www.metalife.com/Genbank/5679306), obtained by PCR A cDNA encoding the mRNA of a full-length protein. The obtained cDNA was inserted into a pUNO vector (InvivoGen) which is a expression vector, and a mouse RORγt expression vector was constructed. The constructed mouse RORγt expression vector was introduced into EL4 cells (mouse T lymphoma cell line) to select medium (added fetal bovine serum, blasticidin S (Blasticidin S), penicillin, Streptomyces in DMEM medium In the culture, the RORγt gene was introduced into the cells.

(2) Evaluation of IL-17 production inhibition

The IL-17 production inhibitory effect of the test compound is to introduce the aforementioned RORγt gene into cells to phorbol 12-Myristate 13-acetate (PMA) and ionomycin. IL-17 production at the time of stimulation was measured. Namely, the RORγt gene was introduced into cells and prepared in the above-mentioned selection medium, and dispensed into 75,000 cells per well in a 96-well flat bottom plate (Corning). At this time, test compounds of various concentrations were simultaneously added. After incubating at 37 ° C for 1 hour in an incubator with 5% CO ₂ concentration, PMA was added to each well at a final concentration of 25 ng/mL and ionomycin at a final concentration of 125 ng/mL, totaling 100 μL at a concentration of 5% CO ₂ . Incubate at 37 ° C for 20 hours in an incubator. Thereafter, the culture supernatant was collected, and the concentration of mouse IL-17 in the supernatant was measured by time-degrading fluorescence using EnVison (Perkin-Elmer) using an HTRF mouse IL-17 kit (Cisbio). . Regarding the inhibition of IL-17 production by the test compound, a graph of the semi-logothmic plot of the concentration of the test compound in the presence of the test compound on the IL-17 production amount, which corresponds to the absence of the test compound. The test compound concentration of the IL-17 production amount of 50% of the IL-17 production amount was calculated as the IC ₅₀ value. The results of inhibition of IL-17 production are shown in Table 1.

In the present test, the compound of the present invention showed an excellent inhibitory effect on IL-17 production. Accordingly, it is used for dryness, dryness arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease (Clone's disease or ulcerative colitis, etc.), and repair syndrome , systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type I diabetes, graft versus host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Behcet's disease, spheroid Nephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis, etc. Autoimmune diseases or the production of IL-17 and colorectal cancer associated with pathogenesis Therapeutic agents and/or prophylactic agents.

(Test Example 2)

Inhibitory effect of IL-23-induced mouse dry dermatitis model

The IL-23-inducible mouse xerodermatitis pattern is known to be dependent on IL-17 (The Journal of Immunology, 186, 1495-1502 (2011)) (The Journal of Immunology, 186, 4481-4489 (2011)).

In the experiment, 5 to 10 male mice of 7 weeks old after BALB/c mice (Charles River, Japan) were used. From day 0 to day 3, mouse IL-23 (R&D Systems, 50 μg/mL in phosphate buffered saline) was administered to mice in a single ear on the 1st day of anesthesia, 1 μg. /only, and induced dermatitis (The Journal of Experimental Medicine, 203, 2577-2587 (2006)) (Nature, 445, 648-651 (2007)). In the same control group, bovine serum albumin (Sigma) was prepared in the same manner as phosphate buffered saline. Gg/mL) 1 μg/head. The dermatitis was evaluated after the final administration of mouse IL-23 for 24 hours (Day 4), and the thickness of the ear shell measured using the thickness gauge minus the IL-23 on day 0 was administered to the ear shell before the start. Thickness of the ear shell is used as an indicator. The test compound was suspended in a 0.5% methylcellulose solution or a 9-10% Kollidon (registered trademark) VA64 solution. The test compound or vehicle is administered orally twice a day from day 0 to day 3. The dermatitis-inhibiting effect by the test compound was calculated as the inhibition rate (%) according to the following formula. The results of the dermatitis inhibitory effect are shown in Table 2.

Inhibition rate (%) = 100 × (ear shell hypertrophy when the vehicle is administered - ear shell hypertrophy when the test compound is administered) / (ear shell hypertrophy when the vehicle is administered - the ear shell hypertrophy of the control group)

As shown above, the compound of the present invention has a dermatitis-inhibiting effect and is effective for dryness.

Formulation Example 1: Capsule

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

Formulation Example 2: Lozenges

The powder of the above-mentioned prescription was mixed, granulated using a corn starch paste, and dried, and then ingot was tableted by a tableting machine to prepare a tablet of 200 mg in one tablet. This tablet can be applied to the sugar coating as necessary.

[Industry use possibility]

The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof has excellent retinol receptor-associated receptor γt inhibitory action and IL-17 production inhibitory action, and is useful as a medicine.

