JP2016108257A - Indoline derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide: a compound or a pharmacologically acceptable salt thereof which inhibits a retinoic acid receptor-related orphan receptor and, due to suppression of Th-17 cell differentiation and/or suppression of IL-17 production, is effective for treatment and/or prevention of psoriasis, multiple sclerosis, rheumatic arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease, asthma, or colon cancer; and a pharmaceutical composition containing the compound.SOLUTION: Provided are a compound represented by the following formula or a pharmacologically acceptable salt thereof, and a pharmaceutical composition containing the compound.SELECTED DRAWING: None

Description

  The present invention has an excellent inhibitory action on retinoic acid receptor-related orphan receptor γt (which may be abbreviated as RORγt in the present specification) and is useful as a therapeutic agent for psoriasis or the like or a pharmacologically acceptable salt thereof. Related to the salt.

  The cause of many autoimmune diseases is unknown, but it has long been known that many diseases are closely related to T cell abnormalities. In particular, helper T cells (Th1 cells) with high IFN-γ production have been reported for a long time, but Th1 cell abnormalities cannot completely explain the pathogenesis of the disease, and Th1 cells are involved. Was questioned. In 2006, the presence of IL-17 high-producing helper T cells (Th17 cells) was reported, suggesting that autoimmune diseases are closely related to abnormalities in Th17 cells. Since then, research on Th17 cells has been conducted energetically, and their relevance has been clarified in several autoimmune diseases, and the importance of Th17 cells has attracted attention. The nuclear receptor RORγt functions in the process in which Th17 cells differentiate from naive T cells and in the process in which Th17 cells produce IL-17. In naive T cells of RORγt knockout mice, differentiation into Th17 cells was suppressed, IL-17 production was suppressed, and the development of Experimental Autoimmune Encephalomyelitis, a pathological model of multiple sclerosis, was suppressed ( Non-patent document 1). In another pathological model, there is a report that RORγt plays an important role in Th17 cell differentiation, IL-17 production, and pathogenesis (Non-patent Documents 2-3). From these findings, it is considered that a substance that suppresses the transcriptional activity of RORγt, that is, an RORγt inhibitor may be a therapeutic agent for autoimmune diseases and the like.

  Since the cause of autoimmune diseases has not been known so far, immunosuppressants that suppress immunity in general have been used for the treatment. However, this treatment method is not expected to have any effect on the cause of autoimmune disease, but is only a coping therapy, so there was often no sufficient treatment effect or relapse without remission. Therefore, in order to achieve a sufficient therapeutic effect and remission, a treatment suitable for the cause of the autoimmune disease is required. Recently, abnormalities in Th17 cells with enhanced IL-17 production have been confirmed as the cause of several autoimmune diseases. However, since there is no method that can treat Th17 cell abnormality at present, a new treatment method that can improve Th17 cell abnormality is required.

Cell, 126, 1121-1133 (2006) The Journal of Clinical Investigation, 122, 2252-2256 (2012) Arthritis and Rheumatology, 66, 579-588 (2014)

  As a result of intensive studies on compounds having an RORγt inhibitory effect, the inventors have found that an indoline compound having a specific chemical structure has a selective and excellent Th17 cell differentiation inhibitory action and IL-17 production inhibitory action. It was found useful for the prevention and treatment of RORγt-related diseases such as autoimmune diseases. The present inventors have found that this indoline compound has psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases (such as Crohn's disease and ulcerative colitis), Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease, asthma Or it discovered that it was useful as an active ingredient of the pharmaceutical for the treatment and / or prevention of colon cancer. The present invention has been completed based on the above findings.

The present invention is as follows.
(1) General formula (I)

[Where:
R ¹ represents a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group or a phenyl group,
A represents a carbonyl group, a sulfinyl group or a sulfonyl group,
Q represents a nitrogen atom or a group represented by the formula = C (R ² )-
R ² represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group,
R ³ represents a hydrogen atom, a C ₂ -C ₇ carboxyalkyl group or a hydroxyl group,
Group of the formula -U-T-has the formula _-CH 2 -CH ₂ - indicates a group represented by or a group of the formula -CH = CH-,
R ⁴ represents a halogen atom or a C ₁ -C ₆ alkyl group,
Y represents a methylene group or an oxygen atom,
L represents a 1,4-phenylene group which may be independently substituted with a group selected from substituent group A or a bicyclic heteroarylene group consisting of a 6-membered ring and a 6-membered ring;
Substituent Group A represents the group consisting of halogen _atom, C 1 -C _{6 alkyl,} C 1 -C ₆ alkoxy group and oxo group,
E represents a hydrogen _atom, C 1 -C ₆ halogenated alkyl _group, C 2 -C ₇ alkoxycarbonyl group, _mono--C 1 -C ₆ alkylaminocarbonyl group, di - _(C 1 -C ₆ alkyl) aminocarbonyl group , A (C ₂ -C ₇ alkoxycarbonyl)-(C ₂ -C ₆ alkenyl) group or a group selected from substituent group B, which may be independently substituted with 1 to 4 C ₃ -C ₆ cycloalkyl Group, C ₃ -C ₆ cycloalkyl group, one substituted with C ₂ -C ₇ carboxyalkyl group, phenyl group, monocyclic heterocyclic group, bicyclic heterocyclic ring consisting of 5-membered ring and 5-membered ring A bicyclic heterocyclic group consisting of a 5-membered ring and a 6-membered ring or a bicyclic heterocyclic group consisting of a 6-membered ring and a 6-membered ring;
However, when the group represented by the formula -A-R ¹ is substituted at the 2-position and the 4-position of the 6-membered ring containing Q is a hydrogen atom, a piperidin-1-yl group, piperidin-3- Yl, piperidin-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, piperazin-1-yl, morpholin-4-yl, pyrrolidin-1-yl and pyrrolidin-3 -Excluding yl groups,
Substituent group B, a halogen _atom, C 1 -C _{6 alkyl,} C 1 -C ₆ halogenated alkyl _group, C 1 -C ₆ hydroxyalkyl _group, C 1 -C ₆ alkoxy _group, C 1 -C ₆ hydroxy Alkoxy group, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, hydroxyl group, carboxy group, C ₂ -C ₇ carboxyalkyl group, C ₂ -C ₇ alkylcarbonyl group, mono-C _2- C ₇ carboxyalkyl aminocarbonyl group, di - _(C 1 -C ₆ alkyl) aminocarbonyl methyl _{group, (C} 2 -C _{7 carboxyalkyl) (C} 2 -C ₇ alkylcarbonyl) amino group, morpholin-4-yl Group, (morpholin-4-yl) methyl group, (1,4-dioxane-2-yl) methyl group, (1,4-dioxane-2-yl) methyloxy And it represents the group consisting of oxo group,
However, when A is a sulfonyl group, _C 2 -C ₇ carboxyalkyl group from Substituent Group B is excluded. Or a pharmacologically acceptable salt thereof.

  In the present invention, the following can be preferably mentioned.

(2) In (1),
The compound whose general formula (I) is general formula (II), or its pharmacologically acceptable salt.

(3) In (1) or (2),
A compound or a pharmacologically acceptable salt thereof, wherein R ¹ is a C ₁ -C ₆ alkyl group.

(4) In (1) or (2),
A compound or a pharmacologically acceptable salt thereof, wherein R ¹ is a methyl group or an ethyl group.

(5) In any one item selected from (1) to (4),
A compound or a pharmacologically acceptable salt thereof, wherein A is a sulfinyl group or a sulfonyl group.

(6) In any one item selected from (1) to (4),
A compound or a pharmacologically acceptable salt thereof, wherein A is a sulfonyl group.

(7) In any one item selected from (1) to (6),
A compound or a pharmacologically acceptable salt thereof, wherein Q is a nitrogen atom.

(8) In any one item selected from (1) to (6),
A compound or a pharmacologically acceptable salt thereof, wherein Q is a group represented by the formula = CH-.

(9) In any one item selected from (1) to (8),
A compound or a pharmacologically acceptable salt thereof, wherein Y is an oxygen atom.

(10) In any one item selected from (1) to (9),
L is a group represented by formula (III-I), a group represented by formula (III-II), a group represented by formula (III-III), or a group represented by formula (III-IV). or a group (wherein the formula (III-V), _{C E} and _{C Y} is a single bond, _{C E} is bonded to the group represented by the formula E, _{C Y} is represented by the formula Y Or a pharmacologically acceptable salt thereof.

(11) In any one item selected from (1) to (10),
E is a hydrogen atom, C ₂ -C ₇ alkoxycarbonyl group or a methyl group, a hydroxyl group, a carboxyl group, and (morpholin-4-yl) may be one or two substituted independently with a group selected from a methyl group C ₃ -C ₆ cycloalkyl group, a monocyclic heterocyclic group, 5-membered ring and the bicyclic compound is a heterocyclic group consisting of the bicyclic heterocyclic group or a 6-membered ring and 6-membered ring composed of 6-membered ring Or a pharmacologically acceptable salt thereof.

(12) In any one item selected from (1) to (10),
E represents a hydrogen atom, an ethoxycarbonyl group, a 4-hydroxycyclohexyl group, a pyridin-4-yl group, a 6- (morpholin-4-ylmethyl) pyridin-3-yl group, a tetrahydro-2H-pyran-4-yl group, Tetrahydro-2H-pyran-3-yl group, 3,6-dihydro-2H-pyran-4-yl group, 2-carboxy-1-methyl-1H-indol-5-yl group, 1-methyl-1H-benz A compound which is an imidazol-6-yl group or a 4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl group or a pharmacologically acceptable salt thereof.

(13) In any one item selected from (1) to (9),
The group represented by the formula E-L- is 4-ethoxycarbonylphenyl group, 4- (4-hydroxycyclohexyl) phenyl, 4- (pyridin-4-yl) phenyl group, 3-methyl-4- [6- (Morpholin-4-ylmethyl) pyridin-3-yl] phenyl group, 4- (tetrahydro-2H-pyran-4-yl) phenyl group, 3-methyl-4- (tetrahydro-2H-pyran-3-yl) phenyl Group, 4- (3,6-dihydro-2H-pyran-4-yl) phenyl group, 3-methyl-4- (2-carboxy-1-methyl-1H-indol-5-yl) phenyl group, 3- Methoxy-4- (1-methyl-1H-benzimidazol-6-yl) phenyl group, 3-methyl-4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1 , 4] Oki 7-yl) phenyl group, 2-methyl-3,4-dihydro-isoquinoline -1 (2H) - one-6-yl group compound or a pharmacologically acceptable salt or quinoxalin-6-yl group.

(14) In (1),
The general formula (I) is the general formula (II), R ¹ is a C ₁ -C ₆ alkyl group, A is a sulfinyl group or a sulfonyl group, Q is a nitrogen atom, and Y is , An oxygen atom, and L is a group represented by the formula (III-I), a group represented by the formula (III-II), a group represented by the formula (III-III), a formula (III-IV) ) Or a group represented by formula (III-V), wherein E represents a hydrogen atom, a C ₂ -C ₇ alkoxycarbonyl group or a methyl group, a hydroxyl group, a carboxy group, and (morpholin-4-yl ) which may be one or two independently substituted by a group selected from methyl C ₃ -C ₆ cycloalkyl group, a monocyclic heterocyclic group, a bicyclic heterocyclic of five-membered ring and 6-membered ring Compound which is a cyclic group or a bicyclic heterocyclic group consisting of 6-membered ring and 6-membered ring Salt.

(15) In (1),
The general formula (I) is the general formula (II), R ¹ is a methyl group or an ethyl group, A is a sulfonyl group, Q is a nitrogen atom, and Y is an oxygen atom. , L is represented by the group represented by the formula (III-I), the group represented by the formula (III-II), the group represented by the formula (III-III), or the formula (III-IV). Or a group represented by formula (III-V), wherein E represents a hydrogen atom, an ethoxycarbonyl group, a 4-hydroxycyclohexyl group, a pyridin-4-yl group, or 6- (morpholin-4-ylmethyl) pyridine- 3-yl group, tetrahydro-2H-pyran-4-yl group, tetrahydro-2H-pyran-3-yl group, 3,6-dihydro-2H-pyran-4-yl group, 2-carboxy-1-methyl- 1H-indol-5-yl group, 1-methyl-1H-be Or a pharmacologically acceptable salt thereof, which is a benzimidazol-6-yl group or 4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl group .

(16) In (1),
The general formula (I) is the general formula (II), R ¹ is a C ₁ -C ₆ alkyl group, A is a sulfinyl group or a sulfonyl group, and Q is represented by the formula = CH-. Y is an oxygen atom, and L is a group represented by the formula (III-I), a group represented by the formula (III-II), or a formula (III-III). group, a group represented by the formula (III-IV), a group represented by or formula (III-V), E is a hydrogen _atom, C 2 -C ₇ alkoxycarbonyl group or a methyl group, a hydroxyl group, a carboxyl group And a C ₃ -C ₆ cycloalkyl group, monocyclic heterocyclic group, 5-membered ring and 6-membered group which may be independently substituted with 1 or 2 groups independently selected from a group selected from (morpholin-4-yl) methyl group A compound which is a bicyclic heterocyclic group consisting of a ring or a bicyclic heterocyclic group consisting of a 6-membered ring and a 6-membered ring, or Its pharmacologically acceptable salt.

(17) In (1),
General formula (I) is general formula (II), R ¹ is a methyl group or an ethyl group, A is a sulfonyl group, Q is a group represented by the formula = CH- Y is an oxygen atom, and L is a group represented by the formula (III-I), a group represented by the formula (III-II), a group represented by the formula (III-III), a formula (III -IV) or a group represented by formula (III-V), wherein E represents a hydrogen atom, an ethoxycarbonyl group, a 4-hydroxycyclohexyl group, a pyridin-4-yl group, or 6- (morpholine). -4-ylmethyl) pyridin-3-yl group, tetrahydro-2H-pyran-4-yl group, tetrahydro-2H-pyran-3-yl group, 3,6-dihydro-2H-pyran-4-yl group, 2 -Carboxy-1-methyl-1H-indol-5-yl group, 1-methyl Compound which is til-1H-benzimidazol-6-yl group or 4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl group or its pharmacology Acceptable salt.

(18) In (1),
The general formula (I) is the general formula (II), R ¹ is a C ₁ -C ₆ alkyl group, A is a sulfinyl group or a sulfonyl group, Q is a nitrogen atom, and Y is A group represented by the formula E-L- is a 4-ethoxycarbonylphenyl group, 4- (4-hydroxycyclohexyl) phenyl, 4- (pyridin-4-yl) phenyl group, 3-methyl -4- [6- (morpholin-4-ylmethyl) pyridin-3-yl] phenyl group, 4- (tetrahydro-2H-pyran-4-yl) phenyl group, 3-methyl-4- (tetrahydro-2H-pyran -3-yl) phenyl group, 4- (3,6-dihydro-2H-pyran-4-yl) phenyl group, 3-methyl-4- (2-carboxy-1-methyl-1H-indol-5-yl) ) Phenyl group, 3- Methoxy-4- (1-methyl-1H-benzimidazol-6-yl) phenyl group, 3-methyl-4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1 , 4] oxazin-7-yl) phenyl group, 2-methyl-3,4-dihydroisoquinolin-1 (2H) -one-6-yl group or quinoxalin-6-yl group or a pharmacologically acceptable salt thereof. Salt.

(19) In (1),
The general formula (I) is the general formula (II), R ¹ is a methyl group or an ethyl group, A is a sulfonyl group, Q is a nitrogen atom, and Y is an oxygen atom. , A group represented by the formula E-L- is 4-ethoxycarbonylphenyl group, 4- (4-hydroxycyclohexyl) phenyl, 4- (pyridin-4-yl) phenyl group, 3-methyl-4- [6 -(Morpholin-4-ylmethyl) pyridin-3-yl] phenyl group, 4- (tetrahydro-2H-pyran-4-yl) phenyl group, 3-methyl-4- (tetrahydro-2H-pyran-3-yl) Phenyl group, 4- (3,6-dihydro-2H-pyran-4-yl) phenyl group, 3-methyl-4- (2-carboxy-1-methyl-1H-indol-5-yl) phenyl group, 3 -Methoxy-4- (1- Methyl-1H-benzimidazol-6-yl) phenyl group, 3-methyl-4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-7- Yl) A compound which is a phenyl group, 2-methyl-3,4-dihydroisoquinolin-1 (2H) -one-6-yl group or quinoxalin-6-yl group or a pharmacologically acceptable salt thereof.

(20) In (1),
The general formula (I) is the general formula (II), R ¹ is a C ₁ -C ₆ alkyl group, A is a sulfinyl group or a sulfonyl group, and Q is represented by the formula = CH-. Y is an oxygen atom, and the group represented by the formula E-L- is 4-ethoxycarbonylphenyl group, 4- (4-hydroxycyclohexyl) phenyl, 4- (pyridin-4-yl) ) Phenyl group, 3-methyl-4- [6- (morpholin-4-ylmethyl) pyridin-3-yl] phenyl group, 4- (tetrahydro-2H-pyran-4-yl) phenyl group, 3-methyl-4 -(Tetrahydro-2H-pyran-3-yl) phenyl group, 4- (3,6-dihydro-2H-pyran-4-yl) phenyl group, 3-methyl-4- (2-carboxy-1-methyl- 1H-Indol-5-yl) fu Phenyl group, 3-methoxy-4- (1-methyl-1H-benzimidazol-6-yl) phenyl group, 3-methyl-4- (4-methyl-3,4-dihydro-2H-pyrido [3,2 -B] [1,4] oxazin-7-yl) phenyl group, 2-methyl-3,4-dihydroisoquinolin-1 (2H) -one-6-yl group or quinoxalin-6-yl group or Its pharmacologically acceptable salt.

(21) In (1),
General formula (I) is general formula (II), R ¹ is a methyl group or an ethyl group, A is a sulfonyl group, Q is a group represented by the formula = CH- Y is an oxygen atom, and the group represented by the formula E-L- is a 4-ethoxycarbonylphenyl group, 4- (4-hydroxycyclohexyl) phenyl, 4- (pyridin-4-yl) phenyl group, 3 -Methyl-4- [6- (morpholin-4-ylmethyl) pyridin-3-yl] phenyl group, 4- (tetrahydro-2H-pyran-4-yl) phenyl group, 3-methyl-4- (tetrahydro-2H) -Pyran-3-yl) phenyl group, 4- (3,6-dihydro-2H-pyran-4-yl) phenyl group, 3-methyl-4- (2-carboxy-1-methyl-1H-indole-5 -Yl) phenyl group, 3-methoxy Ci-4- (1-methyl-1H-benzimidazol-6-yl) phenyl group, 3-methyl-4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1 , 4] oxazin-7-yl) phenyl group, 2-methyl-3,4-dihydroisoquinolin-1 (2H) -one-6-yl group or quinoxalin-6-yl group or a pharmacologically acceptable salt thereof. Salt.

(22) 1- {4-Methyl-5- [4- (pyridin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl ] Ethanon,
1- {5- [4- (3,6-dihydro-2H-pyran-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (Methylsulfonyl) phenyl] ethanone,
1- {5- [4- (4-Hydroxycyclohexyl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl ] Ethanon,
1- {4-Methyl-5- [3-methyl-4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone,
1- (4-Methyl-5- {3-methyl-4- [6- (morpholin-4-ylmethyl) pyridin-3-yl] phenoxy} -2,3-dihydro-1H-indol-1-yl)- 2- [2- (methylsulfonyl) phenyl] ethanone,
1- {5- [3-Methoxy-4- (1-methyl-1H-benzimidazol-6-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone,
2- [2- (Methylsulfonyl) phenyl] -1- {4-methyl-5- [4- (tetrahydro-2H-pyran-4-yl) phenoxy] -2,3-dihydro-1H-indole-1- Il} Ethanon,
1- {5- [4- (4-hydroxycyclohexyl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone,
1- {4-Methyl-5- [3-methyl-4- (tetrahydro-2H-pyran-3-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (Methylsulfonyl) phenyl] ethanone,
1-methyl-5- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] Phenyl} -1H-indole-2-carboxylic acid,
6-[(1-{[2- (Ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -2-methyl-3,4-dihydroisoquinoline -1 (2H) -on,
2- [2- (ethylsulfonyl) phenyl] -1- [4-methyl-5- (quinoxalin-6-yloxy) -2,3-dihydro-1H-indol-1-yl] ethanone, or
Ethyl 4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] benzoate or a pharmacologically acceptable salt thereof Salt.

  (23) A compound described in (22) or a pharmacologically acceptable salt thereof.

(24) 1- {4-Methyl-5- [4- (pyridin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl ] Ethanon,
1- {5- [4- (4-Hydroxycyclohexyl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl ] Ethanon,
2- [2- (Methylsulfonyl) phenyl] -1- {4-methyl-5- [4- (tetrahydro-2H-pyran-4-yl) phenoxy] -2,3-dihydro-1H-indole-1- Il} Ethanon,
1- {5- [4- (4-hydroxycyclohexyl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone,
6-[(1-{[2- (Ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -2-methyl-3,4-dihydroisoquinoline -1 (2H) -on,
2- [2- (ethylsulfonyl) phenyl] -1- [4-methyl-5- (quinoxalin-6-yloxy) -2,3-dihydro-1H-indol-1-yl] ethanone, or
Ethyl 4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] benzoate or a pharmacologically acceptable salt thereof Salt.

  (25) A compound described in (24) or a pharmacologically acceptable salt thereof.

  (26) A pharmaceutical composition comprising as an active ingredient the compound described in any one of (1) to (25) or a pharmacologically acceptable salt thereof.

  (27) The pharmaceutical composition according to (26), wherein the pharmaceutical composition has a retinoic acid receptor-related orphan receptor inhibitory action.

  (28) The pharmaceutical composition according to (26), wherein the pharmaceutical composition is used for the treatment and / or prevention of a disease that is treated and / or prevented by an retinoic acid receptor-related orphan receptor inhibitory action.

  (29) The pharmaceutical composition inhibits a retinoic acid receptor-related orphan receptor, and suppresses Th17 cell differentiation and / or suppresses IL-17 production, whereby symptoms are treated, ameliorated, reduced and / or prevented. (26) The pharmaceutical composition for treatment and / or prevention of a disease.

  (30) A pharmaceutical composition for the treatment and / or prevention of psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease, asthma or colon cancer ( 26) The pharmaceutical composition according to 26).

  (31) The pharmaceutical composition according to (26), wherein the pharmaceutical composition is for the treatment and / or prevention of psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease or chronic obstructive pulmonary disease.

  (32) The pharmaceutical composition according to (26), wherein the pharmaceutical composition is for the treatment and / or prevention of psoriasis.

  (33) The pharmaceutical composition according to (30) or (31), wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

  (34) A retinoic acid receptor-related orphan receptor inhibitor comprising as an active ingredient the compound described in any one of (1) to (25) or a pharmacologically acceptable salt thereof.

  (35) Use of the compound described in any one of (1) to (25) or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition.

  (36) The use according to (35), wherein the pharmaceutical composition is a composition for inhibiting a retinoic acid receptor-related orphan receptor.

  (37) A composition for treating and / or preventing psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease, asthma or colon cancer The use according to (35).

  (38) The use according to (35), wherein the pharmaceutical composition is a composition for treating and / or preventing psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease or chronic obstructive pulmonary disease.

  (39) The use according to (35), wherein the pharmaceutical composition is a composition for treating and / or preventing psoriasis.

  (40) The use according to (37) or (38), wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

  (41) A retinoic acid receptor-related oroprotein, wherein a pharmacologically effective amount of a compound according to any one of (1) to (25) or a pharmacologically acceptable salt thereof is administered to a warm-blooded animal. Fan receptor inhibition method.

  (42) Treatment of diseases and / or diseases in which a pharmacologically effective amount of the compound described in any one of (1) to (25) or a pharmacologically acceptable salt thereof is administered to a warm-blooded animal Prevention method.

  (43) The method according to (42), wherein the disease is psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease, asthma or colon cancer.

  (44) The method according to (42), wherein the disease is psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease or chronic obstructive pulmonary disease.

  (45) The method according to (42), wherein the disease is psoriasis.

  (46) The method according to (43) or (44), wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

  (47) The method according to any one of (41) to (46), wherein the warm-blooded animal is a human.

  In the present invention, the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferable is a chlorine atom or a bromine 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. Preferred is a linear or branched alkyl group having 1 to 4 carbon atoms (C ₁ -C ₄ alkyl group), and more preferred is a methyl group or an ethyl group (C ₁ -C ₂ alkyl group). And even more preferably a methyl 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. A cyclohexyl group is preferred.

In the present invention, the “C ₁ -C ₆ halogenated alkyl group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C ₁ -C ₆ alkyl group”. For example, trifluoromethyl, trichloromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 3,3-difluoropropyl, 2,2,2-trichloroethyl , 2-bromoethyl or 2-fluoroethyl group. Preferred is a group (C ₁ -C ₂ halogenated alkyl group) in which 1 to 5 “halogen atoms” which are the same or different are bonded to a “C ₁ -C ₂ alkyl group”. A fluoromethyl group;

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

In the present invention, the “(C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group” means that one “C ₁ -C ₆ alkoxy group” is the above “C ₁ -C ₆ alkyl group”. It is a group bonded to For example, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-butoxyethyl, 1-butoxyethyl, 1-isobutoxyethyl or 3 -An isopropoxypropyl group, and preferably a group in which one “C ₁ -C ₄ alkoxy group” is bonded to the “C ₁ -C ₄ alkyl group” ((C ₁ -C ₄ alkoxy)- (C ₁ -C ₄ alkyl) group), more preferably, a group in which one of the “C ₁ -C ₂ alkoxy group” is bonded to the “C ₁ -C ₂ alkyl group” ((C ₁ -C ₂ alkoxy) - and _(C 1 -C ₂ alkyl) group), and even more preferably a methoxymethyl group.

In the present invention, the “C ₂ -C ₇ carboxyalkyl group” is a group in which one carboxy group is bonded to the “C ₁ -C ₆ alkyl group”. For example, carboxymethyl, 2-carboxyethyl, 1-carboxyethyl or 3-carboxypropyl group. A group in which one carboxy group is bonded to a “C ₁ -C ₂ alkyl group” is preferable, and a carboxymethyl group is more preferable.

In the present invention, the “C ₁ -C ₆ hydroxyalkyl group” is a group in which one hydroxy group is bonded to the “C ₁ -C ₆ alkyl group”. For example, a 2-hydroxyethyl, 1-hydroxyethyl or 3-hydroxypropyl group. Preferably, one hydroxy group is a group (C ₁ -C ₂ hydroxyalkyl group) bonded to a “C ₁ -C ₂ alkyl group”, and more preferably a 1-hydroxyethyl group.

In the present invention, the “C ₁ -C ₆ hydroxyalkoxy group” is a group in which one hydroxy group is bonded to the “C ₁ -C ₆ alkoxy group”. For example, 2-hydroxyethoxy, 1-hydroxyethoxy or 3-hydroxypropoxy group. Preferably, one hydroxy group is a group (C ₁ -C ₂ hydroxyalkoxy group) bonded to a “C ₁ -C ₂ alkoxy group”, and more preferably a 2-hydroxyethoxy group.

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

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

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

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

In the present invention, the “(C ₂ -C ₇ alkoxycarbonyl)-(C ₂ -C ₆ alkenyl) group” means that one “C ₂ -C ₇ alkoxycarbonyl group” is the above “C ₂ -C ₆ alkenyl”. A group bonded to “group”. (The “C ₂ -C ₆ alkenyl group” is a group having 2 to 6 carbon atoms having one double bond in the “C ₁ -C ₆ alkyl group”.) For example, methoxycarbonyl group It is a tenenyl, ethoxycarbonylethenyl or propoxycarbonylethenyl group, preferably an ethoxycarbonylethenyl group.

In the present invention, the “mono-C ₂ -C ₇ carboxyalkylaminocarbonyl group” is a group in which one amino group to which the “C ₂ -C ₇ carboxyalkyl group” is bonded is bonded to a carbonyl group. For example, carboxymethylaminocarbonyl, 2-carboxyethylaminocarbonyl or 1-carboxyethylaminocarbonyl group, preferably carboxymethylaminocarbonyl group.

