WO2016072402A1 - Cyclic amine derivative - Google Patents

Cyclic amine derivative Download PDF

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Publication number
WO2016072402A1
WO2016072402A1 PCT/JP2015/080982 JP2015080982W WO2016072402A1 WO 2016072402 A1 WO2016072402 A1 WO 2016072402A1 JP 2015080982 W JP2015080982 W JP 2015080982W WO 2016072402 A1 WO2016072402 A1 WO 2016072402A1
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WIPO (PCT)
Prior art keywords
group
methyl
phenyl
compound
dihydro
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PCT/JP2015/080982
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French (fr)
Japanese (ja)
Inventor
雅敏 永持
建徳 五反田
哲司 野口
泰治 後藤
潤子 佐々木
宗史 鳥羽田
利治 吉野
崇 磯部
ベンカタラマナン ラマダス
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第一三共株式会社
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Publication of WO2016072402A1 publication Critical patent/WO2016072402A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the present invention has an excellent inhibitory action on retinoic acid receptor-related orphan receptor ⁇ t (which may be abbreviated as ROR ⁇ t in the present specification) and is useful as a therapeutic agent for psoriasis or the like, or a pharmaceutically acceptable salt thereof.
  • ROR ⁇ t retinoic acid receptor-related orphan receptor ⁇ t
  • Th1 cells IFN- ⁇ high-producing helper T cells
  • Th17 cells IFN- ⁇ high-producing helper T cells
  • the nuclear receptor ROR ⁇ t functions in the process of Th17 cell differentiation from naive T cells and in the process of Th17 cells producing IL-17.
  • naive T cells of ROR ⁇ t knockout mice the 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 obtained ( Non-patent document 1).
  • ROR ⁇ t plays an important role in differentiation into Th17 cells, production of IL-17, and pathogenesis (Non-patent Documents 2-3). From these findings, it is considered that a substance that suppresses the transcriptional activity of ROR ⁇ t, that is, an ROR ⁇ t inhibitor may be a therapeutic agent for autoimmune diseases and the like.
  • cyclic amine derivatives having a specific chemical structure have selective and excellent Th17 cell differentiation inhibitory action and IL-17 production inhibitory action. And found useful for the prevention and treatment of diseases involving ROR ⁇ t such as autoimmune diseases.
  • this cyclic amine derivative is used in psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases (such as Crohn's disease and ulcerative colitis), Sjogren's syndrome, systemic Systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, myocardium Treatment of colorectal cancer in which autoimmune diseases such as symptom, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis, etc. or IL-17 production is involved in pathogenesis And / or useful as an active ingredient
  • R 1 represents a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group or a phenyl group
  • 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
  • R 4 represents a halogen atom or a C 1 -C 6 alkyl group
  • R 5 represents a hydrogen atom or a C 1 -C 6 alkyl group
  • R 6 represents a hydrogen atom, a halogen atom or a C 1 -C 6 alkyl group
  • the group represented by the formula —UT— represents a group represented by
  • Y represents a methylene group or an oxygen atom
  • An alkoxy group a (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, a (C 1 -C 6 alkoxy)-(C 1 -C 6 alkoxy) group, a C 2 -C 7 alkylcarbonyl group, Represents a tetrahydrofuryl group or an oxetyloxy group, E represents a piperidin-1-yl group, a piperidin-3-yl group, a piperidin-4-yl group, 1, 2, 2, which may be independently substituted with 1 to 4 groups independently selected from the substituent group A; Represents a 3,6-tetrahydropyridin-4-yl group, piperazin-1-yl group, morpholin-4-yl group, pyrrolidin-1-yl group or pyrrolidin-3-yl group; Substituent group A includes a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated
  • E is a piperidin-4-yl group, a 1,2,3,6-tetrahydropyridin-4-yl group or a piperazin-1-yl group, each of which is substituted with a group represented by the formula -LR 8 Or a pharmaceutically acceptable salt thereof.
  • R 8 is a C 1 -C 6 alkyl group, C 1 -C 6 hydroxyalkyl group, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, amino group, mono-C 1 -C 6 Selected from alkylamino groups, mono-C 1 -C 6 halogenated alkylamino groups, di- (C 1 -C 6 alkyl) amino groups, morpholin-2-yl groups or halogen atoms and C 1 -C 6 alkyl groups Or a pharmaceutically acceptable salt thereof, which is a pyrrolidin-2-yl group which is independently substituted with 1 to 3 groups.
  • R 8 is a methyl group, 1-hydroxyethyl group, methoxymethyl group, methylamino group, ethylamino group, 2,2-difluoroethylamino group, morpholin-2-yl group or 4,4-difluoro-1-methyl
  • a compound having a pyrrolidin-2-yl group or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt thereof.
  • R 1 is a C 1 -C 6 alkyl group
  • R 2 is a hydrogen atom
  • R 3 is a hydrogen atom
  • R 4 is a C 1 -C 6 alkyl group
  • R 5 is A hydrogen atom or a C 1 -C 6 alkyl group
  • R 6 is a hydrogen atom
  • Q 1 is a nitrogen atom or a group represented by the formula ⁇ CH—
  • a group represented by the formula —UT— is a group represented by the formula —CH 2 —CH 2 — or a group represented by the formula —CH ⁇ CH—.
  • E is one substituted in which piperidin-4-yl group in the group represented by the formula -L-R 8, 1,2,3,6 Tetorahidoropi A lysine-4-yl group or a piperazin-1-yl group
  • L is a carbonyl group or an oxalyl group
  • R 8 is a C 1 -C 6 alkyl group, a C 1 -C 6 hydroxyalkyl group, (C 1- C 6 alkoxy)-(C 1 -C 6 alkyl) group, amino group, mono-C 1 -C 6 alkylamino group, mono-C 1 -C 6 halogenated alkylamino group, di- (C 1- A compound which is a pyr
  • R 1 is a methyl group or an ethyl group
  • R 2 is a hydrogen atom
  • R 3 is a hydrogen atom
  • R 4 is a methyl group
  • R 5 is a hydrogen atom or a methyl group.
  • R 6 is a hydrogen atom
  • Y is an oxygen atom
  • V is a group represented by the formula ⁇ C (R 7 ) —
  • R 7 Is a hydrogen atom or a methyl group
  • E is a piperidin-4-yl group or 1,2,3,6-tetrahydropyridine- substituted at the 1-position with a group represented by the formula -LR 8 a 4-yl group
  • L is a carbonyl group or an oxalyl group
  • R 8 is methyl group, 1-hydroxyethyl group, methoxymethyl group, methyl Amino group, an ethylamino group, 2,2-difluoroethyl group, morpholin-2-yl group or a 4,4-di
  • R 1 is a C 1 -C 6 alkyl group
  • R 2 is a hydrogen atom
  • R 3 is a hydrogen atom
  • R 4 is a C 1 -C 6 alkyl group
  • R 5 is A hydrogen atom or a C 1 -C 6 alkyl group
  • R 6 is a hydrogen atom
  • Q 1 is a nitrogen atom or a group represented by the formula ⁇ CH—
  • a group represented by the formula —UT— is a group represented by the formula —CH 2 —CH 2 — or a group represented by the formula —CH ⁇ CH—.
  • Y is an oxygen atom
  • V is a nitrogen atom
  • E is a piperidin-4-yl group substituted with one group represented by the formula -LR 8 , 1,2,3 , 6-tetrahydropyridin-4-yl group or piperazin-1-yl group
  • L is a carbonyl group or an oxalyl group
  • R 8 is C 1 -C 6 alkyl group, C 1 -C 6 hydroxyalkyl group, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, amino group, mono-C 1 -C 6 alkylamino group, mono-C 1 1 to 3 independently of —C 6 halogenated alkylamino group, di- (C 1 -C 6 alkyl) amino group, morpholin-2-yl group or a group selected from halogen atom and C 1 -C 6 alkyl group
  • R 1 is a methyl group or an ethyl group
  • R 2 is a hydrogen atom
  • R 3 is a hydrogen atom
  • R 4 is a methyl group
  • R 5 is a hydrogen atom or a methyl group.
  • R 6 is a hydrogen atom
  • Y is an oxygen atom
  • V is a nitrogen atom
  • E is represented by the formula —LR 8.
  • L is a carbonyl group or an oxalyl group
  • R 8 is methyl Group, 1-hydroxyethyl group, methoxymethyl group, methylamino group, ethylamino group, 2,2-difluoroethylamino group Morpholin-2-yl group or a 4,4-difluoro-1-methyl pyrrolidine compound or a pharmaceutically acceptable salt thereof is 2-yl group.
  • a pharmaceutical composition comprising, as an active ingredient, the compound described in any one of (1) to (37) or a pharmaceutically acceptable salt thereof.
  • composition according to (38), wherein the pharmaceutical composition is for treatment and / or prevention of a disease that is treated and / or prevented by an inhibitory action of retinoic acid receptor-related orphan receptor ⁇ t. object.
  • the pharmaceutical composition is for the treatment and / or prevention of a disease whose symptoms are treated, ameliorated, reduced and / or prevented by inhibiting Th17 cell differentiation and / or inhibiting IL-17 production.
  • the pharmaceutical composition is psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic Dermatitis, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant (38)
  • the pharmaceutical composition according to (38) for the treatment and / or prevention of cellular arteritis, contact dermatitis, optic neuritis or colon cancer.
  • the pharmaceutical composition is for the treatment and / or prevention of psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome or chronic obstructive pulmonary disease (38)
  • the pharmaceutical composition according to (38) The pharmaceutical composition according to (38).
  • a retinoic acid receptor-related orphan receptor ⁇ t inhibitor comprising as an active ingredient the compound described in any one of (1) to (37) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic skin Inflammation, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell (47)
  • the use according to (47) which is a composition for the treatment and / or prevention of arteritis inflammation, contact dermatitis, optic neuritis or colon cancer.
  • a pharmaceutical composition for treating and / or preventing psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome or chronic obstructive pulmonary disease The use according to (47).
  • Psoriasis Psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, Type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis,
  • a retinoic acid receptor-related auxin wherein a pharmacologically effective amount of a compound according to any one of (1) to (37) or a pharmaceutically acceptable salt thereof is administered to a warm-blooded animal. Fan receptor ⁇ t inhibition method.
  • the disease is psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, Asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell artery (59) The method according to (59), which is inflammation, contact dermatitis, optic neuritis or colon cancer.
  • the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • a fluorine atom or a chlorine atom Preferable is a fluorine atom or a chlorine atom, and more preferable is a fluorine atom.
  • the “C 1 -C 6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms.
  • Preferred is a straight or branched alkyl group having 1 to 3 carbon atoms (C 1 -C 3 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.
  • the “C 3 -C 6 cycloalkyl group” is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. Preferred is a cyclopropyl group.
  • 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”.
  • 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”.
  • an ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 1-butenyl or 5-hexenyl group preferably having 2 to
  • 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), more preferred is a methoxy group, an ethoxy group or a t-butoxy group. More preferably, it is a methoxy group.
  • the “C 1 -C 6 halogenated alkoxy group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 6 alkoxy group”.
  • trifluoromethoxy, trichloromethoxy, difluoromethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 2-bromoethoxy, 2-chloroethoxy, pentafluoroethoxy or 4-fluorobutoxy group preferably A group (C 1 -C 4 halogenated alkoxy group) in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 4 alkoxy group”, and more preferably the same or 1 to 5 different “halogen atoms” are groups (C 1 -C 2 halogenated alkoxy groups) bonded to the “C 1 -C 2 alkoxy group”, and more preferably a difluoromethoxy group is there
  • 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
  • “(C 1 -C 6 alkoxy)-(C 1 -C 6 alkoxy) group” means that one “C 1 -C 6 alkoxy group” is the above “C 1 -C 6 alkoxy group”. It is a group bonded to For example, methoxymethoxy, ethoxymethoxy, propoxymethoxy, isopropoxymethoxy, butoxymethoxy, t-butoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-butoxyethoxy or 3-isopropoxypropoxy group, preferably , one group wherein the "C 1 -C 4 alkoxy group” attached to the "C 1 -C 4 alkoxy group” - with ((C 1 -C 4 alkoxy) (C 1 -C 4 alkoxy) group) There, more preferably, one group wherein the "C 1 -C 2 alkoxy group” attached to the "C 1 -C 2 alkoxy group” ((C 1 -C 1
  • 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”.
  • a carboxymethyl, 2-carboxyethyl, 1-carboxyethyl or 3-carboxypropyl group is preferable, and a carboxymethyl group is more preferable.
  • 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”.
  • one hydroxy group is a group (C 1 -C 2 hydroxyalkyl group) bonded to a “C 1 -C 2 alkyl group”, and more preferably an (R) -1-hydroxyethyl group It is.
  • the “C 1 -C 6 dihydroxyalkyl group” is a group in which two hydroxy groups are bonded to the “C 1 -C 6 alkyl group”.
  • 1,2-dihydroxyethyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl or 2,3-dihydroxypropyl groups 1,2-dihydroxyethyl group is preferred.
  • the “di (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group” means that the two “C 1 -C 6 alkoxy groups” are the above “C 1 -C 6 alkyl groups”. It is a group bonded to A 1,1-diethoxymethyl group is preferred.
  • (C 1 -C 6 alkoxy)-(C 1 -C 6 hydroxyalkyl) group means that one “C 1 -C 6 alkoxy group” is the above “C 1 -C 6 hydroxyalkyl group”.
  • a 1-hydroxy-2-methoxyethyl group is preferred.
  • the “C 3 -C 6 hydroxycycloalkyl group” is a group in which one hydroxy group is bonded to the “C 3 -C 6 cycloalkyl group”.
  • a 1-hydroxycyclopropyl group is preferred.
  • the “C 1 -C 6 cyanoalkyl group” is a group in which one cyano group is bonded to the “C 1 -C 6 alkyl group”.
  • a cyanomethyl, 2-cyanoethyl, 1-cyanoethyl or 3-cyanopropyl group is preferable, and a cyanomethyl group is more preferable.
  • the “mono-C 1 -C 6 alkylamino group” is an amino group to which one “C 1 -C 6 alkyl group” is bonded.
  • a methylamino, ethylamino, propylamino, isopropylamino or butylamino group Preferred is an amino group to which one “C 1 -C 4 alkyl group” is bonded (mono-C 1 -C 4 alkylamino group), and more preferred is a methylamino group or an ethylamino group (mono -C 1 -C 2 alkylamino group).
  • the “mono-C 1 -C 6 halogenated alkylamino group” is a group in which one “C 1 -C 6 halogenated alkyl group” is bonded to an amino group.
  • the “mono-C 1 -C 6 halogenated alkylamino group” is a group in which one “C 1 -C 6 halogenated alkyl group” is bonded to an amino group.
  • 2,2,2-trifluoroethylamino, 3,3,3-trifluoropropylamino, 2,2-difluoroethylamino, 3,3-difluoropropylamino, 2,2,2-trichloroethylamino, 2-bromoethylamino or 2-fluoroethylamino group 2,2,2-trifluoroethylamino, 3,3,3-trifluoropropylamino, 2,2-difluoroethylamino, 3,3-difluoropropy
  • the “di- (C 1 -C 6 alkyl) amino group” is an amino group to which two identical or different “C 1 -C 6 alkyl groups” are bonded.
  • a dimethylamino, diethylamino, dipropylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino or N-butyl-N-methylamino group is an amino group to which two identical or different “C 1 -C 6 alkyl groups” are bonded.
  • a dimethylamino, diethylamino, dipropylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino or N-butyl-N-methylamino group is an amino group to which two identical or different “C 1 -C 6 alkyl groups” are bonded.
  • it is an amino group (di- (C 1 -C 4 alkyl) amino group) in which two identical or different “C 1 -C 4 alkyl groups” are bonded, more preferably a dimethylamino group, A diethylamino group or an N-ethyl-N-methylamino group (di- (C 1 -C 2 alkyl) amino group), and even more preferably a dimethylamino group.
  • (C 2 -C 7 alkylcarbonyloxy)-(C 1 -C 6 alkyl) group means that one “C 2 -C 7 alkylcarbonyloxy group” is the above “C 1 -C 6”. It is a group bonded to “ 6 alkyl group”. Preferably, it is an acetoxymethyl group.
  • (mono-C 3 -C 6 cycloalkylamino)-(C 1 -C 6 alkyl) group means that one “mono-C 3 -C 6 cycloalkylamino group” is “ A group bonded to a “C 1 -C 6 alkyl group”. A mono-cyclopropylaminomethyl group is preferred.
  • (C 2 -C 7 hydroxyalkylcarbonyloxy)-(C 1 -C 6 alkyl) group means that one “C 2 -C 7 hydroxyalkylcarbonyloxy group” is the above “C 1 A group bonded to “—C 6 alkyl group”.
  • a 1-hydroxyethylcarbonyloxyethyl-1-yl group is preferred.
  • (mono-C 1 -C 6 hydroxyalkylamino)-(C 1 -C 6 alkyl) group means that one “mono-C 1 -C 6 hydroxyalkylamino group” is “ A group bonded to a “C 1 -C 6 alkyl group”. A mono-2-hydroxyethylaminomethyl group is preferred.
  • a “C 2 -C 7 alkylcarbonyl group” is a group in which one of the above “C 1 -C 6 alkyl groups” is bonded to a carbonyl group.
  • a carbonyl group For example, an acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl or valeryl group.
  • a group in which one “C 1 -C 4 alkyl group” is bonded to a carbonyl group (C 2 -C 5 alkylcarbonyl group) is preferable, and an acetyl group or a propionyl group (C 2 —) is more preferable.
  • a C 3 alkylcarbonyl group even more preferably more, an acetyl group.
  • the “mono-C 2 -C 7 alkylcarbonylamino group” is a group in which one “C 2 -C 7 alkylcarbonyl group” is bonded to an amino group.
  • methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, or t-butylcarbonylamino group For example, methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, or t-butylcarbonylamino group.
  • a group in which one “C 2 -C 3 alkylcarbonyl group” is bonded to an amino group (C 2 -C 3 alkylcarbonylamino group) is preferable, and a methylcarbonylamino group is more preferable.
  • the “tetrahydrofuryl group” is preferably a 3-tetrahydrofuryl group.
  • the “oxetyloxy group” is preferably a 3-oxetyloxy group.
  • the “tetrahydroxycyclohexyl group” is preferably a 1,3,4,5-tetrahydroxycyclohexyl group.
  • the “piperidin-1-yl group optionally substituted by 1 to 4 groups independently selected from the substituent group A” is selected from the piperidin-1-yl group or the substituent group A.
  • Preferable is a piperidin-1-yl group or a piperidin-1-yl group substituted at the 4-position with a group represented by the formula -LR 8 .
  • the “piperidin-3-yl group optionally substituted by 1 to 4 groups independently selected from the substituent group A” is selected from the piperidin-3-yl group or the substituent group A.
  • Preferred is a piperidin-3-yl group substituted at the 1-position with a group represented by the formula -LR 8 .
  • the “piperidin-4-yl group optionally substituted by 1 to 4 groups independently selected from the substituent group A” is selected from the piperidin-4-yl group or the substituent group A.
  • 1,2,3,6-tetrahydropyridin-4-yl group optionally substituted by 1 to 4 groups independently selected from the substituent group A refers to 1,2,3 , 6-tetrahydropyridin-4-yl group or 1,2,3,6-tetrahydropyridin-4-yl group independently substituted with 1 to 4 groups selected from substituent group A.
  • the “piperazin-1-yl group optionally substituted by 1 to 4 groups independently selected from the substituent group A” is selected from the piperazin-1-yl group or the substituent group A.
  • the “morpholin-4-yl group optionally substituted by 1 to 4 groups independently selected from the substituent group A” is selected from the morpholin-4-yl group or the substituent group A.
  • the “pyrrolidin-1-yl group optionally substituted independently by 1 to 4 groups selected from the substituent group A” is selected from the pyrrolidin-1-yl group or the substituent group A.
  • Preferred is a pyrrolidin-1-yl group which is substituted at the 3-position with a group represented by the formula -LR 8 .
  • the “pyrrolidin-3-yl group optionally substituted with 1 to 4 groups independently selected from the substituent group A” is selected from the pyrrolidin-3-yl group or the substituent group A.
  • Preferred is a pyrrolidin-3-yl group which is substituted at the 1-position with a group represented by the formula -LR 8 .
  • C 1 -C 6 alkyl independently one or two optionally substituted pyrrol-2-yl group in group
  • a 1-methyl-pyrrol-2-yl group is preferred.
  • a morpholin-2-yl group which may be independently substituted with one or two C 1 -C 6 alkyl groups refers to a morpholin-2-yl group or a C 1 -C 6 alkyl group. Is a morpholin-2-yl group substituted by 1 or 2 groups. Preferred are morpholin-2-yl group, 4-methyl-morpholin-2-yl group or 4-ethyl-morpholin-2-yl group.
  • an imidazol-5-yl group which may be independently substituted with one or two C 1 -C 6 alkyl groups independently represents an imidazol-5-yl group or a C 1 -C 6 alkyl group.
  • 1- or 2-substituted imidazol-5-yl group Preferred is an imidazol-5-yl group or a 1-methyl-imidazol-5-yl group.
  • 1 to 5 groups independently selected from “halogen atom, C 1 -C 6 alkyl group, hydroxyl group, C 1 -C 6 hydroxyalkyl group, C 2 -C 7 alkylcarbonyl group and oxo group”
  • the pyrrolidin-2-yl group which may be substituted includes a pyrrolidin-2-yl group or a halogen atom, a C 1 -C 6 alkyl group, a hydroxyl group, a C 1 -C 6 hydroxyalkyl group, a C 2 -C 7 alkyl group.
  • pyrrolidin-2-yl group which is independently substituted with 1 to 5 groups independently selected from a carbonyl group and an oxo group.
  • a pyrrolidin-2-yl group which is independently substituted with 1 to 3 groups independently selected from a halogen atom and a C 1 -C 6 alkyl group, and more preferably 4,4-difluoro- 1-methylpyrrolidin-2-yl group.
  • preferred R 1 is a C 1 -C 6 alkyl group, and more preferred R 1 is a methyl group or an ethyl group.
  • preferred R 2 is a hydrogen atom.
  • R 3 is preferably a hydrogen atom.
  • preferred R 4 is a C 1 -C 6 alkyl group, and more preferred R 4 is a methyl group.
  • preferred R 5 is a hydrogen atom or a C 1 -C 6 alkyl group, more preferred R 5 is a hydrogen atom or a methyl group, and even more preferred R 5 is a hydrogen atom. .
  • preferred R 6 is a hydrogen atom.
  • a preferable group represented by the formula —UT— is a group represented by the formula —CH 2 —CH 2 —.
  • Y is preferably an oxygen atom.
  • R 7 is preferably a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group, and more preferably R 7 is a hydrogen atom or a methyl group.
  • preferred L is a carbonyl group or an oxalyl group.
  • R 8 is preferably a C 1 -C 6 alkyl group, a C 1 -C 6 hydroxyalkyl group, a (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, an amino group, a mono group, -C 1 -C 6 alkylamino group, mono-C 1 -C 6 halogenated alkylamino group, di- (C 1 -C 6 alkyl) amino group, morpholin-2-yl group or halogen atom and C 1 -C A pyrrolidin-2-yl group independently substituted with 1 to 3 groups selected from 6 alkyl groups, more preferably R 8 is a methyl group, a 1-hydroxyethyl group, a methoxymethyl group, a methylamino group; A group, an ethylamino group, a 2,2-difluoroethylamino group, a morpholin-2-yl group or a 4,4
  • a preferred substituent group A is a group represented by the formula —LR 8 , and a more preferred substituent group A is an acetyl group, a (1S) -1-hydroxyethylcarbonyl group, a methoxy group Methylcarbonyl group, (2S) -1,4-dioxane-2-ylcarbonyl group, [(2S) -4,4-difluoro-1-methylpyrrolidin-2-yl] carbonyl group, methylaminooxalyl group, ethylamino An oxalyl group or a 2,2-difluoroethylaminooxalyl group;
  • E is a piperidin-4-yl group, a 1,2,3,6-tetrahydropyridin-4-yl group substituted by one group represented by the formula -LR 8 or Piperazin-1-yl group, more preferably E is 1-acetylpiperidin-4-yl group, 1-[(1S) -1-hydroxyethylcarbonyl] piperidin-4-yl group, 1-methoxymethylcarbonyl Piperidin-4-yl group, 1-[(2S) -1,4-dioxane-2-ylcarbonyl] piperidin-4-yl group, 1- ⁇ [(2S) -4,4-difluoro-1-methylpyrrolidine -2-yl] carbonyl ⁇ piperidin-4-yl group, 1- (methylaminooxalyl) piperidin-4-yl group, 1- (2,2-difluoroethylaminooxalyl) piperidin-4-yl group, 1-acet
  • the compound represented by the general formula (I) of the present invention or a pharmaceutically 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 pharmaceutically acceptable salt thereof has various isomers since an asymmetric carbon atom exists in the molecule.
  • 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.
  • 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 pharmaceutically acceptable salt thereof may also contain an unnatural ratio of atomic isotopes at one or more of atoms constituting such a compound.
  • the atomic isotope include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like.
  • the compound can also be radiolabeled with a radioisotope such as, for example, tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
  • the pharmaceutically acceptable salt 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.
  • 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-butylamine salts, diisopropylamine salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts Guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, trimethylammonium
  • the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be left in the atmosphere or recrystallized to absorb moisture and adsorb 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 pharmaceutically 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 pharmaceutically acceptable salt thereof has a selective and excellent Th17 cell differentiation inhibitory action and IL-17 production inhibitory action, such as autoimmune diseases. It is useful for the treatment and / or prevention of diseases involving ROR ⁇ t and cancer in which IL-17 production is involved in pathogenesis.
  • Specific diseases include psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases (such as Crohn's disease and ulcerative colitis), Sjogren's syndrome, systemic lupus erythematosus, chronic obstruction Pulmonary disease (COPD), atopic dermatitis, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colon cancer.
  • COPD chronic obstruction Pulmonary disease
  • atopic dermatitis asthma
  • type 1 diabetes graft-versus-host disease
  • GvHD graft-versus-host disease
  • alopecia areata
  • Preferred diseases are psoriasis, psoriatic arthritis, ankylosing spondylitis, Sjogren's syndrome or chronic obstructive pulmonary disease (COPD), especially psoriasis or psoriatic arthritis.
  • the compound represented by the general formula (I) of the present invention or a pharmaceutically 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.
  • prevention means to suppress or delay the onset of a disease that is diagnosed as having a high risk of developing the disease targeted by the present invention due to genetic background or chronic inflammation.
  • a disease whose onset risk can be diagnosed by single nucleotide polymorphisms (SNPs) or gene mutations is known.
  • SNPs single nucleotide polymorphisms
  • colorectal cancer it is known that the risk of colorectal cancer is clearly increased due to chronic persistence of colitis.
  • the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has selective and excellent Th17 cell differentiation inhibitory action and IL-17 production inhibitory action. Prophylactic administration to patients diagnosed with a high risk of onset is expected to have an effect of suppressing or delaying onset.
  • the compound represented by the general formula (I) of the present invention can be produced according to the methods A to K described below.
  • solvent used in the reaction of each step of the following methods A to K 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 and cyclopentyl methyl ether; methanol Ethanol, n-propanol, i-propanol, n
  • the base used in the reaction in each step of the following methods A to K 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; sodium fluoride, 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 tri
  • Organic bases such as undec-7-ene (DBU); lithium, alkali metal amides such as diisopropylamide, hexamethyldisilazane lithium and hexamethyldisilazane sodium; or amino acids such as proline.
  • DBU undec-7-ene
  • alkali metal amides such as diisopropylamide, hexamethyldisilazane lithium and hexamethyldisilazane sodium
  • amino acids such as proline.
  • the condensing agent used in the reaction of each step of the following methods A to K is, for example, azodicarboxylic acid dilower alkyl ester-triphenylphosphine such as diethyl ester of azodicarboxylic acid-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 diphenyl phosphoryl azide; phosphoryl chlorides such as diethyl phosphoryl chloride; imidazoles such as N, N′-carbodiimidazole Derivatives
  • reaction temperature varies depending on the solvent, starting material, reagent, etc.
  • reaction time varies depending on the solvent, starting material, reagent, reaction temperature, and the like.
  • 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.
  • an immiscible organic solvent such as ethyl acetate
  • the obtained target compound can be obtained by a conventional method such as recrystallization, reprecipitation, chromatography (for example, silica gel, alumina, magnesium-silica-based florisil, SO3H-silica (manufactured by 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)
  • a target compound insoluble in a solvent the obtained solid crude product can be purified by washing with a solvent.
  • the target compound in each step can be directly used in the next reaction without purification.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , E, Q 1 , Q 2 and V are the same as those described above. Show significance.
  • R 3a represents a group similar to the group in the definition of the group R 3 in addition to the hydroxy group or carboxy group contained in the group R 3 being a hydroxy group or carboxy group which may be protected.
  • E a is the same as the group in the definition of E group, except that the amino group, hydroxy group and / or carboxy group contained in E group may be protected amino group, hydroxy group and / or carboxy group
  • R 8 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.
  • 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.
  • the group represented by the formula —UT— is a group represented by the formula —CH 2 —CH 2 —. It is a method of manufacturing the compound represented by these. (Method A)
  • Step AI is a step for producing a salt of the compound represented by the general formula (III) by reacting the compound represented by the general formula (II) 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 the general formula (III) indicates a 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 the salt of the compound represented by the general formula (III) is reacted with the compound represented by the general formula (IV) or a salt thereof in a solvent in the presence of a condensing agent and a base.
  • a condensing agent and a base the compound represented by the general formula (V).
  • the salt of the compound represented by the general formula (IV) 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 amides, ethers, nitriles or halogenated hydrocarbons, 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.
  • Step A-III the compound represented by the general formula (V) is reacted with the compound represented by the general formula (VI) in a solvent in the presence of a palladium catalyst and a base, and then optionally R 3a and / or amino groups in the E a, by conversion using the known organic chemical methods the groups contained in the groups removal and / or E a protecting group for a hydroxy group and / or carboxy group, the general formula
  • This is a process for producing a compound represented by (Ia).
  • 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 alkali metal carbonates or alkali metal phosphates, and more preferably sodium carbonate, sodium carbonate aqueous solution, potassium phosphate or potassium phosphate aqueous solution.
  • the reaction temperature in this step is usually room temperature to 200 ° C, and preferably 50 ° C to 120 ° 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.
  • the group represented by the formula —UT— is a group represented by the formula —CH 2 —CH 2 —. It is a method of manufacturing the compound represented by these. (Method B)
  • Step BI This step is represented by the general formula (VIII) by reacting the compound represented by the general formula (V) with the compound (VII) in the presence of a palladium catalyst and a base in a solvent. This is a process for producing a compound.
  • Step B-II In this step, the compound represented by the general formula (VIII) is reacted with the compound represented by the general formula (IX) in the presence of a palladium catalyst and a base in a solvent, thereby After carrying out in the same manner as in step A-III, if desired, the amino, hydroxy and / or carboxy-protecting group in R 3a and / or E a is removed and / or a group contained in E a is known This is a step for producing a compound represented by the general formula (Ia) by conversion using an organic chemical method.
  • the group represented by the formula —UT— is a group represented by the formula —CH 2 —CH 2 —. It is a method of manufacturing the compound represented by these. (Method C)
  • Step CI This step comprises reacting a compound represented by the general formula (II) with a compound represented by the general formula (VI) in a solvent in the presence of a palladium catalyst and a base.
  • This is a process for producing a compound represented by the general formula (X), which is carried out in the same manner as in the process A-III.
  • Step C-II This step is carried out in the same manner as Step AI in Method A by reacting a compound represented by the general formula (X) with an acid in a solvent, and is represented by the general formula (XI).
  • the salt of the compound represented by the general formula (XI) indicates a case where hydrochloric acid is used as the acid.
  • Step C-III This step comprises reacting the salt of the compound represented by the general formula (XI) with the compound represented by the general formula (IV) or a salt thereof in the presence of a base in a solvent.
  • This is a step for producing a compound represented by the general formula (Ia) by carrying out in the same manner as in step A-II of the method.
  • Method D A method for producing a compound to be produced.
  • Step DI This step is a step for producing the compound represented by the general formula (Ib) 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 to Method C.
  • 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 from 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.
  • the method E is represented by the general formula (XVI) in which Y is a methylene group among the compounds represented by the general formula (II) used in the AI step of the method A and the CI step of the method C.
  • Step EI a compound represented by the general formula (XIII) 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 E-II This step is the same as Step BI in Method B by reacting the compound represented by general formula (XIII) with compound (VII) 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 (XIV).
  • 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 E-III This step comprises reacting a compound represented by general formula (XIV) with a compound represented by general formula (XV) in a solvent in the presence of a palladium catalyst and a base, This is a step for producing a compound represented by the general formula (XVI), which is carried out in the same manner as in step A-III.
  • Method F is represented by the general formula (XVIII) in which Y is an oxygen atom among the compounds represented by the general formula (II) used in the AI step of Method A and the CI step of Method C.
  • Step FI This step comprises reacting a compound represented by the general formula (XII) with a compound represented by the general formula (XVII) in the presence of a copper catalyst, a promoter and a base in a solvent. In this step, a compound represented by the general formula (XVIII) 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.
  • this step is represented by the general formula (XVIII) by reacting the compound represented by the general formula (XII) with a compound represented by the general formula (XVII) 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.
  • Method G is a method for producing a compound represented by the general formula (XXI) in which Y is an oxygen atom among the compounds represented by the general formula (X) used in the C-II step of Method C. (G method)
  • Step GI This step involves reacting a compound represented by the general formula (VI) with a compound represented by the general formula (XIX) 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 A-III, and is a step for producing a compound represented by the general formula (XX).
  • Step G-II In this step, the compound represented by the general formula (XX) is reacted with the compound represented by the general formula (XII) 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 (XXI), which is carried out in the same manner as in the FI process of Method F.
  • Method H is a method for producing a compound represented by the general formula (IV) or a salt thereof used in Step A-II of Method A and Step C-III of Method C.
  • Q 1 is a nitrogen atom
  • Step HI the compound represented by the general formula (XXII) is reacted with the compound represented by the general formula (XXIII) in the presence of a copper catalyst and a base in a solvent, thereby reacting the compound represented by the general formula (XXIII).
  • XXIV) is a step of 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 H-II This step is a step for producing a compound represented by the general formula (IV) by reacting a compound represented by the general formula (XXIV) 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 or a lithium hydroxide aqueous 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 (IV) is collected from the basic reaction mixture after completion of the reaction.
  • the salt collected depends on the base used in the reaction.
  • Step II a compound represented by the general formula (XXV) is reacted with a compound represented by the general formula (XXVI) in the presence of a base in a solvent to give a compound represented by the general formula (XXVII). 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 I-II This step comprises reacting a compound represented by the general formula (XXVII) with a compound represented by the general formula (XXIII) 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 (XXVIII), which is carried out in the same manner as in the HI process.
  • Step I-III This step is performed in the same manner as in Step H-II of Method H by reacting a compound represented by the general formula (XXVIII) with a base in a solvent, and represented by the general formula (XXIX). The process of manufacturing the compound or its salt.
  • the salt of the compound represented by the general formula (XXIX) is collected from the basic reaction mixture after completion of the reaction.
  • the salt collected depends on the base used in the reaction.
  • this step is carried out by reacting a compound represented by the general formula (XXVIII) in a solvent in the presence of a palladium catalyst in a hydrogen atmosphere to represent the general formula (XXIX). 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, 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.
  • this step involves reacting a compound represented by the general formula (XXVIII) with an acid in a solvent, and then reacting with a base in the solvent.
  • This reaction is a step for producing a compound represented by the general formula (XXIX) or a salt thereof, which is carried out in the same manner as in the H-II step of Method H.
  • 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 J is a method for producing a compound represented by the general formula (XXVIII) used in Step I-III of Method I. (J method)
  • Step JI a compound represented by the general formula (XXX) is reacted with a compound represented by the general formula (XXVI) in the presence of a base, a copper catalyst and a cocatalyst in a solvent.
  • the compound represented by the general formula (XXVIII) is produced.
  • the solvent used in this step is preferably an amide, an ether or a 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.
  • Step KI This step comprises reacting a compound represented by the general formula (XXXI) with a compound represented by the general formula (XXIII) in a solvent in the presence of a copper catalyst and a base, 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 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.
  • the protecting group of “amino group, hydroxy group and / or carboxy group which may be protected” in the definition of R 3a and E a is a chemistry such as hydrogenolysis, hydrolysis, electrolysis and photolysis. This refers to protecting groups that can be cleaved by synthetic methods, and refers to protecting groups commonly used in organic synthetic chemistry (eg, TW Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999 )reference).
  • the “protecting group” of the hydroxy group which 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, but for example, a 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, ⁇ -naphthoyl, ⁇ -naphthoyl, 2-bromobenzoyl, 4- Halogen
  • 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, tetrahydr
  • the “protecting group” of the carboxy group that 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, but for example, the above “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; “Aralkyl group”; or the above-mentioned “silyl group”, preferably a C 1 -C 6 alkyl group or an aralky
  • the “protecting group” of the amino group that may be protected is not particularly limited as long as it is an amino group protecting group used in the field of synthetic organic chemistry.
  • a substituted methylene group that forms a Schiff base preferably an Le carbonyl group, an arylcarbonyl group or an alkoxycarbonyl group, more preferably an alkoxycarbonyl group.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered in various forms.
  • 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 drops, suppositories (rectal administration), and external preparations (transdermal administration).
  • These various preparations are pharmaceutical preparation techniques such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, solvents, bases, etc. It can be formulated using adjuvants that can usually be used in the field.
  • 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, monoglyceride stearate, 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
  • the tablet which gave the normal coating 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.
  • 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.
  • 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.
  • solutions, emulsions or suspensions 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.
  • water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isoforms are used. Examples include stearyl alcohol and polyoxyethylene sorbitan fatty acid esters.
  • 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.
  • an external preparation When used as an external preparation, it can be used as an external solid preparation, an external solution (liniment, lotion), a spray, an ointment, a cream, a gel, or a patch.
  • external preparations can be produced according to a conventional method using solvents, bases, additives, excipients and the like which are usually used for pharmaceuticals.
  • the above-mentioned preparation may contain a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and the like as required, and may further contain other medicines.
  • the amount of the active ingredient compound contained in the preparation is not particularly limited and is appropriately selected within a wide range, but is usually 0.5 to 70% by weight, preferably 1 to 30% by weight, based on the total composition.
  • the amount used varies depending on the symptoms, age, etc. of the patient (warm-blooded animal, 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.
  • the upper limit is 500 mg / kg body weight (preferably 50 mg / kg body weight)
  • 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.
  • elution in column chromatography was performed under observation by TLC (Thin Layer Chromatography).
  • 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 TM Column, INJECT COLUMN TM ), Biotage silica gel (SNAP, SNAP Ultra) or Fuji Silica gel (FL100B, Chromatorex-SO3H) manufactured by Silysia Chemical Ltd. was used.
  • Yamazen's automatic chromatography device YFLC-5405-FC-GRII, W-Prep 2XY
  • Biotage's automatic chromatography device Isolera, SP-1
  • mg milligram
  • g gram
  • mL milliliter
  • MHz megahertz
  • Hz hertz
  • a nuclear magnetic resonance (hereinafter, 1 H-NMR) spectrum is a chemical shift value using tetramethylsilane as a standard substance. Is described in ⁇ value (ppm).
  • CDCl 3 deuterated chloroform
  • 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.
  • MS Mass spectrometry
  • Example 1 (Example 1) (Example 1-1): synthesized in Example (1c) 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
  • Example 1-2 synthesized in Example (1d) tert-butyl 4- ⁇ 4-[(4-methyl-1- ⁇ [2- (methylsulfonyl) phenyl] acetyl ⁇ -2,3-dihydro- 1H-Indol-5-yl) oxy] phenyl ⁇ piperidine-1 (2H) -carboxylate
  • Example 1-3 synthesized in Example (1e) 1- ⁇ 4-methyl-5- [4- (piperidin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl ⁇ -2- [2- (Methylsulfonyl) phenyl] ethanone hydrochloride
  • Example 1-4 synthesized in Example (1f) 1- (5- ⁇ 4- [1- (1,4-dioxane-2-ylcarbonyl) piperidin-4-yl] phenoxy ⁇ -4-methyl -2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
  • Example 1-5 isolated in Example (1g) 1- [5- (4- ⁇ 1-[(2S) -1,4-dioxane-2-ylcarbonyl] piperidin-4-yl ⁇ phenoxy ) -4-Methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone
  • Example 1-6 Isolated in Example (1g) 1- [5- (4- ⁇ 1-[(2R) -1,4-dioxane-2-ylcarbonyl] piperidin-4-yl ⁇ phenoxy ) -4-Methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone
  • 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 No. 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.
  • Example 2 Synthesis in Example (2e) 1- (5- ⁇ 4- [1- (1,4-Dioxane-2-ylcarbonyl) piperidin-4-yl] phenoxy ⁇ -4-methyl-2 , 3-Dihydro-1H-indol-1-yl) -2- [2- (ethylsulfonyl) phenyl] ethanone
  • Triethylamine (580 ⁇ L) was added to a solution of the obtained compound (710 mg) in N, N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 5 minutes. Then 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (874 mg) and the [2- (ethylsulfonyl) phenyl] obtained in the examples Acetic acid (CAS No. 1363179-47-8) (571 mg) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, water (100 mL) was added, and the precipitated solid was collected by filtration and dried.
  • Example 3-1 Synthesis in Example (3c) 1- (5- ⁇ 4- [1- (1,4-dioxane-2-ylcarbonyl) -1,2,3,6-tetrahydropyridine- 4-yl] -3-methylphenoxy ⁇ -4-methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
  • Example 3-2 Synthesis in Example (3d) 1- (5- ⁇ 4- [1- (1,4-Dioxane-2-ylcarbonyl) piperidin-4-yl] -3-methylphenoxy ⁇ -4-Methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
  • 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. Subsequently, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (4.51 g) and [2- (methylsulfonyl) phenyl] were added to the reaction solution. Acetic acid (CAS No. 142336-20-7) (2.82 g) was added, and the mixture was stirred at room temperature for 14 hours 30 minutes.
  • 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.
  • Example 4 Synthesis in Example (4a) 1- ⁇ 5- [4- (1-acetyl-1,2,3,6-tetrahydropyridin-4-yl) -3-methylphenoxy]- 4-Methyl-2,3-dihydro-1H-indol-1-yl ⁇ -2- [2- (methylsulfonyl) phenyl] ethanone
  • Example 4-2 Synthesis in Example (4b) 1- ⁇ 5- [4- (1-acetylpiperidin-4-yl) -3-methylphenoxy] -4-methyl-2,3-dihydro- 1H-Indol-1-yl ⁇ -2- [2- (methylsulfonyl) phenyl] ethanone
  • Triethylamine (95 ⁇ L) was added to a solution of the compound (21.2 mg) obtained in Example (1e) in dichloromethane (8 mL), and the mixture was stirred at room temperature for 5 minutes.
  • Acetic anhydride (35.2 ⁇ L) was added, and the mixture was stirred at room temperature for 2 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 (11.6 mg) as a white solid.
  • Example 6 Synthesis in Example (6c) 1- ⁇ 5- [4- (1-acetylpiperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indole-1- Yl ⁇ -2- [2- (ethylsulfonyl) phenyl] ethanone
  • Example 7 Synthesis in Example (7d) 1- ⁇ 5- [4- (1-acetylpiperidin-4-yl) -3-methoxyphenoxy] -4-methyl-2,3-dihydro-1H- Indol-1-yl ⁇ -2- [2- (methylsulfonyl) phenyl] ethanone
  • Triethylamine 140 ⁇ L was added to a solution of the obtained compound (212 mg) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes. Then 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (211 mg) and [2- (methylsulfonyl) phenyl] acetic acid (CAS No. 142336-) 20-7) (131 mg) was added, and the mixture was stirred at room temperature for 48 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example 8 Synthesis in Example (8c) (2S) -2-hydroxy-1- (4- ⁇ 2-methyl-4-[(4-methyl-1- ⁇ [2- (methylsulfonyl) phenyl] Acetyl ⁇ -2,3-dihydro-1H-indol-5-yl) oxy] phenyl ⁇ piperidin-1-yl) propan-1-one
  • Example 9 Synthesis in Example (9d) (2S) -1- (4- ⁇ 4-[(1- ⁇ [2- (ethylsulfonyl) phenyl] acetyl ⁇ -4-methyl-2,3- Dihydro-1H-indol-5-yl) oxy] -2-methylphenyl ⁇ piperidin-1-yl) -2-hydroxypropan-1-one
  • Triethylamine (230 ⁇ L) was added to a solution of the compound (300 mg) obtained in Example (1e) in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 5 minutes. Next, L-lactic acid (57.1 ⁇ L), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (159 mg) and 1-hydroxybenzotriazole monohydrate (84.9 mg) were added. And stirred at room temperature for 18 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.
  • Example 11-1 Synthesis in Example (11a) (2R) -1- (4- ⁇ 4-[(4-Methyl-1- ⁇ [2- (methylsulfonyl) phenyl] acetyl ⁇ -2, 3-Dihydro-1H-indol-5-yl) oxy] phenyl ⁇ piperidin-1-yl) -1-oxopropan-2-yl acetate
  • Example 11-2 (2R) -2-hydroxy-1- (4- ⁇ 4-[(4-methyl-1- ⁇ [2- (methylsulfonyl) phenyl] acetyl) synthesized in Example (11b) ⁇ -2,3-dihydro-1H-indol-5-yl) oxy] phenyl ⁇ piperidin-1-yl) propan-1-one
  • Example 12 1- [5- (4- ⁇ 1-[(1-hydroxycyclopropyl) carbonyl] piperidin-4-yl ⁇ phenoxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2 -[2- (Methylsulfonyl) phenyl] ethanone
  • Triethylamine (230 ⁇ L) was added to a solution of the compound (300 mg) obtained in Example (1e) in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 5 minutes. Then 1-hydroxy-1-cyclopropanecarboxylic acid (67.9 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (159 mg), 1-hydroxybenzotriazole monohydrate ( 84.9 mg) was added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example 13 Synthesis in Example (13b) (2S) -2,3-dihydroxy-1- (4- ⁇ 4-[(4-methyl-1- ⁇ [2- (methylsulfonyl) phenyl] acetyl ⁇ -2,3-dihydro-1H-indol-5-yl) oxy] phenyl ⁇ piperidin-1-yl) propan-1-one
  • Example 14 Synthesis in Example (14b) (2S) -1- (4- ⁇ 4-[(1- ⁇ [2- (ethylsulfonyl) phenyl] acetyl ⁇ -4-methyl-2,3- Dihydro-1H-indol-5-yl) oxy] -2-methylphenyl ⁇ piperidin-1-yl) -2,3-dihydroxypropan-1-one
  • Example 17 Synthesis in Example (17b) 3-hydroxy-1- (4- ⁇ 4-[(4-methyl-1- ⁇ [2- (methylsulfonyl) phenyl] acetyl ⁇ -2,3- Dihydro-1H-indol-5-yl) oxy] phenyl ⁇ piperidin-1-yl) propan-1-one
  • reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) and amino silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (147 mg) as a white solid.
  • silica gel column chromatography ethyl acetate / dichloromethane
  • amino silica gel column chromatography ethyl acetate / dichloromethane
  • Triethylamine 150 ⁇ L was added to a solution of the compound (300 mg) obtained in Example (1e) in N, N-dimethylformamide (8 mL), and the mixture was stirred at room temperature for 5 minutes. Subsequently, diethoxyacetic acid (98.6 mg) and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (230 mg) were added, and the mixture was stirred at room temperature for 18 hours. Stir. 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.
  • Triethylamine (77 ⁇ L) was added to a solution of the compound (150 mg) obtained in Example (1e) in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 5 minutes. Next, L-lactic acid (35.7 ⁇ L) and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (115 mg) were added, and 18% at room temperature was added. Stir for 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.
  • Triethylamine (205 ⁇ L) was added to a solution of the compound (200 mg) obtained in Example (1e) in N, N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 5 minutes. Subsequently, methoxyacetic acid (34.2 ⁇ L) and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (153 mg) were added, and the mixture was stirred at room temperature for 15 hours. Stir. 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.
  • Example 22-1 Synthesis in Example (22a) 1- (5- ⁇ 4- [1- (1,4-dioxane-2-ylcarbonyl) -1,2,3,6-tetrahydropyridine- 4-yl] -3-fluorophenoxy ⁇ -4-methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
  • Example 22-2 Synthesis in Example (22b) 1- (5- ⁇ 4- [1- (1,4-Dioxane-2-ylcarbonyl) piperidin-4-yl] -3-fluorophenoxy ⁇ -4-Methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
  • Example 23-1 Synthesis in Example (23b) 1- (5- ⁇ 4- [1- (1,4-dioxane-2-ylcarbonyl) -1,2,3,6-tetrahydropyridine- 4-yl] -3-methoxyphenoxy ⁇ -4-methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
  • Example 23-2 Synthesis in Example (23c) 1- (5- ⁇ 4- [1- (1,4-Dioxane-2-ylcarbonyl) piperidin-4-yl] -3-methoxyphenoxy ⁇ -4-Methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
  • 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.
  • 4- (4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (382 mg) and [2- (methylsulfonyl) phenyl] acetic acid (CAS number) were added to the reaction mixture. 142336-20-7) (256 mg) was added, and the mixture was stirred at room temperature for 16 hours 30 minutes.
  • 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.
  • Example 24-1 Synthesis in Example (24c) 1- (5- ⁇ 4- [1- (1,4-Dioxane-2-ylcarbonyl) -1,2,3,6-tetrahydropyridine- 4-yl] -2,5-dimethylphenoxy ⁇ -4-methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
  • Example 24-2 Synthesis in Example (24d) 1- (5- ⁇ 4- [1- (1,4-dioxane-2-ylcarbonyl) piperidin-4-yl] -2,5-dimethyl Phenoxy ⁇ -4-methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
  • N-methylmorpholine (0.153 mL) was added to a solution of the obtained compound (312 mg) in N, N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 15 minutes.
  • 4- (4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (288 mg) and [2- (methylsulfonyl) phenyl] acetic acid (CAS number) were added to the reaction mixture. 142336-20-7) (193 mg) was added, and the mixture was stirred at room temperature for 18 hours 30 minutes.
  • Triethylamine (31 ⁇ L) was added to a solution of the compound (60.0 mg) obtained in Example (1e) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes. Then tetrahydro-3-furanic acid (12.7 ⁇ L), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (46.0 mg) was added. The mixture was further stirred at room temperature for 18 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.
  • Triethylamine (31 ⁇ L) was added to a solution of the compound (60.0 mg) obtained in Example (1e) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes. Next, tetrahydrofuran-2-carboxylic acid (12.8 ⁇ L), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (46.0 mg) were added. The mixture was further stirred at room temperature for 18 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.
  • Triethylamine (31 ⁇ L) was added to a solution of the compound (60 mg) obtained in Example (1e) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes. Next, oxetane-2-carboxylic acid (13.6 mg), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (46.0 mg) were added. The mixture was further stirred at room temperature for 18 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.
  • Triethylamine (31 ⁇ L) was added to a solution of the compound (60.0 mg) obtained in Example (1e) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes. Next, oxetane-3-carboxylic acid (13.6 mg), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (46.0 mg) were added. The mixture was further 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.
  • Example 29 Synthesis in Example (29b) 3-hydroxy-2-methyl-1- (4- ⁇ 4-[(4-methyl-1- ⁇ [2- (methylsulfonyl) phenyl] acetyl ⁇ - 2,3-dihydro-1H-indol-5-yl) oxy] phenyl ⁇ piperidin-1-yl) propan-1-one
  • Example 30-1 Example 30a Synthesis 1- (4- ⁇ 4-[(4-Methyl-1- ⁇ [2- (methylsulfonyl) phenyl] acetyl ⁇ -2,3-dihydro-1H -Indol-5-yl) oxy] phenyl ⁇ piperidin-1-yl) -1-oxopropan-2-yl acetate
  • Example 30-2 synthesized in Example (30b) 2-hydroxy-1- (4- ⁇ 4-[(4-methyl-1- ⁇ [2- (methylsulfonyl) phenyl] acetyl ⁇ -2, 3-Dihydro-1H-indol-5-yl) oxy] phenyl ⁇ piperidin-1-yl) propan-1-one
  • Example 31-1 Synthesis in Example (31b) 1- ⁇ 5- [4- (1- ⁇ [(2S, 4S) -4-fluoropyrrolidin-2-yl] carbonyl ⁇ piperidin-4-yl ) Phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl ⁇ -2- [2- (methylsulfonyl) phenyl] ethanone hydrochloride
  • Example 31-2 Synthesis in Example (31c) 1- ⁇ 5- [4- (1- ⁇ [(2S, 4S) -4-fluoro-1-methylpyrrolidin-2-yl] carbonyl ⁇ piperidine -4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl ⁇ -2- [2- (methylsulfonyl) phenyl] ethanone
  • Example 31-3 Synthesis in Example (31d) 1- [4-Methyl-5- (4- ⁇ 1-[(1-methyl-1H-pyrrol-2-yl) carbonyl] piperidine-4- Yl ⁇ phenoxy) -2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone
  • Triethylamine 100 ⁇ L was added to a solution of the compound (200 mg) obtained in Example (1e) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes. Next, N-acetyl-L-proline (69.7 mg) and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (153 mg) were added. And stirred at room temperature for 18 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.
  • Example 33-1 synthesized in Example (33b) 1- ⁇ 5- [4- (1- ⁇ [(2S, 4R) -4-fluoropyrrolidin-2-yl] carbonyl ⁇ piperidin-4-yl ) Phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl ⁇ -2- [2- (methylsulfonyl) phenyl] ethanone
  • Example 33-2 Synthesis in Example (33c) 1- ⁇ 5- [4- (1- ⁇ [(2S, 4R) -1-acetyl-4-fluoropyrrolidin-2-yl] carbonyl ⁇ piperidine -4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl ⁇ -2- [2- (methylsulfonyl) phenyl] ethanone
  • Triethylamine (22.0 ⁇ L) and acetic anhydride (91.5 ⁇ L) were added to a solution of the compound (50.0 mg) obtained in Example (1e) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 18 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 amino silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (55.1 mg) as a white solid.
  • Example 35 Synthesis in Example (35b) (5S) -5-[(4- ⁇ 4-[(4-Methyl-1- ⁇ [2- (methylsulfonyl) phenyl] acetyl ⁇ -2,3 -Dihydro-1H-indol-5-yl) oxy] phenyl ⁇ piperidin-1-yl) carbonyl] pyrrolidin-2-one
  • Triethylamine 100 ⁇ L was added to a solution of the compound (200 mg) obtained in Example (1e) in N, N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 5 minutes. Subsequently, 1-methyl-5-oxo-L-proline (66.2 mg), 4- (4,6-dimethoxy-1, 3,5-Triazin-2-yl) -4-methylmorpholinium chloride (153 mg) was added, and the mixture was stirred at room temperature for 18 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.
  • Example 37-1 synthesized in Example (37b) 1- ⁇ 5- [4- (1- ⁇ [(2S) -4,4-difluoropyrrolidin-2-yl] carbonyl ⁇ piperidin-4-yl ) Phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl ⁇ -2- [2- (methylsulfonyl) phenyl] ethanone hydrochloride
  • Example 37-2 Synthesis in Example (37c) 1- ⁇ 5- [4- (1- ⁇ [(2S) -1-acetyl-4,4-difluoropyrrolidin-2-yl] carbonyl ⁇ piperidine -4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl ⁇ -2- [2- (methylsulfonyl) phenyl] ethanone
  • Triethylamine (77.0 ⁇ L) was added to a solution of the compound (150 mg) obtained in Example (1e) in N, N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 5 minutes. Next, N-acetyl-D-proline (59.3 mg) and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (115 mg) were added. And stirred at room temperature for 18 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.
  • Example 39-1 Synthesis in Example (39a) 1- (4- ⁇ 4-[(4-Methyl-1- ⁇ [2- (ethylsulfonyl) phenyl] acetyl ⁇ -2,3-dihydro- 1H-Indol-5-yl) oxy] phenyl ⁇ piperidin-1-yl) -1-oxopropan-2-yl acetate
  • Example 39-2 synthesized in Example (39b) 2-hydroxy-1- (4- ⁇ 4-[(4-methyl-1- ⁇ [2- (ethylsulfonyl) phenyl] acetyl ⁇ -2, 3-Dihydro-1H-indol-5-yl) oxy] phenyl ⁇ piperidin-1-yl) propan-1-one
  • Example 40 Synthesis in Example (40b) (2S) -1- (4- ⁇ 4-[(1- ⁇ [2- (ethylsulfonyl) phenyl] acetyl ⁇ -4-methyl-2,3- Dihydro-1H-indol-5-yl) oxy] phenyl ⁇ piperidin-1-yl) -2-hydroxypropan-1-one
  • Triethylamine (33.0 ⁇ L) was added to a solution of the compound (43.0 mg) obtained in Example (1e) in N, N-dimethylformamide (2 mL), and the mixture was stirred at room temperature for 5 minutes. Then 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (33.0 mg) and 2-methoxypropanoic acid (9.93 mg) were added. And stirred at room temperature for 18 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.
  • Example 42-1 Synthesis in Example (42a) 2- (4- ⁇ 4-[(4-Methyl-1- ⁇ [2- (methylsulfonyl) phenyl] acetyl ⁇ -2,3-dihydro- 1H-Indol-5-yl) oxy] phenyl ⁇ piperidin-1-yl) -2-oxoethyl acetate
  • Example 42-2 synthesized in Example (42b) 2-hydroxy-1- (4- ⁇ 4-[(4-methyl-1- ⁇ [2- (methylsulfonyl) phenyl] acetyl ⁇ -2, 3-Dihydro-1H-indol-5-yl) oxy] phenyl ⁇ piperidin-1-yl) ethanone
  • Triethylamine (36.0 ⁇ L) was added to a solution of the compound (70.0 mg) obtained in Example (1e) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes. Then (1R, 3R, 4R, 5R)-( ⁇ )-quinic acid (29.8 mg), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmol Holinium chloride (53.7 mg) was added, and the mixture was stirred at room temperature for 15 hours and further at 75 ° C. for 24 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example 44-1 synthesized in Example (44b) 1- (4-methyl-5- ⁇ 4- [1- (morpholin-2-ylcarbonyl) piperidin-4-yl] phenoxy ⁇ -2,3 -Dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
  • Example 44-2 Synthesis in Example (44c) 1- [5- (4- ⁇ 1-[(4-ethylmorpholin-2-yl) carbonyl] piperidin-4-yl ⁇ phenoxy) -4- Methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone
  • Example 45-1 Synthesis in Example (45d) 1- (4-methyl-5- ⁇ 4- [1- (morpholin-2-ylcarbonyl) piperidin-4-yl] phenoxy ⁇ -2,3 -Dihydro-1H-indol-1-yl) -2- [2- (ethylsulfonyl) phenyl] ethanone
  • Example 45-2 Synthesis in Example (45d) 1- [5- (4- ⁇ 1-[(4-ethylmorpholin-2-yl) carbonyl] piperidin-4-yl ⁇ phenoxy) -4- Methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (ethylsulfonyl) phenyl] ethanone
  • Triethylamine (580 mL) was added to a solution of the obtained compound (1.15 g) in N, N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 5 minutes. Then 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (874 mg) and [2- (ethylsulfonyl) phenyl] acetic acid (CAS No. 1363179- 47-8) (577 mg) was added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Triethylamine 140 ⁇ L was added to a solution of the compound (270 mg) obtained in Example (1e) in N, N-dimethylformamide (6 mL), and the mixture was stirred at room temperature for 5 minutes. Then 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (207 mg) and 1-methylpyrrolidine-2-carboxylic acid (77.3 mg) And stirred at room temperature for 18 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.
  • Example 49 Synthesis in Example (49b) 2- (cyclopropylamino) -1- (4- ⁇ 4-[(4-methyl-1- ⁇ [2- (methylsulfonyl) phenyl] acetyl ⁇ - 2,3-dihydro-1H-indol-5-yl) oxy] phenyl ⁇ piperidin-1-yl) ethanone
  • Example 50 Synthesis in Example (50b) 2-[(2-hydroxyethyl) amino] -1- (4- ⁇ 4-[(4-methyl-1- ⁇ [2- (methylsulfonyl) phenyl] Acetyl ⁇ -2,3-dihydro-1H-indol-5-yl) oxy] phenyl ⁇ piperidin-1-yl) ethanone
  • Example 51-1 synthesized in Example (51c) (5S) -5-[(4- ⁇ 4-[(4-methyl-1- ⁇ [2- (methylsulfonyl) phenyl] acetyl ⁇ -2 , 3-Dihydro-1H-indol-5-yl) oxy] phenyl ⁇ piperidin-1-yl) carbonyl] pyrrolidin-3-one
  • Example 51-2 Synthesis in Example (51d) (5S) -1-methyl-5-[(4- ⁇ 4-[(4-methyl-1- ⁇ [2- (methylsulfonyl) phenyl]) Acetyl ⁇ -2,3-dihydro-1H-indol-5-yl) oxy] phenyl ⁇ piperidin-1-yl) carbonyl] pyrrolidin-3-one
  • N-carbobenzyloxy-L-hydroxyproline (176 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (159 mg), 1-hydroxybenzotriazole monohydrate (84. 9 mg) was added and stirred at room temperature for 18 hours.
  • 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 (methanol / dichloromethane) to give the title compound (170 mg) as a white solid.
  • Example (51a) A solution of the compound (170 mg) obtained in Example (51a) in dichloromethane (4 mL) was added dropwise, and the mixture was further stirred at ⁇ 78 ° C. for 15 minutes. Triethylamine (151 ⁇ L) was added and stirred at room temperature for 18 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 (45.1 mg) as a white solid.
  • Example (33b) The compound (123 mg) obtained in Example (33b) was dissolved in a mixed solution of methanol (3 mL) and dichloromethane (1 mL), 7.5% palladium carbon (24.7 mg), 37% formaldehyde solution (277 ⁇ L) and hydrochloric acid (122 ⁇ L) were added, and the mixture was stirred at room temperature for 18 hours in a hydrogen atmosphere. Ethyl acetate was added to the reaction solution, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (93.6 mg) as a white solid.
  • Example 54 Synthesis in Example (54b) 1- ⁇ 5- [4- (1- ⁇ [(2S, 4R) -4-hydroxypyrrolidin-2-yl] carbonyl ⁇ piperidin-4-yl) phenoxy ] -4-Methyl-2,3-dihydro-1H-indol-1-yl ⁇ -2- [2- (methylsulfonyl) phenyl] ethanone
  • N, N-diisopropylethylamine (94.9 ⁇ L) was added to a solution of the compound (60.0 mg) obtained in Example (1e) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes. . Subsequently, potassium carbonate (15.3 mg), [(2R) -1,4-dioxane-2-yl] methyl methanesulfonic acid (65) synthesized according to a method described in the literature (Journal of Medicinal Chemistry, 2011, 54, 7772) was used. 0.2 mg) and stirred at 80 ° C. for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example 59 Synthesis in Example (59b) 1- (5- ⁇ 4- [1- (2-hydroxyethyl) piperidin-4-yl] phenoxy ⁇ -4-methyl-2,3-dihydro-1H -Indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
  • reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (10 mL) 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.
  • N, N-diisopropylethylamine (126 ⁇ L) was added to a solution of the compound (80.0 mg) obtained in Example (1e) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes.
  • potassium carbonate (30.7 mg) and 2-difluoroethyl methanesulfonic acid (105 mg) synthesized according to a method described in the literature (Journal of Organic Chemistry, 2009, 74, 4547) were added, and the mixture was stirred at 80 ° C. for 12 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example 62 synthesized in Example (62b) (4- ⁇ 4-[(4-methyl-1- ⁇ [2- (methylsulfonyl) phenyl] acetyl ⁇ -2,3-dihydro-1H-indole- 5-yl) oxy] phenyl ⁇ piperidin-1-yl) acetic acid
  • Example 64-1 Synthesis in Example (64a) 1- ⁇ 4-methyl-5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenoxy]- 2,3-Dihydro-1H-indol-1-yl ⁇ -2- [2- (methylsulfonyl) phenyl] ethanone
  • Example 64-2 synthesized in Example (64b) 1- ⁇ 4-methyl-5- [4- (1-methylpiperidin-4-yl) phenoxy] -2,3-dihydro-1H-indole- 1-yl ⁇ -2- [2- (methylsulfonyl) phenyl] ethanone
  • Triethylamine (31.0 ⁇ L) was added to a solution of the compound (60.0 mg) obtained in Example (1e) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes. Then 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (46.0 mg) and morpholin-4-ylacetic acid (19.3 mg) were added. The mixture was further stirred at room temperature for 18 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.
  • Example 79 To a solution of the compound obtained in Example 79 (117 mg) in dichloromethane (4 mL) was added ethylamine hydrochloride (24.8 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (77. 8 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (27.6 mg) and N, N-diisopropylethylamine (0.106 mL) were added and stirred at room temperature. did. After 12 hours, the solution was concentrated under reduced pressure.
  • 2-Fluoroethylamine hydrochloride (34.2 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride were added to a solution of the compound obtained in Example 79 (132 mg) in dichloromethane (4 mL). (87.8 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (31.2 mg), N, N-diisopropylethylamine (0.120 mL) were added. Stir at room temperature. After 12 hours, the solution was concentrated under reduced pressure.
  • Example 79 To a solution of the compound obtained in Example 79 (138 mg) in dichloromethane (4 mL) was added 2,2-difluoroethane-1-amine hydrochloride (42.2 mg), 1-ethyl-3- (3-dimethylaminopropyl). ) Carboximide hydrochloride (91.8 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (32.6 mg), N, N-diisopropylethylamine (0.125) mL) was added and stirred at room temperature. After 12 hours, the solution was concentrated under reduced pressure.
  • Example 79 To a solution of the compound obtained in Example 79 (136 mg) in dichloromethane (4 mL) was added methylamine hydrochloride (31.8 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (90 .4 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (32.1 mg) and N, N-diisopropylethylamine (0.123 mL) were added at room temperature. Stir. 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 (71.0 mg) as a white amorphous solid.
  • N-Propylamine hydrochloride (43.4 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride were added to a solution of the compound obtained in Example 79 (131 mg) in dichloromethane (4 mL). (87.1 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (30.9 mg), N, N-diisopropylethylamine (0.119 mL) were added. Stir at room temperature. After 12 hours, the solution was concentrated under reduced pressure.
  • Example 79 To a solution of the compound obtained in Example 79 (134 mg) in dichloromethane (4 mL) was added isopropylamine hydrochloride (44.4 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (89 0.1 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (31.6 mg) and N, N-diisopropylethylamine (0.121 mL) were added at room temperature. Stir. After 12 hours, the solution was concentrated under reduced pressure.
  • Example 79 To a solution of the compound obtained in Example 79 (133 mg) in dichloromethane (4 mL) was added 2,2,2-trifluoroethylamine hydrochloride (62.5 mg), 1-ethyl-3- (3-dimethylaminopropyl). ) Carboximide hydrochloride (88.4 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (31.4 mg), N, N-diisopropylethylamine (0.121) mL) was added and stirred at room temperature. After 12 hours, the solution was concentrated under reduced pressure.
  • Example 79 To a solution of the compound obtained in Example 79 (0.14 g) in dichloromethane (4 mL) was added N-methylethanamine hydrochloride (0.072 g), 1-ethyl-3- (3-dimethylaminopropyl) carboxyl.
  • Imide hydrochloride (0.096 g), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (0.034 g), N, N-diisopropylethylamine (0.130 mL) And stirred at room temperature. After 12 hours, the solution was concentrated under reduced pressure.
  • Example 79 To a solution of the compound obtained in Example 79 (0.140 g) in dichloromethane (4 mL), ammonium chloride (0.067 g), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (0 096 g) 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (0.034 g) and N, N-diisopropylethylamine (0.130 mL) were added at room temperature. Stir. After 12 hours, the solution was concentrated under reduced pressure.
  • Example 79 To a solution of the compound obtained in Example 79 (750 mg) in dichloromethane (10 mL), morpholine (227 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (499 mg), 3H— 1,2,3-Triazolo [4,5-b] pyridin-3-ol (177 mg) and N, N-diisopropylethylamine (0.680 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 (460 mg) as a white amorphous solid.
  • Example 79 To a solution of the compound obtained in Example 79 (159 mg) in dichloromethane (4 mL) was added azetidine hydrochloride (51.6 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (106 mg). ) 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (37.5 mg) and N, N-diisopropylethylamine (0.144 mL) were added and stirred at room temperature. After 12 hours, the solution was concentrated under reduced pressure.
  • Example 78 To a solution of the compound obtained in Example 78 (237 mg) in 1,4-dioxane (2 mL) was added 1N aqueous sodium hydroxide solution (1.17 mL), and the mixture was stirred at room temperature for 3 hr. The mixture was neutralized with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Recrystallization from ethyl acetate gave the title compound (204 mg) as a pale yellow solid.
  • Example 80-1 Ethyl (4- ⁇ 4-[(1- ⁇ [2- (ethylsulfonyl) phenyl] acetyl ⁇ -4-methyl-2,3-dihydro-1H) synthesized in Example (80a) -Indol-5-yl) oxy] -2-methylphenyl ⁇ piperidin-1-yl) (oxo) acetate
  • Example 80-2 Synthesis in Example (80b) (4- ⁇ 4-[(1- ⁇ [2- (ethylsulfonyl) phenyl] acetyl ⁇ -4-methyl-2,3-dihydro-1H- Indol-5-yl) oxy] -2-methylphenyl ⁇ piperidin-1-yl) (oxo) acetate sodium
  • Example 81-1 Ethyl (4- ⁇ 4-[(1- ⁇ [2- (methylsulfonyl) phenyl] acetyl ⁇ -4-methyl-2,3-dihydro-1H) synthesized in Example (81a) -Indol-5-yl) oxy] -2-methylphenyl ⁇ piperidin-1-yl) (oxo) acetate
  • Example 81-2 Synthesis in Example (81b) (4- ⁇ 4-[(1- ⁇ [2- (methylsulfonyl) phenyl] acetyl ⁇ -4-methyl-2,3-dihydro-1H- Indol-5-yl) oxy] -2-methylphenyl ⁇ piperidin-1-yl) (oxo) acetic acid
  • Example 81-3 Synthesis in Example (81c) 2- (4- ⁇ 4-[(1- ⁇ [2- (methylsulfonyl) phenyl] acetyl ⁇ -4-methyl-2,3-dihydro- 1H-Indol-5-yl) oxy] -2-methylphenyl ⁇ piperidin-1-yl) -N, N-dimethyl-2-oxoacetamide
  • dimethylamine hydrochloride (11.6 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (27.3 mg), 3H-1,2,3-triazolo [4,5- b] Pyridin-3-ol (16.1 mg) was added and stirred at room temperature for 18 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.
  • Triethylamine (49.0 ⁇ L) was added to a solution of the compound (70.0 mg) obtained in Example (81b) in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 5 minutes.
  • Ethylamine hydrochloride (11.6 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (27.3 mg), 3H-1,2,3-triazolo [4,5-b] Pyridin-3-ol (16.1 mg) was added and stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Triethylamine (66.0 ⁇ L) was added to a solution of the compound (100 mg) obtained in Example (80b) in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 5 minutes.
  • Ethylamine hydrochloride (15.6 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (36.7 mg), 3H-1,2,3-triazolo [4,5-b] Pyridin-3-ol (21.7 mg) was added and stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Triethylamine (66.0 ⁇ L) was added to a solution of the compound (100 mg) obtained in Example (80b) in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 5 minutes.
  • Dimethylamine hydrochloride (15.6 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (36.7 mg), 3H-1,2,3-triazolo [4,5- b] Pyridin-3-ol (21.7 mg) was added and stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example 85-1 Ethyl (4- ⁇ 4-[(1- ⁇ [2- (ethylsulfonyl) phenyl] acetyl ⁇ -4-methyl-2,3-dihydro-1H) synthesized in Example (85a) -Indol-5-yl) oxy] phenyl ⁇ piperidin-1-yl) (oxo) acetate
  • Example 85-2 Synthesis in Example (85b) (4- ⁇ 4-[(1- ⁇ [2- (ethylsulfonyl) phenyl] acetyl ⁇ -4-methyl-2,3-dihydro-1H- Indol-5-yl) oxy] phenyl ⁇ piperidin-1-yl) (oxo) acetate sodium
  • Example 85-3 Synthesis in Example (85c) 2- (4- ⁇ 4-[(1- ⁇ [2- (ethylsulfonyl) phenyl] acetyl ⁇ -4-methyl-2,3-dihydro- 1H-Indol-5-yl) oxy] phenyl ⁇ piperidin-1-yl) -N, N-dimethyl-2-oxoacetamide
  • Example 88 Synthesis in Example (88d) 1- (5- ⁇ 4- [1- (1,4-dioxane-2-ylcarbonyl) piperidin-3-yl] phenoxy ⁇ -4-methyl-2 , 3-Dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
  • Triethylamine (86 ⁇ L) was added to a solution of the compound (153 mg) obtained in Example (88c) in dichloromethane (8 mL), and the mixture was stirred at room temperature for 5 minutes.
  • Acetic anhydride (32.1 ⁇ L) was added, and the mixture was stirred at room temperature for 18 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 (118 mg) as a white solid.
  • Example 90 Synthesis in Example (90e) 1- (5- ⁇ 4- [1- (1,4-Dioxane-2-ylcarbonyl) pyrrolidin-3-yl] phenoxy ⁇ -4-methyl-2 , 3-Dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
  • the reaction was performed at 100 ° C. for 5 hours in an atmosphere.
  • 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 (222 mg) as a white solid.