Claims (46)

a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, Wherein R ¹ represents a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group or a phenyl group, and R ² represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkane Oxy group, R ³ represents a hydrogen atom, a C ₂ -C ₇ carboxyalkyl group or a hydroxyl group, R ⁴ represents a halogen atom or a C ₁ -C ₆ alkyl group, and R ⁵ represents a hydrogen atom or a C ₁ -C ₆ alkyl group, R ⁶ And a hydrogen atom, a halogen atom or a C ₁ -C ₆ alkyl group, and R ⁷ represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, a C ₁ -C ₆ hydroxyalkyl group, C ₁ -C ₆ cyanoalkyl, benzyloxy C ₁ -C ₆ alkyl or (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkane) group, R ⁸ represents a hydroxyl group, C ₁ -C ₆ Alkoxy, mono-C ₁ -C ₆ alkylamino or di-(C ₁ -C ₆ alkyl)amine, L represents a single bond, methylene or oxygen atom, and E represents independently 1 or 2 substituted phenyl groups selected from a halogen atom, a C ₁ -C ₆ alkyl group and a C ₁ -C ₆ alkylsulfonyl group; or may be selected from a halogen atom, a C ₁ -C ₆ alkyl group And a C ₁ -C ₆ alkylsulfonyl group-substituted pyridylene group, a thienylene group or a thiazolylene group, and Q ¹ represents a nitrogen atom or a formula represented by CH=CH- Base, Q ² represents a nitrogen atom or formula = The group represented by CH-, the group represented by the formula -UT-, represents a group represented by the formula -CH ₂ -CH ₂ - or a group represented by the formula -CH=CH-, and Y represents a methylene group or an oxygen atom. , V represents a nitrogen atom or a group represented by the formula = C(R ⁹ )-, and R ⁹ represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a C ₂ -C ₆ alkenyl group. , C ₁ -C ₆ alkoxy, C ₁ -C ₆ halogenated alkoxy, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkane), (C ₁ -C ₆ alkoxy)- (C ₁ -C ₆ alkoxy) group, C ₂ -C ₇ alkylcarbonyl group, tetrahydrofuranyl group or oxetyloxy group]. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl, ethyl or cyclopropyl. The compound of claim 1 or 2, wherein R ² is a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 3, wherein R ³ is a hydrogen atom, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 4, wherein R ⁴ is methyl, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 5, wherein R ⁵ is a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is a hydrogen atom. The compound of any one of claims 1 to 7, wherein R ⁷ is a hydrogen atom or a C ₁ -C ₆ alkyl group, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is a hydrogen atom or an ethyl group. The compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R ⁸ is a hydroxyl group. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein L is a single bond. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein E is a benzene which can be independently substituted with 1 or 2 groups selected from a halogen atom and a C ₁ -C ₆ alkyl group. Base or unsubstituted thiazolyl. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein E is 1,4-phenylene, a group represented by formula (II-I), or a formula (II-II) a group represented by the formula or a formula represented by the formula (III) (wherein, C _L and C _V represent a single bond, C _{L is} bonded to a group represented by the formula -L-, and C _{V is} bonded to a 6-membered ring), The compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein Q ¹ is a group represented by the formula =CH-, and Q ² is a nitrogen atom. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Q ¹ is a group represented by the formula =CH-, and Q ² is a group represented by the formula =CH-. The compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein the group represented by the formula -UT- is a group represented by the formula -CH ₂ -CH ₂ -. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Y is an oxygen atom. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein V is a group represented by the formula: C(R ⁹ )-. The compound of any one of claims 1 to 18, wherein R ⁹ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy, or a pharmaceutically acceptable salt thereof, C ₁ -C ₆ halogenated alkoxy, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkane) group, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkoxy) group Or a C ₂ -C ₇ alkylcarbonyl group. The compound of any one of claims 1 to 18, wherein R ⁹ is methyl or methoxy, or a pharmaceutically acceptable salt thereof. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is {2'-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]acetamidine) }}-2,3-dihydro-1H-indol-5-yl)oxy]biphenyl-4-yl}acetic acid, {4'-[(1-{[2-(ethylsulfonyl)) Phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}acetic acid, { 4'-[(1-{[2-(cyclopropylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-2'-Methylbiphenyl-4-yl}acetic acid, {4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2 ,3-dihydro-1H-indol-5-yl)oxy]-2',5'-dimethylbiphenyl-4-yl}acetic acid, {4'-[(1-{[2- (Ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2-fluoro-2'-methyl Phenyl-4-yl}acetic acid, {4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-2-fluoro-2'-methoxy-5'-methylbiphenyl-4-yl}acetic acid, {4'-[(1-{[3-(ethylsulfonyl)pyridine-2) -yl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}acetic acid, {4 '-[(1-{[3-(ethylsulfonyl)-6-methylpyridin-2-yl]ethenyl}-4-methyl-2,3-dihydro-1H-indole- 5-yl)oxy]-2'-methylbiphenyl-4-yl}acetic acid, {4'-[(1-{[3-(ethylsulfonyl)pyridin-2-yl]acetamidine) {-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2',5'-dimethylbiphenyl-4-yl}acetic acid, {4' -[(1-{[3-(ethylsulfonyl)-6-methylpyridin-2-yl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-2',5'-dimethylbiphenyl-4-yl}acetic acid, 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl) Ethyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}propionic acid, 2-{4 '-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]- 2-fluoro-2'-methylbiphenyl-4-yl}pentanoic acid, 2-{4'- [(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2' -methylbiphenyl-4-yl}-5,5,5-trifluoropentanoic acid, 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2',5'-dimethylbiphenyl-4-yl}butyric acid, 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]acetamidine (4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}butyric acid, (2R)-2- {4'-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy ]-2'-Methylbiphenyl-4-yl}butyric acid, (2S)-2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl) 4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}butyric acid, or (5-{4-[ (1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2-yl Phenylphenyl}-1,3-thiazol-2-yl)acetic acid. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is {2'-methyl-4'-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]acetamidine) }}-2,3-Dihydro-1H-indol-5-yl)oxy]biphenyl-4-yl}acetic acid. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3- Dihydro-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}acetic acid. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is {4'-[(1-{[2-(cyclopropylsulfonyl)phenyl]ethinyl}-4-methyl-2, 3-Dihydro-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}acetic acid. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is {4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3) -Dihydro-1H-indol-5-yl)oxy]-2-fluoro-2'-methylbiphenyl-4-yl}acetic acid. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is {4'-[(1-{[3-(ethylsulfonyl)pyridin-2-yl]ethenyl}-4-methyl- 2,3-Dihydro-1H-indol-5-yl)oxy]-2',5'-dimethylbiphenyl-4-yl}acetic acid. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is {4'-[(1-{[3-(ethylsulfonyl)-6-methylpyridin-2-yl]ethenyl}- 4-Methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2',5'-dimethylbiphenyl-4-yl}acetic acid. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2 , 3-dihydro-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}butyric acid. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is (2R)-2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4- Methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}butyric acid. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is (2S)-2-{4'-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4- Methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2'-methylbiphenyl-4-yl}butyric acid. A pharmaceutical composition containing a compound selected from any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition according to claim 31, wherein the pharmaceutical composition is for the treatment and/or prevention of a disease which is treated and/or prevented by the retinoic acid receptor-related orphan receptor γt inhibition. The pharmaceutical composition according to claim 31, wherein the pharmaceutical composition is used for the treatment of a disease which is treated, improved, alleviated and/or prevented by inhibition of Th17 cell differentiation and/or inhibition of IL-17 production. / or prevention. The pharmaceutical composition according to claim 31, wherein the pharmaceutical composition is used for dryness, dryness arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Shering's syndrome, Systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type I diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia , Kawasaki disease, Behchet's disease, spheroid nephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer Treatment and / or prevention. The pharmaceutical composition of claim 31, wherein the pharmaceutical composition is for the treatment and/or prevention of dryness or dryness arthritis. A retinoid acid receptor-associated orphan receptor γt inhibitor comprising a compound selected from any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, as an active ingredient. A use of a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition. The use of claim 37, wherein the pharmaceutical composition is cognac, dry arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, sigma syndrome, systemic lupus erythematosus , chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type I diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Behcet's disease, spheroid nephritis, cardiomyopathy, A composition for the treatment and/or prevention of aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer. The use of claim 37, wherein the pharmaceutical composition is a composition for the treatment and/or prevention of dryness or dry arthritis. A compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease which is treated and/or prevented by a retinoid receptor associated with orphan receptor γt inhibition And/or use in methods of prevention. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, for use in dryness, dryness, arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory Enteropathy, Shering's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type I diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease , Behcet's disease, spheroid nephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer treatment and / or prevention methods Use in. A method for the treatment and/or prevention of a disease, which comprises administering a pharmacologically effective amount of a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, to a warm-blooded animal. The method of claim 42, wherein the disease is treated and/or prevented by inhibition of retinoic acid receptor-related orphan receptor γt. The method of claim 42, wherein the disease is dryness, dryness arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, sedative syndrome, systemic lupus erythematosus, chronic Obstructive Pulmonary Disease (COPD), atopic dermatitis, asthma, type I diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Behcet's disease, spheroid nephritis, cardiomyopathy, dysplasia Anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer. The method of claim 42, wherein the disease is dry or dry arthritis. The method of any one of items 42 to 45, wherein the warm-blooded animal is a human.