In the present invention, the “di- (C ₁ -C ₆ alkyl) aminocarbonylmethyloxy group” is a group in which one of the above “di- (C ₁ -C ₆ alkyl) aminocarbonyl groups” is bonded to a methyloxy group. It is. For example, dimethylaminocarbonylmethyloxy, diethylaminocarbonylmethyloxy or N-ethyl-N-methylaminocarbonylmethyloxy group, preferably dimethylaminocarbonylmethyloxy group.

In the present invention, “(C ₂ -C ₇ carboxyalkyl) (C ₂ -C ₇ alkylcarbonyl) amino group” means one “C ₂ -C ₇ carboxyalkyl group” and one “C ₂ ”. The “—C ₇ alkylcarbonyl group” is a group bonded to an amino group. For example, N- (acetyl) -N- (carboxymethyl) amino, N- (acetyl) -N- (2-carboxyethyl) amino or N- (carboxymethyl) -N- (3,3-dimethylbutanoyl) Amino. Preferred is N- (carboxymethyl) -N- (3,3-dimethylbutanoyl) amino group.

In the present invention, _"C 3 -C ₆ cycloalkyl group which is one substituted with _C 2 -C ₇ carboxyalkyl _group", C 2 -C ₇ carboxyalkyl one substituted with are cyclopropyl group with a group, A cyclobutyl group, a cyclopentyl group or a cyclohexyl group; Preferred is a cyclohexyl group substituted by one C ₂ -C ₇ carboxyalkyl group.

  In the present invention, the “monocyclic heterocyclic group” contains 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, and may further contain 1 or 2 nitrogen atoms. A 4- to 7-membered monocyclic heterocyclic group to which oxygen atoms may be bonded. For example, furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, An “aromatic heterocyclic group” such as a pyrimidinyl or pyrazinyl group, or tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperidyl, piperazinyl, piperazyl, oxazolinyl, Oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, pyrazolidinyl, dioxolanyl, dioxani Or a 5,6-dihydro-4H-1,3 "partially or fully reduced forms saturated heterocyclic group" such as oxazine group. Preferred is a pyridyl group, tetrahydro-2H-pyranyl group or 3,6-dihydro-2H-pyranyl group, and more preferred are pyridin-4-yl group, pyridin-3-yl group, tetrahydro-2H- A pyran-4-yl group, a tetrahydro-2H-pyran-3-yl group or a 3,6-dihydro-2H-pyran-4-yl group, and even more preferably a pyridin-4-yl group or a tetrahydro- 2H-pyran-4-yl group.

  In the present invention, the “bicyclic heterocyclic group consisting of a 5-membered ring and a 5-membered ring” is a group in which two of the 5-membered monocyclic heterocycles are condensed. For example, thienofuranyl, imidazothiazolyl, pyrazolooxazolyl or 6,7-dihydro-5H-pyrrolo [1,2-a] imidazole group. Preferred is a 6,7-dihydro-5H-pyrrolo [1,2-a] imidazol-3-yl group.

  In the present invention, the “bicyclic heterocyclic group consisting of a 5-membered ring and a 6-membered ring” includes the 5-membered monocyclic heterocycle and the 6-membered monocyclic heterocycle or the 5-membered monocyclic heterocycle. This is a group in which the benzene ring is condensed. For example, benzothienyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isobenzofuranyl, indolizinyl, isoindolyl, indolyl group, 1H-pyrrolo [2,3-b] pyridyl or imidazo [1,2-a] pyridyl group . Preferably, it is a benzimidazol-6-yl group or an indol-5-yl group.

  In the present invention, the “bicyclic heterocyclic group consisting of a 6-membered ring and a 6-membered ring” means that the two 6-membered monocyclic heterocycles or the 6-membered monocyclic heterocycle and the benzene ring are condensed. It is a group. For example, chromenyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydroisoquinolyl, quinoxalyl, quinazolinyl or 3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine group. . Preferable is 3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl group.

  In the present invention, the “bicyclic heteroarylene group consisting of a 6-membered ring and a 6-membered ring” removes one hydrogen atom from the carbon atom of the “bicyclic heterocyclic group consisting of a 6-membered ring and a 6-membered ring”. Divalent group. A 1,2,3,4-tetrahydroisoquinolylene group, a quinoxarylene group or an isoquinolylene group is preferred, and a 1,2,3,4-tetrahydroisoquinolylene group or a quinoxarylene group is more preferred.

  In the present invention, the “1,4-phenylene group optionally substituted by 1 to 4 groups independently selected from the substituent group A” is selected from 1,4-phenylene or substituent group A. 1,4-phenylene group which is independently substituted with 1 to 4 groups. Preferred is a 1,4-phenylene group or a 1,4-phenylene group substituted by one methyl group or methoxy group, more preferably a group represented by the formula (III-I): A group represented by formula (III-II) and a group represented by formula (III-III).

In the present invention, “a bicyclic heteroarylene group consisting of a 6-membered ring and a 6-membered ring which may be independently substituted by 1 to 4 groups independently selected from the substituent group A” is a 6-membered ring and a 6-membered ring It is a bicyclic heteroarylene group consisting of a ring or a bicyclic heteroarylene group consisting of a 6-membered ring and a 6-membered ring independently substituted with 1 to 4 groups selected from the substituent group A. Preferable is 1,2,3,4-tetrahydroisoquinolylene group, quinoxarylene group, isoquinolylene group or 2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolylene group, and more preferable. In the present invention, the group represented by the formula (III-IV) or the group represented by the formula (III-V) is independently substituted with 1 to 4 groups independently selected from the substituent group B. which may _C 3 -C ₆ cycloalkyl group optionally _"does, C 3 -C ₆ cycloalkyl group or 1 to independently with a group selected from substituent group B is 4-substituted _C 3 -C ₆ A cycloalkyl group; Preferred is a cyclohexyl group in which a C ₁ -C ₆ hydroxyalkoxy group, a hydroxyl group, a carboxy group or a di- (C ₁ -C ₆ alkyl) aminocarbonylmethyloxy group is substituted at the 4-position, and more preferably , 4-hydroxycyclohexyl group.

In the present invention, “a C ₃ -C ₆ cycloalkyl group which is optionally substituted with a C ₂ -C ₇ carboxyalkyl group which may be independently substituted with 1 to 4 groups independently selected from the substituent group B. Are independently substituted with 1 to 4 C ₃ -C ₆ cycloalkyl groups substituted with a C ₂ -C ₇ carboxyalkyl group or a group selected from Substituent Group B and further substituted with C ₂ -C ₇ is a C ₃ -C ₆ cycloalkyl group substituted by one carboxyalkyl group. Preferred is a cyclohexyl group substituted with one C ₂ -C ₇ carboxyalkyl group, and more preferred is a 4-carboxymethylcyclohexyl group.

In the present invention, the “phenyl group optionally substituted by 1 to 4 groups independently selected from the substituent group B” refers to 1 to 4 groups independently selected from the phenyl group or the substituent group B. This is a phenyl group that is substituted. Preferably, morpholin-4-yl-3-phenyl group or a hydroxyl group, a carboxy _group, C 2 -C ₇ carboxyalkyl group, _mono--C 2 -C ₇ carboxyalkyl aminocarbonyl group or _(C 2 -C ₇ carboxyalkyl ) _(C 2 -C ₇ alkylcarbonyl) a phenyl group which amino group is substituted at 4, more suitably from morpholin-4-yl-3-phenyl or 4-hydroxyphenyl group.

  In the present invention, the “monocyclic heterocyclic group optionally substituted by 1 to 4 groups independently selected from the substituent group B” is selected from the monocyclic heterocyclic group or the substituent group B. A monocyclic heterocyclic group which is independently substituted with 1 to 4 groups. Preferably, pyridin-4-yl group, 6- (morpholin-4-ylmethyl) pyridin-3-yl group, tetrahydro-2H-pyran-4-yl group, tetrahydro-2H-pyran-3-yl group or 3 , 6-dihydro-2H-pyran-4-yl group, more preferably a pyridin-4-yl group or a tetrahydro-2H-pyran-4-yl group.

  In the present invention, “a bicyclic heterocyclic group composed of a 5-membered ring and a 5-membered ring which may be independently substituted with 1 to 4 groups independently selected from the substituent group B” is a 5-membered ring and a 5-membered ring. A bicyclic heterocyclic group consisting of a 5-membered ring and a 5-membered ring independently substituted with 1 to 4 groups independently selected from a group selected from the bicyclic heterocyclic group substituent group B consisting of a member ring. Preferred is a 6,7-dihydro-5H-pyrrolo [1,2-a] imidazol-3-yl group.

  In the present invention, “a bicyclic heterocyclic group composed of a 5-membered ring and a 6-membered ring which may be independently substituted by 1 to 4 groups selected from the substituent group B” is a 5-membered ring and a 6-membered ring. It is a bicyclic heterocyclic group consisting of a 5-membered ring and a 6-membered ring independently substituted with 1 to 4 groups independently of a bicyclic heterocyclic group consisting of a member ring or a group selected from the substituent group B. Preferred is a 1-methyl-1H-benzimidazol-6-yl group or a 2-carboxy-1-methyl-1H-indol-5-yl group.

  In the present invention, “a bicyclic heterocyclic group consisting of a 6-membered ring and a 6-membered ring which may be independently substituted with 1 to 4 groups independently selected from the substituent group B” means a 6-membered ring and a 6-membered ring. It is a bicyclic heterocyclic group consisting of a 6-membered ring and a 6-membered ring independently substituted with 1 to 4 groups independently of a bicyclic heterocyclic group consisting of a member ring or a group selected from the substituent group B. A 4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl group is preferred.

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

In the present invention, A is preferably a sulfinyl group or a sulfonyl group, and more preferably R ¹ is a sulfonyl group.

In the present invention, Q is preferably a nitrogen atom or a group represented by the formula = CH-.
In the present invention, preferred R ² is a hydrogen atom.
In the present invention, R ³ is preferably a hydrogen atom.

In the present invention, the preferred formula -U-T-a group represented the formula _-CH 2 -CH ₂ - is a group represented by.

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

In the present invention, Y is preferably an oxygen atom.
In the present invention, the preferred substituent group A is a methyl group, a methoxy group or an oxo group.

  In the present invention, preferred L is a group represented by the formula (III-I), a group represented by the formula (III-II), a group represented by the formula (III-III), a formula (III-IV) Or a group represented by the formula (III-V).

  In the present invention, a preferred substituent group B is a methyl group, a hydroxyl group, a carboxy group, or a (morpholin-4-yl) methyl group.

In the present invention, preferred E is a hydrogen atom, a C ₂ -C ₇ alkoxycarbonyl group or a group selected from a methyl group, a hydroxyl group, a carboxy group, and a (morpholin-4-yl) methyl group, independently 1 or 2 C ₃ -C ₆ cycloalkyl group which may be substituted, monocyclic heterocyclic group, bicyclic heterocyclic group consisting of 5-membered ring and 6-membered ring or bicyclic consisting of 6-membered ring and 6-membered ring More preferably E is a hydrogen atom, ethoxycarbonyl group, 4-hydroxycyclohexyl group, pyridin-4-yl group, 6- (morpholin-4-ylmethyl) pyridin-3-yl group, tetrahydro- 2H-pyran-4-yl group, tetrahydro-2H-pyran-3-yl group, 3,6-dihydro-2H-pyran-4-yl group, 2-carboxy-1-methyl-1H-indol-5-yl , 1-methyl -1H- benzimidazol-6-yl group or a 4-methyl-3,4-dihydro -2H- pyrido [3,2-b] [1,4] oxazin-7-yl group.

  In the present invention, preferable groups represented by the formula E-L- are 4-ethoxycarbonylphenyl group, 4- (4-hydroxycyclohexyl) phenyl, 4- (pyridin-4-yl) phenyl group, 3-methyl -4- [6- (morpholin-4-ylmethyl) pyridin-3-yl] phenyl group, 4- (tetrahydro-2H-pyran-4-yl) phenyl group, 3-methyl-4- (tetrahydro-2H-pyran -3-yl) phenyl group, 4- (3,6-dihydro-2H-pyran-4-yl) phenyl group, 3-methyl-4- (2-carboxy-1-methyl-1H-indol-5-yl) ) Phenyl group, 3-methoxy-4- (1-methyl-1H-benzimidazol-6-yl) phenyl group, 3-methyl-4- (4-methyl-3,4-dihydro-2H-pyrido [3, -b] [1,4] oxazin-7-yl) phenyl group, 2-methyl-3,4-dihydro-isoquinoline -1 (2H) - a one-6-yl group, or quinoxalin-6-yl group.

  In the invention, the preferred general formula (I) is the general formula (II).

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

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

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

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

  “Pharmaceutically acceptable salt thereof” refers to a salt that has no significant toxicity and can be used as a medicine. The compound represented by the general formula (I) of the present invention can be converted into a salt by reacting with an acid when it has a basic group, or by reacting with a base when it has an acidic group. can do.

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

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

  The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof can be left in the air or recrystallized to absorb moisture and have adsorbed water, It may become a hydrate, and such a hydrate is also included in the salt of the present invention.

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

  The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has a selective and excellent Th17 cell differentiation inhibitory action and IL-17 production inhibitory action, such as an autoimmune disease. It is useful for the treatment and / or prevention of diseases involving RORγt. Specific diseases include psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease, asthma or colon cancer. is there. A preferred disease is psoriasis. In addition, the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is expected to have an effect of selectively preventing and treating an abnormality of Th17 cells, which was impossible with existing treatment methods. The

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

  The solvent used in the reaction in each step of the following methods A to O is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, and is selected from the following solvent group, for example. Solvent groups include hydrocarbons such as pentane, hexane, octane, petroleum ether, ligroin, cyclohexane; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methyl Amides such as 2-pyrrolidinone and hexamethylphosphoric triamide; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, cyclopentyl methyl ether; methanol Ethanol, n-propanol, i-propanol, n-butanol, 2-butanol, 2-methyl-1-propanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, o Alcohols such as octanol, cyclohexanol, methyl cellosolve; sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane; nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ethyl formate, acetic acid Esters such as ethyl, propyl acetate, butyl acetate and diethyl carbonate; ketones such as acetone, methyl ethyl ketone, 4-methyl-2-pentanone, methyl isobutyl ketone, isophorone and cyclohexanone; nitro compounds such as nitroethane and nitrobenzene Halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, chloroform and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene and xylene Carboxylic acids such as acetic acid, formic acid, propionic acid, butyric acid, trifluoroacetic acid; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 2, 6-lutidine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N , N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [ 5.4.0] Undec-7-ene (DBU), amines such as piperidine; water; and , Consisting of a mixed solvent.

  The base used in the reaction in each step of the following methods A to O is, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate; sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate Alkali metal bicarbonates such as sodium acetate, potassium acetate, lithium acetate, alkali metal acetates such as cesium acetate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; Alkali metal hydroxides such as sodium, potassium hydroxide, barium hydroxide and lithium hydroxide; alkali metal phosphates such as sodium phosphate and potassium phosphate; L-proline sodium and L-proline potassium Alkali metal salts such as sodium fluoride and potassium fluoride Inorganic bases such as alkali metal fluorides; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium-t-butoxide, potassium-t-butoxide; sodium trimethylsiloxide, potassium trimethylsiloxide, lithium Alkali metal trialkylsiloxides such as trimethylsiloxide; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 2,6-lutidine, collidine, 4 -Pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-die Ruaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4. 0] Organic bases such as undec-7-ene (DBU); alkali metal amides such as lithium diisopropylamide, hexamethyldisilazane lithium and hexamethyldisilazane sodium; or amino acids such as proline.

  The condensing agent used in the reaction of each step of the following methods A to O is, for example, azodicarboxylic acid di-lower alkyl ester-triphenylphosphine such as azodicarboxylic acid diethyl ester-triphenylphosphine; 1-ethyl- Carbodiimide derivatives such as 3- (3-dimethylaminopropyl) carbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N′-dicyclohexylcarbodiimide; 2-chloro-1-methylpyridinium iodide 2-halo-1-lower alkylpyridinium halides such as diphenyl; phosphoryl chlorides such as diphenylphosphoryl azide; phosphoryl chlorides such as diethyl phosphoryl chloride; imidazoles such as N, N′-carbodiimidazole Conductor; O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, (1H-benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluoro A benzotriazole derivative such as phosphate; or a morpholinium chloride derivative such as 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride.

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

  In the reaction in each step of the following methods A to O, after completion of the reaction, each target compound is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, or remove insoluble matter by filtration, add water and an immiscible organic solvent such as ethyl acetate, and separate the organic layer containing the target compound, It can be obtained by washing with water, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., filtering, and then distilling off the solvent. If necessary, the obtained target compound can be prepared by a conventional method such as recrystallization, reprecipitation, chromatography (for example, silica gel, alumina, magnesium-silica gel type florisil, SO3H-silica (Fuji Silysia)). Adsorption column chromatography method; using a carrier such as Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and Haas), Diaion HP-20 (Mitsubishi Chemical) A method using a synthetic adsorbent such as distributed column chromatography; a method using ion exchange chromatography; a normal phase / reverse phase column chromatography method (preferably high performance liquid chromatography) using silica gel or alkylated silica gel Usually combined with a suitable eluent) Combining the conventional methods in the separation and purification as appropriate, can be separated and purified. For a target compound insoluble in a solvent, the obtained solid crude product can be purified by washing with a solvent. In addition, the target compound in each step can be directly used in the next reaction without purification.

In the reaction of each step of the following methods A to O, R ¹ , A, Q, R ² , R ³ , R ⁴ , Y and L have the same meaning as described above. E ¹ represents a hydrogen atom, a C ₁ -C ₆ halogenated alkyl group, a C ₂ -C ₇ alkoxycarbonyl group, a mono-C ₁ -C ₆ alkylaminocarbonyl group, di- (C ₁ -C ₆ alkyl) aminocarbonyl A group or a (C ₂ -C ₇ alkoxycarbonyl)-(C ₂ -C ₆ alkenyl) group, E ² may be independently substituted with 1 to 4 groups independently selected from the substituent group B C ₃ -C ₆ cycloalkyl _group, C 2 -C ₇ carboxyalkyl _C 3 -C ₆ cycloalkyl group which is one substituted with an alkyl group, a phenyl group, a monocyclic heterocyclic group, 5-membered ring and a 5-membered ring A bicyclic heterocyclic group consisting of or a bicyclic heterocyclic group consisting of a 5-membered ring and a 6-membered ring or a bicyclic heterocyclic group consisting of a 6-membered ring and a 6-membered ring. R ^3a represents a group similar to the group in the definition of the group R ³ except that the hydroxy group and / or carboxy group contained in the group R ³ may be a protected hydroxy group and / or carboxy group. E ^2a represents a hydroxy group and / or carboxy group in which the hydroxy group and / or carboxy group contained in the E ² group may be protected. R ⁵ represents a C ₁ -C ₆ alkyl group or a benzyl group. X ¹ , X ² , X ³ , X ⁴ and X ⁵ represent a halogen atom or a trifluoromethanesulfonyl group. When X ¹ is a bromine atom or an iodine atom, X ² is preferably a chlorine atom or a bromine atom. X ³ is preferably a bromine atom or an iodine atom, and more preferably an iodine atom. X ⁴ is preferably a bromine atom, an iodine atom or a trifluoromethanesulfonyl group. Tf represents a trifluoromethanesulfonyl group.

A method, in the compounds represented by formula (I), the group represented by the formula -U-T-has the formula _-CH 2 -CH ₂ - or a group represented by, E is ^{E 1} This is a method for producing a compound represented by the general formula (Ia).
(Method A)

Step A-I This step is a step for producing a salt of the compound represented by the general formula (V) by reacting the compound represented by the general formula (IV) with an acid in a solvent.
The solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
The acid used in this step is preferably acetic acid or protonic acid, and more preferably 1,4-dioxane solution of trifluoroacetic acid or hydrochloric acid. The salt of the compound represented by general formula (V) shows the case where hydrochloric acid is used.
The reaction temperature in this step is usually −10 ° C. to 50 ° C., preferably 0 ° C. to 30 ° C.
The reaction time in this step is usually 1 minute to 24 hours, preferably 10 minutes to 6 hours.

Step A-II In this step, the salt of the compound represented by the general formula (V) was reacted with the compound represented by the general formula (VI) or a salt thereof in the presence of a condensing agent and a base in a solvent. Thereafter, the hydroxy group and / or the carboxy-protecting group in R ^3a is removed as desired to produce a compound represented by the general formula (Ia).
The salt of the compound represented by the general formula (VI) used in this step is, for example, an alkali metal salt, an organic base salt or an ammonium salt, and preferably a sodium salt.
The solvent used in this step is preferably an amide, ether, nitrile or halogenated hydrocarbon, and more preferably N, N-dimethylformamide.
The condensing agent used in this step is preferably 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N′-dicyclohexylcarbodiimide or 4- (4,6-dimethoxy-1, 3,5-Triazin-2-yl) -4-methylmorpholinium chloride.
The base used in this step is preferably an organic base, and more preferably N-methylmorpholine, triethylamine or diisopropylethylamine.
The reaction temperature in this step is usually 0 ° C. to 60 ° C., preferably 10 ° C. to 30 ° C.
The reaction time in this step is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours.

Method B, among the compounds represented by formula (I), the group represented by the formula -U-T-has the formula _-CH 2 -CH ₂ - or a group represented by, E is ^{E 2} This is a method for producing a compound represented by the general formula (Ib).
(Method B)

Step B-I This step is carried out in the same manner as step A-I in Method A by reacting a compound represented by general formula (VII) with an acid in a solvent, and is represented by general formula (VIII). A step of producing a salt of the compound to be prepared. The salt of the compound represented by the general formula (VIII) shows the case where hydrochloric acid is used.

Step B-II In this step, the salt of the compound represented by the general formula (VIII) is reacted with the compound represented by the general formula (VI) or a salt thereof in a solvent in the presence of a condensing agent and a base. Is a step for producing a compound represented by the general formula (IX), which is carried out in the same manner as in Step A-II of Method A.

Step B-III In this step, the compound represented by the general formula (IX) is reacted with the compound represented by the general formula (X) in the presence of a palladium catalyst and a base in a solvent, and then optionally R ^{In this step,} the hydroxy group and / or the carboxy protecting group in ^3a and / or E ^2a is removed to produce the compound represented by the general formula (Ib).
The solvent used in this step is preferably an ether or an aromatic hydrocarbon, and more preferably 1,2-dimethoxyethane or toluene.
The palladium catalyst used in this step is preferably tetrakis (triphenylphosphine) palladium (0), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane 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, an aqueous sodium carbonate solution, potassium phosphate or an aqueous potassium phosphate solution.
The reaction temperature in this step is usually room temperature to 200 ° C, preferably 50 ° C to 130 ° C.
The reaction time in this step is usually 5 minutes to 24 hours, preferably 20 minutes to 15 hours.
This step can be performed under microwave irradiation.

C method, in the compounds represented by formula (I), the group represented by the formula -U-T-has the formula _-CH 2 -CH ₂ - or a group represented by, E is ^{E 2} This is a method for producing a compound represented by the general formula (Ib).
(Method C)

Step CI This step is represented by the general formula (XII) by reacting the compound represented by the general formula (IX) with the compound (XI) in the presence of a palladium catalyst and a base in a solvent. This is a process for producing a compound.
This process is described in J. Org. Org. Chem. It can implement according to the method described in 1995,60,7508.

Step C-II In this step, the compound represented by the general formula (XII) is reacted with the compound represented by the general formula (XIII) in a solvent in the presence of a palladium catalyst and a base to After carrying out similarly to B-III process, the compound represented by general formula (Ib) is manufactured by removing the protective group of the hydroxy group and / or carboxy group in R < ^3a > and / or E < ^2a > if desired. It is a process.

D method, in the compounds represented by formula (I), the group represented by the formula -U-T-has the formula _-CH 2 -CH ₂ - or a group represented by, E is ^{E 2} This is a method for producing a compound represented by the general formula (Ib).
(Method D)

Step DI This step involves reacting a compound represented by general formula (VII) with a compound represented by general formula (X) in a solvent in the presence of a palladium catalyst and a base. This step is carried out in the same manner as in step B-III, and is a step for producing a compound represented by general formula (XIV).

Step D-II This step is performed in the same manner as Step A-I in Method A by reacting a compound represented by the general formula (XIV) with an acid in a solvent, and represented by the general formula (XV). A step of producing a salt of the compound to be prepared. The salt of the compound represented by general formula (XV) shows the case where hydrochloric acid is used as an acid.

Step D-III This step comprises reacting a salt of a compound represented by the general formula (XV) with a compound represented by the general formula (VI) or a salt thereof in a solvent in the presence of a base. After carrying out in the same manner as in step A-II of the method, the compound represented by the general formula (Ib) is removed by removing the protective group for the hydroxy group and / or carboxy group in R ^3a and / or E ^{2a as} desired. It is a manufacturing process.

E method, in the compounds represented by formula (I), a group a group of the formula -U-T-is represented by the formula -CH = CH-, E is a ^{E 1} This is a method for producing a compound represented by the general formula (Ic).
(E method)

Step EI This step is a step for producing the compound represented by the general formula (Ic) by reacting the compound represented by the general formula (Ia) with an oxidizing agent in a solvent.
The compound represented by the general formula (Ia) used in this step can be produced using Method A.
The solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane or chloroform.
The oxidizing agent used in this step is preferably 2,3-dichloro-5,6-dicyano-p-benzoquinone.
The reaction temperature in this step is room temperature to heating reflux temperature, and the heating reflux temperature varies depending on the solvent. Usually, it is 5 ° C to 150 ° C, preferably 10 ° C to 70 ° C.
The reaction time in this step is usually 30 minutes to 72 hours, preferably 1 hour to 24 hours.

Method F, among the compounds represented by formula (I), a group a group of the formula -U-T-is represented by the formula -CH = CH-, E is a ^{E 2} This is a method for producing a compound represented by the general formula (Id).
(F method)

Step FI This step is carried out in the same manner as Step EI of Method E by reacting a compound represented by the general formula (Ib) with an oxidizing agent in a solvent. It is a process for producing the represented compound.
The compound represented by the general formula (Ib) used in this step can be produced using Method B to Method D.

Method G is a method for producing a compound represented by the general formula (XX) in which Y is a methylene group among the compounds represented by the general formula (IV) used in the AI step of Method A.
(G method)

Step GI In this step, a compound represented by the general formula (XVII) is reacted with a trifluoromethanesulfonylating agent in a solvent in the presence of a base in the presence of a base. It is a manufacturing process.
The solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
The base used in this step is preferably an organic base, and more preferably pyridine.
The trifluoromethanesulfonylating agent used in this step is preferably a trifluoromethanesulfonyl compound, and more preferably trifluoromethanesulfonic anhydride.
The reaction temperature in this step is usually −20 ° C. to 50 ° C., preferably 0 ° C. to 20 ° C.
The reaction time in this step is usually 1 minute to 24 hours, preferably 10 minutes to 6 hours.

Step G-II This step is the same as Step C-I in Method C by reacting the compound represented by formula (XVII) with compound (XI) in the presence of a palladium catalyst and a base in a solvent. And a step for producing a compound represented by the general formula (XVIII).

  The solvent used in this step is preferably an amide, ether, sulfoxide or a mixed solvent thereof, and more preferably a mixed solvent of dimethoxyethane and dimethyl sulfoxide.

Step G-III In this step, the compound represented by the general formula (XVIII) is reacted with the compound represented by the general formula (XIX) in a solvent in the presence of a palladium catalyst and a base, This step is performed in the same manner as in step B-III, and is a step for producing a compound represented by general formula (XX).

The method H is represented by the general formula (XXII) in which Y is a methylene group among the compounds represented by the general formula (VII) used in the BI step of the B method and the DI step of the D method. A method for producing a compound.
(Method H)

Step HI In this step, the compound represented by the general formula (XVIII) is reacted with the compound represented by the general formula (XXI) in the presence of a palladium catalyst and a base in a solvent, thereby This step is carried out in the same manner as in step B-III, and is a step for producing a compound represented by general formula (XXII).