  • Example 92 synthesized in Example (92b) 2-methoxy-1- [4- ⁇ 4-[(4-methyl-1- ⁇ [2- (methylsulfonyl) phenyl] acetyl ⁇ -2,3- Dihydro-1H-indol-5-yl) oxy] phenyl ⁇ -3,6-dihydropyridin-1 (2H) -yl] ethanone
  • Triethylamine (230 ⁇ L) was added to a solution of the compound (300 mg) obtained in Example (92a) in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 5 minutes. Next, L-lactic acid (57.1 ⁇ L), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (159 mg) and 1-hydroxybenzotriazole monohydrate (84.9 mg) were added. And stirred at room temperature for 18 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.
  • Example 94 synthesized in Example (94b) 3-hydroxy-1- (4- ⁇ 4-[(4-methyl-1- ⁇ [2- (methylsulfonyl) phenyl] acetyl ⁇ -2,3- Dihydro-1H-indol-5-yl) oxy] phenyl ⁇ -3,6-dihydropyridin-1 (2H) -yl) propan-1-one
  • Example 95 Synthesis in Example (95b) (2S) -2-hydroxy-1- [4- ⁇ 2-methyl-4-[(4-methyl-1- ⁇ [2- (methylsulfonyl) phenyl] Acetyl ⁇ -2,3-dihydro-1H-indol-5-yl) oxy] phenyl ⁇ -3,6-dihydropyridin-1 (2H) -yl] propan-1-one
  • Example 96 Synthesis in Example (96b) (2S) -2,3-dihydroxy-1- (4- ⁇ 4-[(4-methyl-1- ⁇ [2- (methylsulfonyl) phenyl] acetyl ⁇ -2,3-Dihydro-1H-indol-5-yl) oxy] phenyl ⁇ -3,6-dihydropyridin-1 (2H) -yl) propan-1-one
  • (4S) -2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (100 mg), 4-(()) synthesized according to a method described in the literature (Bioorganic and Medicinal Chemistry Letters, 2004, 14, 3231).
  • 4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (231 mg) was added, and the mixture was stirred at room temperature for 18 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.
  • Example (1b) A solution of sodium carbonate (1.59 g) in a solution of ethanone (2.5 g) and the compound (1.94 g) obtained in Example (103b) in 1,2-dimethoxyethane (50 mL) (10 mL) was added and stirred at room temperature for 5 minutes. Next, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (408 mg) was added and reacted at 130 ° C.

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Abstract

The present invention pertains to a compound having an exceptional effect for inhibiting retinoic-acid-receptor-related orphan receptors γt, or a pharmacologically acceptable salt thereof. A compound represented by general formula (I) (in the formula, R1 represents a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a phenyl group; R2 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, or the like; R3 represents a hydrogen atom, a C2-C7 carboxyalkyl group, or a hydroxyl group; R4 represents a halogen atom or a C1-C6 alkyl group; R5 represents a hydrogen atom or a C1-C6 alkyl group; R6 represents a hydrogen atom, a halogen atom, or a C1-C6 alkyl group; Q1 represents a nitrogen atom or a group represented by the formula =CH-; Q2 represents a nitrogen atom or a group represented by the formula =CH-; a group represented by the formula -U-T- represents a group represented by the formula -CH2-CH2-, or the like; Y represents a methylene group or an oxygen atom; V represents a nitrogen atom or a group represented by the formula =C(R7)-; R7 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, or the like; E represents a piperidine-1-yl group, piperidine-4-yl group, or 1,2,3,6-tetrahydropyridine-4-yl group optionally substituted independently by from one to four groups selected from substituent group A, or the like; substituent group A includes C1-C6 alkyl groups, C1-C6 alkyl halide groups, groups represented by the formula -L-R8, and the like; L represents a carbonyl group, an oxalyl group, or the like; R8 represents a C1-C6 alkyl group, a C1-C6 hydroxyalkyl group, a mono-C1-C6 alkylamino group, or the like), or a pharmacologically acceptable salt thereof.

Description

環状アミン誘導体Cyclic amine derivative
　本発明は、優れたレチノイン酸受容体関連オーファン受容体γｔ（本明細書中ではＲＯＲγｔと略すことがある）の阻害作用を有し、乾癬等の治療薬として有用な化合物又はその薬学上許容される塩に関する。 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 pharmaceutically acceptable salt thereof. Related to the salt.
　自己免疫疾患の多くは原因不明とされているが、多くの疾患でT 細胞異常と関連が深いことが以前から知られている。特にIFN-γ高産生のヘルパーT 細胞（Th1 細胞）は、古くからその関連性が報告されていたが、Th1 細胞の異常では疾患の発症機序を完全に説明できない点もあり、Th1 細胞関与の定説に疑問がもたれていた。2006 年にIL-17 高産生のヘルパーT細胞（Th17 細胞）の存在が報告され、自己免疫疾患はTh17 細胞の異常と関連が深いと提唱された。それ以来、Th17 細胞に関する研究が精力的に行われ、幾つかの自己免疫疾患でその関連性が明らかになり、Th17 細胞の重要性が注目されるようになった。Th17 細胞がナイーブT 細胞より分化する過程、およびTh17細胞がIL-17を産生する過程で、核内受容体のRORγtが機能する。RORγtノックアウトマウスのナイーブT 細胞では、Th17 細胞への分化が抑制され、IL-17産生が抑制され、多発性硬化症の病態モデルであるExperimental Autoimmune Encephalomyelitisの発症が抑制された結果が得られた（非特許文献１）。また別の病態モデルにおいても、RORγtがTh17 細胞への分化、IL-17の産生および病態発症に重要な役割を果たしている報告がある（非特許文献２－３）。これらの知見から、RORγtの転写活性を抑制する物質、つまりRORγt阻害剤は自己免疫疾患などの治療薬になる可能性が考えられる。 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, IFN-γ high-producing helper T cells (Th1 cells) have been reported for a long time, but abnormalities in Th1 cells cannot fully explain the pathogenesis of the disease. Was questioned. In 2006, the presence of IL-17 -rich 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 its 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 of Th17 cell differentiation from naive T cells and in the process of Th17 cells producing IL-17. In naive T cells of RORγt knockout mice, the 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 obtained ( Non-patent document 1). In another pathological model, there is a report that RORγt plays an important role in differentiation into Th17 cells, production of IL-17, 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.
　自己免疫疾患の原因はこれまで不明であったことから、その治療法には、免疫全般を抑制する免疫抑制剤が用いられてきた。しかしこの治療法では自己免疫疾患の原因そのものに対する効果が期待されず、対症療法に過ぎないことから、十分な治療効果が認められなかったり、寛解に至らず再燃することが多かった。そのため十分な治療効果を出し寛解に至るには、自己免疫疾患の原因に適した治療法が必要であった。最近になって幾つかの自己免疫疾患の原因としてIL-17産生が亢進するTh17細胞の異常が確認された。しかし現時点ではTh17細胞の異常を治療できる方法が存在しないことから、Th17細胞の異常を改善できる新たな治療法が必要とされていた。 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 merely a symptomatic treatment, and therefore, a sufficient therapeutic effect was not observed or remission occurred 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.
　発明者らは、RORγｔ阻害作用を有する化合物について鋭意研究を行った結果、特定の化学構造を有する環状アミン誘導体が、選択的かつ優れたTh17細胞の分化阻害作用及びIL-17産生阻害作用を有し、自己免疫疾患などのRORγtが関わる疾患の予防及び治療に有用であることを見出した。本発明者らは、この環状アミン誘導体が、乾癬、乾癬性関節炎、強直性脊椎炎、多発性硬化症、関節リウマチ、炎症性腸疾患（クローン病や潰瘍性大腸炎など）、シェーグレン症候群、全身性エリテマトーデス、慢性閉塞性肺疾患（COPD）、アトピー性皮膚炎、、喘息、一型糖尿病、移植片対宿主病（GvHD）、円形脱毛症、白斑、川崎病、ベーチェット病、糸球体腎炎、心筋症、再生不良性貧血、橋本病、強皮症、巨細胞性動脈炎、接触性皮膚炎、視神経炎などの自己免疫疾患又はIL-17の産生が病態発症に関与している大腸癌の治療及び／又は予防のための医薬の有効成分として有用であることを見出した。本発明は上記の知見を基にして完成された。 As a result of intensive studies on compounds having RORγt inhibitory effects, the inventors have found that cyclic amine derivatives having a specific chemical structure have selective and excellent Th17 cell differentiation inhibitory action and IL-17 production inhibitory action. And found useful for the prevention and treatment of diseases involving RORγt such as autoimmune diseases. The present inventors have found that this cyclic amine derivative is used in psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases (such as Crohn's disease and ulcerative colitis), Sjogren's syndrome, systemic Systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, myocardium Treatment of colorectal cancer in which autoimmune diseases such as symptom, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis, etc. or IL-17 production is involved in pathogenesis And / or useful as an active ingredient of a medicament for prevention. The present invention has been completed based on the above findings.
　本発明は、以下である。
（１）一般式（Ｉ） The present invention is as follows.
(1) General formula (I)
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
［式中、
　Ｒ１は、Ｃ１－Ｃ６アルキル基、Ｃ３－Ｃ６シクロアルキル基又はフェニル基を示し、
　Ｒ２は、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基又はＣ１－Ｃ６アルコキシ基を示し、
　Ｒ３は、水素原子、Ｃ２－Ｃ７カルボキシアルキル基又は水酸基を示し、
　Ｒ４は、ハロゲン原子又はＣ１－Ｃ６アルキル基を示し、
　Ｒ５は、水素原子又はＣ１－Ｃ６アルキル基を示し、
　Ｒ６は、水素原子、ハロゲン原子又はＣ１－Ｃ６アルキル基を示し、
　Ｑ１は、窒素原子又は式＝ＣＨ－で表される基を示し、
　Ｑ２は、窒素原子又は式＝ＣＨ－で表される基を示し、
　式－Ｕ－Ｔ－で表される基は、式－ＣＨ２－ＣＨ２－で表される基又は式－ＣＨ＝ＣＨ－で表される基を示し、
　Ｙは、メチレン基又は酸素原子を示し、
　Ｖは、窒素原子又は式＝Ｃ（Ｒ７）－で表される基を示し、
　Ｒ７は、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ３－Ｃ６シクロアルキル基、Ｃ２－Ｃ６アルケニル基、Ｃ１－Ｃ６アルコキシ基、Ｃ１－Ｃ６ハロゲン化アルコキシ基、（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルキル）基、（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルコキシ）基、Ｃ２－Ｃ７アルキルカルボニル基、テトラヒドロフリル基又はオキセチルオキシ基を示し、
　Ｅは、置換基群Ａから選択される基で独立に１乃至４個置換されていてもよいピペリジン－１－イル基、ピペリジン－３－イル基、ピペリジン－４－イル基、１，２，３，６－テトラヒドロピリジン－４－イル基、ピペラジン－１－イル基、モルホリン－４－イル基、ピロリジン－１－イル基又はピロリジン－３－イル基を示し、
　置換基群Ａは、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６ハロゲン化アルキル基、Ｃ１－Ｃ６ヒドロキシアルキル基、（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルキル）基、カルボキシメチル基、水酸基、モノ－Ｃ２－Ｃ７アルキルカルボニルアミノ基、オキソ基、オキセタン－３－イル基、（１，４－ジオキサン－２－イル）メチル基、Ｅのメチレン部位に２位で結合してスピロ構造を構築する１，３－ジオキソラン及び式－Ｌ－Ｒ８で表される基からなる群を示し、
　Ｌは、カルボニル基、オキサリル基又はスルホニル基を示し、
　Ｒ８は、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６ヒドロキシアルキル基、Ｃ１－Ｃ６ジヒドロキシアルキル基、（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルキル）基、ジ（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルキル）基、（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６ヒドロキシアルキル）基、Ｃ３－Ｃ６ヒドロキシシクロアルキル基、Ｃ１－Ｃ６シアノアルキル基、Ｃ１－Ｃ６アルコキシ基、水酸基、アミノ基、モノ－Ｃ１－Ｃ６アルキルアミノ基、モノ－Ｃ１－Ｃ６ハロゲン化アルキルアミノ基、ジ－（Ｃ１－Ｃ６アルキル）アミノ基、（Ｃ２－Ｃ７アルキルカルボニルオキシ）－（Ｃ１－Ｃ６アルキル）基、（モノ－Ｃ３－Ｃ６シクロアルキルアミノ）－（Ｃ１－Ｃ６アルキル）基、（Ｃ２－Ｃ７ヒドロキシアルキルカルボニルオキシ）－（Ｃ１－Ｃ６アルキル）基、（モノ－Ｃ１－Ｃ６ヒドロキシアルキルアミノ）－（Ｃ１－Ｃ６アルキル）基、テトラヒドロキシシクロヘキシル基、テトラヒドロフラン－２－イル基、テトラヒドロフラン－３－イル基、オキセタン－２－イル基、オキセタン－３－イル基、１，４－ジオキサン－２－イル基、アゼチジン－１－イル基、モルホリン－４－イル基、（モルホリン－４－イル）メチル基、Ｃ１－Ｃ６アルキル基で独立に１又は２個置換されていてもよいピロール－２－イル基、Ｃ１－Ｃ６アルキル基で独立に１又は２個置換されていてもよいモルホリン－２－イル基、Ｃ１－Ｃ６アルキル基で独立に１又は２個置換されていてもよいイミダゾール－５－イル基又はハロゲン原子、Ｃ１－Ｃ６アルキル基、水酸基、Ｃ１－Ｃ６ヒドロキシアルキル基、Ｃ２－Ｃ７アルキルカルボニル基及びオキソ基から選択される基で独立に１乃至５個置換されていてもよいピロリジン－２－イル基を示す。］で表される化合物又はその薬学上許容される塩。 [Where:
R 1 represents a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group or a phenyl group,
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,
R 4 represents a halogen atom or a C 1 -C 6 alkyl group,
R 5 represents a hydrogen atom or a C 1 -C 6 alkyl group,
R 6 represents a hydrogen atom, a halogen atom or a C 1 -C 6 alkyl group,
Q 1 represents a nitrogen atom or a group represented by the formula = CH-
Q 2 represents a nitrogen atom or a group represented by the formula = CH-
The group represented by the formula —UT— represents a group represented by the formula —CH 2 —CH 2 — or a group represented by the formula —CH═CH—.
Y represents a methylene group or an oxygen atom,
V represents a nitrogen atom or a group represented by the formula = C (R 7 )-
R 7 represents a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a C 2 -C 6 alkenyl group, a C 1 -C 6 alkoxy group, or a C 1 -C 6 halogenated group. An alkoxy group, a (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, a (C 1 -C 6 alkoxy)-(C 1 -C 6 alkoxy) group, a C 2 -C 7 alkylcarbonyl group, Represents a tetrahydrofuryl group or an oxetyloxy group,
E represents a piperidin-1-yl group, a piperidin-3-yl group, a piperidin-4-yl group, 1, 2, 2, which may be independently substituted with 1 to 4 groups independently selected from the substituent group A; Represents a 3,6-tetrahydropyridin-4-yl group, piperazin-1-yl group, morpholin-4-yl group, pyrrolidin-1-yl group or pyrrolidin-3-yl group;
Substituent group A includes a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 hydroxyalkyl group, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) Group, carboxymethyl group, hydroxyl group, mono-C 2 -C 7 alkylcarbonylamino group, oxo group, oxetan-3-yl group, (1,4-dioxane-2-yl) methyl group, 2 in the methylene moiety of E A group consisting of 1,3-dioxolane and a group represented by the formula -LR 8 , which are bonded at a position to form a spiro structure;
L represents a carbonyl group, an oxalyl group or a sulfonyl group,
R 8 is a C 1 -C 6 alkyl group, a C 1 -C 6 hydroxyalkyl group, a C 1 -C 6 dihydroxyalkyl group, a (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, a di (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, (C 1 -C 6 alkoxy)-(C 1 -C 6 hydroxyalkyl) group, C 3 -C 6 hydroxycycloalkyl group, C 1- C 6 cyanoalkyl group, C 1 -C 6 alkoxy group, hydroxyl group, amino group, mono-C 1 -C 6 alkylamino group, mono-C 1 -C 6 halogenated alkylamino group, di- (C 1 -C 6 alkyl) amino group, (C 2 -C 7 alkylcarbonyloxy)-(C 1 -C 6 alkyl) group, (mono-C 3 -C 6 cycloalkylamino)-(C 1 -C 6 alkyl) group, (C 2 C 7 hydroxyalkyl carbonyloxy) - (C 1 -C 6 alkyl) group, (mono -C 1 -C 6 hydroxyalkyl amino) - (C 1 -C 6 alkyl) group, tetra-hydroxycyclohexyl group, tetrahydrofuran-2 Yl group, tetrahydrofuran-3-yl group, oxetan-2-yl group, oxetane-3-yl group, 1,4-dioxane-2-yl group, azetidin-1-yl group, morpholin-4-yl group, Morpholin-4-yl) methyl group, C 1 -C 6 alkyl group independently 1 or 2 optionally substituted pyrrol-2-yl group, C 1 -C 6 alkyl group 1 or 2 independently optionally substituted morpholin-2-yl group, C 1 -C 6 alkyl which may be one or two substituted independently by a group imidazol-5-yl group or a halo Emissions atom, C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 hydroxyalkyl group, be C 2 -C 7 are one to five substituents from the alkyl group and oxo group independently a group selected A good pyrrolidin-2-yl group is indicated. Or a pharmaceutically acceptable salt thereof.
　本発明において、好適には、以下を挙げることができる。 In the present invention, the following can be preferably mentioned.
　（２）　（１）において、
　Ｒ１が、Ｃ１－Ｃ６アルキル基である化合物又はその薬学上許容される塩。 (2) In (1),
A compound or a pharmaceutically acceptable salt thereof, wherein R 1 is a C 1 -C 6 alkyl group.
　（３）　（１）において、
　Ｒ１が、メチル基又はエチル基である化合物又はその薬学上許容される塩。 (3) In (1),
A compound or a pharmaceutically acceptable salt thereof, wherein R 1 is a methyl group or an ethyl group.
　（４）　（１）乃至（３）から選択されるいずれか一項において、
　Ｒ２が、水素原子である化合物又はその薬学上許容される塩。 (4) In any one item selected from (1) to (3),
A compound or a pharmaceutically acceptable salt thereof, wherein R 2 is a hydrogen atom.
　（５）　（１）乃至（４）から選択されるいずれか一項において、
　Ｒ３が、水素原子である化合物又はその薬学上許容される塩。 (5) In any one item selected from (1) to (4),
A compound or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom.
　（６）　（１）乃至（５）から選択されるいずれか一項において、
　Ｒ４が、Ｃ１－Ｃ６アルキル基である化合物又はその薬学上許容される塩。 (6) In any one item selected from (1) to (5),
A compound or a pharmaceutically acceptable salt thereof, wherein R 4 is a C 1 -C 6 alkyl group.
　（７）　（１）乃至（５）から選択されるいずれか一項において、
　Ｒ４が、メチル基である化合物又はその薬学上許容される塩。 (7) In any one item selected from (1) to (5),
A compound or a pharmaceutically acceptable salt thereof, wherein R 4 is a methyl group.
　（８）　（１）乃至（７）から選択されるいずれか一項において、
　Ｒ５が、水素原子又はＣ１－Ｃ６アルキル基である化合物又はその薬学上許容される塩。 (8) In any one item selected from (1) to (7),
A compound or a pharmaceutically acceptable salt thereof, wherein R 5 is a hydrogen atom or a C 1 -C 6 alkyl group.
　（９）　（１）乃至（７）から選択されるいずれか一項において、
　Ｒ５が、水素原子又はメチル基である化合物又はその薬学上許容される塩。 (9) In any one item selected from (1) to (7),
A compound or a pharmaceutically acceptable salt thereof, wherein R 5 is a hydrogen atom or a methyl group.
　（１０）　（１）乃至（９）から選択されるいずれか一項において、
　Ｒ６が、水素原子である化合物又はその薬学上許容される塩。 (10) In any one item selected from (1) to (9),
A compound or a pharmaceutically acceptable salt thereof, wherein R 6 is a hydrogen atom.
　（１１）　（１）乃至（１０）から選択されるいずれか一項において、
　Ｑ１が、式＝ＣＨ－で表される基である化合物又はその薬学上許容される塩。 (11) In any one item selected from (1) to (10),
A compound or a pharmaceutically acceptable salt thereof, wherein Q 1 is a group represented by the formula = CH-.
　（１２）　（１）乃至（１１）から選択されるいずれか一項において、
　Ｑ２が、式＝ＣＨ－で表される基である化合物又はその薬学上許容される塩。 (12) In any one item selected from (1) to (11),
A compound or a pharmaceutically acceptable salt thereof, wherein Q 2 is a group represented by the formula = CH-.
　（１３）　（１）乃至（１２）から選択されるいずれか一項において、
　式－Ｕ－Ｔ－で表される基が、式－ＣＨ２－ＣＨ２－で表される基である化合物又はその薬学上許容される塩。 (13) In any one item selected from (1) to (12),
A compound or a pharmaceutically acceptable salt thereof, wherein the group represented by the formula —UT— is a group represented by the formula —CH 2 —CH 2 —.
　（１４）　（１）乃至（１３）から選択されるいずれか一項において、
　Ｙが、酸素原子である化合物又はその薬学上許容される塩。 (14) In any one item selected from (1) to (13),
A compound or a pharmaceutically acceptable salt thereof, wherein Y is an oxygen atom.
　（１５）　（１）乃至（１４）から選択されるいずれか一項において、
　Ｖが、式＝Ｃ（Ｒ７）－で表される基である化合物又はその薬学上許容される塩。 (15) In any one item selected from (1) to (14),
A compound or a pharmaceutically acceptable salt thereof, wherein V is a group represented by the formula = C (R 7 )-.
　（１６）　（１）乃至（１５）から選択されるいずれか一項において、
　Ｒ７が、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基又はＣ１－Ｃ６アルコキシ基である化合物又はその薬学上許容される塩。 (16) In any one item selected from (1) to (15),
A compound or a pharmaceutically acceptable salt thereof, wherein R 7 is a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group.
　（１７）　（１）乃至（１５）から選択されるいずれか一項において、
　Ｒ７が、水素原子又はメチル基である化合物又はその薬学上許容される塩。 (17) In any one item selected from (1) to (15),
A compound or a pharmaceutically acceptable salt thereof, wherein R 7 is a hydrogen atom or a methyl group.
　（１８）　（１）乃至（１４）から選択されるいずれか一項において、
　Ｖが、窒素原子である化合物又はその薬学上許容される塩。 (18) In any one item selected from (1) to (14),
A compound or a pharmaceutically acceptable salt thereof, wherein V is a nitrogen atom.
　（１９）　（１）乃至（１８）から選択されるいずれか一項において、
　Ｅが、式－Ｌ－Ｒ８で表される基で１個置換されているピペリジン－４－イル基、１，２，３，６－テトラヒドロピリジン－４－イル基又はピペラジン－１－イル基である化合物又はその薬学上許容される塩。 (19) In any one item selected from (1) to (18),
E is a piperidin-4-yl group, a 1,2,3,6-tetrahydropyridin-4-yl group or a piperazin-1-yl group, each of which is substituted with a group represented by the formula -LR 8 Or a pharmaceutically acceptable salt thereof.
　（２０）　（１）乃至（１８）から選択されるいずれか一項において、
　Ｅが、式－Ｌ－Ｒ８で表される基で１位が置換されているピペリジン－４－イル基又は１，２，３，６－テトラヒドロピリジン－４－イル基である化合物又はその薬学上許容される塩。 (20) In any one item selected from (1) to (18),
A compound wherein E is a piperidin-4-yl group or a 1,2,3,6-tetrahydropyridin-4-yl group substituted at the 1-position with a group represented by the formula -LR 8 or a pharmaceutical thereof Top acceptable salt.
　（２１）　（１）乃至（１８）から選択されるいずれか一項において、
　置換基群Ａが、式－Ｌ－Ｒ８で表される基である化合物又はその薬学上許容される塩。 (21) In any one item selected from (1) to (18),
A compound or a pharmaceutically acceptable salt thereof, wherein the substituent group A is a group represented by the formula -LR 8 .
　（２２）　（１）乃至（２１）から選択されるいずれか一項において、
　Ｌが、カルボニル基又はオキサリル基である化合物又はその薬学上許容される塩。 (22) In any one item selected from (1) to (21),
A compound or a pharmaceutically acceptable salt thereof, wherein L is a carbonyl group or an oxalyl group.
　（２３）　（１）乃至（２２）から選択されるいずれか一項において、
　Ｒ８が、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６ヒドロキシアルキル基、（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルキル）基、アミノ基、モノ－Ｃ１－Ｃ６アルキルアミノ基、モノ－Ｃ１－Ｃ６ハロゲン化アルキルアミノ基、ジ－（Ｃ１－Ｃ６アルキル）アミノ基、モルホリン－２－イル基又はハロゲン原子及びＣ１－Ｃ６アルキル基から選択される基で独立に１乃至３個置換されているピロリジン－２－イル基である化合物又はその薬学上許容される塩。 (23) In any one item selected from (1) to (22),
R 8 is a C 1 -C 6 alkyl group, C 1 -C 6 hydroxyalkyl group, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, amino group, mono-C 1 -C 6 Selected from alkylamino groups, mono-C 1 -C 6 halogenated alkylamino groups, di- (C 1 -C 6 alkyl) amino groups, morpholin-2-yl groups or halogen atoms and C 1 -C 6 alkyl groups Or a pharmaceutically acceptable salt thereof, which is a pyrrolidin-2-yl group which is independently substituted with 1 to 3 groups.
　（２４）　（１）乃至（２２）から選択されるいずれか一項において、
　Ｒ８が、メチル基、１－ヒドロキシエチル基、メトキシメチル基、メチルアミノ基、エチルアミノ基、２，２―ジフルオロエチルアミノ基、モルホリン－２－イル基又は４，４―ジフルオロ－１－メチルピロリジン－２－イル基である化合物又はその薬学上許容される塩。 (24) In any one item selected from (1) to (22),
R 8 is a methyl group, 1-hydroxyethyl group, methoxymethyl group, methylamino group, ethylamino group, 2,2-difluoroethylamino group, morpholin-2-yl group or 4,4-difluoro-1-methyl A compound having a pyrrolidin-2-yl group or a pharmaceutically acceptable salt thereof.
　（２５）　（１）において、
　Ｒ１が、Ｃ１－Ｃ６アルキル基であり、Ｒ２が、水素原子であり、Ｒ３が、水素原子であり、Ｒ４が、Ｃ１－Ｃ６アルキル基であり、Ｒ５が、水素原子又はＣ１－Ｃ６アルキル基であり、Ｒ６が、水素原子であり、Ｑ１が、窒素原子又は式＝ＣＨ－で表される基であり、Ｑ２が、窒素原子又は式＝ＣＨ－で表される基であり、式－Ｕ－Ｔ－で表される基が、式－ＣＨ２－ＣＨ２－で表される基又は式－ＣＨ＝ＣＨ－で表される基であり、Ｙが、酸素原子であり、Ｖが、式＝Ｃ（Ｒ７）－で表される基であり、Ｒ７が、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基又はＣ１－Ｃ６アルコキシ基であり、Ｅが、式－Ｌ－Ｒ８で表される基で１個置換されているピペリジン－４－イル基、１，２，３，６－テトラヒドロピリジン－４－イル基又はピペラジン－１－イル基であり、Ｌが、カルボニル基又はオキサリル基であり、Ｒ８が、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６ヒドロキシアルキル基、（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルキル）基、アミノ基、モノ－Ｃ１－Ｃ６アルキルアミノ基、モノ－Ｃ１－Ｃ６ハロゲン化アルキルアミノ基、ジ－（Ｃ１－Ｃ６アルキル）アミノ基、モルホリン－２－イル基又はハロゲン原子及びＣ１－Ｃ６アルキル基から選択される基で独立に１乃至３個置換されているピロリジン－２－イル基である化合物又はその薬学上許容される塩。 (25) In (1),
R 1 is a C 1 -C 6 alkyl group, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a C 1 -C 6 alkyl group, and R 5 is A hydrogen atom or a C 1 -C 6 alkyl group, R 6 is a hydrogen atom, Q 1 is a nitrogen atom or a group represented by the formula ═CH—, and Q 2 is a nitrogen atom or a formula = A group represented by CH—, and a group represented by the formula —UT— is a group represented by the formula —CH 2 —CH 2 — or a group represented by the formula —CH═CH—. , Y is an oxygen atom, V is a group represented by the formula = C (R 7 )-, and R 7 is a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group, E is one substituted in which piperidin-4-yl group in the group represented by the formula -L-R 8, 1,2,3,6 Tetorahidoropi A lysine-4-yl group or a piperazin-1-yl group, L is a carbonyl group or an oxalyl group, R 8 is a C 1 -C 6 alkyl group, a C 1 -C 6 hydroxyalkyl group, (C 1- C 6 alkoxy)-(C 1 -C 6 alkyl) group, amino group, mono-C 1 -C 6 alkylamino group, mono-C 1 -C 6 halogenated alkylamino group, di- (C 1- A compound which is a pyrrolidin-2-yl group independently substituted by 1 to 3 groups independently selected from a C 6 alkyl) amino group, a morpholin-2-yl group or a halogen atom and a C 1 -C 6 alkyl group, or Its pharmaceutically acceptable salt.
　（２６）　（１）において、
　Ｒ１が、メチル基又はエチル基であり、Ｒ２が、水素原子であり、Ｒ３が、水素原子であり、Ｒ４が、メチル基であり、Ｒ５が、水素原子又はメチル基であり、Ｒ６が、水素原子であり、Ｑ１が、式＝ＣＨ－で表される基であり、Ｑ２が、式＝ＣＨ－で表される基であり、式－Ｕ－Ｔ－で表される基が、式－ＣＨ２－ＣＨ２－で表される基であり、Ｙが、酸素原子であり、Ｖが、式＝Ｃ（Ｒ７）－で表される基であり、Ｒ７が、水素原子又はメチル基であり、Ｅが、式－Ｌ－Ｒ８で表される基で１位が置換されているピペリジン－４－イル基又は１，２，３，６－テトラヒドロピリジン－４－イル基であり、Ｌが、カルボニル基又はオキサリル基であり、Ｒ８が、メチル基、１－ヒドロキシエチル基、メトキシメチル基、メチルアミノ基、エチルアミノ基、２，２―ジフルオロエチルアミノ基、モルホリン－２－イル基又は４，４―ジフルオロ－１－メチルピロリジン－２－イル基である化合物又はその薬学上許容される塩。 (26) In (1),
R 1 is a methyl group or an ethyl group, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a methyl group, and R 5 is a hydrogen atom or a methyl group. , R 6 is a hydrogen atom, Q 1 is a group represented by the formula = CH-, Q 2 is a group represented by the formula = CH-, and is represented by the formula -UT- Is a group represented by the formula —CH 2 —CH 2 —, Y is an oxygen atom, V is a group represented by the formula ═C (R 7 ) —, and R 7 Is a hydrogen atom or a methyl group, and E is a piperidin-4-yl group or 1,2,3,6-tetrahydropyridine- substituted at the 1-position with a group represented by the formula -LR 8 a 4-yl group, L is a carbonyl group or an oxalyl group, R 8 is methyl group, 1-hydroxyethyl group, methoxymethyl group, methyl Amino group, an ethylamino group, 2,2-difluoroethyl group, morpholin-2-yl group or a 4,4-difluoro-1-methylpyrrolidin-2-yl compound or a pharmaceutically acceptable salt group.
　（２７）　（１）において、
　Ｒ１が、Ｃ１－Ｃ６アルキル基であり、Ｒ２が、水素原子であり、Ｒ３が、水素原子であり、Ｒ４が、Ｃ１－Ｃ６アルキル基であり、Ｒ５が、水素原子又はＣ１－Ｃ６アルキル基であり、Ｒ６が、水素原子であり、Ｑ１が、窒素原子又は式＝ＣＨ－で表される基であり、Ｑ２が、窒素原子又は式＝ＣＨ－で表される基であり、式－Ｕ－Ｔ－で表される基が、式－ＣＨ２－ＣＨ２－で表される基又は式－ＣＨ＝ＣＨ－で表される基であり、Ｙが、酸素原子であり、Ｖが、窒素原子であり、Ｅが、式－Ｌ－Ｒ８で表される基で１個置換されているピペリジン－４－イル基、１，２，３，６－テトラヒドロピリジン－４－イル基又はピペラジン－１－イル基であり、Ｌが、カルボニル基又はオキサリル基であり、Ｒ８が、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６ヒドロキシアルキル基、（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルキル）基、アミノ基、モノ－Ｃ１－Ｃ６アルキルアミノ基、モノ－Ｃ１－Ｃ６ハロゲン化アルキルアミノ基、ジ－（Ｃ１－Ｃ６アルキル）アミノ基、モルホリン－２－イル基又はハロゲン原子及びＣ１－Ｃ６アルキル基から選択される基で独立に１乃至３個置換されているピロリジン－２－イル基である化合物又はその薬学上許容される塩。 (27) In (1),
R 1 is a C 1 -C 6 alkyl group, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a C 1 -C 6 alkyl group, and R 5 is A hydrogen atom or a C 1 -C 6 alkyl group, R 6 is a hydrogen atom, Q 1 is a nitrogen atom or a group represented by the formula ═CH—, and Q 2 is a nitrogen atom or a formula = A group represented by CH—, and a group represented by the formula —UT— is a group represented by the formula —CH 2 —CH 2 — or a group represented by the formula —CH═CH—. , Y is an oxygen atom, V is a nitrogen atom, and E is a piperidin-4-yl group substituted with one group represented by the formula -LR 8 , 1,2,3 , 6-tetrahydropyridin-4-yl group or piperazin-1-yl group, L is a carbonyl group or an oxalyl group, and R 8 is C 1 -C 6 alkyl group, C 1 -C 6 hydroxyalkyl group, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, amino group, mono-C 1 -C 6 alkylamino group, mono-C 1 1 to 3 independently of —C 6 halogenated alkylamino group, di- (C 1 -C 6 alkyl) amino group, morpholin-2-yl group or a group selected from halogen atom and C 1 -C 6 alkyl group A compound or a pharmaceutically acceptable salt thereof, which is a pyrrolidin-2-yl group which is substituted.
　（２８）　（１）において、
　Ｒ１が、メチル基又はエチル基であり、Ｒ２が、水素原子であり、Ｒ３が、水素原子であり、Ｒ４が、メチル基であり、Ｒ５が、水素原子又はメチル基であり、Ｒ６が、水素原子であり、Ｑ１が、式＝ＣＨ－で表される基であり、Ｑ２が、式＝ＣＨ－で表される基であり、式－Ｕ－Ｔ－で表される基が、式－ＣＨ２－ＣＨ２－で表される基であり、Ｙが、酸素原子であり、Ｖが、窒素原子であり、Ｅが、式－Ｌ－Ｒ８で表される基で１位が置換されているピペリジン－４－イル基又は１，２，３，６－テトラヒドロピリジン－４－イル基であり、Ｌが、カルボニル基又はオキサリル基であり、Ｒ８が、メチル基、１－ヒドロキシエチル基、メトキシメチル基、メチルアミノ基、エチルアミノ基、２，２―ジフルオロエチルアミノ基、モルホリン－２－イル基又は４，４―ジフルオロ－１－メチルピロリジン－２－イル基である化合物又はその薬学上許容される塩。 (28) In (1),
R 1 is a methyl group or an ethyl group, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a methyl group, and R 5 is a hydrogen atom or a methyl group. , R 6 is a hydrogen atom, Q 1 is a group represented by the formula = CH-, Q 2 is a group represented by the formula = CH-, and is represented by the formula -UT- Is a group represented by the formula —CH 2 —CH 2 —, Y is an oxygen atom, V is a nitrogen atom, and E is represented by the formula —LR 8. A piperidin-4-yl group or a 1,2,3,6-tetrahydropyridin-4-yl group substituted at the 1-position with a group, L is a carbonyl group or an oxalyl group, and R 8 is methyl Group, 1-hydroxyethyl group, methoxymethyl group, methylamino group, ethylamino group, 2,2-difluoroethylamino group Morpholin-2-yl group or a 4,4-difluoro-1-methyl pyrrolidine compound or a pharmaceutically acceptable salt thereof is 2-yl group.
　（２９）　１－［５－（４－｛１－［（２Ｓ）－１，４－ジオキサン－２－イルカルボニル］ピペリジン－４－イル｝フェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン、
１－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン、
ｔｅｒｔ－ブチル　４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－カルボキシレート、
２－メトキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）エタノン、
１－｛５－［４－（１－｛［（２Ｓ）－４，４－ジフルオロ－１－メチルピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン、
Ｎ－（２，２－ジフルオロエチル）－２－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－２－オキソアセトアミド、
２－（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－Ｎ－メチル－２－オキソアセタミド、
（２Ｓ）－２－ヒドロキシ－１－［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］プロパン－１－オン、
Ｎ－エチル－２－［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］－２－オキソアセトアミド、
Ｎ－メチル－２－［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］－２－オキソアセトアミド、
１－｛５－［４－（４－アセチルピペラジン－１－イル）－３－メチルフェノキシ］４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン、
１－｛５－［（１’－アセチル－１’，２’，３’，６’－テトラヒドロ－２，４’－ビピリジン－５－イル）オキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン、
１－｛５－［４－（１－アセチルピペリジン－４－イル）－３－メチルフェノキシ］－４－メチル－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン、
１－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－メチル－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン、
１－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン、又は、
１－｛５－［４－（１－アセチル－１，２，３，６－テトラヒドロピリジン－４－イル）－２，５－ジメチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン
である化合物又はその薬学上許容される塩。 (29) 1- [5- (4- {1-[(2S) -1,4-Dioxane-2-ylcarbonyl] piperidin-4-yl} phenoxy) -4-methyl-2,3-dihydro-1H -Indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone,
1- {5- [4- (1-acetylpiperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl ] Ethanon,
tert-Butyl 4- {2-Methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl } Piperidine-1-carboxylate,
2-methoxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl } Piperidin-1-yl) ethanone,
1- {5- [4- (1-{[(2S) -4,4-difluoro-1-methylpyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl-2,3 -Dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone,
N- (2,2-difluoroethyl) -2- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole- 5-yl) oxy] phenyl} piperidin-1-yl) -2-oxoacetamide,
2- (4- {4-[(1-{[2- (Ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine-1 -Yl) -N-methyl-2-oxoacetamide,
(2S) -2-hydroxy-1- [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole -5-yl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] propan-1-one,
N-ethyl-2- [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl ) Oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] -2-oxoacetamide,
N-methyl-2- [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl ) Oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] -2-oxoacetamide,
1- {5- [4- (4-Acetylpiperazin-1-yl) -3-methylphenoxy] 4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (ethyl Sulfonyl) phenyl] ethanone,
1- {5-[(1′-acetyl-1 ′, 2 ′, 3 ′, 6′-tetrahydro-2,4′-bipyridin-5-yl) oxy] -4-methyl-2,3-dihydro- 1H-indol-1-yl} -2- [2- (ethylsulfonyl) phenyl] ethanone,
1- {5- [4- (1-Acetylpiperidin-4-yl) -3-methylphenoxy] -4-methyl-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone ,
1- {5- [4- (1-acetylpiperidin-4-yl) phenoxy] -4-methyl-1H-indol-1-yl} -2- [2- (ethylsulfonyl) phenyl] ethanone,
1- {5- [4- (1-acetylpiperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) pyridine -2-yl] ethanone, or
1- {5- [4- (1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl) -2,5-dimethylphenoxy] -4-methyl-2,3-dihydro-1H-indole -1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone or a pharmaceutically acceptable salt thereof.
　（３０）　（２９）に記載してある化合物又はその薬学上許容される塩のうちの化合物。 (30) A compound described in (29) or a pharmaceutically acceptable salt thereof.
　（３１）　１－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン、又はその薬学上許容される塩。 (31) 1- {5- [4- (1-Acetylpiperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methyl Sulfonyl) phenyl] ethanone, or a pharmaceutically acceptable salt thereof.
　（３２）　（２Ｓ）－２－ヒドロキシ－１－［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］プロパン－１－オン、又はその薬学上許容される塩。 (32) (2S) -2-hydroxy-1- [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro- 1H-Indol-5-yl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] propan-1-one, or a pharmaceutically acceptable salt thereof.
　（３３）　Ｎ－メチル－２－［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］－２－オキソアセトアミド、又はその薬学上許容される塩。 (33) N-methyl-2- [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole- 5-yl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] -2-oxoacetamide, or a pharmaceutically acceptable salt thereof.
　（３４）　１－｛５－［４－（１－アセチルピペリジン－４－イル）－３－メチルフェノキシ］－４－メチル－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン、又はその薬学上許容される塩。 (34) 1- {5- [4- (1-Acetylpiperidin-4-yl) -3-methylphenoxy] -4-methyl-1H-indol-1-yl} -2- [2- (methylsulfonyl) Phenyl] ethanone, or a pharmaceutically acceptable salt thereof.
　（３５）　１－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－メチル－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン、又はその薬学上許容される塩。 (35) 1- {5- [4- (1-acetylpiperidin-4-yl) phenoxy] -4-methyl-1H-indol-1-yl} -2- [2- (ethylsulfonyl) phenyl] ethanone, Or a pharmaceutically acceptable salt thereof.
　（３６）　１－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン、又はその薬学上許容される塩。 (36) 1- {5- [4- (1-Acetylpiperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (methyl (Sulfonyl) pyridin-2-yl] ethanone, or a pharmaceutically acceptable salt thereof.
　（３７）　１－｛５－［４－（１－アセチル－１，２，３，６－テトラヒドロピリジン－４－イル）－２，５－ジメチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン、又はその薬学上許容される塩。 (37) 1- {5- [4- (1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl) -2,5-dimethylphenoxy] -4-methyl-2,3-dihydro- 1H-Indol-1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone or a pharmaceutically acceptable salt thereof.
　（３８）　（１）乃至（３７）から選択されるいずれか一項に記載された化合物又はその薬学上許容される塩を有効成分として含有する医薬組成物。 (38) A pharmaceutical composition comprising, as an active ingredient, the compound described in any one of (1) to (37) or a pharmaceutically acceptable salt thereof.
　（３９）　医薬組成物が、レチノイン酸受容体関連オーファン受容体γｔ阻害作用を有する（３８）に記載の医薬組成物。 (39) The pharmaceutical composition according to (38), wherein the pharmaceutical composition has a retinoic acid receptor-related orphan receptor γt inhibitory action.
　（４０）　医薬組成物が、レチノイン酸受容体関連オーファン受容体γｔ阻害作用により、治療及び／又は予防される疾病の治療及び／又は予防のためのものである（３８）に記載の医薬組成物。 (40) The pharmaceutical composition according to (38), wherein the pharmaceutical composition is for treatment and / or prevention of a disease that is treated and / or prevented by an inhibitory action of retinoic acid receptor-related orphan receptor γt. object.
　（４１）　医薬組成物が、Ｔｈ１７細胞分化の抑制及び／又はＩＬ－１７産生の抑制により、症状の治療、改善、軽減及び／又は予防がなされる疾病の治療及び／又は予防のためのものである（３８）に記載の医薬組成物。 (41) The pharmaceutical composition is for the treatment and / or prevention of a disease whose symptoms are treated, ameliorated, reduced and / or prevented by inhibiting Th17 cell differentiation and / or inhibiting IL-17 production. The pharmaceutical composition according to (38).
　（４２）　医薬組成物が、乾癬、乾癬性関節炎、強直性脊椎炎、多発性硬化症、関節リウマチ、炎症性腸疾患、シェーグレン症候群、全身性エリテマトーデス、慢性閉塞性肺疾患（COPD）、アトピー性皮膚炎、喘息、一型糖尿病、移植片対宿主病（GvHD）、円形脱毛症、白斑、川崎病、ベーチェット病、糸球体腎炎、心筋症、再生不良性貧血、橋本病、強皮症、巨細胞性動脈炎、接触性皮膚炎、視神経炎又は大腸癌の治療及び／又は予防のためのものである（３８）に記載の医薬組成物。 (42) The pharmaceutical composition is psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic Dermatitis, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant (38) The pharmaceutical composition according to (38) for the treatment and / or prevention of cellular arteritis, contact dermatitis, optic neuritis or colon cancer.
　（４３）　医薬組成物が、乾癬、乾癬性関節炎、強直性脊椎炎、多発性硬化症、関節リウマチ、炎症性腸疾患、シェーグレン症候群又は慢性閉塞性肺疾患の治療及び／又は予防のためのものである（３８）に記載の医薬組成物。 (43) The pharmaceutical composition is for the treatment and / or prevention of psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome or chronic obstructive pulmonary disease (38) The pharmaceutical composition according to (38).
　（４４）　医薬組成物が、乾癬又は乾癬性関節炎の治療及び／又は予防のための（３８）に記載の医薬組成物。 (44) The pharmaceutical composition according to (38), wherein the pharmaceutical composition is for the treatment and / or prevention of psoriasis or psoriatic arthritis.
　（４５）　炎症性腸疾患が、クローン病又は潰瘍性大腸炎である（４２）又は（４３）に記載の医薬組成物。 (45) The pharmaceutical composition according to (42) or (43), wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
　（４６）　（１）乃至（３７）から選択されるいずれか一項に記載された化合物又はその薬学上許容される塩を有効成分として含有するレチノイン酸受容体関連オーファン受容体γｔ阻害剤。 (46) A retinoic acid receptor-related orphan receptor γt inhibitor comprising as an active ingredient the compound described in any one of (1) to (37) or a pharmaceutically acceptable salt thereof.
　（４７）　医薬組成物を製造するための、（１）乃至（３７）から選択されるいずれか一項に記載された化合物又はその薬学上許容される塩の使用。 (47) Use of the compound described in any one of (1) to (37) or a pharmaceutically acceptable salt thereof for producing a pharmaceutical composition.
　（４８）　医薬組成物がレチノイン酸受容体関連オーファン受容体γｔを阻害するための組成物である（４７）に記載の使用。 (48) The use according to (47), wherein the pharmaceutical composition is a composition for inhibiting retinoic acid receptor-related orphan receptor γt.
　（４９）　医薬組成物が乾癬、乾癬性関節炎、強直性脊椎炎、多発性硬化症、関節リウマチ、炎症性腸疾患、シェーグレン症候群、全身性エリテマトーデス、慢性閉塞性肺疾患（COPD）、アトピー性皮膚炎、喘息、一型糖尿病、移植片対宿主病（GvHD）、円形脱毛症、白斑、川崎病、ベーチェット病、糸球体腎炎、心筋症、再生不良性貧血、橋本病、強皮症、巨細胞性動脈炎、接触性皮膚炎、視神経炎又は大腸癌の治療及び／又は予防のための組成物である（４７）に記載の使用。 (49) The pharmaceutical composition is psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic skin Inflammation, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell (47) The use according to (47), which is a composition for the treatment and / or prevention of arteritis inflammation, contact dermatitis, optic neuritis or colon cancer.
　（５０）　医薬組成物が乾癬、乾癬性関節炎、強直性脊椎炎、多発性硬化症、関節リウマチ、炎症性腸疾患、シェーグレン症候群又は慢性閉塞性肺疾患の治療及び／又は予防のための組成物である（４７）に記載の使用。 (50) A pharmaceutical composition for treating and / or preventing psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome or chronic obstructive pulmonary disease The use according to (47).
　（５１）　医薬組成物が乾癬又は乾癬性関節炎の治療及び／又は予防のための組成物である（４７）に記載の使用。 (51) The use according to (47), wherein the pharmaceutical composition is a composition for treatment and / or prevention of psoriasis or psoriatic arthritis.
　（５２）　炎症性腸疾患が、クローン病又は潰瘍性大腸炎である（４９）又は（５０）に記載の使用。 (52) The use according to (49) or (50), wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
　（５３）　レチノイン酸受容体関連オーファン受容体γｔ阻害作用により治療及び／又は予防される疾病の治療及び／又は予防の方法における使用のための（１）乃至（３７）から選択されるいずれか一項に記載された化合物又はその薬学上許容される塩。 (53) Any one selected from (1) to (37) for use in a method of treatment and / or prevention of a disease that is treated and / or prevented by an inhibitory action of retinoic acid receptor-related orphan receptor γt The compound according to one item or a pharmaceutically acceptable salt thereof.
　（５４）　乾癬、乾癬性関節炎、強直性脊椎炎、多発性硬化症、関節リウマチ、炎症性腸疾患、シェーグレン症候群、全身性エリテマトーデス、慢性閉塞性肺疾患（COPD）、アトピー性皮膚炎、喘息、一型糖尿病、移植片対宿主病（GvHD）、円形脱毛症、白斑、川崎病、ベーチェット病、糸球体腎炎、心筋症、再生不良性貧血、橋本病、強皮症、巨細胞性動脈炎、接触性皮膚炎、視神経炎又は大腸癌の治療及び／又は予防の方法における使用のための（１）乃至（３７）から選択されるいずれか一項に記載された化合物又はその薬学上許容される塩。 (54) Psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, Type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, The compound according to any one of (1) to (37) or a pharmaceutically acceptable salt thereof for use in a method for the treatment and / or prevention of contact dermatitis, optic neuritis or colorectal cancer salt.
　（５５）　乾癬、乾癬性関節炎、強直性脊椎炎、多発性硬化症、関節リウマチ、炎症性腸疾患、シェーグレン症候群又は慢性閉塞性肺疾患の治療及び／又は予防の方法における使用のための（１）乃至（３７）から選択されるいずれか一項に記載された化合物又はその薬学上許容される塩。 (55) for use in a method of treatment and / or prevention of psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome or chronic obstructive pulmonary disease (1) ) To (37), or a pharmaceutically acceptable salt thereof.
　（５６）　乾癬又は乾癬性関節炎の治療及び／又は予防の方法における使用のための（１）乃至（３７）から選択されるいずれか一項に記載された化合物又はその薬学上許容される塩。 (56) The compound or a pharmaceutically acceptable salt thereof described in any one of (1) to (37) for use in a method for treating and / or preventing psoriasis or psoriatic arthritis.
　（５７）　炎症性腸疾患が、クローン病又は潰瘍性大腸炎である（５４）又は（５５）に記載の化合物又はその薬学上許容される塩。 (57) The compound or a pharmaceutically acceptable salt thereof according to (54) or (55), wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
　（５８）　（１）乃至（３７）から選択されるいずれか一項に記載された化合物又はその薬学上許容される塩の薬理的な有効量を温血動物に投与するレチノイン酸受容体関連オーファン受容体γｔ阻害方法。 (58) A retinoic acid receptor-related auxin, wherein a pharmacologically effective amount of a compound according to any one of (1) to (37) or a pharmaceutically acceptable salt thereof is administered to a warm-blooded animal. Fan receptor γt inhibition method.
　（５９）　（１）乃至（３７）から選択されるいずれか一項に記載された化合物又はその薬学上許容される塩の薬理的な有効量を温血動物に投与する疾病の治療及び／又は予防方法。 (59) Treatment of a disease in which a pharmacologically effective amount of the compound described in any one of (1) to (37) or a pharmaceutically acceptable salt thereof is administered to a warm-blooded animal and / or Prevention method.
　（６０）　疾病が乾癬、乾癬性関節炎、強直性脊椎炎、多発性硬化症、関節リウマチ、炎症性腸疾患、シェーグレン症候群、全身性エリテマトーデス、慢性閉塞性肺疾患（COPD）、アトピー性皮膚炎、喘息、一型糖尿病、移植片対宿主病（GvHD）、円形脱毛症、白斑、川崎病、ベーチェット病、糸球体腎炎、心筋症、再生不良性貧血、橋本病、強皮症、巨細胞性動脈炎、接触性皮膚炎、視神経炎又は大腸癌である（５９）に記載の方法。 (60) The disease is psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, Asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell artery (59) The method according to (59), which is inflammation, contact dermatitis, optic neuritis or colon cancer.
　（６１）　疾病が乾癬、乾癬性関節炎、強直性脊椎炎、多発性硬化症、関節リウマチ、炎症性腸疾患、シェーグレン症候群又は慢性閉塞性肺疾患である（５９）に記載の方法。 (61) The method according to (59), wherein the disease is psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome or chronic obstructive pulmonary disease.
　（６２）　疾病が乾癬又は乾癬性関節炎である（５９）に記載の方法。 (62) The method according to (59), wherein the disease is psoriasis or psoriatic arthritis.
　（６３）　炎症性腸疾患が、クローン病又は潰瘍性大腸炎である（６０）又は（６１）に記載の方法。 (63) The method according to (60) or (61), wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
　（６４）　温血動物がヒトである（５８）乃至（６３）から選択されるいずれか一項に記載の方法。 (64) The method according to any one of (58) to (63), wherein the warm-blooded animal is a human.
　本発明において、「ハロゲン原子」は、フッ素原子、塩素原子、臭素原子又は沃素原子である。好適には、フッ素原子又は塩素原子であり、より好適には、フッ素原子である。 In the present invention, the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferable is a fluorine atom or a chlorine atom, and more preferable is a fluorine atom.
　本発明において、「Ｃ１－Ｃ６アルキル基」は、炭素数１乃至６個の直鎖又は分枝鎖アルキル基である。例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓ－ブチル、ｔ－ブチル、ペンチル、イソペンチル、２－メチルブチル、ネオペンチル、１－エチルプロピル、ヘキシル、イソヘキシル、４－メチルペンチル、３－メチルペンチル、２－メチルペンチル、１－メチルペンチル、３，３－ジメチルブチル、２，２－ジメチルブチル、１，１－ジメチルブチル又は１，２－ジメチルブチル基である。好適には、炭素数１乃至３個の直鎖又は分枝鎖アルキル基（Ｃ１－Ｃ３アルキル基）であり、より好適には、メチル基又はエチル基（Ｃ１－Ｃ２アルキル基）であり、更により好適には、メチル基である。 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 straight or branched alkyl group having 1 to 3 carbon atoms (C 1 -C 3 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.
　本発明において、「Ｃ３－Ｃ６シクロアルキル基」は、シクロプロピル基、シクロブチル基、シクロペンチル基又はシクロヘキシル基である。好適には、シクロプロピル基である。 In the present invention, the “C 3 -C 6 cycloalkyl group” is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. Preferred is a cyclopropyl group.
　本発明において、「Ｃ１－Ｃ６ハロゲン化アルキル基」は、同一又は異なる１乃至５個の前記「ハロゲン原子」が前記「Ｃ１－Ｃ６アルキル基」に結合した基である。例えば、トリフルオロメチル、トリクロロメチル、ジフルオロメチル、フルオロメチル、２，２，２－トリフルオロエチル、３，３，３－トリフルオロプロピル、３，３－ジフルオロプロピル、２，２，２－トリクロロエチル、２－ブロモエチル又は２－フルオロエチル基である。好適には、同一又は異なる１乃至５個の「ハロゲン原子」が「Ｃ１－Ｃ３アルキル基」に結合した基（Ｃ１－Ｃ３ハロゲン化アルキル基）であり、より好適には、３，３，３－トリフルオロプロピル基又は３，３－ジフルオロプロピル基である。 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 3 halogenated alkyl group) in which 1 to 5 “halogen atoms” which are the same or different are bonded to a “C 1 -C 3 alkyl group”, more preferably 3 , 3,3-trifluoropropyl group or 3,3-difluoropropyl group.
　本発明において、「Ｃ２－Ｃ６アルケニル基」は、前記「Ｃ１－Ｃ６アルキル基」のうち、１個の二重結合を有する炭素数２乃至６個の基である。例えば、エテニル、１－プロペニル、２－プロペニル、イソプロペニル、１－メチル－２－プロペニル、１－メチル－１－プロペニル、１－ブテニル又は５－ヘキセニル基であり、好適には、炭素数２乃至４個のアルケニル基（Ｃ２－Ｃ４アルケニル基）であり、より好適には、イソプロペニル基である。 In the present invention, the “C 2 -C 6 alkenyl group” is a group having 2 to 6 carbon atoms having one double bond in the “C 1 -C 6 alkyl group”. For example, an ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 1-butenyl or 5-hexenyl group, preferably having 2 to There are four alkenyl groups (C 2 -C 4 alkenyl groups), and more preferably an isopropenyl group.
　本発明において、「Ｃ１－Ｃ６アルコキシ基」は、前記「Ｃ１－Ｃ６アルキル基」が酸素原子に結合した基であり、炭素数１乃至６個の直鎖又は分枝鎖アルコキシ基である。例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓ－ブトキシ、ｔ－ブトキシ、ペントキシ、２－メチルブトキシ、３－エチルプロポキシ、ネオペントキシ、ヘキシルオキシ又は２，３－ジメチルブトキシ基である。好適には、炭素数１乃至４個の直鎖又は分枝鎖アルコキシ基（Ｃ１－Ｃ４アルコキシ基）であり、より好適には、メトキシ基、エトキシ基又はｔ－ブトキシ基であり、更により好適には、メトキシ基である。 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), more preferred is a methoxy group, an ethoxy group or a t-butoxy group. More preferably, it is a methoxy group.
　本発明において、「Ｃ１－Ｃ６ハロゲン化アルコキシ基」は、同一又は異なる１乃至５個の前記「ハロゲン原子」が前記「Ｃ１－Ｃ６アルコキシ基」に結合した基である。例えば、トリフルオロメトキシ、トリクロロメトキシ、ジフルオロメトキシ、フルオロメトキシ、２，２，２－トリフルオロエトキシ、２－ブロモエトキシ、２－クロロエトキシ、ペンタフルオロエトキシ又は４－フルオロブトキシ基であり、好適には、同一又は異なる１乃至５個の前記「ハロゲン原子」が前記「Ｃ１－Ｃ４アルコキシ基」に結合した基（Ｃ１－Ｃ４ハロゲン化アルコキシ基）であり、より好適には、同一又は異なる１乃至５個の前記「ハロゲン原子」が前記「Ｃ１－Ｃ２アルコキシ基」に結合した基（Ｃ１－Ｃ２ハロゲン化アルコキシ基）であり、更により好適には、ジフルオロメトキシ基である。 In the present invention, the “C 1 -C 6 halogenated alkoxy group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 6 alkoxy group”. For example, trifluoromethoxy, trichloromethoxy, difluoromethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 2-bromoethoxy, 2-chloroethoxy, pentafluoroethoxy or 4-fluorobutoxy group, preferably A group (C 1 -C 4 halogenated alkoxy group) in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 4 alkoxy group”, and more preferably the same or 1 to 5 different “halogen atoms” are groups (C 1 -C 2 halogenated alkoxy groups) bonded to the “C 1 -C 2 alkoxy group”, and more preferably a difluoromethoxy group is there.
　本発明において、「（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルキル）基」は、１個の前記「Ｃ１－Ｃ６アルコキシ基」が前記「Ｃ１－Ｃ６アルキル基」に結合した基である。例えば、メトキシメチル、エトキシメチル、プロポキシメチル、イソプロポキシメチル、ブトキシメチル、ｔ－ブトキシメチル、２－メトキシエチル、２－エトキシエチル、２－ブトキシエチル、１－ブトキシエチル、１－イソブトキシエチル又は３－イソプロポキシプロピル基であり、好適には、１個の前記「Ｃ１－Ｃ４アルコキシ基」が前記「Ｃ１－Ｃ３アルキル基」に結合した基（（Ｃ１－Ｃ４アルコキシ）－（Ｃ１－Ｃ３アルキル）基）であり、より好適には、１個の前記「Ｃ１－Ｃ２アルコキシ基」が前記「Ｃ１－Ｃ２アルキル基」に結合した基（（Ｃ１－Ｃ２アルコキシ）－（Ｃ１－Ｃ２アルキル）基）であり、更により好適には、メトキシメチル基又は２－メトキシエチル基である。 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 3 alkyl group” ((C 1 -C 4 alkoxy)- (C 1 -C 3 alkyl) group), more preferably, a group in which one “C 1 -C 2 alkoxy group” is bonded to the “C 1 -C 2 alkyl group” ((C 1 —C 2 alkoxy)-(C 1 -C 2 alkyl) group), and more preferably a methoxymethyl group or a 2-methoxyethyl group.
　本発明において、「（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルコキシ）基」は、１個の前記「Ｃ１－Ｃ６アルコキシ基」が前記「Ｃ１－Ｃ６アルコキシ基」に結合した基である。例えば、メトキシメトキシ、エトキシメトキシ、プロポキシメトキシ、イソプロポキシメトキシ、ブトキシメトキシ、ｔ－ブトキシメトキシ、２－メトキシエトキシ、２－エトキシエトキシ、２－ブトキシエトキシ又は３－イソプロポキシプロポキシ基であり、好適には、１個の前記「Ｃ１－Ｃ４アルコキシ基」が前記「Ｃ１－Ｃ４アルコキシ基」に結合した基（（Ｃ１－Ｃ４アルコキシ）－（Ｃ１－Ｃ４アルコキシ）基）であり、より好適には、１個の前記「Ｃ１－Ｃ２アルコキシ基」が前記「Ｃ１－Ｃ２アルコキシ基」に結合した基（（Ｃ１－Ｃ２アルコキシ）－（Ｃ１－Ｃ２アルコキシ）基）であり、更により好適には、メトキシメトキシ基である。 In the present invention, “(C 1 -C 6 alkoxy)-(C 1 -C 6 alkoxy) group” means that one “C 1 -C 6 alkoxy group” is the above “C 1 -C 6 alkoxy group”. It is a group bonded to For example, methoxymethoxy, ethoxymethoxy, propoxymethoxy, isopropoxymethoxy, butoxymethoxy, t-butoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-butoxyethoxy or 3-isopropoxypropoxy group, preferably , one group wherein the "C 1 -C 4 alkoxy group" attached to the "C 1 -C 4 alkoxy group" - with ((C 1 -C 4 alkoxy) (C 1 -C 4 alkoxy) group) There, more preferably, one group wherein the "C 1 -C 2 alkoxy group" attached to the "C 1 -C 2 alkoxy group" ((C 1 -C 2 alkoxy) - (C 1 -C a 2 alkoxy) group), more preferably more, a methoxymethoxy group.
　本発明において、「Ｃ２－Ｃ７カルボキシアルキル基」は、１個のカルボキシ基が前記「Ｃ１－Ｃ６アルキル基」に結合した基である。例えば、カルボキシメチル、２－カルボキシエチル、１－カルボキシエチル又は３－カルボキシプロピル基である。好適には、１個のカルボキシ基が「Ｃ１－Ｃ２アルキル基」に結合した基であり、より好適には、カルボキシメチル基である。 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, a 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.
　本発明において、「Ｃ１－Ｃ６ヒドロキシアルキル基」は、１個のヒドロキシ基が前記「Ｃ１－Ｃ６アルキル基」に結合した基である。例えば、２－ヒドロキシエチル、１－ヒドロキシエチル、（Ｒ）－１－ヒドロキシエチル、（Ｓ）－１－ヒドロキシエチル又は３－ヒドロキシプロピル基である。好適には、１個のヒドロキシ基が「Ｃ１－Ｃ２アルキル基」に結合した基（Ｃ１－Ｃ２ヒドロキシアルキル基）であり、より好適には、（Ｒ）－１－ヒドロキシエチル基である。 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, 2-hydroxyethyl, 1-hydroxyethyl, (R) -1-hydroxyethyl, (S) -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 an (R) -1-hydroxyethyl group It is.
　本発明において、「Ｃ１－Ｃ６ジヒドロキシアルキル基」は、２個のヒドロキシ基が前記「Ｃ１－Ｃ６アルキル基」に結合した基である。例えば、１，２－ジヒドロキシエチル、１，２－ジヒドロキシプロピル、１，３－ジヒドロキシプロピル又は２，３－ジヒドロキシプロピル基である。好適には、１，２－ジヒドロキシエチル基である。 In the present invention, the “C 1 -C 6 dihydroxyalkyl group” is a group in which two hydroxy groups are bonded to the “C 1 -C 6 alkyl group”. For example, 1,2-dihydroxyethyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl or 2,3-dihydroxypropyl groups. A 1,2-dihydroxyethyl group is preferred.
　本発明において、「ジ（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルキル）基」は、２個の前記「Ｃ１－Ｃ６アルコキシ基」が前記「Ｃ１－Ｃ６アルキル基」に結合した基である。好適には、１，１－ジエトキシメチル基である。 In the present invention, the “di (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group” means that the two “C 1 -C 6 alkoxy groups” are the above “C 1 -C 6 alkyl groups”. It is a group bonded to A 1,1-diethoxymethyl group is preferred.
　本発明において、「（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６ヒドロキシアルキル）基」は、１個の前記「Ｃ１－Ｃ６アルコキシ基」が前記「Ｃ１－Ｃ６ヒドロキシアルキル基」に結合した基である。好適には、１－ヒドロキシ－２－メトキシエチル基である。 In the present invention, “(C 1 -C 6 alkoxy)-(C 1 -C 6 hydroxyalkyl) group” means that one “C 1 -C 6 alkoxy group” is the above “C 1 -C 6 hydroxyalkyl group”. A group bonded to “group”. A 1-hydroxy-2-methoxyethyl group is preferred.
　本発明において、「Ｃ３－Ｃ６ヒドロキシシクロアルキル基」は、１個のヒドロキシ基が前記「Ｃ３－Ｃ６シクロアルキル基」に結合した基である。好適には、１－ヒドロキシシクロプロピル基である。 In the present invention, the “C 3 -C 6 hydroxycycloalkyl group” is a group in which one hydroxy group is bonded to the “C 3 -C 6 cycloalkyl group”. A 1-hydroxycyclopropyl group is preferred.
　本発明において、「Ｃ１－Ｃ６シアノアルキル基」は、１個のシアノ基が前記「Ｃ１－Ｃ６アルキル基」に結合した基である。例えば、シアノメチル、２－シアノエチル、１－シアノエチル又は３－シアノプロピル基である。好適には、１個のシアノ基が「Ｃ１－Ｃ２アルキル基」に結合した基であり、より好適には、シアノメチル基である。 In the present invention, the “C 1 -C 6 cyanoalkyl group” is a group in which one cyano group is bonded to the “C 1 -C 6 alkyl group”. For example, a cyanomethyl, 2-cyanoethyl, 1-cyanoethyl or 3-cyanopropyl group. A group in which one cyano group is bonded to a “C 1 -C 2 alkyl group” is preferable, and a cyanomethyl group is more preferable.
　本発明において、「モノ－Ｃ１－Ｃ６アルキルアミノ基」は、１個の前記「Ｃ１－Ｃ６アルキル基」が結合したアミノ基である。例えば、メチルアミノ、エチルアミノ、プロピルアミノ、イソプロピルアミノ又はブチルアミノ基である。好適には、１個の「Ｃ１－Ｃ４アルキル基」が結合したアミノ基（モノ－Ｃ１－Ｃ４アルキルアミノ基）であり、より好適には、メチルアミノ基又はエチルアミノ基（モノ－Ｃ１－Ｃ２アルキルアミノ基）である。 In the present invention, the “mono-C 1 -C 6 alkylamino group” is an amino group to which one “C 1 -C 6 alkyl group” is bonded. For example, a methylamino, ethylamino, propylamino, isopropylamino or butylamino group. Preferred is an amino group to which one “C 1 -C 4 alkyl group” is bonded (mono-C 1 -C 4 alkylamino group), and more preferred is a methylamino group or an ethylamino group (mono -C 1 -C 2 alkylamino group).
　本発明において、「モノ－Ｃ１－Ｃ６ハロゲン化アルキルアミノ基」は、１個の前記「Ｃ１－Ｃ６ハロゲン化アルキル基」がアミノ基に結合した基である。例えば、２，２，２－トリフルオロエチルアミノ、３，３，３－トリフルオロプロピルアミノ、２，２－ジフルオロエチルアミノ、３，３－ジフルオロプロピルアミノ、２，２，２－トリクロロエチルアミノ、２－ブロモエチルアミノ又は２－フルオロエチルアミノ基である。好適には、１個の「Ｃ１－Ｃ３ハロゲン化アルキル基」が結合したアミノ基（モノ－Ｃ１－Ｃ３ハロゲン化アルキルアミノ基）であり、より好適には、２，２，２－トリフルオロエチルアミノ基、２，２－ジフルオロエチルアミノ基又は２－フルオロエチルアミノ基であり、更により好適には、２，２－ジフルオロエチルアミノ基である。 In the present invention, the “mono-C 1 -C 6 halogenated alkylamino group” is a group in which one “C 1 -C 6 halogenated alkyl group” is bonded to an amino group. For example, 2,2,2-trifluoroethylamino, 3,3,3-trifluoropropylamino, 2,2-difluoroethylamino, 3,3-difluoropropylamino, 2,2,2-trichloroethylamino, 2-bromoethylamino or 2-fluoroethylamino group. Preferred is an amino group to which one “C 1 -C 3 halogenated alkyl group” is bonded (mono-C 1 -C 3 halogenated alkylamino group), and more preferred is 2,2,2 A trifluoroethylamino group, a 2,2-difluoroethylamino group or a 2-fluoroethylamino group, and even more preferably a 2,2-difluoroethylamino group.
　本発明において、「ジ－（Ｃ１－Ｃ６アルキル）アミノ基」は、同一又は異なる２個の前記「Ｃ１－Ｃ６アルキル基」が結合したアミノ基である。例えば、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、Ｎ－エチル－Ｎ－メチルアミノ、Ｎ－メチル－Ｎ－プロピルアミノ又はＮ－ブチル－Ｎ－メチルアミノ基である。好適には、同一又は異なる２個の「Ｃ１－Ｃ４アルキル基」が結合したアミノ基（ジ－（Ｃ１－Ｃ４アルキル）アミノ基）であり、より好適には、ジメチルアミノ基、ジエチルアミノ基又はＮ－エチル－Ｎ－メチルアミノ基（ジ－（Ｃ１－Ｃ２アルキル）アミノ基）であり、更により好適には、ジメチルアミノ基である。 In the present invention, the “di- (C 1 -C 6 alkyl) amino group” is an amino group to which two identical or different “C 1 -C 6 alkyl groups” are bonded. For example, a dimethylamino, diethylamino, dipropylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino or N-butyl-N-methylamino group. Preferably, it is an amino group (di- (C 1 -C 4 alkyl) amino group) in which two identical or different “C 1 -C 4 alkyl groups” are bonded, more preferably a dimethylamino group, A diethylamino group or an N-ethyl-N-methylamino group (di- (C 1 -C 2 alkyl) amino group), and even more preferably a dimethylamino group.
　本発明において、「（Ｃ２－Ｃ７アルキルカルボニルオキシ）－（Ｃ１－Ｃ６アルキル）基」は、１個の前記「Ｃ２－Ｃ７アルキルカルボニルオキシ基」が前記「Ｃ１－Ｃ６アルキル基」に結合した基である。好適には、アセトキシメチル基である。 In the present invention, “(C 2 -C 7 alkylcarbonyloxy)-(C 1 -C 6 alkyl) group” means that one “C 2 -C 7 alkylcarbonyloxy group” is the above “C 1 -C 6”. It is a group bonded to “ 6 alkyl group”. Preferably, it is an acetoxymethyl group.
　本発明において、「（モノ－Ｃ３－Ｃ６シクロアルキルアミノ）－（Ｃ１－Ｃ６アルキル）基」は、１個の前記「モノ－Ｃ３－Ｃ６シクロアルキルアミノ基」が前記「Ｃ１－Ｃ６アルキル基」に結合した基である。好適には、モノ－シクロプロピルアミノメチル基である。 In the present invention, “(mono-C 3 -C 6 cycloalkylamino)-(C 1 -C 6 alkyl) group” means that one “mono-C 3 -C 6 cycloalkylamino group” is “ A group bonded to a “C 1 -C 6 alkyl group”. A mono-cyclopropylaminomethyl group is preferred.
　本発明において、「（Ｃ２－Ｃ７ヒドロキシアルキルカルボニルオキシ）－（Ｃ１－Ｃ６アルキル）基」は、１個の前記「Ｃ２－Ｃ７ヒドロキシアルキルカルボニルオキシ基」が前記「Ｃ１－Ｃ６アルキル基」に結合した基である。好適には、１－ヒドロキシエチルカルボニルオキシエチル－１－イル基である。 In the present invention, “(C 2 -C 7 hydroxyalkylcarbonyloxy)-(C 1 -C 6 alkyl) group” means that one “C 2 -C 7 hydroxyalkylcarbonyloxy group” is the above “C 1 A group bonded to “—C 6 alkyl group”. A 1-hydroxyethylcarbonyloxyethyl-1-yl group is preferred.
　本発明において、「（モノ－Ｃ１－Ｃ６ヒドロキシアルキルアミノ）－（Ｃ１－Ｃ６アルキル）基」は、１個の前記「モノ－Ｃ１－Ｃ６ヒドロキシアルキルアミノ基」が前記「Ｃ１－Ｃ６アルキル基」に結合した基である。好適には、モノ－２－ヒドロキシエチルアミノメチル基である。 In the present invention, “(mono-C 1 -C 6 hydroxyalkylamino)-(C 1 -C 6 alkyl) group” means that one “mono-C 1 -C 6 hydroxyalkylamino group” is “ A group bonded to a “C 1 -C 6 alkyl group”. A mono-2-hydroxyethylaminomethyl group is preferred.
　本発明において、「Ｃ２－Ｃ７アルキルカルボニル基」は、１個の前記「Ｃ１－Ｃ６アルキル基」がカルボニル基に結合した基である。例えば、アセチル、プロピオニル、ブチリル、イソブチリル、ペンタノイル、ピバロイル又はバレリル基である。好適には、１個の「Ｃ1－Ｃ４アルキル基」がカルボニル基に結合した基（Ｃ２－Ｃ５アルキルカルボニル基）であり、より好適には、アセチル基又はプロピオニル基（Ｃ２－Ｃ３アルキルカルボニル基）であり、更により好適には、アセチル基である。 In the present invention, a “C 2 -C 7 alkylcarbonyl group” is a group in which one of the above “C 1 -C 6 alkyl groups” is bonded to a carbonyl group. For example, an acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl or valeryl group. A group in which one “C 1 -C 4 alkyl group” is bonded to a carbonyl group (C 2 -C 5 alkylcarbonyl group) is preferable, and an acetyl group or a propionyl group (C 2 —) is more preferable. a C 3 alkylcarbonyl group), even more preferably more, an acetyl group.
　本発明において、「モノ－Ｃ２－Ｃ７アルキルカルボニルアミノ基」は、１個の前記「Ｃ２－Ｃ７アルキルカルボニル基」がアミノ基に結合した基である。例えば、メチルカルボニルアミノ、エチルカルボニルアミノ、プロピルカルボニルアミノ、又はｔ－ブチルカルボニルアミノ基である。好適には、１個の「Ｃ２－Ｃ３アルキルカルボニル基」がアミノ基に結合した基（Ｃ２－Ｃ３アルキルカルボニルアミノ基）であり、より好適には、メチルカルボニルアミノ基である。 In the present invention, the “mono-C 2 -C 7 alkylcarbonylamino group” is a group in which one “C 2 -C 7 alkylcarbonyl group” is bonded to an amino group. For example, methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, or t-butylcarbonylamino group. A group in which one “C 2 -C 3 alkylcarbonyl group” is bonded to an amino group (C 2 -C 3 alkylcarbonylamino group) is preferable, and a methylcarbonylamino group is more preferable.
　本発明において、「テトラヒドロフリル基」は、好適には、３－テトラヒドロフリル基である。 In the present invention, the “tetrahydrofuryl group” is preferably a 3-tetrahydrofuryl group.
　本発明において、「オキセチルオキシ基」は、好適には、３－オキセチルオキシ基である。 In the present invention, the “oxetyloxy group” is preferably a 3-oxetyloxy group.
　本発明において、「テトラヒドロキシシクロヘキシル基」は、好適には、１，３，４，５－テトラヒドロキシシクロヘキシル基である。 In the present invention, the “tetrahydroxycyclohexyl group” is preferably a 1,3,4,5-tetrahydroxycyclohexyl group.
　本発明において、「置換基群Ａから選択される基で独立に１乃至４個置換されていてもよいピペリジン－１－イル基」は、ピペリジン－１－イル基又は置換基群Ａから選択される基で独立に１乃至４個置換されているピペリジン－１－イル基である。好適には、ピペリジン－１－イル基又は４位が式－Ｌ－Ｒ８で表される基で１個置換されているピペリジン－１－イル基である。 In the present invention, the “piperidin-1-yl group optionally substituted by 1 to 4 groups independently selected from the substituent group A” is selected from the piperidin-1-yl group or the substituent group A. A piperidin-1-yl group which is independently substituted with 1 to 4 groups. Preferable is a piperidin-1-yl group or a piperidin-1-yl group substituted at the 4-position with a group represented by the formula -LR 8 .
　本発明において、「置換基群Ａから選択される基で独立に１乃至４個置換されていてもよいピペリジン－３－イル基」は、ピペリジン－３－イル基又は置換基群Ａから選択される基で独立に１乃至４個置換されているピペリジン－３－イル基である。好適には、１位が式－Ｌ－Ｒ８で表される基で１個置換されているピペリジン－３－イル基である。 In the present invention, the “piperidin-3-yl group optionally substituted by 1 to 4 groups independently selected from the substituent group A” is selected from the piperidin-3-yl group or the substituent group A. A piperidin-3-yl group which is independently substituted with 1 to 4 groups. Preferred is a piperidin-3-yl group substituted at the 1-position with a group represented by the formula -LR 8 .
　本発明において、「置換基群Ａから選択される基で独立に１乃至４個置換されていてもよいピペリジン－４－イル基」は、ピペリジン－４－イル基又は置換基群Ａから選択される基で独立に１乃至４個置換されているピペリジン－４－イル基である。好適には、１位が式－Ｌ－Ｒ８で表される基で１個置換されているピペリジン－４－イル基であり、より好適には、１－アセチルピペリジン－４－イル基、１－［（１Ｓ）－１－ヒドロキシエチルカルボニル］ピペリジン－４－イル基、１－メトキシメチルカルボニルピペリジン－４－イル基、１－［（２Ｓ）－１，４－ジオキサン－２－イルカルボニル］ピペリジン－４－イル基、１－｛［（２Ｓ）－４，４－ジフルオロ－１－メチルピロリジン－２－イル］カルボニル｝ピペリジン－４－イル基、１－（メチルアミノオキサリル）ピペリジン－４－イル基又は１－（２，２－ジフルオロエチルアミノオキサリル）ピペリジン－４－イル基である。 In the present invention, the “piperidin-4-yl group optionally substituted by 1 to 4 groups independently selected from the substituent group A” is selected from the piperidin-4-yl group or the substituent group A. A piperidin-4-yl group which is independently substituted with 1 to 4 groups. Preferred is a piperidin-4-yl group substituted at the 1-position with a group represented by the formula —LR 8 , and more preferred is a 1-acetylpiperidin-4-yl group, -[(1S) -1-hydroxyethylcarbonyl] piperidin-4-yl group, 1-methoxymethylcarbonylpiperidin-4-yl group, 1-[(2S) -1,4-dioxane-2-ylcarbonyl] piperidine -4-yl group, 1-{[(2S) -4,4-difluoro-1-methylpyrrolidin-2-yl] carbonyl} piperidin-4-yl group, 1- (methylaminooxalyl) piperidin-4-yl Or a 1- (2,2-difluoroethylaminooxalyl) piperidin-4-yl group.
　本発明において、「置換基群Ａから選択される基で独立に１乃至４個置換されていてもよい１，２，３，６－テトラヒドロピリジン－４－イル基」は、１，２，３，６－テトラヒドロピリジン－４－イル基又は置換基群Ａから選択される基で独立に１乃至４個置換されている１，２，３，６－テトラヒドロピリジン－４－イル基である。好適には、１位が式－Ｌ－Ｒ８で表される基で１個置換されている１，２，３，６－テトラヒドロピリジン－４－イル基であり、より好適には、１－アセチル－１，２，３，６－テトラヒドロピリジン－４－イル基、１－［（１Ｓ）－１－ヒドロキシエチルカルボニル］－１，２，３，６－テトラヒドロピリジン－４－イル基、１－メチルアミノオキサリル－１，２，３，６－テトラヒドロピリジン－４－イル基又は１－エチルアミノオキサリル－１，２，３，６－テトラヒドロピリジン－４－イル基である。 In the present invention, “1,2,3,6-tetrahydropyridin-4-yl group optionally substituted by 1 to 4 groups independently selected from the substituent group A” refers to 1,2,3 , 6-tetrahydropyridin-4-yl group or 1,2,3,6-tetrahydropyridin-4-yl group independently substituted with 1 to 4 groups selected from substituent group A. Preferred is a 1,2,3,6-tetrahydropyridin-4-yl group substituted at the 1-position with one group represented by the formula —LR 8 , and more preferred is 1- Acetyl-1,2,3,6-tetrahydropyridin-4-yl group, 1-[(1S) -1-hydroxyethylcarbonyl] -1,2,3,6-tetrahydropyridin-4-yl group, 1- [ A methylaminooxalyl-1,2,3,6-tetrahydropyridin-4-yl group or a 1-ethylaminooxalyl-1,2,3,6-tetrahydropyridin-4-yl group.
　本発明において、「置換基群Ａから選択される基で独立に１乃至４個置換されていてもよいピペラジン－１－イル基」は、ピペラジン－１－イル基又は置換基群Ａから選択される基で独立に１乃至４個置換されているピペラジン－１－イル基である。好適には、４位が式－Ｌ－Ｒ８で表される基で１個置換されているピペラジン－１－イル基であり、より好適には、４－アセチルピペラジン－１－イル基である。 In the present invention, the “piperazin-1-yl group optionally substituted by 1 to 4 groups independently selected from the substituent group A” is selected from the piperazin-1-yl group or the substituent group A. A piperazin-1-yl group which is independently substituted with 1 to 4 groups. Preferred is a piperazin-1-yl group substituted at the 4-position with a group represented by the formula —LR 8 , and more preferred is a 4-acetylpiperazin-1-yl group. .
　本発明において、「置換基群Ａから選択される基で独立に１乃至４個置換されていてもよいモルホリン－４－イル基」は、モルホリン－４－イル基又は置換基群Ａから選択される基で独立に１乃至４個置換されているモルホリン－４－イル基である。好適には、モルホリン－４－イル基又は２位若しくは３位が式－Ｌ－Ｒ８で表される基で１個置換されているモルホリン－４－イル基である。 In the present invention, the “morpholin-4-yl group optionally substituted by 1 to 4 groups independently selected from the substituent group A” is selected from the morpholin-4-yl group or the substituent group A. A morpholin-4-yl group which is independently substituted with 1 to 4 groups. Preferred is a morpholin-4-yl group or a morpholin-4-yl group substituted at the 2-position or 3-position with a group represented by the formula -LR 8 .
　本発明において、「置換基群Ａから選択される基で独立に１乃至４個置換されていてもよいピロリジン－１－イル基」は、ピロリジン－１－イル基又は置換基群Ａから選択される基で独立に１乃至４個置換されているピロリジン－１－イル基である。好適には、３位が式－Ｌ－Ｒ８で表される基で１個置換されているピロリジン－１－イル基である。 In the present invention, the “pyrrolidin-1-yl group optionally substituted independently by 1 to 4 groups selected from the substituent group A” is selected from the pyrrolidin-1-yl group or the substituent group A. A pyrrolidin-1-yl group independently substituted with 1 to 4 groups. Preferred is a pyrrolidin-1-yl group which is substituted at the 3-position with a group represented by the formula -LR 8 .
　本発明において、「置換基群Ａから選択される基で独立に１乃至４個置換されていてもよいピロリジン－３－イル基」は、ピロリジン－３－イル基又は置換基群Ａから選択される基で独立に１乃至４個置換されているピロリジン－３－イル基である。好適には、１位が式－Ｌ－Ｒ８で表される基で１個置換されているピロリジン－３－イル基である。 In the present invention, the “pyrrolidin-3-yl group optionally substituted with 1 to 4 groups independently selected from the substituent group A” is selected from the pyrrolidin-3-yl group or the substituent group A. A pyrrolidin-3-yl group independently substituted with 1 to 4 groups. Preferred is a pyrrolidin-3-yl group which is substituted at the 1-position with a group represented by the formula -LR 8 .
　本発明において、「Ｃ１－Ｃ６アルキル基で独立に１又は２個置換されていてもよいピロール－２－イル基」は、ピロール－２－イル基又はＣ１－Ｃ６アルキル基で独立に１又は２個置換されているピロール－２－イル基である。好適には、１－メチル－ピロール－２－イル基である。 In the present invention, "C 1 -C 6 alkyl independently one or two optionally substituted pyrrol-2-yl group in group", independently pyrrol-2-yl group or a C 1 -C 6 alkyl group 1 or 2 substituted pyrrol-2-yl groups. A 1-methyl-pyrrol-2-yl group is preferred.
　本発明において、「Ｃ１－Ｃ６アルキル基で独立に１又は２個置換されていてもよいモルホリン－２－イル基」は、モルホリン－２－イル基又はＣ１－Ｃ６アルキル基で独立に１又は２個置換されているモルホリン－２－イル基である。好適には、モルホリン－２－イル基、４－メチル－モルホリン－２－イル基又は４－エチル－モルホリン－２－イル基である。 In the present invention, “a morpholin-2-yl group which may be independently substituted with one or two C 1 -C 6 alkyl groups” refers to a morpholin-2-yl group or a C 1 -C 6 alkyl group. Is a morpholin-2-yl group substituted by 1 or 2 groups. Preferred are morpholin-2-yl group, 4-methyl-morpholin-2-yl group or 4-ethyl-morpholin-2-yl group.
　本発明において、「Ｃ１－Ｃ６アルキル基で独立に１又は２個置換されていてもよいイミダゾール－５－イル基」は、イミダゾール－５－イル基又はＣ１－Ｃ６アルキル基で独立に１又は２個置換されているイミダゾール－５－イル基である。好適には、イミダゾール－５－イル基又は１－メチル－イミダゾール－５－イル基である。 In the present invention, “an imidazol-5-yl group which may be independently substituted with one or two C 1 -C 6 alkyl groups” independently represents an imidazol-5-yl group or a C 1 -C 6 alkyl group. 1- or 2-substituted imidazol-5-yl group. Preferred is an imidazol-5-yl group or a 1-methyl-imidazol-5-yl group.
　本発明において、「ハロゲン原子、Ｃ１－Ｃ６アルキル基、水酸基、Ｃ１－Ｃ６ヒドロキシアルキル基、Ｃ２－Ｃ７アルキルカルボニル基及びオキソ基から選択される基で独立に１乃至５個置換されていてもよいピロリジン－２－イル基」は、ピロリジン－２－イル基又はハロゲン原子、Ｃ１－Ｃ６アルキル基、水酸基、Ｃ１－Ｃ６ヒドロキシアルキル基、Ｃ２－Ｃ７アルキルカルボニル基及びオキソ基から選択される基で独立に１乃至５個置換されているピロリジン－２－イル基である。好適には、ハロゲン原子及びＣ１－Ｃ６アルキル基から選択される基で独立に１乃至３個置換されているピロリジン－２－イル基であり、より好適には、４，４―ジフルオロ－１－メチルピロリジン－２－イル基である。 In the present invention, 1 to 5 groups independently selected from “halogen atom, C 1 -C 6 alkyl group, hydroxyl group, C 1 -C 6 hydroxyalkyl group, C 2 -C 7 alkylcarbonyl group and oxo group” The pyrrolidin-2-yl group which may be substituted includes a pyrrolidin-2-yl group or a halogen atom, a C 1 -C 6 alkyl group, a hydroxyl group, a C 1 -C 6 hydroxyalkyl group, a C 2 -C 7 alkyl group. It is a pyrrolidin-2-yl group which is independently substituted with 1 to 5 groups independently selected from a carbonyl group and an oxo group. Preferable is a pyrrolidin-2-yl group which is independently substituted with 1 to 3 groups independently selected from a halogen atom and a C 1 -C 6 alkyl group, and more preferably 4,4-difluoro- 1-methylpyrrolidin-2-yl group.
　本発明において、好適なＲ１は、Ｃ１－Ｃ６アルキル基であり、より好適なＲ１は、メチル基又はエチル基である。 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.
　本発明において、好適なＲ２は、水素原子である。 In the present invention, preferred R 2 is a hydrogen atom.
　本発明において、好適なＲ３は、水素原子である。 In the present invention, R 3 is preferably a hydrogen atom.
　本発明において、好適なＲ４は、Ｃ１－Ｃ６アルキル基であり、より好適なＲ４は、メチル基である。 In the present invention, preferred R 4 is a C 1 -C 6 alkyl group, and more preferred R 4 is a methyl group.
　本発明において、好適なＲ５は、水素原子又はＣ１－Ｃ６アルキル基であり、より好適なＲ５は、水素原子又はメチル基であり、更により好適なＲ５は、水素原子である。 In the present invention, preferred R 5 is a hydrogen atom or a C 1 -C 6 alkyl group, more preferred R 5 is a hydrogen atom or a methyl group, and even more preferred R 5 is a hydrogen atom. .
　本発明において、好適なＲ６は、水素原子である。 In the present invention, preferred R 6 is a hydrogen atom.
　本発明において、好適なＱ１は、式＝ＣＨ－で表される基である。 In the present invention, preferred Q 1 is a group represented by the formula = CH-.
　本発明において、好適なＱ２は、式＝ＣＨ－で表される基である。 In the present invention, preferred Q 2 is a group represented by the formula = CH-.
　本発明において、好適な式－Ｕ－Ｔ－で表される基は、式－ＣＨ２－ＣＨ２－で表される基である。 In the present invention, a preferable group represented by the formula —UT— is a group represented by the formula —CH 2 —CH 2 —.
　本発明において、好適なＹは、酸素原子である。 In the present invention, Y is preferably an oxygen atom.
　本発明において、好適なＲ７は、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基又はＣ１－Ｃ６アルコキシ基であり、より好適なＲ７は、水素原子又はメチル基である。 In the present invention, R 7 is preferably a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group, and more preferably R 7 is a hydrogen atom or a methyl group.
　本発明において、好適なＶは、窒素原子、式＝ＣＨ－で表される基又は式＝Ｃ（ＣＨ３）－で表される基である。 In the present invention, preferred V is a nitrogen atom, a group represented by the formula = CH- or a group represented by the formula = C (CH 3 )-.
　本発明において、好適なＬは、カルボニル基又はオキサリル基である。 In the present invention, preferred L is a carbonyl group or an oxalyl group.
　本発明において、好適なＲ８は、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６ヒドロキシアルキル基、（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルキル）基、アミノ基、モノ－Ｃ１－Ｃ６アルキルアミノ基、モノ－Ｃ１－Ｃ６ハロゲン化アルキルアミノ基、ジ－（Ｃ１－Ｃ６アルキル）アミノ基、モルホリン－２－イル基又はハロゲン原子及びＣ１－Ｃ６アルキル基から選択される基で独立に１乃至３個置換されているピロリジン－２－イル基であり、より好適なＲ８は、メチル基、１－ヒドロキシエチル基、メトキシメチル基、メチルアミノ基、エチルアミノ基、２，２―ジフルオロエチルアミノ基、モルホリン－２－イル基又は４，４―ジフルオロ－１－メチルピロリジン－２－イル基である。 In the present invention, R 8 is preferably a C 1 -C 6 alkyl group, a C 1 -C 6 hydroxyalkyl group, a (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, an amino group, a mono group, -C 1 -C 6 alkylamino group, mono-C 1 -C 6 halogenated alkylamino group, di- (C 1 -C 6 alkyl) amino group, morpholin-2-yl group or halogen atom and C 1 -C A pyrrolidin-2-yl group independently substituted with 1 to 3 groups selected from 6 alkyl groups, more preferably R 8 is a methyl group, a 1-hydroxyethyl group, a methoxymethyl group, a methylamino group; A group, an ethylamino group, a 2,2-difluoroethylamino group, a morpholin-2-yl group or a 4,4-difluoro-1-methylpyrrolidin-2-yl group.
　本発明において、好適な置換基群Ａは、式－Ｌ－Ｒ８で表される基であり、より好適な置換基群Ａは、アセチル基、（１Ｓ）－１－ヒドロキシエチルカルボニル基、メトキシメチルカルボニル基、（２Ｓ）－１，４－ジオキサン－２－イルカルボニル基、［（２Ｓ）－４，４－ジフルオロ－１－メチルピロリジン－２－イル］カルボニル基、メチルアミノオキサリル基、エチルアミノオキサリル基又は２，２－ジフルオロエチルアミノオキサリル基である。 In the present invention, a preferred substituent group A is a group represented by the formula —LR 8 , and a more preferred substituent group A is an acetyl group, a (1S) -1-hydroxyethylcarbonyl group, a methoxy group Methylcarbonyl group, (2S) -1,4-dioxane-2-ylcarbonyl group, [(2S) -4,4-difluoro-1-methylpyrrolidin-2-yl] carbonyl group, methylaminooxalyl group, ethylamino An oxalyl group or a 2,2-difluoroethylaminooxalyl group;
　本発明において、好適なＥは、式－Ｌ－Ｒ８で表される基で１個置換されているピペリジン－４－イル基、１，２，３，６－テトラヒドロピリジン－４－イル基又はピペラジン－１－イル基であり、より好適なＥは、１－アセチルピペリジン－４－イル基、１－［（１Ｓ）－１－ヒドロキシエチルカルボニル］ピペリジン－４－イル基、１－メトキシメチルカルボニルピペリジン－４－イル基、１－［（２Ｓ）－１，４－ジオキサン－２－イルカルボニル］ピペリジン－４－イル基、１－｛［（２Ｓ）－４，４－ジフルオロ－１－メチルピロリジン－２－イル］カルボニル｝ピペリジン－４－イル基、１－（メチルアミノオキサリル）ピペリジン－４－イル基、１－（２，２－ジフルオロエチルアミノオキサリル）ピペリジン－４－イル基、１－アセチル－１，２，３，６－テトラヒドロピリジン－４－イル基、１－［（１Ｓ）－１－ヒドロキシエチルカルボニル］－１，２，３，６－テトラヒドロピリジン－４－イル基、１－メチルアミノオキサリル－１，２，３，６－テトラヒドロピリジン－４－イル基、１－エチルアミノオキサリル－１，２，３，６－テトラヒドロピリジン－４－イル基又は４－アセチルピペラジン－１－イル基である。 In the present invention, preferred E is a piperidin-4-yl group, a 1,2,3,6-tetrahydropyridin-4-yl group substituted by one group represented by the formula -LR 8 or Piperazin-1-yl group, more preferably E is 1-acetylpiperidin-4-yl group, 1-[(1S) -1-hydroxyethylcarbonyl] piperidin-4-yl group, 1-methoxymethylcarbonyl Piperidin-4-yl group, 1-[(2S) -1,4-dioxane-2-ylcarbonyl] piperidin-4-yl group, 1-{[(2S) -4,4-difluoro-1-methylpyrrolidine -2-yl] carbonyl} piperidin-4-yl group, 1- (methylaminooxalyl) piperidin-4-yl group, 1- (2,2-difluoroethylaminooxalyl) piperidin-4-yl group, 1-acetyl-1,2,3,6-tetrahydropyridin-4-yl group, 1-[(1S) -1-hydroxyethylcarbonyl] -1,2,3,6-tetrahydropyridin-4-yl group, 1-methylaminooxalyl-1,2,3,6-tetrahydropyridin-4-yl group, 1-ethylaminooxalyl-1,2,3,6-tetrahydropyridin-4-yl group or 4-acetylpiperazine-1 -An yl group.
　本発明の一般式（Ｉ）で表される化合物又はその薬学上許容される塩は、全ての異性体（ケト－エノール異性体、ジアステレオ異性体、光学異性体、回転異性体等）を有する。 The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has all isomers (keto-enol isomer, diastereoisomer, optical isomer, rotational isomer, etc.). .
　本発明の一般式（Ｉ）で表される化合物又はその薬学上許容される塩は、その分子内に不斉炭素原子が存在するので、種々の異性体を有する。本発明の化合物においては、これらの異性体およびこれらの異性体の混合物がすべて単一の式、即ち一般式（Ｉ）で示されている。従って、本発明はこれらの異性体およびこれらの異性体の任意の割合の混合物をもすべて含むものである。 The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has various isomers since an asymmetric carbon atom exists 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.
　上記のような立体異性体は、光学活性な原料化合物を用いるか、又は不斉合成若しくは不斉誘導の手法を用いて本発明に係る化合物を合成するか、或いは合成した本発明に係る化合物を所望により通常の光学分割法又は分離法を用いて単離することにより得ることができる。 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.
　本発明の一般式（Ｉ）で表される化合物又はその薬学上許容される塩は、このような化合物を構成する原子の１以上に、原子同位体の非天然割合も含有し得る。原子同位体としては、例えば、重水素（２Ｈ）、トリチウム（３Ｈ）、ヨウ素－125（１２５Ｉ）又は炭素－14（１４Ｃ）などが挙げられる。また、前記化合物は、例えば、トリチウム（３Ｈ）、ヨウ素－125（１２５Ｉ）又は炭素－14（１４Ｃ）などの放射性同位体で放射性標識され得る。放射性標識された化合物は、治療又は予防剤、研究試薬、例えば、アッセイ試薬、及び診断剤、例えば、インビボ画像診断剤として有用である。本発明の化合物の全ての同位体変異種は、放射性であると否とを問わず、本発明の範囲に包含されるものとする。 The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof may also contain an unnatural ratio of atomic isotopes at one or more of atoms constituting such a compound. Examples of the atomic isotope include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like. The compound can also be radiolabeled with a radioisotope such as, for example, tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
　「その薬学上許容される塩」とは、著しい毒性を有さず、医薬として使用され得る塩をいう。本発明の一般式（Ｉ）で表される化合物は、塩基性の基を有する場合には酸と反応させることにより、又、酸性の基を有する場合には塩基と反応させることにより、塩にすることができる。 “The pharmaceutically acceptable salt” 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.
　塩基性基に基づく塩としては、例えば、弗化水素酸塩、塩酸塩、臭化水素酸塩、沃化水素酸塩のようなハロゲン化水素酸塩、硝酸塩、過塩素酸塩、硫酸塩、燐酸塩等の無機酸塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩のようなＣ１－Ｃ６アルキルスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩のようなアリールスルホン酸塩、酢酸塩、りんご酸塩、フマ－ル酸塩、コハク酸塩、クエン酸塩、アスコルビン酸塩、酒石酸塩、蓚酸塩、マレイン酸塩等の有機酸塩；及び、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩を挙げることができる。 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.
　一方、酸性基に基づく塩としては、例えば、ナトリウム塩、カリウム塩、リチウム塩のようなアルカリ金属塩、カルシウム塩、マグネシウム塩のようなアルカリ土類金属塩、アルミニウム塩、鉄塩等の金属塩；アンモニウム塩のような無機塩、t－ブチルアミン塩、ジイソプロピルアミン塩、ｔ－オクチルアミン塩、ジベンジルアミン塩、モルホリン塩、グルコサミン塩、フェニルグリシンアルキルエステル塩、エチレンジアミン塩、Ｎ－メチルグルカミン塩、グアニジン塩、ジエチルアミン塩、トリエチルアミン塩、ジシクロヘキシルアミン塩、Ｎ，Ｎ’－ジベンジルエチレンジアミン塩、クロロプロカイン塩、プロカイン塩、ジエタノールアミン塩、Ｎ－ベンジルフェネチルアミン塩、ピペラジン塩、テトラメチルアンモニウム塩、トリス（ヒドロキシメチル）アミノメタン塩のような有機塩等のアミン塩；及び、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩を挙げることができる。 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-butylamine salts, diisopropylamine salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts Guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, trimethylammonium salt And amine salts such as organic salts such as s (hydroxymethyl) aminomethane salt; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt and aspartate salt.
　本発明の一般式（Ｉ）で表される化合物又はその薬学上許容される塩は、大気中に放置したり、又は、再結晶をすることにより、水分を吸収し、吸着水が付いたり、水和物となる場合があり、そのような水和物も本発明の塩に包含される。 The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be left in the atmosphere or recrystallized to absorb moisture and adsorb water, It may become a hydrate, and such a hydrate is also included in the salt of the present invention.
　本発明の一般式（Ｉ）で表される化合物又はその薬学上許容される塩は、他のある種の溶媒を吸収し、溶媒和物となる場合があり、そのような溶媒和物も本発明の塩に包含される。 The compound represented by the general formula (I) of the present invention or a pharmaceutically 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.
　本発明の一般式（Ｉ）で表される化合物又はその薬学上許容される塩は、選択的かつ優れたTh17細胞の分化阻害作用及びIL-17産生阻害作用を有し、自己免疫疾患などのRORγtが関わる疾患やIL-17産生が病態発症に関与する癌の治療及び／又は予防に有用である。具体的な疾患としては、乾癬、乾癬性関節炎、強直性脊椎炎、多発性硬化症、関節リウマチ、炎症性腸疾患（クローン病や潰瘍性大腸炎など）、シェーグレン症候群、全身性エリテマトーデス、慢性閉塞性肺疾患（COPD）、アトピー性皮膚炎、喘息、一型糖尿病、移植片対宿主病（GvHD）、円形脱毛症、白斑、川崎病、ベーチェット病、糸球体腎炎、心筋症、再生不良性貧血、橋本病、強皮症、巨細胞性動脈炎、接触性皮膚炎、視神経炎又は大腸癌である。好ましい疾患としては、乾癬、乾癬性関節炎、強直性脊椎炎、シェーグレン症候群又は慢性閉塞性肺疾患（COPD）、特に乾癬または乾癬性関節炎である。また、本発明の一般式（Ｉ）で表される化合物又はその薬学上許容される塩は、既存治療法では不可能であったTh17細胞の異常を選択的に予防及び治療できる効果が期待される。 The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has a selective and excellent Th17 cell differentiation inhibitory action and IL-17 production inhibitory action, such as autoimmune diseases. It is useful for the treatment and / or prevention of diseases involving RORγt and cancer in which IL-17 production is involved in pathogenesis. Specific diseases include psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases (such as Crohn's disease and ulcerative colitis), Sjogren's syndrome, systemic lupus erythematosus, chronic obstruction Pulmonary disease (COPD), atopic dermatitis, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colon cancer. Preferred diseases are psoriasis, psoriatic arthritis, ankylosing spondylitis, Sjogren's syndrome or chronic obstructive pulmonary disease (COPD), especially psoriasis or psoriatic arthritis. In addition, the compound represented by the general formula (I) of the present invention or a pharmaceutically 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
　本発明において、「予防」とは、遺伝的背景または慢性炎症などにより、本発明が対象とする疾患の発症リスクが高いと診断された場合に、その疾患の発症を抑制または遅延させることを意味する。自己免疫疾患の場合は、一塩基多型（SNPs）や遺伝子変異などにより、発症リスクが診断できる疾患が知られている。また、大腸癌の場合は、大腸炎が慢性的に持続することで、大腸癌のリスクが明らかに高まることが知られている。本発明の一般式（I）で表される化合物又はその薬学上許容される塩は、選択的かつ優れたTh17細胞の分化阻害作用及びIL-17産生阻害作用を有するので、このような疾患の発症リスクが高いと診断された患者に対して予防的に投与することにより、発症を抑制または遅延させる効果が期待される。 In the present invention, “prevention” means to suppress or delay the onset of a disease that is diagnosed as having a high risk of developing the disease targeted by the present invention due to genetic background or chronic inflammation. To do. In the case of an autoimmune disease, a disease whose onset risk can be diagnosed by single nucleotide polymorphisms (SNPs) or gene mutations is known. In the case of colorectal cancer, it is known that the risk of colorectal cancer is clearly increased due to chronic persistence of colitis. The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has selective and excellent Th17 cell differentiation inhibitory action and IL-17 production inhibitory action. Prophylactic administration to patients diagnosed with a high risk of onset is expected to have an effect of suppressing or delaying onset.
　本発明の一般式（Ｉ）で表される化合物は、以下に記載するＡ法乃至Ｋ法に従って製造することができる。 The compound represented by the general formula (I) of the present invention can be produced according to the methods A to K described below.
　下記Ａ法乃至Ｋ法の各工程の反応において使用される溶媒は、反応を阻害せず、出発原料をある程度溶解するものであれば特に限定はなく、例えば、下記溶媒群より選択される。溶媒群は、ペンタン、ヘキサン、オクタン、石油エーテル、リグロイン、シクロヘキサンのような炭化水素類；ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン、Ｎ－メチル－２－ピロリジノン、ヘキサメチルリン酸トリアミドのようなアミド類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、１，４－ジオキサン、１，２－ジメトキシエタン、ジエチレングリコールジメチルエーテル、シクロペンチルメチルエーテルのようなエーテル類；メタノール、エタノール、ｎ－プロパノール、ｉ－プロパノール、ｎ－ブタノール、２－ブタノール、２－メチル－１－プロパノール、t－ブタノール、イソアミルアルコール、ジエチレングリコール、グリセリン、オクタノール、シクロヘキサノール、メチルセロソルブのようなアルコール類；ジメチルスルホキシドのようなスルホキシド類；スルホランのようなスルホン類；アセトニトリル、プロピオニトリル、ブチロニトリル、イソブチロニトリルのようなニトリル類；蟻酸エチル、酢酸エチル、酢酸プロピル、酢酸ブチル、炭酸ジエチルのようなエステル類；アセトン、メチルエチルケトン、４-メチル-２-ペンタノン、メチルイソブチルケトン、イソホロン、シクロヘキサノンのようなケトン類；ニトロエタン、ニトロベンゼンのようなニトロ化合物類；ジクロロメタン、１，２－ジクロロエタン、クロロベンゼン、ジクロロベンゼン、クロロホルム、四塩化炭素のようなハロゲン化炭化水素類；ベンゼン、トルエン、キシレンのような芳香族炭化水素類；酢酸、蟻酸、プロピオン酸、ブチリル酸、トリフルオロ酢酸のようなカルボン酸類；Ｎ－メチルモルホリン、トリエチルアミン、トリプロピルアミン、トリブチルアミン、ジイソプロピルエチルアミン、ジシクロヘキシルアミン、Ｎ－メチルピペリジン、ピリジン、２，６－ルチジン、４－ピロリジノピリジン、ピコリン、４－（Ｎ，Ｎ－ジメチルアミノ）ピリジン、２，６－ジ（ｔ－ブチル）－４－メチルピリジン、キノリン、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジエチルアニリン、１，５－ジアザビシクロ［４．３．０］ノナ－５－エン（ＤＢＮ）、１，４－ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）、ピペリジンのようなアミン類；水；及び、これらの混合溶媒からなる。 The solvent used in the reaction of each step of the following methods A to K 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 and cyclopentyl methyl ether; methanol Ethanol, n-propanol, i-propanol, n-butanol, 2-butanol, 2-methyl-1-propanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, 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.
　下記Ａ法乃至Ｋ法の各工程の反応において使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム、炭酸リチウム、炭酸セシウムのようなアルカリ金属炭酸塩類；炭酸水素ナトリウム、炭酸水素カリウム、炭酸水素リチウムのようなアルカリ金属炭酸水素塩類；酢酸ナトリウム、酢酸カリウム、酢酸リチウム、酢酸セシウムのようなアルカリ金属酢酸塩類；水素化リチウム、水素化ナトリウム、水素化カリウムのようなアルカリ金属水素化物類；水酸化ナトリウム、水酸化カリウム、水酸化バリウム、水酸化リチウムのようなアルカリ金属水酸化物類；リン酸ナトリウム、リン酸カリウムのようなアルカリ金属リン酸塩類；Ｌ－プロリンナトリウム、Ｌ－プロリンカリウムのようなアルカリ金属塩類；弗化ナトリウム、弗化カリウムのようなアルカリ金属弗化物類等の無機塩基類；ナトリウムメトキシド、ナトリウムエトキシド、ナトリウム－ｔ－ブトキシド、カリウム－ｔ－ブトキシドのようなアルカリ金属アルコキシド類；ナトリウムトリメチルシロキシド、カリウムトリメチルシロキシド、リチウムトリメチルシロキシドのようなアルカリ金属トリアルキルシロキシド類；Ｎ－メチルモルホリン、トリエチルアミン、トリプロピルアミン、トリブチルアミン、ジイソプロピルエチルアミン、ジシクロヘキシルアミン、Ｎ－メチルピペリジン、ピリジン、２，６－ルチジン、コリジン、４－ピロリジノピリジン、ピコリン、４－（Ｎ，Ｎ－ジメチルアミノ）ピリジン、２，６－ジ（ｔ－ブチル）－４－メチルピリジン、キノリン、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジエチルアニリン、１，５－ジアザビシクロ［４．３．０］ノナ－５－エン（ＤＢＮ）、１，４－ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）のような有機塩基類；リチウム　ジイソプロピルアミド、ヘキサメチルジシラザンリチウム、ヘキサメチルジシラザンナトリウムのようなアルカリ金属アミド類；又は、プロリンのようなアミノ酸である。 The base used in the reaction in each step of the following methods A to K 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; sodium fluoride, 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-di Tyraniline, 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); lithium, alkali metal amides such as diisopropylamide, hexamethyldisilazane lithium and hexamethyldisilazane sodium; or amino acids such as proline.
　下記Ａ法乃至Ｋ法の各工程の反応において使用される縮合剤は、例えば、アゾジカルボン酸ジエチルエステル－トリフェニルホスフィンのようなアゾジカルボン酸ジ低級アルキルエステル－トリフェニルホスフィン類；１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩、Ｎ，Ｎ’－ジシクロヘキシルカルボジイミドのようなカルボジイミド誘導体；２－クロル－１－メチルピリジニウムヨージドのような２－ハロ－１－低級アルキルピリジニウムハライド類；ジフェニルホスホリルアジドのようなジアリールホスホリルアジド類；ジエチルホスホリルクロリドのようなホスホリルクロリド類；Ｎ，Ｎ’－カルボジイミダゾールのようなイミダゾール誘導体；Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムヘキサフルオロホスフェート、（１Ｈ－ベンゾトリアゾール－１－イルオキシ）トリピロリジノホスホニウムヘキサフルオロホスフェートのようなベンゾトリアゾール誘導体；又は、４-（４，６－ジメトキシ－１，３，５-トリアジン－２－イル）－４－メチルモルホリニウムクロリドのようなモルホリニウムクロリド誘導体である。 The condensing agent used in the reaction of each step of the following methods A to K is, for example, azodicarboxylic acid dilower alkyl ester-triphenylphosphine such as diethyl ester of azodicarboxylic acid-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 diphenyl phosphoryl azide; phosphoryl chlorides such as diethyl phosphoryl chloride; imidazoles such as N, N′-carbodiimidazole Derivatives; 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.
　下記Ａ法乃至Ｋ法の各工程の反応において、反応温度は、溶媒、出発原料、試薬等により異なり、反応時間は、溶媒、出発原料、試薬、反応温度等により異なる。 In the reaction of each step of Method A to Method K below, 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.
　下記Ａ法乃至Ｋ法の各工程の反応において、反応終了後、各目的化合物は常法に従って、反応混合物から採取される。例えば、反応混合物を適宜中和し、又、不溶物が存在する場合には濾過により除去した後、水と酢酸エチルのような混和しない有機溶媒を加え、目的化合物を含む有機層を分離し、水等で洗浄後、無水硫酸マグネシウム、無水硫酸ナトリウム等で乾燥、ろ過後、溶剤を留去することによって得られる。得られた目的化合物は必要ならば、常法、例えば再結晶、再沈殿、クロマトグラフィー（例えば、シリカゲル、アルミナ、マグネシウム－シリカゲル系のフロリジル、ＳＯ３Ｈ－シリカ（富士シリシア製）のような担体を用いた吸着カラムクロマトグラフィー法；セファデックスＬＨ－２０（ファルマシア社製）、アンバーライトＸＡＤ－１１（ローム・アンド・ハース社製）、ダイヤイオンＨＰ－２０（三菱化学社製）のような担体を用いた分配カラムクロマトグラフィー等の合成吸着剤を使用する方法；イオン交換クロマトを使用する方法；シリカゲル若しくはアルキル化シリカゲルによる順相・逆相カラムクロマトグラフィー法（好適には、高速液体クロマトグラフィー）を適宜組合せ、適切な溶離剤で溶出する）等の通常、有機化合物の分離精製に慣用されている方法を適宜組合せ、分離、精製することができる。溶媒に不溶の目的化合物では、得られた固体の粗生成物を溶媒で洗浄して、精製することができる。また、各工程の目的化合物は精製することなくそのまま次の反応に使用することもできる。 In the reaction of each step of the following methods A to K, 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 obtained by a conventional method such as recrystallization, reprecipitation, chromatography (for example, silica gel, alumina, magnesium-silica-based florisil, SO3H-silica (manufactured by 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.
　下記Ａ法乃至Ｋ法の各工程の反応において、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｅ、Ｑ１、Ｑ２及びＶは、前述したものと同意義を示す。Ｒ３ａは、Ｒ３の基に含まれるヒドロキシ基またはカルボキシ基が、保護されてもよいヒドロキシ基またはカルボキシ基である他、Ｒ３の基の定義における基と同様の基を示す。Ｅａは、Ｅの基に含まれるアミノ基、ヒドロキシ基及び／又はカルボキシ基が、保護されてもよいアミノ基、ヒドロキシ基及び／又はカルボキシ基である他、Ｅの基の定義における基と同様の基を示し、更に、Ｅの基に含まれる置換基の前駆体になりえる基を含むＥを示す。Ｒ８は、Ｃ１－Ｃ６アルキル基又はベンジル基を示す。Ｘ１、Ｘ２、Ｘ３、Ｘ４及びＸ５は、ハロゲン原子又はトリフルオロメタンスルホニル基を示す。Ｖが、式＝Ｃ（Ｒ７）－で表される基であり、Ｒ６及びＲ７が、ともに水素原子でなく、Ｘ１が、臭素原子又は沃素原子である場合、Ｘ２は、好適には、塩素原子又は臭素原子である。Ｘ３は、好適には、臭素原子又は沃素原子であり、より好適には、沃素原子である。Ｘ４は、好適には、臭素原子、沃素原子又はトリフルオロメタンスルホニル基である。Ｔｆは、トリフルオロメタンスルホニル基を示す。 In the reaction of each step of the following methods A to K, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , E, Q 1 , Q 2 and V are the same as those described above. Show significance. R 3a represents a group similar to the group in the definition of the group R 3 in addition to the hydroxy group or carboxy group contained in the group R 3 being a hydroxy group or carboxy group which may be protected. E a is the same as the group in the definition of E group, except that the amino group, hydroxy group and / or carboxy group contained in E group may be protected amino group, hydroxy group and / or carboxy group And E containing a group that can be a precursor of a substituent contained in the E group. R 8 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 V is a group represented by the formula = C (R 7 )-, R 6 and R 7 are not both hydrogen atoms, and X 1 is a bromine atom or an iodine atom, X 2 is preferably Is 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法は、一般式（Ｉ）で表される化合物の中で、式－Ｕ－Ｔ－で表される基が式－ＣＨ２－ＣＨ２－で表される基である一般式（Ｉａ）で表される化合物を製造する方法である。
（Ａ法） In the method A, in the compound represented by the general formula (I), the group represented by the formula —UT— is a group represented by the formula —CH 2 —CH 2 —. It is a method of manufacturing the compound represented by these.
(Method A)
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
　Ａ－Ｉ工程
　本工程は、溶媒中、一般式（ＩＩ）で表される化合物を、酸と反応させることにより、一般式（ＩＩＩ）で表される化合物の塩を製造する工程である。 Step AI This step is a step for producing a salt of the compound represented by the general formula (III) by reacting the compound represented by the general formula (II) with an acid in a solvent.
　本工程において使用される溶媒は、好適には、ハロゲン化炭化水素類であり、より好適には、ジクロロメタンである。 The solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
　本工程において使用される酸は、好適には、酢酸類又はプロトン酸類であり、より好適には、トリフルオロ酢酸又は塩酸の１，４－ジオキサン溶液である。一般式（ＩＩＩ）で表される化合物の塩は、塩酸類を使用した場合を示す。 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 the general formula (III) indicates a case where hydrochloric acid is used.
　本工程における反応温度は、通常、－１０℃乃至５０℃であり、好適には、０℃乃至３０℃である。 The reaction temperature in this step is usually −10 ° C. to 50 ° C., preferably 0 ° C. to 30 ° C.
　本工程における反応時間は、通常、１分間乃至２４時間であり、好適には、１０分間乃至６時間である。 The reaction time in this step is usually 1 minute to 24 hours, preferably 10 minutes to 6 hours.
　Ａ－ＩＩ工程
　本工程は、溶媒中、縮合剤及び塩基の存在下、一般式（ＩＩＩ）で表される化合物の塩を、一般式（ＩＶ）で表される化合物又はその塩と反応させることにより、一般式（Ｖ）で表される化合物を製造する工程である。 Step A-II In this step, the salt of the compound represented by the general formula (III) is reacted with the compound represented by the general formula (IV) or a salt thereof in a solvent in the presence of a condensing agent and a base. To produce the compound represented by the general formula (V).
　本工程において使用される一般式（ＩＶ）で表される化合物の塩は、例えばアルカリ金属塩、有機塩基塩又はアンモニウム塩であり、好適には、ナトリウム塩である。 The salt of the compound represented by the general formula (IV) used in this step is, for example, an alkali metal salt, an organic base salt or an ammonium salt, and preferably a sodium salt.
　本工程において使用される溶媒は、好適には、アミド類、エーテル類、ニトリル類又はハロゲン化炭化水素類であり、より好適には、Ｎ，Ｎ－ジメチルホルムアミドである。 The solvent used in this step is preferably amides, ethers, nitriles or halogenated hydrocarbons, and more preferably N, N-dimethylformamide.
　本工程において使用される縮合剤は、好適には、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩、Ｎ，Ｎ’－ジシクロヘキシルカルボジイミド又は４-（４，６－ジメトキシ－１，３，５-トリアジン－２－イル）－４－メチルモルホリニウムクロリドである。 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.
　本工程において使用される塩基は、好適には、有機塩基類であり、より好適には、Ｎ－メチルモルホリン、トリエチルアミン又はジイソプロピルエチルアミンである。 The base used in this step is preferably an organic base, and more preferably N-methylmorpholine, triethylamine or diisopropylethylamine.
　本工程における反応温度は、通常、０℃乃至６０℃であり、好適には、１０℃乃至３０℃である。 The reaction temperature in this step is usually 0 ° C. to 60 ° C., preferably 10 ° C. to 30 ° C.
　本工程における反応時間は、通常、５分間乃至４８時間であり、好適には、１時間乃至２４時間である。 The reaction time in this step is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours.
　Ａ－ＩＩＩ工程
　本工程は、溶媒中、パラジウム触媒及び塩基の存在下、一般式（Ｖ）で表される化合物を、一般式（ＶＩ）で表される化合物と反応させた後、所望によりＲ３ａ及び／又はＥａにおけるアミノ基、ヒドロキシ基及び／又はカルボキシ基の保護基を除去及び／又はＥａの基に含まれる基を公知の有機化学的手法を用いて変換することにより、一般式（Ｉａ）で表される化合物を製造する工程である。 Step A-III In this step, the compound represented by the general formula (V) is reacted with the compound represented by the general formula (VI) in a solvent in the presence of a palladium catalyst and a base, and then optionally R 3a and / or amino groups in the E a, by conversion using the known organic chemical methods the groups contained in the groups removal and / or E a protecting group for a hydroxy group and / or carboxy group, the general formula This is a process for producing a compound represented by (Ia).
　本工程において使用される溶媒は、好適には、エーテル類又は芳香族炭化水素類であり、より好適には、１，２－ジメトキシエタン又はトルエンである。 The solvent used in this step is preferably an ether or an aromatic hydrocarbon, and more preferably 1,2-dimethoxyethane or toluene.
　本工程において使用されるパラジウム触媒は、好適には、テトラキス（トリフェニルホスフィン）パラジウム（０）、［１，１′－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド　ジクロロロメタン錯体又はＸＰｈｏｓ－Ｐｄ－Ｇ２（ＩＩ）である。 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).
　本工程において使用される塩基は、好適には、アルカリ金属炭酸塩類又はアルカリ金属リン酸塩類であり、より好適には、炭酸ナトリウム、炭酸ナトリウム水溶液、リン酸カリウム又はリン酸カリウム水溶液である。 The base used in this step is preferably alkali metal carbonates or alkali metal phosphates, and more preferably sodium carbonate, sodium carbonate aqueous solution, potassium phosphate or potassium phosphate aqueous solution.
　本工程における反応温度は、通常、室温乃至２００℃であり、好適には、５０℃乃至１２０℃である。 The reaction temperature in this step is usually room temperature to 200 ° C, and preferably 50 ° C to 120 ° C.
　本工程における反応時間は、通常、５分間乃至２４時間であり、好適には、２０分間乃至１５時間である。 The reaction time in this step is usually 5 minutes to 24 hours, preferably 20 minutes to 15 hours.
　本工程は、マイクロウェーブの照射下で行うことができる。 This step can be performed under microwave irradiation.
　Ｂ法は、一般式（Ｉ）で表される化合物の中で、式－Ｕ－Ｔ－で表される基が式－ＣＨ２－ＣＨ２－で表される基である一般式（Ｉａ）で表される化合物を製造する方法である。
（Ｂ法） In the method B, in the compound represented by the general formula (I), the group represented by the formula —UT— is a group represented by the formula —CH 2 —CH 2 —. It is a method of manufacturing the compound represented by these.
(Method B)
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
　Ｂ－Ｉ工程
　本工程は、溶媒中、パラジウム触媒及び塩基の存在下、一般式（Ｖ）で表される化合物を、化合物（ＶＩＩ）と反応させることにより、一般式（ＶＩＩＩ）で表される化合物を製造する工程である。 Step BI This step is represented by the general formula (VIII) by reacting the compound represented by the general formula (V) with the compound (VII) in the presence of a palladium catalyst and a base in a solvent. This is a process for producing a compound.
　本工程は、Ｊ．Ｏｒｇ．Ｃｈｅｍ．１９９５，６０，７５０８に記載されている方法に準じて実施することができる。 This process is described in J. Org. Chem. It can implement according to the method described in 1995,60,7508.
　Ｂ－ＩＩ工程
　本工程は、溶媒中、パラジウム触媒及び塩基の存在下、一般式（ＶＩＩＩ）で表される化合物を、一般式（ＩＸ）で表される化合物と反応させることにより、Ａ法のＡ－ＩＩＩ工程と同様に行った後、所望によりＲ３ａ及び／又はＥａにおけるアミノ基、ヒドロキシ基及び／又はカルボキシ基の保護基を除去及び／又はＥａの基に含まれる基を公知の有機化学的手法を用いて変換することにより、一般式（Ｉａ）で表される化合物を製造する工程である。 Step B-II In this step, the compound represented by the general formula (VIII) is reacted with the compound represented by the general formula (IX) in the presence of a palladium catalyst and a base in a solvent, thereby After carrying out in the same manner as in step A-III, if desired, the amino, hydroxy and / or carboxy-protecting group in R 3a and / or E a is removed and / or a group contained in E a is known This is a step for producing a compound represented by the general formula (Ia) by conversion using an organic chemical method.
　Ｃ法は、一般式（Ｉ）で表される化合物の中で、式－Ｕ－Ｔ－で表される基が式－ＣＨ２－ＣＨ２－で表される基である一般式（Ｉａ）で表される化合物を製造する方法である。
（Ｃ法） In the method C, in the compound represented by the general formula (I), the group represented by the formula —UT— is a group represented by the formula —CH 2 —CH 2 —. It is a method of manufacturing the compound represented by these.
(Method C)
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
　Ｃ－Ｉ工程
　本工程は、溶媒中、パラジウム触媒及び塩基の存在下、一般式（ＩＩ）で表される化合物を、一般式（ＶＩ）で表される化合物と反応させることにより、Ａ法のＡ－ＩＩＩ工程と同様に行われ、一般式（Ｘ）で表される化合物を製造する工程である。 Step CI This step comprises reacting a compound represented by the general formula (II) with a compound represented by the general formula (VI) in a solvent in the presence of a palladium catalyst and a base. This is a process for producing a compound represented by the general formula (X), which is carried out in the same manner as in the process A-III.
　Ｃ－ＩＩ工程
　本工程は、溶媒中、一般式（Ｘ）で表される化合物を、酸と反応させることにより、Ａ法のＡ－Ｉ工程と同様に行われ、一般式（ＸＩ）で表される化合物の塩を製造する工程である。一般式（ＸＩ）で表される化合物の塩は、酸として、塩酸類を使用した場合を示す。 Step C-II This step is carried out in the same manner as Step AI in Method A by reacting a compound represented by the general formula (X) with an acid in a solvent, and is represented by the general formula (XI). A step of producing a salt of the compound to be prepared. The salt of the compound represented by the general formula (XI) indicates a case where hydrochloric acid is used as the acid.
　Ｃ－ＩＩＩ工程
　本工程は、溶媒中、塩基の存在下、一般式（ＸＩ）で表される化合物の塩を、一般式（ＩＶ）で表される化合物又はその塩と反応させることにより、Ａ法のＡ－ＩＩ工程と同様に行うことにより、一般式（Ｉａ）で表される化合物を製造する工程である。 Step C-III This step comprises reacting the salt of the compound represented by the general formula (XI) with the compound represented by the general formula (IV) or a salt thereof in the presence of a base in a solvent. This is a step for producing a compound represented by the general formula (Ia) by carrying out in the same manner as in step A-II of the method.
　Ｃ－Ｉ工程乃至Ｃ－ＩＩＩ工程の間に、所望により、Ｒ３ａ及び／又はＥａにおけるアミノ基、ヒドロキシ基及び／又はカルボキシ基の保護基を除去及び／又はＥａの基に含まれる基を公知の有機化学的手法を用いて変換する。 During the C-I process to C-III step, if desired, groups contained in the amino group, groups of removal and / or E a protecting group for a hydroxy group and / or carboxy group in R 3a and / or E a Is converted using known organic chemistry techniques.
　Ｄ法は、一般式（Ｉ）で表される化合物の中で、式－Ｕ－Ｔ－で表される基が式－ＣＨ＝ＣＨ－で表される基である一般式（Ｉｂ）で表される化合物を製造する方法である。
（Ｄ法） Method D is a compound represented by the general formula (Ib) in which the group represented by the formula -UT is a group represented by the formula -CH = CH- among the compounds represented by the general formula (I). A method for producing a compound to be produced.
(Method D)
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
　Ｄ－Ｉ工程
　本工程は、溶媒中、一般式（Ｉａ）で表される化合物を、酸化剤と反応させることにより、一般式（Ｉｂ）で表される化合物を製造する工程である。 Step DI This step is a step for producing the compound represented by the general formula (Ib) by reacting the compound represented by the general formula (Ia) with an oxidizing agent in a solvent.
　本工程において使用される一般式（Ｉａ）で表される化合物は、Ａ法乃至Ｃ法を用いて製造することができる。 The compound represented by the general formula (Ia) used in this step can be produced using Method A to Method C.
　本工程において使用される溶媒は、好適には、ハロゲン化炭化水素類であり、より好適には、ジクロロメタン又はクロロホルムである。 The solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane or chloroform.
　本工程において使用される酸化剤は、好適には、２，３－ジクロロ－５，６－ジシアノ－ｐ－ベンゾキノンである。 The oxidizing agent used in this step is preferably 2,3-dichloro-5,6-dicyano-p-benzoquinone.
　本工程における反応温度は、室温乃至加熱還流温度であり、加熱還流温度は、溶媒によって異なる。通常、５℃乃至１５０℃であり、好適には、１０℃乃至７０℃である。 The reaction temperature in this step is from 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.
　本工程における反応時間は、通常、３０分間乃至７２時間であり、好適には、１時間乃至２４時間である。 The reaction time in this step is usually 30 minutes to 72 hours, preferably 1 hour to 24 hours.
　Ｅ法は、Ａ法のＡ－Ｉ工程及びＣ法のＣ－Ｉ工程で用いる一般式（ＩＩ）で表される化合物の中で、Ｙがメチレン基である一般式（ＸＶＩ）で表される化合物を製造する方法である。
（Ｅ法） The method E is represented by the general formula (XVI) in which Y is a methylene group among the compounds represented by the general formula (II) used in the AI step of the method A and the CI step of the method C. A method for producing a compound.
(E method)
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
　Ｅ－Ｉ工程
　本工程は、溶媒中、塩基の存在下、一般式（ＸＩＩ）で表される化合物を、トリフルオロメタンスルホニル化剤と反応させることにより、一般式（ＸＩＩＩ）で表される化合物を製造する工程である。 Step EI In this step, a compound represented by the general formula (XIII) 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.
　本工程において使用される溶媒は、好適には、ハロゲン化炭化水素類であり、より好適には、ジクロロメタンである。 The solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
　本工程において使用される塩基は、好適には、有機塩基類であり、より好適には、ピリジンである。 The base used in this step is preferably an organic base, and more preferably pyridine.
　本工程において使用されるトリフルオロメタンスルホニル化剤は、好適には、トリフルオロメタンスルホニル化合物であり、より好適には、トリフルオロメタンスルホン酸無水物である。 The trifluoromethanesulfonylating agent used in this step is preferably a trifluoromethanesulfonyl compound, and more preferably trifluoromethanesulfonic anhydride.
　本工程における反応温度は、通常、－２０℃乃至５０℃であり、好適には、０℃乃至２０℃である。 The reaction temperature in this step is usually −20 ° C. to 50 ° C., preferably 0 ° C. to 20 ° C.
　本工程における反応時間は、通常、１分間乃至２４時間であり、好適には、１０分間乃至６時間である。 The reaction time in this step is usually 1 minute to 24 hours, preferably 10 minutes to 6 hours.
　Ｅ－ＩＩ工程
　本工程は、溶媒中、パラジウム触媒及び塩基の存在下、一般式（ＸＩＩＩ）で表される化合物を、化合物（ＶＩＩ）と反応させることにより、Ｂ法のＢ－Ｉ工程と同様に行われ、一般式（ＸＩＶ）で表される化合物を製造する工程である。 Step E-II This step is the same as Step BI in Method B by reacting the compound represented by general formula (XIII) with compound (VII) 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 (XIV).
　本工程において使用される溶媒は、好適には、アミド類、エーテル類、スルホキシド類又はこれらの混合溶媒であり、より好適には、ジメトキシエタンとジメチルスルホキシドの混合溶媒である。 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.
　Ｅ－ＩＩＩ工程
　本工程は、溶媒中、パラジウム触媒及び塩基の存在下、一般式（ＸＩＶ）で表される化合物を、一般式（ＸＶ）で表される化合物と反応させることにより、Ａ法のＡ－ＩＩＩ工程と同様に行われ、一般式（ＸＶＩ）で表される化合物を製造する工程である。 Step E-III This step comprises reacting a compound represented by general formula (XIV) with a compound represented by general formula (XV) in a solvent in the presence of a palladium catalyst and a base, This is a step for producing a compound represented by the general formula (XVI), which is carried out in the same manner as in step A-III.
　Ｆ法は、Ａ法のＡ－Ｉ工程及びＣ法のＣ－Ｉ工程で用いる一般式（ＩＩ）で表される化合物の中で、Ｙが酸素原子である一般式（ＸＶＩＩＩ）で表される化合物を製造する方法である。
（Ｆ法） Method F is represented by the general formula (XVIII) in which Y is an oxygen atom among the compounds represented by the general formula (II) used in the AI step of Method A and the CI step of Method C. A method for producing a compound.
(F method)
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
　Ｆ－Ｉ工程
　本工程は、溶媒中、銅触媒、助触媒及び塩基の存在下、一般式（ＸＩＩ）で表される化合物を、一般式（ＸＶＩＩ）で表される化合物と反応させることにより、一般式（ＸＶＩＩＩ）で表される化合物を製造する工程である。 Step FI This step comprises reacting a compound represented by the general formula (XII) with a compound represented by the general formula (XVII) in the presence of a copper catalyst, a promoter and a base in a solvent. In this step, a compound represented by the general formula (XVIII) is produced.
　本工程において使用される溶媒は、好適には、アミド類又はエーテル類であり、より好適には、Ｎ，Ｎ－ジメチルホルムアミド又は１，４－ジオキサンである。 The solvent used in this step is preferably an amide or an ether, and more preferably N, N-dimethylformamide or 1,4-dioxane.
　本工程において使用される銅触媒は、好適には、ヨウ化銅（Ｉ）である。 The copper catalyst used in this step is preferably copper (I) iodide.
　本工程において使用される助触媒は、好適には、Ｎ，Ｎ－ジメチルグリシンである。 The cocatalyst used in this step is preferably N, N-dimethylglycine.
　本工程において使用される塩基は、好適には、アルカリ金属炭酸塩類であり、より好適には、炭酸セシウムである。 The base used in this step is preferably an alkali metal carbonate, and more preferably cesium carbonate.
　本工程における反応温度は、通常、５０℃乃至１５０℃であり、好適には、８０℃乃至１１０℃である。 The reaction temperature in this step is usually 50 ° C. to 150 ° C., preferably 80 ° C. to 110 ° C.
　本工程における反応時間は、通常、３時間乃至７２時間であり、好適には、１２時間乃至４８時間である。 The reaction time in this step is usually 3 hours to 72 hours, preferably 12 hours to 48 hours.
　また、本工程は、溶媒中、塩基の存在下、一般式（ＸＩＩ）で表される化合物を、一般式（ＸＶＩＩ）で表される化合物と反応させることにより、一般式（ＸＶＩＩＩ）で表される化合物を製造する工程である。 Further, this step is represented by the general formula (XVIII) by reacting the compound represented by the general formula (XII) with a compound represented by the general formula (XVII) in the presence of a base in a solvent. This is a process for producing a compound.
　本工程において使用される溶媒は、好適には、アミド類又はエーテル類であり、より好適には、Ｎ，Ｎ－ジメチルホルムアミド又は１，４－ジオキサンである。 The solvent used in this step is preferably an amide or an ether, and more preferably N, N-dimethylformamide or 1,4-dioxane.
　本工程において使用される塩基は、好適には、アルカリ金属炭酸塩類であり、より好適には、炭酸セシウムである。 The base used in this step is preferably an alkali metal carbonate, and more preferably cesium carbonate.
　本工程における反応温度は、通常、５０℃乃至２００℃であり、好適には、８０℃乃至１６０℃である。 The reaction temperature in this step is usually 50 ° C to 200 ° C, preferably 80 ° C to 160 ° C.
　本工程における反応時間は、通常、３時間乃至７２時間であり、好適には、１２時間乃至４８時間である。 The reaction time in this step is usually 3 hours to 72 hours, preferably 12 hours to 48 hours.
　本工程はマイクロウェーブ照射下で行うことができる。その際の反応時間は、通常、１０分間乃至３時間であり、好適には、１５分間乃至９０分間である。 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.
　Ｇ法は、Ｃ法のＣ－ＩＩ工程で用いる一般式（Ｘ）で表される化合物の中で、Ｙが酸素原子である一般式（ＸＸＩ）で表される化合物を製造する方法である。
（Ｇ法） Method G is a method for producing a compound represented by the general formula (XXI) in which Y is an oxygen atom among the compounds represented by the general formula (X) used in the C-II step of Method C.
(G method)
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
　Ｇ－Ｉ工程
　本工程は、溶媒中、パラジウム触媒及び塩基の存在下、一般式（ＶＩ）で表される化合物を、一般式（ＸＩＸ）で表される化合物と反応させることにより、Ａ法のＡ－ＩＩＩ工程と同様に行われ、一般式（ＸＸ）で表される化合物を製造する工程である。 Step GI This step involves reacting a compound represented by the general formula (VI) with a compound represented by the general formula (XIX) 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 A-III, and is a step for producing a compound represented by the general formula (XX).
　Ｇ－ＩＩ工程
　本工程は、溶媒中、銅触媒、助触媒及び塩基の存在下、一般式（ＸＸ）で表される化合物を、一般式（ＸＩＩ）で表される化合物と反応させることにより、Ｆ法のＦ－Ｉ工程と同様に行われ、一般式（ＸＸＩ）で表される化合物を製造する工程である。 Step G-II In this step, the compound represented by the general formula (XX) is reacted with the compound represented by the general formula (XII) 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 (XXI), which is carried out in the same manner as in the FI process of Method F.
　また、本工程は、溶媒中、塩基の存在下、一般式（ＸＸ）で表される化合物を、一般式（ＸＩＩ）で表される化合物と反応させることにより、Ｆ法のＦ－Ｉ工程と同様に行われ、一般式（ＸＸＩ）で表される化合物を製造する工程である。 In addition, in this step, the compound represented by the general formula (XX) is reacted with the compound represented by the general formula (XII) in the presence of a base in a solvent, whereby This is the same step for producing a compound represented by the general formula (XXI).
　Ｈ法は、Ａ法のＡ－ＩＩ工程及びＣ法のＣ－ＩＩＩ工程で用いる一般式（ＩＶ）で表される化合物又はその塩を製造する方法である。ただし、Ｑ１が窒素原子の場合、Ｑ２は式＝ＣＨ－で表される基である。
（Ｈ法） Method H is a method for producing a compound represented by the general formula (IV) or a salt thereof used in Step A-II of Method A and Step C-III of Method C. However, when Q 1 is a nitrogen atom, Q 2 is a group represented by the formula = CH-.
(Method H)
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
　Ｈ－Ｉ工程
　本工程は、溶媒中、銅触媒と塩基の存在下、一般式（ＸＸＩＩ）で表される化合物を、一般式（ＸＸＩＩＩ）で表される化合物と反応させることにより、一般式（ＸＸＩＶ）で表される化合物を製造する工程である。 Step HI In this step, the compound represented by the general formula (XXII) is reacted with the compound represented by the general formula (XXIII) in the presence of a copper catalyst and a base in a solvent, thereby reacting the compound represented by the general formula (XXIII). XXIV) is a step of producing a compound represented by
　本工程において使用される溶媒は、好適には、アミド類又はスルホキシド類であり、より好適には、Ｎ，Ｎ－ジメチルホルムアミド又はジメチルスルホキシドである。 The solvent used in this step is preferably an amide or sulfoxide, and more preferably N, N-dimethylformamide or dimethyl sulfoxide.
　本工程において使用される銅触媒は、好適には、ヨウ化銅（Ｉ）である。 The copper catalyst used in this step is preferably copper (I) iodide.
　本工程において使用される塩基は、好適にはＬ－プロリンのアルカリ金属塩類であり、より好適には、Ｌ－プロリンナトリウムである。 The base used in this step is preferably an alkali metal salt of L-proline, and more preferably sodium L-proline.
　本工程における反応温度は、通常、５０℃乃至１５０℃であり、好適には、７０℃乃至１１０℃である。 The reaction temperature in this step is usually 50 ° C. to 150 ° C., preferably 70 ° C. to 110 ° C.
　本工程における反応時間は、通常、１０分間乃至４８時間であり、好適には、３０分間乃至１２時間である。 The reaction time in this step is usually 10 minutes to 48 hours, preferably 30 minutes to 12 hours.
　Ｈ－ＩＩ工程
　本工程は、溶媒中、一般式（ＸＸＩＶ）で表される化合物を、塩基と反応させることにより、一般式（ＩＶ）で表される化合物を製造する工程である。 Step H-II This step is a step for producing a compound represented by the general formula (IV) by reacting a compound represented by the general formula (XXIV) with a base in a solvent.
　本工程において使用される溶媒は、好適には、エーテル類、アルコール類又はこれらの混合溶媒であり、より好適には、テトラヒドロフランとメタノールの混合溶媒又はテトラヒドロフランとエタノールの混合溶媒である。 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.
　本工程において使用される塩基は、好適には、アルカリ金属水酸化物であり、より好適には、水酸化ナトリウム又は水酸化リチウム水溶液である。 The base used in this step is preferably an alkali metal hydroxide, and more preferably sodium hydroxide or a lithium hydroxide aqueous solution.
　本工程における反応温度は、通常、０℃乃至８０℃であり、好適には、１５℃乃至４５℃である。 The reaction temperature in this step is usually 0 ° C. to 80 ° C., preferably 15 ° C. to 45 ° C.
　本工程における反応時間は、通常、５分間乃至４８時間であり、好適には、１０分間乃至２４時間である。 The reaction time in this step is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
　一般式（ＩＶ）で表される化合物の塩は、反応終了後、塩基性の反応混合物から採取される。採取される塩は、反応に使用される塩基によって異なる。 The salt of the compound represented by the general formula (IV) is collected from the basic reaction mixture after completion of the reaction. The salt collected depends on the base used in the reaction.
　Ｉ法は、Ａ法のＡ－ＩＩ工程及びＣ法のＣ－ＩＩＩ工程で用いる一般式（ＩＶ）で表される化合物又はその塩の中で、Ｑ１が式＝ＣＨ－で表される基であり、Ｑ２が窒素原子であり、Ｒ３ａが水素原子である一般式（ＸＸＩＸ）で表される化合物又はその塩を製造する方法である。
（Ｉ法） Method I is a compound represented by the general formula (IV) or a salt thereof used in Step A-II of Method A and Step C-III of Method C, or a group in which Q 1 is represented by the formula = CH- And Q 2 is a nitrogen atom, and R 3a is a hydrogen atom, or a method for producing a compound represented by the general formula (XXIX) or a salt thereof.
(Method I)
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
　Ｉ－Ｉ工程
　本工程は、溶媒中、塩基の存在下、一般式（ＸＸＶ）で表される化合物を、一般式（ＸＸＶＩ）で表される化合物と反応させることにより、一般式（ＸＸＶＩＩ）で表される化合物を製造する工程である。 Step II In this step, a compound represented by the general formula (XXV) is reacted with a compound represented by the general formula (XXVI) in the presence of a base in a solvent to give a compound represented by the general formula (XXVII). It is a process for producing the represented compound.
　本工程において使用される溶媒は、好適には、アミド類又はスルホキシド類であり、より好適には、ジメチルスルホキシドである。 The solvent used in this step is preferably an amide or sulfoxide, and more preferably dimethyl sulfoxide.
　本工程において使用される塩基は、好適には、無機塩基類であり、より好適には、アルカリ金属炭酸塩類であり、更により好適には、炭酸セシウムである。 The base used in this step is preferably an inorganic base, more preferably an alkali metal carbonate, and even more preferably cesium carbonate.
　本工程における反応温度は、通常、３０℃乃至２００℃であり、好適には、８０℃乃至１２０℃である。 The reaction temperature in this step is usually 30 ° C. to 200 ° C., preferably 80 ° C. to 120 ° C.
　本工程における反応時間は、通常、１時間乃至２４時間であり、好適には、５時間乃至１０時間である。 The reaction time in this step is usually 1 hour to 24 hours, preferably 5 hours to 10 hours.
　Ｉ－ＩＩ工程
　本工程は、溶媒中、銅触媒と塩基の存在下、一般式（ＸＸＶＩＩ）で表される化合物を、一般式（ＸＸＩＩＩ）で表される化合物と反応させることにより、Ｈ法のＨ－Ｉ工程と同様に行われ、一般式（ＸＸＶＩＩＩ）で表される化合物を製造する工程である。 Step I-II This step comprises reacting a compound represented by the general formula (XXVII) with a compound represented by the general formula (XXIII) 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 (XXVIII), which is carried out in the same manner as in the HI process.
　Ｉ－ＩＩＩ工程
　本工程は、溶媒中、一般式（ＸＸＶＩＩＩ）で表される化合物を、塩基と反応させることにより、Ｈ法のＨ－ＩＩ工程と同様に行われ、一般式（ＸＸＩＸ）で表される化合物又はその塩を製造する工程である。 Step I-III This step is performed in the same manner as in Step H-II of Method H by reacting a compound represented by the general formula (XXVIII) with a base in a solvent, and represented by the general formula (XXIX). The process of manufacturing the compound or its salt.
　一般式（ＸＸＩＸ）で表される化合物の塩は、反応終了後、塩基性の反応混合物から採取される。採取される塩は、反応に使用される塩基によって異なる。 The salt of the compound represented by the general formula (XXIX) is collected from the basic reaction mixture after completion of the reaction. The salt collected depends on the base used in the reaction.
　また、Ｒ８がベンジル基の場合、本工程は、溶媒中、パラジウム触媒の存在下、一般式（ＸＸＶＩＩＩ）で表される化合物を、水素雰囲気下反応させることにより、一般式（ＸＸＩＸ）で表される化合物を製造する工程である。 In the case where R 8 is a benzyl group, this step is carried out by reacting a compound represented by the general formula (XXVIII) in a solvent in the presence of a palladium catalyst in a hydrogen atmosphere to represent the general formula (XXIX). This is a process for producing a compound to be produced.
　本工程において使用される溶媒は、好適には、エーテル類、アルコール類、エステル類又はこれらの混合溶媒であり、より好適には、テトラヒドロフラン、メタノール、エタノール、酢酸エチル又はこれらの混合溶媒である。 The solvent used in this step is preferably an ether, alcohol, ester or a mixed solvent thereof, more preferably tetrahydrofuran, methanol, ethanol, ethyl acetate or a mixed solvent thereof.
　本工程において使用されるパラジウム触媒は、好適には、パラジウム－炭素である。 The palladium catalyst used in this step is preferably palladium-carbon.
　本工程における反応温度は、通常、０℃乃至８０℃であり、好適には、室温乃至５０℃である。 The reaction temperature in this step is usually 0 ° C. to 80 ° C., preferably room temperature to 50 ° C.
　本工程における反応時間は、通常、１０分間乃至６０時間であり、好適には、1時間乃至２４時間である。 The reaction time in this step is usually 10 minutes to 60 hours, preferably 1 hour to 24 hours.
　また、２箇所のＲ８のうちの一方がｔｅｒｔ－ブチル基の場合、本工程は、溶媒中、一般式（ＸＸＶＩＩＩ）で表される化合物を、酸と反応させた後、溶媒中、塩基と反応させることにより、Ｈ法のＨ－ＩＩ工程と同様に行われ、一般式（ＸＸＩＸ）で表される化合物又はその塩を製造する工程である。 When one of the two R 8 groups is a tert-butyl group, this step involves reacting a compound represented by the general formula (XXVIII) with an acid in a solvent, and then reacting with a base in the solvent. This reaction is a step for producing a compound represented by the general formula (XXIX) or a salt thereof, which is carried out in the same manner as in the H-II step of Method H.
　本工程において使用される溶媒は、好適には、ハロゲン化炭化水素類であり、より好適には、ジクロロメタンである。 The solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
　本工程において使用される酸は、好適には、トリフルオロ酢酸である。 The acid used in this step is preferably trifluoroacetic acid.
　本工程における反応温度は、通常、－１０℃乃至１００℃であり、好適には、０℃乃至３０℃である。 The reaction temperature in this step is usually −10 ° C. to 100 ° C., preferably 0 ° C. to 30 ° C.
　本工程における反応時間は、通常、１分間乃至２４時間であり、好適には、１時間乃至８時間である。 The reaction time in this step is usually 1 minute to 24 hours, preferably 1 hour to 8 hours.
　Ｊ法は、Ｉ法のＩ－ＩＩＩ工程で用いる一般式（ＸＸＶＩＩＩ）で表される化合物を製造する方法である。
（Ｊ法） Method J is a method for producing a compound represented by the general formula (XXVIII) used in Step I-III of Method I.
(J method)
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
　Ｊ－Ｉ工程
　本工程は、溶媒中、塩基、銅触媒及び助触媒の存在下、一般式（ＸＸＸ）で表される化合物を、一般式（ＸＸＶＩ）で表される化合物と反応させることにより、一般式（ＸＸＶＩＩＩ）で表される化合物を製造する工程である。 Step JI In this step, a compound represented by the general formula (XXX) is reacted with a compound represented by the general formula (XXVI) 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 (XXVIII) is produced.