Method I is a method for producing a compound represented by the general formula (XXV) in which Y is an oxygen atom among the compounds represented by the general formula (IV) used in the AI step of Method A.
(Method I)

Step II In this step, the compound represented by the general formula (XVI) is reacted with the compound represented by the general formula (XXIV) in the presence of a copper catalyst, a promoter and a base in a solvent. In this step, the compound represented by the general formula (XXV) is produced.
The solvent used in this step is preferably an amide or an ether, and more preferably N, N-dimethylformamide or 1,4-dioxane.
The copper catalyst used in this step is preferably copper (I) iodide.
The cocatalyst used in this step is preferably N, N-dimethylglycine.
The base used in this step is preferably an alkali metal carbonate, and more preferably cesium carbonate.
The reaction temperature in this step is usually 50 ° C. to 150 ° C., preferably 80 ° C. to 110 ° C.
The reaction time in this step is usually 3 hours to 72 hours, preferably 12 hours to 48 hours.
Further, this step is represented by the general formula (XXV) by reacting the compound represented by the general formula (XVI) with the compound represented by the general formula (XXIV) in the presence of a base in a solvent. This is a process for producing a compound.
The solvent used in this step is preferably an amide or an ether, and more preferably N, N-dimethylformamide or 1,4-dioxane.
The base used in this step is preferably an alkali metal carbonate, and more preferably cesium carbonate.
The reaction temperature in this step is usually 50 ° C. to 200 ° C., preferably 80 ° C. to 160 ° C.
The reaction time in this step is usually 3 hours to 72 hours, preferably 12 hours to 48 hours.
This step can be performed under microwave irradiation. The reaction time at that time is usually 10 minutes to 3 hours, preferably 15 minutes to 90 minutes.

The method J is represented by the general formula (XXVII) in which Y is an oxygen atom among the compounds represented by the general formula (VII) used in the BI step of the B method and the DI step of the D method. A method for producing a compound.
(J method)

Step JI In this step, the compound represented by the general formula (XVI) is reacted with the compound represented by the general formula (XXVI) in the presence of a copper catalyst, a promoter and a base in a solvent. This is a process for producing a compound represented by the general formula (XXVII), which is carried out in the same manner as in the II process of Method I.
Further, in this step, by reacting the compound represented by the general formula (XVI) with the compound represented by the general formula (XXVI) in the presence of a base in a solvent, This is the same step for producing a compound represented by the general formula (XXVII).

Method K is a method for producing a compound represented by the general formula (XXIX) in which Y is an oxygen atom among the compounds represented by the general formula (XIV) used in the D-II step of Method D.
(K method)

Step KI In this step, the compound represented by the general formula (X) is reacted with the compound represented by the general formula (XXVI) in the presence of a palladium catalyst and a base in a solvent. This is a step for producing a compound represented by the general formula (XXVIII), which is carried out in the same manner as in the step B-III.

Step K-II In this step, the compound represented by the general formula (XXVIII) is reacted with the compound represented by the general formula (XVI) in the presence of a copper catalyst, a promoter and a base in a solvent. This is a step for producing a compound represented by the general formula (XXIX), which is carried out in the same manner as in step II of Method I.
Further, in this step, the compound represented by the general formula (XXVIII) is reacted with the compound represented by the general formula (XVI) in the presence of a base in a solvent, thereby allowing the steps I to I of Method I to be performed. This is the same step for producing a compound represented by the general formula (XXIX).

Method L is a compound represented by the general formula (VI) or a salt thereof used in Step A-II of Method A, Step B-II of Method B, and Step D-III of Method D, wherein A is a sulfonyl group. This is a method for producing a compound represented by the general formula (XXXIII) or a salt thereof.
(L method)

Step LI In this step, the compound represented by the general formula (XXX) is reacted with the compound represented by the general formula (XXXI) in the presence of a copper catalyst and a base in a solvent, thereby reacting with the general formula (XXXI). XXXII) is a process for producing a compound represented by
The solvent used in this step is preferably an amide or sulfoxide, and more preferably N, N-dimethylformamide or dimethyl sulfoxide.
The copper catalyst used in this step is preferably copper (I) iodide.
The base used in this step is preferably an alkali metal salt of L-proline, and more preferably sodium L-proline.
The reaction temperature in this step is usually 50 ° C. to 150 ° C., preferably 70 ° C. to 110 ° C.
The reaction time in this step is usually 10 minutes to 48 hours, preferably 30 minutes to 12 hours.

Step L-II This step is a step for producing a compound represented by the general formula (XXXIII) by reacting a compound represented by the general formula (XXXII) with a base in a solvent.
The solvent used in this step is preferably an ether, an alcohol or a mixed solvent thereof, more preferably a mixed solvent of tetrahydrofuran and methanol or a mixed solvent of tetrahydrofuran and ethanol.
The base used in this step is preferably an alkali metal hydroxide, and more preferably sodium hydroxide, an aqueous sodium hydroxide solution, lithium hydroxide or an aqueous lithium hydroxide solution.
The reaction temperature in this step is usually 0 ° C. to 80 ° C., preferably 15 ° C. to 45 ° C.
The reaction time in this step is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
The salt of the compound represented by the general formula (XXXIII) is collected from the basic reaction mixture after completion of the reaction. The salt collected depends on the base used in the reaction.

Method M is a compound represented by the general formula (VI) or a salt thereof used in Step A-II of Method A, Step B-II of Method B and Step D-III of Method D, wherein A is a sulfonyl group And R ^3a is a hydrogen atom, and a method for producing a compound represented by the general formula (XXXVIII) or a salt thereof.
(M method)

Step M-I In this step, the compound represented by the general formula (XXXIV) is reacted with the compound represented by the general formula (XXXV) in the presence of a base in a solvent to form the compound represented by the general formula (XXXVI). It is a process for producing the represented compound.
The solvent used in this step is preferably an amide or sulfoxide, and more preferably dimethyl sulfoxide.
The base used in this step is preferably an inorganic base, more preferably an alkali metal carbonate, and even more preferably cesium carbonate.
The reaction temperature in this step is usually 30 ° C to 200 ° C, preferably 80 ° C to 120 ° C.
The reaction time in this step is usually 1 hour to 24 hours, preferably 5 hours to 10 hours.

Step M-II In this step, the compound represented by the general formula (XXXVI) is reacted with the compound represented by the general formula (XXXI) in a solvent in the presence of a copper catalyst and a base. This is a process for producing a compound represented by the general formula (XXXVII), which is carried out in the same manner as in the LI process.

Step M-III This step is performed in the same manner as step L-II of Method L by reacting a compound represented by general formula (XXXVII) with a base in a solvent, and is represented by general formula (XXXVIII). The process of manufacturing the compound or its salt.
The salt of the compound represented by the general formula (XXXVIII) is collected from the basic reaction mixture after completion of the reaction. The salt collected depends on the base used in the reaction.
In the case where R ⁵ is a benzyl group, this step is carried out by reacting a compound represented by the general formula (XXXVII) in a solvent in the presence of a palladium catalyst in a hydrogen atmosphere to represent the general formula (XXXVIII). This is a process for producing a compound to be produced.
The solvent used in this step is preferably an ether, alcohol, 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 preferably palladium-carbon.
The reaction temperature in this step is usually 0 ° C. to 80 ° C., preferably room temperature to 50 ° C.
The reaction time in this step is usually 10 minutes to 60 hours, preferably 1 hour to 24 hours.
In addition, when one of the two R ⁵ groups is a tert-butyl group, in this step, after reacting the compound represented by the general formula (XXXVII) with an acid in a solvent, This reaction is a step for producing a compound represented by the general formula (XXXVIII) or a salt thereof, which is carried out in the same manner as in the L-II step of Method L.
The solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
The acid used in this step is preferably trifluoroacetic acid.
The reaction temperature in this step is usually −10 ° C. to 100 ° C., preferably 0 ° C. to 30 ° C.
The reaction time in this step is usually 1 minute to 24 hours, preferably 1 hour to 8 hours.

Method N is a method for producing a compound represented by the general formula (XXXVII) used in Step M-III of Method M.
(N method)

Step N-I This step involves reacting a compound represented by the general formula (XXXIX) with a compound represented by the general formula (XXXV) in the presence of a base, a copper catalyst and a cocatalyst in a solvent. In this step, the compound represented by the general formula (XXXVII) is produced.
The solvent used in this step is preferably an amide, ether or sulfoxide, and more preferably 1,4-dioxane.
The base used in this step is preferably an inorganic base, more preferably an alkali metal carbonate, and even more preferably cesium carbonate.
The copper catalyst used in this step is preferably copper (I) iodide or copper (I) chloride.
The cocatalyst used in this step is preferably picolinic acid.
The reaction temperature in this step is usually 30 ° C to 200 ° C, preferably 80 ° C to 120 ° C.
The reaction time in this step is usually 1 hour to 24 hours, preferably 5 hours to 12 hours.

Method O is a compound represented by the general formula (VI) or a salt thereof used in Step A-II of Method A, Step B-II of Method B and Step D-III of Method D, wherein A is a sulfonyl group This is a method for producing a compound represented by the general formula (XXXIII) or a salt thereof.
(O method)

Step O-I In this step, the compound represented by the general formula (XL) is reacted with the compound represented by the general formula (XXXI) in the presence of a copper catalyst and a base in a solvent. XXXIII) is a process for producing a compound represented by
The solvent used in this step is preferably an amide or sulfoxide, and more preferably N, N-dimethylformamide or dimethyl sulfoxide.
The copper catalyst used in this step is preferably copper (I) iodide.
The base used in this step is preferably an alkali metal hydroxide, and more preferably sodium hydroxide or an aqueous sodium hydroxide solution.
The reaction temperature in this step is usually 50 ° C. to 150 ° C., preferably 70 ° C. to 110 ° C.
The reaction time in this step is usually 10 minutes to 48 hours, preferably 30 minutes to 12 hours.
Formulas (IV), (VI), (VII), (X), (XIII), (XVI), (XIX), (XXI), (XXIV), (XXVI), (XXX), (XXXI), The compounds represented by (XXXIV), (XXXV), (XXXIX), and (XL) are known compounds, or can be easily produced according to a known method or a similar method using a known compound as a starting material.

In the above, the protecting group of “optionally protected hydroxy group and / or carboxy group” in the definition of R ^3a and E ^a is a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis. A protecting group that can be cleaved, and indicates a protecting group commonly used in organic synthetic chemistry (see, for example, TW Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)). .

In the above, the “protecting group” of the hydroxy group that may be protected is not particularly limited as long as it is a protecting group of a hydroxy group used in the field of synthetic organic chemistry. For example, the formyl group, the “C ₂ — C ₇ alkylcarbonyl group ”, C ₂ -C ₇ halogenated alkylcarbonyl group such as 2,2,2-trichloroethylcarbonyl, alkoxyalkylcarbonyl group such as methoxyacetyl, acryloyl, propioroyl, methacryloyl, crotonoyl, isocrotonoyl, (E) an “alkylcarbonyl group” such as an unsaturated alkylcarbonyl group such as 2-methyl-2-butenoyl; an arylcarbonyl group such as benzoyl, α-naphthoyl, β-naphthoyl, 2-bromobenzoyl, 4- Halogenated arylcarbos such as chlorobenzoyl Group, 2,4,6-trimethylbenzoyl, _C 1 -C ₆ alkylated arylcarbonyl groups such as 4-toluoyl, _4-C 1 -C ₆ alkoxylated arylcarbonyl groups such as anisoyl, 4-nitrobenzoyl 2-nitro-benzo nitrated arylcarbonyl group such as yl, 2- (methoxycarbonyl) C ₂ -C ₇ alkoxycarbonyl arylcarbonyl group such as benzoyl, etc. arylated arylcarbonyl group such as 4-phenylbenzoyl “Arylcarbonyl group”; C ₂ -C ₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, halogen such as 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, or tri- (C ₁ -C ₆ alkyl) silyl group "Alkoxycarbonyl groups" such as substituted _C 2 -C ₇ alkoxycarbonyl group; tetrahydropyran-2-yl, 3-bromo-tetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran - “Tetrahydropyranyl or tetrahydrothiopyranyl group” such as 2-yl, 4-methoxytetrahydrothiopyran-4-yl; “tetrahydrofuranyl or tetrahydro such as tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl” thiofuranyl group "; trimethylsilyl, triethylsilyl, isopropyl dimethylsilyl, t- butyl dimethylsilyl, methyl diisopropylsilyl, methyldi -t- butylsilyl, tri as triisopropylsilyl - _(C 1 -C ₆ alkyl) System Group, diphenylmethyl silyl, diphenyl butylsilyl, diphenyl isopropylsilyl, such as phenyl diisopropylsilyl (C ₁ -C ₆ alkyl) diarylsilyl or di - (C ₁ -C ₆ alkyl) "silyl group such as an aryl silyl group A (C ₁ -C ₆ alkoxy) methyl group such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, 2-methoxy such as ethoxymethyl _(C 1 -C ₆ alkoxy) - _(C 1 -C ₆ alkoxy) methyl group, 2,2,2-trichloroethoxymethyl, such as bis (2-chloroethoxy) methyl _{(C 1} - “Alkoxymethyl groups” such as C ₆ halogenated alkoxy) methyl; “Substituted ethyl groups” such as toxiethyl, (C ₁ -C ₆ alkoxy) ethyl groups such as 1- (isopropoxy) ethyl, and halogenated ethyl groups such as 2,2,2-trichloroethyl; benzyl, α- A C ₁ -C ₆ alkyl group substituted with 1 to 3 aryl groups such as naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, 4- Methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4- bromobenzyl, _4-cyano-C 1 -C ₆ alkyl such as _benzyl, C 1 -C ₆ alkoxy, nitro Halogen, "aralkyl group" such as C ₁ -C ₆ alkyl radicals in which an aryl ring is substituted with 1 to 3 aryl groups substituted with a cyano group; vinyloxycarbonyl, "alkenyloxycarbonyl such as allyloxycarbonyl group "; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl oxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitro such as benzyloxycarbonyl, 1 or 2 _C 1 -C ₆ An “aralkyloxycarbonyl group” in which an aryl ring may be substituted with an alkoxy or nitro group, preferably an alkylcarbonyl group, a silyl group or an aralkyl group.

In the above, the “protecting group” of the carboxy group which may be protected is not particularly limited as long as it is a protecting group of the carboxy group used in the field of synthetic organic chemistry. For example, the “C ₁ -C ₆ alkyl” group "; vinyl, _C 2 -C ₆ alkenyl groups such as allyl; ethynyl, 1-propynyl, 2-propynyl, 1-methyl-2-propynyl, _C 2 -C ₆ alkynyl groups such as 1-butynyl, wherein A “C ₁ -C ₆ halogenated alkyl group”; the “C ₁ -C ₆ hydroxyalkyl group”; a (C ₂ -C ₇ alkylcarbonyl)-(C ₁ -C ₆ alkyl) group such as acetylmethyl; An “aralkyl group”; or the above-mentioned “silyl group”, preferably a C ₁ -C ₆ alkyl group or an aralkyl group.

  Processes that require protection and deprotection are known methods (for example, the method described in “Protective Groups in Organic Synthesis” (Theodora W. Greene, Peter GMWuts, 1999, published by Wiley-Interscience Publication)). It is done accordingly.

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

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

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

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

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

  Moreover, a coloring agent, a preservative, a fragrance | flavor, a flavoring agent, a sweetening agent, etc. can also be included in said formulation as needed, and also other pharmaceuticals can be included.

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

  The amount used varies depending on the symptoms, age, etc. of the patient (warm-blooded animal, especially human), but in the case of oral administration, the lower limit is 0.001 mg / kg body weight (preferably 0.01 mg / kg) per dose. Body weight), the upper limit is 500 mg / kg body weight (preferably 50 mg / kg body weight), and in the case of intravenous administration, the lower limit is 0.005 mg / kg body weight (preferably 0.05 mg / kg). It is desirable to administer 50 mg / kg body weight (preferably 5 mg / kg body weight) as an upper limit, once or several times per day, depending on the symptoms.

  EXAMPLES Hereinafter, although an Example and a test example are given and this invention is demonstrated further in detail, the scope of the present invention is not limited to these.

In the examples, elution in column chromatography was performed under observation by TLC (Thin Layer Chromatography). In TLC observation, silica gel 60F ₂₅₄ manufactured by Merck was used as a TLC plate, a solvent used as an elution solvent in column chromatography was used as a developing solvent, and a UV detector was used as a detection method. Silica gel for the column is Merck silica gel SK-85 (230-400 mesh), Yamazen silica gel (Hi-Flash ^™ Column, INJECT COLUMN ^™ ), Biotage silica gel (SNAP, SNAP Ultra) or Fuji Silica gel (FL100B, Chromatorex-SO3H) manufactured by Silysia Chemical Ltd. was used. In addition to normal column chromatography, Yamazen's automated chromatography device (YFLC-5405-FC-GRII, W-Prep 2XY) and Biotage's automated chromatography device (Isolera, SP-1) are used as appropriate. did. The abbreviations used in the examples have the following significance.
mg: milligram, g: gram, mL: milliliter, MHz: megahertz, Hz: hertz

In the following examples, nuclear magnetic resonance (hereinafter, ¹ H-NMR) spectra are described with chemical shift values in terms of δ values (ppm) using tetramethylsilane as a standard substance. As the measurement solvent, CDCl ₃ : deuterated chloroform, MeOH-d ₄ : deuterated methanol or DMSO-d ₆ : deuterated dimethyl sulfoxide was used. The split pattern is s for single line, d for double line, t for triple line, q for quadruple line, quint for quintet line, sext for hexan line, hept for heptet, m for multiple line, broad for br It showed in.

  Mass spectrometry (hereinafter referred to as MS) was performed by APCI (Atmospheric Pressure Chemical Ionization) method, FAB (Fast Atom Bombardment) method, EI (Electron Ionization) method, or ESI (Electron Spray Ionization) method. For some measurements, a model that automatically uses ESI and APCI as the ionization method was used.

Example 1
1- (4-Methyl-5-{[3 '-(morpholin-4-yl) biphenyl-4-yl] oxy} -2,3-dihydro-1H-indol-1-yl) -2- [2- (Methylsulfonyl) phenyl] ethanone

Example 1a tert-Butyl 5- (4-Bromophenoxy) -4-methyl-2,3-dihydro-1H-indole-1-carboxylate Known (International Publication No. WO2007 / 129745) tert-Butyl 5- To a solution of hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylate (10.0 g) and 1-bromo-4-iodobenzene (13.6 g) in dioxane (150 mL) Copper (I) chloride (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 saturated aqueous sodium hydrogen carbonate solution (30 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was washed with hexane, collected by filtration and dried to give the title compound (12.8 g) as a white solid.
¹ H-NMR (400 MHz, 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).

Example 1b 1- [5- (4-Bromophenoxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone To a solution of the compound obtained in 1a (12.8 g) in dichloromethane (10 mL) was added 4N hydrochloric acid dioxane solution (20 mL), and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure and dried under reduced pressure to give crude 5- (4-bromophenoxy) -4-methyl-2,3-dihydro-1H-indole hydrochloride (11.0 g) as a gray solid. Obtained.
Triethylamine (8.9 mL) was added to a solution of the obtained compound (11.0 g) in N, N-dimethylformamide (30 mL), and the mixture was stirred at room temperature for 5 minutes. 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (13.3 g) and 2- (2-methylsulfonylphenyl) acetic acid (8.27) g) was added, and the mixture was further stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, water (100 mL) was added, and the precipitated solid was collected by filtration. The obtained solid was washed with hexane to obtain the title compound (15.2 g) as a light brown solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.03 (3H, s), 3.13-3.22 (5H, m), 4.28 (2H, t, J = 8.5 Hz), 4.33 (2H, s), 6.77-6.85 (3H, m), 7.44-7.51 (3H, m), 7.52-7.62 (1H, m), 7.65-7.74 (1H, m), 7.87 (1H, d, J = 8.5 Hz), 7.97 ( (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 500, 502 (M + H) ⁺ .

Example 1c 1- (4-Methyl-5-{[3 ′-(morpholin-4-yl) biphenyl-4-yl] oxy} -2,3-dihydro-1H-indol-1-yl)- 2- [2- (Methylsulfonyl) phenyl] ethanone Compound (80.0 mg) obtained in Example 1b, 1,2-dimethoxyethane (3 mL) of 3- (morpholino) phenylboronic acid (463 mg) To the solution was added an aqueous solution (1 mL) of sodium carbonate (50.8 mg), and the mixture was stirred at room temperature for 5 minutes. [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (13.1 mg) was added, and the mixture was reacted at 130 ° C. for 1 hour in a microwave reactor. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (69.8 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.15 (3H, s), 3.13 (3H, s), 3.16-3.29 (6H, m), 3.88 (4H, t, J = 4.9 Hz), 4.30 ( 2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.83 (1H, d, J = 8.5 Hz), 6.85-6.98 (3H, m), 7.02-7.11 (2H, m), 7.31-7.38 (2H, m), 7.45-7.56 (3H, m), 7.60-7.64 (1H, m), 8.00 (1H, d, J = 8.5 Hz), 8.08 (1H, t, J = 7.9 Hz).
MS (APCI) m / z: 583 (M + H) ⁺ .

(Example 2)
1- {4-Methyl-5- [4- (pyridin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone

A solution of the compound obtained in Example 1b (50.0 mg) and 4-pyridineboronic acid (18.4 mg) in 1,2-dimethoxyethane (2 mL) in an aqueous solution of sodium carbonate (31.8 mg) ( 1 mL) was added and stirred at room temperature for 5 minutes. [1,1′-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (8.2 mg) was added and reacted at 130 ° C. for 1 hour in a microwave reactor. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (26.7 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.13 (3H, s), 3.13 (3H, s), 3.24 (2H, t, J = 8.5 Hz), 4.31 (2H, t, J = 8.5 Hz) , 4.38 (2H, s), 6.86 (1H, d, J = 8.5 Hz), 6.97-7.01 (2H, m), 7.37 (1H, d, J = 7.3 Hz), 7.50-7.67 (6H, m), 8.03 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz), 8.62-8.65 (2H, m).
MS (APCI) m / z: 499 (M + H) ⁺ .

(Example 3)
1- {5- [4- (3,6-dihydro-2H-pyran-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (Methylsulfonyl) phenyl] ethanone

Sodium carbonate was added to a solution of the compound obtained in Example 1b (50.0 mg) and 3,6-dihydro-2H-pyran-4-boronic acid (31.5 mg) in 1,2-dimethoxyethane (2 mL). (31.8 mg) in water (1 mL) was added and stirred at room temperature for 5 minutes. [1,1′-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (8.2 mg) was added and reacted at 130 ° C. for 40 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (37.7 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.12 (3H, s), 2.45-2.53 (2H, br m), 3.12 (3H, s), 3.15-3.26 (2H, m), 3.93 (2H, t, J = 5.5 Hz), 4.25-4.34 (4H, m), 4.37 (2H, s), 6.04 (1H, s), 6.79 (1H, d, J = 8.5 Hz), 6.84 (2H, d, J = 9.2 Hz), 7.31 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.52 (1H, t, J = 7.3 Hz), 7.62 (1H, t, J = 7.3 Hz), 7.98 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 504 (M + H) ⁺ .

Example 4
1- {4-Methyl-5- [4- (2-methylpyridin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl ] Ethanon

Sodium carbonate (31.8 mg) was added to a solution of the compound obtained in Example 1b (50.0 mg) and 4-picoline-4-boronic acid (20.5 mg) in 1,2-dimethoxyethane (2 mL). Aqueous solution (1 mL) was added and stirred at room temperature for 5 minutes. [1,1′-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (8.2 mg) was added and reacted at 130 ° C. for 40 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (25.0 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.13 (3H, s), 2.61 (3H, s), 3.13 (3H, s), 3.24 (2H, t, J = 8.5 Hz), 4.31 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.85 (1H, d, J = 8.5 Hz), 6.93-7.00 (2H, m), 7.25-7.28 (1H, br m), 7.33 (1H, s), 7.37 (1H, d, J = 8.5 Hz), 7.50-7.58 (3H, m), 7.62 (1H, t, J = 7.9 Hz), 8.02 (1H, d, J = 9.2 Hz), 8.08 ( 1H, d, J = 7.9 Hz), 8.51 (1H, d, J = 9.2 Hz).
MS (APCI) m / z: 513 (M + H) ⁺ .

(Example 5)
1- {5-[(4′-hydroxybiphenyl-4-yl) oxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] Ethanon

Example 5a 1- {5- [4- (1,4-Dioxaspiro [4.5] dec-7-en-8-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indole -1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone The compound obtained in Example 1b (100 mg), 1,4-dioxa-spiro [4,5] dec-7-ene-8. -To a solution of boronic acid pinacol ester (79.8 mg) in 1,2-dimethoxyethane (3 mL) was added an aqueous solution (1 mL) of sodium carbonate (63.6 mg), and the mixture was stirred at room temperature for 5 minutes. [1,1′-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (16.3 mg) was added, and the mixture was reacted at 130 ° C. for 40 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (108 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.91 (2H, t, J = 6.7 Hz), 2.11 (3H, s), 2.41-2.49 (2H, br m), 2.57-2.68 (2H, m) , 3.12 (3H, s), 3.21 (2H, t, J = 8.5 Hz), 4.02 (4H, s), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 5.88-5.95 ( 1H, m), 6.74-6.84 (3H, m), 7.31 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.50-7.54 (1H, m), 7.60-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).
MS (APCI) m / z: 560 (M + H) ⁺ .

Example 5b 1- {5-[(4′-hydroxybiphenyl-4-yl) oxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- ( Methylsulfonyl) phenyl] ethanone To a solution of the compound obtained in Example 5a (98.0 mg) in tetrahydrofuran (3 mL) was added 5N aqueous hydrochloric acid (213 μL), and the mixture was stirred at 70 ° C. for 7 hr. The reaction mixture was concentrated under reduced pressure, neutralized with 2N aqueous sodium hydroxide solution (1 mL), and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (32.1 mg) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.07 (3H, s), 3.11-3.27 (5H, m), 4.23-4.35 (4H, m), 6.81 (2H, d, J = 8.5 Hz ), 6.87 (1H, d, J = 9.2 Hz), 7.41 (1H, d, J = 8.5 Hz), 7.45-7.52 (3H, m), 7.58 (1H, t, J = 7.0 Hz), 7.70 (1H , t, J = 7.0 Hz), 7.87 (1H, d, J = 8.5 Hz), 7.97 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 514 (M + H) ⁺ .

(Example 6)
Ethyl (2E) -3- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} prop -2-enoate

Sodium carbonate (63.6 mg) was added to a solution of the compound obtained in Example 1b (100 mg) and 2- (ethoxycarbonyl) vinylboronic acid pinacol ester (67.8 mg) in 1,2-dimethoxyethane (2 mL). Aqueous solution (1 mL) was added and stirred at room temperature for 5 minutes. [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (16.3 mg) was added, and the mixture was reacted at 130 ° C. for 15 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (92.5 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.33 (3H, t, J = 7.0 Hz), 2.09 (3H, s), 3.13 (3H, s), 3.19-3.27 (2H, m), 4.21- 4.33 (4H, m), 4.37 (2H, s), 6.32 (1H, d, J = 15.9 Hz), 6.80-6.91 (3H, m), 7.37 (1H, d, J = 7.9 Hz), 7.45 (2H , d, J = 8.5 Hz), 7.53 (1H, t, J = 7.9 Hz), 7.61-7.65 (2H, m), 8.01 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = (7.9 Hz).
MS (APCI) m / z: 520 (M + H) ⁺ .

(Example 7)
1- {5- [4- (3-chloropyridin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl ] Ethanon

The compound obtained in Example 1b (50.0 mg), 3-chloro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (47.9) mg) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (8.16 mg) in 1,2-dimethoxyethane (2 mL) was added sodium carbonate (31.8 mg) aqueous solution (0.5 mL) was added, and the mixture was reacted at 130 ° C. for 25 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (36.1 mg) as a light brown. Obtained as a colored solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.15 (3H, s), 3.13 (3H, s), 3.24 (2H, t, J = 8.2 Hz), 4.31 (2H, t, J = 8.5 Hz) , 4.37 (2H, s), 6.88 (1H, d, J = 9.1 Hz), 7.25-7.29 (1H, m), 6.96 (2H, d, J = 8.5 Hz), 7.37 (1H, d, J = 7.9 Hz), 7.43 (2H, d, J = 8.5 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.63 (1H, t, J = 7.3 Hz), 8.03 (1H, d, J = 8.5 Hz) , 8.08 (1H, d, J = 7.9 Hz), 8.50 (1H, d, J = 4.9 Hz), 8.65 (1H, s).
MS (APCI) m / z: 533 (M + H) ⁺ .