　本工程において使用される溶媒は、好適には、アミド類、エーテル類又はスルホキシド類であり、より好適には、１，４－ジオキサンである。 The solvent used in this step is preferably an amide, an ether or a sulfoxide, and more preferably 1,4-dioxane.
　本工程において使用される塩基は、好適には、無機塩基類であり、より好適には、アルカリ金属炭酸塩類であり、更により好適には、炭酸セシウムである。 The base used in this step is preferably an inorganic base, more preferably an alkali metal carbonate, and even more preferably cesium carbonate.
　本工程において使用される銅触媒は、好適には、ヨウ化銅（Ｉ）又は塩化銅（Ｉ）である。 The copper catalyst used in this step is preferably copper (I) iodide or copper (I) chloride.
　本工程において使用される助触媒は、好適には、ピコリン酸である。 The cocatalyst used in this step is preferably picolinic acid.
　本工程における反応温度は、通常、３０℃乃至２００℃であり、好適には、８０℃乃至１２０℃である。 The reaction temperature in this step is usually 30 ° C. to 200 ° C., preferably 80 ° C. to 120 ° C.
　本工程における反応時間は、通常、１時間乃至２４時間であり、好適には、５時間乃至１２時間である。 The reaction time in this step is usually 1 hour to 24 hours, preferably 5 hours to 12 hours.
　Ｋ法は、Ａ法のＡ－ＩＩ工程及びＣ法のＣ－ＩＩＩ工程で用いる一般式（ＩＶ）で表される化合物の中で、Ｑ１が式＝ＣＨ－で表される基であり、Ｑ２が式＝ＣＨ－で表される基である一般式（ＸＸＸＩＩ）で表される化合物を製造する方法である。
（Ｋ法） Method K is a group represented by general formula (IV) used in Step A-II of Method A and Step C-III of Method C, wherein Q 1 is represented by the formula = CH- This is a method for producing a compound represented by the general formula (XXXII), wherein Q 2 is a group represented by the formula = CH-.
(K method)
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
　Ｋ－Ｉ工程
　本工程は、溶媒中、銅触媒と塩基の存在下、一般式（ＸＸＸＩ）で表される化合物を、一般式（ＸＸＩＩＩ）で表される化合物と反応させることにより、一般式（ＸＸＸＩＩ）で表される化合物を製造する工程である。 Step KI This step comprises reacting a compound represented by the general formula (XXXI) with a compound represented by the general formula (XXIII) in a solvent in the presence of a copper catalyst and a base, XXXII) is a process for producing a compound represented by
　本工程において使用される溶媒は、好適には、アミド類又はスルホキシド類であり、より好適には、Ｎ，Ｎ－ジメチルホルムアミド又はジメチルスルホキシドである。 The solvent used in this step is preferably an amide or sulfoxide, and more preferably N, N-dimethylformamide or dimethyl sulfoxide.
　本工程において使用される銅触媒は、好適には、ヨウ化銅（Ｉ）である。 The copper catalyst used in this step is preferably copper (I) iodide.
　本工程において使用される塩基は、好適にはアルカリ金属水酸化物であり、より好適には、水酸化ナトリウム又は水酸化ナトリウム水溶液である。 The base used in this step is preferably an alkali metal hydroxide, and more preferably sodium hydroxide or an aqueous sodium hydroxide solution.
　本工程における反応温度は、通常、５０℃乃至１５０℃であり、好適には、７０℃乃至１１０℃である。 The reaction temperature in this step is usually 50 ° C. to 150 ° C., preferably 70 ° C. to 110 ° C.
　本工程における反応時間は、通常、１０分間乃至４８時間であり、好適には、３０分間乃至１２時間である。 The reaction time in this step is usually 10 minutes to 48 hours, preferably 30 minutes to 12 hours.
　一般式（ＩＩ）、（ＩＶ）、（ＶＩ）、（ＩＸ）、（ＸＩＩ）、（ＸＶ）、（ＸＶＩＩ）、（ＸＩＸ）、（ＸＸＩＩ）、（ＸＸＩＩＩ）、（ＸＸＶ）、（ＸＸＶＩ）、（ＸＸＸ）及び（ＸＸＸＩ）で表される化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。 Formulas (II), (IV), (VI), (IX), (XII), (XV), (XVII), (XIX), (XXII), (XXIII), (XXV), (XXVI), The compounds represented by (XXX) and (XXXI) 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.
　上記において、Ｒ３ａ及びＥａの定義における「保護されてもよいアミノ基、ヒドロキシ基及び／又はカルボキシ基」の保護基とは、加水素分解、加水分解、電気分解、光分解のような化学的方法により開裂し得る保護基をいい、有機合成化学で一般的に用いられる保護基を示す（例えば、T. W. Greeneら，Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. （1999年）参照）。 In the above, the protecting group of “amino group, hydroxy group and / or carboxy group which may be protected” in the definition of R 3a and E a is a chemistry such as hydrogenolysis, hydrolysis, electrolysis and photolysis. This refers to protecting groups that can be cleaved by synthetic methods, and refers to protecting groups commonly used in organic synthetic chemistry (eg, TW Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999 )reference).
　上記において、保護されてもよいヒドロキシ基の「保護基」は、有機合成化学の分野で使用されるヒドロキシ基の保護基であれば特に限定はされないが、例えば、ホルミル基、前記「Ｃ２－Ｃ７アルキルカルボニル基」、２，２，２－トリクロロエチルカルボニルのようなＣ２－Ｃ７ハロゲン化アルキルカルボニル基、メトキシアセチルのようなアルコキシアルキルカルボニル基、アクリロイル、プロピオロイル、メタクリロイル、クロトノイル、イソクロトノイル、（Ｅ）－２－メチル－２－ブテノイルのような不飽和アルキルカルボニル基等の「アルキルカルボニル基」；ベンゾイル、α－ナフトイル、β－ナフトイルのようなアリールカルボニル基、２－ブロモベンゾイル、４－クロロベンゾイルのようなハロゲン化アリールカルボニル基、２，４，６－トリメチルベンゾイル、４－トルオイルのようなＣ１－Ｃ６アルキル化アリールカルボニル基、４－アニソイルのようなＣ１－Ｃ６アルコキシ化アリールカルボニル基、４－ニトロベンゾイル、２－ニトロベンゾイルのようなニトロ化アリールカルボニル基、２－（メトキシカルボニル）ベンゾイルのようなＣ２－Ｃ７アルコキシカルボニル化アリールカルボニル基、４－フェニルベンゾイルのようなアリール化アリールカルボニル基等の「アリールカルボニル基」；メトキシカルボニル、エトキシカルボニルのようなＣ２－Ｃ７アルコキシカルボニル基、２，２，２－トリクロロエトキシカルボニル、２－トリメチルシリルエトキシカルボニルのようなハロゲン又はトリ－（Ｃ１－Ｃ６アルキル）シリル基で置換されたＣ２－Ｃ７アルコキシカルボニル基等の「アルコキシカルボニル基」；テトラヒドロピラン－２－イル、３－ブロモテトラヒドロピラン－２－イル、４－メトキシテトラヒドロピラン－４－イル、テトラヒドロチオピラン－２－イル、４－メトキシテトラヒドロチオピラン－４－イルのような「テトラヒドロピラニル又はテトラヒドロチオピラニル基」；テトラヒドロフラン－２－イル、テトラヒドロチオフラン－２－イルのような「テトラヒドロフラニル又はテトラヒドロチオフラニル基」；トリメチルシリル、トリエチルシリル、イソプロピルジメチルシリル、ｔ－ブチルジメチルシリル、メチルジイソプロピルシリル、メチルジ－ｔ－ブチルシリル、トリイソプロピルシリルのようなトリ－（Ｃ１－Ｃ６アルキル）シリル基、ジフェニルメチルシリル、ジフェニルブチルシリル、ジフェニルイソプロピルシリル、フェニルジイソプロピルシリルのような（Ｃ１－Ｃ６アルキル）ジアリールシリル又はジ－（Ｃ１－Ｃ６アルキル）アリールシリル基等の「シリル基」；メトキシメチル、１，１－ジメチル－１－メトキシメチル、エトキシメチル、プロポキシメチル、イソプロポキシメチル、ブトキシメチル、ｔ－ブトキシメチルのような（Ｃ１－Ｃ６アルコキシ）メチル基、２－メトキシエトキシメチルのような（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルコキシ）メチル基、２，２，２－トリクロロエトキシメチル、ビス（２－クロロエトキシ）メチルのような（Ｃ１－Ｃ６ハロゲン化アルコキシ）メチル等の「アルコキシメチル基」；１－エトキシエチル、１－（イソプロポキシ）エチルのような（Ｃ１－Ｃ６アルコキシ）エチル基、２，２，２－トリクロロエチルのようなハロゲン化エチル基等の「置換エチル基」；ベンジル、α－ナフチルメチル、β－ナフチルメチル、ジフェニルメチル、トリフェニルメチル、α－ナフチルジフェニルメチル、９－アンスリルメチルのような１乃至３個のアリール基で置換されたＣ１－Ｃ６アルキル基、４－メチルベンジル、２，４，６－トリメチルベンジル、３，４，５－トリメチルベンジル、４－メトキシベンジル、４－メトキシフェニルジフェニルメチル、２－ニトロベンジル、４－ニトロベンジル、４－クロロベンジル、４－ブロモベンジル、４－シアノベンジルのようなＣ１－Ｃ６アルキル、Ｃ１－Ｃ６アルコキシ、ニトロ、ハロゲン、シアノ基でアリール環が置換された１乃至３個のアリール基で置換されたＣ１－Ｃ６アルキル基等の「アラルキル基」；ビニルオキシカルボニル、アリルオキシカルボニルのような「アルケニルオキシカルボニル基」；ベンジルオキシカルボニル、４－メトキシベンジルオキシカルボニル、３，４－ジメトキシベンジルオキシカルボニル、２－ニトロベンジルオキシカルボニル、４－ニトロベンジルオキシカルボニルのような、１又は２個のＣ１－Ｃ６アルコキシ又はニトロ基でアリール環が置換されていてもよい「アラルキルオキシカルボニル基」であり、好適には、アルキルカルボニル基、シリル基又はアラルキル基である。 In the above, the “protecting group” of the hydroxy group which 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, but for example, a 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 Nyl group, 2,4,6-trimethylbenzoyl, C 1 -C 6 alkylated arylcarbonyl group such as 4-toluoyl, C 1 -C 6 alkoxylated arylcarbonyl group such as 4-anisoyl, 4-nitrobenzoyl Nitrated arylcarbonyl groups such as 2-nitrobenzoyl, C 2 -C 7 alkoxycarbonylated arylcarbonyl groups such as 2- (methoxycarbonyl) benzoyl, arylated arylcarbonyl groups such as 4-phenylbenzoyl, etc. “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, ethyl halide 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 "; one or two C 1 -C 6 such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl 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.
　上記において、保護されてもよいカルボキシ基の「保護基」は、有機合成化学の分野で使用されるカルボキシ基の保護基であれば特に限定はされないが、例えば、前記「Ｃ１－Ｃ６アルキル基」；ビニル、アリルのようなＣ２－Ｃ６アルケニル基；エチニル、１－プロピニル、２－プロピニル、１－メチル－２－プロピニル、１－ブチニルのようなＣ２－Ｃ６アルキニル基；前記「Ｃ１－Ｃ６ハロゲン化アルキル基」；前記「Ｃ１－Ｃ６ヒドロキシアルキル基」；アセチルメチルのような（Ｃ２－Ｃ７アルキルカルボニル）－（Ｃ１－Ｃ６アルキル）基；前記「アラルキル基」；又は前記「シリル基」であり、好適には、Ｃ１－Ｃ６アルキル基又はアラルキル基である。 In the above, the “protecting group” of the carboxy group that 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, but for example, the above “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; “Aralkyl group”; or the above-mentioned “silyl group”, preferably a C 1 -C 6 alkyl group or an aralkyl group.
　上記において、保護されてもよいアミノ基の「保護基」は、有機合成化学の分野で使用されるアミノ基の保護基であれば特に限定はされないが、例えば、前記「ヒドロキシ基の保護基」における、「アルキルカルボニル基」；「アリールカルボニル基」；「アルコキシカルボニル基」；「シリル基」；「アラルキル基」；「アルケニルオキシカルボニル基」；又は「アラルキルオキシカルボニル基」と同様な基を示すか或いはＮ，Ｎ－ジメチルアミノメチレン、ベンジリデン、４－メトキシベンジリデン、４－ニトロベンジリデン、サリシリデン、５－クロロサリシリデン、ジフェニルメチレン、（５－クロロ－２－ヒドロキシフェニル）フェニルメチレンのような「シッフ塩基を形成する置換されたメチレン基」であり、好適には、アルキルカルボニル基、アリールカルボニル基又はアルコキシカルボニル基であり、より好適には、アルコキシカルボニル基である。 In the above, the “protecting group” of the amino group that may be protected is not particularly limited as long as it is an amino group protecting group used in the field of synthetic organic chemistry. “Alkylcarbonyl group”; “arylcarbonyl group”; “alkoxycarbonyl group”; “silyl group”; “aralkyl group”; “alkenyloxycarbonyl group”; or “aralkyloxycarbonyl group” Or “N, N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene, 5-chlorosalicylidene, diphenylmethylene, (5-chloro-2-hydroxyphenyl) phenylmethylene, etc. A substituted methylene group that forms a Schiff base, preferably an Le carbonyl group, an arylcarbonyl group or an alkoxycarbonyl group, more preferably an alkoxycarbonyl group.
　保護・脱保護が必要な工程は、既知の方法（例えば、”Protective Groups in Organic Synthesis” (Theodora W. Greene、Peter G. M.Wuts著、 1999年、Wiley-Interscience Publication発行)等に記載の方法）に準じて行われる。 Processes that require protection / deprotection are described in known methods (for example, “Protective Groups in Organic Synthesis” (written by Theodora W. Greene, Peter G. M.Wuts, 1999, published by Wiley-Interscience Publication)). Method).
　本発明の化合物又はその薬学上許容される塩は、種々の形態で投与することができる。その投与形態としては、例えば、錠剤、カプセル剤、顆粒剤、乳剤、丸剤、散剤、シロップ剤（液剤）等による経口投与、または注射剤（静脈内、筋肉内、皮下または腹腔内投与）、点滴剤、坐剤（直腸投与）、外用剤（経皮投与）等による非経口投与を挙げることができる。これらの各種製剤は、常法に従って主薬に賦形剤、結合剤、崩壊剤、滑沢剤、矯味矯臭剤、溶解補助剤、懸濁剤、コーティング剤、溶媒、基剤等の医薬の製剤技術分野において通常使用し得る補助剤を用いて製剤化することができる。 The compound of the present invention or a pharmaceutically 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 drops, suppositories (rectal administration), and external preparations (transdermal administration). These various preparations are pharmaceutical preparation techniques such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, solvents, bases, etc. It can be formulated using adjuvants that can usually be used in the field.
　錠剤として使用する場合、担体として、例えば、乳糖、白糖、塩化ナトリウム、グルコース、尿素、デンプン、炭酸カルシウム、カオリン、結晶セルロース、ケイ酸等の賦形剤；水、エタノール、プロパノール、単シロップ、グルコース液、デンプン液、ゼラチン溶液、カルボキシメチルセルロース、セラック、メチルセルロース、リン酸カリウム、ポリビニルピロリドン等の結合剤；乾燥デンプン、アルギン酸ナトリウム、寒天末、ラミナラン末、炭酸水素ナトリウム、炭酸カルシウム、ポリオキシエチレンソルビタン脂肪酸エステル、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、デンプン、乳糖等の崩壊剤；白糖、ステアリン、カカオバター、水素添加油等の崩壊抑制剤；第４級アンモニウム塩類、ラウリル硫酸ナトリウム等の吸収促進剤；グリセリン、デンプン等の保湿剤；デンプン、乳糖、カオリン、ベントナイト、コロイド状ケイ酸等の吸着剤；精製タルク、ステアリン酸塩、硼酸末、ポリエチレングリコール等の潤沢剤等を使用することができる。また、必要に応じ通常の剤皮を施した錠剤、例えば糖衣錠、ゼラチン被包錠、腸溶被錠、フィルムコーティング錠あるいは二重錠、多層錠とすることができる。 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, monoglyceride stearate, 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; Use of lubricants such as purified talc, stearate, boric acid powder and polyethylene glycol can do. Moreover, it can be set as the tablet which gave the normal coating as needed, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, and a multilayer tablet.
　丸剤として使用する場合、担体として、例えば、グルコース、乳糖、カカオバター、デンプン、硬化植物油、カオリン、タルク等の賦形剤；アラビアゴム末、トラガント末、ゼラチン、エタノール等の結合剤；ラミナラン、寒天等の崩壊剤等を使用することができる。 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.
　坐剤として使用する場合、担体としてこの分野で従来公知のものを広く使用でき、例えばポリエチレングリコール、カカオバター、高級アルコール、高級アルコールのエステル類、ゼラチン、半合成グリセリド等を挙げることができる。 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.
　注射剤として使用する場合、液剤、乳剤または懸濁剤として使用することができる。これらの液剤、乳剤または懸濁剤は、殺菌され、血液と等張であることが好ましい。これら液剤、乳剤または懸濁剤の製造に用いる溶媒は、医療用の希釈剤として使用できるものであれば特に限定はなく、例えば、水、エタノール、プロピレングリコール、エトキシ化イソステアリルアルコール、ポリオキシ化イソステアリルアルコール、ポリオキシエチレンソルビタン脂肪酸エステル類等を挙げることができる。なお、この場合、等張性の溶液を調製するのに充分な量の食塩、グルコースまたはグリセリンを製剤中に含んでいてもよく、また通常の溶解補助剤、緩衝剤、無痛化剤等を含んでいてもよい。 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.
　外用剤として使用する場合、外用固形剤、外用液剤（リニメント剤、ローション剤）、スプレー剤、軟膏剤、クリーム剤、ゲル剤または貼付剤として使用することができる。これらの外用剤は、通常医薬品に用いられる溶媒、基剤、添加剤、賦形剤等を用いて常法にしたがって製造することができる。 When used as an external preparation, it can be used as an external solid preparation, an external solution (liniment, lotion), a spray, an ointment, a cream, a gel, or a patch. These external preparations can be produced according to a conventional method using solvents, bases, additives, excipients and the like which are usually used for pharmaceuticals.
　また、上記の製剤には、必要に応じて、着色剤、保存剤、香料、風味剤、甘味剤等を含めることもでき、更に、他の医薬品を含めることもできる。 In addition, the above-mentioned preparation may contain a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and the like as required, and may further contain other medicines.
　上記製剤に含まれる有効成分化合物の量は、特に限定されず広範囲に適宜選択されるが、通常、全組成物中０．５乃至７０重量％、好ましくは１乃至３０重量％含む。 The amount of the active ingredient compound contained in the preparation is not particularly limited and is appropriately selected within a wide range, but is usually 0.5 to 70% by weight, preferably 1 to 30% by weight, based on the total composition.
　その使用量は患者（温血動物、特に人間）の症状、年齢等により異なるが、経口投与の場合には、１回当り、下限として０．００１ｍｇ／ｋｇ体重（好ましくは、０．０１ｍｇ／ｋｇ体重）、上限として、５００ｍｇ／ｋｇ体重（好ましくは、５０ｍｇ／ｋｇ体重）を、静脈内投与の場合には、１回当り、下限として０．００５ｍｇ／ｋｇ体重（好ましくは、０．０５ｍｇ／ｋｇ体重）、上限として、５０ｍｇ／ｋｇ体重（好ましくは、５ｍｇ／ｋｇ体重）を１日当り１乃至数回症状に応じて投与することが望ましい。 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.
　以下、実施例および試験例を挙げて本発明を更に詳細に説明するが、本発明の範囲はこれらに限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the scope of the present invention is not limited thereto.
　実施例中、カラムクロマトグラフィーにおける溶出はＴＬＣ（Ｔｈｉｎ　Ｌａｙｅｒ　Ｃｈｒｏｍａｔｏｇｒａｐｈｙ，薄層クロマトグラフィー)による観察下に行われた。ＴＬＣ観察においては、ＴＬＣプレートとしてメルク（Ｍｅｒｃｋ)社製のシリカゲル６０Ｆ２５４を、展開溶媒としてはカラムクロマトグラフィーで溶出溶媒として用いられた溶媒を、検出法としてＵＶ検出器を採用した。カラム用シリカゲルはメルク社製のシリカゲルＳＫ－８５（２３０～４００メッシュ)、山善社製のシリカゲル（Ｈｉ－ＦｌａｓｈＴＭＣｏｌｕｍｎ、ＩＮＪＥＣＴ　ＣＯＬＵＭＮＴＭ）、バイオタージ社製のシリカゲル（ＳＮＡＰ、ＳＮＡＰ　Ｕｌｔｒａ）あるいは富士シリシア化学社製のシリカゲル（ＦＬ１００Ｂ、クロマトレックス－ＳＯ３Ｈ）を用いた。通常のカラムクロマトグラフィーの他に、山善社の自動クロマトグラフィー装置（ＹＦＬＣ－５４０５－ＦＣ－ＧＲＩＩ、Ｗ－Ｐｒｅｐ ２ＸＹ）、およびバイオタージ社の自動クロマトグラフィー装置（Ｉｓｏｌｅｒａ、ＳＰ－１）を適宜使用した。尚、実施例で用いる略号は、次のような意義を有する。
ｍｇ：ミリグラム、ｇ：グラム、ｍＬ：ミリリットル、ＭＨｚ：メガヘルツ、Ｈｚ：ヘルツ
　以下の実施例において、核磁気共鳴（以下、1H-NMR)スペクトルは、テトラメチルシランを標準物質として、ケミカルシフト値をδ値(ppm)にて記載した。測定溶媒は、ＣＤＣｌ3:重クロロホルム、ＭｅＯＨ－ｄ４：重メタノールあるいは、ＤＭＳＯ－ｄ６：重ジメチルスルホキシドを用いた。分裂パターンは一重線をs、二重線をd、三重線をt、四重線をq、五重線をquint、六重線をsext、七重線をhept、多重線をm、ブロードをbrで示した。 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 the usual column chromatography, Yamazen's automatic chromatography device (YFLC-5405-FC-GRII, W-Prep 2XY) and Biotage's automatic 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, a nuclear magnetic resonance (hereinafter, 1 H-NMR) spectrum is a chemical shift value using tetramethylsilane as a standard substance. Is described in δ value (ppm). 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.
　質量分析（以下、ＭＳ)は、ＡＰＣＩ（Atmospheric Pressure Chemical Ionization）法、ＦＡＢ(Fast Atom Bombardment) 法、ＥＩ(Electron Ionization)法、もしくはＥＳＩ（Electron Spray Ionization)法で行った。また、一部測定にはイオン化法としてESIとAPCIを自動で使い分け測定している機種を用いた。 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.
　（実施例１）
　（実施例１－１）：実施例（１ｃ）で合成
ｔｅｒｔ－ブチル　４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－カルボキシレート (Example 1)
(Example 1-1): synthesized in Example (1c) 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
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
　（実施例１－２）：実施例（１ｄ）で合成
ｔｅｒｔ－ブチル　４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１（２Ｈ）－カルボキシレート (Example 1-2): synthesized in Example (1d) tert-butyl 4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro- 1H-Indol-5-yl) oxy] phenyl} piperidine-1 (2H) -carboxylate
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　（実施例１－３）：実施例（１ｅ）で合成
１－｛４－メチル－５－［４－（ピペリジン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン塩酸塩 Example 1-3: synthesized in Example (1e) 1- {4-methyl-5- [4- (piperidin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl } -2- [2- (Methylsulfonyl) phenyl] ethanone hydrochloride
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
　（実施例１－４）：実施例（１ｆ）で合成
１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）ピペリジン－４－イル］フェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン Example 1-4: synthesized in Example (1f) 1- (5- {4- [1- (1,4-dioxane-2-ylcarbonyl) piperidin-4-yl] phenoxy} -4-methyl -2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
　（実施例１－５）：実施例（１ｇ）で単離
１－［５－（４－｛１－［（２Ｓ）－１，４－ジオキサン－２－イルカルボニル］ピペリジン－４－イル｝フェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン Example 1-5: isolated in Example (1g) 1- [5- (4- {1-[(2S) -1,4-dioxane-2-ylcarbonyl] piperidin-4-yl} phenoxy ) -4-Methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
　（実施例１－６）：実施例（１ｇ）で単離
１－［５－（４－｛１－［（２Ｒ）－１，４－ジオキサン－２－イルカルボニル］ピペリジン－４－イル｝フェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン Example 1-6: Isolated in Example (1g) 1- [5- (4- {1-[(2R) -1,4-dioxane-2-ylcarbonyl] piperidin-4-yl} phenoxy ) -4-Methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
（１ａ）　ｔｅｒｔ－ブチル　５－（４－ブロモフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　公知（ＷＯ２００７／１２９７４５）のｔｅｒｔ－ブチル　５－ヒドロキシ－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート（１０　ｇ）及び１－ブロモ－４－ヨードベンゼン（１３．６　ｇ）のジオキサン（１５０　ｍＬ）溶液にヨウ化銅（Ｉ）（１．５３　ｇ）、Ｎ，Ｎ－ジメチルグリシン（１．６６　ｇ）、炭酸セシウム（２６．１　ｇ）を加え、１００℃で２４時間攪拌した。反応液に飽和塩化アンモニウム水溶液（６０　ｍＬ）、飽和炭酸水素ナトリウム水溶液（３０　ｍＬ）を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をヘキサンで洗浄後、ろ取、乾燥することで、標記化合物（１２．８　ｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) 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)。
（１ｂ）　１－［５－（４－ブロモフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（１ａ）で得られた化合物（１２．８　ｇ）のジクロロメタン（１０　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（２０　ｍＬ）を加え、室温で５時間攪拌した。反応液を減圧下濃縮し、減圧乾燥することで、粗製の５－（４－ブロモフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール塩酸塩（１１　ｇ）を灰色固体として得た。 (1a) tert-butyl 5- (4-bromophenoxy) -4-methyl-2,3-dihydro-1H-indole-1-carboxylate tert-butyl 5-hydroxy-4-methyl known (WO2007 / 129745) Copper (I) iodide (1) was added to a solution of -2,3-dihydro-1H-indole-1-carboxylate (10 g) and 1-bromo-4-iodobenzene (13.6 g) in dioxane (150 mL). 0.53 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).
(1b) 1- [5- (4-Bromophenoxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone Example (1a) 4N hydrochloric acid dioxane solution (20 mL) was added to a solution of the compound (12.8 g) obtained in 1) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture 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. .
　得られた化合物（１１　ｇ）のＮ，Ｎ－ジメチルホルムアミド（３０　ｍＬ）溶液にトリエチルアミン（８．９　ｍＬ）を加え、室温で５分間攪拌した。４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（１３．３　ｇ）及び[２－（メチルスルホニル）フェニル]酢酸（ＣＡＳ番号１４２３３６－２０－７）（８．２７　ｇ）を加え、さらに室温で１２時間攪拌した。反応液を減圧下濃縮後、水（１００　ｍＬ）を加え、析出した固体をろ取した。得られた固体をヘキサンで洗浄することで、標記化合物（１５．２　ｇ）を淡褐色固体として得た。
1H-NMR (400 MHz, DMSO-d6) 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)+。
（１ｃ）　ｔｅｒｔ－ブチル　４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－カルボキシレート
　実施例（１ｂ）で得られた化合物（５００　ｍｇ）、１－ｔｅｒｔ－ブトキシカルボニル－４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）－３，６－ジヒドロ－２Ｈ－ピリジン（４６３　ｍｇ）の１，２－ジメトキシエタン（１０　ｍＬ）溶液に炭酸ナトリウム（３１７　ｍｇ）の水溶液（３　ｍＬ）を加え、室温で５分間撹拌した。［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（８１．６　ｍｇ）を加え、マイクロウェーブ反応装置にて、１３０℃で３０分間反応させた。反応液を室温に冷却後、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（２１９．４　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) 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)+。
（１ｄ）　ｔｅｒｔ－ブチル　４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１（２Ｈ）－カルボキシレート
　実施例（１ｃ）で得られた化合物（２１９　ｍｇ）をテトラヒドロフラン（４　ｍＬ）及び酢酸エチル（４　ｍＬ）に溶解し、７．５％パラジウム炭素（７７．５　ｍｇ）を加え、水素雰囲気下、室温で４時間撹拌した。反応液中の不溶物をろ去し、減圧下で溶媒を留去することで標記化合物（２０５　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) 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)+。
（１ｅ）　１－｛４－メチル－５－［４－（ピペリジン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン塩酸塩
　実施例（１ｄ）で得られた化合物（２０５　ｍｇ）のジクロロメタン（１．５　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（２　ｍＬ）を加え、室温で３時間攪拌した。反応液を減圧下濃縮し、残渣を酢酸エチルで洗浄後ろ取し、乾燥することで標記化合物（１９７　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.48-1.71 (2H, m), 1.97-2.22 (6H, m), 2.66-2.79 (1H, m), 2.92-3.04 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.2 Hz), 3.57-3.66 (2H, m), 4.29 (2H, t, J = 8.2 Hz), 4.37 (2H, s), 6.76 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.14 (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).
MS(APCI) m/z: 505 (M+H)+。
（１ｆ）　１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）ピペリジン－４－イル］フェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（１ｅ）で得られた化合物（２１．２　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（２　ｍＬ）溶液にトリエチルアミン（１１．７　μＬ）を加え、室温で５分間攪拌した。４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（１７．４　ｍｇ）及び１，４－ジオキサン－２－カルボン酸（６．７　ｍｇ）を加え、室温で１２時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１９．０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.57-1.72 (2H, m), 1.84-1.93 (2H, m), 2.14 (3H, s), 2.59-2.78 (2H, m), 3.03-3.11 (1H, m), 3.12 (3H, s), 3.15-3.27 (2H, m), 3.68-3.90 (5H, m), 3.91-3.98 (1H, m), 4.05-4.16 (1H, m), 4.25-4.34 (3H, m), 4.36 (2H, s), 4.63-4.76 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.07-7.13 (2H, m), 7.35-7.39 (1H, m), 7.47-7.56 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 619 (M+H)+。
（１ｇ）
（１ｇ－１）　１－［５－（４－｛１－［（２Ｓ）－１，４－ジオキサン－２－イルカルボニル］ピペリジン－４－イル｝フェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン
及び
（１ｇ－２）　１－［５－（４－｛１－［（２Ｒ）－１，４－ジオキサン－２－イルカルボニル］ピペリジン－４－イル｝フェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（１ｆ）で得られた化合物（１４．５ｇ）をＣＨＩＲＡＬＰＡＫ　ＩＡ（メタノール／アセトニトリル）を用いて光学分割し、光学異性体２種、前ピーク（１ｇ－１、６．２　ｇ、９８　％ｅｅ）、後ピーク（１ｇ－２、６．５　ｇ、９８　％ｅｅ）をそれぞれ白色固体として得た。
（１ｇ－１）
1H-NMR (400 MHz, CDCl3) δ: 1.57-1.72 (2H, m), 1.84-1.93 (2H, m), 2.14 (3H, s), 2.59-2.78 (2H, m), 3.03-3.11 (1H, m), 3.12 (3H, s), 3.15-3.27 (2H, m), 3.68-3.90 (5H, m), 3.91-3.98 (1H, m), 4.05-4.16 (1H, m), 4.25-4.34 (3H, m), 4.36 (2H, s), 4.63-4.76 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.07-7.13 (2H, m), 7.35-7.39 (1H, m), 7.47-7.56 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 619 (M+H)+。
（１ｇ－２）
1H-NMR (400 MHz, CDCl3) δ: 1.57-1.72 (2H, m), 1.84-1.93 (2H, m), 2.14 (3H, s), 2.59-2.78 (2H, m), 3.03-3.11 (1H, m), 3.12 (3H, s), 3.15-3.27 (2H, m), 3.68-3.90 (5H, m), 3.91-3.98 (1H, m), 4.05-4.16 (1H, m), 4.25-4.34 (3H, m), 4.36 (2H, s), 4.63-4.76 (1H, m), 6.76 (1H, d, J= 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.07-7.13 (2H, m), 7.35-7.39 (1H, m), 7.47-7.56 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 619 (M+H)+。 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 No. 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) + .
(1c) 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 (500 mg) obtained in Example (1b), 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) and 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 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 (219.4 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) + .
(1d) 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 (1c) 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) + .
(1e) 1- {4-Methyl-5- [4- (piperidin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl Ethanone hydrochloride To a solution of the compound (205 mg) obtained in Example (1d) in dichloromethane (1.5 mL) was added 4N hydrochloric acid dioxane solution (2 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethyl acetate and collected after drying to give the title compound (197 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48-1.71 (2H, m), 1.97-2.22 (6H, m), 2.66-2.79 (1H, m), 2.92-3.04 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.2 Hz), 3.57-3.66 (2H, m), 4.29 (2H, t, J = 8.2 Hz), 4.37 (2H, s), 6.76 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.14 (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).
MS (APCI) m / z: 505 (M + H) + .
(1f) 1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) piperidin-4-yl] phenoxy} -4-methyl-2,3-dihydro-1H-indole-1 -Yl) -2- [2- (methylsulfonyl) phenyl] ethanone To a solution of the compound obtained in Example (1e) (21.2 mg) in N, N-dimethylformamide (2 mL) was added triethylamine (11.7). μL) was added and stirred at room temperature for 5 minutes. 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (17.4 mg) and 1,4-dioxane-2-carboxylic acid (6.7 mg) was added and stirred at room temperature for 12 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 (19.0 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.57-1.72 (2H, m), 1.84-1.93 (2H, m), 2.14 (3H, s), 2.59-2.78 (2H, m), 3.03-3.11 (1H, m), 3.12 (3H, s), 3.15-3.27 (2H, m), 3.68-3.90 (5H, m), 3.91-3.98 (1H, m), 4.05-4.16 (1H, m), 4.25 -4.34 (3H, m), 4.36 (2H, s), 4.63-4.76 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.07- 7.13 (2H, m), 7.35-7.39 (1H, m), 7.47-7.56 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 619 (M + H) + .
(1g)
(1g-1) 1- [5- (4- {1-[(2S) -1,4-Dioxane-2-ylcarbonyl] piperidin-4-yl} phenoxy) -4-methyl-2,3-dihydro -1H-Indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone and (1g-2) 1- [5- (4- {1-[(2R) -1,4-dioxane- 2-ylcarbonyl] piperidin-4-yl} phenoxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone Example (1f) The compound (14.5 g) obtained in (1) was optically resolved using CHIRALPAK IA (methanol / acetonitrile), and two optical isomers, front peak (1 g-1, 6.2 g, 98% ee), rear peak (1g-2, .5 g, 98% ee) were respectively obtained as a white solid.
(1g-1)
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.57-1.72 (2H, m), 1.84-1.93 (2H, m), 2.14 (3H, s), 2.59-2.78 (2H, m), 3.03-3.11 (1H, m), 3.12 (3H, s), 3.15-3.27 (2H, m), 3.68-3.90 (5H, m), 3.91-3.98 (1H, m), 4.05-4.16 (1H, m), 4.25 -4.34 (3H, m), 4.36 (2H, s), 4.63-4.76 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.07- 7.13 (2H, m), 7.35-7.39 (1H, m), 7.47-7.56 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 619 (M + H) + .
(1g-2)
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.57-1.72 (2H, m), 1.84-1.93 (2H, m), 2.14 (3H, s), 2.59-2.78 (2H, m), 3.03-3.11 (1H, m), 3.12 (3H, s), 3.15-3.27 (2H, m), 3.68-3.90 (5H, m), 3.91-3.98 (1H, m), 4.05-4.16 (1H, m), 4.25 -4.34 (3H, m), 4.36 (2H, s), 4.63-4.76 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.07- 7.13 (2H, m), 7.35-7.39 (1H, m), 7.47-7.56 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 619 (M + H) + .
　（実施例２）：実施例（２ｅ）で合成
１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）ピペリジン－４－イル］フェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（エチルスルホニル）フェニル］エタノン Example 2: Synthesis in Example (2e) 1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) piperidin-4-yl] phenoxy} -4-methyl-2 , 3-Dihydro-1H-indol-1-yl) -2- [2- (ethylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
（２ａ）　１－［５－（４－ブロモフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（エチルスルホニル）フェニル］エタノン
　実施例（１ａ）で得られた化合物（１２．８　ｇ）のジクロロメタン（１０　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（２０　ｍＬ）を加え、室温で５時間攪拌した。反応液を減圧下濃縮し、減圧乾燥することで、粗製の５－（４－ブロモフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール塩酸塩（１１　ｇ）を灰色固体として得た。 (2a) 1- [5- (4-Bromophenoxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (ethylsulfonyl) phenyl] ethanone Example (1a) 4N hydrochloric acid dioxane solution (20 mL) was added to a solution of the compound (12.8 g) obtained in 1) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture 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. .
　得られた化合物（７１０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１０　ｍＬ）溶液にトリエチルアミン（５８０　μＬ）を加え、室温で５分間攪拌した。次いで４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（８７４　ｍｇ）及び実施例で得られた[２－（エチルスルホニル）フェニル]酢酸（ＣＡＳ番号１３６３１７９－４７－８）（５７１　ｍｇ）を加え、室温で１２時間攪拌した。反応液を減圧下濃縮し、水（１００　ｍＬ）を加えて析出した固体をろ取、乾燥した。得られた固体を酢酸エチル／ヘキサン（１／５）の混合溶媒で洗浄することで、標記化合物（１．１７　ｇ）を淡橙色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.27 (3H, t, J = 7.3 Hz), 2.08 (3H, s), 3.15-3.26 (4H, m), 4.22-4.30 (2H, m), 4.37 (2H, s), 6.70-6.80 (3H, m), 7.34-7.43 (3H, m), 7.51 (1H, t, J = 7.9 Hz), 7.63 (1H, t, J = 7.9 Hz), 7.96-8.07 (2H, m).
MS(APCI) m/z: 514 (M+H)+。
（２ｂ）　ｔｅｒｔ－ブチル　４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－カルボキシレート
　実施例（２ａ）で得られた化合物（５００　ｍｇ）、１－ｔｅｒｔ－ブトキシカルボニル－４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）－３，６－ジヒドロ－２Ｈ－ピリジン（３６０　ｍｇ）の１，２－ジメトキシエタン（１２　ｍＬ）溶液に炭酸ナトリウム（３０９　ｍｇ）水溶液（３　ｍＬ）を加え、室温で５分間撹拌した。次いで［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（７９．４　ｍｇ）を加え、マイクロウェーブ反応装置にて、１３０℃で３０分間反応させた。反応液を室温に冷却後、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（４６１　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.26 (3H, t, J = 7.3 Hz), 1.49 (9H, s), 2.12 (3H, s), 2.43-2.54 (2H, br m), 3.16-3.28 (4H, m), 3.58-3.68 (2H, m), 4.02-4.09 (2H, br m), 4.27 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 5.95 (1H, br s), 6.75-6.87 (3H, m), 7.25-7.31 (2H, m), 7.39 (1H, d, J = 7.9 Hz), 7.48-7.53 (1H, m), 7.58-7.66 (1H, m), 7.98 (1H, d, J= 9.2 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 617 (M+H)+。
（２ｃ）　ｔｅｒｔ－ブチル　４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－カルボキシレート
　実施例（２ｂ）で得られた化合物（４６１　ｍｇ）をテトラヒドロフラン（１０　ｍＬ）及び酢酸エチル（１０　ｍＬ）に溶解し、７．５％パラジウム炭素（９２．４　ｍｇ）を加え、水素雰囲気下、室温で１０時間撹拌した。反応液に酢酸エチルを加え、不溶物をろ去後、ろ液を減圧下で溶媒を留去することで標記化合物（４４８　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.26 (3H, t, J = 7.3 Hz), 1.48 (9H, s), 1.51-1.66 (2H, m), 1.73-1.84 (2H, m), 2.13 (3H, s), 2.55-2.66 (1H, m), 2.70-2.87 (2H, br m), 3.13-3.26 (4H, m), 4.16-4.28 (4H, m), 4.37 (2H, s), 6.77 (1H, d, J = 9.2 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.39 (1H, d, J = 7.9 Hz), 7.45-7.53 (1H, m), 7.60-7.64 (1H, m), 7.96 (1H, d, J= 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 619 (M+H)+。
（２ｄ）　２－［２－（エチルスルホニル）フェニル］－１－｛４－メチル－５－［４－（ピペリジン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝エタノン塩酸塩
　実施例（２ｃ）で得られた化合物（４４８　ｍｇ）のジクロロメタン（１．５　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（３　ｍＬ）を加え、室温で２時間攪拌した。反応液を減圧下濃縮し、残渣を酢酸エチルで洗浄後、ろ取、乾燥することで標記化合物（３８６　ｍｇ）を白色固体として得た。
MS(APCI) m/z: 519 (M+H)+。
（２ｅ）　１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）ピペリジン－４－イル］フェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（エチルスルホニル）フェニル］エタノン
　実施例（２ｄ）で得られた化合物（２００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にトリエチルアミン（１００　μＬ）を加え、室温で５分間攪拌した。次いで４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（１４９　ｍｇ）及び１，４－ジオキサン－２－カルボン酸（５７．１　ｍｇ）を加え、室温で１６時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１３６　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.26 (3H, t, J = 7.3 Hz), 1.59-1.77 (2H, m), 1.83-1.97 (2H, m), 2.12 (3H, s), 2.57-2.81 (2H, m), 2.99-3.15 (1H, m), 3.16-3.27 (4H, m), 3.67-3.90 (5H, m), 3.90-3.98 (1H, m), 4.07-4.16 (1H, m), 4.24-4.34 (3H, m), 4.37 (2H, s), 4.65-4.79 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.06-7.14 (2H, m), 7.33-7.44 (1H, m), 7.51 (1H, t, J= 7.6 Hz), 7.63 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 633 (M+H)+。 Triethylamine (580 μL) was added to a solution of the obtained compound (710 mg) in N, N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 5 minutes. Then 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (874 mg) and the [2- (ethylsulfonyl) phenyl] obtained in the examples Acetic acid (CAS No. 1363179-47-8) (571 mg) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, water (100 mL) was added, and the precipitated solid was collected by filtration and dried. The obtained solid was washed with a mixed solvent of ethyl acetate / hexane (1/5) to give the title compound (1.17 g) as a pale orange solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.08 (3H, s), 3.15-3.26 (4H, m), 4.22-4.30 (2H, m), 4.37 (2H, s), 6.70-6.80 (3H, m), 7.34-7.43 (3H, m), 7.51 (1H, t, J = 7.9 Hz), 7.63 (1H, t, J = 7.9 Hz), 7.96 -8.07 (2H, m).
MS (APCI) m / z: 514 (M + H) + .
(2b) tert-butyl 4- {4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} 4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl}- 3,6-Dihydropyridine-1 (2H) -carboxylate Compound (500 mg) obtained in Example (2a), 1-tert-butoxycarbonyl-4- (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl) -3,6-dihydro-2H-pyridine (360 mg) in 1,2-dimethoxyethane (12 mL) and aqueous sodium carbonate (309 mg) (3 mL). In addition, the mixture was stirred at room temperature for 5 minutes. Next, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (79.4 mg) was added and 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 (461 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.49 (9H, s), 2.12 (3H, s), 2.43-2.54 (2H, br m), 3.16 -3.28 (4H, m), 3.58-3.68 (2H, m), 4.02-4.09 (2H, br m), 4.27 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 5.95 (1H, br s), 6.75-6.87 (3H, m), 7.25-7.31 (2H, m), 7.39 (1H, d, J = 7.9 Hz), 7.48-7.53 (1H, m), 7.58-7.66 (1H, m ), 7.98 (1H, d, J = 9.2 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 617 (M + H) + .
(2c) tert-butyl 4- {4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} 4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine 1-Carboxylate Compound (461 mg) obtained in Example (2b) was dissolved in tetrahydrofuran (10 mL) and ethyl acetate (10 mL), and 7.5% palladium carbon (92.4 mg) was added. The mixture was stirred at room temperature for 10 hours under a hydrogen atmosphere. Ethyl acetate was added to the reaction mixture, the insoluble material was removed by filtration, and the filtrate was evaporated under reduced pressure to give the title compound (448 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.48 (9H, s), 1.51-1.66 (2H, m), 1.73-1.84 (2H, m), 2.13 (3H, s), 2.55-2.66 (1H, m), 2.70-2.87 (2H, br m), 3.13-3.26 (4H, m), 4.16-4.28 (4H, m), 4.37 (2H, s) , 6.77 (1H, d, J = 9.2 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.39 (1H, d, J = 7.9 Hz), 7.45 -7.53 (1H, m), 7.60-7.64 (1H, m), 7.96 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 619 (M + H) + .
(2d) 2- [2- (Ethylsulfonyl) phenyl] -1- {4-methyl-5- [4- (piperidin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl } Ethanone hydrochloride To a solution of the compound obtained in Example (2c) (448 mg) in dichloromethane (1.5 mL) was added 4N hydrochloric acid dioxane solution (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethyl acetate, collected by filtration and dried to give the title compound (386 mg) as a white solid.
MS (APCI) m / z: 519 (M + H) + .
(2e) 1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) piperidin-4-yl] phenoxy} -4-methyl-2,3-dihydro-1H-indole-1 -Yl) -2- [2- (ethylsulfonyl) phenyl] ethanone Triethylamine (100 μL) was added to a solution of the compound obtained in Example (2d) (200 mg) in N, N-dimethylformamide (5 mL). And stirred at room temperature for 5 minutes. Then 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (149 mg) and 1,4-dioxane-2-carboxylic acid (57.1 mg) ) And stirred at room temperature for 16 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 (136 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.59-1.77 (2H, m), 1.83-1.97 (2H, m), 2.12 (3H, s), 2.57-2.81 (2H, m), 2.99-3.15 (1H, m), 3.16-3.27 (4H, m), 3.67-3.90 (5H, m), 3.90-3.98 (1H, m), 4.07-4.16 (1H , m), 4.24-4.34 (3H, m), 4.37 (2H, s), 4.65-4.79 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.06-7.14 (2H, m), 7.33-7.44 (1H, m), 7.51 (1H, t, J = 7.6 Hz), 7.63 (1H, t, J = 7.6 Hz), 7.97 (1H, d , J = 8.5 Hz), 8.03 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 633 (M + H) + .
　（実施例３）
　（実施例３－１）：実施例（３ｃ）で合成
１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）－１，２，３，６－テトラヒドロピリジン－４－イル］－３－メチルフェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン (Example 3)
Example 3-1: Synthesis in Example (3c) 1- (5- {4- [1- (1,4-dioxane-2-ylcarbonyl) -1,2,3,6-tetrahydropyridine- 4-yl] -3-methylphenoxy} -4-methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
　（実施例３－２）：実施例（３ｄ）で合成
１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）ピペリジン－４－イル］－３－メチルフェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン Example 3-2: Synthesis in Example (3d) 1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) piperidin-4-yl] -3-methylphenoxy} -4-Methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
（３ａ）ｔｅｒｔ－ブチル　５－（４－ブロモ－３－メチルフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　１－ブロモ－４－ヨード－２－メチルベンゼン（１２．５　ｇ）及びｔｅｒｔ－ブチル　５－ヒドロキシ－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート（７．００　ｇ）の１，４－ジオキサン（２５０　ｍＬ）溶液にヨウ化銅（Ｉ）（１０７　ｍｇ）、Ｎ，Ｎ－ジメチルグリシン（１１６　ｍｇ）及び炭酸セシウム（１８．３　ｇ）を加え、１００℃で５時間３０分攪拌した。室温に冷却後に一晩静置し、再度１００℃で９時間攪拌し、反応液をセライトろ過した。得られたろ液を減圧下で濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／ヘキサン）で精製することで、標記化合物（５．２６　ｇ）を無色固体として得た。
1H-NMR (400 MHz, CDCl3) 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)。
（３ｂ）１－［５－（４－ブロモ－３－メチルフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（３ａ）で得られた化合物（５．２５　ｇ）のジクロロメタン（５０　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（５０　ｍＬ）を加え、室温で３時間攪拌した。反応液を濃縮し、粗製の５－（４－ブロモ－３－メチルフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール塩酸塩（４．５４　ｇ）を得た。 (3a) tert-butyl 5- (4-bromo-3-methylphenoxy) -4-methyl-2,3-dihydro-1H-indole-1-carboxylate 1-bromo-4-iodo-2-methylbenzene ( 12.5 g) and tert-butyl 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylate (7.00 g) in 1,4-dioxane (250 mL) Copper (I) chloride (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 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).
(3b) 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 (5.25 g) obtained in Example (3a) 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 mixture was concentrated to obtain crude 5- (4-bromo-3-methylphenoxy) -4-methyl-2,3-dihydro-1H-indole hydrochloride (4.54 g).
　得られた化合物（４．５４　ｇ）のＮ，Ｎ－ジメチルホルムアミド（１００　ｍＬ）溶液にＮ－メチルモルホリン（２．０７　ｍＬ）を加え、室温で１０分間攪拌した。次いで、反応液に４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（４．５１　ｇ）及び［２－（メチルスルホニル）フェニル］酢酸（ＣＡＳ番号１４２３３６－２０－７）（２．８２　ｇ）を加え、室温で１４時間３０分攪拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／ヘキサン→酢酸エチル／ジクロロメタン）で精製することで、標記化合物（７．１４　ｇ）を無色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.10 (3H, s), 2.33 (3H, s), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.59-6.55 (1H, m), 6.74-6.80 (2H, m), 7.34-7.42 (2H, m), 7.50-7.55 (1H, m), 7.60-7.65 (1H, m), 7.99 (1H, d, J = 8.5 Hz), 8.06-8.10 (1H, m).
MS (APCI) m/z: 514 (M+H)+。
（３ｃ）　１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）－１，２，３，６－テトラヒドロピリジン－４－イル］－３－メチルフェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（３ｂ）で得られた化合物（１００　ｍｇ）、実施例（１０３ｂ）で得られた化合物（７５．４　ｍｇ）の１，２－ジメトキシエタン（３　ｍＬ）溶液に炭酸ナトリウム（６１．８　ｍｇ）の水溶液（１　ｍＬ）を加え、室温で５分間撹拌した。次に［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（１５．９　ｍｇ）を加え、マイクロウェーブ反応装置にて、１３０℃で３０分間反応させた。反応液を室温に冷却後、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（９８．９　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.13 (3H, s), 2.22 (3H, s), 2.30-2.40 (1H, br m), 3.12 (3H, s), 3.22 (2H, t, J = 8.2 Hz), 3.59-4.06 (10H, m), 4.22-4.37 (6H, m), 5.53 (0.5H, s), 5.57 (0.5H, s), 6.60-6.72 (1H, m), 6.63-6.70 (2H, m), 6.96 (1H, d, J = 8.5 Hz), 7.36 (1H, d, J = 6.7 Hz), 7.49-7.55 (1H, m), 7.58-7.66 (1H, m), 7.98 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J= 6.7 Hz).
MS(APCI) m/z: 631 (M+H)+。
（３ｄ）　１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）ピペリジン－４－イル］－３－メチルフェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（３ｃ）で得られた化合物（９８．９　ｍｇ）をテトラヒドロフラン（２　ｍＬ）及び酢酸エチル（２　ｍＬ）に溶解し、７．５％パラジウム炭素（１９．８　ｍｇ）を加え、水素雰囲気下、室温で４時間撹拌した。反応液に酢酸エチルを加え、不溶物をろ去後、ろ液を減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（６４．０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.58-1.72 (2H, m), 1.75-1.87 (2H, m), 2.13 (3H, s), 2.30 (3H, s), 2.56-2.76 (1H, m), 2.82-2.97 (1H, m), 3.04-3.28 (6H, m), 3.63-3.91 (5H, m), 3.91-3.99 (1H, m), 4.09-4.18 (1H, m), 4.26-4.38 (5H, m), 4.67-4.82 (1H, m), 6.64-6.72 (2H, m), 6.73-6.79 (1H, m), 6.99-7.08 (1H, m), 7.34-7.40 (1H, m), 7.48-7.55 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 7.9 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 633 (M+H)+。 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. Subsequently, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (4.51 g) and [2- (methylsulfonyl) phenyl] were added to the reaction solution. Acetic acid (CAS No. 142336-20-7) (2.82 g) was added, and the mixture was stirred at room temperature for 14 hours 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), 6.59-6.55 (1H, m), 6.74-6.80 (2H, m), 7.34-7.42 (2H, m), 7.50-7.55 (1H, m) , 7.60-7.65 (1H, m), 7.99 (1H, d, J = 8.5 Hz), 8.06-8.10 (1H, m).
MS (APCI) m / z: 514 (M + H) + .
(3c) 1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) -1,2,3,6-tetrahydropyridin-4-yl] -3-methylphenoxy} -4 -Methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone Compound (100 mg) obtained in Example (3b), Example (103b) An aqueous solution (1 mL) of sodium carbonate (61.8 mg) was added to a 1,2-dimethoxyethane (3 mL) solution of the compound obtained in (75.4 mg) and stirred at room temperature for 5 minutes. Next, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (15.9 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 / dichloromethane) to give the title compound (98.9 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.13 (3H, s), 2.22 (3H, s), 2.30-2.40 (1H, br m), 3.12 (3H, s), 3.22 (2H, t, J = 8.2 Hz), 3.59-4.06 (10H, m), 4.22-4.37 (6H, m), 5.53 (0.5H, s), 5.57 (0.5H, s), 6.60-6.72 (1H, m), 6.63 -6.70 (2H, m), 6.96 (1H, d, J = 8.5 Hz), 7.36 (1H, d, J = 6.7 Hz), 7.49-7.55 (1H, m), 7.58-7.66 (1H, m), 7.98 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 6.7 Hz).
MS (APCI) m / z: 631 (M + H) + .
(3d) 1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) piperidin-4-yl] -3-methylphenoxy} -4-methyl-2,3-dihydro-1H -Indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone The compound (98.9 mg) obtained in Example (3c) was added to tetrahydrofuran (2 mL) and ethyl acetate (2 mL). After dissolution, 7.5% palladium carbon (19.8 mg) was added, and the mixture was stirred at room temperature for 4 hours under 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 / dichloromethane) to give the title compound (64.0 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.58-1.72 (2H, m), 1.75-1.87 (2H, m), 2.13 (3H, s), 2.30 (3H, s), 2.56-2.76 (1H , m), 2.82-2.97 (1H, m), 3.04-3.28 (6H, m), 3.63-3.91 (5H, m), 3.91-3.99 (1H, m), 4.09-4.18 (1H, m), 4.26 -4.38 (5H, m), 4.67-4.82 (1H, m), 6.64-6.72 (2H, m), 6.73-6.79 (1H, m), 6.99-7.08 (1H, m), 7.34-7.40 (1H, m), 7.48-7.55 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 7.9 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 633 (M + H) + .
　（実施例４）
　（実施例４－１）：実施例（４ａ）で合成
１－｛５－［４－（１－アセチル－１，２，３，６－テトラヒドロピリジン－４－イル）－３－メチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン Example 4
Example 4-1: Synthesis in Example (4a) 1- {5- [4- (1-acetyl-1,2,3,6-tetrahydropyridin-4-yl) -3-methylphenoxy]- 4-Methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
　（実施例４－２）：実施例（４ｂ）で合成
１－｛５－［４－（１－アセチルピペリジン－４－イル）－３－メチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン Example 4-2: Synthesis in Example (4b) 1- {5- [4- (1-acetylpiperidin-4-yl) -3-methylphenoxy] -4-methyl-2,3-dihydro- 1H-Indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
（４ａ）　１－｛５－［４－（１－アセチル－１，２，３，６－テトラヒドロピリジン－４－イル）－３－メチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（３ｂ）で得られた化合物（２００　ｍｇ）、１－［４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）－３，６－ジヒドロピリジン－１（２Ｈ）－イル］エタノン（１４６　ｍｇ）の１，２－ジメトキシエタン（６　ｍＬ）溶液に炭酸ナトリウム（１２３　ｍｇ）の水溶液（２　ｍＬ）を加え、室温で５分間撹拌した。次いで［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（３１．８　ｍｇ）を加え、マイクロウェーブ反応装置にて、１３０℃で１５分間反応させた。反応液を室温に冷却後、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（２２２　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.13 (3H, s), 2.16 (3H, d, J = 4.9 Hz), 2.22 (3H, s), 2.31-2.43 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.59-3.67 (1H, m), 3.75-3.82 (1H, m), 4.07-4.10 (1H, br m), 4.18-4.21 (1H, br m), 4.29 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 5.53 (0.5H, s), 5.59 (0.5H, s), 6.61-6.66 (1H, m), 6.70 (1H, s), 6.79 (1H, d, J = 8.5 Hz), 6.96 (1H, d, J= 7.9 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.50-7.55 (1H, m), 7.59-7.65 (1H, m), 7.98 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J= 7.9 Hz).
MS(APCI) m/z: 559 (M+H)+。
（４ｂ）　１－｛５－［４－（１－アセチルピペリジン－４－イル）－３－メチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（４ａ）で得られた化合物（２２２　ｍｇ）をメタノール（３　ｍＬ）及び酢酸エチル（２　ｍＬ）に溶解し、７．５％パラジウム炭素（４４．４　ｍｇ）を加え、水素雰囲気下、６０℃で４時間撹拌した。反応液に酢酸エチルを加え、不溶物をろ去後、ろ液を減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（４６．９　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.48-1.65 (2H, m), 1.72-1.86 (2H, m), 2.13 (3H, s), 2.22 (1H, s), 2.22 (3H, s), 2.56-2.67 (1H, m), 2.81-2.95 (1H, m), 3.12 (3H, s), 3.17-3.25 (3H, m), 3.60-3.66 (0.5H, m), 3.74-3.83 (0.5H, m), 3.88-3.98 (1H, m), 4.04-4.11 (0.4H, br m), 4.18-4.22 (0.6H, br m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.75-4.86 (0.6H, m), 5.50-5.61 (0.4H, m), 6.61-6.71 (2H, m), 6.77 (1H, t, J = 8.9 Hz), 7.03 (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).
MS(APCI) m/z: 561 (M+H)+。 (4a) 1- {5- [4- (1-acetyl-1,2,3,6-tetrahydropyridin-4-yl) -3-methylphenoxy] -4-methyl-2,3-dihydro-1H- Indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone Compound (200 mg) obtained in Example (3b), 1- [4- (4,4,5,5-tetramethyl) -1,3,2-dioxaborolan-2-yl) -3,6-dihydropyridin-1 (2H) -yl] ethanone (146 mg) in 1,2-dimethoxyethane (6 mL) in sodium carbonate (123 mg ) (2 mL) was added and stirred at room temperature for 5 minutes. Next, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (31.8 mg) was added and 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 (222 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.13 (3H, s), 2.16 (3H, d, J = 4.9 Hz), 2.22 (3H, s), 2.31-2.43 (2H, m), 3.12 ( 3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.59-3.67 (1H, m), 3.75-3.82 (1H, m), 4.07-4.10 (1H, br m), 4.18-4.21 (1H , br m), 4.29 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 5.53 (0.5H, s), 5.59 (0.5H, s), 6.61-6.66 (1H, m), 6.70 (1H, s), 6.79 (1H, d, J = 8.5 Hz), 6.96 (1H, d, J = 7.9 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.50-7.55 (1H, m) , 7.59-7.65 (1H, m), 7.98 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 559 (M + H) + .
(4b) 1- {5- [4- (1-Acetylpiperidin-4-yl) -3-methylphenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [ 2- (Methylsulfonyl) phenyl] ethanone The compound (222 mg) obtained in Example (4a) was dissolved in methanol (3 mL) and ethyl acetate (2 mL), and 7.5% palladium carbon (44.4) was dissolved. mg) was added, and the mixture was stirred at 60 ° C. for 4 hours under 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 / dichloromethane) to give the title compound (46.9 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48-1.65 (2H, m), 1.72-1.86 (2H, m), 2.13 (3H, s), 2.22 (1H, s), 2.22 (3H, s ), 2.56-2.67 (1H, m), 2.81-2.95 (1H, m), 3.12 (3H, s), 3.17-3.25 (3H, m), 3.60-3.66 (0.5H, m), 3.74-3.83 ( 0.5H, m), 3.88-3.98 (1H, m), 4.04-4.11 (0.4H, br m), 4.18-4.22 (0.6H, br m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.75-4.86 (0.6H, m), 5.50-5.61 (0.4H, m), 6.61-6.71 (2H, m), 6.77 (1H, t, J = 8.9 Hz), 7.03 (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).
MS (APCI) m / z: 561 (M + H) + .
　（実施例５）
１－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン (Example 5)
1- {5- [4- (1-acetylpiperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl ] Ethanon
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
　実施例（１ｅ）で得られた化合物（２１．２　ｍｇ）のジクロロメタン（８　ｍＬ）溶液にトリエチルアミン（９５　μＬ）を加え、室温で５分間攪拌した。無水酢酸（３５．２　μＬ）を加え、室温で２時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１１．６　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.53-1.65 (2H, m), 1.80-1.93 (2H, m), 2.13 (6H, s), 2.55-2.74 (2H, m), 3.12 (3H, s), 3.14-3.25 (3H, m), 3.89-3.96 (1H, m), 4.29 (2H, t, J= 8.5 Hz), 4.38 (2H, s), 4.74-4.82 (1H, m), 6.77 (1H, d, J = 7.9 Hz), 6.80-6.84 (2H, m), 7.07-7.11 (2H, m), 7.36 (1H, d, J= 7.9 Hz), 7.49-7.55 (1H, m), 7.58-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 547 (M+H)+。 Triethylamine (95 μL) was added to a solution of the compound (21.2 mg) obtained in Example (1e) in dichloromethane (8 mL), and the mixture was stirred at room temperature for 5 minutes. Acetic anhydride (35.2 μL) was added, and the mixture was stirred at room temperature for 2 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 (11.6 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.53-1.65 (2H, m), 1.80-1.93 (2H, m), 2.13 (6H, s), 2.55-2.74 (2H, m), 3.12 (3H , s), 3.14-3.25 (3H, m), 3.89-3.96 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 4.74-4.82 (1H, m), 6.77 (1H, d, J = 7.9 Hz), 6.80-6.84 (2H, m), 7.07-7.11 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.49-7.55 (1H, m) , 7.58-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 547 (M + H) + .
　（実施例６）：実施例（６ｃ）で合成
１－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン Example 6: Synthesis in Example (6c) 1- {5- [4- (1-acetylpiperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indole-1- Yl} -2- [2- (ethylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
（６ａ）　ｔｅｒｔ－ブチル　５－［４－（１－アセチル－１，２，３，６－テトラヒドロピリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　実施例（１ａ）で得られた化合物（２００　ｍｇ）と１－［４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）－３，６－ジヒドロピリジン－１（２Ｈ）－イル］エタノン（１４９　ｍｇ）の１，２－ジメトキシエタン（６　ｍＬ）溶液に炭酸ナトリウム（１５７　ｍｇ）の水溶液（２　ｍＬ）を加え、室温で５分間撹拌した。［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（４０．４　ｍｇ）を加え、マイクロウェーブ反応装置にて、１３０℃で１５分間反応させた。反応液を室温に冷却後、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（１４９　ｍｇ）を淡褐色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.56 (9H, s), 2.06 (3H, s), 2.15 (3H, d, J = 11.5 Hz), 2.48-2.61 (2H, m), 3.03 (2H, t, J = 8.8 Hz), 3.57-3.69 (1H, m), 3.99-4.07 (2H, br m), 4.10-4.15 (2H, m), 4.18-4.27 (1H, m), 5.93 (0.5H, s), 5.99 (0.5H, s), 6.74-6.86 (3H, m), 7.24-7.30 (1H, m), 7.32-7.39 (1H, m), 7.61-7.77 (1H, br m).
MS(APCI) m/z: 449 (M+H)+。
（６ｂ）　ｔｅｒｔ－ブチル　５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　実施例（６ａ）で得られた化合物（３０７　ｍｇ）をメタノール（５　ｍＬ）及び酢酸エチル（５　ｍＬ）に溶解し、７．５％パラジウム炭素（６２．０　ｍｇ）を加え、水素雰囲気下、室温で１０時間撹拌した。反応液に酢酸エチルを加え、不溶物をろ去し、ろ液を減圧下で溶媒を留去することで標記化合物（２０７　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.56 (11H, br m), 1.81-1.93 (2H, m), 2.07 (3H, s), 2.13 (3H, s), 2.53-2.76 (2H, m), 3.03 (2H, t, J = 8.9 Hz), 3.10-3.21 (1H, m), 3.86-3.96 (1H, m), 3.97-4.09 (2H, br m), 4.74-4.82 (1H, m), 6.74-6.85 (3H, m), 7.08 (2H, d, J = 8.5 Hz), 7.59-7.75 (1H, br m).
MS(APCI) m/z: 451 (M+H)+。
（６ｃ）　１－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン
　実施例（６ｂ）で得られた化合物（２０７　ｍｇ）のジクロロメタン（１　ｍＬ）溶液にトリフルオロ酢酸（３　ｍＬ）を加え、室温で１８時間攪拌した。反応液を減圧濃縮後、飽和炭酸水素ナトリウム水溶液（１５　ｍＬ）を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下で濃縮することで、粗製の１－（４－｛４－［（４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）エタノン（１２２　ｍｇ）を茶色固体として得た。 (6a) tert-butyl 5- [4- (1-acetyl-1,2,3,6-tetrahydropyridin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indole-1- Carboxylate Compound (200 mg) obtained in Example (1a) and 1- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6 To a solution of -dihydropyridin-1 (2H) -yl] ethanone (149 mg) in 1,2-dimethoxyethane (6 mL) was added an aqueous solution (2 mL) of sodium carbonate (157 mg), and the mixture was stirred at room temperature for 5 minutes. [1,1′-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (40.4 mg) was added and 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 (149 mg) as a pale brown solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.56 (9H, s), 2.06 (3H, s), 2.15 (3H, d, J = 11.5 Hz), 2.48-2.61 (2H, m), 3.03 ( 2H, t, J = 8.8 Hz), 3.57-3.69 (1H, m), 3.99-4.07 (2H, br m), 4.10-4.15 (2H, m), 4.18-4.27 (1H, m), 5.93 (0.5 H, s), 5.99 (0.5H, s), 6.74-6.86 (3H, m), 7.24-7.30 (1H, m), 7.32-7.39 (1H, m), 7.61-7.77 (1H, br m).
MS (APCI) m / z: 449 (M + H) + .
(6b) tert-butyl 5- [4- (1-acetylpiperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indole-1-carboxylate obtained in Example (6a) The compound (307 mg) was dissolved in methanol (5 mL) and ethyl acetate (5 mL), 7.5% palladium carbon (62.0 mg) was added, and the mixture was stirred at room temperature for 10 hr in a hydrogen atmosphere. Ethyl acetate was added to the reaction solution, the insoluble material was removed by filtration, and the solvent was distilled off from the filtrate under reduced pressure to obtain the title compound (207 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.56 (11H, br m), 1.81-1.93 (2H, m), 2.07 (3H, s), 2.13 (3H, s), 2.53-2.76 (2H, m), 3.03 (2H, t, J = 8.9 Hz), 3.10-3.21 (1H, m), 3.86-3.96 (1H, m), 3.97-4.09 (2H, br m), 4.74-4.82 (1H, m ), 6.74-6.85 (3H, m), 7.08 (2H, d, J = 8.5 Hz), 7.59-7.75 (1H, br m).
MS (APCI) m / z: 451 (M + H) + .
(6c) 1- {5- [4- (1-acetylpiperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (ethyl (Sulfonyl) phenyl] ethanone Trifluoroacetic acid (3 mL) was added to a solution of the compound (207 mg) obtained in Example (6b) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (15 mL) 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 to give crude 1- (4- {4-[(4-methyl-2,3-dihydro-1H -Indol-5-yl) oxy] phenyl} piperidin-1-yl) ethanone (122 mg) was obtained as a brown solid.
　得られた化合物（１２２　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液に４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（１４５　ｍｇ）及び[２－（エチルスルホニル）フェニル]酢酸（ＣＡＳ番号１３６３１７９－４７－８）（９５．７　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１７４　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.26 (3H, t, J = 7.3 Hz), 1.51-1.67 (2H, m), 1.83-1.93 (2H, m), 2.13 (6H, s), 2.56-2.75 (2H, m), 3.10-3.24 (5H, m), 3.87-3.96 (1H, m), 4.27 (2H, t, J= 8.5 Hz), 4.37 (2H, s), 4.74-4.81 (1H, m), 6.77 (1H, d, J = 7.3 Hz), 6.80-6.84 (2H, m), 7.07-7.11 (2H, m), 7.39 (1H, d, J= 7.3 Hz), 7.47-7.53 (1H, m), 7.60-7.65 (1H, m), 7.97 (1H, d, J = 7.9 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 561 (M+H)+。 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride was added to a solution of the obtained compound (122 mg) in N, N-dimethylformamide (3 mL). (145 mg) and [2- (ethylsulfonyl) phenyl] acetic acid (CAS No. 1363179-47-8) (95.7 mg) were added, and the mixture was stirred at room temperature for 18 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 (174 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.51-1.67 (2H, m), 1.83-1.93 (2H, m), 2.13 (6H, s), 2.56-2.75 (2H, m), 3.10-3.24 (5H, m), 3.87-3.96 (1H, m), 4.27 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 4.74-4.81 ( 1H, m), 6.77 (1H, d, J = 7.3 Hz), 6.80-6.84 (2H, m), 7.07-7.11 (2H, m), 7.39 (1H, d, J = 7.3 Hz), 7.47-7.53 (1H, m), 7.60-7.65 (1H, m), 7.97 (1H, d, J = 7.9 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 561 (M + H) + .
　（実施例７）：実施例（７ｄ）で合成
１－｛５－［４－（１－アセチルピペリジン－４－イル）－３－メトキシフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン Example 7: Synthesis in Example (7d) 1- {5- [4- (1-acetylpiperidin-4-yl) -3-methoxyphenoxy] -4-methyl-2,3-dihydro-1H- Indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
（７ａ）ｔｅｒｔ－ブチル　５－（４－ブロモ－３－メトキシフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　１－ブロモ－４－ヨード－２－メトキシベンゼン（１．５１　ｇ）及びｔｅｒｔ－ブチル　５－ヒドロキシ－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート（６００　ｍｇ）の１，４－ジオキサン（８　ｍＬ）溶液にヨウ化銅（Ｉ）（２２．９　ｍｇ）、Ｎ，Ｎ－ジメチルグリシン（２４．８　ｍｇ）及び炭酸セシウム（１．５７　ｇ）を加え、１００℃で６時間攪拌した。室温に冷却後に一晩静置し、再度１００℃で９時間攪拌し、反応液をセライトろ過した。得られたろ液を減圧下で濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／ヘキサン）で精製することで、標記化合物（５２９　ｍｇ）を無色固体として得た。
1H-NMR (400 MHz, CDCl3) 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)。
（７ｂ）　ｔｅｒｔ－ブチル　５－［４－（１－アセチル－１，２，３，６－テトラヒドロピリジン－４－イル）－３－メトキシフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　実施例（７ａ）で得られた化合物（２００　ｍｇ）、１－［４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）－３，６－ジヒドロピリジン－１（２Ｈ）－イル］エタノン（１７３　ｍｇ）の１，２－ジメトキシエタン（６　ｍＬ）溶液に炭酸ナトリウム（６１．８　ｍｇ）の水溶液（２　ｍＬ）を加え、室温で５分間撹拌した。次いで［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（３７．６　ｍｇ）を加え、マイクロウェーブ反応装置にて、１３０℃で１５分間反応させた。反応液を室温に冷却後、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（２１４　ｍｇ）を茶色油状物として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.56 (9H, s), 1.48-1.62 (2H, m), 2.08 (3H, s), 2.14 (3H, d, J= 7.3 Hz), 2.46-2.57 (2H, br m), 2.99-3.08 (2H, m), 3.56-3.63 (1H, m), 3.75 (3H, s), 3.99-4.07 (2H, m), 4.17-4.21 (1H, br m), 5.71 (0.5H, s), 5.75 (0.5H, s), 6.28 (1H, d, J = 8.5 Hz), 6.51 (1H, br s), 6.76-6.86 (1H, br m), 6.98 (1H, d, J = 8.5 Hz), 7.59-7.78 (1H, br m)。
（７ｃ）　ｔｅｒｔ－ブチル　５－［４－（１－アセチルピペリジン－４－イル）－３－メトキシフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　実施例（７ｂ）で得られた化合物（２１４　ｍｇ）をメタノール（３　ｍＬ）及び酢酸エチル（２　ｍＬ）に溶解し、７．５％パラジウム炭素（４３．０　ｍｇ）を加え、水素雰囲気下、室温で１８時間撹拌した。反応液に酢酸エチルを加え、不溶物をろ去後、ろ液を減圧下で濃縮することで、標記化合物（１９５　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.50-1.63 (11H, m), 1.77-1.94 (2H, m), 2.08 (3H, s), 2.12 (3H, s), 2.53-2.70 (1H, m), 2.98-3.23 (4H, m), 3.77 (3H, s), 3.85-3.93 (1H, m), 3.97-4.08 (2H, br m), 4.73-4.81 (1H, m), 6.25-6.32 (1H, m), 6.52 (1H, br s), 6.75-6.85 (1H, br m), 6.90-6.97 (1H, m), 7.59-7.74 (1H, br m).
MS(APCI) m/z: 461 (M+H)+。
（７ｄ）　１－｛５－［４－（１－アセチルピペリジン－４－イル）－３－メトキシフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（７ｃ）で得られた化合物（１９５　ｍｇ）のジクロロメタン（１　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（３　ｍＬ）を加え、室温で１８時間攪拌した。反応液を減圧下濃縮し、減圧乾燥することで、粗製の１－（４－｛２－メトキシ－４－［（４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）エタノン塩酸塩（２１２　ｍｇ）を白色固体として得た。 (7a) tert-butyl 5- (4-bromo-3-methoxyphenoxy) -4-methyl-2,3-dihydro-1H-indole-1-carboxylate 1-bromo-4-iodo-2-methoxybenzene ( 1.51 g) and tert-butyl 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylate (600 mg) in 1,4-dioxane (8 mL) in copper iodide (I) (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).