(Example 8)
1- {4-Methyl-5- [4- (1-methyl-1H-imidazol-5-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methyl Sulfonyl) phenyl] ethanone

Example 8a 2- [2- (Methylsulfonyl) phenyl] -1- {4-methyl-5- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) -Yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} ethanone To a 1,4-dioxane (8 mL) solution of the compound obtained in Example 1b (500 mg) in [1,1 ′ -Bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (14.6 mg), 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'- Bi-1,3,2-dioxaborolane (381 mg) and potassium acetate (294 mg) were added, and the mixture was stirred at 100 ° C. for 7 hours. After cooling to room temperature, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (401 mg) as a colorless solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.33 (12H, s), 2.08 (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), 6.78-6.88 (3H, m), 7.36 (1H, d, J = 7.3 Hz), 7.49-7.55 (1H, m), 7.59-7.65 (1H , m), 7.73 (2H, d, J = 8.5 Hz), 7.99 (1H, d, J = 9.1 Hz), 8.08 (1H, dd, J = 7.9, 1.2 Hz).

Example 8b 1- {4-Methyl-5- [4- (1-methyl-1H-imidazol-5-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (Methylsulfonyl) phenyl] ethanone The compound obtained in Example 8a (40.0 mg), 5-bromo-1-methyl-1H-imidazole (23.5 mg) and [1,1′-bis (Diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (5.97 mg) in 1,2-dimethoxyethane (2 mL) in aqueous solution of sodium carbonate (23.2 mg) (0.5 mL) And reacted at 130 ° C. for 20 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate / dichloromethane) and silica gel column chromatography (methanol / ethyl acetate / dichloromethane). This gave the title compound (17.6 mg) as a light brown amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.14 (3H, s), 3.12 (3H, s), 3.23 (2H, t, J = 8.5 Hz), 3.64 (3H, s), 4.30 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.84 (1H, d, J = 8.5 Hz), 6.93 (2H, d, J = 8.5 Hz), 7.04 (1H, s), 7.29 (2H, d, J = 8.5 Hz), 7.37 (1H, d, J = 7.3 Hz), 7.47-7.55 (2H, m), 7.58-7.65 (1H, m), 8.02 (1H, d, J = 8.5 Hz), 8.08 (1H, dd, J = 7.9, 1.2 Hz).
MS (APCI) m / z: 502 (M + H) ⁺ .

Example 9
1- {4-Methyl-5- [4- (1-methyl-1H-pyrazol-5-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methyl Sulfonyl) phenyl] ethanone

The compound (40.0 mg) obtained in Example 1b, 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole ( 33.3 mg) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (6.53 mg) in 1,2-dimethoxyethane (2 mL) were added to sodium carbonate (2 mL). 25.4 mg) of an aqueous solution (0.5 mL) was added, and the mixture was reacted at 130 ° C. for 20 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (34.8 mg) as a light brown. Obtained as a color amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.14 (3H, s), 3.12 (3H, s), 3.23 (2H, t, J = 8.5 Hz), 3.87 (3H, s), 4.30 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.24-6.28 (1H, m), 6.85 (1H, d, J = 8.5 Hz), 6.94 (2H, d, J = 8.5 Hz), 7.32 ( 2H, d, J = 8.5 Hz), 7.37 (1H, d, J = 7.3 Hz), 7.48-7.56 (2H, m), 7.59-7.65 (1H, m), 8.02 (1H, d, J = 8.5 Hz ), 8.08 (1H, dd, J = 7.9, 1.2 Hz).
MS (APCI) m / z: 502 (M + H) ⁺ .

(Example 10)
1- (5- {4- [2- (1,4-Dioxane-2-ylmethoxy) pyridin-4-yl] phenoxy} -4-methyl-2,3-dihydro-1H-indol-1-yl)- 2- [2- (Methylsulfonyl) phenyl] ethanone

Example 10a 4-Bromo-2- (1,4-dioxane-2-ylmethoxy) pyridine To a solution of 4-bromopyridin-2-ol (200 mg) in toluene (3 mL), 1,4-dioxane-2 -Ylmethanol (136 mg) and cyanomethylenetributylphosphorane (555 mg) were added, and the mixture was stirred at 100 ° C. for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (185 mg) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.47-3.54 (1H, m), 3.62-3.89 (5H, m), 3.95-4.02 (1H, m), 4.27-4.36 (2H, m), 7.00 -7.06 (2H, m), 7.96 (1H, d, J = 5.5 Hz).
MS (APCI) m / z: 274 (M + H) ⁺ .

Example 10b 1- (5- {4- [2- (1,4-Dioxane-2-ylmethoxy) pyridin-4-yl] phenoxy} -4-methyl-2,3-dihydro-1H-indole- 1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone The compound obtained in Example 10a (40.1 mg), the compound obtained in Example 8a (40.0 mg) and [1, 1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (5.97 mg) in 1,2-dimethoxyethane (2 mL) was added to an aqueous solution of sodium carbonate (23.2 mg) (0 0.5 mL) was added, and the mixture was reacted at 130 ° C. for 20 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (41.8 mg) Obtained as a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.13 (3H, s), 3.13 (3H, s), 3.23 (2H, t, J = 8.5 Hz), 3.50-3.59 (1H, m), 3.63- 3.93 (5H, m), 3.99-4.07 (1H, m), 4.30 (2H, t, J = 8.5 Hz), 4.34-4.42 (4H, m), 6.85 (1H, d, J = 8.5 Hz), 6.91 -7.00 (3H, m), 7.06-7.10 (1H, m), 7.37 (1H, d, J = 7.3 Hz), 7.50-7.57 (3H, m), 7.60-7.65 (1H, m), 8.02 (1H , d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz), 8.14 (1H, d, J = 5.5 Hz).
MS (APCI) m / z: 615 (M + H) ⁺ .

(Example 11)
1- {5- [4- (6,7-dihydro-5H-pyrrolo [1,2-a] imidazol-3-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indole-1- Yl} -2- [2- (methylsulfonyl) phenyl] ethanone

The compound obtained in Example 8a (40.0 mg), 3-bromo-6,7-dihydro-5H-pyrrolo [1,2-a] imidazole (27.3 mg) and [1,1′-bis (Diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (5.97 mg) in 1,2-dimethoxyethane (2 mL) in aqueous solution of sodium carbonate (23.2 mg) (0.5 mL) And reacted at 130 ° C. for 20 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, the solvent was removed under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (8.0 mg). Obtained as a brown amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.13 (3H, s), 2.58-2.69 (2H, m), 2.89-2.99 (2H, m), 3.12 (3H, s), 3.23 (2H, t , J = 8.2 Hz), 4.08-4.15 (2H, m), 4.30 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.81 (1H, d, J = 9.1 Hz), 6.90 (2H , d, J = 8.5 Hz), 7.12-7.18 (1H, m), 7.33-7.39 (3H, m), 7.52 (1H, t, J = 7.6 Hz), 7.60-7.65 (1H, m), 8.00 ( 1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).

(Example 12)
1- {4-Methyl-5- [4- (1-methyl-1H-benzimidazol-6-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- ( Methylsulfonyl) phenyl] ethanone

The compound obtained in Example 1b (50.0 mg), (1-methyl-1H-benzoimidazol-6-yl) boronic acid (35.2 mg) and [1,1′-bis (diphenylphosphino) To a solution of ferrocene] dichloropalladium (II) dichloromethane complex (8.16 mg) in 1,2-dimethoxyethane (2 mL), an aqueous solution (0.5 mL) of sodium carbonate (31.8 mg) was added. The reaction was allowed to proceed at 130 ° C. for 20 minutes. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (dichloromethane / hexane → ethyl acetate / dichloromethane) to give the title compound (44. 6 mg) was obtained as a yellow amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.17 (3H, s), 3.24 (2H, t, J = 7.9 Hz), 3.13 (3H, s), 3.88 (3H, s), 4.30 (2H, t, J = 7.9 Hz), 4.38 (2H, s), 6.85 (1H, d, J = 8.5 Hz), 6.91-7.01 (2H, m), 7.32-7.66 (7H, m), 7.76-7.91 (2H , m), 8.01 (1H, d, J = 9.1 Hz), 8.08 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 552 (M + H) ⁺ .

(Example 13)
1- {4-Methyl-5- [3-methyl-4- (pyridin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) Phenyl] ethanone

Example 13a tert-butyl 5- (4-bromo-3-methylphenoxy) -4-methyl-2,3-dihydro-1H-indole-1-carboxylate 1-bromo-4-iodo-2-methyl Copper iodide was added to a solution of benzene (12.5 g) and tert-butyl 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylate (7.00 g) in dioxane (250 mL). (I) (107 mg), N, N-dimethylglycine (116 mg) and cesium carbonate (18.3 g) were added, and the mixture was stirred at 100 ° C. for 5 hours and 30 minutes. After cooling to room temperature, the mixture was allowed to stand overnight, stirred again at 100 ° C. for 9 hours, and the reaction solution was filtered through Celite. The obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / hexane) to give the title compound (5.26 g) as a colorless solid.
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).

Example 13b 1- [5- (4-Bromo-3-methylphenoxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl Ethanone To a solution of the compound obtained in Example 13a (5.25 g) in dichloromethane (50 mL) was added 4N hydrochloric acid dioxane solution (50 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated to obtain crude 5- (4-bromo-3-methylphenoxy) -4-methyl-2,3-dihydro-1H-indole hydrochloride (4.54 g).
N-methylmorpholine (2.07 mL) was added to a solution of the obtained compound (4.54 g) in N, N-dimethylformamide (100 mL), and the mixture was stirred at room temperature for 10 minutes. 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (4.51 g) and [2- (methylsulfonyl) phenyl] acetic acid ( 2.82 g) was added, and the mixture was stirred at room temperature for 14 hours and 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / hexane → ethyl acetate / dichloromethane) to obtain the title compound (7.14 g) as a colorless solid.
¹ H-NMR (400 MHz, 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), 6.55-6.59 (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) ⁺ .

Example 13c 1- {4-Methyl-5- [3-methyl-4- (pyridin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2 -(Methylsulfonyl) phenyl] ethanone The compound obtained in Example 13b (50.0 mg), 4-pyridineboronic acid (23.9 mg) and [1,1'-bis (diphenylphosphino) ferrocene] dichloro An aqueous solution (0.5 mL) of sodium carbonate (30.9 mg) was added to a solution of palladium (II) dichloromethane complex (8.0 mg) in 1,2-dimethoxyethane (2 mL), and the mixture was added to the microwave reactor. And reacted at 130 ° C. for 25 minutes. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (47.8 mg) as a light brown. Obtained as a colored solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.15 (3H, s), 2.25 (3H, s), 3.13 (3H, s), 3.24 (2H, t, J = 8.5 Hz), 4.30 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.73-6.78 (1H, m), 6.79-6.82 (1H, m), 6.84 (1H, d, J = 8.5 Hz), 7.13 (1H, d , J = 7.9 Hz), 7.22-7.27 (2H, m), 7.34-7.39 (1H, m), 7.49-7.56 (1H, m), 7.60-7.65 (1H, m), 8.02 (1H, d, J = 9.1 Hz), 8.08 (1H, dd, J = 7.9, 1.2 Hz), 8.63 (2H, s).
MS (APCI) m / z: 513 (M + H) ⁺ .

(Example 14)
2- [4- (Methylsulfonyl) phenyl] -1- {4-methyl-5- [4- (trifluoromethyl) phenoxy] -2,3-dihydro-1H-indol-1-yl} ethanone

Example 14a 4-methyl-5- [4- (trifluoromethyl) phenoxy] -2,3-dihydro-1H-indole-1-carboxylate tert-butyl 1-iodo-4- (trifluoromethyl) Benzene (0.035 mL) and tert-butyl 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylate (0.040 g) of 1,4-dioxane (1.5 mL) ) Copper (I) iodide (0.0061 g), N, N-dimethylglycine (0.0066 g) and cesium carbonate (0.052 g) were added to the solution, and the mixture was stirred at 90 ° C. for 4 hours and 30 minutes. A saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (0.029 g) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.55 (9H, s), 2.03 (3H, s), 2.98-3.09 (2H, m), 3.95-4.11 (2H, m), 6.77-6.95 (3H , m), 7.51 (2H, d, J = 8.6 Hz), 7.64-7.78 (1H, m).

Example 14b 2- [4- (methylsulfonyl) phenyl] -1- {4-methyl-5- [4- (trifluoromethyl) phenoxy] -2,3-dihydro-1H-indol-1-yl } Ethanone To a solution of the compound obtained in Example 14a (0.0286 g) in 1,4-dioxane (0.5 mL) was added 4N hydrochloric acid dioxane solution (0.5 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated to give crude 4-methyl-5- [4- (trifluoromethyl) phenoxy] -2,3-dihydro-1H-indole.
To a solution of the obtained compound and [4- (methylsulfonyl) phenyl] acetic acid (0.017 g) in N, N-dimethylformamide (1 mL), triethylamine (0.030 mL), N- [3- (dimethylamino ) Propyl] -N′-ethylcarbodiimide hydrochloride (0.021 g), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (0.0049 g) was added at room temperature. The mixture was stirred for 6 hours and 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (0.0319 g) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.07 (3H, s), 3.06 (3H, s), 3.14-3.23 (2H, m), 3.92 (2H, s), 4.16-4.25 (2H, m ), 6.83-6.95 (3H, m), 7.48-7.57 (4H, m), 7.91-7.98 (2H, m), 8.06-8.13 (1H, m).
MS (APCI) m / z: 490 (M + H) ⁺ .

(Example 15)
1- {4-Methyl-5- [4- (pyridin-3-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone

Example 15a tert-Butyl 4-methyl-5- [4- (pyridin-3-yl) phenoxy] -2,3-dihydro-1H-indole-1-carboxylate Compound obtained in Example 1a ( An aqueous solution (1 mL) of sodium carbonate (44.8 mg) was added to a solution of 70 mg) and 3-pyridylboronic acid (26 mg) in 1,2-dimethoxyethane (3 mL), and the mixture was stirred at room temperature for 5 minutes. [1,1′-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (11.5 mg) was added and reacted at 130 ° C. for 1 hour in a microwave reactor. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (62.6 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.59 (9H, s), 2.09 (3H, s), 3.05 (2H, t, J = 8.5 Hz), 3.99-4.12 (2H, br m), 6.80 -6.89 (1H, br m), 6.95 (2H, d, J = 8.5 Hz), 7.31-7.37 (1H, m), 7.48 (2H, d, J = 8.5 Hz), 7.65-7.80 (1H, br m ), 7.83 (1H, d, J = 7.9 Hz), 8.54-8.56 (1H, m), 8.80-8.82 (1H, m).

Example 15b 1- {4-Methyl-5- [4- (pyridin-3-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) ) Phenyl] ethanone To a solution of the compound obtained in Example 15a (62.6 mg) in dichloromethane (1 mL) was added 4N hydrochloric acid dioxane solution (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and dried under reduced pressure to give crude 4-methyl-5- [4- (pyridin-3-yl) phenoxy] -2,3-dihydro-1H-indole hydrochloride (83.6). mg) was obtained as a yellow solid.
Triethylamine (43.3 μL) was added to a solution of the obtained compound (83.6 mg) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes. 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (64.5 mg) and 2- (2-methylsulfonylphenyl) acetic acid (40 mg) And stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (58.1 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.15 (3H, s), 3.13 (3H, s), 3.24 (2H, t, J = 8.5 Hz), 4.31 (2H, t, J = 8.5 Hz) , 4.38 (2H, s), 6.85 (1H, d, J = 8.5 Hz), 6.97 (2H, d, J = 8.5 Hz), 7.31-7.41 (2H, m), 7.46-7.56 (3H, m), 7.63 (1H, t, J = 7.3 Hz), 7.83 (1H, d, J = 7.3 Hz), 8.02 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz), 8.56 ( 1H, s), 8.81 (1H, s).
MS (APCI) m / z: 499 (M + H) ⁺ .

(Example 16)
1- {4-Methyl-5- [2-methyl-4- (pyridin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) Phenyl] ethanone

Example 16a tert-butyl 5- (4-bromo-2-methylphenoxy) -4-methyl-2,3-dihydro-1H-indole-1-carboxylate tert-butyl 5-hydroxy-4-methyl- Copper (I) iodide (38.1 mg) was added to a solution of 2,3-dihydro-1H-indole-1-carboxylate (250 mg) and 5-bromo-2-iodotoluene (212 μL) in dioxane (5 mL). ), N, N-dimethylglycine (41.2 mg) and cesium carbonate (651 mg) were added, and the mixture was stirred at 100 ° C. for 24 hours. Saturated aqueous ammonium chloride solution (6 mL) and saturated aqueous sodium hydrogen carbonate solution (3 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was washed with hexane, collected by filtration and dried to give the title compound (57.5 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.55 (9H, s), 2.06 (3H, s), 2.30 (3H, s), 3.02 (2H, t, J = 8.9 Hz), 3.98-4.07 ( 2H, br m), 6.38-6.48 (1H, br m), 6.60-6.80 (1H, m), 7.14 (1H, d, J = 7.3 Hz), 7.33 (1H, s), 7.63 (1H, d, J = 8.5 Hz).

Example 16b 1- [5- (4-Bromophenoxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone To a solution of the compound obtained in 16a (57.5 mg) in dichloromethane (1 mL) was added 4N dioxane hydrochloride solution (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and dried under reduced pressure to give crude 5- (4-bromo-2-methylphenoxy) -4-methyl-2,3-dihydro-1H-indole hydrochloride (48.8 mg). Was obtained as a yellow solid.
Triethylamine (38.3 μL) was added to a solution of the obtained compound (48.8 mg) in N, N-dimethylformamide (2 mL), and the mixture was stirred at room temperature for 5 minutes. 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (57.1 mg) and 2- (2-methylsulfonylphenyl) acetic acid (35.3) mg) was added, and the mixture was further stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (57.5 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.13 (3H, s), 2.28 (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), 6.48 (1H, d, J = 8.5 Hz), 6.62 (1H, d, J = 8.5 Hz), 7.17 (1H, d, J = 8.5 Hz) , 7.36 (2H, d, J = 7.3 Hz), 7.48-7.56 (1H, m), 7.58-7.68 (1H, m), 7.90-8.00 (1H, m), 8.04-8.11 (1H, m).
MS (APCI) m / z: 514, 516 (M + H) ⁺ .

Example 16c 1- {4-Methyl-5- [2-methyl-4- (pyridin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2 -(Methylsulfonyl) phenyl] ethanone To a solution of the compound obtained in Example 16b (40 mg), 4-pyridineboronic acid (14.3 mg) in 1,2-dimethoxyethane (2 mL), sodium carbonate (24. 7 mg) in water (1 mL) was added and stirred at room temperature for 5 minutes. [1,1′-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (6.3 mg) was added and reacted at 130 ° C. for 1 hour in a microwave reactor. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (21.1 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.15 (3H, s), 2.41 (3H, s), 3.13 (3H, s), 3.18-3.30 (2H, m), 4.25-4.34 (2H, m ), 4.37 (2H, s), 6.68-6.85 (2H, m), 7.32-7.39 (2H, br m), 7.47 (2H, s), 7.50-7.58 (2H, br m), 7.59-7.67 (1H , m), 7.96-8.03 (1H, m), 8.05-8.12 (1H, m), 8.56-8.67 (2H, br m).
MS (APCI) m / z: 513 (M + H) ⁺ .

(Example 17)
1- {5- [4- (4-Hydroxycyclohexyl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl ] Ethanon

Example 17a tert-butyl 5- [4- (1,4-dioxaspiro [4.5] dec-7-en-8-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indole -1-carboxylate 8- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,4-dioxaspiro [4.5] dec-7-ene (987 mg ), The compound obtained in Example 1a (1.00 g), chloro (2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl) [2- (2 ′ -Amino-1,1′-biphenyl)] palladium (II) (97.3 mg), tripotassium phosphate (1.05 g), toluene (10 mL), water (5 mL) at 100 ° C. Stir. After 10 hours, the mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.25 g) as a white amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50-1.65 (9H, m), 1.88-1.95 (2H, m), 2.06 (3H, s), 2.42-2.49 (2H, m), 2.60-2.67 (2H, m), 2.98-3.07 (2H, m), 3.96-4.09 (6H, m), 5.88-5.93 (1H, m), 6.75-6.83 (3H, m), 7.26-7.33 (2H, m) , 7.57-7.76 (1H, m).

Example 17b tert-butyl 5- [4- (1,4-dioxaspiro [4.5] dec-8-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indole-1-carboxy Rate 7.5% palladium carbon (80 mg) was added to a solution of the compound obtained in Example 17a (835 mg) in dichloromethane (4 mL) and ethanol (10 mL), and the mixture was stirred at room temperature in a hydrogen atmosphere. After 10 hours, the title compound (841 mg) was obtained as a colorless oil by filtration through celite and concentration under reduced pressure.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48-1.91 (17H, m), 2.08 (3H, s), 2.46-2.57 (1H, m), 2.98-3.07 (2H, m), 3.91-4.09 (6H, m), 6.69-6.85 (3H, m), 7.05-7.18 (2H, m), 7.55-7.76 (1H, m).

Example 17c [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 picolinic acid (0.193 g) are suspended in 1,4-dioxane (7.5 mL) at 100 ° C. Stir for 7 hours. The reaction solution was allowed to stand at room temperature overnight and then stirred at 100 ° C. for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 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 residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.091 g) as a pale yellow oil. .
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).

Example 17d [3- (Methylsulfonyl) pyridin-2-yl] acetic acid The compound (0.0533 g) obtained in Example 17c was dissolved in methanol (1.5 mL), and 2N aqueous sodium hydroxide solution was obtained. (0.75 mL) was added, and the mixture was stirred at 50 ° C. for 2 hours and 30 minutes. The reaction solution was allowed to stand at room temperature overnight and then neutralized by adding 1N hydrochloric acid. The reaction solution was extracted three times with a dichloromethane / ethanol (19: 1) mixed solvent, and the organic layer was dried over sodium sulfate. The organic layer was concentrated under reduced pressure to obtain the title compound (0.0322 g) as a yellow oil.
¹ H-NMR (400 MHz, 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).

Example 17e 1- {5- [4- (1,4-Dioxaspiro [4.5] dec-8-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl } -2- [3- (Methylsulfonyl) pyridin-2-yl] ethanone A 4N hydrochloric acid dioxane solution (6 mL) was added to a dichloromethane solution (3 mL) of the compound obtained in Example 17b (841 mg) at room temperature. Stir with. After 3 hours, the mixture was concentrated under reduced pressure, suspended in ethyl acetate, and collected by filtration to give 5- [4- (1,4-dioxaspiro [4.5] dec-8-yl) phenoxy] -4-methyl. -2,3-Dihydro-1H-indole hydrochloride (694 mg) was obtained.
The obtained compound (523 mg), the compound obtained in Example 17d (309 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (374 mg), 3H-1,2, A mixture of 3-triazolo [4,5-b] pyridin-3-ol (177 mg), N, N-diisopropylethylamine (0.680 mL), N, N-dimethylformamide (4 mL) was stirred at room temperature. . After 12 hours, the reaction solution was directly purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (653 mg) as a white amorphous solid.
MS (APCI) m / z: 563 (M + H) ⁺ .

Example 17f 4- {4-[(4-Methyl-1-{[3- (methylsulfonyl) pyridin-2-yl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy ] Phenyl} cyclohexanone To a solution of the compound obtained in Example 17e (653 mg) in acetone (8 mL) was added 35% aqueous hydrochloric acid (4 mL), and the mixture was stirred at room temperature for 5 hours. After neutralization with saturated aqueous sodium hydrogen carbonate, the acetone was distilled off by concentration under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (362 mg) as an amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.83-1.99 (3H, m), 2.14 (3H, s), 2.16-2.26 (2H, m), 2.45-2.54 (4H, m), 3.18-3.29 (5H, m), 4.30-4.38 (2H, m), 4.61 (2H, s), 6.75-6.79 (1H, m), 6.80-6.86 (2H, m), 7.12-7.18 (2H, m), 7.45 -7.51 (1H, m), 7.92-7.97 (1H, m), 8.34-8.38 (1H, m), 8.78-8.82 (1H, m).
MS (APCI) m / z: 519 (M + H) ⁺ .

Example 17g 1- {5- [4- (4-Hydroxycyclohexyl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) Pyridin-2-yl] ethanone To a solution of the compound obtained in Example 17f (362 mg) in tetrahydrofuran (3 mL) and methanol (3 mL) was added sodium borohydride (26.4 mg) in an ice bath to add 30. Stir for minutes. Saturated aqueous ammonium chloride solution was added to return to room temperature, and the mixture was concentrated under reduced pressure. Water was added to the residue and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (220 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35-1.56 (5H, m), 1.86-1.96 (2H, m), 2.04-2.17 (5H, m), 2.39-2.52 (1H, m), 3.18 -3.28 (5H, m), 3.62-3.73 (1H, m), 4.30-4.38 (2H, m), 4.61 (2H, s), 6.73-6.83 (3H, m), 7.07-7.13 (2H, m) , 7.44-7.50 (1H, m), 7.90-7.96 (1H, m), 8.33-8.38 (1H, m), 8.77-8.82 (1H, m).
MS (APCI) m / z: 521 (M + H) ⁺ .

(Example 18)
1- (5- {4- [4- (2-hydroxyethoxy) cyclohexyl] phenoxy} -4-methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) Phenyl] ethanone

Example 18a tert-butyl 4-methyl-5- [4- (4-oxocyclohexyl) phenoxy] -2,3-dihydro-1H-indole-1-carboxylate Compound (248) obtained in Example 17b To a solution of mg) in acetone (1.5 mL), 4N hydrochloric acid dioxane solution (3 mL) was added and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain crude 4- {4-[(4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl} cyclohexanone hydrochloride.
N, N-diisopropylethylamine (0.278 mL) and di-tert-butyl dicarbonate (174 mg) were added to a solution of the obtained compound in N, N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 2 hours. . Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (152 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49-1.64 (9H, m), 1.83-1.97 (2H, m), 2.08 (3H, s), 2.16-2.26 (2H, m), 2.44-2.54 (4H, m), 2.93-3.06 (3H, m), 3.97-4.10 (2H, m), 6.75-6.85 (3H, m), 7.10-7.16 (2H, m), 7.60-7.76 (1H, m) .

Example 18b tert-Butyl 5- [4- (4-hydroxycyclohexyl) phenoxy] -4-methyl-2,3-dihydro-1H-indole-1-carboxylate Compound obtained in Example 18a (152 mg) in tetrahydrofuran (1 mL) and methanol (2 mL) were added sodium borohydride (13.6 mg), and the mixture was stirred at 0 ° C. After 1 hour, a saturated aqueous ammonium chloride solution was added and the mixture was concentrated under reduced pressure. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (75 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35-1.63 (14H, m), 1.87-1.96 (2H, m), 2.04-2.13 (5H, m), 2.40-2.51 (1H, m), 2.98 -3.07 (2H, m), 3.62-3.73 (1H, m), 3.97-4.09 (2H, m), 6.73-6.83 (3H, m), 7.06-7.11 (2H, m), 7.60-7.72 (1H, m).

Example 18c tert-butyl 5- {4- [4- (2-ethoxy-2-oxoethoxy) cyclohexyl] phenoxy} -4-methyl-2,3-dihydro-1H-indole-1-carboxylate Rhodium (II) acetate dimer (2.25 mg) was added to a dichloromethane solution of the compound obtained in Example 18b (72 mg), ethyl diazoacetate (0.0358 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 3 hours. did. After adding water and extracting with ethyl acetate, the organic layer was washed with water and saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (47 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.25-1.33 (3H, m), 1.38-1.61 (13H, m), 1.88-1.98 (2H, m), 2.07 (3H, s), 2.14-2.22 (2H, m), 2.41-2.52 (1H, m), 2.98-3.06 (2H, m), 3.35-3.45 (1H, m), 3.97-4.08 (2H, m), 4.15 (2H, s), 4.23 (2H, q, J = 7.2 Hz), 6.74-6.81 (3H, m), 7.05-7.10 (2H, m), 7.58-7.74 (1H, m).

Example 18d Ethyl [(4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] Phenyl} cyclohexyl) oxy] acetate A 4N hydrochloric acid dioxane solution (1 mL) was added to a solution of the compound obtained in Example 18c (45.0 mg) in dichloromethane (1 mL), and the mixture was stirred at room temperature. After 3 hours, the reaction was concentrated to give crude ethyl [(4- {4-[(4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl} cyclohexyl) oxy] acetate. The hydrochloride salt was obtained.
The obtained compound and [2- (methylsulfonyl) phenyl] acetic acid (38.0 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (34.0 mg), 3H-1, A mixture of 2,3-triazolo [4,5-b] pyridin-3-ol (12.0 mg), N, N-diisopropylethylamine (0.046 mL) and dichloromethane (3 mL) was stirred at room temperature. After 12 hours, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (45.0 mg) as a colorless amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.24-1.33 (3H, m), 1.38-1.52 (4H, m), 1.88-1.99 (2H, m), 2.11-2.23 (5H, m), 2.42 -2.54 (1H, m), 3.12 (3H, s), 3.17-3.25 (2H, m), 3.35-3.46 (1H, m), 4.15 (2H, s), 4.19-4.32 (4H, m), 4.36 (2H, s), 6.74-6.82 (3H, m), 7.06-7.12 (2H, m), 7.34-7.38 (1H, m), 7.49-7.55 (1H, m), 7.59-7.64 (1H, m) , 7.94-7.98 (1H, m), 8.05-8.09 (1H, m).

Example 18e 1- (5- {4- [4- (2-hydroxyethoxy) cyclohexyl] phenoxy} -4-methyl-2,3-dihydro-1H-indol-1-yl) -2- [2 -(Methylsulfonyl) phenyl] ethanone A solution of the compound (44.0 mg) obtained in Example 18d in tetrahydrofuran (2 mL) was cooled to 0 ° C., and lithium borohydride (2.4 mg) was added. After warming to room temperature, the mixture was stirred for 2 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (29.0 mg) as a white amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.33-1.52 (4H, m), 1.90-1.99 (2H, m), 2.12-2.21 (5H, m), 2.42-2.53 (1H, m), 3.12 (3H, s), 3.17-3.25 (2H, m), 3.27-3.40 (2H, m), 3.59-3.64 (2H, m), 3.70-3.77 (2H, m), 4.25-4.32 (2H, m) , 4.36 (2H, s), 6.74-6.83 (3H, m), 7.08-7.13 (2H, m), 7.34-7.38 (1H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.94-7.98 (1H, m), 8.06-8.10 (1H, m).
MS (APCI) m / z: 564 (M + H) ⁺ .

(Example 19)
N, N-dimethyl-2-[(4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) Oxy] phenyl} cyclohexyl) oxy] acetamide

To a solution of the compound obtained in Example 18d (329 mg) in 1,4-dioxane (2 mL) was added 1N aqueous sodium hydroxide solution (1.09 mL), and the mixture was stirred at room temperature for 3 hr. The mixture was neutralized with 1N aqueous hydrochloric acid and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude [(4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3 -Dihydro-1H-indol-5-yl) oxy] phenyl} cyclohexyl) oxy] acetic acid was obtained.
Dimethylamine hydrochloride (40.2 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (63.1 mg) were added to a solution of the obtained compound (95 mg) in dichloromethane (5 mL). 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (22.4 mg) and N, N-diisopropylethylamine (0.0638 mL) were added and stirred at room temperature. After 12 hours, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (77.0 mg) as a white amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35-1.52 (4H, m), 1.87-1.97 (2H, m), 2.10-2.24 (5H, m), 2.41-2.52 (1H, m), 2.97 (3H, s), 3.06 (3H, s), 3.12 (3H, s), 3.18-3.25 (2H, m), 3.36-3.47 (1H, m), 4.21 (2H, s), 4.25-4.32 (2H , m), 4.36 (2H, s), 6.74-6.82 (3H, m), 7.06-7.11 (2H, m), 7.34-7.38 (1H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.94-7.99 (1H, m), 8.05-8.10 (1H, m).
MS (APCI) m / z: 605 (M + H) ⁺ .

(Example 20)
1- {5- [4- (2-chloropyridin-4-yl) -3-methylphenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- ( Methylsulfonyl) phenyl] ethanone

The compound obtained in Example 8a (200 mg), 2-chloro-4-iodopyridine (171 mg) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (29. An aqueous solution (2 mL) of sodium carbonate (113 mg) was added to a solution of 1 mg) of 1,2-dimethoxyethane (8 mL) and reacted at 130 ° C. for 20 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / hexane → ethyl acetate / dichloromethane) to give the title compound (86.7). mg) was obtained as a pale yellow amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.14 (3H, s), 2.25 (3H, s), 3.13 (3H, s), 3.24 (2H, t, J = 8.2 Hz), 4.31 (2H, t, J = 8.2 Hz), 4.37 (2H, s), 6.76 (1H, dd, J = 8.2, 2.7 Hz), 6.79-6.82 (1H, m), 6.84 (1H, d, J = 8.5 Hz), 7.11 (1H, d, J = 7.9 Hz), 7.15-7.20 (1H, m), 7.25-7.30 (1H, m), 7.34-7.40 (1H, m), 7.50-7.56 (1H, m), 7.59- 7.66 (1H, m), 8.02 (1H, d, J = 8.5 Hz), 8.08 (1H, dd, J = 7.9, 1.2 Hz), 8.40 (1H, d, J = 5.5 Hz).
MS (APCI) m / z: 547 (M + H) ⁺ .

(Example 21)
1- {4-Methyl-5- [3-methyl-4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone

The compound obtained in Example 1b (50.0 mg), 4-methyl-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,4- Dihydro-2H-pyrido [3,2-b] [1,4] oxazine (40.3 mg) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (7.94 mg) in 1,2-dimethoxyethane (2 mL) was added an aqueous solution (0.5 mL) of sodium carbonate (30.9 mg) and reacted at 130 ° C. for 20 minutes in a microwave reactor. . The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, the solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (38.3 mg) as a light brown. Obtained as a color amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.15 (3H, s), 2.24 (3H, s), 3.13 (3H, s), 3.15 (3H, s), 3.23 (2H, t, J = 8.5 Hz), 3.45-3.51 (2H, m), 4.26-4.32 (4H, m), 4.37 (2H, s), 6.70 (1H, dd, J = 8.5, 2.4 Hz), 6.76-6.80 (1H, m) , 6.83 (1H, d, J = 8.5 Hz), 6.88-6.92 (1H, m), 7.09 (1H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.49-7.55 ( 1H, m), 7.59-7.65 (1H, m), 7.71 (1H, d, J = 2.4 Hz), 8.00 (1H, d, J = 8.5 Hz), 8.08 (1H, dd, J = 7.9, 1.2 Hz ).
MS (APCI) m / z: 584 (M + H) ⁺ .

(Example 22)
1- (4-Methyl-5- {3-methyl-4- [6- (morpholin-4-ylmethyl) pyridin-3-yl] phenoxy} -2,3-dihydro-1H-indol-1-yl)- 2- [2- (Methylsulfonyl) phenyl] ethanone

The compound obtained in Example 1b (50.0 mg), [6- (morpholin-4-ylmethyl) pyridin-3-yl] boronic acid (32.4 mg) and [1,1′-bis (diphenylphosphine) Fino) ferrocene] dichloropalladium (II) dichloromethane complex (7.94 mg) in 1,2-dimethoxyethane (2 mL) was added sodium carbonate (30.9 mg) in water (0.5 mL), The reaction was carried out at 130 ° C. for 20 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to NH silica gel column chromatography (dichloromethane) and silica gel column chromatography (ethyl acetate / dichloromethane → methanol / ethyl acetate / dichloromethane). The title compound (59.5 mg) was obtained as a light brown amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.16 (3H, s), 2.23 (3H, s), 2.52-2.61 (4H, m), 3.13 (3H, s), 3.24 (2H, t, J = 8.2 Hz), 3.70 (2H, s), 3.74-3.80 (4H, m), 4.30 (2H, t, J = 8.2 Hz), 4.37 (2H, s), 6.73-6.79 (1H, m), 6.80 -6.87 (2H, m), 7.12 (1H, d, J = 8.5 Hz), 7.34-7.55 (3H, m), 7.57-7.65 (2H, m), 8.01 (1H, d, J = 8.5 Hz), 8.08 (1H, dd, J = 7.9, 1.2 Hz), 8.50-8.56 (1H, m).
MS (APCI) m / z: 612 (M + H) ⁺ .

(Example 23)
1- {5- [4- (imidazo [1,2-a] pyridin-3-yl) -3-methylphenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2 -[2- (Methylsulfonyl) phenyl] ethanone

Compound obtained in Example 8a (50.0 mg), 3-bromoimidazo [1,2-a] pyridine (35.1 mg) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) To a solution of dichloromethane complex (7.27 mg) in 1,2-dimethoxyethane (2 mL), an aqueous solution (0.5 mL) of sodium carbonate (28.3 mg) was added, and microwave reaction apparatus was used. And reacted at 130 ° C. for 20 minutes. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane, ethyl acetate / hexane) to give the title compound (20. 6 mg) was obtained as a colorless amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.10 (3H, s), 2.17 (3H, s), 3.13 (3H, s), 3.25 (2H, t, J = 8.5 Hz), 4.31 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.74-6.82 (2H, m), 6.86-6.90 (2H, m), 7.15-7.26 (1H, m), 7.37 (1H, d, J = 7.9 Hz), 7.50-7.56 (1H, m), 7.58 (1H, s), 7.60-7.65 (1H, m), 7.67 (1H, d, J = 9.1 Hz), 7.76 (1H, d, J = 7.3 Hz), 8.04 (1H, d, J = 8.5 Hz), 8.08 (1H, dd, J = 7.9, 1.2 Hz).
MS (APCI) m / z: 552 (M + H) ⁺ .

(Example 24)
1- {4-Methyl-5- [3-methyl-4- (1H-pyrrolo [2,3-b] pyridin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone

The compound obtained in Example 8a (50.0 mg), 4-bromo-1H-pyrrolo [2,3-b] pyridine (35.1 mg) and [1,1′-bis (diphenylphosphino) ferrocene ] To a 1,2-dimethoxyethane (2 mL) solution of dichloropalladium (II) dichloromethane complex (7.27 mg), an aqueous solution (0.5 mL) of sodium carbonate (28.3 mg) was added, and the microwave reaction The apparatus was reacted at 130 ° C. for 20 minutes. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane, ethyl acetate / hexane) to give the title compound (26. 1 mg) was obtained as a colorless amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.17-2.23 (6H, m), 3.13 (3H, s), 3.25 (2H, t, J = 8.5 Hz), 4.31 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.26-6.40 (1H, m), 6.75-6.82 (1H, m), 6.84-6.91 (2H, m), 6.99 (1H, d, J = 5.5 Hz), 7.28 -7.32 (1H, m), 7.37 (1H, d, J = 7.9 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.63 (1H, t, J = 7.3 Hz), 8.03 (1H, d, J = 9.1 Hz), 8.08 (1H, d, J = 7.9 Hz), 8.33 (1H, d, J = 4.9 Hz), 9.03 (1H, s).
MS (APCI) m / z: 552 (M + H) ⁺ .

(Example 25)
1-[(2S) -1,4-dioxan-2-ylmethyl] -5- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2, 3-Dihydro-1H-indol-5-yl) oxy] phenyl} pyridin-2 (1H) -one

Example 25a 5-bromo-1-[(2S) -1,4-dioxan-2-ylmethyl-2 (1H) -one 5-bromopyridin-2 (1H) -one (200 mg) of N, Sodium hydride (50.6 mg) was added to an N-dimethylformamide (5 mL) solution, and the mixture was stirred at room temperature for 15 minutes. (2S) -1,4-dioxan-2-ylmethylmethanesulfonate (271 mg) was added to the reaction solution, heated to 100 ° C., and stirred for 2 hours. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure. Dichloromethane was added to the resulting residue, and the resulting insoluble solid was collected by filtration and dried to obtain the title compound (230 mg) as a solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: δ: 3.22 (1H, dd, J = 11.2, 9.4 Hz), 3.40-3.54 (2H, m), 3.63 (1H, d, J = 10.3 Hz ), 3.69-3.87 (4H, m), 3.95-4.03 (1H, m), 6.39 (1H, d, J = 9.7 Hz), 7.54 (1H, dd, J = 9.7, 3.0 Hz), 7.88 (1H, d, J = 3.0 Hz).
MS (APCI) m / z: 274 (M + H) ⁺ .

Example 25b 1-[(2S) -1,4-dioxan-2-ylmethyl] -5- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] Acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} pyridin-2 (1H) -one The compound obtained in Example 8a (60.0 mg), obtained in Example 25a. To a solution of 1,2'-dimethoxyethane (3 mL) of the compound (58.6 mg) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (8.73 mg), An aqueous solution (0.5 mL) of sodium carbonate (34.0 mg) was added, and the mixture was reacted at 130 ° C. for 20 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol / ethyl acetate / dichloromethane) to give the title compound (21.8 mg). Was obtained as a light brown amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.14 (3H, s), 2.24 (3H, s), 3.13 (3H, s), 3.23 (2H, t, J = 8.2 Hz), 3.27-3.37 ( 1H, m), 3.51-3.61 (1H, m), 3.63-3.79 (4H, m), 3.87-3.99 (2H, m), 4.20-4.33 (3H, m), 4.37 (2H, s), 6.60 ( 1H, d, J = 9.1 Hz), 6.71 (1H, dd, J = 8.5, 2.4 Hz), 6.76-6.79 (1H, m), 6.81 (1H, d, J = 8.5 Hz), 7.07 (1H, d , J = 8.5 Hz), 7.25-7.38 (3H, m), 7.53 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 8.00 (1H, d, J = 8.5 Hz) ), 8.08 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 629 (M + H) ⁺ .

(Example 26)
1- [5- (4- {1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-indol-5-yl} -3-methylphenoxy) -4-methyl-2,3- Dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone

Example 26a 1-[(2S) -1,4-dioxan-2-ylmethyl] -5-iodo-1H-indole 5-Iodo-1H-indole (500 mg) N, N-dimethylformamide (6 mL) To the solution was added sodium hydride (90.5 mg), and the mixture was stirred at room temperature for 15 minutes. (2S) -1,4-dioxan-2-ylmethylmethanesulfonate (484 mg) was added to the reaction solution, heated to 60 ° C., and stirred for 7 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with a 1: 1 (v / v) mixed solvent of ethyl acetate and hexane. The combined organic layers were dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (523 mg) as a pale brown oil. Obtained as a thing.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.29 (1H, dd, J = 11.5, 10.3 Hz), 3.52-3.61 (1H, m), 3.64-3.73 (3H, m), 3.76-3.82 (1H , m), 3.87-3.95 (1H, m), 4.06-4.17 (2H, m), 6.45 (1H, d, J = 3.6 Hz), 7.10 (1H, d, J = 3.6 Hz), 7.21 (1H, d, J = 8.5 Hz), 7.29 (1H, dd, J = 8.5, 1.8 Hz), 7.74 (1H, d, J = 1.8 Hz).

Example 26b 1- [5- (4- {1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-indol-5-yl} -3-methylphenoxy) -4-methyl -2,3-Dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone The compound obtained in Example 8a (50.0 mg), obtained in Example 26a. To a solution of compound (45.8 mg) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (7.27 mg) in 1,2-dimethoxyethane (3 mL) was added carbonic acid. An aqueous solution (0.5 mL) of sodium (28.3 mg) was added, and the mixture was reacted at 130 ° C. for 20 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (11.1 mg) Obtained as a yellow amorphous solid.
MS (APCI) m / z: 651 (M + H) ⁺ .

(Example 27)
1- {5- [3-Methoxy-4- (1-methyl-1H-benzimidazol-6-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (Methylsulfonyl) phenyl] ethanone

Example 27a tert-butyl 5- (4-bromo-3-methoxyphenoxy) -4-methyl-2,3-dihydro-1H-indole-1-carboxylate 1-bromo-4-iodo-2-methoxy Copper iodide (I) was added to a solution of benzene (1.51 g) and tert-butyl 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylate (600 mg) in dioxane (8 mL). ) (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 6 hours. After cooling to room temperature, the mixture was allowed to stand overnight, stirred again at 100 ° C. for 9 hours, and the reaction solution was filtered through Celite. The obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / hexane) to give the title compound (529 mg) as a colorless solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.55 (9H, s), 2.05 (3H, s), 3.03 (2H, t, J = 8.8 Hz), 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).

Example 27b 1- [5- (4-Bromo-3-methoxyphenoxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl Ethanone To a solution of the compound obtained in Example 27a (400 mg) in dichloromethane (4 mL) was added 4N hydrochloric acid dioxane solution (4 mL), and the mixture was stirred at room temperature for 2 hours 30 minutes. The reaction solution was concentrated to obtain crude 5- (4-bromo-3-methoxyphenoxy) -4-methyl-2,3-dihydro-1H-indole hydrochloride (336 mg).
N-methylmorpholine (0.202 mL) was added to a solution of the obtained compound (336 mg) in N, N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 15 minutes. To the reaction solution was added 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (382 mg) and [2- (methylsulfonyl) phenyl] acetic acid (256 mg). ) And stirred at room temperature for 16 hours and 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / hexane → ethyl acetate / dichloromethane) to obtain the title compound (534 mg) as a colorless solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.11 (3H, s), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 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) ⁺ .

Example 27c 1- {5- [3-Methoxy-4- (1-methyl-1H-benzimidazol-6-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indole-1- Yl} -2- [2- (methylsulfonyl) phenyl] ethanone The compound obtained in Example 27b (50.0 mg), (1-methyl-1H-benzimidazol-6-yl) boronic acid (24.9) mg) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (7.70 mg) in 1,2-dimethoxyethane (2 mL) was added sodium carbonate (30.0). mg) aqueous solution (0.5 mL) was added, and the mixture was reacted at 130 ° C. for 20 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic layers are dried over sodium sulfate, the solvent is distilled off under reduced pressure, and the resulting residue is purified by silica gel column chromatography (ethyl acetate / dichloromethane) and NH silica gel column chromatography (ethyl acetate / dichloromethane). Gave the title compound (18.3 mg) as a colorless solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.19 (3H, s), 3.13 (3H, s), 3.24 (2H, t, J = 8.5 Hz), 3.78 (3H, s), 3.85 (3H, s), 4.31 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.45 (1H, dd, J = 8.5, 2.4 Hz), 6.64-6.67 (1H, m), 6.88 (1H, d , J = 8.5 Hz), 7.22-7.26 (1H, m), 7.37 (1H, d, J = 7.3 Hz), 7.39-7.43 (1H, m), 7.46-7.57 (2H, m), 7.60-7.66 ( 1H, m), 7.80 (1H, d, J = 8.5 Hz), 7.86 (1H, s), 8.02 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 582 (M + H) ⁺ .

(Example 28)
1- (methoxymethyl) -5- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl ) Oxy] phenyl} pyridin-2 (1H) -one

Example 28a 1- (methoxymethyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one 5- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-ol (200 mg) in N, N-dimethylformamide (5 mL) in sodium hydride (36. 2 mg) was added and stirred at room temperature for 15 minutes. Chloro (methoxy) methane (0.136 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. Water was poured into the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The combined organic layers were dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the crude title compound (240 mg) as an oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.31 (12H, s), 3.41 (3H, s), 5.31 (2H, s), 6.53 (1H, d, J = 9.1 Hz), 7.60 (1H, dd, J = 9.1, 2.4 Hz), 7.84 (1H, d, J = 2.4 Hz).
MS (APCI) m / z: 266 (M + H) ⁺ .

Example 28b 1- (methoxymethyl) -5- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H- Indol-5-yl) oxy] phenyl} pyridin-2 (1H) -one The compound obtained in Example 1b (50.0 mg), the compound obtained in Example 28a (51.5 mg) and [1 , 1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (7.94 mg) in 1,2-dimethoxyethane (2 mL) and aqueous solution of sodium carbonate (20.6 mg) ( 0.5 mL) was added, and the mixture was reacted at 130 ° C. for 20 minutes in a microwave reaction apparatus. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic layers are dried over sodium sulfate, the solvent is distilled off under reduced pressure, and the resulting residue is purified by silica gel column chromatography (ethyl acetate / dichloromethane) and NH silica gel column chromatography (ethyl acetate / dichloromethane). Gave the title compound (15.4 mg) as a light brown amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.14 (3H, s), 2.24 (3H, s), 3.13 (3H, s), 3.23 (2H, t, J = 8.5 Hz), 3.44 (3H, s), 4.30 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 5.35 (2H, s), 6.61 (1H, d, J = 9.8 Hz), 6.72 (1H, dd, J = 8.5 , 2.4 Hz), 6.76-6.84 (2H, m), 7.07 (1H, d, J = 8.5 Hz), 7.26-7.71 (5H, m), 8.00 (1H, d, J = 8.5 Hz), 8.08 (1H , d, J = 6.7 Hz).
MS (APCI) m / z: 573 (M + H) ⁺ .

(Example 29)
2- [2- (Methylsulfonyl) phenyl] -1- {4-methyl-5- [4- (tetrahydro-2H-pyran-4-yl) phenoxy] -2,3-dihydro-1H-indole-1- Il} Ethanon

The compound (24 mg) obtained in Example 3 was dissolved in ethanol (1 mL) and ethyl acetate (1 mL), 7.5% palladium carbon (4.8 mg) was added, and the mixture was added under a hydrogen atmosphere at room temperature. Stir for 4 hours. The insoluble material in the reaction solution was removed by filtration, and the solvent was distilled off under reduced pressure to obtain the title compound (20.6 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.71-1.82 (4H, m), 2.13 (3H, s), 2.62-2.74 (1H, m), 3.12 (3H, s), 3.17-3.25 (2H , m), 3.48-3.56 (2H, m), 4.03-4.10 (2H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.13 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.52 (1H, t, J = 7.0 Hz) , 7.62 (1H, t, J = 7.9 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 506 (M + H) ⁺ .

(Example 30)
1- {5- [4- (4-Hydroxycyclohexyl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone

Example 30a 1- {5- [4- (1,4-Dioxaspiro [4.5] dec-8-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl } -2- [2- (Methylsulfonyl) phenyl] ethanone The compound obtained in Example 5a (55.6 mg) was dissolved in methanol (3 mL), and 7.5% palladium carbon (11.1 mg). And stirred at room temperature for 18 hours under a hydrogen atmosphere and then stirred at 60 ° C. for 4.5 hours. The insoluble material in the reaction solution was removed by filtration, and the solvent was distilled off under reduced pressure to obtain the title compound (84.8 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.61-1.90 (8H, m), 2.13 (3H, s), 2.47-2.58 (1H, br m), 3.12 (3H, s), 3.21 (2H, t, J = 8.2 Hz), 3.98 (4H, s), 4.28 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 6.74-6.84 (3H, m), 7.14 (2H, d, J = 7.9 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.96 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

Example 30b 4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} cyclohexanone To a solution of the compound obtained in Example 30a (84.8 mg) in acetone (5 mL) was added p-toluenesulfonic acid monohydrate (10 mg), and the mixture was stirred at 45 ° C. for 4 hours. Saturated aqueous sodium hydrogen carbonate solution was added to neutralize the reaction mixture, and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (26.9 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.84-1.96 (2H, m), 2.13 (3H, s), 2.16-2.27 (2H, m), 2.44-2.54 (4H, m), 2.94-3.04 (1H, 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), 6.77 (1H, d, J = 9.2 Hz), 6.83 (2H, d, J = 9.2 Hz), 7.15 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

Example 30c 1- {5- [4- (4-hydroxycyclohexyl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) Phenyl] ethanone The compound obtained in Example 30b (26.9 mg) was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL), and sodium borohydride (0.98 mg) was added under ice-cooling. Stir at room temperature for 2 hours. 1N Hydrochloric acid (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (24.7 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.36-1.57 (4H, m), 1.85-1.96 (2H, m), 2.04-2.16 (5H, m), 2.40-2.50 (1H, m), 3.12 (3H, s), 3.21 (2H, t, J = 8.5 Hz), 3.64-3.74 (1H, m), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.71-6.84 ( 3H, m), 7.10 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.60-7.64 (1H, m), 7.96 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 520 (M + H) ⁺ .

(Example 31)
1- {4-Methyl-5- [3-methyl-4- (tetrahydro-2H-pyran-3-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (Methylsulfonyl) phenyl] ethanone

Example 31a 1- {5- [4- (3,4-Dihydro-2H-pyran-5-yl) -3-methylphenoxy] -4-methyl-2,3-dihydro-1H-indole-1 -Yl} -2- [2- (methylsulfonyl) phenyl] ethanone Compound obtained in Example 13b (60 mg), 2- (3,4-dihydro-2H-pyran-5-yl) -4,4 , 5,5-tetramethyl-1,3,2-dioxaborolane (36.8 mg) in 1,2-dimethoxyethane (3 mL) was added an aqueous solution (1 mL) of sodium carbonate (37.1 mg). And stirred at room temperature for 5 minutes. Next, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (9.53 mg) was added, and the mixture was reacted at 130 ° C. for 40 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (31.3 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.92-2.01 (2H, m), 2.13 (3H, s), 2.18-2.24 (2H, m), 2.26 (3H, s), 3.12 (3H, s ), 3.22 (2H, t, J = 8.5 Hz), 3.99-4.07 (2H, m), 4.29 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.33 (1H, s), 6.62 (1H, dd, J = 8.5, 2.4 Hz), 6.70 (1H, d, J = 2.4 Hz), 6.79 (1H, d, J = 8.5 Hz), 7.01 (1H, d, J = 7.9 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.49-7.56 (1H, m), 7.62 (1H, d, J = 8.5 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).

Example 31b 1- {4-Methyl-5- [3-methyl-4- (tetrahydro-2H-pyran-3-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl}- 2- [2- (Methylsulfonyl) phenyl] ethanone The compound obtained in Example 31a (31.3 mg) was dissolved in methanol (3 mL), and 7.5% palladium carbon (6.26 mg) was added. The mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. Ethyl acetate was added to the reaction mixture, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (10.6 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.66-1.84 (2H, m), 1.90-1.99 (1H, m), 2.13 (3H, s), 2.31 (3H, s), 2.94-3.04 (1H , br m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.32 (1H, t, J = 10.7 Hz), 3.42-3.51 (1H, m), 3.67-3.77 (1H , m), 3.85-3.93 (1H, m), 3.98-4.05 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.63-6.72 (2H, m), 6.76 (1H, d, J = 8.5 Hz), 7.08 (1H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.3 Hz), 7.62 ( 1H, t, J = 7.3 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 520 (M + H) ⁺ .

(Example 32)
1- {4-Methyl-5- [3-methyl-4- (tetrahydro-2H-pyran-2-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (Methylsulfonyl) phenyl] ethanone

Example 32a 1- {5- [4- (3,4-Dihydro-2H-pyran-6-yl) -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (Methylsulfonyl) phenyl] ethanone 1,2- of the compound obtained in Example 13b (60.0 mg), 3,4-dihydro-2H-pyran-6-boronic acid (36.8 mg) An aqueous solution (1 mL) of sodium carbonate (37.1 mg) was added to a dimethoxyethane (3 mL) solution, and the mixture was stirred at room temperature for 5 minutes. Next, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (9.5 mg) was added, and the mixture was reacted at 130 ° C. for 40 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (31.6 mg) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.88-1.94 (2H, m), 2.11 (3H, d, J = 9.2 Hz), 2.14-2.21 (2H, m), 2.30 (3H, s), 3.13 (3H, s), 3.21 (2H, t, J = 8.5 Hz), 4.07-4.17 (2H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.78 (1H , t, J = 4.0 Hz), 6.59-6.63 (1H, m), 6.65-6.70 (1H, m), 6.78 (1H, d, J = 8.5 Hz), 7.14-7.19 (1H, m), 7.36 ( 1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.3 Hz), 7.62 (1H, t, J = 7.3 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).