(7b) tert-butyl 5- [4- (1-acetyl-1,2,3,6-tetrahydropyridin-4-yl) -3-methoxyphenoxy] -4-methyl-2,3-dihydro-1H- Indole-1-carboxylate Compound obtained in Example (7a) (200 mg), 1- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) To a solution of −3,6-dihydropyridin-1 (2H) -yl] ethanone (173 mg) in 1,2-dimethoxyethane (6 mL), an aqueous solution (2 mL) of sodium carbonate (61.8 mg) was added. For 5 minutes. Next, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (37.6 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 / dichloromethane) to give the title compound (214 mg) as a brown oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.56 (9H, s), 1.48-1.62 (2H, m), 2.08 (3H, s), 2.14 (3H, d, J = 7.3 Hz), 2.46- 2.57 (2H, br m), 2.99-3.08 (2H, m), 3.56-3.63 (1H, m), 3.75 (3H, s), 3.99-4.07 (2H, m), 4.17-4.21 (1H, br m ), 5.71 (0.5H, s), 5.75 (0.5H, s), 6.28 (1H, d, J = 8.5 Hz), 6.51 (1H, br s), 6.76-6.86 (1H, br m), 6.98 ( 1H, d, J = 8.5 Hz), 7.59-7.78 (1H, br m).
(7c) tert-Butyl 5- [4- (1-Acetylpiperidin-4-yl) -3-methoxyphenoxy] -4-methyl-2,3-dihydro-1H-indole-1-carboxylate Example (7b) ) Was dissolved in methanol (3 mL) and ethyl acetate (2 mL), 7.5% palladium carbon (43.0 mg) was added, and the mixture was added under a hydrogen atmosphere at room temperature for 18 hours. Stir. Ethyl acetate was added to the reaction solution, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (195 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.50-1.63 (11H, m), 1.77-1.94 (2H, m), 2.08 (3H, s), 2.12 (3H, s), 2.53-2.70 (1H , m), 2.98-3.23 (4H, m), 3.77 (3H, s), 3.85-3.93 (1H, m), 3.97-4.08 (2H, br m), 4.73-4.81 (1H, m), 6.25- 6.32 (1H, m), 6.52 (1H, br s), 6.75-6.85 (1H, br m), 6.90-6.97 (1H, m), 7.59-7.74 (1H, br m).
MS (APCI) m / z: 461 (M + H) + .
(7d) 1- {5- [4- (1-Acetylpiperidin-4-yl) -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 (7c) (195 mg) in dichloromethane (1 mL) was added 4N hydrochloric acid dioxane solution (3 mL), and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure and dried under reduced pressure to give crude 1- (4- {2-methoxy-4-[(4-methyl-2,3-dihydro-1H-indol-5-yl) oxy]. Phenyl} piperidin-1-yl) ethanone hydrochloride (212 mg) was obtained as a white solid.
　得られた化合物（２１２　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液にトリエチルアミン（１４０　μＬ）を加え、室温で５分間攪拌した。次いで４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（２１１　ｍｇ）及び[２－（メチルスルホニル）フェニル]酢酸（ＣＡＳ番号１４２３３６－２０－７）（１３１　ｍｇ）を加え、室温で４８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１７４　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.47-1.60 (2H, m), 1.75-1.92 (2H, m), 2.12 (3H, s), 2.14 (3H, s), 2.57-2.68 (1H, m), 3.03-3.26 (7H, m), 3.78 (3H, s), 3.85-3.93 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.71-4.80 (1H, m), 6.32 (1H, dd, J = 8.5, 2.4 Hz), 6.52 (1H, d, J = 2.4 Hz), 6.78 (1H, d, J = 8.5 Hz), 6.96 (1H, d, J = 8.5 Hz), 7.36 (1H, d, J = 8.5 Hz), 7.50-7.55 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J= 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 577 (M+H)+。 Triethylamine (140 μL) was added to a solution of the obtained compound (212 mg) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes. Then 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (211 mg) and [2- (methylsulfonyl) phenyl] acetic acid (CAS No. 142336-) 20-7) (131 mg) was added, and the mixture was stirred at room temperature for 48 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 (174 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.47-1.60 (2H, m), 1.75-1.92 (2H, m), 2.12 (3H, s), 2.14 (3H, s), 2.57-2.68 (1H , m), 3.03-3.26 (7H, m), 3.78 (3H, s), 3.85-3.93 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.71- 4.80 (1H, m), 6.32 (1H, dd, J = 8.5, 2.4 Hz), 6.52 (1H, d, J = 2.4 Hz), 6.78 (1H, d, J = 8.5 Hz), 6.96 (1H, d , J = 8.5 Hz), 7.36 (1H, d, J = 8.5 Hz), 7.50-7.55 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 577 (M + H) + .
　(実施例８)：実施例（８ｃ）で合成
（２Ｓ）－２－ヒドロキシ－１－（４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）プロパン－１－オン Example 8: Synthesis in Example (8c) (2S) -2-hydroxy-1- (4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] Acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) propan-1-one
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
（８ａ）　ｔｅｒｔ－ブチル　４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－カルボキシレート
　実施例（９５ａ）で得られた化合物（２　ｇ）をジクロロメタン（１０　ｍＬ）及びメタノール（１０　ｍＬ）に溶解し、１０％パラジウム炭素（４００　ｍｇ）を加え水素雰囲気下、室温で１０時間撹拌した。反応液にジクロロメタンを加え、不溶物をろ去後、ろ液を減圧下で濃縮することで標記化合物（１．０８　ｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.48 (9H, s), 1.51-1.65 (2H, m), 1.67-1.77 (2H, m), 2.13 (3H, s), 2.29 (3H, s), 2.70-2.88 (3H, br m), 3.12 (3H, s), 3.21 (2H, t, J = 8.5 Hz), 4.18-4.32 (4H, m), 4.36 (2H, s), 6.63-6.71 (2H, m), 6.76 (1H, d, J = 8.5 Hz), 7.05 (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), 7.96 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz)。
（８ｂ）　１－｛４－メチル－５－［３－メチル－４－（ピペリジン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン塩酸塩
　実施例（８ａ）で得られた化合物（１．０８　ｇ）のジクロロメタン（２　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（２　ｍＬ）を加え、室温で３時間攪拌した。混合液を減圧下濃縮し、得られた固体を酢酸エチルで洗浄後ろ取し、乾燥させることで標記化合物（１．１２　ｇ）を白色固体として得た。
MS (APCI) m/z: 519 (M+H)+。
（８ｃ）　（２Ｓ）－２－ヒドロキシ－１－（４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）プロパン－１－オン
　実施例（８ｂ）で得られた化合物（２００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にトリエチルアミン（１０９　μＬ）を加え、室温で５分間攪拌した。次いでＬ－乳酸（３７．１　μＬ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（８２．９　ｍｇ）、１－ヒドロキシベンゾトリアゾール一水和物（５５．２　ｍｇ）を加え、室温で１８時間攪拌した。混合液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１７８　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.36 (3H, dd, J = 15.9, 6.1 Hz), 1.48-1.67 (2H, m), 1.79-1.92 (2H, m), 2.13 (3H, s), 2.30 (3H, s), 2.69-2.83 (1H, m), 2.86-2.97 (1H, m), 3.12 (3H, s), 3.13-3.25 (3H, m), 3.77-3.88 (1H, m), 3.94 (1H, br s), 4.29 (2H, t, J= 8.5 Hz), 4.36 (2H, s), 4.44-4.60 (1H, m), 4.64-4.87 (1H, m), 6.63-6.71 (2H, m), 6.76 (1H, d, J = 8.5 Hz), 6.99-7.06 (1H, m), 7.36 (1H, d, J= 8.5 Hz), 7.48-7.55 (1H, m), 7.58-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 591 (M+H)+。 (8a) tert-butyl 4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) Oxy] phenyl} piperidine-1-carboxylate The compound (2 g) obtained in Example (95a) was dissolved in dichloromethane (10 mL) and methanol (10 mL), and 10% palladium carbon (400 mg) was added. The mixture was stirred at room temperature for 10 hours under a hydrogen atmosphere. Dichloromethane was added to the reaction solution, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.08 g) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48 (9H, s), 1.51-1.65 (2H, m), 1.67-1.77 (2H, m), 2.13 (3H, s), 2.29 (3H, s ), 2.70-2.88 (3H, br m), 3.12 (3H, s), 3.21 (2H, t, J = 8.5 Hz), 4.18-4.32 (4H, m), 4.36 (2H, s), 6.63-6.71 (2H, m), 6.76 (1H, d, J = 8.5 Hz), 7.05 (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), 7.96 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
(8b) 1- {4-Methyl-5- [3-methyl-4- (piperidin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- ( Methylsulfonyl) phenyl] ethanone hydrochloride To a solution of the compound (1.08 g) obtained in Example (8a) in dichloromethane (2 mL) was added 4N hydrochloric acid dioxane solution (2 mL), and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the resulting solid was washed with ethyl acetate and collected after drying to give the title compound (1.12 g) as a white solid.
MS (APCI) m / z: 519 (M + H) + .
(8c) (2S) -2-hydroxy-1- (4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro- 1H-Indol-5-yl) oxy] phenyl} piperidin-1-yl) propan-1-one To a solution of the compound obtained in Example (8b) (200 mg) in N, N-dimethylformamide (5 mL). Triethylamine (109 μL) was added and stirred at room temperature for 5 minutes. L-lactic acid (37.1 μL), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (82.9 mg), 1-hydroxybenzotriazole monohydrate (55.2 mg) And stirred at room temperature for 18 hours. Water was added to the mixture 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) to give the title compound (178 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.36 (3H, dd, J = 15.9, 6.1 Hz), 1.48-1.67 (2H, m), 1.79-1.92 (2H, m), 2.13 (3H, s ), 2.30 (3H, s), 2.69-2.83 (1H, m), 2.86-2.97 (1H, m), 3.12 (3H, s), 3.13-3.25 (3H, m), 3.77-3.88 (1H, m ), 3.94 (1H, br s), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.44-4.60 (1H, m), 4.64-4.87 (1H, m), 6.63-6.71 (2H, m), 6.76 (1H, d, J = 8.5 Hz), 6.99-7.06 (1H, m), 7.36 (1H, d, J = 8.5 Hz), 7.48-7.55 (1H, m), 7.58- 7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 591 (M + H) + .
　（実施例９）：実施例（９ｄ）で合成
（２Ｓ）－１－（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］－２－メチルフェニル｝ピペリジン－１－イル）－２－ヒドロキシプロパン－１－オン Example 9: Synthesis in Example (9d) (2S) -1- (4- {4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3- Dihydro-1H-indol-5-yl) oxy] -2-methylphenyl} piperidin-1-yl) -2-hydroxypropan-1-one
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
（９ａ）　ｔｅｒｔ－ブチル　４－｛２－メチル－４－［（４－メチル－１－｛［２－（エチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－カルボキシレート
　実施例（１ｂ）と同様の手法により合成した１－［５－（４－ブロモフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（エチルスルホニル）フェニル］エタノン（２　ｇ）、１－ｔｅｒｔ－ブトキシカルボニル－４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）－３，６－ジヒドロ－２Ｈ－ピリジン（１．４　ｇ）の１，２－ジメトキシエタン（３６　ｍＬ）溶液に炭酸ナトリウム（１．２　ｇ）の水溶液（１２　ｍＬ）を加え、室温で５分間撹拌した。次いで［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（１２３　ｍｇ）を加え、マイクロウェーブ反応装置にて、１３０℃で１５分間反応させた。さらに同反応を３回実施し、室温に冷却後、全ての反応液を合わせ、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（１．６７　ｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ : 1.26 (3H, t, J = 7.3 Hz), 1.50 (9H, s), 2.13 (3H, s), 2.22 (3H, s), 2.27-2.38 (2H, br m), 3.21 (4H, q, J = 7.3 Hz), 3.55-3.65 (2H, m), 3.99-4.05 (2H, br m), 4.27 (2H, t, J = 8.2 Hz), 4.37 (2H, s), 5.53 (1H, br s), 6.63 (1H, d, J = 8.2 Hz), 6.69 (1H, s), 6.79 (1H, d, J = 8.5 Hz), 6.98 (1H, t, J = 7.9 Hz), 7.39 (1H, d, J = 6.7 Hz), 7.47-7.53 (1H, m), 7.59-7.64 (1H, m), 7.98 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 6.7 Hz)。
（９ｂ）　ｔｅｒｔ－ブチル　４－｛２－メチル－４－［（４－メチル－１－｛［２－（エチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－カルボキシレート
　実施例（９ａ）で得られた化合物（１．１　ｇ）をジクロロメタン（１０　ｍＬ）及びメタノール（１０　ｍＬ）に溶解し、１０％パラジウム炭素（２２０　ｍｇ）を加え水素雰囲気下、室温で１０時間撹拌した。反応液にジクロロメタンを加え不溶物をろ去後、ろ液を減圧下で濃縮することで標記化合物（１．２７　ｇ）を白色固体として得た。
MS (APCI) m/z: 633 (M+H)+。
（９ｃ）　１－｛４－メチル－５－［３－メチル－４－（ピペリジン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン塩酸塩
　実施例（９ｂ）で得られた化合物（１．２７　ｇ）のジクロロメタン（２　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（２　ｍＬ）を加え、室温で７時間攪拌した。反応液を減圧下濃縮し、残渣を酢酸エチルで洗浄後ろ取し、乾燥させることで標記化合物（１．１５　ｇ）を白色固体として得た。
MS(APCI) m/z: 533 (M+H)+。
（９ｄ）　（２Ｓ）－１－（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］－２－メチルフェニル｝ピペリジン－１－イル）－２－ヒドロキシプロパン－１－オン
　実施例（９ｃ）で得られた化合物（１５０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にトリエチルアミン（１１０　μＬ）を加え、室温で５分間攪拌した。次いでＬ－乳酸（２７．１　μＬ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（６０．６　ｍｇ）、１－ヒドロキシベンゾトリアゾール一水和物（４０．４　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１０９　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.26 (3H, t, J = 7.3 Hz), 1.36 (3H, dd, J = 15.9, 6.7 Hz), 1.46-1.66 (2H, m), 1.78-1.92 (2H, m), 2.12 (3H, s), 2.30 (3H, s), 2.70-2.79 (1H, m), 2.84-3.00 (1H, m), 3.10-3.26 (5H, m), 3.78-3.88 (1H, m), 3.94 (1H, d, J = 7.3 Hz), 4.27 (2H, t, J = 7.9 Hz), 4.37 (2H, s), 4.45-4.58 (1H, m), 4.71-4.83 (1H, m), 6.63-6.71 (2H, m), 6.76 (1H, d, J = 9.2 Hz), 6.99-7.05 (1H, m), 7.39 (1H, d, J = 9.2 Hz), 7.47-7.53 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 605.2 (M+H)+。 (9a) tert-butyl 4- {2-methyl-4-[(4-methyl-1-{[2- (ethylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) Oxy] phenyl} -3,6-dihydropyridine-1 (2H) -carboxylate 1- [5- (4-bromophenoxy) -4-methyl-2,3-synthesized by a method similar to Example (1b) Dihydro-1H-indol-1-yl] -2- [2- (ethylsulfonyl) phenyl] ethanone (2 g), 1-tert-butoxycarbonyl-4- (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl) -3,6-dihydro-2H-pyridine (1.4 g) in 1,2-dimethoxyethane (36 mL) in aqueous solution of sodium carbonate (1.2 g) Liquid (12 mL) was added and stirred at room temperature for 5 minutes. Next, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (123 mg) was added and reacted at 130 ° C. for 15 minutes in a microwave reactor. Further, the same reaction was carried out three times, and after cooling to room temperature, all the reaction solutions were combined, 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 (1.67 g) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.50 (9H, s), 2.13 (3H, s), 2.22 (3H, s), 2.27-2.38 ( 2H, br m), 3.21 (4H, q, J = 7.3 Hz), 3.55-3.65 (2H, m), 3.99-4.05 (2H, br m), 4.27 (2H, t, J = 8.2 Hz), 4.37 (2H, s), 5.53 (1H, br s), 6.63 (1H, d, J = 8.2 Hz), 6.69 (1H, s), 6.79 (1H, d, J = 8.5 Hz), 6.98 (1H, t , J = 7.9 Hz), 7.39 (1H, d, J = 6.7 Hz), 7.47-7.53 (1H, m), 7.59-7.64 (1H, m), 7.98 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 6.7 Hz).
(9b) tert-butyl 4- {2-methyl-4-[(4-methyl-1-{[2- (ethylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) Oxy] phenyl} piperidine-1-carboxylate Compound (1.1 g) obtained in Example (9a) was dissolved in dichloromethane (10 mL) and methanol (10 mL), and 10% palladium on carbon (220 mg). And stirred at room temperature for 10 hours under hydrogen atmosphere. Dichloromethane was added to the reaction solution, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.27 g) as a white solid.
MS (APCI) m / z: 633 (M + H) + .
(9c) 1- {4-Methyl-5- [3-methyl-4- (piperidin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- ( Ethylsulfonyl) phenyl] ethanone hydrochloride To a solution of the compound (1.27 g) obtained in Example (9b) in dichloromethane (2 mL) was added 4N hydrochloric acid dioxane solution (2 mL), and the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethyl acetate and collected after drying to give the title compound (1.15 g) as a white solid.
MS (APCI) m / z: 533 (M + H) + .
(9d) (2S) -1- (4- {4-[(1-{[2- (Ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy] -2-methylphenyl} piperidin-1-yl) -2-hydroxypropan-1-one To a solution of the compound obtained in Example (9c) (150 mg) in N, N-dimethylformamide (5 mL) Triethylamine (110 μL) was added and stirred at room temperature for 5 minutes. L-lactic acid (27.1 μL), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (60.6 mg), 1-hydroxybenzotriazole monohydrate (40.4 mg) And stirred at room temperature for 18 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 (109 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.36 (3H, dd, J = 15.9, 6.7 Hz), 1.46-1.66 (2H, m), 1.78- 1.92 (2H, m), 2.12 (3H, s), 2.30 (3H, s), 2.70-2.79 (1H, m), 2.84-3.00 (1H, m), 3.10-3.26 (5H, m), 3.78- 3.88 (1H, m), 3.94 (1H, d, J = 7.3 Hz), 4.27 (2H, t, J = 7.9 Hz), 4.37 (2H, s), 4.45-4.58 (1H, m), 4.71-4.83 (1H, m), 6.63-6.71 (2H, m), 6.76 (1H, d, J = 9.2 Hz), 6.99-7.05 (1H, m), 7.39 (1H, d, J = 9.2 Hz), 7.47- 7.53 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 605.2 (M + H) + .
　（実施例１０）
（２Ｓ）－２－ヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）プロパン－１－オン (Example 10)
(2S) -2-Hydroxy-1- (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl ) Oxy] phenyl} piperidin-1-yl) propan-1-one
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
　実施例（１ｅ）で得られた化合物（３００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にトリエチルアミン（２３０　μＬ）を加え、室温で５分間攪拌した。次いでＬ－乳酸（５７．１　μＬ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（１５９　ｍｇ）、１－ヒドロキシベンゾトリアゾール一水和物（８４．９　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１５２　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.35 (3H, dd, J = 13.1, 6.4 Hz), 1.57-1.73 (2H, m), 1.86-2.00 (2H, m), 2.13 (3H, s), 2.63-2.82 (2H, m), 3.02-3.15 (4H, m), 3.15-3.25 (2H, m), 3.71-3.87 (1H, m), 3.88-3.96 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.44-4.56 (1H, m), 4.67-4.82 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.79-6.86 (2H, m), 7.06-7.15 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.49-7.55 (1H, m), 7.59-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 577 (M+H)+。 Triethylamine (230 μL) was added to a solution of the compound (300 mg) obtained in Example (1e) in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 5 minutes. Next, L-lactic acid (57.1 μL), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (159 mg) and 1-hydroxybenzotriazole monohydrate (84.9 mg) were added. And stirred at room temperature for 18 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 (152 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.35 (3H, dd, J = 13.1, 6.4 Hz), 1.57-1.73 (2H, m), 1.86-2.00 (2H, m), 2.13 (3H, s ), 2.63-2.82 (2H, m), 3.02-3.15 (4H, m), 3.15-3.25 (2H, m), 3.71-3.87 (1H, m), 3.88-3.96 (1H, m), 4.29 (2H , t, J = 8.5 Hz), 4.36 (2H, s), 4.44-4.56 (1H, m), 4.67-4.82 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.79-6.86 ( 2H, m), 7.06-7.15 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.49-7.55 (1H, m), 7.59-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 577 (M + H) + .
　（実施例１１）
　（実施例１１－１）：実施例（１１ａ）で合成
（２Ｒ）－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－１－オキソプロパン－２－イル　アセテート (Example 11)
Example 11-1: Synthesis in Example (11a) (2R) -1- (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2, 3-Dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) -1-oxopropan-2-yl acetate
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
　（実施例１１－２）：実施例（１１ｂ）で合成
（２Ｒ）－２－ヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）プロパン－１－オン Example 11-2: (2R) -2-hydroxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl) synthesized in Example (11b) } -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) propan-1-one
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
（１１ａ）　（２Ｒ）－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－１－オキソプロパン－２－イル　アセテート
　実施例（１ｅ）で得られた化合物（３１．６　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液にトリエチルアミン（１６　μＬ）を加え、室温で５分間攪拌した。次いで（Ｓ）－（－）－２－アセトキシプロピオン酸（９．３　ｍｇ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（２４．２　ｍｇ）を加え、室温で１８時間攪拌した。反応物に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（３１．７　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.42-1.49 (3H, m), 1.51-1.63 (2H, m), 1.83-1.98 (2H, br m), 2.13 (3H, s), 2.14 (3H, s), 2.63-2.79 (2H, m), 3.08-3.26 (6H, m), 3.88-3.99 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.70-4.79 (1H, br m), 5.40-5.50 (1H, m), 6.77 (1H, d, J = 9.2 Hz), 6.79-6.88 (2H, m), 7.05-7.15 (2H, m), 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)。
（１１ｂ）　（２Ｒ）－２－ヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）プロパン－１－オン
　実施例（１ａ）で得られた化合物（３１．７　ｍｇ）のテトラヒドロフラン（２　ｍＬ）と水（５００　μＬ）の混合溶液に１Ｎ水酸化ナトリウム水溶液（７６．９　μＬ）を加え、室温で１５時間撹拌した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１０．０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.35 (3H, dd, J = 13.4, 6.7 Hz), 1.56-1.70 (2H, m), 1.82-1.98 (2H, m), 2.12 (3H, s), 2.68-2.82 (2H, m), 3.09-3.27 (6H, m), 3.74-3.87 (1H, m), 3.98-4.06 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.45-4.53 (1H, m), 4.69-4.84 (1H, m), 6.67-6.85 (3H, m), 7.04-7.12 (2H, m), 7.34-7.39 (1H, m), 7.49-7.54 (1H, m), 7.57-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 577 (M+H)+。 (11a) (2R) -1- (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) Oxy] phenyl} piperidin-1-yl) -1-oxopropan-2-yl acetate Triethylamine was added to a solution of the compound obtained in Example (1e) (31.6 mg) in N, N-dimethylformamide (3 mL). (16 μL) was added and stirred at room temperature for 5 minutes. Then (S)-(−)-2-acetoxypropionic acid (9.3 mg), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (24.2 mg) was added and stirred at room temperature for 18 hours. Water was added to the reaction product 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) to give the title compound (31.7 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.42-1.49 (3H, m), 1.51-1.63 (2H, m), 1.83-1.98 (2H, br m), 2.13 (3H, s), 2.14 ( 3H, s), 2.63-2.79 (2H, m), 3.08-3.26 (6H, m), 3.88-3.99 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s) , 4.70-4.79 (1H, br m), 5.40-5.50 (1H, m), 6.77 (1H, d, J = 9.2 Hz), 6.79-6.88 (2H, m), 7.05-7.15 (2H, m), 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).
(11b) (2R) -2-hydroxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole- 5-yl) oxy] phenyl} piperidin-1-yl) propan-1-one A mixture of the compound (31.7 mg) obtained in Example (1a) in tetrahydrofuran (2 mL) and water (500 μL). To the mixture, 1N aqueous sodium hydroxide solution (76.9 μL) was added, and the mixture was stirred at room temperature for 15 hours. 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 (10.0 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.35 (3H, dd, J = 13.4, 6.7 Hz), 1.56-1.70 (2H, m), 1.82-1.98 (2H, m), 2.12 (3H, s ), 2.68-2.82 (2H, m), 3.09-3.27 (6H, m), 3.74-3.87 (1H, m), 3.98-4.06 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.45-4.53 (1H, m), 4.69-4.84 (1H, m), 6.67-6.85 (3H, m), 7.04-7.12 (2H, m), 7.34-7.39 (1H, m ), 7.49-7.54 (1H, m), 7.57-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 577 (M + H) + .
　（実施例１２）
１－［５－（４－｛１－［（１－ヒドロキシシクロプロピル）カルボニル］ピペリジン－４－イル｝フェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン Example 12
1- [5- (4- {1-[(1-hydroxycyclopropyl) carbonyl] piperidin-4-yl} phenoxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2 -[2- (Methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
　実施例（１ｅ）で得られた化合物（３００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にトリエチルアミン（２３０　μＬ）を加え、室温で５分間攪拌した。次いで１－ヒドロキシ－１－シクロプロパンカルボン酸（６７．９　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（１５９　ｍｇ）、１－ヒドロキシベンゾトリアゾール一水和物（８４．９　ｍｇ）を加え、室温で５時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（２３３　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ:0.94-1.03 (2H, m), 1.10-1.19 (2H, m), 1.60-1.69 (2H, m), 1.87-1.95 (2H, m), 2.13 (3H, s), 2.68-2.77 (1H, m), 2.84 (1H, s), 2.90-3.01 (2H, 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), 4.60-4.71 (2H, m), 6.75-6.78 (1H, m), 6.80-6.84 (2H, m), 7.08-7.13 (2H, m), 7.35-7.38 (1H, m), 7.49-7.55 (1H, m), 7.59-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 589 (M+H)+。 Triethylamine (230 μL) was added to a solution of the compound (300 mg) obtained in Example (1e) in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 5 minutes. Then 1-hydroxy-1-cyclopropanecarboxylic acid (67.9 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (159 mg), 1-hydroxybenzotriazole monohydrate ( 84.9 mg) was added, and the mixture was stirred at room temperature for 5 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 (233 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.94-1.03 (2H, m), 1.10-1.19 (2H, m), 1.60-1.69 (2H, m), 1.87-1.95 (2H, m), 2.13 (3H, s), 2.68-2.77 (1H, m), 2.84 (1H, s), 2.90-3.01 (2H, 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), 4.60-4.71 (2H, m), 6.75-6.78 (1H, m), 6.80-6.84 (2H, m), 7.08-7.13 ( 2H, m), 7.35-7.38 (1H, m), 7.49-7.55 (1H, m), 7.59-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 589 (M + H) + .
　（実施例１３）：実施例（１３ｂ）で合成
（２Ｓ）－２,３－ジヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）プロパン－１－オン Example 13: Synthesis in Example (13b) (2S) -2,3-dihydroxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl } -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) propan-1-one
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
（１３ａ）　１－｛５－［４－（１－｛［（４Ｓ）－２，２－ジメチル－１，３－ジオキソラン－４－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（１ｅ）で得られた化合物（３００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（８　ｍＬ）溶液にトリエチルアミン（１５０　μＬ）を加え、室温で５分間攪拌した。文献記載の方法（Ｂｉｏｏｒｇａｎｉｃ　ａｎｄ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ　Ｌｅｔｔｅｒｓ，２００４，１４，３２３１）に従って合成した（４Ｓ）－２，２－ジメチル－１，３－ジオキソラン－４－カルボン酸（１００　ｍｇ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（２３０　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロエタン）で精製することで、標記化合物（３７７　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.40-1.45 (6H, m), 1.51-1.72 (2H, m), 1.84-1.95 (2H, m), 2.13 (3H, s), 2.62-2.79 (2H, m), 3.01-3.25 (6H, m), 4.10-4.19 (1H, m), 4.22-4.32 (3H, m), 4.36 (2H, s), 4.41-4.51 (1H, m), 4.67-4.76 (2H, m), 7.97 (1H, d, J = 9.2 Hz), 6.80-6.86 (2H, m), 7.06-7.11 (2H, m), 7.36 (1H, d, J = 6.7 Hz), 7.49-7.55 (1H, m), 7.58-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 6.7 Hz)。
（１３ｂ）　（２Ｓ）－２，３－ジヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）プロパン－１－オン
　実施例（１３ａ）で得られた化合物（２００　ｍｇ）のジクロロメタン（１　ｍＬ）と水（５００　μＬ）の混合溶液に４Ｎ塩酸ジオキサン溶液（２　ｍＬ）を加え、室温で６時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮することで、標記化合物（１６３　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.52-1.69 (1H, m), 1.89-1.99 (2H, m), 2.12 (3H, s), 2.33-2.40 (1H, m), 2.70-2.82 (2H, m), 3.12 (3H, s), 3.15-3.24 (3H, m), 3.57-3.66 (1H, m), 3.74-3.80 (1H, m), 3.85-3.95 (1H, m), 3.98-4.02 (1H, m), 4.29 (3H, t, J = 8.5 Hz), 4.36 (2H, s), 4.45-4.55 (1H, m), 4.67-4.80 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.05-7.13 (2H, m), 7.33-7.38 (1H, m), 7.48-7.56 (1H, m), 7.58-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 593 (M+H)+。 (13a) 1- {5- [4- (1-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl -2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone N, N-dimethylformamide of the compound (300 mg) obtained in Example (1e) ( 8 mL) solution was added triethylamine (150 μL) and stirred at room temperature for 5 minutes. (4S) -2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (100 mg), 4- (4,4) synthesized according to a method described in the literature (Bioorganic and Medicinal Chemistry Letters, 2004, 14, 3231). 6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (230 mg) was added, and the mixture was stirred at room temperature for 18 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 / dichloroethane) to give the title compound (377 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.40-1.45 (6H, m), 1.51-1.72 (2H, m), 1.84-1.95 (2H, m), 2.13 (3H, s), 2.62-2.79 (2H, m), 3.01-3.25 (6H, m), 4.10-4.19 (1H, m), 4.22-4.32 (3H, m), 4.36 (2H, s), 4.41-4.51 (1H, m), 4.67 -4.76 (2H, m), 7.97 (1H, d, J = 9.2 Hz), 6.80-6.86 (2H, m), 7.06-7.11 (2H, m), 7.36 (1H, d, J = 6.7 Hz), 7.49-7.55 (1H, m), 7.58-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 6.7 Hz).
(13b) (2S) -2,3-dihydroxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H- Indol-5-yl) oxy] phenyl} piperidin-1-yl) propan-1-one A mixed solution of the compound obtained in Example (13a) (200 mg) in dichloromethane (1 mL) and water (500 μL). Was added 4N dioxane hydrochloride solution (2 mL) and stirred at room temperature for 6 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 to give the title compound (163 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.52-1.69 (1H, m), 1.89-1.99 (2H, m), 2.12 (3H, s), 2.33-2.40 (1H, m), 2.70-2.82 (2H, m), 3.12 (3H, s), 3.15-3.24 (3H, m), 3.57-3.66 (1H, m), 3.74-3.80 (1H, m), 3.85-3.95 (1H, m), 3.98 -4.02 (1H, m), 4.29 (3H, t, J = 8.5 Hz), 4.36 (2H, s), 4.45-4.55 (1H, m), 4.67-4.80 (1H, m), 6.77 (1H, d , J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.05-7.13 (2H, m), 7.33-7.38 (1H, m), 7.48-7.56 (1H, m), 7.58-7.66 ( 1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 593 (M + H) + .
　（実施例１４）：実施例（１４ｂ）で合成
（２Ｓ）－１－（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］－２－メチルフェニル｝ピペリジン－１－イル）－２，３－ジヒドロキシプロパン－１－オン Example 14: Synthesis in Example (14b) (2S) -1- (4- {4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3- Dihydro-1H-indol-5-yl) oxy] -2-methylphenyl} piperidin-1-yl) -2,3-dihydroxypropan-1-one
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
（１４ａ）　１－｛５－［４－（１－｛［（４Ｓ）－２，２－ジメチル－１，３－ジオキソラン－４－イル］カルボニル｝ピペリジン－４－イル）－３－メチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン
　実施例（９ｃ）で得られた化合物（２００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（８　ｍＬ）溶液にトリエチルアミン（９７　μＬ）を加え、室温で５分間攪拌した。次いで（４Ｓ）－２，２－ジメチル－１，３－ジオキソラン－４－カルボン酸（６２．０　ｍｇ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（１４５　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１６０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.26 (3H, t, J = 7.3 Hz), 1.43 (6H, d, J = 9.8 Hz), 1.52-1.72 (2H, m), 1.76-1.89 (2H, m), 2.12 (3H, s), 2.30 (3H, s), 2.64-2.78 (1H, m), 2.86-2.98 (1H, m), 3.03-3.14 (1H, m), 3.16-3.28 (4H, m), 4.12-4.19 (1H, m), 4.23-4.31 (3H, m), 4.37 (2H, s), 4.41-4.47 (1H, m), 4.69-4.80 (2H, m), 6.62-6.72 (2H, m), 6.77 (1H, d, J = 8.5 Hz), 6.98-7.06 (1H, m), 7.39 (1H, d, J = 7.9 Hz), 7.46-7.55 (1H, m), 7.58-7.67 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz)。
（１４ｂ）　（２Ｓ）－１－（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］－２－メチルフェニル｝ピペリジン－１－イル）－２，３－ジヒドロキシプロパン－１－オン
　実施例（１４ａ）で得られた化合物（１６０　ｍｇ）のジクロロメタン（１　ｍＬ）と水（５００　μＬ）の混合溶液に４Ｎ塩酸ジオキサン溶液（２　ｍＬ）を加え、室温で１８時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮することで、標記化合物（１２７　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.26 (3H, t, J = 7.3 Hz), 1.56-1.67 (2H, m), 1.79-1.91 (2H, m), 2.12 (3H, s), 2.29 (3H, d, J = 9.8 Hz), 2.35-2.43 (1H, m), 2.73-2.82 (1H, m), 2.87-2.98 (1H, m), 3.13-3.26 (5H, m), 3.60-3.67 (1H, m), 3.75-3.82 (1H, m), 3.88-3.97 (1H, m), 4.00-4.04 (1H, m), 4.27 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 4.47-4.56 (1H, m), 4.70-4.80 (1H, m), 6.64-6.70 (2H, m), 6.77 (1H, d, J = 8.5 Hz), 6.98-7.04 (1H, m), 7.40 (1H, d, J = 7.3 Hz), 7.47-7.54 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 621 (M+H)+。 (14a) 1- {5- [4- (1-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] carbonyl} piperidin-4-yl) -3-methylphenoxy] -4-Methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (ethylsulfonyl) phenyl] ethanone N, N of the compound (200 mg) obtained in Example (9c) -Triethylamine (97 μL) was added to a dimethylformamide (8 mL) solution and stirred at room temperature for 5 minutes. Next, (4S) -2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (62.0 mg), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl)- 4-Methylmorpholinium chloride (145 mg) was added, and the mixture was stirred at room temperature for 18 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 (160 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.43 (6H, d, J = 9.8 Hz), 1.52-1.72 (2H, m), 1.76-1.89 ( 2H, m), 2.12 (3H, s), 2.30 (3H, s), 2.64-2.78 (1H, m), 2.86-2.98 (1H, m), 3.03-3.14 (1H, m), 3.16-3.28 ( 4H, m), 4.12-4.19 (1H, m), 4.23-4.31 (3H, m), 4.37 (2H, s), 4.41-4.47 (1H, m), 4.69-4.80 (2H, m), 6.62- 6.72 (2H, m), 6.77 (1H, d, J = 8.5 Hz), 6.98-7.06 (1H, m), 7.39 (1H, d, J = 7.9 Hz), 7.46-7.55 (1H, m), 7.58 -7.67 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).
(14b) (2S) -1- (4- {4-[(1-{[2- (Ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy] -2-methylphenyl} piperidin-1-yl) -2,3-dihydroxypropan-1-one The compound obtained in Example (14a) (160 mg) in dichloromethane (1 mL) and water (500 μL) 4N dioxane hydrochloride solution (2 mL) was added to the mixed solution, and the mixture was stirred at room temperature for 18 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 to give the title compound (127 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.56-1.67 (2H, m), 1.79-1.91 (2H, m), 2.12 (3H, s), 2.29 (3H, d, J = 9.8 Hz), 2.35-2.43 (1H, m), 2.73-2.82 (1H, m), 2.87-2.98 (1H, m), 3.13-3.26 (5H, m), 3.60- 3.67 (1H, m), 3.75-3.82 (1H, m), 3.88-3.97 (1H, m), 4.00-4.04 (1H, m), 4.27 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 4.47-4.56 (1H, m), 4.70-4.80 (1H, m), 6.64-6.70 (2H, m), 6.77 (1H, d, J = 8.5 Hz), 6.98-7.04 (1H, m) , 7.40 (1H, d, J = 7.3 Hz), 7.47-7.54 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 621 (M + H) + .
　（実施例１５）
１－（４－メチル－５－｛４－［１－（メチルスルホニル）ピペリジン－４－イル］フェノキシ｝－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン (Example 15)
1- (4-Methyl-5- {4- [1- (methylsulfonyl) piperidin-4-yl] phenoxy} -2,3-dihydro-1H-indol-1-yl) -2- [2- (methyl Sulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
　実施例（１ｅ）で得られた化合物（１００　ｍｇ）のジクロロメタン（５　ｍＬ）溶液にメタンスルホニルクロリド（１７．３　μＬ）、トリエチルアミン （５１　μＬ）を加え、室温で１８時間攪拌した。反応液を減圧下で濃縮し、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１０６　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.75-1.87 (2H, m), 1.90-1.98 (2H, m), 2.13 (3H, s), 2.47-2.62 (1H, m), 2.70-2.80 (2H, m), 2.82 (3H, s), 3.12 (3H, s), 3.16-3.25 (2H, m), 3.87-3.98 (2H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.77 (1H, d, J = 7.9 Hz), 6.83 (2H, d, J = 8.5 Hz), 7.11 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.49-7.55 (1H, m), 7.58-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 583 (M+H)+。 Methanesulfonyl chloride (17.3 μL) and triethylamine (51 μL) were added to a solution of the compound (100 mg) obtained in Example (1e) in dichloromethane (5 mL), and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (106 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.75-1.87 (2H, m), 1.90-1.98 (2H, m), 2.13 (3H, s), 2.47-2.62 (1H, m), 2.70-2.80 (2H, m), 2.82 (3H, s), 3.12 (3H, s), 3.16-3.25 (2H, m), 3.87-3.98 (2H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.77 (1H, d, J = 7.9 Hz), 6.83 (2H, d, J = 8.5 Hz), 7.11 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.49-7.55 (1H, m), 7.58-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 583 (M + H) + .
　（実施例１６）
１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）プロパン－１，２－ジオン (Example 16)
1- (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine-1 -Il) propane-1,2-dione
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
　実施例（１ｅ）で得られた化合物（１４３　ｍｇ）のジクロロメタン（４　ｍＬ）溶液に２－オキソプロパン酸（０．０２７　ｍＬ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（１０１　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（３６．０　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１３８　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（１３１　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (500 MHz, CDCl3) δ: 1.60-1.73 (2H, m), 1.85-1.98 (2H, m), 2.12 (3H, s), 2.45 (3H, s), 2.70-2.81 (2H, m), 3.09-3.24 (6H, m), 3.85-3.93 (1H, m), 4.25-4.32 (2H, m), 4.36 (2H, s), 4.62-4.67 (1H, m), 6.75-6.85 (3H, m), 7.08-7.13 (2H, m), 7.35-7.38 (1H, m), 7.50-7.55 (1H, m), 7.60-7.64 (1H, m), 7.96-7.99 (1H, m), 8.06-8.10 (1H, m).
MS (APCI) m/z: 575 (M+H)+。 To a solution of the compound (143 mg) obtained in Example (1e) in dichloromethane (4 mL) was added 2-oxopropanoic acid (0.027 mL), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride. Salt (101 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (36.0 mg), N, N-diisopropylethylamine (0.138 mL) was added at room temperature. Stir with. 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 (131 mg) as a white amorphous solid.
1 H-NMR (500 MHz, CDCl 3 ) δ: 1.60-1.73 (2H, m), 1.85-1.98 (2H, m), 2.12 (3H, s), 2.45 (3H, s), 2.70-2.81 (2H , m), 3.09-3.24 (6H, m), 3.85-3.93 (1H, m), 4.25-4.32 (2H, m), 4.36 (2H, s), 4.62-4.67 (1H, m), 6.75-6.85 (3H, m), 7.08-7.13 (2H, m), 7.35-7.38 (1H, m), 7.50-7.55 (1H, m), 7.60-7.64 (1H, m), 7.96-7.99 (1H, m) , 8.06-8.10 (1H, m).
MS (APCI) m / z: 575 (M + H) + .
　（実施例１７）：実施例（１７ｂ）で合成
３－ヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）プロパン－１－オン Example 17: Synthesis in Example (17b) 3-hydroxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3- Dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) propan-1-one
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
（１７ａ）　１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－３－（プロプ－２－エン－１－イルオキシ）プロパン－１－オン
　実施例（１ｅ）で得られた化合物（３００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（８　ｍＬ）溶液にトリエチルアミン（１５０　μＬ）を加え、室温で５分間攪拌した。３－アリルオキシプロピオン酸（８１．７　μＬ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（２３０　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（２１３　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.48-1.66 (2H, m), 1.81-1.94 (2H, m), 2.13 (3H, s), 2.57-2.76 (4H, m), 3.04-3.25 (6H, m), 3.79 (2H, t, J = 7.0 Hz), 3.96-4.05 (3H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.73-4.84 (1H, m), 5.18 (1H, d, J = 10.4 Hz), 5.28 (1H, d, J = 17.1 Hz), 5.85-5.99 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.09 (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)。
（１７ｂ）　３－ヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）プロパン－１－オン
　実施例（１７ａ）で得られた化合物（２１３　ｍｇ）のテトラヒドロフラン（５　ｍＬ）溶液に１，３－ジメチルバルビツール酸（１０７　ｍｇ）、テトラキス（トリフェニルホスフィン）パラジウム（０）（２０．０　ｍｇ）を加え、窒素雰囲気下、９０℃で７時間撹拌した。反応液を減圧下で濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）およびアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することにより標記化合物（１４７　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.51-1.64 (2H, m), 1.85-1.95 (2H, m), 2.13 (3H, s), 2.54-2.75 (4H, m), 3.06-3.15 (4H, m), 3.21 (2H, t, J = 8.5 Hz), 3.48-3.56 (1H, m), 3.85-3.95 (3H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.75-4.82 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 8.5 Hz), 7.49-7.54 (1H, m), 7.59-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 577 (M+H)+。 (17a) 1- (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} Piperidin-1-yl) -3- (prop-2-en-1-yloxy) propan-1-one N, N-dimethylformamide (8 mL) of the compound obtained in Example (1e) (300 mg) Triethylamine (150 μL) was added to the solution and stirred at room temperature for 5 minutes. 3-allyloxypropionic acid (81.7 μL), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (230 mg) was added, and room temperature was added. For 18 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 (213 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48-1.66 (2H, m), 1.81-1.94 (2H, m), 2.13 (3H, s), 2.57-2.76 (4H, m), 3.04-3.25 (6H, m), 3.79 (2H, t, J = 7.0 Hz), 3.96-4.05 (3H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.73-4.84 ( 1H, m), 5.18 (1H, d, J = 10.4 Hz), 5.28 (1H, d, J = 17.1 Hz), 5.85-5.99 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.09 (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).
(17b) 3-hydroxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) Oxy] phenyl} piperidin-1-yl) propan-1-one To a solution of the compound obtained in Example (17a) (213 mg) in tetrahydrofuran (5 mL), 1,3-dimethylbarbituric acid (107 mg), Tetrakis (triphenylphosphine) palladium (0) (20.0 mg) was added, and the mixture was stirred at 90 ° C. for 7 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) and amino silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (147 mg) as a white solid. Got as.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.51-1.64 (2H, m), 1.85-1.95 (2H, m), 2.13 (3H, s), 2.54-2.75 (4H, m), 3.06-3.15 (4H, m), 3.21 (2H, t, J = 8.5 Hz), 3.48-3.56 (1H, m), 3.85-3.95 (3H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 ( 2H, s), 4.75-4.82 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 8.5 Hz), 7.49-7.54 (1H, m), 7.59-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 577 (M + H) + .
　（実施例１８）
２，２－ジエトキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）エタノン (Example 18)
2,2-diethoxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy ] Phenyl} piperidin-1-yl) ethanone
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
　実施例（１ｅ）で得られた化合物（３００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（８　ｍＬ）溶液にトリエチルアミン（１５０　μＬ）を加え、室温で５分間攪拌した。次いでジエトキシ酢酸（９８．６　ｍｇ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（２３０　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（３５３　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.20-1.29 (6H, m), 1.53-1.66 (2H, m), 1.81-1.93 (2H, m), 2.13 (3H, s), 2.62-2.78 (2H, m), 2.95-3.08 (1H, m), 3.12 (3H, s), 3.14-3.24 (2H, m), 3.55-3.67 (2H, m), 3.68-3.80 (2H, m), 4.28 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.48-4.58 (1H, m), 4.63-4.73 (1H, m), 4.99 (1H, s), 6.74-6.86 (3H, m), 7.05-7.14 (2H, m), 7.36 (1H, d, J = 7.3 Hz), 7.48-7.55 (1H, m), 7.58-7.67 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 635 (M+H)+。 Triethylamine (150 μL) was added to a solution of the compound (300 mg) obtained in Example (1e) in N, N-dimethylformamide (8 mL), and the mixture was stirred at room temperature for 5 minutes. Subsequently, diethoxyacetic acid (98.6 mg) and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (230 mg) were added, and the mixture was stirred at room temperature for 18 hours. Stir. 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 (353 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.20-1.29 (6H, m), 1.53-1.66 (2H, m), 1.81-1.93 (2H, m), 2.13 (3H, s), 2.62-2.78 (2H, m), 2.95-3.08 (1H, m), 3.12 (3H, s), 3.14-3.24 (2H, m), 3.55-3.67 (2H, m), 3.68-3.80 (2H, m), 4.28 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.48-4.58 (1H, m), 4.63-4.73 (1H, m), 4.99 (1H, s), 6.74-6.86 (3H, m ), 7.05-7.14 (2H, m), 7.36 (1H, d, J = 7.3 Hz), 7.48-7.55 (1H, m), 7.58-7.67 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 635 (M + H) + .
　（実施例１９）
（２Ｓ）－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－１－オキソプロパン－２－イル　（２Ｓ）－２－ヒドロキシプロパノエート (Example 19)
(2S) -1- (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl } Piperidin-1-yl) -1-oxopropan-2-yl (2S) -2-hydroxypropanoate
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
　実施例（１ｅ）で得られた化合物（１５０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にトリエチルアミン（７７　μＬ）を加え、室温で５分間攪拌した。次いでＬ－乳酸（３５．７　μＬ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（１１５　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロエタン）で精製することで、標記化合物（２６．６　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.47-1.60 (8H, m), 1.83-1.95 (2H, m), 2.13 (3H, s), 2.64-2.78 (2H, m), 3.09-3.14 (4H, m), 3.16-3.26 (3H, m), 3.84-3.96 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.35-4.38 (3H, m), 4.66-4.78 (1H, m), 5.45-5.55 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.06-7.14 (2H, m), 7.33-7.38 (1H, m), 7.49-7.57 (1H, m), 7.58-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 649 (M+H)+。 Triethylamine (77 μL) was added to a solution of the compound (150 mg) obtained in Example (1e) in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 5 minutes. Next, L-lactic acid (35.7 μL) and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (115 mg) were added, and 18% at room temperature was added. Stir for 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 / dichloroethane) to give the title compound (26.6 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.47-1.60 (8H, m), 1.83-1.95 (2H, m), 2.13 (3H, s), 2.64-2.78 (2H, m), 3.09-3.14 (4H, m), 3.16-3.26 (3H, m), 3.84-3.96 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.35-4.38 (3H, m), 4.66-4.78 (1H , m), 5.45-5.55 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.06-7.14 (2H, m), 7.33-7.38 ( 1H, m), 7.49-7.57 (1H, m), 7.58-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 649 (M + H) + .
　（実施例２０）
２－メトキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）エタノン (Example 20)
2-methoxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl } Piperidin-1-yl) ethanone
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
　実施例（１ｅ）で得られた化合物（２００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（４　ｍＬ）溶液にトリエチルアミン（２０５　μＬ）を加え、室温で５分間攪拌した。次いでメトキシ酢酸（３４．２　μＬ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（１５３　ｍｇ）を加え、室温で１５時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１２５　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ:1.53-1.66 (2H, m), 1.84-1.94 (2H, m), 2.13 (3H, s), 2.60-2.79 (2H, m), 3.03-3.14 (4H, m), 3.16-3.26 (2H, m), 3.46 (3H, s), 3.93-4.03 (1H, m), 4.06-4.21 (2H, m), 4.28 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.69-4.77 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.47-7.55 (1H, m), 7.58-7.64 (1H, m), 7.97 (1H, d, J = 7.9 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 577 (M+H)+。 Triethylamine (205 μL) was added to a solution of the compound (200 mg) obtained in Example (1e) in N, N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 5 minutes. Subsequently, methoxyacetic acid (34.2 μL) and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (153 mg) were added, and the mixture was stirred at room temperature for 15 hours. Stir. 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 (125 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.53-1.66 (2H, m), 1.84-1.94 (2H, m), 2.13 (3H, s), 2.60-2.79 (2H, m), 3.03-3.14 (4H, m), 3.16-3.26 (2H, m), 3.46 (3H, s), 3.93-4.03 (1H, m), 4.06-4.21 (2H, m), 4.28 (2H, t, J = 8.2 Hz ), 4.36 (2H, s), 4.69-4.77 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.47-7.55 (1H, m), 7.58-7.64 (1H, m), 7.97 (1H, d, J = 7.9 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 577 (M + H) + .
　（実施例２１）
３－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－３－オキソプロパンニトリル (Example 21)
3- (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine-1 -Yl) -3-oxopropanenitrile
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
　２－シアノ酢酸（１００　ｍｇ）のジクロロメタン（３　ｍＬ）溶液に塩化オキザリル（１５１　μＬ）、Ｎ，Ｎ－ジメチルホルムアミド（９．０５　μＬ）を加え、室温で１時間撹拌した。反応液を減圧下で濃縮し、粗製の２－シアノアセチルクロリド（１２１　ｍｇ）を茶色油状物で得た。 Oxalyl chloride (151 μL) and N, N-dimethylformamide (9.05 μL) were added to a solution of 2-cyanoacetic acid (100 mg) in dichloromethane (3 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain crude 2-cyanoacetyl chloride (121 mg) as a brown oil.
　実施例（１ｅ）で得られた化合物（６１．９　ｍｇ）のジクロロメタン（３　ｍＬ）溶液に上記２－シアノアセチルクロリド（１２１　ｍｇ）、トリエチルアミン（２４０μＬ）を順次加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（４０．６　ｍｇ）を淡黄色固体として得た。
1H-NMR (400 MHz, CDCl3) δ:1.53-1.72 (1H, m), 1.86-2.01 (2H, m), 2.12 (3H, s), 2.66-2.80 (2H, m), 3.12 (3H, s), 3.18-3.36 (3H, m), 3.52 (2H, d, J = 3.1 Hz), 3.78-3.86 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.68-4.78 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.10 (3H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.48-7.57 (1H, m), 7.60-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 572 (M+H)+。 The above 2-cyanoacetyl chloride (121 mg) and triethylamine (240 μL) were sequentially added to a solution of the compound (61.9 mg) obtained in Example (1e) in dichloromethane (3 mL), and the mixture was stirred at room temperature for 18 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 (40.6 mg) as a pale yellow solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.53-1.72 (1H, m), 1.86-2.01 (2H, m), 2.12 (3H, s), 2.66-2.80 (2H, m), 3.12 (3H , s), 3.18-3.36 (3H, m), 3.52 (2H, d, J = 3.1 Hz), 3.78-3.86 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.68-4.78 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.10 (3H, d, J = 8.5 Hz), 7.36 ( 1H, d, J = 7.9 Hz), 7.48-7.57 (1H, m), 7.60-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz) ).
MS (APCI) m / z: 572 (M + H) + .
　（実施例２２）
　（実施例２２－１）：実施例（２２ａ）で合成
１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）－１，２，３，６－テトラヒドロピリジン－４－イル］－３－フルオロフェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン (Example 22)
Example 22-1: Synthesis in Example (22a) 1- (5- {4- [1- (1,4-dioxane-2-ylcarbonyl) -1,2,3,6-tetrahydropyridine- 4-yl] -3-fluorophenoxy} -4-methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
　（実施例２２－２）：実施例（２２ｂ）で合成
１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）ピペリジン－４－イル］－３－フルオロフェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン Example 22-2: Synthesis in Example (22b) 1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) piperidin-4-yl] -3-fluorophenoxy} -4-Methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
（２２ａ）　１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）－１，２，３，６－テトラヒドロピリジン－４－イル］－３－フルオロフェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン
　１－［５－（４－ブロモ－３－フルオロフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン（６５．５　ｍｇ）、実施例（１０３ｂ）で得られた化合物（６１．３　ｍｇ）の１，２－ジメトキシエタン（３　ｍＬ）溶液に炭酸ナトリウム（４０．２　ｍｇ）の水溶液（１　ｍＬ）を加え、室温で５分間撹拌した。次いで［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（１０．３　ｍｇ）を加え、マイクロウェーブ反応装置にて、１３０℃で４０分間反応させた。反応液を室温に冷却後、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（３４．１　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.10 (3H, s), 2.43-2.68 (2H, br m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.64-3.89 (7H, m), 3.93-4.00 (1H, m), 4.20-4.39 (1H, m), 4.21-4.37 (6H, m), 5.89 (1H, br s), 6.54 (1H, d, J = 11.0 Hz), 6.63 (1H, d, J = 11.0 Hz), 6.82 (1H, d, J = 8.5 Hz), 7.13 (1H, t, J = 8.5 Hz), 7.37 (1H, d, J = 7.9 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.63 (1H, t, J = 7.6 Hz), 8.01 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz)。
（２２ｂ）　１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）ピペリジン－４－イル］－３－フルオロフェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（２２ａ）で得られた化合物（３４．１　ｍｇ）をテトラヒドロフラン（２　ｍＬ）及び酢酸エチル（２　ｍＬ）に溶解し、７．５％パラジウム炭素（７．０　ｍｇ）を加え水素雰囲気下、室温で１５時間撹拌した。反応液に酢酸エチルを加え不溶物をろ去し、ろ液を減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（２８．３　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.57-1.75 (2H, m), 1.81-1.96 (2H, m), 2.10 (3H, s), 2.24-2.35 (1H, m), 2.58-2.72 (1H, m), 2.98-3.14 (4H, m), 3.17-3.25 (2H, m), 3.68-3.90 (5H, m), 3.91-3.97 (1H, m), 4.02-4.16 (1H, m), 4.27-4.38 (5H, m), 4.67-4.77 (1H, m), 6.50-6.57 (1H, m), 6.60-6.64 (1H, m), 6.78-6.82 (1H, m), 7.01-7.10 (1H, m), 7.36 (1H, d, J = 7.9 Hz), 7.49-7.56 (1H, m), 7.60-7.65 (1H, m), 8.00 (1H, d, J = 8.5 Hz), 8.06-8.10 (1H, m).
MS(APCI) m/z: 637 (M+H)+。 (22a) 1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) -1,2,3,6-tetrahydropyridin-4-yl] -3-fluorophenoxy} -4 -Methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone 1- [5- (4-Bromo-3-fluorophenoxy) -4-methyl- 2,3-Dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone (65.5 mg), compound obtained in Example (103b) (61.3 mg) To a 1,2-dimethoxyethane (3 mL) solution was added an aqueous solution (1 mL) of sodium carbonate (40.2 mg), and the mixture was stirred at room temperature for 5 minutes. Next, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (10.3 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 (34.1 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.10 (3H, s), 2.43-2.68 (2H, br m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.64 -3.89 (7H, m), 3.93-4.00 (1H, m), 4.20-4.39 (1H, m), 4.21-4.37 (6H, m), 5.89 (1H, br s), 6.54 (1H, d, J = 11.0 Hz), 6.63 (1H, d, J = 11.0 Hz), 6.82 (1H, d, J = 8.5 Hz), 7.13 (1H, t, J = 8.5 Hz), 7.37 (1H, d, J = 7.9 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.63 (1H, t, J = 7.6 Hz), 8.01 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz) .
(22b) 1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) piperidin-4-yl] -3-fluorophenoxy} -4-methyl-2,3-dihydro-1H -Indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone The compound (34.1 mg) obtained in Example (22a) was added to tetrahydrofuran (2 mL) and ethyl acetate (2 mL). After dissolution, 7.5% palladium carbon (7.0 mg) was added, and the mixture was stirred at room temperature for 15 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. The obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (28.3 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3) δ: 1.57-1.75 (2H, m), 1.81-1.96 (2H, m), 2.10 (3H, s), 2.24-2.35 (1H, m), 2.58-2.72 (1H, m), 2.98-3.14 (4H, m), 3.17-3.25 (2H, m), 3.68-3.90 (5H, m), 3.91-3.97 (1H, m), 4.02-4.16 (1H, m) , 4.27-4.38 (5H, m), 4.67-4.77 (1H, m), 6.50-6.57 (1H, m), 6.60-6.64 (1H, m), 6.78-6.82 (1H, m), 7.01-7.10 ( 1H, m), 7.36 (1H, d, J = 7.9 Hz), 7.49-7.56 (1H, m), 7.60-7.65 (1H, m), 8.00 (1H, d, J = 8.5 Hz), 8.06-8.10 (1H, m).
MS (APCI) m / z: 637 (M + H) + .
　（実施例２３）
　（実施例２３－１）：実施例（２３ｂ）で合成
１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）－１，２，３，６－テトラヒドロピリジン－４－イル］－３－メトキシフェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン (Example 23)
Example 23-1: Synthesis in Example (23b) 1- (5- {4- [1- (1,4-dioxane-2-ylcarbonyl) -1,2,3,6-tetrahydropyridine- 4-yl] -3-methoxyphenoxy} -4-methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
　（実施例２３－２）：実施例（２３ｃ）で合成
１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）ピペリジン－４－イル］－３－メトキシフェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン Example 23-2: Synthesis in Example (23c) 1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) piperidin-4-yl] -3-methoxyphenoxy} -4-Methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
（２３ａ）１－［５－（４－ブロモ－３－メトキシフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（７ａ）で得られた化合物（４００　ｍｇ）のジクロロメタン（４　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（４　ｍＬ）を加え、室温で２時間３０分攪拌した。反応液を濃縮し、粗製の５－（４－ブロモ－３－メトキシフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール塩酸塩（３３６　ｍｇ）を得た。 (23a) 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 (400 mg) obtained in Example (7a) 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 mixture was concentrated to obtain crude 5- (4-bromo-3-methoxyphenoxy) -4-methyl-2,3-dihydro-1H-indole hydrochloride (336 mg).
　得られた化合物（３３６　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１０　ｍＬ）溶液にＮ－メチルモルホリン（０．２０２　ｍＬ）を加え、室温で１５分間攪拌した。反応液に４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（３８２　ｍｇ）及び［２－（メチルスルホニル）フェニル］酢酸（ＣＡＳ番号１４２３３６－２０－７）（２５６　ｍｇ）を加え、室温で１６時間３０分攪拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／ヘキサン→酢酸エチル／ジクロロメタン）で精製することで、標記化合物（５３４　ｍｇ）を無色固体として得た。
1H-NMR (400 MHz, CDCl3) 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)+。
（２３ｂ）　１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）－１，２，３，６－テトラヒドロピリジン－４－イル］－３－メトキシフェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（２３ａ）で得られた化合物（７０．０　ｍｇ）及び実施例（１０３ｂ）で得られた化合物（６４．０　ｍｇ）の１，２－ジメトキシエタン（３　ｍＬ）溶液に炭酸ナトリウム（４０．２　ｍｇ）の水溶液（１　ｍＬ）を加え、室温で５分間撹拌した。次いで［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（１０．８　ｍｇ）を加え、マイクロウェーブ反応装置にて、１３０℃で１時間反応させた。反応液を室温に冷却後、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（４０．６　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.13 (3H, s), 2.46-2.62 (2H, br m), 3.13 (3H, s), 3.18-3.26 (2H, m), 3.59-3.91 (10H, m), 3.92-3.99 (1H, m), 4.07-4.22 (1H, m), 4.24-4.40 (6H, m), 5.69-5.78 (1H, m), 6.26-6.34 (1H, m), 6.52 (1H, br s), 6.81 (1H, d, J = 9.2 Hz), 7.00 (1H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.60-7.64 (1H, m), 7.99 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz)。
（２３ｃ）　１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）ピペリジン－４－イル］－３－メトキシフェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（２３ｂ）で得られたか化合物（３５．２　ｍｇ）をテトラヒドロフラン（２　ｍＬ）及び酢酸エチル（２　ｍＬ）に溶解し、７．５％パラジウム炭素（７．０　ｍｇ）を加え水素雰囲気下、室温で１５時間撹拌した。反応液に酢酸エチルを加え、不溶物をろ去し、ろ液を減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（３１．３　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.54-1.66 (2H, m), 1.78-1.97 (2H, m), 2.14 (3H, s), 2.23-2.34 (1H, m), 2.58-2.75 (1H, m), 3.05-3.15 (4H, m), 3.18-3.25 (2H, m), 3.64-3.98 (9H, m), 4.03-4.15 (1H, m), 4.24-4.39 (5H, m), 4.63-4.76 (1H, m), 6.28-6.33 (1H, m), 6.48-6.53 (1H, m), 6.75-6.82 (1H, m), 6.91-7.03 (1H, m), 7.33-7.40 (1H, m), 7.47-7.55 (1H, m), 7.59-7.67 (1H, m), 7.93-7.99 (1H, m), 8.05-8.11 (1H, m).
MS(APCI) m/z: 649 (M+H)+。 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. 4- (4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (382 mg) and [2- (methylsulfonyl) phenyl] acetic acid (CAS number) were added to the reaction mixture. 142336-20-7) (256 mg) was added, and the mixture was stirred at room temperature for 16 hours 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) + .
(23b) 1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) -1,2,3,6-tetrahydropyridin-4-yl] -3-methoxyphenoxy} -4 -Methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone The compound (70.0 mg) obtained in Example (23a) and Example ( An aqueous solution (1 mL) of sodium carbonate (40.2 mg) was added to a solution of the compound obtained in 103b) (64.0 mg) in 1,2-dimethoxyethane (3 mL) and stirred at room temperature for 5 minutes. Next, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (10.8 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 / dichloromethane) to give the title compound (40.6 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.13 (3H, s), 2.46-2.62 (2H, br m), 3.13 (3H, s), 3.18-3.26 (2H, m), 3.59-3.91 ( 10H, m), 3.92-3.99 (1H, m), 4.07-4.22 (1H, m), 4.24-4.40 (6H, m), 5.69-5.78 (1H, m), 6.26-6.34 (1H, m), 6.52 (1H, br s), 6.81 (1H, d, J = 9.2 Hz), 7.00 (1H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.60-7.64 (1H, m), 7.99 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
(23c) 1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) piperidin-4-yl] -3-methoxyphenoxy} -4-methyl-2,3-dihydro-1H -Indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone The compound obtained in Example (23b) or compound (35.2 mg) was added to tetrahydrofuran (2 mL) and ethyl acetate (2 mL). After dissolution, 7.5% palladium carbon (7.0 mg) was added, and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. Ethyl acetate was added to the reaction solution, 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 / dichloromethane) to give the title compound (31.3 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.54-1.66 (2H, m), 1.78-1.97 (2H, m), 2.14 (3H, s), 2.23-2.34 (1H, m), 2.58-2.75 (1H, m), 3.05-3.15 (4H, m), 3.18-3.25 (2H, m), 3.64-3.98 (9H, m), 4.03-4.15 (1H, m), 4.24-4.39 (5H, m) , 4.63-4.76 (1H, m), 6.28-6.33 (1H, m), 6.48-6.53 (1H, m), 6.75-6.82 (1H, m), 6.91-7.03 (1H, m), 7.33-7.40 ( 1H, m), 7.47-7.55 (1H, m), 7.59-7.67 (1H, m), 7.93-7.99 (1H, m), 8.05-8.11 (1H, m).
MS (APCI) m / z: 649 (M + H) + .
　（実施例２４）
　（実施例２４－１）：実施例（２４ｃ）で合成
１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）－１，２，３，６－テトラヒドロピリジン－４－イル］－２，５－ジメチルフェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン (Example 24)
Example 24-1: Synthesis in Example (24c) 1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) -1,2,3,6-tetrahydropyridine- 4-yl] -2,5-dimethylphenoxy} -4-methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
　（実施例２４－２）：実施例（２４ｄ）で合成
１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）ピペリジン－４－イル］－２，５－ジメチルフェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン Example 24-2: Synthesis in Example (24d) 1- (5- {4- [1- (1,4-dioxane-2-ylcarbonyl) piperidin-4-yl] -2,5-dimethyl Phenoxy} -4-methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
（２４ａ）ｔｅｒｔ－ブチル　５－（４－ブロモ－２，５－ジメチルフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　１－ブロモ－２，５－ジメチル－４－ヨードベンゼン（１．５０　ｇ）及びｔｅｒｔ－ブチル　５－ヒドロキシ－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート（６００　ｍｇ）の１，４－ジオキサン（９　ｍＬ）溶液にヨウ化銅（Ｉ）（２２．９　ｍｇ）、Ｎ，Ｎ－ジメチルグリシン（２４．８　ｍｇ）及び炭酸セシウム（１．５７　ｇ）を加え、１００℃で４時間３０分攪拌した。室温に冷却後に一晩静置し、再度１００℃で９時間攪拌し、反応液をセライトろ過した。得られたろ液を減圧下で濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／ヘキサン）で精製することで、標記化合物（５８７　ｍｇ）を淡黄色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.56 (9H, s), 2.07 (3H, s), 2.20-2.27 (6H, m), 3.03 (2H, t, J= 8.8 Hz), 3.99-4.08 (2H, m), 6.40-6.48 (1H, m), 6.58-6.71 (1H, m), 7.19-7.70 (2H, m)。 (24a) tert-butyl 5- (4-bromo-2,5-dimethylphenoxy) -4-methyl-2,3-dihydro-1H-indole-1-carboxylate 1-bromo-2,5-dimethyl-4 A solution of iodobenzene (1.50 g) and tert-butyl 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylate (600 mg) in 1,4-dioxane (9 mL) Were added copper (I) iodide (22.9 mg), N, N-dimethylglycine (24.8 mg) and cesium carbonate (1.57 g), and the mixture was stirred at 100 ° C. for 4 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 (587 mg) as a pale yellow amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.56 (9H, s), 2.07 (3H, s), 2.20-2.27 (6H, m), 3.03 (2H, t, J = 8.8 Hz), 3.99- 4.08 (2H, m), 6.40-6.48 (1H, m), 6.58-6.71 (1H, m), 7.19-7.70 (2H, m).
　（２４ｂ）１－［５－（４－ブロモ－２，５－ジメチルフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（２４ａ）で得られた化合物（３００　ｍｇ）のジクロロメタン（４　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（４　ｍＬ）を加え、室温で１時間攪拌した。反応液を濃縮し、粗製の５－（４－ブロモ－２，５－ジメチルフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール塩酸塩（３１２　ｍｇ）を得た。 (24b) 1- [5- (4-Bromo-2,5-dimethylphenoxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl Ethanone To a solution of the compound (300 mg) obtained in Example (24a) in dichloromethane (4 mL) was added 4N hydrochloric acid dioxane solution (4 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain crude 5- (4-bromo-2,5-dimethylphenoxy) -4-methyl-2,3-dihydro-1H-indole hydrochloride (312 mg).
　得られた化合物（３１２　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（４　ｍＬ）溶液にＮ－メチルモルホリン（０．１５３　ｍＬ）を加え、室温で１５分間攪拌した。反応液に４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（２８８　ｍｇ）及び［２－（メチルスルホニル）フェニル］酢酸（ＣＡＳ番号１４２３３６－２０－７）（１９３　ｍｇ）を加え、室温で１８時間３０分攪拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／ヘキサン→酢酸エチル／ジクロロメタン）で精製することで、標記化合物（３８３　ｍｇ）を無色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.13 (3H, s), 2.21-2.30 (6H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.2 Hz), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.49 (1H, s), 6.61 (1H, d, J = 8.5 Hz), 7.34-7.38 (2H, m), 7.49-7.55 (1H, m), 7.59-7.64 (1H, m), 7.94 (1H, d, J = 8.5 Hz), 8.05-8.10 (1H, m).
MS (APCI) m/z: 528 (M+H)+。
（２４ｃ）　１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）－１，２，３，６－テトラヒドロピリジン－４－イル］－２，５－ジメチルフェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（２４ｂ）で得られた化合物（７０．０　ｍｇ）、実施例（１０３ｂ）で得られた化合物（６４．２　ｍｇ）の１，２－ジメトキシエタン（３ｍＬ）溶液に炭酸ナトリウム（４２．１　ｍｇ）の水溶液（１　ｍＬ）を加え、室温で５分間撹拌した。［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（１０．８　ｍｇ）を加え、マイクロウェーブ反応装置にて、１３０℃で１時間反応させた。反応液を室温に冷却後、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（３１．１　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.15 (6H, d, J = 11.6 Hz), 2.24 (3H, s), 2.31-2.52 (2H, m), 3.12 (3H, s), 3.23 (2H, t, J = 8.5 Hz), 3.60-3.92 (7H, m), 3.94-4.02 (1H, m), 4.06-4.18 (1H, m), 4.19-4.38 (6H, m), 5.50-5.60 (1H, m), 6.45 (1H, s), 6.62 (1H, d, J = 8.5 Hz), 6.92 (1H, s), 7.36 (1H, d, J = 7.9 Hz), 7.53 (1H, d, J = 7.9 Hz), 7.61 (1H, d, J = 7.9 Hz), 7.94 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz)。
（２４ｄ）　１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）ピペリジン－４－イル］－２，５－ジメチルフェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（２４ｃ）で得られた化合物（３１．１　ｍｇ）をテトラヒドロフラン（２　ｍＬ）及び酢酸エチル（２　ｍＬ）に溶解し、７．５％パラジウム炭素（７．０　ｍｇ）を加え水素雰囲気下、室温で１５時間撹拌した。反応液に酢酸エチルを加え不溶物をろ去し、ろ液を減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１９．３　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.62-1.73 (2H, m), 1.76-1.88 (2H, m), 2.16 (3H, s), 2.22 (6H, s), 2.59-2.72 (1H, m), 2.81-2.94 (1H, m), 3.09 (3H, s), 3.18-3.26 (2H, m), 3.66-4.01 (7H, m), 4.10-4.18 (1H, m), 4.25-4.40 (5H, m), 4.68-4.78 (1H, m), 6.46 (1H, s), 6.57 (1H, d, J = 8.5 Hz), 6.94-7.02 (1H, m), 7.33-7.39 (1H, m), 7.47-7.56 (1H, m), 7.61-7.62 (1H, m), 7.92 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 647 (M+H)+。 N-methylmorpholine (0.153 mL) was added to a solution of the obtained compound (312 mg) in N, N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 15 minutes. 4- (4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (288 mg) and [2- (methylsulfonyl) phenyl] acetic acid (CAS number) were added to the reaction mixture. 142336-20-7) (193 mg) was added, and the mixture was stirred at room temperature for 18 hours 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 (383 mg) as a colorless solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.13 (3H, s), 2.21-2.30 (6H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.2 Hz), 4.28 ( 2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.49 (1H, s), 6.61 (1H, d, J = 8.5 Hz), 7.34-7.38 (2H, m), 7.49-7.55 (1H , m), 7.59-7.64 (1H, m), 7.94 (1H, d, J = 8.5 Hz), 8.05-8.10 (1H, m).
MS (APCI) m / z: 528 (M + H) + .
(24c) 1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) -1,2,3,6-tetrahydropyridin-4-yl] -2,5-dimethylphenoxy} -4-Methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone The compound (70.0 mg) obtained in Example (24b), An aqueous solution (1 mL) of sodium carbonate (42.1 mg) was added to a solution of the compound (64.2 mg) obtained in Example (103b) 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 (10.8 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 / dichloromethane) to give the title compound (31.1 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.15 (6H, d, J = 11.6 Hz), 2.24 (3H, s), 2.31-2.52 (2H, m), 3.12 (3H, s), 3.23 ( 2H, t, J = 8.5 Hz), 3.60-3.92 (7H, m), 3.94-4.02 (1H, m), 4.06-4.18 (1H, m), 4.19-4.38 (6H, m), 5.50-5.60 ( 1H, m), 6.45 (1H, s), 6.62 (1H, d, J = 8.5 Hz), 6.92 (1H, s), 7.36 (1H, d, J = 7.9 Hz), 7.53 (1H, d, J = 7.9 Hz), 7.61 (1H, d, J = 7.9 Hz), 7.94 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
(24d) 1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) piperidin-4-yl] -2,5-dimethylphenoxy} -4-methyl-2,3-dihydro -1H-Indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone The compound (31.1 mg) obtained in Example (24c) was added to tetrahydrofuran (2 mL) and ethyl acetate (2 mL). ), 7.5% palladium carbon (7.0 mg) was added, and the mixture was stirred at room temperature for 15 hours in 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. The obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (19.3 mg) as a white solid.
1H-NMR (400 MHz, CDCl 3 ) δ: 1.62-1.73 (2H, m), 1.76-1.88 (2H, m), 2.16 (3H, s), 2.22 (6H, s), 2.59-2.72 (1H, m), 2.81-2.94 (1H, m), 3.09 (3H, s), 3.18-3.26 (2H, m), 3.66-4.01 (7H, m), 4.10-4.18 (1H, m), 4.25-4.40 ( 5H, m), 4.68-4.78 (1H, m), 6.46 (1H, s), 6.57 (1H, d, J = 8.5 Hz), 6.94-7.02 (1H, m), 7.33-7.39 (1H, m) , 7.47-7.56 (1H, m), 7.61-7.62 (1H, m), 7.92 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 647 (M + H) + .
　（実施例２５）
２－［２－（メチルスルホニル）フェニル］－１－（４－メチル－５－｛４－［１－（テトラヒドロフラン－３－イルカルボニル）ピペリジン－４－イル］フェノキシ｝－２，３－ジヒドロ－１Ｈ－インドール－１－イル）エタノン (Example 25)
2- [2- (Methylsulfonyl) phenyl] -1- (4-methyl-5- {4- [1- (tetrahydrofuran-3-ylcarbonyl) piperidin-4-yl] phenoxy} -2,3-dihydro- 1H-Indol-1-yl) ethanone
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
　実施例（１ｅ）で得られた化合物（６０．０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液にトリエチルアミン（３１　μＬ）を加え、室温で５分間攪拌した。次いでテトラヒドロ－３－フラン酸（１２．７　μＬ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（４６．０　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（５７．０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.48-1.62 (2H, m), 1.85-1.99 (2H, m), 2.05-2.17 (4H, m), 2.18-2.36 (1H, m), 2.57-2.77 (2H, m), 3.06-3.32 (7H, m), 3.83-3.95 (3H, m), 3.99-4.07 (2H, m), 4.28 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.72-4.85 (1H, m), 6.76 (1H, d, J = 9.2 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.33-7.39 (1H, m), 7.50-7.54 (1H, m), 7.60-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.05-8.09 (1H, m).
MS(APCI) m/z: 603 (M+H)+。 Triethylamine (31 μL) was added to a solution of the compound (60.0 mg) obtained in Example (1e) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes. Then tetrahydro-3-furanic acid (12.7 μL), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (46.0 mg) was added. The mixture was further stirred at room temperature for 18 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 (57.0 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48-1.62 (2H, m), 1.85-1.99 (2H, m), 2.05-2.17 (4H, m), 2.18-2.36 (1H, m), 2.57 -2.77 (2H, m), 3.06-3.32 (7H, m), 3.83-3.95 (3H, m), 3.99-4.07 (2H, m), 4.28 (2H, t, J = 8.2 Hz), 4.36 (2H , s), 4.72-4.85 (1H, m), 6.76 (1H, d, J = 9.2 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.33 -7.39 (1H, m), 7.50-7.54 (1H, m), 7.60-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.05-8.09 (1H, m).
MS (APCI) m / z: 603 (M + H) + .
　（実施例２６）
２－［２－（メチルスルホニル）フェニル］－１－（４－メチル－５－｛４－［１－（テトラヒドロフラン－２－イルカルボニル）ピペリジン－４－イル］フェノキシ｝－２，３－ジヒドロ－１Ｈ－インドール－１－イル）エタノン (Example 26)
2- [2- (Methylsulfonyl) phenyl] -1- (4-methyl-5- {4- [1- (tetrahydrofuran-2-ylcarbonyl) piperidin-4-yl] phenoxy} -2,3-dihydro- 1H-Indol-1-yl) ethanone
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
　実施例（１ｅ）で得られた化合物（６０．０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液にトリエチルアミン（３１　μＬ）を加え、室温で５分間攪拌した。次いでテトラヒドロフラン－２－カルボン酸（１２．８　μＬ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（４６．０　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（５３．４　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ:1.59-1.75 (2H, m), 1.82-1.94 (2H, m), 1.99-2.17 (5H, m), 2.23-2.35 (1H, m), 2.59-2.76 (2H, m), 3.02-3.15 (4H, m), 3.16-3.26 (3H, m), 3.82-3.92 (1H, m), 3.93-4.03 (1H, m), 4.14-4.21 (1H, m), 4.28 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.61-4.70 (1H, m), 4.70-4.78 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 7.9 Hz), 7.10 (2H, d, J = 7.9 Hz), 7.31-7.40 (1H, m), 7.48-7.55 (1H, m), 7.59-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz)。
MS(APCI) m/z: 603 (M+H)+。 Triethylamine (31 μL) was added to a solution of the compound (60.0 mg) obtained in Example (1e) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes. Next, tetrahydrofuran-2-carboxylic acid (12.8 μL), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (46.0 mg) were added. The mixture was further stirred at room temperature for 18 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 (53.4 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.59-1.75 (2H, m), 1.82-1.94 (2H, m), 1.99-2.17 (5H, m), 2.23-2.35 (1H, m), 2.59 -2.76 (2H, m), 3.02-3.15 (4H, m), 3.16-3.26 (3H, m), 3.82-3.92 (1H, m), 3.93-4.03 (1H, m), 4.14-4.21 (1H, m), 4.28 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.61-4.70 (1H, m), 4.70-4.78 (1H, m), 6.76 (1H, d, J = 8.5 Hz ), 6.81 (2H, d, J = 7.9 Hz), 7.10 (2H, d, J = 7.9 Hz), 7.31-7.40 (1H, m), 7.48-7.55 (1H, m), 7.59-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 603 (M + H) + .
　（実施例２７）
１－（４－メチル－５－｛４－［１－（オキセタン－２－イルカルボニル）ピペリジン－４－イル］フェノキシ｝－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン (Example 27)
1- (4-Methyl-5- {4- [1- (oxetan-2-ylcarbonyl) piperidin-4-yl] phenoxy} -2,3-dihydro-1H-indol-1-yl) -2- [ 2- (Methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
　実施例（１ｅ）で得られた化合物（６０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液にトリエチルアミン（３１　μＬ）を加え、室温で５分間攪拌した。次いでオキセタン－２－カルボン酸（１３．６　ｍｇ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（４６．０　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（４４．０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ:1.47-1.71 (2H, m), 1.80-1.93 (2H, m), 2.12 (3H, s), 2.63-2.88 (3H, m), 2.99-3.25 (7H, m), 3.74-3.88 (1H, m), 4.28 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.54-4.62 (1H, m), 4.64-4.77 (2H, m), 5.38 (1H, q, J = 8.1 Hz), 6.76 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.04-7.12 (2H, m), 7.36 (1H, d, J = 7.3 Hz), 7.52 (1H, t, J = 7.3 Hz), 7.58-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 589 (M+H)+。 Triethylamine (31 μL) was added to a solution of the compound (60 mg) obtained in Example (1e) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes. Next, oxetane-2-carboxylic acid (13.6 mg), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (46.0 mg) were added. The mixture was further stirred at room temperature for 18 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 (44.0 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.47-1.71 (2H, m), 1.80-1.93 (2H, m), 2.12 (3H, s), 2.63-2.88 (3H, m), 2.99-3.25 (7H, m), 3.74-3.88 (1H, m), 4.28 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.54-4.62 (1H, m), 4.64-4.77 (2H, m ), 5.38 (1H, q, J = 8.1 Hz), 6.76 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.04-7.12 (2H, m), 7.36 (1H , d, J = 7.3 Hz), 7.52 (1H, t, J = 7.3 Hz), 7.58-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 589 (M + H) + .
　（実施例２８）
１－（４－メチル－５－｛４－［１－（オキセタン－３－イルカルボニル）ピペリジン－４－イル］フェノキシ｝－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン (Example 28)
1- (4-Methyl-5- {4- [1- (oxetan-3-ylcarbonyl) piperidin-4-yl] phenoxy} -2,3-dihydro-1H-indol-1-yl) -2- [ 2- (Methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
　実施例（１ｅ）で得られた化合物（６０．０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液にトリエチルアミン（３１　μＬ）を加え、室温で５分間攪拌した。次いでオキセタン－３－カルボン酸（１３．６　ｍｇ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（４６．０　ｍｇ）を加え、室温で１５時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１９．９　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ:1.49-1.65 (2H, m), 1.84-1.93 (2H, m), 2.12 (3H, s), 2.60-2.76 (2H, m), 3.03-3.14 (4H, m), 3.21 (2H, t, J = 8.5 Hz), 3.34-3.45 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.76-4.86 (3H, m), 4.92-5.01 (2H, m), 6.73-6.86 (4H, m), 7.08 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.49-7.57 (1H, m), 7.57-7.67 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 589 (M+H)+。 Triethylamine (31 μL) was added to a solution of the compound (60.0 mg) obtained in Example (1e) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes. Next, oxetane-3-carboxylic acid (13.6 mg), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (46.0 mg) were added. The mixture was further 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 (19.9 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.49-1.65 (2H, m), 1.84-1.93 (2H, m), 2.12 (3H, s), 2.60-2.76 (2H, m), 3.03-3.14 (4H, m), 3.21 (2H, t, J = 8.5 Hz), 3.34-3.45 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.76-4.86 ( 3H, m), 4.92-5.01 (2H, m), 6.73-6.86 (4H, m), 7.08 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.49-7.57 (1H, m), 7.57-7.67 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 589 (M + H) + .
　（実施例２９）：実施例（２９ｂ）で合成
３－ヒドロキシ－２－メチル－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）プロパン－１－オン Example 29: Synthesis in Example (29b) 3-hydroxy-2-methyl-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl}- 2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) propan-1-one
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
（２９ａ）　３－（ベンジルオキシ）－２－メチル－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）プロパン－１－オン
　実施例（１ｅ）で得られた化合物（６０．０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液にトリエチルアミン（３１　μＬ）を加え、室温で５分間攪拌した。次いで３－ベンジルオキシ－２－メチルプロパン酸（２５．８　ｍｇ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（４６．０　ｍｇ）を加え、室温で１５時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（６２．６　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.15 (3H, dd, J = 13.1, 7.0 Hz), 1.56-1.67 (2H, m), 1.76-1.95 (2H, m), 2.13 (3H, s), 2.55-2.77 (2H, m), 3.03-3.15 (5H, m), 3.21 (2H, t, J = 8.5 Hz), 3.42-3.56 (1H, m), 3.69-3.80 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.43-4.61 (2H, m), 4.76-4.88 (1H, m), 6.70-6.84 (3H, m), 6.92-7.02 (1H, m), 7.09 (1H, d, J = 8.5 Hz), 7.28-7.39 (5H, m), 7.52 (1H, t, J = 7.3 Hz), 7.62 (1H, t, J = 7.3 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 6.7 Hz)。
（２９ｂ）　３－ヒドロキシ－２－メチル－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）プロパン－１－オン
　実施例（２９ａ）で得られた化合物（６２．６　ｍｇ）をエタノール（３　ｍＬ）及び酢酸エチル（４　ｍＬ）に溶解し、７．５％パラジウム炭素（１２．５　ｍｇ）を加え水素雰囲気下、室温で１８時間撹拌した。７．５％パラジウム炭素（１２．５　ｍｇ）を追加後、６０℃で水素雰囲気下、さらに６時間撹拌した。反応液に酢酸エチルを加え不溶物をろ去し、ろ液を減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン→メタノール／酢酸エチル）で精製することで、標記化合物（３２．１　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.18 (3H, dd, J = 14.6, 7.3 Hz), 1.53-1.67 (2H, m), 1.84-1.98 (2H, m), 2.13 (3H, s), 2.54-2.76 (2H, m), 2.84-2.93 (1H, m), 3.12 (3H, s), 3.15-3.29 (3H, m), 3.70-3.79 (2H, m), 3.96-4.06 (1H, m), 4.28 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.74-4.85 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.34-7.38 (1H, m), 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 = 8.5 Hz).
MS(APCI) m/z: 591 (M+H)+。 (29a) 3- (Benzyloxy) -2-methyl-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H -Indol-5-yl) oxy] phenyl} piperidin-1-yl) propan-1-one A solution of the compound obtained in Example (1e) (60.0 mg) in N, N-dimethylformamide (3 mL) Triethylamine (31 μL) was added to the mixture and stirred at room temperature for 5 minutes. Then 3-benzyloxy-2-methylpropanoic acid (25.8 mg), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (46. 0 mg) was added, and the mixture was 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 / hexane) to give the title compound (62.6 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.15 (3H, dd, J = 13.1, 7.0 Hz), 1.56-1.67 (2H, m), 1.76-1.95 (2H, m), 2.13 (3H, s ), 2.55-2.77 (2H, m), 3.03-3.15 (5H, m), 3.21 (2H, t, J = 8.5 Hz), 3.42-3.56 (1H, m), 3.69-3.80 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.43-4.61 (2H, m), 4.76-4.88 (1H, m), 6.70-6.84 (3H, m), 6.92-7.02 ( 1H, m), 7.09 (1H, d, J = 8.5 Hz), 7.28-7.39 (5H, m), 7.52 (1H, t, J = 7.3 Hz), 7.62 (1H, t, J = 7.3 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 6.7 Hz).
(29b) 3-hydroxy-2-methyl-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole- 5-yl) oxy] phenyl} piperidin-1-yl) propan-1-one The compound (62.6 mg) obtained in Example (29a) was dissolved in ethanol (3 mL) and ethyl acetate (4 mL). 7.5% palladium carbon (12.5 mg) was added, and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. After adding 7.5% palladium carbon (12.5 mg), the mixture was further stirred at 60 ° C. in a hydrogen atmosphere for 6 hours. Ethyl acetate was added to the reaction mixture, 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 / dichloromethane → methanol / ethyl acetate) to give the title compound (32.1 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.18 (3H, dd, J = 14.6, 7.3 Hz), 1.53-1.67 (2H, m), 1.84-1.98 (2H, m), 2.13 (3H, s ), 2.54-2.76 (2H, m), 2.84-2.93 (1H, m), 3.12 (3H, s), 3.15-3.29 (3H, m), 3.70-3.79 (2H, m), 3.96-4.06 (1H , m), 4.28 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.74-4.85 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.34-7.38 (1H, m), 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 = 8.5 Hz).
MS (APCI) m / z: 591 (M + H) + .
　（実施例３０）
　（実施例３０－１）：実施例（３０ａ）合成
１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－１－オキソプロパン－２－イル　アセテート (Example 30)
Example 30-1: Example 30a Synthesis 1- (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H -Indol-5-yl) oxy] phenyl} piperidin-1-yl) -1-oxopropan-2-yl acetate
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
　（実施例３０－２）：実施例（３０ｂ）で合成
２－ヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）プロパン－１－オン Example 30-2: synthesized in Example (30b) 2-hydroxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2, 3-Dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) propan-1-one
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
（３０ａ）　１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－１－オキソプロパン－２－イル　アセテート
　実施例（１ｅ）で得られた化合物（１５０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にトリエチルアミン（７７　μＬ）を加え、室温で５分間攪拌した。次いで（±）－２－アセトキシプロピオン酸（３７．４　μＬ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（１１５　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（７７．５　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.42-1.49 (3H, m), 1.51-1.63 (2H, m), 1.83-1.98 (2H, br m), 2.13 (3H, s), 2.14 (3H, s), 2.63-2.79 (2H, m), 3.08-3.26 (6H, m), 3.88-3.99 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.70-4.79 (1H, br m), 5.40-5.50 (1H, m), 6.77 (1H, d, J = 9.2 Hz), 6.79-6.88 (2H, m), 7.05-7.15 (2H, m), 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)。
（３０ｂ）　２－ヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）プロパン－１－オン
　実施例（３０ａ）で得られた化合物（３１．７　ｍｇ）のテトラヒドロフラン（４　ｍＬ）とメタノール（１　ｍＬ）の混合溶液に１Ｎ水酸化ナトリウム水溶液（１８８　μＬ）を加え、室温で１８時間撹拌した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（５６．８　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.35 (3H, dd, J = 13.4, 6.7 Hz), 1.57-1.67 (2H, m), 1.86-1.98 (2H, m), 2.12 (3H, s), 2.68-2.79 (2H, m), 3.09-3.25 (6H, m), 3.79-3.86 (1H, m), 3.90-3.98 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.45-4.55 (1H, m), 4.68-4.80 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.80-6.85 (2H, m), 7.05-7.12 (2H, m), 7.36 (1H, d, J = 7.3 Hz), 7.47-7.55 (1H, m), 7.59-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 577 (M+H)+。 (30a) 1- (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} Piperidin-1-yl) -1-oxopropan-2-yl acetate To a solution of the compound obtained in Example (1e) (150 mg) in N, N-dimethylformamide (5 mL) was added triethylamine (77 μL). And stirred at room temperature for 5 minutes. (±) -2-Acetoxypropionic acid (37.4 μL), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (115 mg) And stirred at room temperature for 18 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 (77.5 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.42-1.49 (3H, m), 1.51-1.63 (2H, m), 1.83-1.98 (2H, br m), 2.13 (3H, s), 2.14 ( 3H, s), 2.63-2.79 (2H, m), 3.08-3.26 (6H, m), 3.88-3.99 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s) , 4.70-4.79 (1H, br m), 5.40-5.50 (1H, m), 6.77 (1H, d, J = 9.2 Hz), 6.79-6.88 (2H, m), 7.05-7.15 (2H, m), 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).
(30b) 2-hydroxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) Oxy] phenyl} piperidin-1-yl) propan-1-one To a mixed solution of the compound (31.7 mg) obtained in Example (30a) in tetrahydrofuran (4 mL) and methanol (1 mL) was added 1N hydroxide. Sodium aqueous solution (188 μL) was added, and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to obtain the title compound (56.8 mg) as a white solid.
1H-NMR (400 MHz, CDCl 3 ) δ: 1.35 (3H, dd, J = 13.4, 6.7 Hz), 1.57-1.67 (2H, m), 1.86-1.98 (2H, m), 2.12 (3H, s) , 2.68-2.79 (2H, m), 3.09-3.25 (6H, m), 3.79-3.86 (1H, m), 3.90-3.98 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.45-4.55 (1H, m), 4.68-4.80 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.80-6.85 (2H, m), 7.05-7.12 (2H , m), 7.36 (1H, d, J = 7.3 Hz), 7.47-7.55 (1H, m), 7.59-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 577 (M + H) + .
　（実施例３１）
　（実施例３１－１）：実施例（３１ｂ）で合成
１－｛５－［４－（１－｛［（２Ｓ，４Ｓ）－４－フルオロピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン塩酸塩 (Example 31)
Example 31-1: Synthesis in Example (31b) 1- {5- [4- (1-{[(2S, 4S) -4-fluoropyrrolidin-2-yl] carbonyl} piperidin-4-yl ) Phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone hydrochloride
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056
　（実施例３１－２）：実施例（３１ｃ）で合成
１－｛５－［４－（１－｛［（２Ｓ，４Ｓ）－４－フルオロ－１－メチルピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン Example 31-2: Synthesis in Example (31c) 1- {5- [4- (1-{[(2S, 4S) -4-fluoro-1-methylpyrrolidin-2-yl] carbonyl} piperidine -4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057
　（実施例３１－３）：実施例（３１ｄ）で合成
１－［４－メチル－５－（４－｛１－［（１－メチル－１Ｈ－ピロール－２－イル）カルボニル］ピペリジン－４－イル｝フェノキシ）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン Example 31-3: Synthesis in Example (31d) 1- [4-Methyl-5- (4- {1-[(1-methyl-1H-pyrrol-2-yl) carbonyl] piperidine-4- Yl} phenoxy) -2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058
（３１ａ）　ｔｅｒｔ－ブチル　（２Ｓ，４Ｓ）－４－フルオロ－２－［（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）カルボニル］ピロリジン－１－カルボキシレート
　実施例（１ｅ）で得られた化合物（３００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（８　ｍＬ）溶液にトリエチルアミン（１５０　μＬ）を加え、室温で５分間攪拌した。次いでＮ－ｔｅｒｔ－ブトキシカルボニル－シス－４－フルオロ－Ｌ－プロリン（１５５　ｍｇ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（２３０　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（３３８　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.48 (9H, s), 1.52-1.66 (2H, br m), 1.81-1.97 (2H, br m), 2.13 (3H, s), 2.17-2.32 (1H, m), 2.34-2.57 (1H, br m), 2.60-2.79 (2H, br m), 3.03-3.27 (6H, m), 3.72-3.99 (3H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.61-4.87 (2H, m), 5.15 (0.5H, br s), 5.29 (0.5H, br s), 6.73-6.87 (3H, m), 7.01-7.14 (2H, m), 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)。
（３１ｂ）　１－｛５－［４－（１－｛［（２Ｓ，４Ｓ）－４－フルオロピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン塩酸塩
　実施例（３１ａ）で得られた化合物（３３８　ｍｇ）のジクロロメタン（１　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（２　ｍＬ）を加え、室温で５時間撹拌した。減圧下にて溶媒を留去し、析出した固体を酢酸エチルで洗浄することで、標記化合物（３０８　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.61-1.74 (2H, m), 1.85-1.96 (2H, m), 2.13 (3H, s), 2.68-2.79 (2H, m), 2.80-2.92 (1H, m), 3.02-3.25 (8H, m), 3.41-3.56 (1H, m), 3.84-4.00 (2H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.72-4.86 (1H, m), 5.04-5.18 (0.5H, br m), 5.22-5.29 (0.5H, br m), 6.77 (1H, d, J = 8.5 Hz), 6.79-6.85 (2H, m), 7.04-7.15 (2H, m), 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), 8.08 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 620 (M+H)+。
（３１ｃ）　１－｛５－［４－（１－｛［（２Ｓ，４Ｓ）－４－フルオロ－１－メチルピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（３１ｂ）で得られた化合物（３０８　ｍｇ）をメタノール（６　ｍＬ）及びジクロロメタン（２　ｍＬ）溶液に溶解し、７．５％パラジウム炭素（７５．０　ｍｇ）、３７％ホルムアルデヒド液（１．７５　ｍＬ）、塩酸（２８８　μＬ）を加え水素雰囲気下、室温で１８時間撹拌した。反応液に酢酸エチルを加え不溶物をろ去後、ろ液を減圧下で濃縮した。得られた残渣に１Ｎ水酸化ナトリウム水溶液を加えて中和し、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をアミノカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（２６２　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.56-1.67 (2H, m), 1.85-1.94 (2H, m), 2.13 (3H, s), 2.17-2.32 (1H, m), 2.39 (3H, s), 2.52-2.78 (3H, br m), 2.98-3.15 (6H, m), 3.17-3.26 (2H, m), 3.29-3.47 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.53-4.60 (0.5H, br m), 4.63-4.72 (0.5H, br m), 4.75-4.85 (1H, m), 5.04-5.11 (0.5H, br m), 5.16-5.25 (0.5H, br m), 6.74-6.85 (3H, m), 7.10 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.61 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 634 (M+H)+。
（３１ｄ）　１－［４－メチル－５－（４－｛１－［（１－メチル－１Ｈ－ピロール－２－イル）カルボニル］ピペリジン－４－イル｝フェノキシ）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（３１ｃ）で得られた化合物（２６２　ｍｇ）のクロロホルム（１５　ｍＬ）溶液に２，３－ジクロロ－５，６－ジシアノ－１，４－ベンゾキノン（１９７　ｍｇ）を２時間おきに３回で加え、７５℃で６時間撹拌した。反応液に水を加え、ジクロロメタンで抽出した。有機層を水で３回および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をアミノカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（３４．７　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.59-1.73 (2H, m), 1.85-1.95 (2H, m), 2.13 (3H, s), 2.69-2.79 (1H, m), 2.92-3.04 (2H, m), 3.12 (3H, s), 3.17-3.26 (2H, m), 3.80 (3H, s), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.59-4.70 (2H, m), 6.07-6.10 (1H, m), 6.35-6.37 (1H, m), 6.68-6.71 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.83 (2H, d, J = 8.5 Hz), 7.12 (2H, d, J = 8.5 Hz), 7.34-7.38 (1H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 612 (M+H)+。 (31a) tert-butyl (2S, 4S) -4-fluoro-2-[(4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3- Dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) carbonyl] pyrrolidine-1-carboxylate N, N-dimethylformamide (300 mg) of the compound obtained in Example (1e) (300 mg) 8 mL) solution was added triethylamine (150 μL) and stirred at room temperature for 5 minutes. N-tert-butoxycarbonyl-cis-4-fluoro-L-proline (155 mg), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium Chloride (230 mg) was added and stirred at room temperature for 18 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 (338 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48 (9H, s), 1.52-1.66 (2H, br m), 1.81-1.97 (2H, br m), 2.13 (3H, s), 2.17-2.32 (1H, m), 2.34-2.57 (1H, br m), 2.60-2.79 (2H, br m), 3.03-3.27 (6H, m), 3.72-3.99 (3H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.61-4.87 (2H, m), 5.15 (0.5H, br s), 5.29 (0.5H, br s), 6.73-6.87 (3H, m), 7.01 -7.14 (2H, m), 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).
(31b) 1- {5- [4- (1-{[(2S, 4S) -4-fluoropyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl-2,3- Dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone hydrochloride To a solution of the compound obtained in Example (31a) (338 mg) in dichloromethane (1 mL) was added 4N dioxane hydrochloride. The solution (2 mL) was added and stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the precipitated solid was washed with ethyl acetate to obtain the title compound (308 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.61-1.74 (2H, m), 1.85-1.96 (2H, m), 2.13 (3H, s), 2.68-2.79 (2H, m), 2.80-2.92 (1H, m), 3.02-3.25 (8H, m), 3.41-3.56 (1H, m), 3.84-4.00 (2H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s ), 4.72-4.86 (1H, m), 5.04-5.18 (0.5H, br m), 5.22-5.29 (0.5H, br m), 6.77 (1H, d, J = 8.5 Hz), 6.79-6.85 (2H , m), 7.04-7.15 (2H, m), 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), 8.08 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 620 (M + H) + .
(31c) 1- {5- [4- (1-{[(2S, 4S) -4-fluoro-1-methylpyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl- 2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone The compound (308 mg) obtained in Example (31b) was dissolved in methanol (6 mL) and dichloromethane ( 2 mL), 7.5% palladium carbon (75.0 mg), 37% formaldehyde solution (1.75 mL) and hydrochloric acid (288 μL) were added, and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. Ethyl acetate was added to the reaction solution, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was neutralized with 1N aqueous sodium hydroxide solution, 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 amino column chromatography (ethyl acetate / dichloromethane) to give the title compound (262 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.56-1.67 (2H, m), 1.85-1.94 (2H, m), 2.13 (3H, s), 2.17-2.32 (1H, m), 2.39 (3H , s), 2.52-2.78 (3H, br m), 2.98-3.15 (6H, m), 3.17-3.26 (2H, m), 3.29-3.47 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.53-4.60 (0.5H, br m), 4.63-4.72 (0.5H, br m), 4.75-4.85 (1H, m), 5.04-5.11 (0.5H, br m ), 5.16-5.25 (0.5H, br m), 6.74-6.85 (3H, m), 7.10 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.61 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 634 (M + H) + .
(31d) 1- [4-Methyl-5- (4- {1-[(1-methyl-1H-pyrrol-2-yl) carbonyl] piperidin-4-yl} phenoxy) -2,3-dihydro-1H -Indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone To a solution of the compound obtained in Example (31c) (262 mg) in chloroform (15 mL) was added 2,3-dichloro-5, 6-Dicyano-1,4-benzoquinone (197 mg) was added 3 times every 2 hours and stirred at 75 ° C. for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed 3 times with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amino column chromatography (ethyl acetate / dichloromethane) to give the title compound (34.7 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.59-1.73 (2H, m), 1.85-1.95 (2H, m), 2.13 (3H, s), 2.69-2.79 (1H, m), 2.92-3.04 (2H, m), 3.12 (3H, s), 3.17-3.26 (2H, m), 3.80 (3H, s), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.59- 4.70 (2H, m), 6.07-6.10 (1H, m), 6.35-6.37 (1H, m), 6.68-6.71 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.83 (2H, d, J = 8.5 Hz), 7.12 (2H, d, J = 8.5 Hz), 7.34-7.38 (1H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H , d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 612 (M + H) + .
　（実施例３２）
１－｛５－［４－（１－｛［（２Ｓ）－１－アセチルピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン (Example 32)
1- {5- [4- (1-{[(2S) -1-acetylpyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indole -1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059
　実施例（１ｅ）で得られた化合物（２００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液にトリエチルアミン（１００　μＬ）を加え、室温で５分間攪拌した。次いでＮ－アセチル－Ｌ－プロリン（６９．７　ｍｇ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（１５３　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１８６　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ:1.54-1.74 (2H, m), 1.80-2.03 (5H, m), 2.09-2.22 (7H, m), 2.57-2.76 (2H, m), 3.07-3.32 (6H, m), 3.48-3.58 (1H, m), 3.67-3.76 (1H, m), 4.02-4.15 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.68-4.79 (1H, m), 4.87-4.98 (1H, m), 6.74-6.87 (3H, m), 7.06-7.17 (2H, 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), 8.07 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 644 (M+H)+。 Triethylamine (100 μL) was added to a solution of the compound (200 mg) obtained in Example (1e) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes. Next, N-acetyl-L-proline (69.7 mg) and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (153 mg) were added. And stirred at room temperature for 18 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 amino silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (186 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.54-1.74 (2H, m), 1.80-2.03 (5H, m), 2.09-2.22 (7H, m), 2.57-2.76 (2H, m), 3.07 -3.32 (6H, m), 3.48-3.58 (1H, m), 3.67-3.76 (1H, m), 4.02-4.15 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H , s), 4.68-4.79 (1H, m), 4.87-4.98 (1H, m), 6.74-6.87 (3H, m), 7.06-7.17 (2H, 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), 8.07 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 644 (M + H) + .
　（実施例３３）
　（実施例３３－１）：実施例（３３ｂ）で合成
１－｛５－［４－（１－｛［（２Ｓ，４Ｒ）－４－フルオロピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン (Example 33)
Example 33-1: synthesized in Example (33b) 1- {5- [4- (1-{[(2S, 4R) -4-fluoropyrrolidin-2-yl] carbonyl} piperidin-4-yl ) Phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060
　（実施例３３－２）：実施例（３３ｃ）で合成
１－｛５－［４－（１－｛［（２Ｓ，４Ｒ）－1－アセチル－４－フルオロピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン Example 33-2: Synthesis in Example (33c) 1- {5- [4- (1-{[(2S, 4R) -1-acetyl-4-fluoropyrrolidin-2-yl] carbonyl} piperidine -4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061
（３３ａ）　ｔｅｒｔ－ブチル　（２Ｓ，４Ｒ）－４－フルオロ－２－［（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）カルボニル］ピロリジン－１－カルボキシレート
　実施例（１ｅ）で得られた化合物（３００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にトリエチルアミン（１５０　μＬ）を加え、室温で５分間攪拌した。次いでＮ－ｔｅｒｔ－ブトキシカルボニル－トランス－４－フルオロ－Ｌ－プロリン（１５５　ｍｇ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（２３０　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（３２７　ｍｇ）を黄色油状物として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.47 (9H, s), 1.51-1.75 (2H, m), 1.80-2.02 (2H, m), 2.07-2.27 (4H, m), 2.38-2.59 (1H, m), 2.61-2.79 (2H, m), 3.12 (3H, s), 3.15-3.27 (3H, m), 3.58-4.07 (3H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.69-4.98 (2H, m), 5.10-5.35 (1H, m), 6.73-6.88 (3H, m), 7.02-7.16 (2H, m), 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)。
（３３ｂ）　１－｛５－［４－（１－｛［（２Ｓ，４Ｒ）－４－フルオロピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（３３ａ）で得られた化合物（２７８　ｍｇ）のジクロロメタン（１．５　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（３　ｍＬ）を加え、室温で５時間撹拌した。減圧下にて溶媒を留去し、残渣に飽和炭酸水素ナトリウム水溶液を加えて中和し、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮することで標記化合物（１５５　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.59-1.75 (2H, m), 1.86-1.97 (2H, m), 2.13 (3H, s), 2.27-2.44 (1H, m), 2.64-2.80 (2H, m), 3.05-3.26 (9H, m), 3.31-3.51 (1H, m), 3.99-4.07 (1H, m), 4.16-4.26 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.71-4.82 (1H, m), 5.18-5.24 (0.5H, br m), 5.33-5.38 (0.5H, br m), 6.77 (1H, d, J = 8.5 Hz), 6.80-6.85 (2H, m), 7.03-7.14 (2H, m), 7.36 (1H, d, J = 7.3 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).
MS(APCI) m/z: 620 (M+H)+。
（３３ｃ）　１－｛５－［４－（１－｛［（２Ｓ，４Ｒ）－１－アセチル－４－フルオロピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（３３ｂ）で得られた化合物（３０．０　ｍｇ）のジクロロメタン（２　ｍＬ）溶液に無水酢酸（５４．９　μＬ）を加え、室温で１８時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン→メタノール／ジクロロメタン）で精製することで、標記化合物（３３．２　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.46-1.60 (2H, m), 1.95-2.15 (10H, m), 2.62-2.78 (2H, m), 3.06-3.15 (4H, m), 3.15-3.26 (2H, m), 3.76-4.00 (2H, m), 4.04-4.32 (3H, m), 4.36 (2H, s), 4.63-4.78 (1H, m), 5.01-5.13 (1H, m), 5.23-5.29 (0.5H, m), 5.36-5.44 (0.5H, m), 6.70-6.84 (3H, m), 7.02-7.16 (2H, m), 7.32-7.40 (1H, m), 7.47-7.55 (1H, m), 7.57-7.65 (1H, m), 7.92-7.99 (1H, m), 8.02-8.09 (1H, m).
MS(APCI) m/z: 662 (M+H)+。 (33a) tert-butyl (2S, 4R) -4-fluoro-2-[(4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3- Dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) carbonyl] pyrrolidine-1-carboxylate N, N-dimethylformamide (300 mg) of the compound obtained in Example (1e) (300 mg) 5 mL) solution was added triethylamine (150 μL) and stirred at room temperature for 5 minutes. N-tert-butoxycarbonyl-trans-4-fluoro-L-proline (155 mg), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium Chloride (230 mg) was added and stirred at room temperature for 18 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 (327 mg) as a yellow oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.47 (9H, s), 1.51-1.75 (2H, m), 1.80-2.02 (2H, m), 2.07-2.27 (4H, m), 2.38-2.59 (1H, m), 2.61-2.79 (2H, m), 3.12 (3H, s), 3.15-3.27 (3H, m), 3.58-4.07 (3H, m), 4.29 (2H, t, J = 8.5 Hz ), 4.36 (2H, s), 4.69-4.98 (2H, m), 5.10-5.35 (1H, m), 6.73-6.88 (3H, m), 7.02-7.16 (2H, m), 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).
(33b) 1- {5- [4- (1-{[(2S, 4R) -4-fluoropyrrolidin-2-yl] carbonyl} piperidin-4-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 (33a) (278 mg) in dichloromethane (1.5 mL) was added 4N dioxane hydrochloride. Solution (3 mL) was added and stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the residue was neutralized with a saturated aqueous sodium hydrogen carbonate solution, 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 to give the title compound (155 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.59-1.75 (2H, m), 1.86-1.97 (2H, m), 2.13 (3H, s), 2.27-2.44 (1H, m), 2.64-2.80 (2H, m), 3.05-3.26 (9H, m), 3.31-3.51 (1H, m), 3.99-4.07 (1H, m), 4.16-4.26 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.71-4.82 (1H, m), 5.18-5.24 (0.5H, br m), 5.33-5.38 (0.5H, br m), 6.77 (1H, d, J = 8.5 Hz), 6.80-6.85 (2H, m), 7.03-7.14 (2H, m), 7.36 (1H, d, J = 7.3 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).
MS (APCI) m / z: 620 (M + H) + .
(33c) 1- {5- [4- (1-{[(2S, 4R) -1-acetyl-4-fluoropyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl- 2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone A solution of the compound (30.0 mg) obtained in Example (33b) in dichloromethane (2 mL) Acetic anhydride (54.9 μL) was added to the solution and stirred at room temperature for 18 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 amino silica gel column chromatography (ethyl acetate / dichloromethane → methanol / dichloromethane) to give the title compound (33.2 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.46-1.60 (2H, m), 1.95-2.15 (10H, m), 2.62-2.78 (2H, m), 3.06-3.15 (4H, m), 3.15 -3.26 (2H, m), 3.76-4.00 (2H, m), 4.04-4.32 (3H, m), 4.36 (2H, s), 4.63-4.78 (1H, m), 5.01-5.13 (1H, m) , 5.23-5.29 (0.5H, m), 5.36-5.44 (0.5H, m), 6.70-6.84 (3H, m), 7.02-7.16 (2H, m), 7.32-7.40 (1H, m), 7.47- 7.55 (1H, m), 7.57-7.65 (1H, m), 7.92-7.99 (1H, m), 8.02-8.09 (1H, m).
MS (APCI) m / z: 662 (M + H) + .
　（実施例３４）
１－｛５－［４－（１－｛［（２Ｓ，４Ｓ）－１－アセチル－４－フルオロピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン (Example 34)
1- {5- [4- (1-{[(2S, 4S) -1-acetyl-4-fluoropyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl-2,3 -Dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062
　実施例（１ｅ）で得られた化合物（５０．０　ｍｇ）のジクロロメタン（２　ｍＬ）溶液にトリエチルアミン（２２．０　μＬ）、無水酢酸（９１．５　μＬ）を加え、室温で１８時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（５５．１　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.51-1.70 (2H, m), 1.78-2.02 (3H, m), 2.13 (6H, s), 2.17-2.35 (1H, m), 2.63-2.77 (2H, m), 3.12 (3H, s), 3.15-3.28 (3H, m), 3.83-4.06 (3H, m), 4.29 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 4.65-4.80 (1H, m), 4.96-5.08 (1H, m), 5.22-5.29 (0.6H, m), 5.37-5.41 (0.4H, m), 6.73-6.86 (3H, m), 7.07-7.15 (2H, m), 7.36 (1H, d, J = 7.3 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 662 (M+H)+。 Triethylamine (22.0 μL) and acetic anhydride (91.5 μL) were added to a solution of the compound (50.0 mg) obtained in Example (1e) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 18 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 amino silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (55.1 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.51-1.70 (2H, m), 1.78-2.02 (3H, m), 2.13 (6H, s), 2.17-2.35 (1H, m), 2.63-2.77 (2H, m), 3.12 (3H, s), 3.15-3.28 (3H, m), 3.83-4.06 (3H, m), 4.29 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 4.65-4.80 (1H, m), 4.96-5.08 (1H, m), 5.22-5.29 (0.6H, m), 5.37-5.41 (0.4H, m), 6.73-6.86 (3H, m), 7.07-7.15 (2H, m), 7.36 (1H, d, J = 7.3 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 662 (M + H) + .
　（実施例３５）：実施例（３５ｂ）で合成
（５Ｓ）－５－［（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）カルボニル］ピロリジン－２－オン Example 35: Synthesis in Example (35b) (5S) -5-[(4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3 -Dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) carbonyl] pyrrolidin-2-one
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063
（３５ａ）　ベンジル　（２Ｓ）－２－［（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）カルボニル］－５－オキソピロリジン－１－カルボキシレート
　実施例（１ｅ）で得られた化合物（２００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（４　ｍＬ）溶液にトリエチルアミン（１００　μＬ）を加え、室温で５分間攪拌した。次いでベンジルオキシ－Ｌ－ピログルタミン酸（１１６　ｍｇ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（１５３　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（２２１　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.47-1.65 (2H, m), 1.81-2.00 (2H, m), 2.12 (3H, t, J = 8.9 Hz), 2.22-2.36 (1H, m), 2.43-2.56 (1H, m), 2.60-2.83 (3H, m), 3.12 (3H, s), 3.16-3.27 (3H, m), 3.84-3.95 (1H, m), 4.07-4.16 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.67-4.75 (1H, m), 5.00-5.10 (1H, m), 5.19-5.35 (2H, m), 6.71-6.84 (3H, m), 6.98-7.05 (1H, m), 7.09 (1H, d, J = 8.5 Hz), 7.22-7.40 (6H, m), 7.50-7.55 (1H, m), 7.57-7.67 (1H, m), 7.95-8.00 (1H, m), 8.07 (1H, d, J = 7.9 Hz)。
（３５ｂ）　（５Ｓ）－５－［（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）カルボニル］ピロリジン－２－オン
　実施例（３５ａ）で得られた化合物（２２１　ｍｇ）をメタノール（３　ｍＬ）及び酢酸エチル（３　ｍＬ）に溶解し、７．５％パラジウム炭素（４４．５　ｍｇ）を加え水素雰囲気下、室温で６時間撹拌した。反応液に酢酸エチルを加え不溶物をろ去し、ろ液を減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１６２　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.56-1.69 (2H, m), 1.87-1.99 (2H, m), 2.08-2.21 (4H, m), 2.33-2.57 (3H, m), 2.66-2.79 (2H, m), 3.12 (3H, s), 3.15-3.26 (3H, m), 3.82-3.91 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.50-4.58 (1H, m), 4.69-4.80 (1H, m), 5.81 (1H, br s), 6.76 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.47-7.55 (1H, m), 7.57-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 616 (M+H)+。 (35a) Benzyl (2S) -2-[(4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole-5 Yl) oxy] phenyl} piperidin-1-yl) carbonyl] -5-oxopyrrolidine-1-carboxylate N, N-dimethylformamide (4 mL) solution of the compound obtained in Example (1e) (200 mg) Triethylamine (100 μL) was added to the mixture and stirred at room temperature for 5 minutes. Subsequently, benzyloxy-L-pyroglutamic acid (116 mg), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (153 mg) were added, and room temperature was added. For 18 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 (221 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.47-1.65 (2H, m), 1.81-2.00 (2H, m), 2.12 (3H, t, J = 8.9 Hz), 2.22-2.36 (1H, m ), 2.43-2.56 (1H, m), 2.60-2.83 (3H, m), 3.12 (3H, s), 3.16-3.27 (3H, m), 3.84-3.95 (1H, m), 4.07-4.16 (1H , m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.67-4.75 (1H, m), 5.00-5.10 (1H, m), 5.19-5.35 (2H, m), 6.71-6.84 (3H, m), 6.98-7.05 (1H, m), 7.09 (1H, d, J = 8.5 Hz), 7.22-7.40 (6H, m), 7.50-7.55 (1H, m), 7.57- 7.67 (1H, m), 7.95-8.00 (1H, m), 8.07 (1H, d, J = 7.9 Hz).
(35b) (5S) -5-[(4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) ) Oxy] phenyl} piperidin-1-yl) carbonyl] pyrrolidin-2-one The compound (221 mg) obtained in Example (35a) was dissolved in methanol (3 mL) and ethyl acetate (3 mL). 0.5% palladium carbon (44.5 mg) was added, and the mixture was stirred at room temperature for 6 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. The obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (162 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.56-1.69 (2H, m), 1.87-1.99 (2H, m), 2.08-2.21 (4H, m), 2.33-2.57 (3H, m), 2.66 -2.79 (2H, m), 3.12 (3H, s), 3.15-3.26 (3H, m), 3.82-3.91 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s ), 4.50-4.58 (1H, m), 4.69-4.80 (1H, m), 5.81 (1H, br s), 6.76 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz) ), 7.09 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.47-7.55 (1H, m), 7.57-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 616 (M + H) + .
　（実施例３６）
（５Ｓ）－１－メチル－５－［（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）カルボニル］ピロリジン－２－オン (Example 36)
(5S) -1-methyl-5-[(4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole-5 Yl) oxy] phenyl} piperidin-1-yl) carbonyl] pyrrolidin-2-one
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
　実施例（１ｅ）で得られた化合物（２００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（４　ｍＬ）溶液にトリエチルアミン（１００　μＬ）を加え、室温で５分間攪拌した。次いで文献記載の方法（Ｂｉｏｏｒｇａｎｉｃ　ａｎｄ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ　Ｌｅｔｔｅｒｓ，２０１０，２０，５０８０）に従って合成した１－メチル－５－オキソ－Ｌ－プロリン（６６．２　ｍｇ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（１５３　ｍｇ）を加え、室温で１８時間攪拌した。反応混合物に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン→メタノール／ジクロロメタン）で精製することで、標記化合物（５．３　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.53-1.68 (2H, m), 1.89-2.02 (3H, m), 2.13 (3H, s), 2.29-2.42 (2H, m), 2.46-2.59 (1H, m), 2.65-2.79 (2H, m), 2.85 (3H, d, J = 11.0 Hz), 3.12 (3H, s), 3.16-3.28 (3H, m), 3.86-3.96 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.41-4.46 (1H, m), 4.72-4.82 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.80-6.87 (2H, m), 7.07-7.13 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.49-7.53 (1H, m), 7.58-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 630 (M+H)+。 Triethylamine (100 μL) was added to a solution of the compound (200 mg) obtained in Example (1e) in N, N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 5 minutes. Subsequently, 1-methyl-5-oxo-L-proline (66.2 mg), 4- (4,6-dimethoxy-1, 3,5-Triazin-2-yl) -4-methylmorpholinium chloride (153 mg) was added, and the mixture was stirred at room temperature for 18 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 → methanol / dichloromethane) to give the title compound (5.3 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.53-1.68 (2H, m), 1.89-2.02 (3H, m), 2.13 (3H, s), 2.29-2.42 (2H, m), 2.46-2.59 (1H, m), 2.65-2.79 (2H, m), 2.85 (3H, d, J = 11.0 Hz), 3.12 (3H, s), 3.16-3.28 (3H, m), 3.86-3.96 (1H, m ), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.41-4.46 (1H, m), 4.72-4.82 (1H, m), 6.77 (1H, d, J = 8.5 Hz) , 6.80-6.87 (2H, m), 7.07-7.13 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.49-7.53 (1H, m), 7.58-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 630 (M + H) + .
　（実施例３７）
　（実施例３７－１）：実施例（３７ｂ）で合成
１－｛５－［４－（１－｛［（２Ｓ）－４,４－ジフルオロピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン塩酸塩 (Example 37)
Example 37-1: synthesized in Example (37b) 1- {5- [4- (1-{[(2S) -4,4-difluoropyrrolidin-2-yl] carbonyl} piperidin-4-yl ) Phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone hydrochloride
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065
　（実施例３７－２）：実施例（３７ｃ）で合成
１－｛５－［４－（１－｛［（２Ｓ）－１－アセチル－４，４－ジフルオロピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン Example 37-2: Synthesis in Example (37c) 1- {5- [4- (1-{[(2S) -1-acetyl-4,4-difluoropyrrolidin-2-yl] carbonyl} piperidine -4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066
（３７ａ）　ｔｅｒｔ－ブチル　（２Ｓ）－４，４－ジフルオロ－２－［（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）カルボニル］ピロリジン－１－カルボキシレート
　実施例（１ｅ）で得られた化合物（５２４　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にトリエチルアミン（２７０　μＬ）を加え、室温で５分間攪拌した。次いでＮ－ｔｅｒｔ－ブトキシカルボニル－４，４－ジフルオロ－Ｌ－プロリン（２９２　ｍｇ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（４０２　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（５１５　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.47 (9H, s), 1.50-1.73 (2H, m), 1.81-1.99 (2H, m), 2.12 (3H, s), 2.21-2.49 (1H, m), 2.58-2.78 (3H, m), 3.06-3.32 (6H, m), 3.78-4.04 (3H, m), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.67-4.83 (1H, m), 4.86-4.99 (1H, m), 6.72-6.88 (3H, m), 7.02-7.15 (2H, m), 7.32-7.40 (1H, m), 7.47-7.56 (1H, m), 7.57-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 6.7 Hz)。
（３７ｂ）　１－｛５－［４－（１－｛［（２Ｓ）－４,４－ジフルオロピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン塩酸塩
　実施例（３７ａ）で得られた化合物（５１５　ｍｇ）のジクロロメタン（１　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（２　ｍＬ）を加え、室温で４時間撹拌した。減圧下にて溶媒を留去し、析出した固体を酢酸エチルで洗浄することで、標記化合物（４８４　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, DMSO-d6) δ: 1.39-1.69 (2H, m), 1.76-1.88 (2H, m), 2.05 (3H, s), 2.53-2.69 (1H, m), 2.72-2.83 (2H, m), 2.92-3.23 (7H, m), 3.62-3.87 (3H, m), 4.23-4.36 (4H, m), 4.43-4.54 (1H, m), 4.96 (0.5H, t, J = 8.5 Hz), 5.04 (0.5H, t, J = 8.5 Hz), 6.71-6.83 (3H, m), 7.14-7.26 (2H, m), 7.48 (1H, d, J = 7.9 Hz), 7.55-7.60 (1H, m), 7.68-7.71 (1H, m), 7.84 (1H, d, J = 8.5 Hz), 7.97 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 638 (M+H)+。
（３７ｃ）　１－｛５－［４－（１－｛［（２Ｓ）－１－アセチル－４，４－ジフルオロピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（３７ｂ）で得られた化合物（３２．７　ｍｇ）のジクロロメタン（３　ｍＬ）溶液にトリエチルアミン（１４．０　μＬ）、無水酢酸（５．８２　μＬ）を加え、室温で３時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１７．２　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.53-1.67 (2H, m), 1.82-2.19 (10H, m), 2.59-2.81 (2H, m), 3.12 (2H, s), 3.16-3.28 (6H, m), 3.46-3.56 (1H, m), 4.24-4.32 (2H, m), 4.36 (2H, s), 4.66-4.78 (1H, m), 5.05-5.17 (1H, m), 6.74-6.87 (3H, m), 7.06-7.15 (2H, m), 7.36 (1H, d, J = 7.3 Hz), 7.49-7.55 (1H, m), 7.58-7.68 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 680 (M+H)+。 (37a) tert-butyl (2S) -4,4-difluoro-2-[(4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3- Dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) carbonyl] pyrrolidine-1-carboxylate N, N-dimethylformamide of the compound (524 mg) obtained in Example (1e) ( 5 mL) solution was added triethylamine (270 μL) and stirred at room temperature for 5 minutes. N-tert-butoxycarbonyl-4,4-difluoro-L-proline (292 mg), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium Chloride (402 mg) was added and stirred at room temperature for 18 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 (515 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.47 (9H, s), 1.50-1.73 (2H, m), 1.81-1.99 (2H, m), 2.12 (3H, s), 2.21-2.49 (1H , m), 2.58-2.78 (3H, m), 3.06-3.32 (6H, m), 3.78-4.04 (3H, m), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.67-4.83 (1H, m), 4.86-4.99 (1H, m), 6.72-6.88 (3H, m), 7.02-7.15 (2H, m), 7.32-7.40 (1H, m), 7.47-7.56 (1H , m), 7.57-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 6.7 Hz).
(37b) 1- {5- [4- (1-{[(2S) -4,4-Difluoropyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl-2,3- Dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone hydrochloride To a solution of the compound obtained in Example (37a) (515 mg) in dichloromethane (1 mL) was added 4N dioxane hydrochloride. The solution (2 mL) was added and stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the precipitated solid was washed with ethyl acetate to obtain the title compound (484 mg) as a white solid.
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 1.39-1.69 (2H, m), 1.76-1.88 (2H, m), 2.05 (3H, s), 2.53-2.69 (1H, m), 2.72 -2.83 (2H, m), 2.92-3.23 (7H, m), 3.62-3.87 (3H, m), 4.23-4.36 (4H, m), 4.43-4.54 (1H, m), 4.96 (0.5H, t , J = 8.5 Hz), 5.04 (0.5H, t, J = 8.5 Hz), 6.71-6.83 (3H, m), 7.14-7.26 (2H, m), 7.48 (1H, d, J = 7.9 Hz), 7.55-7.60 (1H, m), 7.68-7.71 (1H, m), 7.84 (1H, d, J = 8.5 Hz), 7.97 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 638 (M + H) + .
(37c) 1- {5- [4- (1-{[(2S) -1-acetyl-4,4-difluoropyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl- 2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone A solution of the compound obtained in Example (37b) (32.7 mg) in dichloromethane (3 mL) Were added triethylamine (14.0 μL) and acetic anhydride (5.82 μL), and the mixture was stirred at room temperature for 3 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 amino silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (17.2 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.53-1.67 (2H, m), 1.82-2.19 (10H, m), 2.59-2.81 (2H, m), 3.12 (2H, s), 3.16-3.28 (6H, m), 3.46-3.56 (1H, m), 4.24-4.32 (2H, m), 4.36 (2H, s), 4.66-4.78 (1H, m), 5.05-5.17 (1H, m), 6.74 -6.87 (3H, m), 7.06-7.15 (2H, m), 7.36 (1H, d, J = 7.3 Hz), 7.49-7.55 (1H, m), 7.58-7.68 (1H, m), 7.97 (1H , d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 680 (M + H) + .
　（実施例３８）
１－｛５－［４－（１－｛［（２Ｒ）－１－アセチルピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン (Example 38)
1- {5- [4- (1-{[(2R) -1-acetylpyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indole -1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067
　実施例（１ｅ）で得られた化合物（１５０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（４　ｍＬ）溶液にトリエチルアミン（７７．０　μＬ）を加え、室温で５分間攪拌した。次いでＮ－アセチル－Ｄ－プロリン（５９．３　ｍｇ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（１１５　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１０９　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.54-1.74 (2H, m), 1.80-2.03 (5H, m), 2.09-2.22 (7H, m), 2.57-2.76 (2H, m), 3.07-3.32 (6H, m), 3.48-3.58 (1H, m), 3.67-3.76 (1H, m), 4.02-4.15 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.68-4.79 (1H, m), 4.87-4.98 (1H, m), 6.74-6.87 (3H, m), 7.06-7.17 (2H, 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), 8.07 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 644 (M+H)+。 Triethylamine (77.0 μL) was added to a solution of the compound (150 mg) obtained in Example (1e) in N, N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 5 minutes. Next, N-acetyl-D-proline (59.3 mg) and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (115 mg) were added. And stirred at room temperature for 18 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 (109 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.54-1.74 (2H, m), 1.80-2.03 (5H, m), 2.09-2.22 (7H, m), 2.57-2.76 (2H, m), 3.07 -3.32 (6H, m), 3.48-3.58 (1H, m), 3.67-3.76 (1H, m), 4.02-4.15 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H , s), 4.68-4.79 (1H, m), 4.87-4.98 (1H, m), 6.74-6.87 (3H, m), 7.06-7.17 (2H, 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), 8.07 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 644 (M + H) + .
　（実施例３９）
　（実施例３９－１）：実施例（３９ａ）で合成
１－（４－｛４－［（４－メチル－１－｛［２－（エチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－１－オキソプロパン－２－イル　アセテート (Example 39)
Example 39-1: Synthesis in Example (39a) 1- (4- {4-[(4-Methyl-1-{[2- (ethylsulfonyl) phenyl] acetyl} -2,3-dihydro- 1H-Indol-5-yl) oxy] phenyl} piperidin-1-yl) -1-oxopropan-2-yl acetate
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068
　（実施例３９－２）：実施例（３９ｂ）で合成
２－ヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（エチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）プロパン－１－オン Example 39-2: synthesized in Example (39b) 2-hydroxy-1- (4- {4-[(4-methyl-1-{[2- (ethylsulfonyl) phenyl] acetyl} -2, 3-Dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) propan-1-one
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069
（３９ａ）　１－（４－｛４－［（４－メチル－１－｛［２－（エチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－１－オキソプロパン－２－イル　アセテート
　実施例（２ｄ）で得られた化合物（６０．０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液にトリエチルアミン（３０．０　μＬ）を加え、室温で５分間攪拌した。次いで４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（４４．９　ｍｇ）及び（±）－２－アセトキシプロピオン酸（１４．６　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（４０．９　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) : 1.26 (3H, t, J = 6.7 Hz), 1.43-1.49 (3H, m), 1.50-1.60 (2H, m), 1.78-1.96 (2H, m), 2.12 (3H, s), 2.14 (3H, s), 2.60-2.77 (2H, m), 3.15-3.24 (5H, m), 3.88-4.01 (1H, br m), 4.27 (2H, t, J = 8.2 Hz), 4.37 (2H, s), 4.68-4.80 (1H, br m), 5.40-5.48 (1H, m), 6.72-6.85 (3H, m), 7.06-7.15 (2H, m), 7.39 (1H, d, J = 6.7 Hz), 7.50 (1H, t, J = 7.0 Hz), 7.62 (1H, t, J = 7.0 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 6.7 Hz)。
（３９ｂ）　２－ヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（エチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）プロパン－１－オン
　実施例（３９ａ）で得られた化合物（１６０　ｍｇ）のテトラヒドロフラン（１０　ｍＬ）とメタノール（２　ｍＬ）の混合溶液に１Ｎ水酸化ナトリウム水溶液（３９０　μＬ）を加え、室温で４８時間撹拌した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（８５．６　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.26 (3H, t, J = 7.3 Hz), 1.35 (3H, dd, J = 13.4, 6.7 Hz), 1.57-1.68 (2H, m), 1.87-2.00 (2H, m), 2.12 (3H, s), 2.65-2.82 (2H, m), 3.13-3.24 (5H, m), 3.76-3.85 (1H, m), 3.90-3.95 (1H, m), 4.27 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 4.45-4.53 (1H, m), 4.68-4.80 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.07-7.12 (2H, m), 7.39 (1H, d, J = 7.9 Hz), 7.47-7.54 (1H, m), 7.59-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 591 (M+H)+。 (39a) 1- (4- {4-[(4-Methyl-1-{[2- (ethylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} Piperidin-1-yl) -1-oxopropan-2-yl acetate To a solution of the compound obtained in Example (2d) (60.0 mg) in N, N-dimethylformamide (3 mL), triethylamine (30.0 μL) was added and stirred at room temperature for 5 minutes. Then 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (44.9 mg) and (±) -2-acetoxypropionic acid (14.6 mg) was added and stirred at room temperature for 18 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 (40.9 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ): 1.26 (3H, t, J = 6.7 Hz), 1.43-1.49 (3H, m), 1.50-1.60 (2H, m), 1.78-1.96 (2H, m) , 2.12 (3H, s), 2.14 (3H, s), 2.60-2.77 (2H, m), 3.15-3.24 (5H, m), 3.88-4.01 (1H, br m), 4.27 (2H, t, J = 8.2 Hz), 4.37 (2H, s), 4.68-4.80 (1H, br m), 5.40-5.48 (1H, m), 6.72-6.85 (3H, m), 7.06-7.15 (2H, m), 7.39 (1H, d, J = 6.7 Hz), 7.50 (1H, t, J = 7.0 Hz), 7.62 (1H, t, J = 7.0 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H , d, J = 6.7 Hz).
(39b) 2-hydroxy-1- (4- {4-[(4-methyl-1-{[2- (ethylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) Oxy] phenyl} piperidin-1-yl) propan-1-one 1N aqueous sodium hydroxide solution in a mixed solution of the compound obtained in Example (39a) (160 mg) in tetrahydrofuran (10 mL) and methanol (2 mL) (390 μL) was added and stirred at room temperature for 48 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to obtain the title compound (85.6 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.35 (3H, dd, J = 13.4, 6.7 Hz), 1.57-1.68 (2H, m), 1.87- 2.00 (2H, m), 2.12 (3H, s), 2.65-2.82 (2H, m), 3.13-3.24 (5H, m), 3.76-3.85 (1H, m), 3.90-3.95 (1H, m), 4.27 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 4.45-4.53 (1H, m), 4.68-4.80 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.07-7.12 (2H, m), 7.39 (1H, d, J = 7.9 Hz), 7.47-7.54 (1H, m), 7.59-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 591 (M + H) + .
　（実施例４０）：実施例（４０ｂ）で合成
（２Ｓ）－１－（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－２－ヒドロキシプロパン－１－オン Example 40: Synthesis in Example (40b) (2S) -1- (4- {4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3- Dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) -2-hydroxypropan-1-one
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070
（４０ａ）　（２Ｓ）－２－（ベンジルオキシ）－１－（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）プロパン－１－オン
　実施例（２ｄ）で得られた化合物（８０．０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液にトリエチルアミン（２９．２　μＬ）を加え、室温で５分間攪拌した。次いで４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（６０．０　ｍｇ）及びＯ－ベンジル－Ｄ－酪酸（３１．２　ｍｇ）を加え、室温で２４時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（７７．８　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.26 (3H, t, J = 7.3 Hz), 1.47 (3H, d, J = 6.7 Hz), 1.50-1.62 (2H, m), 1.78-1.93 (2H, br m), 2.12 (3H, s), 2.59-2.75 (2H, m), 2.96-3.11 (1H, m), 3.13-3.25 (4H, m), 4.23-4.32 (2H, m), 4.33-4.41 (4H, m), 4.42-4.49 (1H, m), 4.56-4.68 (1H, m), 4.73-4.82 (1H, m), 6.77 (1H, d, J = 9.2 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.07 (2H, d, J = 8.5 Hz), 7.32-7.36 (5H, m), 7.39 (1H, d, J = 6.7 Hz), 7.50 (1H, t, J = 7.0 Hz), 7.62 (1H, t, J = 7.0 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 6.7 Hz)。
（４０ｂ）　（２Ｓ）－１－（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－２－ヒドロキシプロパン－１－オン
　実施例（４０ａ）で得られた化合物（１６０　ｍｇ）をエタノール（２　ｍＬ）及び酢酸エチル（２　ｍＬ）に溶解し、７．５％パラジウム炭素（１５．６　ｍｇ）を加え水素雰囲気下、室温で１８時間撹拌した。反応液に酢酸エチルを加え不溶物をろ去し、ろ液を減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン→メタノール／酢酸エチル）で精製することで、標記化合物（４５．９　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.26 (3H, t, J = 7.3 Hz), 1.35 (3H, dd, J = 13.4, 6.7 Hz), 1.56-1.69 (2H, m), 1.86-1.98 (2H, m), 2.12 (3H, s), 2.66-2.79 (2H, m), 3.07-3.24 (5H, m), 3.76-3.85 (1H, m), 3.90-3.95 (1H, m), 4.27 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 4.44-4.53 (1H, m), 4.69-4.82 (1H, m), 6.71-6.87 (3H, m), 7.05-7.12 (2H, m), 7.39 (1H, d, J = 7.3 Hz), 7.50 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 7.9 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 591 (M+H)+。 (40a) (2S) -2- (Benzyloxy) -1- (4- {4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H -Indol-5-yl) oxy] phenyl} piperidin-1-yl) propan-1-one A solution of the compound obtained in Example (2d) (80.0 mg) in N, N-dimethylformamide (3 mL) Triethylamine (29.2 μL) was added to the solution and stirred at room temperature for 5 minutes. Then 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (60.0 mg) and O-benzyl-D-butyric acid (31.2 mg) And stirred at room temperature for 24 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 / hexane) to give the title compound (77.8 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.47 (3H, d, J = 6.7 Hz), 1.50-1.62 (2H, m), 1.78-1.93 ( 2H, br m), 2.12 (3H, s), 2.59-2.75 (2H, m), 2.96-3.11 (1H, m), 3.13-3.25 (4H, m), 4.23-4.32 (2H, m), 4.33 -4.41 (4H, m), 4.42-4.49 (1H, m), 4.56-4.68 (1H, m), 4.73-4.82 (1H, m), 6.77 (1H, d, J = 9.2 Hz), 6.81 (2H , d, J = 8.5 Hz), 7.07 (2H, d, J = 8.5 Hz), 7.32-7.36 (5H, m), 7.39 (1H, d, J = 6.7 Hz), 7.50 (1H, t, J = 7.0 Hz), 7.62 (1H, t, J = 7.0 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 6.7 Hz).
(40b) (2S) -1- (4- {4-[(1-{[2- (Ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy] phenyl} piperidin-1-yl) -2-hydroxypropan-1-one The compound (160 mg) obtained in Example (40a) was dissolved in ethanol (2 mL) and ethyl acetate (2 mL). 7.5% palladium carbon (15.6 mg) was added, and the mixture was stirred at room temperature for 18 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. The obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane → methanol / ethyl acetate) to give the title compound (45.9 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.35 (3H, dd, J = 13.4, 6.7 Hz), 1.56-1.69 (2H, m), 1.86- 1.98 (2H, m), 2.12 (3H, s), 2.66-2.79 (2H, m), 3.07-3.24 (5H, m), 3.76-3.85 (1H, m), 3.90-3.95 (1H, m), 4.27 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 4.44-4.53 (1H, m), 4.69-4.82 (1H, m), 6.71-6.87 (3H, m), 7.05-7.12 ( 2H, m), 7.39 (1H, d, J = 7.3 Hz), 7.50 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 7.9 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 591 (M + H) + .
　（実施例４１）
１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－２－メトキシプロパン－１－オン (Example 41)
1- (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl } Piperidin-1-yl) -2-methoxypropan-1-one
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071
　実施例（１ｅ）で得られた化合物（４３．０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（２　ｍＬ）溶液にトリエチルアミン（３３．０　μＬ）を加え、室温で５分間攪拌した。次いで４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（３３．０　ｍｇ）及び２－メトキシプロパン酸（９．９３　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（２７．７　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.39 (3H, dd, J = 12.8, 6.7 Hz), 1.56-1.67 (2H, m), 1.85-1.94 (2H, m), 2.13 (3H, s), 2.57-2.80 (2H, m), 3.02-3.14 (4H, m), 3.17-3.24 (2H, m), 3.35 (3H, dd, J = 12.8, 6.1 Hz), 4.09-4.39 (6H, m), 4.73-4.83 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.61 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 591 (M+H)+。 Triethylamine (33.0 μL) was added to a solution of the compound (43.0 mg) obtained in Example (1e) in N, N-dimethylformamide (2 mL), and the mixture was stirred at room temperature for 5 minutes. Then 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (33.0 mg) and 2-methoxypropanoic acid (9.93 mg) were added. And stirred at room temperature for 18 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 (27.7 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.39 (3H, dd, J = 12.8, 6.7 Hz), 1.56-1.67 (2H, m), 1.85-1.94 (2H, m), 2.13 (3H, s ), 2.57-2.80 (2H, m), 3.02-3.14 (4H, m), 3.17-3.24 (2H, m), 3.35 (3H, dd, J = 12.8, 6.1 Hz), 4.09-4.39 (6H, m ), 4.73-4.83 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.36 (1H , d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.61 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d , J = 7.9 Hz).
MS (APCI) m / z: 591 (M + H) + .
　（実施例４２）
　（実施例４２－１）：実施例（４２ａ）で合成
２－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－２－オキソエチル　アセテート (Example 42)
Example 42-1: Synthesis in Example (42a) 2- (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro- 1H-Indol-5-yl) oxy] phenyl} piperidin-1-yl) -2-oxoethyl acetate
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072
　（実施例４２－２）：実施例（４２ｂ）で合成
２－ヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）エタノン Example 42-2: synthesized in Example (42b) 2-hydroxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2, 3-Dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) ethanone
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000073
（４２ａ）　２－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－２－オキソエチル　アセテート
　実施例（１ｅ）で得られた化合物（７０．０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液にトリエチルアミン（３６．０　μＬ）を加え、室温で５分間攪拌した。次いでアセトキシ酢酸（１８．３　ｍｇ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（５３．７　ｍｇ）を加え、室温で１５時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（６５．６　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.54-1.69 (2H, m), 1.84-1.96 (2H, m), 2.13 (3H, s), 2.20 (3H, s), 2.62-2.77 (2H, m), 3.07-3.25 (6H, m), 3.69-3.80 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.67-4.79 (3H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.05 (2H, t, 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).
MS(APCI) m/z: 605 (M+H)+。
（４２ｂ）　２－ヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）エタノン
　実施例（４２ａ）で得られた化合物（４５．６　ｍｇ）のテトラヒドロフラン（２．５　ｍＬ）とメタノール（１　ｍＬ）の混合溶液に１Ｎ水酸化ナトリウム水溶液（２２６　μＬ）を加え、室温で２．５時間撹拌した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（３６．８　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.51-1.69 (2H, m), 1.85-1.96 (2H, m), 2.12 (3H, s), 2.67-2.84 (2H, m), 3.01-3.15 (4H, m), 3.15-3.27 (2H, m), 3.54-3.65 (1H, m), 3.71 (1H, t, J = 4.3 Hz), 4.20 (2H, t, J = 4.3 Hz), 4.23-4.31 (2H, m), 4.36 (2H, s), 4.70-4.78 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.0 Hz), 7.62 (1H, t, J = 7.0 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 563 (M+H)+。 (42a) 2- (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} Piperidin-1-yl) -2-oxoethyl acetate To a solution of the compound (70.0 mg) obtained in Example (1e) in N, N-dimethylformamide (3 mL) was added triethylamine (36.0 μL), Stir at room temperature for 5 minutes. Next, acetoxyacetic acid (18.3 mg) and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (53.7 mg) were added, and at room temperature. Stir 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 (65.6 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.54-1.69 (2H, m), 1.84-1.96 (2H, m), 2.13 (3H, s), 2.20 (3H, s), 2.62-2.77 (2H , m), 3.07-3.25 (6H, m), 3.69-3.80 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.67-4.79 (3H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.05 (2H, t, 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).
MS (APCI) m / z: 605 (M + H) + .
(42b) 2-hydroxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) Oxy] phenyl} piperidin-1-yl) ethanone 1N aqueous sodium hydroxide solution in a mixed solution of the compound (45.6 mg) obtained in Example (42a) in tetrahydrofuran (2.5 mL) and methanol (1 mL) (226 μL) was added and stirred at room temperature for 2.5 hours. 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 (36.8 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.51-1.69 (2H, m), 1.85-1.96 (2H, m), 2.12 (3H, s), 2.67-2.84 (2H, m), 3.01-3.15 (4H, m), 3.15-3.27 (2H, m), 3.54-3.65 (1H, m), 3.71 (1H, t, J = 4.3 Hz), 4.20 (2H, t, J = 4.3 Hz), 4.23- 4.31 (2H, m), 4.36 (2H, s), 4.70-4.78 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.09 (2H , d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.0 Hz), 7.62 (1H, t, J = 7.0 Hz), 7.97 (1H, d , J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 563 (M + H) + .
　（実施例４３）
２－［２－（メチルスルホニル）フェニル］－１－｛４－メチル－５－［４－（１－｛［１Ｒ，３Ｓ，４Ｒ，５Ｓ］－１，３，４，５－テトラヒドロキシシクロヘキシル｝カルボニル）ピペリジン－４－イル］フェノキシ｝－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝エタノン (Example 43)
2- [2- (Methylsulfonyl) phenyl] -1- {4-methyl-5- [4- (1-{[1R, 3S, 4R, 5S] -1,3,4,5-tetrahydroxycyclohexyl} Carbonyl) piperidin-4-yl] phenoxy} -2,3-dihydro-1H-indol-1-yl} ethanone
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074
　実施例（１ｅ）で得られた化合物（７０．０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液にトリエチルアミン（３６．０　μＬ）を加え、室温で５分間攪拌した。次いで（１Ｒ，３Ｒ，４Ｒ，５Ｒ）－（－）－キナ酸（２９．８　ｍｇ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（５３．７　ｍｇ）を加え、室温で１５時間、さらに７５℃で２４時間撹拌した。室温まで冷却後、反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン→メタノール／酢酸エチル）で精製することで、標記化合物（１３．０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.60-1.73 (2H, m), 1.84-1.97 (2H, m), 2.07-2.50 (7H, m), 2.70-2.82 (2H, m), 3.12 (3H, s), 3.21-3.23 (2H, m), 3.41-3.52 (1H, m), 3.69-3.77 (1H, m), 3.95-4.09 (5H, m), 4.18-4.24 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.56-4.75 (2H, br m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.09 (2H, d, J = 8.5 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), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).
MS(APCI) m/z: 679 (M+H)+。 Triethylamine (36.0 μL) was added to a solution of the compound (70.0 mg) obtained in Example (1e) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes. Then (1R, 3R, 4R, 5R)-(−)-quinic acid (29.8 mg), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmol Holinium chloride (53.7 mg) was added, and the mixture was stirred at room temperature for 15 hours and further at 75 ° C. for 24 hours. After cooling to room temperature, 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 / hexane → methanol / ethyl acetate) to give the title compound (13.0 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.60-1.73 (2H, m), 1.84-1.97 (2H, m), 2.07-2.50 (7H, m), 2.70-2.82 (2H, m), 3.12 (3H, s), 3.21-3.23 (2H, m), 3.41-3.52 (1H, m), 3.69-3.77 (1H, m), 3.95-4.09 (5H, m), 4.18-4.24 (1H, m) , 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.56-4.75 (2H, br m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.09 (2H, d, J = 8.5 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) ), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).
MS (APCI) m / z: 679 (M + H) + .