Example 32b 1- {4-Methyl-5- [3-methyl-4- (tetrahydro-2H-pyran-2-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl}- 2- [2- (methylsulfonyl) phenyl] ethanone The compound obtained in Example 32a (31.6 mg) was dissolved in methanol (3 mL), and 7.5% palladium carbon (6.3 mg) was added. The mixture was stirred at 60 ° C. for 5 hours in a hydrogen atmosphere. Ethyl acetate was added to the reaction solution, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (8.5 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.56-1.81 (4H, m), 1.91-1.98 (1H, m), 2.10 (3H, s), 2.29 (3H, s), 3.12 (3H, s ), 3.21 (2H, t, J = 8.5 Hz), 3.56-3.66 (1H, m), 4.09-4.16 (2H, m), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s) , 4.39-4.45 (1H, m), 6.63-6.72 (2H, m), 6.75 (1H, d, J = 8.5 Hz), 7.31-7.38 (2H, m), 7.49-7.54 (1H, m), 7.59 -7.64 (1H, m), 7.95 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 520 (M + H) ⁺ .

(Example 33)
1- (5- {4- [1- (1,4-Dioxane-2-ylmethyl) -1H-pyrazol-5-yl] phenoxy} -4-methyl-2,3-dihydro-1H-indole-1- Yl) -2- [2- (methylsulfonyl) phenyl] ethanone

Example 33a 5- (4-bromophenyl) -1- (1,4-dioxan-2-ylmethyl) -1H-pyrazole (1,4-dioxan-2-ylmethyl) hydrazine hydrochloride (624 mg) Triethylamine (650 μL), 1- (4-bromophenyl) -3- (dimethylamino) prop-2-en-1-one (CAS number: 73387-60-7) (300 mg) in an ethanol (5 mL) solution. ) In ethanol (5 mL) was added and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound and 3- (4-bromophenyl) -1- (1,4-dioxan-2-ylmethyl) -1H-pyrazole. A mixture of (322 mg) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.21-3.37 (1H, m), 3.62-3.77 (4H, m), 3.95-4.21 (4H, m), 6.28 (1H, s), 7.35 (2H , d, J = 7.9 Hz), 7.55-7.61 (3H, m).

Example 33b tert-butyl 5- {4- [1- (1,4-dioxan-2-ylmethyl) -1H-pyrazol-5-yl] phenoxy} -4-methyl-2,3-dihydro-1H -Indole-1-carboxylate of tert-butyl 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylate (205 mg) and the compound obtained in Experimental Example 33a (322 mg) Copper (I) iodide (31.3 mg), N, N-dimethylglycine (33.9 mg) and cesium carbonate (535 mg) were added to a dioxane (10 mL) solution, and the mixture was stirred at 100 ° C. for 6 hours. Saturated aqueous ammonium chloride solution (6 mL) and saturated aqueous sodium hydrogen carbonate solution (3 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (148 mg) as a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.24 (9H, br s), 2.09 (3H, s), 2.98-3.10 (1H, m), 3.27-3.36 (1H, m), 3.51-3.61 ( 1H, m), 3.62-3.77 (4H, m), 3.99-4.22 (6H, m), 6.26 (1H, dd, J = 17.1, 1.8 Hz), 6.83-6.96 (2H, m), 7.35 (2H, d, J = 8.5 Hz), 7.53-7.62 (2H, m), 7.65-7.70 (1H, br m).

Example 33c 1- (5- {4- [1- (1,4-Dioxane-2-ylmethyl) -1H-pyrazol-5-yl] phenoxy} -4-methyl-2,3-dihydro-1H -Indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone To a solution of the compound obtained in Example 33b (148 mg) in dichloromethane (1 mL) was added 4N hydrochloric acid dioxane solution (2 mL). And stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and dried under reduced pressure to give crude 5- {4- [1- (1,4-dioxane-2-ylmethyl) -1H-pyrazol-5-yl] phenoxy} -4-methyl. -2,3-Dihydro-1H-indole hydrochloride (130 mg) was obtained as a yellow solid.
Triethylamine (130 μL) was added to a solution of the obtained compound (130 mg) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes. 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (126 mg) and 2- (2-methylsulfonylphenyl) acetic acid (78.1 mg) And stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (76.9 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.14 (3H, s), 3.13 (3H, s), 3.18-3.35 (3H, m), 3.51-3.60 (1H, m), 3.63-3.77 (4H , m), 3.99-4.21 (3H, m), 4.30 (2H, t, J = 8.2 Hz), 4.37 (2H, s), 6.24 (1H, s), 6.86 (1H, d, J = 8.5 Hz) , 6.93 (2H, d, J = 8.5 Hz), 7.37 (3H, d, J = 7.9 Hz), 7.49-7.58 (2H, m), 7.62 (1H, t, J = 7.6 Hz), 8.02 (1H, d, J = 7.9 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 588 (M + H) ⁺ .

(Example 34)
2'-methyl-4 '-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] biphenyl-4-carvone Acid sodium salt

Example 34a 2'-Methyl-4 '-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] Biphenyl-4-carboxylic acid ethyl ester Compound (50.0 mg) obtained in Example 13b, 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) 1,2-dimethoxyethane (2 mL) of ethyl benzoate (53.7 mg) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (7.9 mg) ) An aqueous solution (0.5 mL) of sodium carbonate (20.6 mg) was added to the solution, and the mixture was reacted in a microwave reactor for 15 minutes at 130 ° C. After cooling the reaction solution to room temperature. Water was poured and the mixture was extracted three times with ethyl acetate, the combined organic layers were dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (dichloromethane / hexane → ethyl acetate / dichloromethane). The title compound (50.8 mg) was obtained as a colorless amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.41 (3H, t, J = 7.3 Hz), 2.16 (3H, s), 2.22 (3H, s), 3.13 (3H, s), 3.24 (2H, t, J = 8.5 Hz), 4.30 (2H, t, J = 8.5 Hz), 4.35-4.44 (4H, m), 6.72-6.77 (1H, m), 6.78-6.81 (1H, m), 6.84 (1H , d, J = 9.1 Hz), 7.13 (1H, d, J = 7.9 Hz), 7.35-7.41 (3H, m), 7.49-7.55 (1H, m), 7.60-7.66 (1H, m), 8.01 ( 1H, d, J = 9.1 Hz), 8.05-8.10 (3H, m).
MS (APCI) m / z: 584 (M + H) ⁺ .

Example 34b 2′-methyl-4 ′-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] Biphenyl-4-carboxylic acid sodium salt The compound (49.0 mg) obtained in Example 34a was dissolved in tetrahydrofuran (1 mL) and ethanol (1 mL), and 1N aqueous sodium hydroxide solution (0.252 mL) was added thereto. ) Was added. The reaction mixture was stirred at room temperature for 19 hours 30 minutes, and the precipitated solid was collected by filtration and dried to give the title compound (36.6 mg) as a colorless solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.09 (3H, s), 2.18 (3H, s), 3.17-3.25 (5H, m), 4.29 (2H, t, J = 7.9 Hz), 4.34 (2H, s), 6.67 (1H, dd, J = 8.5, 2.4 Hz), 6.77-6.80 (1H, m), 6.83 (1H, d, J = 8.5 Hz), 7.13 (1H, d, J = 8.5 Hz), 7.16 (2H, d, J = 7.9 Hz), 7.47-7.51 (1H, m), 7.55-7.61 (1H, m), 7.67-7.73 (1H, m), 7.84 (2H, d, J = 7.9 Hz), 7.87 (1H, d, J = 8.5 Hz), 7.97 (1H, dd, J = 7.9, 1.2 Hz).
MS (APCI) m / z: 556 (M + H) ⁺ .

(Example 35)
1-methyl-5- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] Phenyl} -1H-indole-2-carboxylic acid

Example 35a 5-Bromo-1-methyl-1H-indole-2-carboxylic acid ethyl ester 5-Bromo-1H-indole-2-carboxylic acid ethyl ester (500 mg) N, N-dimethylformamide (6 To the solution, sodium hydride (82.0 mg) was added and stirred at room temperature for 50 minutes. To the reaction solution was added iodomethane (0.139 mL), heated to 60 ° C., and further stirred for 3 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with a 1: 1 (v / v) mixed solvent of ethyl acetate and hexane. The combined organic layers were dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane / hexane) to give the title compound (544 mg) as a colorless solid. It was.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.41 (3H, t, J = 7.3 Hz), 4.06 (3H, s), 4.38 (2H, q, J = 7.3 Hz), 7.25-7.29 (1H, m), 7.22 (1H, s), 7.42 (1H, dd, J = 9.1, 1.8 Hz), 7.78-7.82 (1H, m).

Example 35b 1-Methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole-2-carboxylic acid ethyl ester In Example 35a To a 1,4-dioxane (8 mL) solution of the obtained compound (300 mg), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (15.6 mg), 4 , 4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (405 mg) and potassium acetate (313 mg), 100 The mixture was stirred at ° C for 3 hours and 10 minutes. After cooling to room temperature, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (278 mg) as a pale yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.37 (12H, s), 1.42 (3H, t, J = 7.3 Hz), 4.08 (3H, s), 4.38 (2H, q, J = 7.3 Hz) , 7.30 (1H, s), 7.37 (1H, d, J = 8.5 Hz), 7.77 (1H, d, J = 8.5 Hz), 8.20 (1H, s).
MS (APCI) m / z: 330 (M + H) ⁺ .

Example 35c Ethyl 1-methyl-5- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole- 5-yl) oxy] phenyl} -1H-indole-2-carboxylate The compound obtained in Example 13b (50.0 mg), the compound obtained in Example 35b (48.0 mg) and [1, 1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (7.9 mg) in 1,2-dimethoxyethane (2 mL) was added to an aqueous solution of sodium carbonate (20.6 mg) (0 0.5 mL) was added, and the mixture was reacted at 130 ° C. for 20 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (44.1 mg) as a pale product. Obtained as a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42 (3H, t, J = 7.3 Hz), 2.18 (3H, s), 2.23 (3H, s), 3.13 (3H, s), 3.24 (2H, t, J = 8.2 Hz), 4.11 (3H, s), 4.30 (2H, t, J = 8.2 Hz), 4.35-4.44 (4H, m), 6.72-6.76 (1H, m), 6.81 (1H, d , J = 2.4 Hz), 6.85 (1H, d, J = 8.5 Hz), 7.18 (1H, d, J = 8.5 Hz), 7.27-7.33 (2H, m), 7.35-7.43 (2H, m), 7.49 -7.55 (1H, m), 7.57 (1H, s), 7.59-7.64 (1H, m), 8.00 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 637 (M + H) ⁺ .

Example 35d 1-methyl-5- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole-5 -Yl) oxy] phenyl} -1H-indole-2-carboxylic acid The compound obtained in Example 35c (43.0 mg) was dissolved in tetrahydrofuran (2 mL) and ethanol (2 mL), and 1N sodium hydroxide was dissolved. Aqueous solution (0.203 mL) was added and stirred at room temperature for 16 hours, and then the reaction mixture was warmed to 50 ° C. and stirred for 4 hours. 1N Aqueous sodium hydroxide solution (0.200 mL) was added, and the mixture was further stirred at 50 ° C. for 3 hr 40 min. After cooling the reaction solution to room temperature, 1N hydrochloric acid (0.420 mL) was added, and the organic solvent was distilled off under reduced pressure. Water was added to the residue, and extraction was performed 3 times with dichloromethane. The combined organic layers were dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (42.0 mg) as a light brown amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.18 (3H, s), 2.24 (3H, s), 3.13 (3H, s), 3.24 (2H, t, J = 8.5 Hz), 4.12 (3H, s), 4.30 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 6.75 (1H, dd, J = 8.5, 2.4 Hz), 6.82 (1H, d, J = 2.4 Hz), 6.86 ( 1H, d, J = 8.5 Hz), 7.18 (1H, d, J = 8.5 Hz), 7.32-7.39 (2H, m), 7.40-7.46 (2H, m), 7.52 (1H, t, J = 7.3 Hz ), 7.58-7.65 (2H, m), 8.01 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 609 (M + H) ⁺ .

(Example 36)
1-methyl-6- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] Phenyl} -1H-indole-2-carboxylic acid

Example 36a Ethyl 5-bromo-1-methyl-1H-indole-2-carboxylate Ethyl 6-bromo-1H-indole-2-carboxylate (500 mg) N, N-dimethylformamide (5 mL) Sodium hydride (82.0 mg) was added to the solution and stirred at room temperature for 20 minutes. To the reaction solution was added iodomethane (0.139 mL), heated to 60 ° C., and further stirred for 1 hour and 15 minutes. The reaction mixture was cooled to room temperature, water was poured, and the precipitated solid was collected by filtration and dried to give the title compound (444 mg) as a colorless solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.41 (3H, t, J = 7.1 Hz), 4.04 (3H, s), 4.38 (2H, q, J = 7.1 Hz), 7.22-7.27 (2H, m), 7.53 (1H, d, J = 8.5 Hz), 7.55-7.57 (1H, m).

Example 36b 1-methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole-2-carboxylic acid ethyl ester In Example 36a To a 1,4-dioxane (8 mL) solution of the obtained compound (220 mg), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (11.4 mg), 4 , 4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (297 mg) and potassium acetate (230 mg), 100 The mixture was stirred at ° C for 3 hours and 30 minutes. After cooling to room temperature, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane / hexane) to give the title compound (232 mg) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.38 (12H, s), 1.41 (3H, t, J = 7.3 Hz), 4.12 (3H, s), 4.38 (2H, q, J = 7.3 Hz) , 7.28 (1H, s), 7.57 (1H, d, J = 7.9 Hz), 7.67 (1H, d, J = 7.9 Hz), 7.91 (1H, s).
MS (APCI) m / z: 330 (M + H) ⁺ .

Example 36c 1-methyl-6- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole-5 -Yl) oxy] phenyl} -1H-indole-2-carboxylic acid ethyl ester The compound obtained in Example 13b (80.0 mg), the compound obtained in Example 36b (102 mg) and [1 , 1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (12.7 mg) in 1,2-dimethoxyethane (3 mL) solution in aqueous solution of sodium carbonate (33.0 mg) ( 0.5 mL) was added, and the mixture was reacted at 130 ° C. for 25 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (94.2 mg) Obtained as a yellow amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42 (3H, t, J = 7.0 Hz), 2.18 (3H, s), 2.25 (3H, s), 3.13 (3H, s), 3.24 (2H, t, J = 8.5 Hz), 4.08 (3H, s), 4.30 (2H, t, J = 8.5 Hz), 4.34-4.42 (4H, m), 6.76 (1H, dd, J = 8.5, 2.4 Hz), 6.82 (1H, d, J = 2.4 Hz), 6.86 (1H, d, J = 8.5 Hz), 7.11 (1H, d, J = 8.5 Hz), 7.21 (1H, d, J = 8.5 Hz), 7.25- 7.31 (1H, m), 7.33 (1H, s), 7.37 (1H, d, J = 7.3 Hz), 7.53 (1H, t, J = 7.9 Hz), 7.63 (1H, t, J = 7.6 Hz), 7.67 (1H, d, J = 7.9 Hz), 8.01 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 637 (M + H) ⁺ .

Example 36d 1-methyl-6- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole-5 -Yl) oxy] phenyl} -1H-indole-2-carboxylic acid The compound obtained in Example 36c (93.0 mg) was dissolved in tetrahydrofuran (2 mL) and ethanol (2 mL), and 1N water was added thereto. Aqueous sodium oxide (0.438 mL) was added. After stirring at room temperature for 20 hours and 40 minutes, 1N hydrochloric acid (0.450 mL) was added, and the organic solvent was distilled off under reduced pressure. Water was added to the residue, and the precipitated solid was collected by filtration and dried to obtain the title compound (78.9 mg) as a colorless solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.18 (3H, s), 2.26 (3H, s), 3.13 (3H, s), 3.24 (2H, t, J = 8.2 Hz), 4.09 (3H, s), 4.31 (2H, t, J = 8.2 Hz), 4.38 (2H, s), 6.76 (1H, dd, J = 8.2, 2.7 Hz), 6.81-6.83 (1H, m), 6.86 (1H, d , J = 9.1 Hz), 7.10-7.15 (1H, m), 7.21 (1H, d, J = 8.5 Hz), 7.30 (1H, s), 7.37 (1H, d, J = 6.7 Hz), 7.46 (1H , s), 7.50-7.55 (1H, m), 7.59-7.65 (1H, m), 7.70 (1H, d, J = 8.5 Hz), 8.01 (1H, d, J = 9.1 Hz), 8.08 (1H, dd, J = 7.9, 1.2 Hz).
MS (APCI) m / z: 609 (M + H) ⁺ .

(Example 37)
Cis-4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} Cyclohexanecarboxylic acid

Example 37a Methyl 4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) Oxy] phenyl} cyclohex-3-ene-1-carboxylate Compound obtained in Example 13b (300 mg), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Yl) -3-cyclohexene-1-carboxylic acid methyl ester (232 mg) in 1,2-dimethoxyethane (8 mL) was added with an aqueous solution (2 mL) of sodium carbonate (185 mg), and the mixture was stirred at room temperature for 5 minutes. Stir. Next, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (47.7 mg) was added and reacted at 130 ° C. for 20 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (178 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.78-1.90 (1H, m), 2.08-2.13 (4H, m), 2.20 (3H, s), 2.23-2.32 (2H, br m), 2.37- 2.46 (2H, br m), 2.59-2.70 (1H, m), 3.12 (3H, s), 3.16-3.26 (2H, m), 3.72 (3H, s), 4.29 (2H, t, J = 8.2 Hz ), 4.36 (2H, s), 5.50-5.58 (1H, br m), 6.62 (1H, d, J = 8.5 Hz), 6.68 (1H, s), 6.78 (1H, d, J = 8.5 Hz), 6.95 (1H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 ( 1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

Example 37b Methyl 4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) Oxy] phenyl} cyclohexanecarboxylate The compound obtained in Example 37a (178 mg) was dissolved in methanol (5 mL), 7.5% palladium carbon (35.6 mg) was added, and the mixture was added at 50 ° C. under a hydrogen atmosphere. For 4 hours. After allowing to cool, methanol was added to the reaction mixture, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (150 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.58-1.75 (3H, m), 1.85-1.95 (1H, m), 2.05-2.19 (4H, m), 2.22-2.34 (5H, m), 2.61 -2.69 (1H, m), 2.71-2.79 (1H, br m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.45-3.54 (1H, m), 3.73 (3H, s), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.65 (2H, d, J = 7.9 Hz), 6.75 (1H, d, J = 8.5 Hz), 7.07 (1H, d, J = 9.2 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.53 (1H, d, J = 7.3 Hz), 7.61 (1H, d, J = 7.3 Hz), 7.95 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).

Example 37c Cis-4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl ) Oxy] phenyl} cyclohexanecarboxylic acid Dissolved in a mixed solution of the compound obtained in Example 37b in tetrahydrofuran (2 mL) and methanol (2 mL), 1N aqueous sodium hydroxide solution (655 μL) was added, and 60 ° C. For 13 hours. After allowing to cool, the reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane → methanol / dichloromethane) to give the title compound (36.7 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.36-1.74 (4H, m), 1.85-1.92 (2H, m), 2.10-2.19 (5H, m), 2.27 (3H, s), 2.37-2.48 (1H, m), 2.61-2.71 (1H, m), 3.12 (3H, s), 3.14-3.26 (2H, m), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.63-6.70 (2H, m), 6.76 (1H, d, J = 8.5 Hz), 7.06 (1H, d, J = 7.9 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.52 (1H, t , J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.96 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 562 (M + H) ⁺ .

(Example 38)
(4- {2-Methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} cyclohexyl ) Acetic acid

Example 38a Methyl (4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) ) Oxy] phenyl} cyclohex-3-en-1-yl) acetate Compound obtained in Example 13b (100 mg), methyl 2- (4- (4,4,5,5-tetramethyl-1,3) , 2-Dioxaborolan-2-yl) cyclohex-3-enyl) acetate (CAS number 1109277-66-8) (81.7 mg) in 1,2-dimethoxyethane (3 mL) in sodium carbonate (61.8 mg) in water (1 mL) was added and stirred at room temperature for 5 minutes. Next, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (15.9 mg) was added and reacted at 130 ° C. for 1 hour 30 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (38.7 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.39-1.49 (1H, m), 1.81-1.88 (1H, m), 2.10-2.24 (8H, m), 2.25-2.37 (5H, m), 3.12 (3H, s), 3.16-3.25 (2H, m), 3.70 (3H, s), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 5.45-5.52 (1H, br m) , 6.59-6.64 (1H, m), 6.67 (1H, s), 6.78 (1H, d, J = 9.2 Hz), 6.95 (1H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 9.2 Hz), 8.07 (1H, d, J = 7.9 Hz) .

Example 38b Methyl (4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) ) Oxy] phenyl} cyclohexyl) acetate The compound obtained in Example 38a (48.4 mg) was dissolved in a mixed solvent of methanol (2 mL) and ethyl acetate (2 mL), and 7.5% palladium on carbon (10 0.2 mg) was added, and the mixture was stirred at 50 ° C. for 5 hours and 30 minutes in a hydrogen atmosphere. After allowing to cool, methanol was added to the reaction mixture, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (48.4 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.09-1.22 (1H, m), 1.36-1.63 (1H, m), 1.64-1.74 (2H, m), 1.79-1.92 (2H, m), 2.13 (3H, s), 2.27 (3H, s), 2.32-2.42 (1H, m), 2.49 (1H, d, J = 7.9 Hz), 2.56-2.73 (1H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.68 (3H, s), 3.68 (3H, s), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.64-6.70 (2H , br m), 6.76 (1H, d, J = 8.5 Hz), 7.04-7.16 (1H, m), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.3 Hz), 7.62 (1H, t, J = 7.3 Hz), 7.96 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).

Example 38c (4- {2-Methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) Oxy] phenyl} cyclohexyl) acetic acid The compound obtained in Example 38b (2 mL) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), 1N aqueous sodium hydroxide solution (410 μL) was added, and the mixture was stirred at 50 ° C. Stir for 13 hours. After allowing to cool, the reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane → methanol / dichloromethane) to give the title compound (25.8 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.15-1.23 (1H, m), 1.41-1.69 (3H, m), 1.71-1.77 (2H, m), 1.78-1.98 (2H, m), 2.13 (3H, s), 2.26 (3H, s), 2.28-2.32 (1H, m), 2.36-2.44 (1H, m), 2.54 (1H, d, J = 7.3 Hz), 2.59-2.70 (1H, m ), 3.12 (3H, s), 3.17-3.27 (2H, m), 4.28 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 6.66 (2H, d, J = 7.3 Hz), 6.76 (1H, d, J = 8.5 Hz), 7.07-7.15 (1H, m), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.3 Hz), 7.62 (1H, t, J = 7.3 Hz), 7.96 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).
MS (APCI) m / z: 576 (M + H) ⁺ _.

(Example 39)
N- (3,3-dimethylbutanoyl) -N- {4 '-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indole-5 -Yl) oxy] -2'-methylbiphenyl-4-yl} glycine

Example 39a Ethyl N- (3,3-dimethylbutanoyl) -N- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] glycinate To a solution of known ethyl N- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] glycinate (WO2009148052) (110 mg) in dichloromethane (1 mL) 3,3-Dimethylbutyryl chloride (0.0601 mL), N, N-diisopropylethylamine (0.0942 mL), and 4-dimethylaminopyridine (2.20 mg) were added and reacted at room temperature for 3 hours. . Water was added to the reaction solution, extracted with dichloromethane, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (109 mg) as a pale yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.96 (9H, s), 1.26 (3H, t, J = 6.7 Hz), 1.36 (12H, s), 2.10 (2H, s), 4.20 (2H, q, J = 6.9 Hz), 4.33 (2H, s), 7.30 (2H, d, J = 7.9 Hz), 7.84 (2H, d, J = 7.9 Hz).

Example 39b 1- [5- (4-Bromo-3-methylphenoxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (ethylsulfonyl) phenyl Ethanone N, N-dimethylformamide of 5- (4-bromo-3-methylphenoxy) -4-methyl-2,3-dihydro-1H-indole hydrochloride (300 mg) obtained in Example (13b) (5 mL) N-methylmorpholine (0.184 mL) was added to the solution and stirred at room temperature for 25 minutes. Then, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (348 mg) and [2- (ethylsulfonyl) phenyl] acetic acid ( 229 mg), and the mixture was stirred at room temperature for 15 hours and 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / hexane → ethyl acetate / dichloromethane) to give the title compound (421 mg) as a colorless solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 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) ⁺ .

Example 39c Ethyl N- (3,3-dimethylbutanoyl) -N- {4 '-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro -1H-Indol-5-yl) oxy] -2'-methylbiphenyl-4-yl} glycinate Example 1 in a solution of the compound obtained in Example 39b (200 mg) in 1,2-dimethoxyethane (5 mL). Boronic acid ester obtained in 39a (229 mg), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (30.9 mg), sodium carbonate (120 mg), water (1.5 mL) And reacted at 130 ° C. for 30 minutes in a microwave reactor. Water (3 mL) and saturated brine (3 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (207 mg) as a colorless amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.99 (9H, s), 1.21-1.33 (6H, m), 2.12-2.17 (5H, m), 2.20-2.25 (3H, m), 3.18-3.26 (4H, m), 4.22 (2H, q, J = 7.1 Hz), 4.26-4.33 (2H, m), 4.35-4.39 (4H, m), 6.72-6.77 (1H, m), 6.78-6.82 (1H , m), 6.85 (1H, d, J = 8.5 Hz), 7.15 (1H, d, J = 8.5 Hz), 7.29-7.34 (4H, m), 7.38-7.42 (1H, m), 7.48-7.54 ( 1H, m), 7.59-7.66 (1H, m), 7.98-8.05 (2H, m).
MS (APCI) m / z: 725 (M + H) ⁺ .

Example 39d N- (3,3-dimethylbutanoyl) -N- {4 '-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro- 1H-Indol-5-yl) oxy] -2′-methylbiphenyl-4-yl} glycine 2M in a solution of the compound obtained in Example 39c (205 mg) in ethanol / tetrahydrofuran (1: 1) (2 mL). Sodium hydroxide aqueous solution (0.848 mL) was added, and it stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, water (6 mL) was added to make a suspension, 2M hydrochloric acid (0.860 mL) was added, and the mixture was stirred for 30 min. The title compound (181 mg) was obtained as a white solid by drying.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.90 (9H, s), 1.11 (3H, t, J = 7.3 Hz), 2.05-2.10 (5H, m), 2.20 (3H, s), 3.17-3.25 (2H, m), 3.26-3.36 (2H, m), 4.23-4.34 (6H, m), 6.67-6.71 (1H, m), 6.80-6.85 (2H, m), 7.18 (1H, d , J = 8.5 Hz), 7.34-7.41 (4H, m), 7.48-7.52 (1H, m), 7.55-7.61 (1H, m), 7.68-7.75 (1H, m), 7.86 (1H, d, J = 8.5 Hz), 7.89-7.93 (1H, m), 12.68 (1H, s).
MS (APCI) m / z: 697 (M + H) ⁺ .

(Example 40)
N-({4 ′-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -2′-methylbiphenyl -4-yl} carbonyl) glycine

Example 40a Ethyl N- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoyl] glycinate Glycine ethyl ester hydrochloride (293 mg) N, 4-Methylmorpholine (0.230 mL) was added to a suspension of N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 40 minutes. 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid (400 mg), 4- (4,6-dimethoxy-1,3, 5-Triazin-2-yl) -4-methylmorpholinium chloride (580 mg) and N, N-dimethylformamide (2 mL) were added and reacted at room temperature for 3 hours. Water (16 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (253 mg) as a colorless amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.32 (3H, t, J = 7.3 Hz), 1.36 (12H, s), 4.22-4.31 (4H, m), 6.64-6.73 (1H, m), 7.80 (2H, d, J = 7.9 Hz), 7.88 (2H, d, J = 7.9 Hz).