　（実施例４４）
　（実施例４４－１）：実施例（４４ｂ）で合成
１－（４－メチル－５－｛４－［１－（モルホリン－２－イルカルボニル）ピペリジン－４－イル］フェノキシ｝－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン (Example 44)
Example 44-1: synthesized in Example (44b) 1- (4-methyl-5- {4- [1- (morpholin-2-ylcarbonyl) piperidin-4-yl] phenoxy} -2,3 -Dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000075
　（実施例４４－２）：実施例（４４ｃ）で合成
１－［５－（４－｛１－［（４－エチルモルホリン－２－イル）カルボニル］ピペリジン－４－イル｝フェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン Example 44-2: Synthesis in Example (44c) 1- [5- (4- {1-[(4-ethylmorpholin-2-yl) carbonyl] piperidin-4-yl} phenoxy) -4- Methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076
（４４ａ）　１－［５－（４－｛１－［（４－ベンジルモルホリン－２－イル）カルボニル］ピペリジン－４－イル｝フェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（１ｅ）で得られた化合物（７０．０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液にトリエチルアミン（７２．０　μＬ）を加え、室温で５分間攪拌した。次いで４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（５３．７　ｍｇ）及び４－ベンジル－２－モルホリンカルボン酸塩酸塩（４０．０　ｍｇ）を加え、室温で４時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１００　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.43-1.67 (2H, m), 1.79-1.90 (2H, m), 2.12 (3H, s), 2.20-2.33 (1H, m), 2.36-2.49 (1H, m), 2.55-2.75 (3H, m), 2.92-3.07 (2H, m), 3.10-3.20 (4H, m), 3.21 (2H, t, J = 8.5 Hz), 3.49-3.62 (2H, m), 3.65-3.75 (1H, m), 3.89-3.97 (1H, m), 4.04-4.13 (1H, m), 4.29 (3H, t, J = 8.5 Hz), 4.36 (2H, s), 4.66-4.74 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 7.9 Hz), 7.04-7.12 (2H, m), 7.28-7.40 (5H, m), 7.52 (1H, t, J = 7.0 Hz), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz)。
（４４ｂ）　１－（４－メチル－５－｛４－［１－（モルホリン－２－イルカルボニル）ピペリジン－４－イル］フェノキシ｝－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（４４ａ）で得られた化合物（１００　ｍｇ）をエタノール（２　ｍＬ）及び酢酸エチル（２　ｍＬ）に溶解し、７．５％パラジウム炭素（２０．１　ｍｇ）を加え水素雰囲気下、６５℃で３時間撹拌した。反応液に酢酸エチルを加え不溶物をろ去後、ろ液を減圧下で濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（４６．９　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.59-1.72 (2H, m), 1.84-1.93 (2H, m), 2.13 (3H, s), 2.60-2.76 (2H, m), 2.82-2.99 (2H, m), 3.03-3.25 (8H, m), 3.62-3.71 (1H, m), 3.83-3.90 (1H, m), 4.10-4.17 (1H, m), 4.22-4.31 (3H, m), 4.36 (2H, s), 4.69-4.77 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.06-7.12 (2H, m), 7.36 (1H, d, J = 8.5 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 = 8.5 Hz).
　MS(APCI) m/z: 618 (M+H)+。
（４４ｃ）　１－［５－（４－｛１－［（４－エチルモルホリン－２－イル）カルボニル］ピペリジン－４－イル｝フェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（４４ｂ）で得られた化合物（１．５２　ｇ）のテトラヒドロフラン（３０　ｍＬ）とメタノール（１０　ｍＬ）の混合溶液に酢酸（８４５　μＬ）、アセトアルデヒド（１８４　μＬ）、ナトリウムトリアセトキシボロヒドリド（７８２　ｍｇ）を加え、室温で１８時間撹拌した。反応液を減圧下にて溶媒を留去し、飽和炭酸水素ナトリウム（１０　ｍＬ）を加えて酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（５５８　ｍｇ）を淡黄色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.11 (3H, t, J = 7.3 Hz), 1.60-1.73 (2H, m), 1.82-1.93 (2H, m), 2.12 (3H, s), 2.17-2.27 (1H, m), 2.33-2.39 (1H, m), 2.44-2.53 (2H, m), 2.60-2.81 (3H, m), 2.92-3.00 (1H, m), 3.01-3.13 (4H, m), 3.18-3.25 (2H, m), 3.64-3.77 (1H, m), 3.92-4.02 (1H, m), 4.06-4.17 (1H, m), 4.29 (3H, t, J = 8.5 Hz), 4.36 (2H, s), 4.68-4.79 (1H, m), 6.73-6.84 (3H, m), 7.05-7.13 (2H, m), 7.33-7.39 (1H, m), 7.50-7.54 (1H, m), 7.58-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 646 (M+H)+。 (44a) 1- [5- (4- {1-[(4-Benzylmorpholin-2-yl) carbonyl] piperidin-4-yl} phenoxy) -4-methyl-2,3-dihydro-1H-indole- 1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone To a solution of the compound obtained in Example (1e) (70.0 mg) in N, N-dimethylformamide (3 mL) was added triethylamine (72. 0 μL) was added and stirred at room temperature for 5 minutes. Then 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (53.7 mg) and 4-benzyl-2-morpholinecarboxylic acid hydrochloride (40 0.0 mg), and the mixture was stirred at room temperature for 4 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 (100 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.43-1.67 (2H, m), 1.79-1.90 (2H, m), 2.12 (3H, s), 2.20-2.33 (1H, m), 2.36-2.49 (1H, m), 2.55-2.75 (3H, m), 2.92-3.07 (2H, m), 3.10-3.20 (4H, m), 3.21 (2H, t, J = 8.5 Hz), 3.49-3.62 (2H , m), 3.65-3.75 (1H, m), 3.89-3.97 (1H, m), 4.04-4.13 (1H, m), 4.29 (3H, t, J = 8.5 Hz), 4.36 (2H, s), 4.66-4.74 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 7.9 Hz), 7.04-7.12 (2H, m), 7.28-7.40 (5H, m) , 7.52 (1H, t, J = 7.0 Hz), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
(44b) 1- (4-Methyl-5- {4- [1- (morpholin-2-ylcarbonyl) piperidin-4-yl] phenoxy} -2,3-dihydro-1H-indol-1-yl)- 2- [2- (Methylsulfonyl) phenyl] ethanone The compound (100 mg) obtained in Example (44a) was dissolved in ethanol (2 mL) and ethyl acetate (2 mL), and 7.5% palladium carbon ( 20.1 mg) was added, and the mixture was stirred at 65 ° C. for 3 hours under a hydrogen atmosphere. Ethyl acetate was added to the reaction solution, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (46.9 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.59-1.72 (2H, m), 1.84-1.93 (2H, m), 2.13 (3H, s), 2.60-2.76 (2H, m), 2.82-2.99 (2H, m), 3.03-3.25 (8H, m), 3.62-3.71 (1H, m), 3.83-3.90 (1H, m), 4.10-4.17 (1H, m), 4.22-4.31 (3H, m) , 4.36 (2H, s), 4.69-4.77 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.06-7.12 (2H, m), 7.36 (1H, d, J = 8.5 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 = 8.5 Hz).
MS (APCI) m / z: 618 (M + H) + .
(44c) 1- [5- (4- {1-[(4-Ethylmorpholin-2-yl) carbonyl] piperidin-4-yl} phenoxy) -4-methyl-2,3-dihydro-1H-indole- 1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone Acetic acid was added to a mixed solution of the compound (1.52 g) obtained in Example (44b) in tetrahydrofuran (30 mL) and methanol (10 mL). (845 μL), acetaldehyde (184 μL) and sodium triacetoxyborohydride (782 mg) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was evaporated under reduced pressure, saturated sodium hydrogen carbonate (10 mL) 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 amino silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (558 mg) as a pale yellow solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.11 (3H, t, J = 7.3 Hz), 1.60-1.73 (2H, m), 1.82-1.93 (2H, m), 2.12 (3H, s), 2.17-2.27 (1H, m), 2.33-2.39 (1H, m), 2.44-2.53 (2H, m), 2.60-2.81 (3H, m), 2.92-3.00 (1H, m), 3.01-3.13 (4H , m), 3.18-3.25 (2H, m), 3.64-3.77 (1H, m), 3.92-4.02 (1H, m), 4.06-4.17 (1H, m), 4.29 (3H, t, J = 8.5 Hz ), 4.36 (2H, s), 4.68-4.79 (1H, m), 6.73-6.84 (3H, m), 7.05-7.13 (2H, m), 7.33-7.39 (1H, m), 7.50-7.54 (1H , m), 7.58-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 646 (M + H) + .
　（実施例４５）
　（実施例４５－１）：実施例（４５ｄ）で合成
１－（４－メチル－５－｛４－［１－（モルホリン－２－イルカルボニル）ピペリジン－４－イル］フェノキシ｝－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（エチルスルホニル）フェニル］エタノン (Example 45)
Example 45-1: Synthesis in Example (45d) 1- (4-methyl-5- {4- [1- (morpholin-2-ylcarbonyl) piperidin-4-yl] phenoxy} -2,3 -Dihydro-1H-indol-1-yl) -2- [2- (ethylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000077
　（実施例４５－２）：実施例（４５ｄ）で合成
１－［５－（４－｛１－［（４－エチルモルホリン－２－イル）カルボニル］ピペリジン－４－イル｝フェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（エチルスルホニル）フェニル］エタノン Example 45-2: Synthesis in Example (45d) 1- [5- (4- {1-[(4-ethylmorpholin-2-yl) carbonyl] piperidin-4-yl} phenoxy) -4- Methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (ethylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000078
（４５ａ）　（４－ベンジルモルホリン－２－イル）［４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）－３，６－ジヒドロピリジン－１（２Ｈ）－イル］メタノン
　１，２，３，６－テトラヒドロピリジン－４－イル－ボロン酸　ピナコールエステル塩酸塩（ＣＡＳ番号１１２１０５７－７５－７）（３６９　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１０　ｍＬ）溶液にトリエチルアミン（３１０　μＬ）を加え、室温で５分間攪拌した。次いで４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（４９９　ｍｇ）及び４－ベンジルモルホリン－２－カルボン酸（３７０　ｍｇ）を加え、室温で１５時間攪拌した。反応液に水を加え酢酸エチルで抽出し、有機層を飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下で濃縮することにより標記化合物（３９０　ｍｇ）を茶色油状物として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.24 (12H, s), 1.56-1.69 (2H, m), 2.17-2.45 (3H, m), 2.63-2.73 (1H, m), 3.44-3.75 (4H, m), 3.84-4.15 (4H, m), 4.18-4.31 (0.5H, m), 6.42 (0.5H, s), 6.48 (1H, s), 7.28-7.35 (5H, m)。
（４５ｂ）　ｔｅｒｔ－ブチル　５－（４－｛１－［（４－ベンジルモルホリン－２－イル）カルボニル］－１，２，３，６－テトラヒドロピリジン－４－イル｝フェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　実施例（１ａ）で得られた化合物（３１７　ｍｇ）及び実施例（４５ａ）で得られた化合物（３９０　ｍｇ）の１，２－ジメトキシエタン（１０　ｍＬ）溶液に炭酸ナトリウム（２４９　ｍｇ）の水溶液（３　ｍＬ）を加え、室温で５分間撹拌した。次いで［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（６４．１　ｍｇ）を加え、マイクロウェーブ反応装置にて、１３０℃で１時間反応した。反応液を室温に冷却後、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（３５６　ｍｇ）を茶色油状物として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.56 (9H, s), 2.06 (3H, s), 2.21-2.33 (1H, m), 2.35-2.60 (3H, m), 2.65-2.75 (1H, m), 2.87-2.98 (1H, m), 3.03 (2H, t, J = 8.5 Hz), 3.50-3.90 (5H, m), 3.92-4.39 (6H, m), 5.90 (0.5H, s), 5.96 (0.5H, s), 6.81 (3H, d, J = 8.5 Hz), 7.20-7.37 (7H, m), 7.68 (1H, br s)。
（４５ｃ）　１－［５－（４－｛１－［（４－ベンジルモルホリン－２－イル）カルボニル］ピペリジン－４－イル｝フェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（エチルスルホニル）フェニル］エタノン
　実施例（４５ｂ）で得られた化合物（３５６　ｍｇ）のジクロロメタン（２　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（４　ｍＬ）を加え、室温で４時間攪拌した。反応液を減圧下濃縮し、減圧乾燥することで、粗製の（４－ベンジルモルホリン－２－イル）［４－｛４－［（４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］メタノン塩酸塩（３２０　ｍｇ）を茶色固体として得た。 (45a) (4-Benzylmorpholin-2-yl) [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydropyridine-1 (2H ) -Yl] methanone 1,2,3,6-tetrahydropyridin-4-yl-boronic acid pinacol ester hydrochloride (CAS No. 1121057-75-7) (369 mg) in N, N-dimethylformamide (10 mL) Triethylamine (310 μL) was added to the solution and stirred at room temperature for 5 minutes. Then 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (499 mg) and 4-benzylmorpholine-2-carboxylic acid (370 mg) were added. 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 saturated aqueous sodium hydrogen carbonate solution and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (390 mg) as a brown oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.24 (12H, s), 1.56-1.69 (2H, m), 2.17-2.45 (3H, m), 2.63-2.73 (1H, m), 3.44-3.75 (4H, m), 3.84-4.15 (4H, m), 4.18-4.31 (0.5H, m), 6.42 (0.5H, s), 6.48 (1H, s), 7.28-7.35 (5H, m).
(45b) tert-butyl 5- (4- {1-[(4-benzylmorpholin-2-yl) carbonyl] -1,2,3,6-tetrahydropyridin-4-yl} phenoxy) -4-methyl- 2,3-Dihydro-1H-indole-1-carboxylate 1,2-dimethoxyethane of the compound (317 mg) obtained in Example (1a) and the compound (390 mg) obtained in Example (45a) An aqueous solution (3 mL) of sodium carbonate (249 mg) was added to the (10 mL) solution, and the mixture was stirred at room temperature for 5 minutes. Next, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (64.1 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 (356 mg) as a brown oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.56 (9H, s), 2.06 (3H, s), 2.21-2.33 (1H, m), 2.35-2.60 (3H, m), 2.65-2.75 (1H , m), 2.87-2.98 (1H, m), 3.03 (2H, t, J = 8.5 Hz), 3.50-3.90 (5H, m), 3.92-4.39 (6H, m), 5.90 (0.5H, s) , 5.96 (0.5H, s), 6.81 (3H, d, J = 8.5 Hz), 7.20-7.37 (7H, m), 7.68 (1H, br s).
(45c) 1- [5- (4- {1-[(4-Benzylmorpholin-2-yl) carbonyl] piperidin-4-yl} phenoxy) -4-methyl-2,3-dihydro-1H-indole- 1-yl] -2- [2- (ethylsulfonyl) phenyl] ethanone To a solution of the compound obtained in Example (45b) (356 mg) in dichloromethane (2 mL) was added 4N hydrochloric acid dioxane solution (4 mL). Stir at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure and dried under reduced pressure to give crude (4-benzylmorpholin-2-yl) [4- {4-[(4-methyl-2,3-dihydro-1H-indole-5- Yl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] methanone hydrochloride (320 mg) was obtained as a brown solid.
　得られた化合物（１．１５ｇ）のＮ，Ｎ－ジメチルホルムアミド（１０　ｍＬ）溶液にトリエチルアミン（５８０　ｍＬ）を加え、室温で５分間攪拌した。次いで４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（８７４　ｍｇ）及び[２－（エチルスルホニル）フェニル]酢酸（ＣＡＳ番号１３６３１７９－４７－８）（５７７　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１．４２　ｇ）を茶色液体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.26 (3H, t, J = 7.9 Hz), 1.95-2.15 (5H, m), 2.21-2.33 (1H, m), 2.37-2.54 (3H, m), 2.67-2.79 (1H, m), 3.18-3.27 (4H, m), 3.51-3.89 (5H, m), 3.90-4.02 (1H, m), 4.07-4.40 (6H, m), 5.91 (0.4H, br s), 5.96 (0.6H, br s), 6.75-6.85 (3H, m), 7.29-7.35 (5H, m), 7.40 (1H, d, J = 7.9 Hz), 7.45-7.53 (2H, m), 7.57-7.65 (1H, m), 7.92-8.05 (3H, m)。
（４５ｄ）
（４５ｄ－１）　１－（４－メチル－５－｛４－［１－（モルホリン－２－イルカルボニル）ピペリジン－４－イル］フェノキシ｝－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（エチルスルホニル）フェニル］エタノン
及び
（４５ｄ－２）　１－［５－（４－｛１－［（４－エチルモルホリン－２－イル）カルボニル］ピペリジン－４－イル｝フェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（エチルスルホニル）フェニル］エタノン
　実施例（４５ｃ）で得られた化合物（１．４２　ｇ）をエタノール（１０　ｍＬ）及び酢酸エチル（１０　ｍＬ）に溶解し、７．５％パラジウム炭素（２８４　ｍｇ）を加え水素雰囲気下、６０℃で８時間撹拌した。反応液に酢酸エチルを加え不溶物をろ去後、ろ液を減圧下で濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物４５ｄ－１（５４７　ｍｇ）を白色固体として、標記化合物４５ｄ－２（６１６　ｍｇ）を淡黄色固体で得た。
（４５ｄ－１）
1H-NMR (400 MHz, CDCl3) δ: 1.26 (3H, t, J = 7.0 Hz), 1.60-1.72 (2H, m), 1.84-1.93 (2H, m), 2.12 (3H, s), 2.57-2.78 (2H, m), 2.81-2.98 (2H, m), 3.03-3.26 (7H, m), 3.60-3.71 (1H, m), 3.80-3.91 (1H, m), 4.08-4.18 (1H, m), 4.20-4.29 (3H, m), 4.37 (2H, s), 4.68-4.78 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.05-7.15 (2H, m), 7.39 (1H, d, J = 7.9 Hz), 7.48-7.55 (1H, m), 7.60-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 632 (M+H)+。
（４５ｄ－２）
1H-NMR (400 MHz, CDCl3) δ: 1.11 (3H, t, J = 7.3 Hz), 1.26 (3H, t, J = 7.3 Hz), 1.60-1.74 (2H, m), 1.81-1.95 (2H, m), 2.12 (3H, s), 2.16-2.25 (1H, m), 2.29-2.39 (1H, m), 2.43-2.54 (2H, m), 2.58-2.81 (3H, m), 2.93-3.29 (6H, m), 3.62-3.81 (1H, m), 3.93-4.01 (1H, m), 4.05-4.15 (1H, m), 4.22-4.33 (3H, m), 4.37 (2H, s), 4.68-4.78 (1H, m), 6.73-6.85 (3H, m), 7.05-7.15 (2H, m), 7.39 (1H, d, J = 7.9 Hz), 7.46-7.55 (1H, m), 7.57-7.66 (1H, m), 7.96 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 660 (M+H)+。 Triethylamine (580 mL) was added to a solution of the obtained compound (1.15 g) in N, N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 5 minutes. Then 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (874 mg) and [2- (ethylsulfonyl) phenyl] acetic acid (CAS No. 1363179- 47-8) (577 mg) was added, and the mixture was stirred at room temperature for 18 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 (1.42 g) as a brown liquid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.9 Hz), 1.95-2.15 (5H, m), 2.21-2.33 (1H, m), 2.37-2.54 (3H, m ), 2.67-2.79 (1H, m), 3.18-3.27 (4H, m), 3.51-3.89 (5H, m), 3.90-4.02 (1H, m), 4.07-4.40 (6H, m), 5.91 (0.4 H, br s), 5.96 (0.6H, br s), 6.75-6.85 (3H, m), 7.29-7.35 (5H, m), 7.40 (1H, d, J = 7.9 Hz), 7.45-7.53 (2H m), 7.57-7.65 (1H, m), 7.92-8.05 (3H, m).
(45d)
(45d-1) 1- (4-Methyl-5- {4- [1- (morpholin-2-ylcarbonyl) piperidin-4-yl] phenoxy} -2,3-dihydro-1H-indol-1-yl ) -2- [2- (Ethylsulfonyl) phenyl] ethanone and (45d-2) 1- [5- (4- {1-[(4-ethylmorpholin-2-yl) carbonyl] piperidin-4-yl} Phenoxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (ethylsulfonyl) phenyl] ethanone Compound (1.42 g) obtained in Example (45c) Was dissolved in ethanol (10 mL) and ethyl acetate (10 mL), 7.5% palladium carbon (284 mg) was added, and the mixture was stirred at 60 ° C. for 8 hours in a hydrogen atmosphere. Ethyl acetate was added to the reaction solution, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound 45d-1 (547 mg) as a white solid and the title compound 45d-2 (616 mg) as a pale yellow solid. Obtained.
(45d-1)
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.0 Hz), 1.60-1.72 (2H, m), 1.84-1.93 (2H, m), 2.12 (3H, s), 2.57-2.78 (2H, m), 2.81-2.98 (2H, m), 3.03-3.26 (7H, m), 3.60-3.71 (1H, m), 3.80-3.91 (1H, m), 4.08-4.18 (1H , m), 4.20-4.29 (3H, m), 4.37 (2H, s), 4.68-4.78 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.05-7.15 (2H, m), 7.39 (1H, d, J = 7.9 Hz), 7.48-7.55 (1H, m), 7.60-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 632 (M + H) + .
(45d-2)
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.11 (3H, t, J = 7.3 Hz), 1.26 (3H, t, J = 7.3 Hz), 1.60-1.74 (2H, m), 1.81-1.95 ( 2H, m), 2.12 (3H, s), 2.16-2.25 (1H, m), 2.29-2.39 (1H, m), 2.43-2.54 (2H, m), 2.58-2.81 (3H, m), 2.93- 3.29 (6H, m), 3.62-3.81 (1H, m), 3.93-4.01 (1H, m), 4.05-4.15 (1H, m), 4.22-4.33 (3H, m), 4.37 (2H, s), 4.68-4.78 (1H, m), 6.73-6.85 (3H, m), 7.05-7.15 (2H, m), 7.39 (1H, d, J = 7.9 Hz), 7.46-7.55 (1H, m), 7.57- 7.66 (1H, m), 7.96 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 660 (M + H) + .
　（実施例４６）
１－［４－メチル－５－（４－｛１－［（１－メチルピロリジン－２－イル）カルボニル］ピペリジン－４－イル｝フェノキシ）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン (Example 46)
1- [4-Methyl-5- (4- {1-[(1-methylpyrrolidin-2-yl) carbonyl] piperidin-4-yl} phenoxy) -2,3-dihydro-1H-indol-1-yl ] -2- [2- (Methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000079
　実施例（１ｅ）で得られた化合物（２７０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（６　ｍＬ）溶液にトリエチルアミン（１４０　μＬ）を加え、室温で５分間攪拌した。次いで４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（２０７　ｍｇ）及び１－メチルピロリジン－２－カルボン酸（７７．３　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１０６　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.45-1.65 (2H, m), 1.76-2.00 (2H, m), 2.13 (3H, s), 2.18-2.28 (1H, m), 2.36 (3H, d, J = 6.1 Hz), 2.56-2.76 (2H, m), 3.03-3.25 (9H, m), 4.21-4.31 (3H, m), 4.36 (2H, s), 4.71-4.79 (4H, br m), 6.76 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.05-7.13 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.49-7.55 (1H, m), 7.60-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 616 (M+H)+。 Triethylamine (140 μL) was added to a solution of the compound (270 mg) obtained in Example (1e) in N, N-dimethylformamide (6 mL), and the mixture was stirred at room temperature for 5 minutes. Then 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (207 mg) and 1-methylpyrrolidine-2-carboxylic acid (77.3 mg) And stirred at room temperature for 18 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 amino silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (106 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.45-1.65 (2H, m), 1.76-2.00 (2H, m), 2.13 (3H, s), 2.18-2.28 (1H, m), 2.36 (3H , d, J = 6.1 Hz), 2.56-2.76 (2H, m), 3.03-3.25 (9H, m), 4.21-4.31 (3H, m), 4.36 (2H, s), 4.71-4.79 (4H, br m), 6.76 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.05-7.13 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.49- 7.55 (1H, m), 7.60-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 616 (M + H) + .
　（実施例４７）
１－｛５－［４－（１－｛［（２Ｓ）－４，４－ジフルオロ－１－メチルピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン (Example 47)
1- {5- [4- (1-{[(2S) -4,4-difluoro-1-methylpyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl-2,3 -Dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000080
　実施例（３７ｂ）で得られた化合物（２７２　ｍｇ）のテトラヒドロフラン（６　ｍＬ）とメタノール（２　ｍＬ）の混合溶液に酢酸（１３８　μＬ）、ホルムアルデヒド液（３７％）（４５．１　μＬ）、ナトリウムトリアセトキシボロヒドリド（１２８　ｍｇ）を加え、室温で４時間撹拌した。反応液を減圧下で濃縮後、飽和炭酸水素ナトリウム水溶液（１０　ｍＬ）を加えて酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（５７．６　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.59-1.72 (2H, m), 1.86-1.98 (2H, m), 2.13 (3H, s), 2.37-2.58 (5H, m), 2.62-2.79 (3H, m), 3.05-3.24 (6H, m), 3.48-3.62 (2H, m), 4.17-4.33 (3H, m), 4.36 (2H, s), 4.77-4.85 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.04-7.14 (2H, m), 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).
MS(APCI) m/z: 652 (M+H)+。 To a mixed solution of the compound (272 mg) obtained in Example (37b) in tetrahydrofuran (6 mL) and methanol (2 mL), acetic acid (138 μL), formaldehyde solution (37%) (45.1 μL), sodium Triacetoxyborohydride (128 mg) was added and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (10 mL) 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 (57.6 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.59-1.72 (2H, m), 1.86-1.98 (2H, m), 2.13 (3H, s), 2.37-2.58 (5H, m), 2.62-2.79 (3H, m), 3.05-3.24 (6H, m), 3.48-3.62 (2H, m), 4.17-4.33 (3H, m), 4.36 (2H, s), 4.77-4.85 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.04-7.14 (2H, m), 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).
MS (APCI) m / z: 652 (M + H) + .
　（実施例４８）
１－［５－（４－｛１－［（４－メチルモルホリン－２－イル）カルボニル］ピペリジン－４－イル｝フェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン (Example 48)
1- [5- (4- {1-[(4-Methylmorpholin-2-yl) carbonyl] piperidin-4-yl} phenoxy) -4-methyl-2,3-dihydro-1H-indol-1-yl ] -2- [2- (Methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000081
Figure JPOXMLDOC01-appb-C000081
　実施例（４４ｂ）で得られた化合物（１９１　ｍｇ）のテトラヒドロフラン（６　ｍＬ）とメタノール（２　ｍＬ）の混合溶液に酢酸（１０６　μＬ）、ホルムアルデヒド液（３７％）（３４．７　μＬ）、ナトリウムトリアセトキシボロヒドリド（９８．７　ｍｇ）を加え、室温で４時間撹拌した。反応液を減圧下で濃縮後、飽和炭酸水素ナトリウム水溶液（１０　ｍＬ）を加えて酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン→メタノール／酢酸エチル）で精製することで、標記化合物（５８．６　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.61-1.76 (2H, m), 1.82-1.95 (2H, m), 2.12 (3H, s), 2.20-2.30 (1H, m), 2.33-2.44 (4H, m), 2.59-2.77 (3H, m), 2.86-2.94 (1H, m), 3.00-3.13 (4H, m), 3.21 (2H, t, J = 8.5 Hz), 3.67-3.80 (1H, m), 3.92-3.99 (1H, m), 4.06-4.15 (1H, m), 4.24-4.33 (3H, m), 4.36 (2H, s), 4.69-4.77 (1H, m), 6.73-6.85 (3H, m), 7.10 (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).
MS(APCI) m/z: 632 (M+H)+。 To a mixed solution of the compound obtained in Example (44b) (191 mg) in tetrahydrofuran (6 mL) and methanol (2 mL), acetic acid (106 μL), formaldehyde solution (37%) (34.7 μL), sodium Triacetoxyborohydride (98.7 mg) was added and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (10 mL) 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 amino silica gel column chromatography (ethyl acetate / dichloromethane → methanol / ethyl acetate) to give the title compound (58.6 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.61-1.76 (2H, m), 1.82-1.95 (2H, m), 2.12 (3H, s), 2.20-2.30 (1H, m), 2.33-2.44 (4H, m), 2.59-2.77 (3H, m), 2.86-2.94 (1H, m), 3.00-3.13 (4H, m), 3.21 (2H, t, J = 8.5 Hz), 3.67-3.80 (1H , m), 3.92-3.99 (1H, m), 4.06-4.15 (1H, m), 4.24-4.33 (3H, m), 4.36 (2H, s), 4.69-4.77 (1H, m), 6.73-6.85 (3H, m), 7.10 (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).
MS (APCI) m / z: 632 (M + H) + .
　　（実施例４９）：実施例（４９ｂ）で合成
２－（シクロプロピルアミノ）－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）エタノン Example 49: Synthesis in Example (49b) 2- (cyclopropylamino) -1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl}- 2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) ethanone
Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000082
（４９ａ）　（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）（オキソ）アセトアルデヒド
　実施例１８で得られた化合物（２４３　ｍｇ）のジクロロメタン（２　ｍＬ）溶液にトリフルオロ酢酸（２　ｍＬ）を加え、室温で１８時間撹拌した。反応液を減圧下で濃縮し、飽和炭酸水素ナトリウム水溶液（１０　ｍＬ）を加えて中和後、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮することで、標記化合物（３４３　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.52-1.74 (2H, m), 1.81-1.97 (2H, m), 2.12 (3H, s), 2.65-2.89 (2H, m), 3.05-3.27 (6H, m), 4.19-4.33 (3H, m), 4.36 (2H, s), 4.68 (1H, br s), 6.71-6.87 (3H, m), 7.09 (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)。
（４９ｂ）　（２－（シクロプロピルアミノ）－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）エタノン
　実施例（４９ａ）で得られた化合物（１００　ｍｇ）のテトラヒドロフラン（３　ｍＬ）とメタノール（１　ｍＬ）の混合溶液に酢酸（６１．３　μＬ）、シクロプロピルアミン（１８．４　μＬ）、ナトリウムトリアセトキシボロヒドリド（５６．７　ｍｇ）を加え、室温で１８時間撹拌した。反応液を減圧下にて濃縮後、飽和炭酸水素ナトリウム水溶液（１０　ｍＬ）を加えて酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（ジクロロメタン／酢酸エチル）で精製することで、標記化合物（２．５　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 0.35-0.46 (4H, m), 1.55-1.69 (2H, m), 1.82-1.95 (2H, m), 2.13 (3H, s), 2.18-2.25 (1H, m), 2.64-2.72 (1H, m), 3.04-3.15 (4H, m), 3.16-3.26 (2H, m), 3.44-3.60 (3H, m), 3.82-3.93 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.73-4.83 (1H, m), 6.74-6.85 (3H, m), 7.09 (2H, d, J = 8.5 Hz), 7.33-7.39 (1H, m), 7.48-7.55 (1H, m), 7.58-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 602 (M+H)+。 (49a) (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine- 1-yl) (oxo) acetaldehyde To a solution of the compound obtained in Example 18 (243 mg) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, neutralized with a saturated aqueous sodium hydrogen carbonate solution (10 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 to give the title compound (343 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.52-1.74 (2H, m), 1.81-1.97 (2H, m), 2.12 (3H, s), 2.65-2.89 (2H, m), 3.05-3.27 (6H, m), 4.19-4.33 (3H, m), 4.36 (2H, s), 4.68 (1H, br s), 6.71-6.87 (3H, m), 7.09 (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).
(49b) (2- (Cyclopropylamino) -1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole) -5-yl) oxy] phenyl} piperidin-1-yl) ethanone To a mixed solution of the compound (100 mg) obtained in Example (49a) in tetrahydrofuran (3 mL) and methanol (1 mL), acetic acid (61. 3 μL), cyclopropylamine (18.4 μL) and sodium triacetoxyborohydride (56.7 mg) were added, and the mixture was stirred at room temperature for 18 hours. (10 mL) 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 resulting residue was purified by amino silica gel column chromatography (dichloromethane / ethyl acetate) to obtain the title compound (2.5 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.35-0.46 (4H, m), 1.55-1.69 (2H, m), 1.82-1.95 (2H, m), 2.13 (3H, s), 2.18-2.25 (1H, m), 2.64-2.72 (1H, m), 3.04-3.15 (4H, m), 3.16-3.26 (2H, m), 3.44-3.60 (3H, m), 3.82-3.93 (1H, m) , 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.73-4.83 (1H, m), 6.74-6.85 (3H, m), 7.09 (2H, d, J = 8.5 Hz), 7.33-7.39 (1H, m), 7.48-7.55 (1H, m), 7.58-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz) .
MS (APCI) m / z: 602 (M + H) + .
　（実施例５０）：実施例（５０ｂ）で合成
２－[（２－ヒドロキシエチル）アミノ]－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）エタノン Example 50: Synthesis in Example (50b) 2-[(2-hydroxyethyl) amino] -1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] Acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) ethanone
Figure JPOXMLDOC01-appb-C000083
Figure JPOXMLDOC01-appb-C000083
（５０ａ）　（２－｛［２－（ベンジルオキシ）エチル］アミノ｝－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）エタノン
　実施例（４９ａ）で得られた化合物（１００　ｍｇ）のテトラヒドロフラン（３　ｍＬ）とメタノール（１　ｍＬ）の混合溶液に酢酸（６１．３　μＬ）、２－ベンジルオキシ－１－エタンアミン（４０．５　ｍｇ）、ナトリウムトリアセトキシボロヒドリド（５６．７　ｍｇ）を加え、室温で３時間撹拌した。反応液を減圧下にて濃縮後、飽和炭酸水素ナトリウム水溶液（１０　ｍＬ）を加えて酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（３６．３　ｍｇ）を無色油状物として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.49-1.63 (2H, m), 1.81-1.92 (2H, m), 2.13 (3H, s), 2.59-2.76 (2H, m), 2.83-2.92 (2H, m), 3.00-3.15 (4H, m), 3.22 (2H, t, J = 8.5 Hz), 3.47-3.56 (2H, m), 3.62 (2H, t, J = 5.2 Hz), 3.77-3.90 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.55 (2H, s), 4.72-4.83 (1H, m), 6.77 (1H, d, J = 9.2 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.08 (2H, d, J = 8.5 Hz), 7.22-7.39 (6H, m), 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)。
（５０ｂ）　２－［（２－ヒドロキシエチル）アミノ］－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）エタノン
　実施例（５０ａ）で得られた化合物（３６．３　ｍｇ）をメタノール（１　ｍＬ）及びジクロロメタン（１　ｍＬ）に溶解し、７．５％パラジウム炭素（７．０　ｍｇ）を加え水素雰囲気下、室温で１８時間撹拌した。反応液に酢酸エチルを加え、不溶物をろ去し、ろ液を減圧下で濃縮することで、標記化合物（２４．６　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.65-1.80 (4H, m), 1.84-1.97 (2H, m), 2.12 (3H, s), 2.65-2.82 (2H, m), 3.11 (3H, s), 3.16-3.33 (4H, m), 3.64-3.75 (1H, m), 3.91-4.11 (3H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.63-4.72 (1H, m), 6.73-6.85 (3H, m), 7.09 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.47-7.55 (1H, m), 7.58-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 606 (M+H)+。 (50a) (2-{[2- (benzyloxy) ethyl] amino} -1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2, 3-Dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) ethanone Compound (100 mg) of tetrahydrofuran (3 mL) and methanol (1 mL) obtained in Example (49a) Acetic acid (61.3 μL), 2-benzyloxy-1-ethanamine (40.5 mg) and sodium triacetoxyborohydride (56.7 mg) were added to the mixed solution, and the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (10 mL) was added, and the mixture was extracted with ethyl acetate.The organic layer was washed with water and saturated brine, and anhydrous sodium sulfate. After 燥, and concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (36.3 mg) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.49-1.63 (2H, m), 1.81-1.92 (2H, m), 2.13 (3H, s), 2.59-2.76 (2H, m), 2.83-2.92 (2H, m), 3.00-3.15 (4H, m), 3.22 (2H, t, J = 8.5 Hz), 3.47-3.56 (2H, m), 3.62 (2H, t, J = 5.2 Hz), 3.77- 3.90 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.55 (2H, s), 4.72-4.83 (1H, m), 6.77 (1H, d, J = 9.2 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.08 (2H, d, J = 8.5 Hz), 7.22-7.39 (6H, m), 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).
(50b) 2-[(2-hydroxyethyl) amino] -1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro- 1H-Indol-5-yl) oxy] phenyl} piperidin-1-yl) ethanone The compound obtained in Example (50a) (36.3 mg) was dissolved in methanol (1 mL) and dichloromethane (1 mL). , 7.5% palladium carbon (7.0 mg) was added, and the mixture was stirred at room temperature for 18 hours under 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 to obtain the title compound (24.6 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.65-1.80 (4H, m), 1.84-1.97 (2H, m), 2.12 (3H, s), 2.65-2.82 (2H, m), 3.11 (3H , s), 3.16-3.33 (4H, m), 3.64-3.75 (1H, m), 3.91-4.11 (3H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.63-4.72 (1H, m), 6.73-6.85 (3H, m), 7.09 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.47-7.55 (1H, m) , 7.58-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 606 (M + H) + .
　（実施例５１）
　（実施例５１－１）：実施例（５１ｃ）で合成
（５Ｓ）－５－［（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）カルボニル］ピロリジン－３－オン (Example 51)
Example 51-1: synthesized in Example (51c) (5S) -5-[(4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2 , 3-Dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) carbonyl] pyrrolidin-3-one
Figure JPOXMLDOC01-appb-C000084
Figure JPOXMLDOC01-appb-C000084
　（実施例５１－２）：実施例（５１ｄ）で合成
（５Ｓ）－１－メチル－５－［（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）カルボニル］ピロリジン－３－オン Example 51-2: Synthesis in Example (51d) (5S) -1-methyl-5-[(4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl]) Acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) carbonyl] pyrrolidin-3-one
Figure JPOXMLDOC01-appb-C000085
Figure JPOXMLDOC01-appb-C000085
（５１ａ）　ベンジル　（２Ｓ，４Ｒ）－４－ヒドロキシ－２－［（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）カルボニル］ピロリジン－１－カルボキシレート
　実施例（１ｅ）で得られた（３００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にトリエチルアミン（２３０　μＬ）を加え、室温で５分間攪拌した。次いでＮ－カルボベンジルオキシ－Ｌ－ヒドロキシプロリン（１７６　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（１５９　ｍｇ）、１－ヒドロキシベンゾトリアゾール一水和物（８４．９　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／ジクロロメタン）で精製することで、標記化合物（１７０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.64-1.92 (2H, m), 2.51-2.81 (5H, m), 2.59-2.79 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.54-3.67 (1H, m), 3.69-3.84 (1H, m), 4.07-4.19 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.49-5.23 (6H, m), 5.30 (2H, s), 6.71-6.90 (4H, m), 7.00-7.14 (2H, m), 7.27-7.40 (5H, m), 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 = 6.7 Hz)。
（５１ｂ）　ベンジル　（２Ｓ）－２－［（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）カルボニル］－４－オキソピロリジン－１－カルボキシレート
　オキザリルクロリド（２１．４　μＬ）のジクロロメタン（２　ｍＬ）溶液を窒素雰囲気下、－７８℃に冷却し、ジメチルスルホキシド（３３．８　μＬ）を滴下し、１５分間撹拌した。実施例（５１ａ）で得られた化合物（１７０　ｍｇ）のジクロロメタン（４　ｍＬ）溶液を滴下し、さらに－７８℃で１５分間撹拌した。トリエチルアミン（１５１　μＬ）を加え、室温で１８時間撹拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（４５．１　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.78-1.99 (2H, m), 2.13 (3H, s), 2.41-2.95 (4H, m), 3.06-3.28 (6H, m), 3.93-4.14 (3H, m), 4.23-4.32 (3H, m), 4.36 (2H, s), 4.62-4.73 (1H, m), 5.07-5.35 (4H, m), 6.73-6.86 (4H, m), 7.04-7.13 (2H, m), 7.30-7.40 (5H, m), 7.52 (1H, t, J = 7.6 Hz), 7.61 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz)。
（５１ｃ）　（５Ｓ）－５－［（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）カルボニル］ピロリジン－３－オン
　実施例（５１ｂ）で得られた化合物（４５．１　ｍｇ）をメタノール（２　ｍＬ）及び酢酸エチル（２　ｍＬ）に溶解し、７．５％パラジウム炭素（１０．０　ｍｇ）を加え素雰囲気下、室温で１８時間撹拌した。反応液に酢酸エチルを加え不溶物をろ去し、ろ液を減圧下で濃縮することで標記化合物（４０．０　ｍｇ）を白色固体として得た。
（５１ｄ）　（５Ｓ）－１－メチル－５－［（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）カルボニル］ピロリジン－３－オン
　実施例（５１ｃ）で得られた化合物（４０．０　ｍｇ）のジクロロメタン（１　ｍＬ）とメタノール（２　ｍＬ）の混合溶液に塩酸（３９８　μＬ）、ホルムアルデヒド液（３７％）（２４２　μＬ）、７．５％パラジウム炭素（１０．０　ｍｇ）を加え水素雰囲気下、室温で１８時間撹拌した。反応液に酢酸エチルを加え不溶物をろ去し、ろ液を減圧下で濃縮した後、１Ｎ水酸化ナトリウム水溶液（１０　ｍＬ）を加えて酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン→メタノール／酢酸エチル）で精製することで、標記化合物（９．０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.57-1.67 (2H, m), 1.88-1.99 (2H, m), 2.13 (3H, s), 2.48-2.78 (7H, m), 2.88-3.01 (1H, m), 3.12 (3H, s), 3.16-3.25 (3H, m), 3.50-3.63 (1H, m), 3.88-3.98 (1H, m), 4.16-4.22 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.76-4.87 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.80-6.85 (2H, m), 7.07-7.15 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.9 Hz), 7.62 (1H, t, J = 7.9 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 630 (M+H)+。 (51a) benzyl (2S, 4R) -4-hydroxy-2-[(4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro- 1H-Indol-5-yl) oxy] phenyl} piperidin-1-yl) carbonyl] pyrrolidine-1-carboxylate (300 mg) of N, N-dimethylformamide obtained in Example (1e) (5 mL) Triethylamine (230 μL) was added to the solution and stirred at room temperature for 5 minutes. Then N-carbobenzyloxy-L-hydroxyproline (176 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (159 mg), 1-hydroxybenzotriazole monohydrate (84. 9 mg) was added and stirred at room temperature for 18 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 (methanol / dichloromethane) to give the title compound (170 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.64-1.92 (2H, m), 2.51-2.81 (5H, m), 2.59-2.79 (2H, m), 3.12 (3H, s), 3.22 (2H , t, J = 8.5 Hz), 3.54-3.67 (1H, m), 3.69-3.84 (1H, m), 4.07-4.19 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 ( 2H, s), 4.49-5.23 (6H, m), 5.30 (2H, s), 6.71-6.90 (4H, m), 7.00-7.14 (2H, m), 7.27-7.40 (5H, m), 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 = 6.7 Hz).
(51b) Benzyl (2S) -2-[(4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole-5 Yl) oxy] phenyl} piperidin-1-yl) carbonyl] -4-oxopyrrolidine-1-carboxylate Oxalyl chloride (21.4 μL) in dichloromethane (2 mL) was cooled to −78 ° C. under a nitrogen atmosphere. Dimethyl sulfoxide (33.8 μL) was added dropwise and stirred for 15 minutes. A solution of the compound (170 mg) obtained in Example (51a) in dichloromethane (4 mL) was added dropwise, and the mixture was further stirred at −78 ° C. for 15 minutes. Triethylamine (151 μL) was added and stirred at room temperature for 18 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 (45.1 mg) as a white solid.
1H-NMR (400 MHz, CDCl 3 ) δ: 1.78-1.99 (2H, m), 2.13 (3H, s), 2.41-2.95 (4H, m), 3.06-3.28 (6H, m), 3.93-4.14 ( 3H, m), 4.23-4.32 (3H, m), 4.36 (2H, s), 4.62-4.73 (1H, m), 5.07-5.35 (4H, m), 6.73-6.86 (4H, m), 7.04- 7.13 (2H, m), 7.30-7.40 (5H, m), 7.52 (1H, t, J = 7.6 Hz), 7.61 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz) ), 8.08 (1H, d, J = 7.9 Hz).
(51c) (5S) -5-[(4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) ) Oxy] phenyl} piperidin-1-yl) carbonyl] pyrrolidin-3-one The compound (45.1 mg) obtained in Example (51b) was dissolved in methanol (2 mL) and ethyl acetate (2 mL). 7.5% palladium carbon (10.0 mg) was added, and the mixture was stirred at room temperature for 18 hours under an atmosphere. Ethyl acetate was added to the reaction solution, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (40.0 mg) as a white solid.
(51d) (5S) -1-Methyl-5-[(4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole -5-yl) oxy] phenyl} piperidin-1-yl) carbonyl] pyrrolidin-3-one The compound obtained in Example (51c) (40.0 mg) in dichloromethane (1 mL) and methanol (2 mL) To the mixed solution were added hydrochloric acid (398 μL), formaldehyde solution (37%) (242 μL), and 7.5% palladium carbon (10.0 mg), and the mixture was stirred at room temperature for 18 hours in a hydrogen atmosphere. Ethyl acetate was added to the reaction solution, insolubles were removed by filtration, the filtrate was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution (10 mL) 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 amino silica gel column chromatography (ethyl acetate / dichloromethane → methanol / ethyl acetate) to give the title compound (9.0 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.57-1.67 (2H, m), 1.88-1.99 (2H, m), 2.13 (3H, s), 2.48-2.78 (7H, m), 2.88-3.01 (1H, m), 3.12 (3H, s), 3.16-3.25 (3H, m), 3.50-3.63 (1H, m), 3.88-3.98 (1H, m), 4.16-4.22 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.76-4.87 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.80-6.85 (2H, m), 7.07- 7.15 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.9 Hz), 7.62 (1H, t, J = 7.9 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 630 (M + H) + .
　（実施例５２）
１－｛５－［４－（１－｛［（４Ｒ）－４－フルオロ－１－メチルピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン (Example 52)
1- {5- [4- (1-{[(4R) -4-fluoro-1-methylpyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro -1H-Indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000086
　実施例（３３ｂ）で得られた化合物（１２３　ｍｇ）をメタノール（３　ｍＬ）及びジクロロメタン（１　ｍＬ）の混合溶液に溶解し、７．５％パラジウム炭素（２４．７　ｍｇ）、３７％ホルムアルデヒド液（２７７　μＬ）、塩酸（１２２　μＬ）を加え水素雰囲気下、室温で１８時間撹拌した。反応液に酢酸エチルを加え不溶物をろ去後、ろ液を減圧下で濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（９３．６　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.57-1.70 (2H, m), 1.86-2.00 (2H, m), 2.13 (3H, s), 2.18-2.34 (2H, m), 2.43 (3H, d, J = 9.2 Hz), 2.56-2.79 (3H, m), 3.07-3.27 (6H, m), 3.57-3.71 (2H, br m), 4.11-4.22 (1H, br m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.77-4.86 (1H, m), 5.16-5.20 (0.5H, m), 5.30-5.35 (0.5H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.06-7.13 (2H, m), 7.33-7.39 (1H, m), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 634 (M+H)+。 The compound (123 mg) obtained in Example (33b) was dissolved in a mixed solution of methanol (3 mL) and dichloromethane (1 mL), 7.5% palladium carbon (24.7 mg), 37% formaldehyde solution (277 μL) and hydrochloric acid (122 μL) were added, and the mixture was stirred at room temperature for 18 hours in a hydrogen atmosphere. Ethyl acetate was added to the reaction solution, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (93.6 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.57-1.70 (2H, m), 1.86-2.00 (2H, m), 2.13 (3H, s), 2.18-2.34 (2H, m), 2.43 (3H , d, J = 9.2 Hz), 2.56-2.79 (3H, m), 3.07-3.27 (6H, m), 3.57-3.71 (2H, br m), 4.11-4.22 (1H, br m), 4.29 (2H , t, J = 8.2 Hz), 4.36 (2H, s), 4.77-4.86 (1H, m), 5.16-5.20 (0.5H, m), 5.30-5.35 (0.5H, m), 6.77 (1H, d , J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.06-7.13 (2H, m), 7.33-7.39 (1H, m), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 634 (M + H) + .
　（実施例５３）
１－｛５－［４－（１－｛［（２Ｓ）－４，４－ジフルオロ－１－（２－ヒドロキシエチル）ピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン (Example 53)
1- {5- [4- (1-{[(2S) -4,4-difluoro-1- (2-hydroxyethyl) pyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4- Methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000087
Figure JPOXMLDOC01-appb-C000087
　実施例（３７ｂ）で得られた化合物（７４．２　ｍｇ）のジクロロメタン（１　ｍＬ）とメタノール（２　ｍＬ）の混合溶液に塩酸（７１．３　μＬ）、（ｔｅｒｔ－ブチルジメチルシロキシ）アセトアルデヒド（２２２　μＬ）、７．５％パラジウム炭素（１５ｍｇ）を加え水素雰囲気下、室温で３日間撹拌した。反応液にジクロロメタンを加え不溶物をろ去し、ろ液を減圧下で濃縮後、水を加えて酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン→メタノール／ジクロロメタン）で精製することで、標記化合物（６．８　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.55-1.64 (2H, m), 1.87-1.98 (2H, m), 2.12 (3H, s), 2.24-2.41 (1H, m), 2.48-2.82 (5H, m), 2.85-2.98 (1H, m), 3.06-3.26 (6H, m), 3.46-3.76 (3H, m), 3.82-3.89 (1H, m), 3.95-4.03 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.74-4.84 (1H, m), 6.74-6.85 (3H, m), 7.05-7.13 (2H, m), 7.32-7.40 (1H, m), 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).
MS(APCI) m/z: 682 (M+H)+。 To a mixed solution of the compound (74.2 mg) obtained in Example (37b) in dichloromethane (1 mL) and methanol (2 mL), hydrochloric acid (71.3 μL), (tert-butyldimethylsiloxy) acetaldehyde (222) μL) and 7.5% palladium carbon (15 mg) were added, and the mixture was stirred at room temperature for 3 days under a hydrogen atmosphere. Dichloromethane was added to the reaction solution, the insoluble material was removed by filtration, the filtrate 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 amino silica gel column chromatography (ethyl acetate / dichloromethane → methanol / dichloromethane) to give the title compound (6.8 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.55-1.64 (2H, m), 1.87-1.98 (2H, m), 2.12 (3H, s), 2.24-2.41 (1H, m), 2.48-2.82 (5H, m), 2.85-2.98 (1H, m), 3.06-3.26 (6H, m), 3.46-3.76 (3H, m), 3.82-3.89 (1H, m), 3.95-4.03 (1H, m) , 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.74-4.84 (1H, m), 6.74-6.85 (3H, m), 7.05-7.13 (2H, m), 7.32-7.40 (1H, m), 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).
MS (APCI) m / z: 682 (M + H) + .
　（実施例５４）：実施例（５４ｂ）で合成
１－｛５－［４－（１－｛［（２Ｓ，４Ｒ）－４－ヒドロキシピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン Example 54: Synthesis in Example (54b) 1- {5- [4- (1-{[(2S, 4R) -4-hydroxypyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy ] -4-Methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000088
Figure JPOXMLDOC01-appb-C000088
（５４ａ）　ｔｅｒｔ－ブチル　（２Ｓ，４Ｒ）－４－（ベンジルオキシ）－２－［（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）カルボニル］ピロリジン－１－カルボキシレート
　実施例（１ｅ）で得られた化合物（２００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にトリエチルアミン（１００　μＬ）を加え、室温で５分間攪拌した。次いでｔｅｒｔ－ブトキシカルボニル－Ｏ－ベンジル－Ｌ－４－ヒドロキシプロリン（１４２　ｍｇ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（１５３　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（２７８　ｍｇ）を無色油状物として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.46 (9H, s), 1.54-1.71 (2H, m), 1.80-1.98 (2H, m), 2.12 (3H, s), 2.20-2.39 (1H, m), 2.56-2.79 (2H, m), 2.91-3.08 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.54-3.84 (2H, m), 4.03-4.33 (4H, m), 4.36 (2H, s), 4.42-4.63 (2H, m), 4.68-4.93 (2H, m), 6.73-6.87 (3H, m), 7.00-7.15 (2H, m), 7.29-7.37 (6H, m), 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 = 7.3 Hz)。
（５４ｂ）　１－｛５－［４－（１－｛［（２Ｓ，４Ｒ）－４－ヒドロキシピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（５４ａ）で得られた化合物（２７８　ｍｇ）のジクロロメタン（２　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（４　ｍＬ）を加え、室温で１８時間撹拌した。反応液にヘキサン（１０　ｍＬ）を加え、減圧下で溶媒を留去した。残渣を酢酸エチル／ヘキサン（１／１）で洗浄してろ取し、粗製の１－｛５－［４－（１－｛［（２Ｓ，４Ｒ）－４－（ベンジルオキシ）ピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン塩酸塩（２５９　ｍｇ）を白色固体で得た。 (54a) tert-butyl (2S, 4R) -4- (benzyloxy) -2-[(4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2 , 3-Dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) carbonyl] pyrrolidine-1-carboxylate N, N— of the compound (200 mg) obtained in Example (1e) Triethylamine (100 μL) was added to a dimethylformamide (5 mL) solution, and the mixture was stirred at room temperature for 5 minutes. Then tert-butoxycarbonyl-O-benzyl-L-4-hydroxyproline (142 mg), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (153 mg) was added, and the mixture was stirred at room temperature for 18 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 (278 mg) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.46 (9H, s), 1.54-1.71 (2H, m), 1.80-1.98 (2H, m), 2.12 (3H, s), 2.20-2.39 (1H , m), 2.56-2.79 (2H, m), 2.91-3.08 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.54-3.84 (2H, m), 4.03-4.33 (4H, m), 4.36 (2H, s), 4.42-4.63 (2H, m), 4.68-4.93 (2H, m), 6.73-6.87 (3H, m), 7.00-7.15 (2H, m ), 7.29-7.37 (6H, m), 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 = 7.3 Hz).
(54b) 1- {5- [4- (1-{[(2S, 4R) -4-hydroxypyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl-2,3- Dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone A solution of the compound obtained in Example (54a) (278 mg) in dichloromethane (2 mL) in 4N dioxane hydrochloride ( 4 mL) was added and stirred at room temperature for 18 hours. Hexane (10 mL) was added to the reaction solution, and the solvent was distilled off under reduced pressure. The residue was washed with ethyl acetate / hexane (1/1) and collected by filtration to give crude 1- {5- [4- (1-{[(2S, 4R) -4- (benzyloxy) pyrrolidin-2-yl]. ] Carbonyl} piperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone hydrochloride (259 mg) Obtained as a white solid.
　得られた化合物（１００　ｍｇ）をメタノール（２　ｍＬ）及び酢酸エチル（２　ｍＬ）に溶解し、７．５％パラジウム炭素（２０．０　ｍｇ）を加え水素雰囲気下、室温で５時間撹拌した。反応液に酢酸エチルを加え不溶物をろ去し、ろ液を減圧下で濃縮乾燥することで標記化合物（６３．７　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.59-1.70 (2H, m), 1.82-1.95 (2H, m), 1.98-2.08 (2H, m), 2.13 (3H, s), 2.29-2.36 (1H, m), 2.59-2.79 (2H, m), 3.02-3.27 (6H, m), 3.45-3.62 (2H, m), 4.11-4.21 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.49-4.59 (1H, m), 4.75-4.84 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.80-6.85 (2H, m), 7.03-7.14 (2H, m), 7.36 (1H, d, J = 7.3 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).
MS(APCI) m/z: 618 (M+H)+。 The obtained compound (100 mg) was dissolved in methanol (2 mL) and ethyl acetate (2 mL), 7.5% palladium carbon (20.0 mg) was added, and the mixture was stirred at room temperature for 5 hours under hydrogen atmosphere. Ethyl acetate was added to the reaction solution, the insoluble material was removed by filtration, and the filtrate was concentrated and dried under reduced pressure to obtain the title compound (63.7 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.59-1.70 (2H, m), 1.82-1.95 (2H, m), 1.98-2.08 (2H, m), 2.13 (3H, s), 2.29-2.36 (1H, m), 2.59-2.79 (2H, m), 3.02-3.27 (6H, m), 3.45-3.62 (2H, m), 4.11-4.21 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.49-4.59 (1H, m), 4.75-4.84 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.80-6.85 (2H, m), 7.03-7.14 (2H, m), 7.36 (1H, d, J = 7.3 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d , J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).
MS (APCI) m / z: 618 (M + H) + .
　（実施例５５）
１－｛５－［４－（１－｛［（２Ｓ，４Ｒ）－４－ヒドロキシ－１－メチルピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン (Example 55)
1- {5- [4- (1-{[(2S, 4R) -4-hydroxy-1-methylpyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl-2,3 -Dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000089
Figure JPOXMLDOC01-appb-C000089
　実施例（５４ｂ）で得られた１－｛５－［４－（１－｛［（２Ｓ，４Ｒ）－４－ヒドロキシピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン（１５０　ｍｇ）をメタノール（３　ｍＬ）及びジクロロメタン（１　ｍＬ）に溶解し、７．５％パラジウム炭素（３０．０　ｍｇ）、３７％ホルムアルデヒド液（８５４　μＬ）、塩酸（１４１　μＬ）を加え水素雰囲気下、室温で８時間撹拌した。反応液に酢酸エチルを加え不溶物をろ去し、ろ液を減圧下で濃縮した。得られた残渣に１Ｎ水酸化ナトリウム水溶液を加えて中和し、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（８５．３　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.59-1.70 (2H, m), 1.82-1.95 (2H, m), 1.98-2.08 (2H, m), 2.13 (3H, s), 2.29-2.36 (1H, m), 2.40 (3H, d, J = 8.5 Hz), 2.59-2.79 (2H, m), 3.02-3.27 (6H, m), 3.45-3.62 (2H, m), 4.11-4.21 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.49-4.59 (1H, m), 4.75-4.84 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.09 (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).
MS(APCI) m/z: 632 (M+H)+。 1- {5- [4- (1-{[(2S, 4R) -4-hydroxypyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4- obtained in Example (54b) Methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone (150 mg) was dissolved in methanol (3 mL) and dichloromethane (1 mL), 7 0.5% palladium carbon (30.0 mg), 37% formaldehyde solution (854 μL) and hydrochloric acid (141 μL) were added, and the mixture was stirred at room temperature for 8 hours in 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. The resulting residue was neutralized with 1N aqueous sodium hydroxide solution, 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 amino silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (85.3 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.59-1.70 (2H, m), 1.82-1.95 (2H, m), 1.98-2.08 (2H, m), 2.13 (3H, s), 2.29-2.36 (1H, m), 2.40 (3H, d, J = 8.5 Hz), 2.59-2.79 (2H, m), 3.02-3.27 (6H, m), 3.45-3.62 (2H, m), 4.11-4.21 (1H , m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.49-4.59 (1H, m), 4.75-4.84 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.09 (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).
MS (APCI) m / z: 632 (M + H) + .
　（実施例５６）
２－［２－（メチルスルホニル）フェニル］－１－（４－メチル－５－｛４－［１－（３，３，３－トリフルオロプロピル）ピペリジン－４－イル］フェノキシ｝－２，３－ジヒドロ－１Ｈ－インドール－１－イル）エタノン (Example 56)
2- [2- (Methylsulfonyl) phenyl] -1- (4-methyl-5- {4- [1- (3,3,3-trifluoropropyl) piperidin-4-yl] phenoxy} -2,3 -Dihydro-1H-indol-1-yl) ethanone
Figure JPOXMLDOC01-appb-C000090
Figure JPOXMLDOC01-appb-C000090
　実施例（１ｅ）で得られた化合物（１００　ｍｇ）のテトラヒドロフラン（３　ｍＬ）とメタノール（１　ｍＬ）の混合溶液にトリエチルアミン（１８．０　μＬ）、酢酸（３８．１　μＬ）、３，３，３－トリフルオロプロピルアルデヒド（１８．６　ｍｇ）、ナトリウムトリアセトキシボロヒドリド（３５．３　ｍｇ）を加え、室温で１８時間撹拌した。反応液を減圧下で濃縮後、得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１０．５　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.55-2.00 (4H, m), 2.13 (3H, s), 2.31-2.52 (2H, m), 2.61-2.69 (2H, m), 2.98-3.07 (2H, m), 3.12 (3H, s), 3.21 (2H, t, J = 8.2 Hz), 3.82-3.91 (1H, m), 4.01-4.18 (1H, m), 4.28 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 5.48-5.59 (1H, m), 6.76-6.85 (3H, m), 7.12 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.53 (1H, t, J = 7.3 Hz), 7.61 (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: 601 (M+H)+。 To a mixed solution of the compound (100 mg) obtained in Example (1e) in tetrahydrofuran (3 mL) and methanol (1 mL), triethylamine (18.0 μL), acetic acid (38.1 μL), 3, 3, 3-Trifluoropropylaldehyde (18.6 mg) and sodium triacetoxyborohydride (35.3 mg) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by amino silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (10.5 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.55-2.00 (4H, m), 2.13 (3H, s), 2.31-2.52 (2H, m), 2.61-2.69 (2H, m), 2.98-3.07 (2H, m), 3.12 (3H, s), 3.21 (2H, t, J = 8.2 Hz), 3.82-3.91 (1H, m), 4.01-4.18 (1H, m), 4.28 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 5.48-5.59 (1H, m), 6.76-6.85 (3H, m), 7.12 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.53 (1H, t, J = 7.3 Hz), 7.61 (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: 601 (M + H) + .
　（実施例５７）
１－［５－（４－｛１－［（２Ｓ）－１，４－ジオキサン－２－イルメチル］ピペリジン－４－イル｝フェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン (Example 57)
1- [5- (4- {1-[(2S) -1,4-Dioxane-2-ylmethyl] piperidin-4-yl} phenoxy) -4-methyl-2,3-dihydro-1H-indole-1 -Yl] -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000091
Figure JPOXMLDOC01-appb-C000091
　実施例（１ｅ）で得られた化合物（６０．０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液にＮ，Ｎ－ジイソプロピルエチルアミン（９４．９　μＬ）を加え、室温で５分間撹拌した。次いで炭酸カリウム（１５．３　ｍｇ）、文献記載の方法（Ｊｏｕｒｎａｌ　ｏｆ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ，２０１１，５４，７７７２）に従って合成した［（２Ｒ）－１，４－ジオキサン－２－イル］メチル　メタンスルホン酸（６５．２　ｍｇ）を加え、８０℃で２４時間撹拌した。反応液に水を加えて酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン→メタノール／酢酸エチル）で精製することで、標記化合物（３７．７　ｍｇ）を黄色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.51-1.65 (2H, m), 1.74-1.85 (2H, m), 2.02-2.14 (4H, m), 2.17-2.32 (1H, br m), 2.37-2.53 (2H, m), 2.98-3.13 (5H, m), 3.14-3.25 (2H, m), 3.25-3.34 (1H, m), 3.56-3.64 (1H, m), 3.68-3.87 (6H, m), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.72-6.88 (3H, m), 7.12 (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), 7.96 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 605 (M+H)+。 N, N-diisopropylethylamine (94.9 μL) was added to a solution of the compound (60.0 mg) obtained in Example (1e) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes. . Subsequently, potassium carbonate (15.3 mg), [(2R) -1,4-dioxane-2-yl] methyl methanesulfonic acid (65) synthesized according to a method described in the literature (Journal of Medicinal Chemistry, 2011, 54, 7772) was used. 0.2 mg) and stirred at 80 ° C. for 24 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 → methanol / ethyl acetate) to give the title compound (37.7 mg) as a yellow solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.51-1.65 (2H, m), 1.74-1.85 (2H, m), 2.02-2.14 (4H, m), 2.17-2.32 (1H, br m), 2.37-2.53 (2H, m), 2.98-3.13 (5H, m), 3.14-3.25 (2H, m), 3.25-3.34 (1H, m), 3.56-3.64 (1H, m), 3.68-3.87 (6H , m), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.72-6.88 (3H, m), 7.12 (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), 7.96 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = (7.9 Hz).
MS (APCI) m / z: 605 (M + H) + .
　（実施例５８）
１－［５－（４－｛１－［（２Ｒ）－１，４－ジオキサン－２－イルメチル］ピペリジン－４－イル｝フェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン (Example 58)
1- [5- (4- {1-[(2R) -1,4-Dioxane-2-ylmethyl] piperidin-4-yl} phenoxy) -4-methyl-2,3-dihydro-1H-indole-1 -Yl] -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000092
Figure JPOXMLDOC01-appb-C000092
　実施例（１ｅ）で得られた化合物（８０．０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液に炭酸カリウム（６１．３　ｍｇ）、文献記載の方法（Ｊｏｕｒｎａｌ　ｏｆ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ，２０１１，５４，７７７２）により合成した［（２Ｓ）－１，４－ジオキサン－２－イル］メチル　メタンスルホン酸（４３．５　ｍｇ）を加え、８０℃で１５時間撹拌した。反応液に水を加えて酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン→メタノール／酢酸エチル）で精製することで、標記化合物（６．５　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.53-1.66 (2H, m), 1.73-1.87 (2H, m), 2.02-2.16 (4H, m), 2.18-2.30 (1H, m), 2.39-2.54 (2H, m), 2.97-3.14 (5H, m), 3.14-3.25 (2H, m), 3.25-3.36 (1H, m), 3.54-3.66 (1H, m), 3.67-3.87 (6H, m), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.72-6.87 (3H, m), 7.12 (2H, d, J = 8.5 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 = 7.3 Hz).
MS(APCI) m/z: 605 (M+H)+。 To a solution of the compound (80.0 mg) obtained in Example (1e) in N, N-dimethylformamide (3 mL), potassium carbonate (61.3 mg), a method described in the literature (Journal of Medicinal Chemistry, 2011, 54,7772) [(2S) -1,4-dioxane-2-yl] methyl methanesulfonic acid (43.5 mg) was added, and the mixture was stirred at 80 ° C. 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 → methanol / ethyl acetate) to give the title compound (6.5 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.53-1.66 (2H, m), 1.73-1.87 (2H, m), 2.02-2.16 (4H, m), 2.18-2.30 (1H, m), 2.39 -2.54 (2H, m), 2.97-3.14 (5H, m), 3.14-3.25 (2H, m), 3.25-3.36 (1H, m), 3.54-3.66 (1H, m), 3.67-3.87 (6H, m), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.72-6.87 (3H, m), 7.12 (2H, d, J = 8.5 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 = 7.3 Hz).
MS (APCI) m / z: 605 (M + H) + .
　（実施例５９）：実施例（５９ｂ）で合成
１－（５－｛４－［１－（２－ヒドロキシエチル）ピペリジン－４－イル］フェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン Example 59: Synthesis in Example (59b) 1- (5- {4- [1- (2-hydroxyethyl) piperidin-4-yl] phenoxy} -4-methyl-2,3-dihydro-1H -Indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000093
Figure JPOXMLDOC01-appb-C000093
（５９ａ）　１－（５－｛４－［１－（２－｛［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシ｝エチル）ピペリジン－４－イル］フェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（１ｅ）で得られた化合物（１００　ｍｇ）のテトラヒドロフラン（３　ｍＬ）とメタノール（１　ｍＬ）の混合溶液に酢酸（６３．５　μＬ）、（ｔｅｒｔ－ブチルジメチルシロキシ）アルデヒド（４８．３　ｍｇ）、ナトリウムトリアセトキシボロヒドリド（５８．８　ｍｇ）を加え、室温で１５時間撹拌した。反応液を減圧下にて濃縮し、飽和炭酸水素ナトリウム水溶液（１０　ｍＬ）を加えて酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。 (59a) 1- (5- {4- [1- (2-{[tert-Butyl (dimethyl) silyl] oxy} ethyl) piperidin-4-yl] phenoxy} -4-methyl-2,3-dihydro- 1H-Indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone A mixed solution of the compound (100 mg) obtained in Example (1e) in tetrahydrofuran (3 mL) and methanol (1 mL) Acetic acid (63.5 μL), (tert-butyldimethylsiloxy) aldehyde (48.3 mg) and sodium triacetoxyborohydride (58.8 mg) were added to the mixture, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (10 mL) 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.
　得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（３６．９　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 0.08 (6H, s), 0.90 (9H, s), 1.86-1.94 (2H, m), 2.06 (3H, s), 2.29-2.39 (2H, m), 2.41-2.58 (3H, m), 2.72 (2H, t, J = 6.1 Hz), 3.13 (3H, s), 3.18-3.29 (4H, m), 3.85 (2H, t, J = 6.1 Hz), 4.29 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.74-6.85 (3H, m), 7.14 (2H, d, J = 9.2 Hz), 7.37 (1H, d, J = 7.9 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.60-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz)。
（５９ｂ）　１－（５－｛４－［１－（２－ヒドロキシエチル）ピペリジン－４－イル］フェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（５９ａ）で得られた化合物（３６．９　ｍｇ）のテトラヒドロフラン（１　ｍＬ）溶液にテトラブチルアンモニウムフルオリド（１　ｍｏｌ／Ｌテトラヒドロフラン溶液、２３．７　μＬ）を加え、室温で１５時間撹拌した。反応液を減圧下で濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／ジクロロメタン）で精製することで、標記化合物（２７．８　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.39-1.52 (1H, m), 1.62-1.75 (1H, m), 1.85-2.17 (5H, m), 2.36-2.49 (2H, m), 2.51-2.63 (1H, m), 2.73-2.84 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.27-3.39 (3H, m), 3.74-3.83 (2H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.77 (1H, d, J = 8.5 Hz), 6.80-6.85 (2H, m), 7.14 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.50-7.54 (1H, m), 7.57-7.68 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 604 (M+H)+。 The obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (36.9 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.08 (6H, s), 0.90 (9H, s), 1.86-1.94 (2H, m), 2.06 (3H, s), 2.29-2.39 (2H, m ), 2.41-2.58 (3H, m), 2.72 (2H, t, J = 6.1 Hz), 3.13 (3H, s), 3.18-3.29 (4H, m), 3.85 (2H, t, J = 6.1 Hz) , 4.29 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.74-6.85 (3H, m), 7.14 (2H, d, J = 9.2 Hz), 7.37 (1H, d, J = 7.9 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.60-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
(59b) 1- (5- {4- [1- (2-hydroxyethyl) piperidin-4-yl] phenoxy} -4-methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (Methylsulfonyl) phenyl] ethanone Tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 23.7) was added to a solution of the compound (36.9 mg) obtained in Example (59a) in tetrahydrofuran (1 mL). μL) was added and stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol / dichloromethane) to give the title compound (27.8 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.39-1.52 (1H, m), 1.62-1.75 (1H, m), 1.85-2.17 (5H, m), 2.36-2.49 (2H, m), 2.51 -2.63 (1H, m), 2.73-2.84 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.27-3.39 (3H, m), 3.74-3.83 (2H , m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.77 (1H, d, J = 8.5 Hz), 6.80-6.85 (2H, m), 7.14 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.50-7.54 (1H, m), 7.57-7.68 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 ( (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 604 (M + H) + .
　（実施例６０）
１－（５－｛４－［１－（２－メトキシエチル）ピペリジン－４－イル］フェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン (Example 60)
1- (5- {4- [1- (2-methoxyethyl) piperidin-4-yl] phenoxy} -4-methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (Methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000094
Figure JPOXMLDOC01-appb-C000094
　実施例（１ｅ）で得られた化合物（８０．０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液に炭酸カリウム（６１．３　ｍｇ）、２－ブロモエチルメチルエーテル（２０．８　μＬ）を加え、８０℃で１２時間撹拌した。反応液に水を加えて酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（４６．２　ｍｇ）を淡黄色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.59-1.68 (2H, m), 1.76-1.87 (2H, m), 2.40-2.49 (5H, m), 2.41-2.49 (1H, m), 2.61 (2H, t, J = 5.5 Hz), 3.02-3.14 (5H, m), 3.21 (2H, t, J = 7.9 Hz), 3.36 (3H, s), 3.54 (2H, t, J = 5.5 Hz), 4.28 (2H, t, J = 7.9 Hz), 4.36 (2H, s), 6.74-6.87 (3H, m), 7.13 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.61 (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: 563 (M+H)+。 To a solution of the compound (80.0 mg) obtained in Example (1e) in N, N-dimethylformamide (3 mL) was added potassium carbonate (61.3 mg) and 2-bromoethyl methyl ether (20.8 μL). And stirred at 80 ° C. for 12 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 amino silica gel column chromatography (ethyl acetate / hexane) to give the title compound (46.2 mg) as a pale yellow solid.
1 H-NMR (400 MHz, CDCl 3) δ: 1.59-1.68 (2H, m), 1.76-1.87 (2H, m), 2.40-2.49 (5H, m), 2.41-2.49 (1H, m), 2.61 (2H, t, J = 5.5 Hz), 3.02-3.14 (5H, m), 3.21 (2H, t, J = 7.9 Hz), 3.36 (3H, s), 3.54 (2H, t, J = 5.5 Hz) , 4.28 (2H, t, J = 7.9 Hz), 4.36 (2H, s), 6.74-6.87 (3H, m), 7.13 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.61 (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: 563 (M + H) + .
　（実施例６１）
１－（５－｛４－［１－（３，３－ジフルオロプロピル）ピペリジン－４－イル］フェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン (Example 61)
1- (5- {4- [1- (3,3-Difluoropropyl) piperidin-4-yl] phenoxy} -4-methyl-2,3-dihydro-1H-indol-1-yl) -2- [ 2- (Methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000095
Figure JPOXMLDOC01-appb-C000095
　実施例（１ｅ）で得られた化合物（８０．０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液にＮ，Ｎ－ジイソプロピルエチルアミン（１２６　μＬ）を加え、室温で５分間撹拌した。次いで炭酸カリウム（３０．７　ｍｇ）、文献記載の方法（Ｊｏｕｒｎａｌ　ｏｆ　Ｏｒｇａｎｉｃ　Ｃｈｅｍｉｓｔｒｙ，２００９，７４，４５４７）に従って合成した２－ジフルオロエチル　メタンスルホン酸（１０５　ｍｇ）を加え、８０℃で１２時間撹拌した。反応液に水を加えて酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をアミノカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（１５．５　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.70-1.86 (4H, m), 2.13 (3H, s), 2.29 (2H, t, J = 5.5 Hz), 2.38-2.52 (1H, m), 2.69-2.83 (2H, m), 3.00-3.07 (2H, m), 3.12 (3H, s), 3.21 (2H, t, J = 8.5 Hz), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 5.75-5.80 (0.2H, m), 5.89-5.94 (0.5H, m), 6.03-6.09 (0.3H, m), 6.73-6.85 (3H, m), 7.12 (2H, d, J = 8.5 Hz), 7.35-7.38 (1H, m), 7.49-7.55 (1H, m), 7.59-7.64 (1H, m), 7.96 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 569 (M+H)+。 N, N-diisopropylethylamine (126 μL) was added to a solution of the compound (80.0 mg) obtained in Example (1e) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes. Next, potassium carbonate (30.7 mg) and 2-difluoroethyl methanesulfonic acid (105 mg) synthesized according to a method described in the literature (Journal of Organic Chemistry, 2009, 74, 4547) were added, and the mixture was stirred at 80 ° C. for 12 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 amino column chromatography (ethyl acetate / hexane) to give the title compound (15.5 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.70-1.86 (4H, m), 2.13 (3H, s), 2.29 (2H, t, J = 5.5 Hz), 2.38-2.52 (1H, m), 2.69-2.83 (2H, m), 3.00-3.07 (2H, m), 3.12 (3H, s), 3.21 (2H, t, J = 8.5 Hz), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 5.75-5.80 (0.2H, m), 5.89-5.94 (0.5H, m), 6.03-6.09 (0.3H, m), 6.73-6.85 (3H, m), 7.12 (2H, d , J = 8.5 Hz), 7.35-7.38 (1H, m), 7.49-7.55 (1H, m), 7.59-7.64 (1H, m), 7.96 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 569 (M + H) + .