Example 40b Ethyl N-({4 '-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -2'-methylbiphenyl-4-yl} carbonyl) glycinate To a solution of the compound obtained in Example 13b (150 mg) in 1,2-dimethoxyethane (4 mL), the compound obtained in Example 40a (142 mg ), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (23.2 mg), sodium carbonate (90.2 mg), water (1 mL), and 130 ° C. in a microwave reactor. For 20 minutes. Water (1 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate and dichloromethane and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to obtain the title compound (105 mg) as a milky white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.11 (3H, t, J = 7.3 Hz), 1.21 (3H, t, J = 7.0 Hz), 2.08 (3H, s), 2.20 (3H, s), 3.16-3.37 (4H, m), 3.99-4.03 (2H, m), 4.13 (2H, q, J = 7.0 Hz), 4.25-4.35 (4H, m), 6.69-6.75 (1H, m) , 6.81-6.87 (2H, m), 7.18 (1H, d, J = 8.5 Hz), 7.44 (2H, d, J = 8.5 Hz), 7.48-7.53 (1H, m), 7.55-7.61 (1H, m ), 7.68-7.75 (1H, m), 7.84-7.95 (4H, m), 8.99 (1H, t, J = 5.8 Hz).
MS (APCI) m / z: 655 (M + H) ⁺ .

Example 40c N-({4 '-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy]- 2′-Methylbiphenyl-4-yl} carbonyl) glycine The compound (102 mg) obtained in Example 40b was dissolved in ethanol (5.5 mL) and tetrahydrofuran (5.5 mL), and 2M aqueous sodium hydroxide solution was obtained. (0.312 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water (10 mL) was added to make a suspension, and 2M hydrochloric acid (0.320 mL) was added. The insoluble material was collected by filtration and dried under reduced pressure at 65 ° C. to give the title compound (90.3 mg) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.11 (3H, t, J = 7.3 Hz), 2.09 (3H, s), 2.20 (3H, s), 3.16-3.41 (4H, m), 3.93 (2H, d, J = 5.5 Hz), 4.23-4.37 (4H, m), 6.68-6.76 (1H, m), 6.80-6.87 (2H, m), 7.18 (1H, d, J = 7.9 Hz) , 7.44 (2H, d, J = 8.5 Hz), 7.50 (1H, d, J = 6.7 Hz), 7.54-7.63 (1H, m), 7.68-7.76 (1H, m), 7.83-7.96 (4H, m ), 8.84-8.91 (1H, m), 12.63 (1H, br s).
MS (APCI) m / z: 627 (M + H) ⁺ .

(Example 41)
7-[(1-{[2- (Ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -2-methyl-3,4-dihydroisoquinoline -1 (2H) -on

Example 41a tert-butyl 4-methyl-5-[(1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl) oxy] -2,3-dihydro-1H-indole-1- Carboxylates 7-bromo-3,4-dihydro-2H-isoquinolin-1-one (1.09 g) and tert-butyl 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxy To a solution of rate (1.00 g) in 1,4-dioxane (15 mL), copper (I) iodide (0.153 g), N, N-dimethylglycine (0.166 g) and cesium carbonate (2. 61 g) was added and stirred at 95 ° C. for 12 hours. After allowing to cool, ethyl acetate was added to the reaction solution, and the insoluble material was removed by filtration. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (0.960 g) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.51-1.61 (9H, m), 2.05 (3H, s), 2.91-3.05 (4H, m), 3.52-3.59 (2H, m), 4.08 (2H , br s), 5.94 (1H, br s), 6.78 (1H, d, J = 9.1 Hz), 7.01 (1H, br s), 7.12 (2H, t, J = 8.8 Hz), 7.49 (1H, d , J = 2.4 Hz).

Example 41b tert-butyl 4-methyl-5-[(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl) oxy] -2,3-dihydro-1H- Indole-1-carboxylate To a solution of the compound obtained in Example 41a (380 mg) and methyl iodide (0.120 mL) in N, N-dimethylformamide (8 mL) at room temperature, sodium hydride (46 0.2 mg) and stirred at the same temperature for 6 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution, and ethyl acetate was added to separate the layers. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give a mixture containing the title compound (370 mg).

Example 41c 7-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -2-methyl-3 , 4-Dihydroisoquinolin-1 (2H) -one The mixture (250 mg) obtained in Example 41b was dissolved in dichloromethane (5 mL), trifluoroacetic acid (8.00 mL) was added, and the mixture was stirred at room temperature for 3 hr. did. The reaction solution was concentrated under reduced pressure and then dried to obtain crude 2-methyl-7-[(4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -3,4-dihydroisoquinoline-1. (2H) -one trifluoroacetate (259 mg) was obtained as a brown oil.
To a 1,4-dioxane (8 mL) solution of the obtained compound (160 mg) and [2- (ethylsulfonyl) phenyl] acetic acid (95.1 mg), N, N-diisopropylethylamine (0.175 mL), 4- (4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (128 mg) was sequentially added, and the mixture was stirred at room temperature for 12 hours. Ethyl acetate and water were added to the reaction solution for liquid separation. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (196 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3 Hz), 2.10 (3H, s), 2.95 (2H, t, J = 6.7 Hz), 3.12 (3H, s) , 3.16-3.25 (4H, m), 3.54 (2H, t, J = 6.7 Hz), 4.27 (2H, t, J = 8.5 Hz), 4.39 (2H, s), 6.77 (1H, d, J = 8.5 Hz), 7.00 (1H, dd, J = 8.5, 2.4 Hz), 7.10 (1H, d, J = 8.5 Hz), 7.41 (1H, d, J = 7.9 Hz), 7.50 (2H, dd, J = 9.1 , 6.1 Hz), 7.63 (1H, t, J = 7.3 Hz), 7.96 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 519 (M + H) ⁺ .

(Example 42)
6-[(1-{[2- (Ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -2-methyl-3,4-dihydroisoquinoline -1 (2H) -on

Example 42a tert-butyl 4-methyl-5-[(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) oxy] -2,3-dihydro-1H-indole-1- Carboxylate 6-Bromo-3,4-dihydro-2H-isoquinolin-1-one (1.09 g) and tert-butyl 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxy To a solution of the rate (1.00 g) in 1,4-dioxane (15 mL), copper (I) iodide (0.153 g), N, N-dimethylglycine (0.166 g), cesium carbonate (2. 61 g) was added and stirred at 95 ° C. for 12 hours. After allowing to cool, ethyl acetate was added to the reaction solution, and the insoluble material was removed by filtration. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (1.58 g) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.51 (9H, s), 2.00 (3H, s), 2.79-2.95 (4H, m), 3.04 (2H, t, J = 8.5 Hz), 3.97 (2H, t, J = 8.8 Hz), 6.69-6.76 (2H, m), 6.85 (1H, d, J = 8.5 Hz), 7.52-7.59 (2H, m), 8.02 (1H, br s).

Example 42b tert-butyl 4-methyl-5-[(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) oxy] -2,3-dihydro-1H- Indole-1-carboxylate To a solution of the compound obtained in Example 42a (360 mg) and methyl iodide (0.114 mL) in N, N-dimethylformamide (8 mL) at room temperature, sodium hydride (43. 8 mg) was added, and the mixture was stirred at the same temperature for 3 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution, and ethyl acetate was added to separate the layers. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give a mixture containing the title compound (373 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.24-1.63 (9H, m), 2.03 (3H, s), 2.91 (2H, t, J = 7.3 Hz), 3.03 (2H, t, J = 8.5 Hz), 3.13 (3H, s), 3.53 (2H, t, J = 6.7 Hz), 4.04 (2H, br s), 6.58 (1H, s), 6.76 (1H, dd, J = 8.5, 2.4 Hz) , 6.83 (1H, d, J = 8.5 Hz), 7.71 (1H, br s), 7.99 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 409 (M + H) ⁺ .

Example 42c 6-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -2-methyl-3 , 4-Dihydroisoquinolin-1 (2H) -one The compound (70.0 mg) obtained in Example 42b was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (8.00 mL) was added at room temperature. Stir for 3 hours. The reaction solution was concentrated under reduced pressure and then dried to obtain crude 2-methyl-6-[(4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -3,4-dihydroisoquinoline-1. (2H) -one trifluoroacetate (73.0 mg) was obtained as a brown oil.
To a 1,4-dioxane (8 mL) solution of the obtained compound (72.0 mg) and [2- (ethylsulfonyl) phenyl] acetic acid (42.8 mg), N, N-diisopropylethylamine (0.079 mL) was added. ) And 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (57.8 mg) were sequentially added and stirred at room temperature for 6 hours. Ethyl acetate and water were added to the reaction solution for liquid separation. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (76.0 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.08 (3H, s), 2.92 (2H, t, J = 6.4 Hz), 3.13 (3H, s) , 3.16-3.26 (4H, m), 3.53 (2H, t, J = 6.7 Hz), 4.29 (2H, t, J = 8.2 Hz), 4.38 (2H, s), 6.60 (1H, d, J = 1.8 Hz), 6.77 (1H, dd, J = 8.5, 2.4 Hz), 6.84 (1H, d, J = 8.5 Hz), 7.40 (1H, d, J = 7.9 Hz), 7.51 (1H, dd, J = 10.1 , 5.2 Hz), 7.61-7.65 (1H, m), 7.98-8.05 (3H, m).
MS (APCI) m / z: 519 (M + H) ⁺ .

(Example 43)
1- {4-Methyl-5-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) oxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (Ethylsulfonyl) phenyl] ethanone

Example 43a tert-butyl 4-methyl-5-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) oxy] -2,3-dihydro-1H-indole-1- To a solution of the compound (56 mg) obtained in Example 42b in tetrahydrofuran (5 mL) was added borane-tetrahydrofuran complex (1M tetrahydrofuran solution, 720 μL), and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (63.6 mg) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.57 (9H, s), 2.06 (3H, s), 2.62 (3H, s), 2.83-2.95 (2H, br m), 3.03 (2H, t, J = 8.5 Hz), 3.10-3.25 (2H, m), 3.80 (1H, d, J = 15.9 Hz), 3.97-4.09 (2H, br m), 4.14-4.21 (1H, m), 6.62 (1H, s), 6.71-6.76 (1H, m), 6.76-6.82 (1H, br m), 6.93 (1H, d, J = 8.5 Hz), 7.61-7.76 (1H, br m).

Example 43b 1- {4-Methyl-5-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) oxy] -2,3-dihydro-1H-indole-1- Yl} -2- [2- (ethylsulfonyl) phenyl] ethanone To a solution of the compound obtained in Example 43a (63.6 mg) in dichloromethane (1 mL) was added 4N hydrochloric acid dioxane solution (2 mL), and at room temperature. Stir for 2 hours. The reaction solution was concentrated under reduced pressure and dried under reduced pressure to give crude 2-methyl-6-[(4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -1,2,3. , 4-Tetrahydroisoquinoline hydrochloride (53.3 mg) was obtained as a colorless oil.
Triethylamine (45 μL) was added to a solution of the obtained compound (53.3 mg) in N, N-dimethylformamide (2 mL), and the mixture was stirred at room temperature for 5 minutes. 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (66.9 mg) and 2- (2-ethylsulfonylphenyl) acetic acid (44.1) mg) was added, and the mixture was further stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (62.8 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3 Hz), 2.05 (3H, s), 2.69 (3H, s), 2.86-3.02 (2H, m), 3.16- 3.28 (5H, m), 3.30-3.38 (1H, m), 3.87 (1H, d, J = 15.3 Hz), 4.24-4.33 (3H, m), 4.37 (2H, s), 6.65 (1H, s) , 6.73-6.81 (2H, m), 6.98 (1H, d, J = 8.5 Hz), 7.39 (1H, d, J = 7.9 Hz), 7.51 (1H, t, J = 7.9 Hz), 7.63 (1H, t, J = 7.9 Hz), 7.96-8.06 (2H, m).
MS (APCI) m / z: 505 (M + H) ⁺ .

(Example 44)
2- [2- (Ethylsulfonyl) phenyl] -1- [4-methyl-5- (quinoxalin-6-yloxy) -2,3-dihydro-1H-indol-1-yl] ethanone

Example 44a tert-butyl 4-methyl-5- (quinoxalin-6-yloxy) -2,3-dihydro-1H-indole-1-carboxylate 6-bromoquinoxaline (4.61 g) and tert-butyl To a solution of 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylate (5.00 g) in 1,4-dioxane (15 mL) was added copper (I) iodide (0.763). g), N, N-dimethylglycine (0.827 g) and cesium carbonate (13.1 g) were added, and the mixture was stirred at 90 ° C. for 25 hours. After allowing to cool, ethyl acetate was added to the reaction solution, and the insoluble material was removed by filtration. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane → methanol / dichloromethane) to obtain a mixture containing the title compound (0.370 g).

Example 44b 2- [2- (ethylsulfonyl) phenyl] -1- [4-methyl-5- (quinoxalin-6-yloxy) -2,3-dihydro-1H-indol-1-yl] ethanone To a solution of the mixture obtained in Example 44a (365 mg) in dichloromethane (7 mL) was added trifluoroacetic acid (7.00 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and dried to obtain crude 6-[(4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] quinoxaline trifluoroacetate (378 mg). .
To a solution of the obtained compound (350 mg) and [2- (ethylsulfonyl) phenyl] acetic acid (225 mg) in N, N-dimethylformamide (7 mL), N, N-diisopropylethylamine (0.413 mL), 4 -(4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (303 mg) was sequentially added and stirred at room temperature for 12 hours. Ethyl acetate and water were added to the reaction solution for liquid separation. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (110 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 2.11 (3H, s), 3.18-3.27 (4H, m), 4.31 (2H, t, J = 8.5 Hz), 4.41 (2H, s), 6.94 (1H, d, J = 8.5 Hz), 7.17 (1H, d, J = 3.1 Hz), 7.42 (1H, d, J = 7.3 Hz), 7.50-7.66 ( 3H, m), 8.04-8.08 (3H, m), 8.73 (2H, d, J = 4.3 Hz).
MS (APCI) m / z: 488 (M + H) ⁺ .

(Example 45)
1- [5- (Isoquinolin-6-yloxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone

Example 45a tert-butyl 5- (isoquinolin-6-yloxy) -4-methyl-2,3-dihydro-1H-indole-1-carboxylate 6-bromoisoquinoline (250 mg) in dioxane (2.0 mL) solution was added tert-butyl 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylate (150 mg), copper (I) iodide (15.0 mg), N, N-dimethylglycine (16.2 mg) and cesium carbonate (262 mg) were added. After stirring at 100 ° C. for 8 hours, the reaction solution is filtered, and water (8.0 mL), saturated aqueous sodium hydrogen carbonate solution (2.0 mL), and ethyl acetate (3.0 mL) are added to the filtrate and the phases are separated. The aqueous layer was extracted 3 times with ethyl acetate. The organic layers were combined and concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate / dichloromethane) to give the title compound (126 mg) as a white solid.
NMR (400 MHz, CDCl ₃ ) δ: 1.55 (9H, br s), 2.03 (3H, s), 3.04 (2H, t, J = 8.8 Hz), 4.05 (2H, br s), 6.85 (1H, s ), 6.88 (1H, d, J = 8.0 Hz), 7.32 (1H, dd, J = 2.5, 8.5 Hz), 7.38 (1H, d, J = 6.0 Hz), 7.73 (1H, br s), 7.90 ( 1H, d, J = 9.0 Hz), 8.38 (1H, d, J = 6.0 Hz), 9.11 (1H, s).
MS (m / z) 377 (M + H) ⁺ .

Example 45b 6-[(4-Methyl-2,3-dihydro-1H-indol-5-yl) oxy] isoquinoline dihydrochloride Dichloromethane (3. 5 mg) of the compound obtained in Example 45a (124 mg). 0 mL) solution was added 4N hydrochloric acid dioxane solution (3.00 mL) and stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure and dried to obtain the title compound (108 mg) as a white solid.
NMR (400 MHz, DMSO-d ₆ ) δ: 2.08 (3H, s), 3.19 (2H, t, J = 7.8 Hz), 3.76 (2H, t, J = 7.8 Hz), 7.19 (1H, d, J = 8.0 Hz), 7.31 (1H, d, J = 8.5 Hz), 7.37 (1H, d, J = 2.5 Hz), 7.79 (1H, dd, J = 2.5, 9.0 Hz), 8.30 (1H, d, J = 6.5 Hz), 8.55 (1H, d, J = 6.5 Hz), 8.56 (1H, d, J = 9.5 Hz), 9.75 (1H, s).
MS (m / z) 277 (M + H) ^<+> .

Example 45c 1- [5- (isoquinolin-6-yloxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone To the compound (54.5 mg) obtained in Example 45b, N, N-dimethylformamide (1.0 mL), [2- (methylsulfonyl) phenyl] acetic acid (50.0 mg), 1-ethyl-3 -(3-Dimethylaminopropyl) carboximide hydrochloride (45.0 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (32.0 mg), and diisopropylethylamine (0.136 mL) was added and stirred at room temperature. After 18 hours, ethyl acetate (3.0 mL), saturated aqueous sodium hydrogen carbonate solution (1.0 mL), and water (7.0 mL) were added to the reaction mixture, and after liquid separation, the aqueous layer was added with ethyl acetate. Extracted once. The organic layers were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol / ethyl acetate) to obtain the title compound (68.7 mg) as a white solid.
NMR (400 MHz, 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), 4.36 ( 2H, s), 6.86-6.90 (2H, m), 7.31-7.37 (2H, m), 7.40 (1H, d, J = 6.0 Hz), 7.48-7.53 (1H, m), 7.58-7.63 (1H, m), 7.91 (1H, d, J = 9.0 Hz), 8.03-8.07 (2H, m), 8.39 (1H, d, J = 6.0 Hz), 9.12 (1H, s).
MS (m / z) 473 (M + H) ^<+> .

(Example 46)
1- [5- (Isoquinolin-6-yloxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfinyl) phenyl] ethanone

To the compound (45.0 mg) obtained in Example 45b, N, N-dimethylformamide (1.0 mL), [2- (methylsulfinyl) phenyl] acetic acid (30.0 mg), 1-ethyl- 3- (3-Dimethylaminopropyl) carboximide hydrochloride (37.0 mg, 0.193 mmol), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (26.0 mg), and diisopropylethylamine (0.0665 mL). After 20 hours, ethyl acetate (3.0 mL), saturated aqueous sodium hydrogen carbonate solution (1.0 mL), and water (7.0 mL) were added to the reaction solution, and after separation, the aqueous layer was added with ethyl acetate. Extracted once. The organic layers were combined and concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (methanol / ethyl acetate) to obtain the title compound (50.7 mg) as a white solid.
NMR (400 MHz, CDCl ₃ ) δ: 2.08 (3H, s), 2.84 (3H, s), 3.16-3.27 (2H, m), 3.94 (1H, d, J = 16.5 Hz), 4.10 (1H, d , J = 16.5 Hz), 4.22-4.36 (2H, m), 6.86 (1H, d, J = 2.5 Hz), 6.90 (1H, d, J = 9.0 Hz), 7.27 (1H, d, J = 7.0 Hz ), 7.32 (1H, dd, J = 2.5, 8.5 Hz), 7.38 (1H, d, J = 6.0 Hz), 7.46-7.50 (1H, m), 7.56-7.57 (1H, m), 7.91 (1H, d, J = 8.5 Hz), 8.01-8.05 (2H, m), 8.39 (1H, d, J = 6.0 Hz), 9.12 (1H, s).
MS (m / z) 457 (M + H) ⁺ .

(Example 47)
1- {5- [4- (1-Acetylpiperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) phenyl ] Ethanon

Example 47a tert-butyl 5- (4-bromophenoxy) -4-methyl-2,3-dihydro-1H-indole-1-carboxylate tert-butyl 5-hydroxy-4-methyl-2,3- To a solution of dihydro-1H-indole-1-carboxylate (10 g) and 1-bromo-4-iodobenzene (13.6 g) in dioxane (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 saturated aqueous sodium hydrogen carbonate solution (30 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was washed with hexane, collected by filtration and dried to give the title compound (12.8 g) as a white solid.
¹ H-NMR (400 MHz, 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).

Example 47b 1- [5- (4-Bromophenoxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone To a solution of the compound obtained in 47a (12.8 g) in dichloromethane (10 mL) was added 4N dioxane hydrochloride solution (20 mL), and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure and dried under reduced pressure to obtain crude 5- (4-bromophenoxy) -4-methyl-2,3-dihydro-1H-indole hydrochloride (11 g) as a gray solid. .
Triethylamine (8.9 mL) was added to a solution of the obtained compound (11 g) in N, N-dimethylformamide (30 mL), and the mixture was stirred at room temperature for 5 minutes. 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (13.3 g) and [2- (methylsulfonyl) phenyl] acetic acid (CAS number 142336) -20-7) (8.27 g) was added, and the mixture was further stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, water (100 mL) was added, and the precipitated solid was collected by filtration. The obtained solid was washed with hexane to obtain the title compound (15.2 g) as a light brown solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.03 (3H, s), 3.13-3.22 (5H, m), 4.28 (2H, t, J = 8.5 Hz), 4.33 (2H, s), 6.77-6.85 (3H, m), 7.44-7.51 (3H, m), 7.52-7.62 (1H, m), 7.65-7.74 (1H, m), 7.87 (1H, d, J = 8.5 Hz), 7.97 ( (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 500 (M + H) ⁺ .

Example 47c tert-butyl 4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] Phenyl} -3,6-dihydropyridine-1 (2H) -carboxylate Compound obtained in Example 47b (500 mg), 1-tert-butoxycarbonyl-4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) -3,6-dihydro-2H-pyridine (463 mg) in 1,2-dimethoxyethane (10 mL) solution in sodium carbonate (317 mg) in water (3 mL) ) And stirred at room temperature for 5 minutes. [1,1′-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (81.6 mg) was added, and the mixture was reacted at 130 ° C. for 30 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (219 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49 (9H, s), 2.12 (3H, s), 2.45-2.54 (2H, m), 3.12 (3H, s), 3.21 (2H, t, J = 8.5 Hz), 3.56-3.69 (2H, m), 4.08 (2H, d, J = 15.3 Hz), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 5.96 (1H, br s), 6.79 (1H, d, J = 8.5 Hz), 6.83 (2H, d, J = 8.5 Hz), 7.24-7.33 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.47- 7.55 (1H, m), 7.60-7.64 (1H, m), 7.98 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 603 (M + H) ⁺ .

Example 47d tert-butyl 4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] Phenyl} piperidine-1 (2H) -carboxylate The compound (219 mg) obtained in Example 47c was dissolved in tetrahydrofuran (4 mL) and ethyl acetate (4 mL), and 7.5% palladium on carbon (77.5 mg), and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The insoluble material in the reaction solution was removed by filtration, and the solvent was distilled off under reduced pressure to obtain the title compound (205 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 (9H, s), 1.54-1.64 (2H, m), 1.74-1.85 (2H, m), 2.13 (3H, s), 2.53-2.64 (1H , m), 2.73-2.86 (2H, m), 3.12 (3H, s), 3.21 (2H, t, J = 8.2 Hz), 4.13-4.33 (4H, m), 4.36 (2H, s), 6.71- 6.85 (3H, m), 7.10 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.48-7.55 (1H, m), 7.57-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 549 (M + H) ⁺ .

Example 47e 4- {4-[(4-Methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine-1-carboxylate tert-butyl Obtained in Example 47d The compound (0.100 g) was suspended in ethanol (1.5 mL) and water (0.5 mL), potassium hydroxide (0.557 g) was added, and the mixture was stirred at 90 ° C. for 7.5 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (0.0521 g) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 (9H, s), 1.50-1.64 (2H, m), 1.74-1.83 (2H, m), 2.05 (3H, s), 2.52-2.64 (1H , m), 2.70-2.85 (2H, m), 2.95-3.02 (2H, m), 3.57-3.64 (2H, m), 4.14-4.30 (2H, m), 6.47 (1H, d, J = 7.9 Hz ), 6.67 (1H, d, J = 7.9 Hz), 6.78 (2H, d, J = 8.5 Hz), 7.07 (2H, d, J = 8.5 Hz).

Example 47f 4- {4-[(4-Methyl-1-{[3- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine Tert-Butyl-1-carboxylate Triethylamine (0 mL) was added to a solution of the compound obtained in Example 47e (0.052 g) and [3- (methylsulfonyl) phenyl] acetic acid (0.027 g) in dichloromethane (2 mL). .035 mL), N- [3- (dimethylamino) propyl] -N′-ethylcarbodiimide hydrochloride (0.037 g), 3H-1,2,3-triazolo [4,5-b] pyridine-3 -All (0.0086 g) was added and stirred at room temperature for 1 hour 30 minutes. Water was added to the reaction mixture and the mixture was extracted with a mixed solvent of ethyl acetate and dichloromethane (4: 1), and then the organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (0.035 g) as a white amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 (9H, s), 1.51-1.64 (2H, m), 1.75-1.85 (2H, m), 2.12 (3H, s), 2.55-2.65 (1H , m), 2.72-2.84 (2H, m), 3.08 (3H, s), 3.14-3.21 (2H, m), 3.90 (2H, s), 4.16-4.30 (4H, m), 6.77-6.83 (3H , m), 7.10 (2H, d, J = 8.5 Hz), 7.55-7.68 (2H, m), 7.84-7.89 (2H, m), 8.00-8.04 (1H, m).

Example 47g 1- {4-Methyl-5- [4- (piperidin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) ) Phenyl] ethanone The compound obtained in Example 47f (0.0337 g) was dissolved in dichloromethane (0.8 mL), trifluoroacetic acid (0.2 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted three times with a mixed solvent of dichloromethane and ethanol (19: 1). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (0.0326 g) as a pale yellow amorphous solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.76-1.90 (2H, m), 1.91-2.00 (2H, m), 2.11 (3H, s), 2.62-2.73 (1H, m), 2.84-2.94 (2H, m), 3.09 (3H, s), 3.15-3.22 (2H, m), 3.34-3.42 (2H, m), 3.91 (2H, s), 4.18-4.25 (2H, m), 6.77-6.84 (3H, m), 7.12 (2H, d, J = 8.5 Hz), 7.56-7.67 (2H, m), 7.85-7.89 (2H, m), 8.01 (1H, d, J = 8.5 Hz).

Example 47h 1- {5- [4- (1-acetylpiperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (Methylsulfonyl) phenyl] ethanone To a solution of the compound obtained in Example 47g (0.0326 g) in dichloromethane (1.5 mL) at 0 ° C., triethylamine (0.0269 mL), acetic anhydride (0.0122 mL). 4-dimethylaminopyridine (0.0008 g) was added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / dichloromethane → ethanol / dichloromethane) to give the title compound (0.0242 g) as a white amorphous solid. Obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.55-1.66 (2H, m), 1.81-1.94 (2H, m), 2.11 (3H, s), 2.13 (3H, s), 2.55-2.75 (2H , m), 3.08 (3H, s), 3.10-3.21 (3H, m), 3.86-3.96 (3H, m), 4.17-4.24 (2H, m), 4.72-4.82 (1H, m), 6.77-6.84 (3H, m), 7.06-7.11 (2H, m), 7.55-7.68 (2H, m), 7.85-7.90 (2H, m), 8.02 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 547 (M + H) ⁺ .

(Example 48)
1- {5- [4- (1-Acetylpiperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [4-bromo-2- ( Methylsulfonyl) phenyl] ethanone

Example 48a [4-Bromo-2- (methylsulfonyl) phenyl] acetonitrile Sodium cyanide (0.451 g) was dissolved in N, N-dimethylformamide (25 mL) and water (1 mL). -Bromo-1- (bromomethyl) -2- (methylsulfonyl) benzene (2.00 g) was added, followed by stirring at 75 ° C for 1 hour. After adding water to the reaction mixture and extracting with ethyl acetate, the organic layer was washed with water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (0.395 g) as a pale yellow solid.
¹ H-NMR (400MHz, CDCl ₃ ) δ: 3.18 (3H, s), 4.27 (2H, s), 7.51-7.57 (1H, m), 7.80-7.85 (1H, m), 8.21-8.26 (1H, m).

Example 48b [4-Bromo-2- (methylsulfonyl) phenyl] acetic acid The compound (0.395 g) obtained in Example 48a was dissolved in ethanol (2 mL) and water (2 mL), and water was added. After adding potassium oxide (0.486 g), the mixture was stirred at 80 ° C. for 2 hours. 1N Hydrochloric acid was added to the reaction mixture at 0 ° C., and the mixture was diluted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Dichloromethane was added to the residue and the resulting solid was collected by filtration to give the title compound (0.202 g) as a pale yellow solid.
¹ H-NMR (400MHz, CDCl ₃ + MeOH-d ₄ ) δ: 3.17 (3H, s), 4.15 (2H, s), 7.27-7.36 (1H, m), 7.69-7.80 (1H, m), 8.16 -8.25 (1H, m).

Example 48c 4- {4-[(1-{[4-Bromo-2- (methylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy Tert-butyl phenyl} piperidine-1-carboxylate Triethylamine was added to a solution of the compound obtained in Example 47e (0.0846 g) and the compound obtained in Example 48b (0.0878 g) in dichloromethane (2 mL). (0.0574 mL), N- [3- (dimethylamino) propyl] -N′-ethylcarbodiimide hydrochloride (0.0596 g), 3H-1,2,3-triazolo [4,5-b] pyridine -3-ol (0.0141 g) was added and stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with a mixed solvent of ethyl acetate and dichloromethane (4: 1), and then the organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (0.112 g) as a white solid.
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.48 (9H, s), 1.52-1.61 (2H, m), 1.75-1.85 (2H, m), 2.14 (3H, s), 2.55-2.65 (1H, m), 2.73-2.84 (2H, m), 3.14 (3H, s), 3.18-3.26 (2H, m), 4.18-4.33 (6H, m), 6.75-6.84 (3H, m), 7.08-7.13 ( 2H, m), 7.21-7.25 (2H, m), 7.71-7.76 (1H, m), 7.92-7.97 (1H, m), 8.19-8.22 (1H, m).

Example 48d 2- [4-Bromo-2- (methylsulfonyl) phenyl] -1- {4-methyl-5- [4- (piperidin-4-yl) phenoxy] -2,3-dihydro-1H -Indol-1-yl} ethanone The compound (0.110 g) obtained in Example 48c was dissolved in dichloromethane (1.6 mL), trifluoroacetic acid (0.4 mL) was added, and then at room temperature. Stir overnight. The reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, extracted with a mixed solvent of ethyl acetate and dichloromethane (4: 1), and the organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (0.119 g) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.68-1.81 (2H, m), 1.83-1.92 (2H, m), 2.13 (3H, s), 2.57-2.67 (1H, m), 2.76-2.86 (2H, m), 3.14 (3H, s), 3.18-3.33 (4H, m), 4.23-4.32 (4H, m), 6.75-6.84 (3H, m), 7.13 (2H, d, J = 8.5 Hz ), 7.21-7.25 (1H, m), 7.71-7.75 (1H, m), 7.92-7.96 (1H, m), 8.19-8.22 (1H, m).

Example 48e 1- {5- [4- (1-acetylpiperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [4- Bromo-2- (methylsulfonyl) phenyl] ethanone Triethylamine (0.0848 mL), acetic anhydride (0.0386) at 0 ° C. in a solution of the compound (0.119 g) obtained in Example 48d in dichloromethane (3 mL). mL) and 4-dimethylaminopyridine (0.0025 g) were added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / dichloromethane → methanol / dichloromethane) to give the title compound (0.09888 g) as a white amorphous solid. Obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.56-1.65 (2H, m), 1.82-1.93 (2H, m), 2.13 (3H, s), 2.13 (3H, s), 2.56-2.75 (2H , m), 3.10-3.26 (6H, m), 3.88-3.96 (1H, m), 4.23-4.32 (4H, m), 4.73-4.82 (1H, m), 6.75-6.84 (3H, m), 7.10 (2H, d, J = 8.5 Hz), 7.23 (1H, d, J = 7.9 Hz), 7.71-7.75 (1H, m), 7.93-7.96 (1H, m), 8.19-8.21 (1H, m).
MS (APCI / ESI) m / z: 625, 627 (M + H) ⁺ .

(Example 49)
[4 ′-({1-[(2-acetylphenyl) acetyl] -4-methyl-2,3-dihydro-1H-indol-5-yl} oxy) -2′-methylbiphenyl-4-yl] acetic acid

Example 49a tert-butyl 5-{[4 '-(2-ethoxy-2-oxoethyl) -2-methylbiphenyl-4-yl] oxy} -4-methyl-2,3-dihydro-1H-indole -1-Carboxylate 2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] ethyl acetate (1.53 g), obtained in Example 1a Compound (2.00 g), chloro (2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl) [2- (2′-amino-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 the mixture was 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 over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.27 g) as a pale yellow amorphous solid. .
¹ H-NMR (400MHz, 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).

Example 49b {2'-Methyl-4 '-[(4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] biphenyl-4-yl} acetic acid ethyl ester Obtained in Example 49a Trifluoroacetic acid (3 mL) was added to a dichloromethane (30 mL) solution of the obtained compound (2.27 g), and the mixture was stirred at room temperature for 6 hours. The reaction solution was neutralized by adding saturated aqueous sodium hydrogen carbonate solution at 0 ° C., extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (1.84 g) as a light brown oil.
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).

Example 49c [4 ′-({1-[(2-acetylphenyl) acetyl] -4-methyl-2,3-dihydro-1H-indol-5-yl} oxy) -2′-methylbiphenyl- 4-yl] ethyl acetate Triethylamine (0.166 mL) was added to a solution of the compound obtained in Example 49b (0.240 g) and 2- (2-acetylphenyl) acetic acid (0.140 g) in dichloromethane (6 mL). ), N- [3- (dimethylamino) propyl] -N′-ethylcarbodiimide hydrochloride (0.172 g), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol ( 0.0407 g) was added and stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with a mixed solvent of ethyl acetate and dichloromethane (4: 1), and then the organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (0.153 g) as a pale yellow oil.
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.28 (3H, t, J = 7.3 Hz), 2.14 (3H, s), 2.22 (3H, s), 2.61 (3H, s), 3.18-3.26 (2H , m), 3.65 (2H, s), 4.10-4.22 (4H, m), 4.29-4.37 (2H, m), 6.69-6.85 (3H, m), 7.11 (1H, d, J = 7.9 Hz), 7.23-7.33 (5H, m), 7.38-7.53 (2H, m), 7.84-7.89 (1H, m), 7.98-8.02 (1H, m).

Example 49d [4 ′-({1-[(2-acetylphenyl) acetyl] -4-methyl-2,3-dihydro-1H-indol-5-yl} oxy) -2′-methylbiphenyl- 4-yl] acetic acid The compound (0.050 g) obtained in Example 49c was dissolved in tetrahydrofuran (0.3 mL) and ethanol (0.3 mL), and 2N aqueous sodium hydroxide ( 0.6 mL) was added, followed by stirring at room temperature for 30 minutes. The reaction mixture was neutralized with 1N hydrochloric acid, diluted with a mixed solvent of ethyl acetate and dichloromethane (4: 1), and washed with saturated brine. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane → ethanol / dichloromethane) to obtain the title compound (0.033 g) as a pale yellow solid.
¹ H-NMR (400MHz, CDCl ₃ + MeOH-d ₄ ) δ: 2.15 (3H, s), 2.21 (3H, s), 2.62 (3H, s), 3.19-3.27 (2H, m), 3.64 (2H , s), 4.12 (2H, s), 4.30-4.37 (2H, m), 6.68-6.85 (3H, m), 7.10 (1H, d, J = 8.5 Hz), 7.23-7.34 (5H, m), 7.39-7.54 (2H, m), 7.86-7.90 (1H, m), 7.95-8.00 (1H, m).
MS (APCI) m / z: 534 (M + H) ⁺ .

(Example 50)
Ethyl 4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] benzoate

Example 50a 4-Methyl-5- [4- (trifluoromethyl) phenoxy] -2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl p-bromobenzoic acid ethyl ester (5.97 mL) and tert-butyl 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylate (5.00 g) in 1,4-dioxane (15 mL) in copper iodide (15 mL). I) (0.763 g), N, N-dimethylglycine (0.827 g) and cesium carbonate (13.1 g) were added, and the mixture was stirred at 95 ° C. for 26 hours. After allowing to cool, ethyl acetate was added to the reaction solution, and the insoluble material was removed by filtration. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (1.81 g) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.37 (3H, t, J = 7.3 Hz), 1.56 (9H, s), 2.02 (3H, s), 3.03 (2H, t, J = 8.5 Hz) , 4.04 (2H, br s), 4.35 (2H, q, J = 7.1 Hz), 6.80-6.89 (4H, m), 7.96 (2H, d, J = 8.5 Hz).

Example 50b Ethyl 4-[(1-{[2- (Ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] benzoate In Example 50a To a solution of the obtained compound (1.07 g) in dichloromethane (5 mL) was added trifluoroacetic acid (8.00 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and dried to obtain crude ethyl 4-[(4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] benzoate trifluoroacetate (1.11 g). Got.
To a 1,4-dioxane (8 mL) solution of the obtained compound (1.05 g) and [2- (ethylsulfonyl) phenyl] acetic acid (0.641 g), N, N-diisopropylethylamine (1.18 mL) was added. ) And 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (0.865 g) were sequentially added, and the mixture was stirred at room temperature for 36 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (1.06 g) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.02-1.16 (6H, m), 2.00 (3H, d, J = 9.8 Hz), 3.15-3.39 (5H, m), 4.24-4.35 (4H m), 6.85-6.91 (3H, m), 7.48-7.54 (1H, m), 7.55-7.61 (1H, m), 7.69-7.75 (1H, m), 7.85-7.95 (4H, m).

(Example 51)
4-[(1-{[2- (Ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -N-methyl-N-propylbenzamide

Example 51a 4-[(1-{[2- (Ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] benzoic acid In Example 50b Tetrahydrofuran (5 mL), ethanol (5 mL), 1N aqueous sodium hydroxide solution (4.00 mL) were added to the obtained compound (1.20 g), and the mixture was stirred at room temperature for 5 days and then at 50 ° C. for 12 hours. did. 1N hydrochloric acid (4.00 mL) was added, and the solvent was distilled off under reduced pressure. Ethyl acetate and water were added for liquid separation, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Dichloromethane (2 mL) and diethyl ether (2 mL) were added to the obtained residue, and the mixture was stirred at room temperature for 5 hours, filtered and dried to obtain the title compound (0.700 g) as a white solid.

Example 51b 4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -N-methyl-N -Propylbenzamide To a solution of the compound obtained in Example 51a (98.0 mg) and N-methylpropylamine (62.9 μL) in N, N-dimethylformamide (8 mL) was added N, N-diisopropylethylamine (94). .4 μL) and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (69.3 mg) were sequentially added and stirred at room temperature for 15 hours. . Ethyl acetate and water were added for liquid separation, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (109 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.70-1.04 (3H, m), 1.23-1.31 (3H, m), 2.09 (3H, s), 2.92-3.09 (3H, br m), 3.17- 3.29 (5H, m), 3.48 (1H, br s), 3.40-3.54 (2H, m), 4.28 (2H, t, J = 8.2 Hz), 4.38 (2H, s), 6.79-6.91 (3H, m ), 7.29-7.43 (3H, m), 7.51 (1H, td, J = 7.6, 1.2 Hz), 7.63 (1H, td, J = 7.5, 1.4 Hz), 7.97-8.06 (2H, m).
MS (APCI) m / z: 535 (M + H) ⁺ .

(Example 52)
1- [5- (3-Bromophenoxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone

Example 52a tert-butyl 5- (3-bromophenoxy) -4-methyl-2,3-dihydro-1H-indole-1-carboxylate 1-bromo-3-iodobenzene (1.70 g) and A solution of tert-butyl 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylate (1.00 g) in dioxane (12 mL) with copper (I) iodide (76.4 mg). ), N, N-dimethylglycine (82.7 mg) and cesium carbonate (2.61 g) were added, and the mixture was stirred at 100 ° C. for 3 hours and 30 minutes. After cooling to room temperature, the reaction solution was filtered through celite. The obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (455 mg) as a colorless solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.52-1.60 (9H, m), 2.04 (3H, s), 3.03 (2H, t, J = 8.8 Hz), 3.95-4.10 (2H, m), 6.75-6.86 (2H, m), 6.96 (1H, s), 7.08-7.16 (2H, m), 7.25-7.76 (1H, m).

Example 52b 1- [5- (3-Bromophenoxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone To a solution of the compound obtained in 52a (450 mg) in dichloromethane (3 mL) was added 4N dioxane hydrochloride solution (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain crude 5- (3-bromophenoxy) -4-methyl-2,3-dihydro-1H-indole hydrochloride (374 mg).
N-methylmorpholine (0.184 mL) was added to a solution of the obtained compound (374 mg) in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 10 minutes. To the reaction solution was added 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (616 mg) and [2- (methylsulfonyl) phenyl] acetic acid (286 mg). ) And stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (538 mg) as a colorless solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.09 (3H, s), 3.13 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 4.30 (2H, t, J = 8.5 Hz) , 4.37 (2H, s), 6.78-6.85 (2H, m), 6.96-7.00 (1H, m), 7.14 (2H, d, J = 5.5 Hz), 7.37 (1H, d, J = 6.7 Hz), 7.50-7.55 (1H, m), 7.60-7.65 (1H, m), 8.01 (1H, d, J = 9.1 Hz), 8.08 (1H, dd, J = 7.9, 1.2 Hz).

(Example 53)
1- {4-Methyl-5- [3-methyl-4- (tetrahydro-2H-pyran-2-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (Methylsulfonyl) phenyl] ethanone

The compound obtained in Example 32a (31.6 mg) was dissolved in methanol (3 mL), 7.5% palladium carbon (6.32 mg) was added, and the mixture was stirred at 60 ° C. for 5 hours in a hydrogen atmosphere. . Ethyl acetate was added to the reaction solution, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (7.4 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.12 (3H, s), 2.30 (3H, s), 3.13 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 4.29 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.63-6.72 (2H, m), 6.78 (1H, d, J = 8.5 Hz), 6.83 (1H, d, J = 7.3 Hz), 7.16 ( 1H, t, J = 7.6 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.59-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.04-8.11 (1H, m).
MS (APCI) m / z: 436 (M + H) ⁺ .

(Test Example 1)
Inhibitory effects on IL-17 production of RORγt gene-introduced cells (1) Preparation of RORγt gene-introduced cells The base sequence of mRNA encoding the full-length amino acid sequence of mouse (Mus musculus) RORgamma t protein (GenBank Accession Number AF163668:
), MRNA cDNA encoding the full-length protein was obtained by PCR. The obtained cDNA was inserted into a pUNO vector (InvivoGen) as an expression vector to construct a mouse RORγt expression vector. The constructed mouse RORγt expression vector is introduced into EL4 cells (mouse T lymphoma cell line) and cultured in a selective medium (DMEM medium supplemented with fetal bovine serum, Blasticidin S, penicillin, streptomycin). Cells were obtained.
(2) Evaluation of IL-17 production inhibitory action IL-17 production inhibitory action of the test compound is the result of IL-17 production when RORγt gene-introduced cells are stimulated with phorbol 12-Myristate 13-acetate (PMA) and ionomycin. Measured with That is, RORγt gene-introduced cells were prepared in the above-mentioned selective medium, and dispensed into a 96-well flat bottom plate (Corning) at 75,000 cells per well. At this time, various concentrations of test compounds were added simultaneously. After in 5% CO ₂ concentration in the incubator and incubated for 1 hour at 37 ° C., PMA final concentration 25 ng / mL, final concentration ionomycin 125 ng / mL, 5% CO ₂ concentration in the incubator with the addition sum 100μL to each well Incubated for 20 hours at 37 ° C. Thereafter, the culture supernatant was collected, and the mouse IL-17 concentration in the supernatant was measured as time-resolved fluorescence with EnVison (Perkin Elmer) using the HTRF mouse IL-17 kit (Cisbio). About the IL-17 production inhibitory effect by the test compound, from the graph in which the test compound concentration is semilogarithmically plotted against the IL-17 production amount in the presence of the test compound, 50% of the IL-17 production amount in the absence of the test compound The concentration of the test compound corresponding to the amount of IL-17 produced was calculated as the IC ₅₀ value. The results of the IL-17 production inhibitory action are shown in Table 1.

(Table 1)
―――――――――――――――――――――――――――――――――――――
Example IC ₅₀ value (nM) Example IC ₅₀ value (nM) Example IC ₅₀ value (nM)
―――――――――――――――――――――――――――――――――――――
1 33.9 2 14 3 17.7
4 25.9 5 36.3 6 36.6
7 39.4 8 83.6 9 55
10 19 11 84.1 12 48
13 37.4 14 318 15 43
16 15.3 17 6.1 18 37.1
19 91.7 20 20.4 21 22.1
22 27.2 23 36.3 24 85.3
25 37.1 26 27.4 27 25.9
28 31.2 29 16.8 30 17.5
31 15.8 32 29.9 33 35.6
34 172 35 24.3 36 66.2
37 117 38 352 39 51.2
40 545 41 43.4 42 26.6
43 82.7 44 34.8 45 62.5
46 50.7 47 485 48 118
49 406 50 10.3 51 79.96
52 120 53 133
―――――――――――――――――――――――――――――――――――――

  In this test, the compound of the present invention showed an excellent IL-17 production inhibitory action. Therefore, therapeutic agents for psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases (such as Crohn's disease and ulcerative colitis), Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease, asthma or colon cancer and / or Useful as a preventive agent.

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

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

The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent retinoic acid receptor-related orphan receptor γt inhibitory action and is useful as a medicine.

Claims (30)

Formula (I)
[Where:
R ¹ represents a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group or a phenyl group,
A represents a carbonyl group, a sulfinyl group or a sulfonyl group,
Q represents a nitrogen atom or a group represented by the formula = C (R ² )-
R ² represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group,
R ³ represents a hydrogen atom, a C ₂ -C ₇ carboxyalkyl group or a hydroxyl group,
Group of the formula -U-T-has the formula _-CH 2 -CH ₂ - indicates a group represented by or a group of the formula -CH = CH-,
R ⁴ represents a halogen atom or a C ₁ -C ₆ alkyl group,
Y represents a methylene group or an oxygen atom,
L represents a 1,4-phenylene group which may be independently substituted with a group selected from substituent group A or a bicyclic heteroarylene group consisting of a 6-membered ring and a 6-membered ring;
Substituent Group A represents the group consisting of halogen _atom, C 1 -C _{6 alkyl,} C 1 -C ₆ alkoxy group and oxo group,
E represents a hydrogen _atom, C 1 -C ₆ halogenated alkyl _group, C 2 -C ₇ alkoxycarbonyl group, _mono--C 1 -C ₆ alkylaminocarbonyl group, di - _(C 1 -C ₆ alkyl) aminocarbonyl group , A (C ₂ -C ₇ alkoxycarbonyl)-(C ₂ -C ₆ alkenyl) group or a group selected from substituent group B, which may be independently substituted with 1 to 4 C ₃ -C ₆ cycloalkyl Group, C ₃ -C ₆ cycloalkyl group, one substituted with C ₂ -C ₇ carboxyalkyl group, phenyl group, monocyclic heterocyclic group, bicyclic heterocyclic ring consisting of 5-membered ring and 5-membered ring A bicyclic heterocyclic group consisting of a 5-membered ring and a 6-membered ring or a bicyclic heterocyclic group consisting of a 6-membered ring and a 6-membered ring;
However, when the group represented by the formula -A-R ¹ is substituted at the 2-position and the 4-position of the 6-membered ring containing Q is a hydrogen atom, a piperidin-1-yl group, piperidin-3- Yl, piperidin-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, piperazin-1-yl, morpholin-4-yl, pyrrolidin-1-yl and pyrrolidin-3 -Excluding yl groups,
Substituent group B, a halogen _atom, C 1 -C _{6 alkyl,} C 1 -C ₆ halogenated alkyl _group, C 1 -C ₆ hydroxyalkyl _group, C 1 -C ₆ alkoxy _group, C 1 -C ₆ hydroxy Alkoxy group, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, hydroxyl group, carboxy group, C ₂ -C ₇ carboxyalkyl group, C ₂ -C ₇ alkylcarbonyl group, mono-C _2- C ₇ carboxyalkyl aminocarbonyl group, di - _(C 1 -C ₆ alkyl) aminocarbonyl methyl _{group, (C} 2 -C _{7 carboxyalkyl) (C} 2 -C ₇ alkylcarbonyl) amino group, morpholin-4-yl Group, (morpholin-4-yl) methyl group, (1,4-dioxane-2-yl) methyl group, (1,4-dioxane-2-yl) methyloxy And it represents the group consisting of oxo group,
However, when A is a sulfonyl group, _C 2 -C ₇ carboxyalkyl group from Substituent Group B is excluded. Or a pharmacologically acceptable salt thereof. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein the general formula (I) is the general formula (II).
The compound or pharmacologically acceptable salt thereof according to claim 1 or 2, wherein R ¹ is a methyl group or an ethyl group.   The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein A is a sulfonyl group.   The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 4, wherein Q is a nitrogen atom.   The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 4, wherein Q is a group represented by the formula = CH-.   The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 6, wherein Y is an oxygen atom. The L is a group represented by the formula (III-I), a group represented by the formula (III-II), or a group represented by the formula (III-III). A group represented by formula (III-IV) or a group represented by formula (III-V) (wherein _CE and _CY represent a single bond, _CE represents formula E bound, C _Y in the group represented, bonded to the group of the formula Y.) compound or a pharmacologically acceptable salt thereof is.
In any one selected from claims 1 to 8, E is selected from hydrogen atom, C ₂ -C ₇ alkoxycarbonyl group or a methyl group, a hydroxyl group, a carboxy group and (morpholin-4-yl) methyl A C ₃ -C ₆ cycloalkyl group, monocyclic heterocyclic group, bicyclic heterocyclic group or 6-membered ring consisting of a 5-membered ring and a 6-membered ring, which may be independently substituted with 1 or 2 groups Or a pharmacologically acceptable salt thereof, which is a bicyclic heterocyclic group consisting of a 6-membered ring.   9. The compound according to claim 1, wherein E is a hydrogen atom, an ethoxycarbonyl group, a 4-hydroxycyclohexyl group, a pyridin-4-yl group, or 6- (morpholin-4-ylmethyl) pyridine-3. -Yl group, tetrahydro-2H-pyran-4-yl group, tetrahydro-2H-pyran-3-yl group, 3,6-dihydro-2H-pyran-4-yl group, 2-carboxy-1-methyl-1H -Indol-5-yl group, 1-methyl-1H-benzimidazol-6-yl group or 4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-7 -A compound which is an yl group or a pharmacologically acceptable salt thereof.   The group represented by the formula E-L- according to any one of claims 1 to 7, wherein the group represented by the formula E-L- is 4-ethoxycarbonylphenyl group, 4- (4-hydroxycyclohexyl) phenyl, 4- (pyridine-4). -Yl) phenyl group, 3-methyl-4- [6- (morpholin-4-ylmethyl) pyridin-3-yl] phenyl group, 4- (tetrahydro-2H-pyran-4-yl) phenyl group, 3-methyl -4- (tetrahydro-2H-pyran-3-yl) phenyl group, 4- (3,6-dihydro-2H-pyran-4-yl) phenyl group, 3-methyl-4- (2-carboxy-1- Methyl-1H-indol-5-yl) phenyl group, 3-methoxy-4- (1-methyl-1H-benzimidazol-6-yl) phenyl group, 3-methyl-4- (4-methyl-3,4) − Hydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) phenyl group, 2-methyl-3,4-dihydroisoquinolin-1 (2H) -one-6-yl group or quinoxaline A compound having a -6-yl group or a pharmacologically acceptable salt thereof. 1- {4-methyl-5- [4- (pyridin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone,
1- {5- [4- (3,6-dihydro-2H-pyran-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (Methylsulfonyl) phenyl] ethanone,
1- {5- [4- (4-Hydroxycyclohexyl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl ] Ethanon,
1- {4-Methyl-5- [3-methyl-4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone,
1- (4-Methyl-5- {3-methyl-4- [6- (morpholin-4-ylmethyl) pyridin-3-yl] phenoxy} -2,3-dihydro-1H-indol-1-yl)- 2- [2- (methylsulfonyl) phenyl] ethanone,
1- {5- [3-Methoxy-4- (1-methyl-1H-benzimidazol-6-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone,
2- [2- (Methylsulfonyl) phenyl] -1- {4-methyl-5- [4- (tetrahydro-2H-pyran-4-yl) phenoxy] -2,3-dihydro-1H-indole-1- Il} Ethanon,
1- {5- [4- (4-hydroxycyclohexyl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone,
1- {4-Methyl-5- [3-methyl-4- (tetrahydro-2H-pyran-3-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (Methylsulfonyl) phenyl] ethanone,
1-methyl-5- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] Phenyl} -1H-indole-2-carboxylic acid,
6-[(1-{[2- (Ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -2-methyl-3,4-dihydroisoquinoline -1 (2H) -on,
2- [2- (ethylsulfonyl) phenyl] -1- [4-methyl-5- (quinoxalin-6-yloxy) -2,3-dihydro-1H-indol-1-yl] ethanone, or
Ethyl 4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] benzoate or a pharmacologically acceptable salt thereof Salt. 1- {4-methyl-5- [4- (pyridin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone,
1- {5- [4- (4-Hydroxycyclohexyl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl ] Ethanon,
2- [2- (Methylsulfonyl) phenyl] -1- {4-methyl-5- [4- (tetrahydro-2H-pyran-4-yl) phenoxy] -2,3-dihydro-1H-indole-1- Il} Ethanon,
1- {5- [4- (4-hydroxycyclohexyl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone,
6-[(1-{[2- (Ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -2-methyl-3,4-dihydroisoquinoline -1 (2H) -on,
2- [2- (ethylsulfonyl) phenyl] -1- [4-methyl-5- (quinoxalin-6-yloxy) -2,3-dihydro-1H-indol-1-yl] ethanone, or
Ethyl 4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] benzoate or a pharmacologically acceptable salt thereof Salt.   A pharmaceutical composition comprising as an active ingredient the compound according to any one of claims 1 to 13 or a pharmacologically acceptable salt thereof.   The pharmaceutical composition according to claim 14, which has a retinoic acid receptor-related orphan receptor inhibitory action.   The pharmaceutical composition according to claim 14, for treating and / or preventing a disease to be treated and / or prevented by an inhibitory action of retinoic acid receptor-related orphan receptor.   A pharmaceutical composition inhibits a retinoic acid receptor-related orphan receptor and treats, improves, reduces and / or prevents symptoms by suppressing Th17 cell differentiation and / or suppressing IL-17 production. The pharmaceutical composition according to claim 14 for treatment and / or prevention.   Claim 14 for the treatment and / or prevention of psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease, asthma or colon cancer The pharmaceutical composition as described.   The pharmaceutical composition according to claim 14 for the treatment and / or prevention of psoriasis.   The pharmaceutical composition according to claim 18, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.   A retinoic acid receptor-related orphan receptor inhibitor comprising the compound according to any one of claims 1 to 13 or a pharmacologically acceptable salt thereof as an active ingredient.   Use of a compound according to any one of claims 1 to 13 or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition.   23. Use according to claim 22, wherein the pharmaceutical composition is a composition for inhibiting a retinoic acid receptor-related orphan receptor.   The pharmaceutical composition is a composition for the treatment and / or prevention of psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease, asthma or colon cancer Item 23. Use according to Item 22.   The use according to claim 22, wherein the pharmaceutical composition is a composition for the treatment and / or prevention of psoriasis.   A method for inhibiting a retinoic acid receptor-related orphan receptor, comprising administering to a warm-blooded animal a pharmacologically effective amount of the compound according to any one of claims 1 to 13 or a pharmacologically acceptable salt thereof. .   A method for treating and / or preventing a disease, comprising administering to a warm-blooded animal a pharmacologically effective amount of the compound according to any one of claims 1 to 13 or a pharmacologically acceptable salt thereof.   28. The method of claim 27, wherein the disease is psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease, asthma or colon cancer.   23. The method of claim 22, wherein the disease is psoriasis.   30. The method according to any one of claims 26 to 29, wherein the warm-blooded animal is a human.