　（実施例６２）：実施例（６２ｂ）で合成
（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）酢酸 Example 62: synthesized in Example (62b) (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole- 5-yl) oxy] phenyl} piperidin-1-yl) acetic acid
Figure JPOXMLDOC01-appb-C000096
Figure JPOXMLDOC01-appb-C000096
（６２ａ）　メチル　（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）アセテート
　実施例（１ｅ）で得られた化合物（４２．６　ｍｇ）のジクロロメタン（３　ｍＬ）溶液にブロモ酢酸メチル（９．３　μＬ）、トリエチルアミン（２９．４　μＬ）を加え、室温で１８時間撹拌した。反応液に水を加えて酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（３２．８　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.78-1.91 (4H, m), 2.13 (3H, s), 2.23-2.32 (2H, m), 2.39-2.56 (1H, m), 3.00-3.08 (2H, m), 3.12 (3H, s), 3.21 (2H, t, J = 8.5 Hz), 3.26 (2H, s), 3.74 (3H, s), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.73-6.83 (3H, m), 7.13 (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), 7.96 (1H, d, J = 9.1 Hz), 8.07 (1H, t, J = 3.9 Hz)。
（６２ｂ）　（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）酢酸
　実施例（６２ａ）で得られた化合物（３２．８　ｍｇ）のテトラヒドロフラン（１　ｍＬ）とメタノール（１　ｍＬ）の混合溶液に２Ｎ水酸化ナトリウム水溶液（７１．１　μＬ）を加え、室温で１８時間撹拌した。反応液を減圧下で濃縮し、水を加えてジクロロメタンで水層を洗浄した。得られた水層を１Ｎ塩酸で中和後、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮、乾燥することで、標記化合物（１２．２　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.62-2.14 (7H, m), 2.59-2.79 (1H, m), 3.00-3.24 (5H, m), 3.40 (3H, s), 3.55 (2H, s), 4.17-4.41 (5H, m), 6.58-6.86 (3H, m), 7.03-7.18 (1H, m), 7.25-7.38 (1H, m), 7.42-7.63 (3H, m), 7.92 (1H, d, J= 8.5 Hz), 8.03 (1H, d, J = 8.5 Hz).
　MS(APCI) m/z: 563 (M+H)+。 (62a) Methyl (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine -1-yl) acetate To a solution of the compound (42.6 mg) obtained in Example (1e) in dichloromethane (3 mL) was added methyl bromoacetate (9.3 μL) and triethylamine (29.4 μL), Stir at room temperature for 18 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 (32.8 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.78-1.91 (4H, m), 2.13 (3H, s), 2.23-2.32 (2H, m), 2.39-2.56 (1H, m), 3.00-3.08 (2H, m), 3.12 (3H, s), 3.21 (2H, t, J = 8.5 Hz), 3.26 (2H, s), 3.74 (3H, s), 4.28 (2H, t, J = 8.5 Hz) , 4.36 (2H, s), 6.73-6.83 (3H, m), 7.13 (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), 7.96 (1H, d, J = 9.1 Hz), 8.07 (1H, t, J = 3.9 Hz).
(62b) (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine- 1-yl) acetic acid To a mixed solution of the compound (32.8 mg) obtained in Example (62a) in tetrahydrofuran (1 mL) and methanol (1 mL) was added 2N aqueous sodium hydroxide solution (71.1 μL). And stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, water was added, and the aqueous layer was washed with dichloromethane. The obtained aqueous layer 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, concentrated and dried under reduced pressure to give the title compound (12.2 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.62-2.14 (7H, m), 2.59-2.79 (1H, m), 3.00-3.24 (5H, m), 3.40 (3H, s), 3.55 (2H , s), 4.17-4.41 (5H, m), 6.58-6.86 (3H, m), 7.03-7.18 (1H, m), 7.25-7.38 (1H, m), 7.42-7.63 (3H, m), 7.92 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 563 (M + H) + .
　（実施例６３）
１－（４－メチル－５－｛４－［１－（オキセタン－３－イル）ピペリジン－４－イル］フェノキシ｝－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン (Example 63)
1- (4-Methyl-5- {4- [1- (oxetan-3-yl) piperidin-4-yl] phenoxy} -2,3-dihydro-1H-indol-1-yl) -2- [2 -(Methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000097
Figure JPOXMLDOC01-appb-C000097
　実施例（１ｅ）で得られた化合物（５０．０　ｍｇ）のジクロロメタン（２　ｍＬ）溶液にナトリウムトリアセトキシボロヒドリド（２７．３　ｍｇ）、２－オキセタノン（８５．７　ｍｇ）を加え、室温で１８時間撹拌した。反応液に水を加えて酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（３８．３　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.70-1.98 (6H, m), 2.13 (3H, s), 2.39-2.52 (1H, m), 2.80-2.92 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 7.9 Hz), 3.45-3.53 (1H, m), 4.28 (2H, t, J = 7.9 Hz), 4.36 (2H, s), 4.63-4.71 (4H, m), 6.71-6.87 (3H, m), 7.13 (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).
MS(APCI) m/z: 561 (M+H)+。 Sodium triacetoxyborohydride (27.3 mg) and 2-oxetanone (85.7 mg) were added to a solution of the compound (50.0 mg) obtained in Example (1e) in dichloromethane (2 mL) at room temperature. Stir for 18 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 (38.3 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.70-1.98 (6H, m), 2.13 (3H, s), 2.39-2.52 (1H, m), 2.80-2.92 (2H, m), 3.12 (3H , s), 3.22 (2H, t, J = 7.9 Hz), 3.45-3.53 (1H, m), 4.28 (2H, t, J = 7.9 Hz), 4.36 (2H, s), 4.63-4.71 (4H, m), 6.71-6.87 (3H, m), 7.13 (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).
MS (APCI) m / z: 561 (M + H) + .
　（実施例６４）
　（実施例６４－１）：実施例（６４ａ）で合成
１－｛４－メチル－５－［４－（１－メチル－１，２，３，６－テトラヒドロピリジン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン (Example 64)
Example 64-1: Synthesis in Example (64a) 1- {4-methyl-5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenoxy]- 2,3-Dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000098
Figure JPOXMLDOC01-appb-C000098
　（実施例６４－２）：実施例（６４ｂ）で合成
１－｛４－メチル－５－［４－（１－メチルピペリジン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン Example 64-2: synthesized in Example (64b) 1- {4-methyl-5- [4- (1-methylpiperidin-4-yl) phenoxy] -2,3-dihydro-1H-indole- 1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000099
Figure JPOXMLDOC01-appb-C000099
（６４ａ）　１－｛４－メチル－５－［４－（１－メチル－１，２，３，６－テトラヒドロピリジン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（１ｂ）で得られた化合物（２００　ｍｇ）、１－メチル－１，２、３，６－テトラヒドロピリジン－４－ボロン酸　ピナコールエステル（５３．５　ｍｇ）の１，２－ジメトキシエタン（２　ｍＬ）溶液に炭酸ナトリウム（５０．８　ｍｇ）の水溶液（１　ｍＬ）を加え、室温で５分間撹拌した。次いで［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（１３．１　ｍｇ）を加え、マイクロウェーブ反応装置にて、１３０℃で１時間反応させた。反応液を室温に冷却後、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（４０．７　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.47-1.62 (2H, br m), 2.12 (3H, s), 2.52-2.62 (2H, br m), 2.64-2.73 (2H, br m), 3.12 (3H, s), 3.21 (2H, t, J = 8.5 Hz), 3.49 (3H, s), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 5.98 (1H, br s), 6.75-6.86 (3H, m), 7.22-7.32 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.98 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 517 (M+H)+。
（６４ｂ）　１－｛４－メチル－５－［４－（１－メチルピペリジン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（６４ａ）で得られた化合物（２２．０　ｍｇ）をエタノール（２　ｍＬ）及びメタノール（１　ｍＬ）に溶解し、７．５％パラジウム炭素（４．０　ｍｇ）を加え水素雰囲気下、室温で２４時間撹拌した。反応液にメタノールを加え不溶物をろ去、ろ液を減圧下で濃縮することで、標記化合物（２４．５　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.38-1.83 (3H, m), 1.95-2.08 (2H, m), 2.11 (3H, s), 2.36-2.52 (1H, br m), 2.62-2.90 (5H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.47-3.59 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.72-6.87 (3H, m), 7.16 (1H, d, J = 8.5 Hz), 7.23-7.31 (1H, m), 7.36 (1H, d, J = 7.3 Hz), 7.48-7.56 (1H, m), 7.58-7.67 (1H, m), 7.98 (1H, t, J = 7.9 Hz), 8.07 (1H, d, J = 7.3 Hz).
MS(APCI) m/z: 519 (M+H)+。 (64a) 1- {4-Methyl-5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenoxy] -2,3-dihydro-1H-indole-1- Yl} -2- [2- (methylsulfonyl) phenyl] ethanone Compound (200 mg) obtained in Example (1b), 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol An aqueous solution (1 mL) of sodium carbonate (50.8 mg) was added to a solution of ester (53.5 mg) in 1,2-dimethoxyethane (2 mL), and the mixture was stirred at room temperature for 5 minutes. Next, [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 amino silica gel column chromatography (ethyl acetate / hexane) to give the title compound (40.7 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.47-1.62 (2H, br m), 2.12 (3H, s), 2.52-2.62 (2H, br m), 2.64-2.73 (2H, br m), 3.12 (3H, s), 3.21 (2H, t, J = 8.5 Hz), 3.49 (3H, s), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 5.98 (1H, br s), 6.75-6.86 (3H, m), 7.22-7.32 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t , J = 7.6 Hz), 7.98 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 517 (M + H) + .
(64b) 1- {4-Methyl-5- [4- (1-methylpiperidin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methyl Sulfonyl) phenyl] ethanone The compound (22.0 mg) obtained in Example (64a) was dissolved in ethanol (2 mL) and methanol (1 mL), and 7.5% palladium carbon (4.0 mg) was dissolved. In addition, the mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere. Methanol was added to the reaction solution, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (24.5 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.38-1.83 (3H, m), 1.95-2.08 (2H, m), 2.11 (3H, s), 2.36-2.52 (1H, br m), 2.62- 2.90 (5H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.47-3.59 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.37 (2H , s), 6.72-6.87 (3H, m), 7.16 (1H, d, J = 8.5 Hz), 7.23-7.31 (1H, m), 7.36 (1H, d, J = 7.3 Hz), 7.48-7.56 ( 1H, m), 7.58-7.67 (1H, m), 7.98 (1H, t, J = 7.9 Hz), 8.07 (1H, d, J = 7.3 Hz).
MS (APCI) m / z: 519 (M + H) + .
　（実施例６５）
１－（４－｛４－［４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル］オキシ］フェニル｝ピペリジン－１－イル）－２－（モルホリン－４－イル）エタノン (Example 65)
1- (4- {4- [4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl] oxy] phenyl} piperidine-1- Yl) -2- (morpholin-4-yl) ethanone
Figure JPOXMLDOC01-appb-C000100
Figure JPOXMLDOC01-appb-C000100
　実施例（１ｅ）で得られた化合物（６０．０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液にトリエチルアミン（３１．０　μＬ）を加え、室温で５分間攪拌した。次いで４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（４６．０　ｍｇ）及びモルホリン－４－イル酢酸（１９．３　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン→メタノール／酢酸エチル）で精製することで、標記化合物（５１．５　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.49-1.68 (2H, m), 1.83-1.95 (2H, m), 2.13 (3H, s), 2.47-2.76 (6H, m), 3.03-3.33 (8H, m), 3.65-3.78 (4H, m), 4.13-4.23 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.70-4.78 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 7.9 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.49-7.55 (1H, m), 7.60-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 632 (M+H)+。 Triethylamine (31.0 μL) was added to a solution of the compound (60.0 mg) obtained in Example (1e) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 5 minutes. Then 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (46.0 mg) and morpholin-4-ylacetic acid (19.3 mg) were added. The mixture was further stirred at room temperature for 18 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 → methanol / ethyl acetate) to give the title compound (51.5 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.49-1.68 (2H, m), 1.83-1.95 (2H, m), 2.13 (3H, s), 2.47-2.76 (6H, m), 3.03-3.33 (8H, m), 3.65-3.78 (4H, m), 4.13-4.23 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.70-4.78 (1H, m ), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 7.9 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.49-7.55 (1H, m), 7.60-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 632 (M + H) + .
　（実施例６６）
Ｎ，Ｎ－ジメチル－２－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－２－オキソアセトアミド Example 66
N, N-dimethyl-2- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy ] Phenyl} piperidin-1-yl) -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000101
Figure JPOXMLDOC01-appb-C000101
　実施例７９で得られた化合物（１３４　ｍｇ）のジクロロメタン（４　ｍＬ）溶液にジメチルアミン塩酸塩（５６．８　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（６６．８　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（３１．６　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．２０２　ｍＬ）を加えて室温で撹拌した。１２時間後、反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（メタノール／酢酸エチル）で精製することで標記化合物（１０１　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.60-1.77 (2H, m), 1.85-1.98 (2H, m), 2.12 (3H, s), 2.69-2.83 (2H, m), 3.01 (3H, s), 3.04 (3H, s), 3.12 (3H, s), 3.14-3.25 (3H, m), 3.72-3.80 (1H, m), 4.25-4.32 (2H, m), 4.36 (2H, s), 4.66-4.74 (1H, m), 6.74-6.85 (3H, m), 7.07-7.13 (2H, m), 7.34-7.38 (1H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.95-8.00 (1H, m), 8.07-8.08 (1H, m).
MS (APCI) m/z: 604 (M+H)+。 Dimethylamine hydrochloride (56.8 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (66) were added to a solution of the compound obtained in Example 79 (134 mg) in dichloromethane (4 mL). 8 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (31.6 mg) and N, N-diisopropylethylamine (0.202 mL) were added at room temperature. Stir. After 12 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / ethyl acetate) to obtain the title compound (101 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.60-1.77 (2H, m), 1.85-1.98 (2H, m), 2.12 (3H, s), 2.69-2.83 (2H, m), 3.01 (3H , s), 3.04 (3H, s), 3.12 (3H, s), 3.14-3.25 (3H, m), 3.72-3.80 (1H, m), 4.25-4.32 (2H, m), 4.36 (2H, s ), 4.66-4.74 (1H, m), 6.74-6.85 (3H, m), 7.07-7.13 (2H, m), 7.34-7.38 (1H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.95-8.00 (1H, m), 8.07-8.08 (1H, m).
MS (APCI) m / z: 604 (M + H) + .
　（実施例６７）
Ｎ－エチル－２－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－２－オキソアセトアミド (Example 67)
N-ethyl-2- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl } Piperidin-1-yl) -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000102
Figure JPOXMLDOC01-appb-C000102
　実施例７９で得られた化合物（１１７　ｍｇ）のジクロロメタン（４　ｍＬ）溶液にエチルアミン塩酸塩（２４．８　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（７７．８　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（２７．６　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１０６　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール／酢酸エチル）で精製することで標記化合物（７８．０　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (500 MHz, CDCl3) δ: 1.20 (3H, t, J = 7.3 Hz), 1.60-1.79 (2H, m), 1.88-1.97 (2H, m), 2.12 (3H, s), 2.70-2.82 (2H, m), 3.09-3.25 (6H, m), 3.31-3.38 (2H, m), 4.25-4.32 (2H, m), 4.36 (2H, s), 4.65-4.72 (1H, m), 5.12-5.19 (1H, m), 6.75-6.85 (3H, m), 7.08-7.20 (3H, m), 7.34-7.38 (1H, m), 7.49-7.54 (1H, m), 7.59-7.64 (1H, m), 7.95-7.99 (1H, m), 8.06-8.09 (1H, m).
MS (APCI) m/z: 604 (M+H)+。 To a solution of the compound obtained in Example 79 (117 mg) in dichloromethane (4 mL) was added ethylamine hydrochloride (24.8 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (77. 8 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (27.6 mg) and N, N-diisopropylethylamine (0.106 mL) were added and stirred at room temperature. did. 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 (78.0 mg) as a white amorphous solid.
1 H-NMR (500 MHz, CDCl 3 ) δ: 1.20 (3H, t, J = 7.3 Hz), 1.60-1.79 (2H, m), 1.88-1.97 (2H, m), 2.12 (3H, s), 2.70-2.82 (2H, m), 3.09-3.25 (6H, m), 3.31-3.38 (2H, m), 4.25-4.32 (2H, m), 4.36 (2H, s), 4.65-4.72 (1H, m ), 5.12-5.19 (1H, m), 6.75-6.85 (3H, m), 7.08-7.20 (3H, m), 7.34-7.38 (1H, m), 7.49-7.54 (1H, m), 7.59-7.64 (1H, m), 7.95-7.99 (1H, m), 8.06-8.09 (1H, m).
MS (APCI) m / z: 604 (M + H) + .
　（実施例６８）
Ｎ－（２－フルオロエチル）－２－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－２－オキソアセトアミド Example 68
N- (2-fluoroethyl) -2- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole-5- Yl) oxy] phenyl} piperidin-1-yl) -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000103
Figure JPOXMLDOC01-appb-C000103
　実施例７９で得られた化合物（１３２　ｍｇ）のジクロロメタン（４　ｍＬ）溶液に２－フルオロエチルアミン塩酸塩（３４．２　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（８７．８　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（３１．２　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１２０　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール／酢酸エチル）で精製することで標記化合物（８７．０　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.60-1.81 (2H, m), 1.87-2.00 (2H, m), 2.12 (3H, s), 2.71-2.84 (2H, m), 3.08-3.26 (6H, m), 3.56-3.70 (2H, m), 4.24-4.33 (2H, m), 4.36 (2H, s), 4.46-4.51 (1H, m), 4.57-4.63 (1H, m), 4.65-4.74 (1H, m), 5.07-5.15 (1H, m), 6.75-6.85 (3H, m), 7.08-7.13 (2H, m), 7.34-7.38 (1H, m), 7.48-7.56 (2H, m), 7.59-7.65 (1H, m), 7.95-8.00 (1H, m), 8.06-8.10 (1H, m).
MS (APCI) m/z: 622 (M+H)+。 2-Fluoroethylamine hydrochloride (34.2 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride were added to a solution of the compound obtained in Example 79 (132 mg) in dichloromethane (4 mL). (87.8 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (31.2 mg), N, N-diisopropylethylamine (0.120 mL) were added. Stir 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 (87.0 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.60-1.81 (2H, m), 1.87-2.00 (2H, m), 2.12 (3H, s), 2.71-2.84 (2H, m), 3.08-3.26 (6H, m), 3.56-3.70 (2H, m), 4.24-4.33 (2H, m), 4.36 (2H, s), 4.46-4.51 (1H, m), 4.57-4.63 (1H, m), 4.65 -4.74 (1H, m), 5.07-5.15 (1H, m), 6.75-6.85 (3H, m), 7.08-7.13 (2H, m), 7.34-7.38 (1H, m), 7.48-7.56 (2H, m), 7.59-7.65 (1H, m), 7.95-8.00 (1H, m), 8.06-8.10 (1H, m).
MS (APCI) m / z: 622 (M + H) + .
　（実施例６９）
Ｎ－（２，２－ジフルオロエチル）－２－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－２－オキソアセトアミド (Example 69)
N- (2,2-difluoroethyl) -2- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole- 5-yl) oxy] phenyl} piperidin-1-yl) -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000104
Figure JPOXMLDOC01-appb-C000104
　実施例７９で得られた化合物（１３８　ｍｇ）のジクロロメタン（４　ｍＬ）溶液に２，２－ジフルオロエタン－１－アミン塩酸塩（４２．２　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（９１．８　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（３２．６　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１２５　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール／酢酸エチル）で精製することで標記化合物（１１０　ｍｇ）を淡黄色アモルファス固体として得た。
1H-NMR (500 MHz, CDCl3) δ: 1.61-1.79 (2H, m), 1.90-1.99 (2H, m), 2.12 (3H, s), 2.72-2.84 (2H, m), 3.09-3.25 (6H, m), 3.64-3.75 (2H, m), 4.26-4.31 (2H, m), 4.36 (2H, s), 4.66-4.72 (1H, m), 5.08-5.15 (1H, m), 5.75-6.01 (1H, m), 6.75-6.85 (3H, m), 7.08-7.13 (2H, m), 7.34-7.38 (1H, m), 7.46-7.56 (2H, m), 7.59-7.64 (1H, m), 7.95-7.99 (1H, m), 8.06-8.09 (1H, m).
MS (APCI) m/z: 640 (M+H)+。 To a solution of the compound obtained in Example 79 (138 mg) in dichloromethane (4 mL) was added 2,2-difluoroethane-1-amine hydrochloride (42.2 mg), 1-ethyl-3- (3-dimethylaminopropyl). ) Carboximide hydrochloride (91.8 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (32.6 mg), N, N-diisopropylethylamine (0.125) mL) was 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 obtain the title compound (110 mg) as a pale yellow amorphous solid.
1 H-NMR (500 MHz, CDCl 3 ) δ: 1.61-1.79 (2H, m), 1.90-1.99 (2H, m), 2.12 (3H, s), 2.72-2.84 (2H, m), 3.09-3.25 (6H, m), 3.64-3.75 (2H, m), 4.26-4.31 (2H, m), 4.36 (2H, s), 4.66-4.72 (1H, m), 5.08-5.15 (1H, m), 5.75 -6.01 (1H, m), 6.75-6.85 (3H, m), 7.08-7.13 (2H, m), 7.34-7.38 (1H, m), 7.46-7.56 (2H, m), 7.59-7.64 (1H, m), 7.95-7.99 (1H, m), 8.06-8.09 (1H, m).
MS (APCI) m / z: 640 (M + H) + .
　（実施例７０）
Ｎ－メチル－２－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－２－オキソアセトアミド (Example 70)
N-methyl-2- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl } Piperidin-1-yl) -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000105
Figure JPOXMLDOC01-appb-C000105
　実施例７９で得られた化合物（１３６　ｍｇ）のジクロロメタン（４　ｍＬ）溶液にメチルアミン塩酸塩（３１．８　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（９０．４　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（３２．１　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１２３　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール／酢酸エチル）で精製することで標記化合物（７１．０　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.58-1.81 (2H, m), 1.87-1.98 (2H, m), 2.12 (3H, s), 2.70-2.83 (2H, m), 2.89 (3H, d, J = 5.1 Hz), 3.08-3.25 (6H, m), 4.25-4.32 (2H, m), 4.36 (2H, s), 4.64-4.72 (1H, m), 5.11-5.19 (1H, m), 6.75-6.85 (3H, m), 7.08-7.22 (3H, m), 7.34-7.39 (1H, m), 7.50-7.56 (1H, m), 7.59-7.65 (1H, m), 7.95-8.00 (1H, m), 8.06-8.10 (1H, m).
MS (APCI) m/z: 590 (M+H)+。 To a solution of the compound obtained in Example 79 (136 mg) in dichloromethane (4 mL) was added methylamine hydrochloride (31.8 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (90 .4 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (32.1 mg) and N, N-diisopropylethylamine (0.123 mL) were added at room temperature. Stir. 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 (71.0 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.58-1.81 (2H, m), 1.87-1.98 (2H, m), 2.12 (3H, s), 2.70-2.83 (2H, m), 2.89 (3H , d, J = 5.1 Hz), 3.08-3.25 (6H, m), 4.25-4.32 (2H, m), 4.36 (2H, s), 4.64-4.72 (1H, m), 5.11-5.19 (1H, m ), 6.75-6.85 (3H, m), 7.08-7.22 (3H, m), 7.34-7.39 (1H, m), 7.50-7.56 (1H, m), 7.59-7.65 (1H, m), 7.95-8.00 (1H, m), 8.06-8.10 (1H, m).
MS (APCI) m / z: 590 (M + H) + .
　（実施例７１）
２－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－２－オキソ－Ｎ－プロピルアセトアミド (Example 71)
2- (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine-1 -Yl) -2-oxo-N-propylacetamide
Figure JPOXMLDOC01-appb-C000106
Figure JPOXMLDOC01-appb-C000106
　実施例７９で得られた化合物（１３１　ｍｇ）のジクロロメタン（４　ｍＬ）溶液にｎ－プロピルアミン塩酸塩（４３．４　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（８７．１　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（３０．９　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１１９　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール／酢酸エチル）で精製することで標記化合物（９２．０　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 0.96 (3H, t, J = 7.4 Hz), 1.52-1.80 (4H, m), 1.87-1.98 (2H, m), 2.12 (3H, s), 2.70-2.83 (2H, m), 3.08-3.31 (8H, m), 4.25-4.32 (2H, m), 4.36 (2H, s), 4.65-4.73 (1H, m), 5.11-5.19 (1H, m), 6.75-6.84 (3H, m), 7.08-7.24 (3H, m), 7.34-7.39 (1H, m), 7.49-7.56 (1H, m), 7.59-7.65 (1H, m), 7.95-8.00 (1H, m), 8.06-8.10 (1H, m).
MS (APCI) m/z: 618 (M+H)+。 N-Propylamine hydrochloride (43.4 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride were added to a solution of the compound obtained in Example 79 (131 mg) in dichloromethane (4 mL). (87.1 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (30.9 mg), N, N-diisopropylethylamine (0.119 mL) were added. Stir 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 (92.0 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.96 (3H, t, J = 7.4 Hz), 1.52-1.80 (4H, m), 1.87-1.98 (2H, m), 2.12 (3H, s), 2.70-2.83 (2H, m), 3.08-3.31 (8H, m), 4.25-4.32 (2H, m), 4.36 (2H, s), 4.65-4.73 (1H, m), 5.11-5.19 (1H, m ), 6.75-6.84 (3H, m), 7.08-7.24 (3H, m), 7.34-7.39 (1H, m), 7.49-7.56 (1H, m), 7.59-7.65 (1H, m), 7.95-8.00 (1H, m), 8.06-8.10 (1H, m).
MS (APCI) m / z: 618 (M + H) + .
　（実施例７２）
２－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－２－オキソ－Ｎ－（プロパン－２－イル）アセトアミド (Example 72)
2- (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine-1 -Yl) -2-oxo-N- (propan-2-yl) acetamide
Figure JPOXMLDOC01-appb-C000107
Figure JPOXMLDOC01-appb-C000107
　実施例７９で得られた化合物（１３４　ｍｇ）のジクロロメタン（４　ｍＬ）溶液にイソプロピルアミン塩酸塩（４４．４　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（８９．１　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（３１．６　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１２１　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（９２．０　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (500 MHz, CDCl3) δ: 1.19-1.24 (6H, m), 1.59-1.80 (2H, m), 1.88-1.97 (2H, m), 2.12 (3H, s), 2.70-2.81 (2H, m), 3.09-3.25 (6H, m), 4.00-4.10 (1H, m), 4.25-4.32 (2H, m), 4.36 (2H, s), 4.65-4.71 (1H, m), 5.13-5.19 (1H, m), 6.75-6.84 (3H, m), 6.99-7.14 (3H, m), 7.35-7.38 (1H, m), 7.49-7.54 (1H, m), 7.59-7.64 (1H, m), 7.95-7.99 (1H, m), 8.06-8.09 (1H, m).
MS (APCI) m/z: 618 (M+H)+。 To a solution of the compound obtained in Example 79 (134 mg) in dichloromethane (4 mL) was added isopropylamine hydrochloride (44.4 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (89 0.1 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (31.6 mg) and N, N-diisopropylethylamine (0.121 mL) were added at room temperature. Stir. 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 (92.0 mg) as a white amorphous solid.
1 H-NMR (500 MHz, CDCl 3 ) δ: 1.19-1.24 (6H, m), 1.59-1.80 (2H, m), 1.88-1.97 (2H, m), 2.12 (3H, s), 2.70-2.81 (2H, m), 3.09-3.25 (6H, m), 4.00-4.10 (1H, m), 4.25-4.32 (2H, m), 4.36 (2H, s), 4.65-4.71 (1H, m), 5.13 -5.19 (1H, m), 6.75-6.84 (3H, m), 6.99-7.14 (3H, m), 7.35-7.38 (1H, m), 7.49-7.54 (1H, m), 7.59-7.64 (1H, m), 7.95-7.99 (1H, m), 8.06-8.09 (1H, m).
MS (APCI) m / z: 618 (M + H) + .
　（実施例７３）
２－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－２－オキソ－Ｎ－（２，２，２－トリフルオロエチル）アセトアミド (Example 73)
2- (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine-1 -Yl) -2-oxo-N- (2,2,2-trifluoroethyl) acetamide
Figure JPOXMLDOC01-appb-C000108
Figure JPOXMLDOC01-appb-C000108
　実施例７９で得られた化合物（１３３　ｍｇ）のジクロロメタン（４　ｍＬ）溶液に２，２，２－トリフルオロエチルアミン塩酸塩（６２．５　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（８８．４　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（３１．４　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１２１　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（１２０　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.62-1.80 (2H, m), 1.90-2.00 (2H, m), 2.12 (3H, s), 2.73-2.85 (2H, m), 3.09-3.25 (6H, m), 3.87-4.03 (2H, m), 4.25-4.31 (2H, m), 4.36 (2H, s), 4.66-4.72 (1H, m), 5.09-5.16 (1H, m), 6.75-6.85 (3H, m), 7.08-7.13 (2H, m), 7.34-7.38 (1H, m), 7.50-7.55 (1H, m), 7.57-7.65 (2H, m), 7.96-7.99 (1H, m), 8.06-8.09 (1H, m).
MS (APCI) m/z: 658 (M+H)+。 To a solution of the compound obtained in Example 79 (133 mg) in dichloromethane (4 mL) was added 2,2,2-trifluoroethylamine hydrochloride (62.5 mg), 1-ethyl-3- (3-dimethylaminopropyl). ) Carboximide hydrochloride (88.4 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (31.4 mg), N, N-diisopropylethylamine (0.121) mL) was 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 (ethyl acetate / hexane) to give the title compound (120 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.62-1.80 (2H, m), 1.90-2.00 (2H, m), 2.12 (3H, s), 2.73-2.85 (2H, m), 3.09-3.25 (6H, m), 3.87-4.03 (2H, m), 4.25-4.31 (2H, m), 4.36 (2H, s), 4.66-4.72 (1H, m), 5.09-5.16 (1H, m), 6.75 -6.85 (3H, m), 7.08-7.13 (2H, m), 7.34-7.38 (1H, m), 7.50-7.55 (1H, m), 7.57-7.65 (2H, m), 7.96-7.99 (1H, m), 8.06-8.09 (1H, m).
MS (APCI) m / z: 658 (M + H) + .
　（実施例７４）
Ｎ－エチル－Ｎ－メチル－２－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－２－オキソアセトアミド (Example 74)
N-ethyl-N-methyl-2- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl ) Oxy] phenyl} piperidin-1-yl) -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000109
Figure JPOXMLDOC01-appb-C000109
　実施例７９で得られた化合物（０．１４　ｇ）のジクロロメタン（４　ｍＬ）溶液にＮ－メチルエタンアミン塩酸塩（０．０７２　ｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（０．０９６　ｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（０．０３４　ｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１３０　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール／酢酸エチル）で精製することで標記化合物（１２５　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.25 (3H, q, J = 7.3 Hz), 1.61-1.76 (2H, m), 1.85-1.98 (2H, m), 2.12 (3H, s), 2.68-2.82 (2H, m), 2.99 (3H, d, J = 7.8 Hz), 3.09-3.25 (6H, m), 3.27-3.55 (2H, m), 3.71-3.80 (1H, m), 4.24-4.32 (2H, m), 4.36 (2H, s), 4.65-4.74 (1H, m), 6.74-6.85 (3H, m), 7.07-7.13 (2H, m), 7.34-7.38 (1H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.95-7.99 (1H, m), 8.05-8.10 (1H, m).
MS (APCI) m/z: 618 (M+H)+。 To a solution of the compound obtained in Example 79 (0.14 g) in dichloromethane (4 mL) was added N-methylethanamine hydrochloride (0.072 g), 1-ethyl-3- (3-dimethylaminopropyl) carboxyl. Imide hydrochloride (0.096 g), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (0.034 g), N, N-diisopropylethylamine (0.130 mL) 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 (125 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.25 (3H, q, J = 7.3 Hz), 1.61-1.76 (2H, m), 1.85-1.98 (2H, m), 2.12 (3H, s), 2.68-2.82 (2H, m), 2.99 (3H, d, J = 7.8 Hz), 3.09-3.25 (6H, m), 3.27-3.55 (2H, m), 3.71-3.80 (1H, m), 4.24- 4.32 (2H, m), 4.36 (2H, s), 4.65-4.74 (1H, m), 6.74-6.85 (3H, m), 7.07-7.13 (2H, m), 7.34-7.38 (1H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.95-7.99 (1H, m), 8.05-8.10 (1H, m).
MS (APCI) m / z: 618 (M + H) + .
　（実施例７５）
２－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－２－オキソアセトアミド (Example 75)
2- (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine-1 -Yl) -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000110
Figure JPOXMLDOC01-appb-C000110
　実施例７９で得られた化合物（０．１４０　ｇ）のジクロロメタン（４　ｍＬ）溶液に塩化アンモニウム（０．０６７　ｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（０．０９６　ｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（０．０３４　ｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１３０　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール／酢酸エチル）で精製することで標記化合物（７６．０　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.61-1.81 (2H, m), 1.88-1.99 (2H, m), 2.12 (3H, s), 2.71-2.84 (2H, m), 3.09-3.26 (6H, m), 4.25-4.32 (2H, m), 4.36 (2H, s), 4.64-4.72 (1H, m), 4.93-5.01 (1H, m), 5.51-5.62 (1H, m), 6.75-6.85 (3H, m), 6.90-7.00 (1H, m), 7.08-7.13 (2H, m), 7.34-7.39 (1H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.95-7.99 (1H, m), 8.06-8.10 (1H, m).
MS (APCI) m/z: 576 (M+H)+。 To a solution of the compound obtained in Example 79 (0.140 g) in dichloromethane (4 mL), ammonium chloride (0.067 g), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (0 096 g) 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (0.034 g) and N, N-diisopropylethylamine (0.130 mL) were added at room temperature. Stir. 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 (76.0 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.61-1.81 (2H, m), 1.88-1.99 (2H, m), 2.12 (3H, s), 2.71-2.84 (2H, m), 3.09-3.26 (6H, m), 4.25-4.32 (2H, m), 4.36 (2H, s), 4.64-4.72 (1H, m), 4.93-5.01 (1H, m), 5.51-5.62 (1H, m), 6.75 -6.85 (3H, m), 6.90-7.00 (1H, m), 7.08-7.13 (2H, m), 7.34-7.39 (1H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.95-7.99 (1H, m), 8.06-8.10 (1H, m).
MS (APCI) m / z: 576 (M + H) + .
　（実施例７６）
１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－２－（モルホリン－４－イル）エタン－１，２－ジオン (Example 76)
1- (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine-1 -Yl) -2- (morpholin-4-yl) ethane-1,2-dione
Figure JPOXMLDOC01-appb-C000111
Figure JPOXMLDOC01-appb-C000111
　実施例７９で得られた化合物（７５０　ｍｇ）のジクロロメタン（１０　ｍＬ）溶液にモルホリン（２２７　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（４９９　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（１７７　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．６８０　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール／酢酸エチル）で精製することで標記化合物（４６０　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.59-1.75 (2H, m), 1.88-1.98 (2H, m), 2.12 (3H, s), 2.70-2.83 (2H, m), 3.10-3.29 (6H, m), 3.43-3.48 (2H, m), 3.62-3.84 (7H, m), 4.25-4.32 (2H, m), 4.36 (2H, s), 4.64-4.72 (1H, m), 6.74-6.84 (3H, m), 7.07-7.13 (2H, m), 7.34-7.38 (1H, m), 7.50-7.55 (1H, m), 7.59-7.65 (1H, m), 7.95-7.99 (1H, m), 8.06-8.09 (1H, m).
MS (APCI) m/z: 646 (M+H)+。 To a solution of the compound obtained in Example 79 (750 mg) in dichloromethane (10 mL), morpholine (227 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (499 mg), 3H— 1,2,3-Triazolo [4,5-b] pyridin-3-ol (177 mg) and N, N-diisopropylethylamine (0.680 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 (460 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.59-1.75 (2H, m), 1.88-1.98 (2H, m), 2.12 (3H, s), 2.70-2.83 (2H, m), 3.10-3.29 (6H, m), 3.43-3.48 (2H, m), 3.62-3.84 (7H, m), 4.25-4.32 (2H, m), 4.36 (2H, s), 4.64-4.72 (1H, m), 6.74 -6.84 (3H, m), 7.07-7.13 (2H, m), 7.34-7.38 (1H, m), 7.50-7.55 (1H, m), 7.59-7.65 (1H, m), 7.95-7.99 (1H, m), 8.06-8.09 (1H, m).
MS (APCI) m / z: 646 (M + H) + .
　（実施例７７）
１－（アゼチジン－１－イル）－２－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）エタン－１，２－ジオン (Example 77)
1- (azetidin-1-yl) -2- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole-5 -Yl) oxy] phenyl} piperidin-1-yl) ethane-1,2-dione
Figure JPOXMLDOC01-appb-C000112
Figure JPOXMLDOC01-appb-C000112
　実施例７９で得られた化合物（１５９　ｍｇ）のジクロロメタン（４　ｍＬ）溶液にアゼチジン塩酸塩（５１．６　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（１０６　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（３７．５　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１４４　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール／酢酸エチル）で精製することで標記化合物（１０８　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.59-1.76 (2H, m), 1.87-1.96 (2H, m), 2.12 (3H, s), 2.32-2.43 (2H, m), 2.68-2.79 (2H, m), 3.10-3.25 (6H, m), 4.07-4.17 (3H, m), 4.25-4.38 (6H, m), 4.61-4.68 (1H, m), 6.74-6.84 (3H, m), 7.07-7.12 (2H, m), 7.34-7.38 (1H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.95-7.99 (1H, m), 8.05-8.09 (1H, m).
MS (APCI) m/z: 616 (M+H)+。 To a solution of the compound obtained in Example 79 (159 mg) in dichloromethane (4 mL) was added azetidine hydrochloride (51.6 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (106 mg). ) 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (37.5 mg) and N, N-diisopropylethylamine (0.144 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 (108 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.59-1.76 (2H, m), 1.87-1.96 (2H, m), 2.12 (3H, s), 2.32-2.43 (2H, m), 2.68-2.79 (2H, m), 3.10-3.25 (6H, m), 4.07-4.17 (3H, m), 4.25-4.38 (6H, m), 4.61-4.68 (1H, m), 6.74-6.84 (3H, m) , 7.07-7.12 (2H, m), 7.34-7.38 (1H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.95-7.99 (1H, m), 8.05-8.09 ( 1H, m).
MS (APCI) m / z: 616 (M + H) + .
　（実施例７８）
エチル　（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）（オキソ）アセテート (Example 78)
Ethyl (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine-1- Yl) (oxo) acetate
Figure JPOXMLDOC01-appb-C000113
Figure JPOXMLDOC01-appb-C000113
　実施例（１ｅ）で得られた化合物（２１５　ｍｇ）にジクロロメタン（４　ｍＬ）、Ｎ，Ｎ－ジイソプロピルアミン（０．２０８　ｍＬ）、エチルクロログリコシル酸（０．０６２　ｍＬ）を加えて室温で撹拌した。２時間後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（２３９　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.38 (3H, t, J = 7.0 Hz), 1.59-1.77 (2H, m), 1.86-1.97 (2H, m), 2.12 (3H, s), 2.69-2.82 (2H, m), 3.12 (3H, s), 3.15-3.26 (3H, m), 3.72-3.81 (1H, m), 4.24-4.40 (6H, m), 4.61-4.70 (1H, m), 6.74-6.79 (1H, m), 6.80-6.85 (2H, m), 7.08-7.13 (2H, m), 7.34-7.39 (1H, m), 7.49-7.56 (1H, m), 7.59-7.65 (1H, m), 7.95-8.00 (1H, m), 8.05-8.10 (1H, m)。 Dichloromethane (4 mL), N, N-diisopropylamine (0.208 mL), and ethylchloroglycosyl acid (0.062 mL) were added to the compound (215 mg) obtained in Example (1e), and the mixture was stirred at room temperature. did. After 2 hours, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (239 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.38 (3H, t, J = 7.0 Hz), 1.59-1.77 (2H, m), 1.86-1.97 (2H, m), 2.12 (3H, s), 2.69-2.82 (2H, m), 3.12 (3H, s), 3.15-3.26 (3H, m), 3.72-3.81 (1H, m), 4.24-4.40 (6H, m), 4.61-4.70 (1H, m ), 6.74-6.79 (1H, m), 6.80-6.85 (2H, m), 7.08-7.13 (2H, m), 7.34-7.39 (1H, m), 7.49-7.56 (1H, m), 7.59-7.65 (1H, m), 7.95-8.00 (1H, m), 8.05-8.10 (1H, m).
　（実施例７９）
（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）（オキソ）酢酸 (Example 79)
(4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl ) (Oxo) acetic acid
Figure JPOXMLDOC01-appb-C000114
Figure JPOXMLDOC01-appb-C000114
　実施例７８で得られた化合物（２３７　ｍｇ）の１，４－ジオキサン（２　ｍＬ）溶液に１Ｎ水酸化ナトリウム水溶液（１．１７　ｍＬ）を加えて室温で３時間撹拌した。１Ｎ塩酸水溶液で中和した後、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、ろ過、減圧濃縮した。酢酸エチルで再結晶することで標記化合物（２０４　ｍｇ）を淡黄色個体として得た。
1H-NMR (400 MHz, DMSO-d6) δ: 1.39-1.57 (2H, m), 1.76-1.87 (2H, m), 1.98-2.08 (4H, m), 2.71-2.83 (2H, m), 3.13-3.40 (6H, m), 3.58-3.67 (1H, m), 4.21-4.40 (4H, m), 6.73-6.80 (3H, m), 7.14-7.21 (2H, m), 7.45-7.50 (1H, m), 7.55-7.61 (1H, m), 7.66-7.73 (1H, m), 7.81-7.87 (1H, m), 7.94-7.99 (1H, m)。 To a solution of the compound obtained in Example 78 (237 mg) in 1,4-dioxane (2 mL) was added 1N aqueous sodium hydroxide solution (1.17 mL), and the mixture was stirred at room temperature for 3 hr. The mixture was neutralized with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Recrystallization from ethyl acetate gave the title compound (204 mg) as a pale yellow solid.
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 1.39-1.57 (2H, m), 1.76-1.87 (2H, m), 1.98-2.08 (4H, m), 2.71-2.83 (2H, m) , 3.13-3.40 (6H, m), 3.58-3.67 (1H, m), 4.21-4.40 (4H, m), 6.73-6.80 (3H, m), 7.14-7.21 (2H, m), 7.45-7.50 ( 1H, m), 7.55-7.61 (1H, m), 7.66-7.73 (1H, m), 7.81-7.87 (1H, m), 7.94-7.99 (1H, m).
　（実施例８０）
　（実施例８０－１）：実施例（８０ａ）で合成
エチル　（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］－２－メチルフェニル｝ピペリジン－１－イル）（オキソ）アセテート (Example 80)
Example 80-1: Ethyl (4- {4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H) synthesized in Example (80a) -Indol-5-yl) oxy] -2-methylphenyl} piperidin-1-yl) (oxo) acetate
Figure JPOXMLDOC01-appb-C000115
Figure JPOXMLDOC01-appb-C000115
　（実施例８０－２）：実施例（８０ｂ）で合成
（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］－２－メチルフェニル｝ピペリジン－１－イル）（オキソ）酢酸ナトリウム Example 80-2: Synthesis in Example (80b) (4- {4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H- Indol-5-yl) oxy] -2-methylphenyl} piperidin-1-yl) (oxo) acetate sodium
Figure JPOXMLDOC01-appb-C000116
Figure JPOXMLDOC01-appb-C000116
（８０ａ）　エチル　（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］－２－メチルフェニル｝ピペリジン－１－イル）（オキソ）アセテート
　実施例（９ｃ）で得られた化合物（４００　ｍｇ）のジクロロメタン（８　ｍＬ）溶液にトリエチルアミン（１９０　μＬ）、エチルクロログリコシル酸（８６．０　μＬ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。 (80a) Ethyl (4- {4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -2- Methylphenyl} piperidin-1-yl) (oxo) acetate To a solution of the compound obtained in Example (9c) (400 mg) in dichloromethane (8 mL) was added triethylamine (190 μL) and ethylchloroglycosyl acid (86.0 μL). ) And stirred at room temperature for 18 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.
　得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（３９９　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.21-1.30 (6H, m), 1.60-1.74 (2H, m), 1.78-1.90 (2H, m), 2.12 (3H, s), 2.30 (3H, s), 2.71-2.83 (1H, m), 2.86-2.99 (1H, m), 3.15-3.29 (5H, m), 3.73-3.84 (1H, m), 4.27 (2H, t, J = 8.5 Hz), 4.33-4.38 (4H, m), 4.63-4.73 (1H, m), 6.66-6.70 (2H, m), 6.77 (1H, d, J = 8.5 Hz), 7.04 (1H, d, J = 8.5 Hz), 7.39 (1H, d, J = 7.9 Hz), 7.50 (1H, t, J = 7.6 Hz), 7.60-7.64 (1H, m), 7.97 (1H, d, J = 9.2 Hz), 8.03 (1H, d, J = 7.9 Hz)。
（８０ｂ）　（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］－２－メチルフェニル｝ピペリジン－１－イル）（オキソ）酢酸ナトリウム
　実施例（８０ａ）で得られた化合物（３９９　ｍｇ）のテトラヒドロフラン（２　ｍＬ）とエタノール（２　ｍＬ）の混合溶液に２Ｎの水酸化ナトリウム水溶液（３７８　μＬ）を加え、室温で１８時間撹拌した。反応液を減圧下濃縮し、得られた残渣を水で洗浄後ろ取し、減圧乾燥することにより標記化合物（４３３　ｍｇ）を淡桃色固体で得た。
1H-NMR (400 MHz, DMSO-d6) δ: 1.10 (3H, t, J = 7.3 Hz), 1.26-1.49 (2H, m), 1.55-1.69 (2H, m), 2.04 (3H, s), 2.26 (3H, s), 2.81-3.03 (2H, m), 3.19 (2H, t, J = 8.5 Hz), 3.29 (2H, q, J = 7.3 Hz), 3.37-3.48 (1H, m), 3.76-3.88 (1H, m), 4.21-4.41 (5H, m), 6.54-6.58 (1H, m), 6.66-6.68 (1H, m), 6.75 (1H, d, J = 8.5 Hz), 7.06 (1H, d, J = 8.5 Hz), 7.48-7.51 (1H, m), 7.55-7.60 (1H, m), 7.68-7.73 (1H, m), 7.82 (1H, d, J = 8.5 Hz), 7.91 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 605 (M+H)+。 The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (399 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.21-1.30 (6H, m), 1.60-1.74 (2H, m), 1.78-1.90 (2H, m), 2.12 (3H, s), 2.30 (3H , s), 2.71-2.83 (1H, m), 2.86-2.99 (1H, m), 3.15-3.29 (5H, m), 3.73-3.84 (1H, m), 4.27 (2H, t, J = 8.5 Hz ), 4.33-4.38 (4H, m), 4.63-4.73 (1H, m), 6.66-6.70 (2H, m), 6.77 (1H, d, J = 8.5 Hz), 7.04 (1H, d, J = 8.5 Hz), 7.39 (1H, d, J = 7.9 Hz), 7.50 (1H, t, J = 7.6 Hz), 7.60-7.64 (1H, m), 7.97 (1H, d, J = 9.2 Hz), 8.03 ( 1H, d, J = 7.9 Hz).
(80b) (4- {4-[(1-{[2- (Ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -2-methyl Phenyl} piperidin-1-yl) (oxo) acetate sodium A solution of the compound obtained in Example (80a) (399 mg) in tetrahydrofuran (2 mL) and ethanol (2 mL) was mixed with 2N aqueous sodium hydroxide ( 378 μL) and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was washed with water, collected after being dried under reduced pressure, and the title compound (433 mg) was obtained as a pale pink solid.
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 1.10 (3H, t, J = 7.3 Hz), 1.26-1.49 (2H, m), 1.55-1.69 (2H, m), 2.04 (3H, s ), 2.26 (3H, s), 2.81-3.03 (2H, m), 3.19 (2H, t, J = 8.5 Hz), 3.29 (2H, q, J = 7.3 Hz), 3.37-3.48 (1H, m) , 3.76-3.88 (1H, m), 4.21-4.41 (5H, m), 6.54-6.58 (1H, m), 6.66-6.68 (1H, m), 6.75 (1H, d, J = 8.5 Hz), 7.06 (1H, d, J = 8.5 Hz), 7.48-7.51 (1H, m), 7.55-7.60 (1H, m), 7.68-7.73 (1H, m), 7.82 (1H, d, J = 8.5 Hz), 7.91 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 605 (M + H) + .
　（実施例８１）
　（実施例８１－１）：実施例（８１ａ）で合成
エチル　（４－｛４－［（１－｛［２－（メチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］－２－メチルフェニル｝ピペリジン－１－イル）（オキソ）アセテート (Example 81)
Example 81-1: Ethyl (4- {4-[(1-{[2- (methylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H) synthesized in Example (81a) -Indol-5-yl) oxy] -2-methylphenyl} piperidin-1-yl) (oxo) acetate
Figure JPOXMLDOC01-appb-C000117
Figure JPOXMLDOC01-appb-C000117
　（実施例８１－２）：実施例（８１ｂ）で合成
（４－｛４－［（１－｛［２－（メチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］－２－メチルフェニル｝ピペリジン－１－イル）（オキソ）酢酸 Example 81-2: Synthesis in Example (81b) (4- {4-[(1-{[2- (methylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H- Indol-5-yl) oxy] -2-methylphenyl} piperidin-1-yl) (oxo) acetic acid
Figure JPOXMLDOC01-appb-C000118
Figure JPOXMLDOC01-appb-C000118
　（実施例８１－３）：実施例（８１ｃ）で合成
２－（４－｛４－［（１－｛［２－（メチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］－２－メチルフェニル｝ピペリジン－１－イル）－Ｎ，Ｎ－ジメチル－２－オキソアセタミド Example 81-3: Synthesis in Example (81c) 2- (4- {4-[(1-{[2- (methylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro- 1H-Indol-5-yl) oxy] -2-methylphenyl} piperidin-1-yl) -N, N-dimethyl-2-oxoacetamide
Figure JPOXMLDOC01-appb-C000119
Figure JPOXMLDOC01-appb-C000119
（８１ａ）　エチル　（４－｛４－［（１－｛［２－（メチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］－２－メチルフェニル｝ピペリジン－１－イル）（オキソ）アセテート
　実施例（８ｂ）で得られた化合物（２００　ｍｇ）のジクロロメタン（５　ｍＬ）溶液にトリエチルアミン（１００　μＬ）、エチルクロログリコシル酸（４４．１　μＬ）を加え、室温で２時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（２０９　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.38 (3H, t, J = 7.0 Hz), 1.60-1.76 (2H, m), 1.79-1.92 (2H, m), 2.12 (3H, s), 2.30 (3H, s), 2.70-2.83 (1H, m), 2.86-2.99 (1H, m), 3.12 (3H, s), 3.15-3.29 (3H, m), 3.72-3.84 (1H, m), 4.24-4.42 (6H, m), 4.61-4.74 (1H, m), 6.64-6.71 (2H, m), 6.76 (1H, d, J = 8.5 Hz), 7.04 (1H, d, J = 7.9 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.47-7.55 (1H, m), 7.60-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz)。
（８１ｂ）　（４－｛４－［（１－｛［２－（メチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］－２－メチルフェニル｝ピペリジン－１－イル）（オキソ）酢酸
　実施例（８１ａ）で得られた化合物（２０９　ｍｇ）のテトラヒドロフラン（２　ｍＬ）とエタノール（２　ｍＬ）の混合溶液に２Ｎの水酸化ナトリウム水溶液（２５３　μＬ）を加え、室温で１８時間撹拌した。反応液を減圧下濃縮し、１Ｎ塩酸で中和し、再度減圧濃縮した後、残渣を水で洗浄後ろ取、乾燥することにより標記化合物（１４５　ｍｇ）を白色固体で得た。
1H-NMR (400 MHz, DMSO-d6) δ: 1.22-1.51 (2H, m), 1.57-1.70 (2H, m), 2.04 (3H, s), 2.26 (3H, s), 2.44-2.62 (1H, m), 2.80-2.91 (1H, m), 2.94-3.05 (1H, m), 3.13-3.24 (5H, m), 3.76-3.92 (1H, br m), 4.22-4.39 (5H, m), 6.57 (1H, dd, J = 8.5, 3.1 Hz), 6.67 (1H, d, J = 3.1 Hz), 6.74 (1H, d, J = 9.2 Hz), 7.06 (1H, d, J = 8.5 Hz), 7.48 (1H, d, J = 7.9 Hz), 7.53-7.60 (1H, m), 7.66-7.73 (1H, m), 7.83 (1H, d, J = 9.2 Hz), 7.96 (1H, d, J = 7.9 Hz)。
（８１ｃ）　２－（４－｛４－［（１－｛［２－（メチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］－２－メチルフェニル｝ピペリジン－１－イル）－Ｎ，Ｎ－ジメチル－２－オキソアセタミド
　実施例（８１ｂ）で得られた化合物（７０．０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にトリエチルアミン（４９．０　μＬ）を加え、室温で５分間攪拌した。次いでジメチルアミン塩酸塩（１１．６　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（２７．３　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（１６．１　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。 (81a) Ethyl (4- {4-[(1-{[2- (methylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -2- Methylphenyl} piperidin-1-yl) (oxo) acetate A solution of the compound obtained in Example (8b) (200 mg) in dichloromethane (5 mL) was added to triethylamine (100 μL), ethylchloroglycosyl acid (44.1 μL). ) And stirred at room temperature for 2 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 / hexane) to give the title compound (209 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.38 (3H, t, J = 7.0 Hz), 1.60-1.76 (2H, m), 1.79-1.92 (2H, m), 2.12 (3H, s), 2.30 (3H, s), 2.70-2.83 (1H, m), 2.86-2.99 (1H, m), 3.12 (3H, s), 3.15-3.29 (3H, m), 3.72-3.84 (1H, m), 4.24-4.42 (6H, m), 4.61-4.74 (1H, m), 6.64-6.71 (2H, m), 6.76 (1H, d, J = 8.5 Hz), 7.04 (1H, d, J = 7.9 Hz) , 7.36 (1H, d, J = 7.9 Hz), 7.47-7.55 (1H, m), 7.60-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
(81b) (4- {4-[(1-{[2- (methylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -2-methyl Phenyl} piperidin-1-yl) (oxo) acetic acid To a mixed solution of the compound (209 mg) obtained in Example (81a) in tetrahydrofuran (2 mL) and ethanol (2 mL) was added 2N aqueous sodium hydroxide solution (253). μL) was added and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, neutralized with 1N hydrochloric acid, and concentrated again under reduced pressure. The residue was washed with water, collected and dried to give the title compound (145 mg) as a white solid.
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 1.22-1.51 (2H, m), 1.57-1.70 (2H, m), 2.04 (3H, s), 2.26 (3H, s), 2.44-2.62 (1H, m), 2.80-2.91 (1H, m), 2.94-3.05 (1H, m), 3.13-3.24 (5H, m), 3.76-3.92 (1H, br m), 4.22-4.39 (5H, m ), 6.57 (1H, dd, J = 8.5, 3.1 Hz), 6.67 (1H, d, J = 3.1 Hz), 6.74 (1H, d, J = 9.2 Hz), 7.06 (1H, d, J = 8.5 Hz) ), 7.48 (1H, d, J = 7.9 Hz), 7.53-7.60 (1H, m), 7.66-7.73 (1H, m), 7.83 (1H, d, J = 9.2 Hz), 7.96 (1H, d, J = 7.9 Hz).
(81c) 2- (4- {4-[(1-{[2- (methylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -2 -Methylphenyl} piperidin-1-yl) -N, N-dimethyl-2-oxoacetamide Triethylamine was added to a solution of the compound obtained in Example (81b) (70.0 mg) in N, N-dimethylformamide (5 mL). (49.0 μL) was added and stirred at room temperature for 5 minutes. Next, dimethylamine hydrochloride (11.6 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (27.3 mg), 3H-1,2,3-triazolo [4,5- b] Pyridin-3-ol (16.1 mg) was added and stirred at room temperature for 18 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.
　得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（４６．６　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.57-1.75 (2H, m), 1.79-1.92 (2H, m), 2.12 (3H, s), 2.30 (3H, s), 2.73-2.83 (2H, m), 3.01 (3H, s), 3.04 (3H, s), 3.12 (3H, s), 3.15-3.26 (3H, m), 3.72-3.82 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.67-4.77 (1H, m), 6.63-6.71 (2H, m), 6.76 (1H, d, J = 8.5 Hz), 7.04 (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), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).
MS(APCI) m/z: 618 (M+H)+。 The obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (46.6 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.57-1.75 (2H, m), 1.79-1.92 (2H, m), 2.12 (3H, s), 2.30 (3H, s), 2.73-2.83 (2H , m), 3.01 (3H, s), 3.04 (3H, s), 3.12 (3H, s), 3.15-3.26 (3H, m), 3.72-3.82 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.67-4.77 (1H, m), 6.63-6.71 (2H, m), 6.76 (1H, d, J = 8.5 Hz), 7.04 (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), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).
MS (APCI) m / z: 618 (M + H) + .
　（実施例８２）
Ｎ－エチル－２－（４－｛４－［（１－｛［２－（メチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］－２－メチルフェニル｝ピペリジン－１－イル）－２－オキソアセタミド (Example 82)
N-ethyl-2- (4- {4-[(1-{[2- (methylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy]- 2-Methylphenyl} piperidin-1-yl) -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000120
Figure JPOXMLDOC01-appb-C000120
　実施例（８１ｂ）で得られた化合物（７０．０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にトリエチルアミン（４９．０　μＬ）を加え、室温で５分間攪拌した。エチルアミン塩酸塩（１１．６　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（２７．３　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（１６．１　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（２３．５　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.21 (3H, t, J = 6.7 Hz), 1.60-1.90 (4H, m), 2.12 (3H, s), 2.31 (3H, s), 2.69-2.85 (1H, m), 2.91-2.98 (1H, m), 3.10-3.25 (6H, m), 3.35 (2H, q, J = 6.7 Hz), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.64-4.76 (1H, m), 5.09-5.25 (1H, m), 6.62-6.71 (2H, m), 6.76 (1H, d, J = 8.5 Hz), 7.04 (1H, d, J = 9.2 Hz), 7.13-7.20 (1H, m), 7.36 (1H, d, J = 6.7 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 = 6.7 Hz).
MS(APCI) m/z: 618 (M+H)+。 Triethylamine (49.0 μL) was added to a solution of the compound (70.0 mg) obtained in Example (81b) in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 5 minutes. Ethylamine hydrochloride (11.6 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (27.3 mg), 3H-1,2,3-triazolo [4,5-b] Pyridin-3-ol (16.1 mg) was added and stirred at room temperature for 18 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 (23.5 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.21 (3H, t, J = 6.7 Hz), 1.60-1.90 (4H, m), 2.12 (3H, s), 2.31 (3H, s), 2.69- 2.85 (1H, m), 2.91-2.98 (1H, m), 3.10-3.25 (6H, m), 3.35 (2H, q, J = 6.7 Hz), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.64-4.76 (1H, m), 5.09-5.25 (1H, m), 6.62-6.71 (2H, m), 6.76 (1H, d, J = 8.5 Hz), 7.04 (1H, d , J = 9.2 Hz), 7.13-7.20 (1H, m), 7.36 (1H, d, J = 6.7 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 = 6.7 Hz).
MS (APCI) m / z: 618 (M + H) + .
　（実施例８３）
Ｎ－エチル－２－（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］－２－メチルフェニル｝ピペリジン－１－イル）－２－オキソアセタミド (Example 83)
N-ethyl-2- (4- {4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy]- 2-Methylphenyl} piperidin-1-yl) -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000121
Figure JPOXMLDOC01-appb-C000121
　実施例（８０ｂ）で得られた化合物（１００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にトリエチルアミン（６６．０　μＬ）を加え、室温で５分間攪拌した。エチルアミン塩酸塩（１５．６　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（３６．７　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（２１．７　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（４９．０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.21 (3H, t, J = 7.3 Hz), 1.26 (3H, t, J = 7.3 Hz), 1.58-1.90 (4H, m), 2.12 (3H, s), 2.30 (3H, s), 2.73-2.83 (1H, m), 2.87-2.99 (1H, m), 3.09-3.26 (5H, m), 3.31-3.40 (2H, m), 4.27 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 4.66-4.76 (1H, m), 5.13-5.24 (1H, m), 6.63-6.71 (2H, m), 6.77 (1H, d, J = 8.5 Hz), 7.04 (1H, d, J = 8.5 Hz), 7.11-7.22 (1H, m), 7.39 (1H, d, J = 7.9 Hz), 7.51 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 632 (M+H)+。 Triethylamine (66.0 μL) was added to a solution of the compound (100 mg) obtained in Example (80b) in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 5 minutes. Ethylamine hydrochloride (15.6 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (36.7 mg), 3H-1,2,3-triazolo [4,5-b] Pyridin-3-ol (21.7 mg) was added and stirred at room temperature for 18 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 (49.0 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.21 (3H, t, J = 7.3 Hz), 1.26 (3H, t, J = 7.3 Hz), 1.58-1.90 (4H, m), 2.12 (3H, s), 2.30 (3H, s), 2.73-2.83 (1H, m), 2.87-2.99 (1H, m), 3.09-3.26 (5H, m), 3.31-3.40 (2H, m), 4.27 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 4.66-4.76 (1H, m), 5.13-5.24 (1H, m), 6.63-6.71 (2H, m), 6.77 (1H, d, J = 8.5 Hz), 7.04 (1H, d, J = 8.5 Hz), 7.11-7.22 (1H, m), 7.39 (1H, d, J = 7.9 Hz), 7.51 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 632 (M + H) + .
　（実施例８４）
２－（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］－２－メチルフェニル｝ピペリジン－１－イル）－Ｎ，Ｎ－ジメチル－２－オキソアセタミド (Example 84)
2- (4- {4-[(1-{[2- (Ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -2-methylphenyl } Piperidin-1-yl) -N, N-dimethyl-2-oxoacetamide
Figure JPOXMLDOC01-appb-C000122
Figure JPOXMLDOC01-appb-C000122
　実施例（８０ｂ）で得られた化合物（１００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にトリエチルアミン（６６．０　μＬ）を加え、室温で５分間攪拌した。次いでジメチルアミン塩酸塩（１５．６　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（３６．７　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（２１．７　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（２４．５　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.26 (3H, t, J = 7.6 Hz), 1.51-1.76 (2H, m), 1.78-1.90 (2H, m), 2.12 (3H, s), 2.30 (3H, s), 2.74-2.84 (1H, m), 2.86-2.98 (1H, m), 3.02 (3H, s), 3.04 (3H, s), 3.16-3.27 (5H, m), 3.72-3.82 (1H, m), 4.27 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 4.67-4.76 (1H, m), 6.62-6.71 (2H, m), 6.76 (1H, d, J = 8.5 Hz), 7.04 (1H, d, J = 8.5 Hz), 7.40 (1H, d, J = 7.9 Hz), 7.48-7.53 (1H, m), 7.60-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 632 (M+H)+。 Triethylamine (66.0 μL) was added to a solution of the compound (100 mg) obtained in Example (80b) in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 5 minutes. Dimethylamine hydrochloride (15.6 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (36.7 mg), 3H-1,2,3-triazolo [4,5- b] Pyridin-3-ol (21.7 mg) was added and stirred at room temperature for 18 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 (24.5 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.6 Hz), 1.51-1.76 (2H, m), 1.78-1.90 (2H, m), 2.12 (3H, s), 2.30 (3H, s), 2.74-2.84 (1H, m), 2.86-2.98 (1H, m), 3.02 (3H, s), 3.04 (3H, s), 3.16-3.27 (5H, m), 3.72- 3.82 (1H, m), 4.27 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 4.67-4.76 (1H, m), 6.62-6.71 (2H, m), 6.76 (1H, d, J = 8.5 Hz), 7.04 (1H, d, J = 8.5 Hz), 7.40 (1H, d, J = 7.9 Hz), 7.48-7.53 (1H, m), 7.60-7.66 (1H, m), 7.97 ( 1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 632 (M + H) + .
　（実施例８５）
　（実施例８５－１）：実施例（８５ａ）で合成
エチル　（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）（オキソ）アセテート (Example 85)
Example 85-1: Ethyl (4- {4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H) synthesized in Example (85a) -Indol-5-yl) oxy] phenyl} piperidin-1-yl) (oxo) acetate
Figure JPOXMLDOC01-appb-C000123
Figure JPOXMLDOC01-appb-C000123
　（実施例８５－２）：実施例（８５ｂ）で合成
（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）（オキソ）酢酸ナトリウム Example 85-2: Synthesis in Example (85b) (4- {4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H- Indol-5-yl) oxy] phenyl} piperidin-1-yl) (oxo) acetate sodium
Figure JPOXMLDOC01-appb-C000124
Figure JPOXMLDOC01-appb-C000124
　（実施例８５－３）：実施例（８５ｃ）で合成
２－（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－Ｎ，Ｎ－ジメチル－２－オキソアセタミド Example 85-3: Synthesis in Example (85c) 2- (4- {4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro- 1H-Indol-5-yl) oxy] phenyl} piperidin-1-yl) -N, N-dimethyl-2-oxoacetamide
Figure JPOXMLDOC01-appb-C000125
Figure JPOXMLDOC01-appb-C000125
（８５ａ）　エチル　（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）（オキソ）アセテート
　実施例（２ｄ）で得られた化合物（３．２５　ｇ）のジクロロメタン（３０　ｍＬ）溶液に、氷冷下、ジイソプロピルエチルアミン（２．９９　ｍＬ）、クロログリオキシル酸エチル（０．７８２　ｍＬ）を加え、室温で２時間攪拌した。減圧下、溶媒を留去し、シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（２．９１　ｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.28 (3H, t, J = 7.3 Hz), 1.38 (3H, t, J = 7.3 Hz), 1.61-1.76 (2H, m), 1.85-1.97 (2H, m), 2.11 (3H, s), 2.69-2.83 (2H, m), 3.16-3.29 (5H, m), 3.72-3.82 (1H, m), 4.22-4.41 (6H, m), 4.61-4.70 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.39 (1H, d, J = 7.9 Hz), 7.47-7.54 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J= 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 619 (M+H)+。
（８５ｂ）　（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）（オキソ）酢酸ナトリウム
　実施例（８５ａ）で得られた化合物（２．６１　ｇ）のテトラヒドロフラン（１５　ｍＬ）溶液に１Ｎの水酸化ナトリウム水溶液（６．０　ｍＬ）を加え、室温で２８時間撹拌した。減圧下、溶媒を留去し、減圧乾燥することにより標記化合物（２．７０　ｇ）を白色固体として得た。本化合物は精製することなく、次工程に用いた。
（８５ｃ）　２－（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－Ｎ，Ｎ－ジメチル－２－オキソアセタミド
　実施例（８５ｂ）で得られた化合物（４５０　ｍｇ）のジクロロメタン（８　ｍＬ）懸濁液にジイソプロピルエチルアミン（０．３７７　ｍＬ）、ジメチルアミン塩酸塩（２４０　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（２１１　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（１００　ｍｇ）を加え、室温で１０時間攪拌した。溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン→メタノール／ジクロロメタン）で精製することで、標記化合物（２５６　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.26 (3H, t, J = 7.3 Hz), 1.60-1.78 (2H, m), 1.85-1.98 (2H, m), 2.12 (3H, s), 2.68-2.83 (2H, m), 3.01 (3H, s), 3.04 (3H, s), 3.15-3.26 (5H, m), 3.71-3.81 (1H, m), 4.20 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 4.65-4.74 (1H, m), 6.75-6.84 (3H, m), 7.05 (2H, d, J= 8.5 Hz), 7.39 (1H, d, J = 7.3 Hz), 7.50 (1H, t, J = 7.3 Hz), 7.58-7.65 (1H, m), 7.97 (1H, d, J= 8.5 Hz), 8.03 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 618 (M+H)+。 (85a) ethyl (4- {4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine 1-yl) (oxo) acetate A solution of the compound obtained in Example (2d) (3.25 g) in dichloromethane (30 mL) was added with diisopropylethylamine (2.99 mL), chloroglyoxylic acid under ice-cooling. Ethyl (0.782 mL) was added and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (2.91 g) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.28 (3H, t, J = 7.3 Hz), 1.38 (3H, t, J = 7.3 Hz), 1.61-1.76 (2H, m), 1.85-1.97 ( 2H, m), 2.11 (3H, s), 2.69-2.83 (2H, m), 3.16-3.29 (5H, m), 3.72-3.82 (1H, m), 4.22-4.41 (6H, m), 4.61- 4.70 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.39 (1H, d, J = 7.9 Hz), 7.47-7.54 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 619 (M + H) + .
(85b) (4- {4-[(1-{[2- (Ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine- 1-yl) (oxo) acetic acid sodium salt To a solution of the compound (2.61 g) obtained in Example (85a) in tetrahydrofuran (15 mL) was added 1N aqueous sodium hydroxide solution (6.0 mL), and the mixture was stirred at room temperature. Stir for 28 hours. The solvent was distilled off under reduced pressure, followed by drying under reduced pressure to obtain the title compound (2.70 g) as a white solid. This compound was used in the next step without purification.
(85c) 2- (4- {4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl} Piperidin-1-yl) -N, N-dimethyl-2-oxoacetamide To a suspension of the compound obtained in Example (85b) (450 mg) in dichloromethane (8 mL) was added diisopropylethylamine (0.377 mL), dimethyl Amine hydrochloride (240 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (211 mg), 3H-1,2,3-triazolo [4,5-b] pyridine-3- All (100 mg) was added and stirred at room temperature for 10 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane → methanol / dichloromethane) to give the title compound (256 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.60-1.78 (2H, m), 1.85-1.98 (2H, m), 2.12 (3H, s), 2.68-2.83 (2H, m), 3.01 (3H, s), 3.04 (3H, s), 3.15-3.26 (5H, m), 3.71-3.81 (1H, m), 4.20 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 4.65-4.74 (1H, m), 6.75-6.84 (3H, m), 7.05 (2H, d, J = 8.5 Hz), 7.39 (1H, d, J = 7.3 Hz ), 7.50 (1H, t, J = 7.3 Hz), 7.58-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 618 (M + H) + .
　（実施例８６）
Ｎ－エチル－２－（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－２－オキソアセタミド (Example 86)
N-ethyl-2- (4- {4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl } Piperidin-1-yl) -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000126
Figure JPOXMLDOC01-appb-C000126
　実施例（８５ｂ）で得られた化合物（３００　ｍｇ）のジクロロメタン（８　ｍＬ）懸濁液にジイソプロピルエチルアミン（０．２５２　ｍＬ）、エチルアミン塩酸塩（２００　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（１４１　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（６６．６　ｍｇ）を加え、室温で２４時間攪拌した。溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／ジクロロメタン）で精製することで、標記化合物（２０１　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.21 (3H, t, J = 7.3 Hz), 1.26 (3H, t, J = 7.3 Hz), 1.58-1.81 (2H, m), 1.88-1.99 (2H, m), 2.12 (3H, s), 2.70-2.83 (2H, m), 3.09-3.26 (5H, m), 3.31-3.40 (2H, m), 4.27 (2H, t, J= 8.5 Hz), 4.37 (2H, s), 4.65-4.74 (1H, m), 5.11-5.20 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.08-7.19 (3H, m), 7.39 (1H, d, J = 7.3 Hz), 7.50 (1H, t, J = 7.3 Hz), 7.62 (1H, t, J = 7.3 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 618 (M+H)+。 To a suspension of the compound (300 mg) obtained in Example (85b) in dichloromethane (8 mL) was added diisopropylethylamine (0.252 mL), ethylamine hydrochloride (200 mg), 1-ethyl-3- (3- Dimethylaminopropyl) carboximide hydrochloride (141 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (66.6 mg) was added, and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol / dichloromethane) to give the title compound (201 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.21 (3H, t, J = 7.3 Hz), 1.26 (3H, t, J = 7.3 Hz), 1.58-1.81 (2H, m), 1.88-1.99 ( 2H, m), 2.12 (3H, s), 2.70-2.83 (2H, m), 3.09-3.26 (5H, m), 3.31-3.40 (2H, m), 4.27 (2H, t, J = 8.5 Hz) , 4.37 (2H, s), 4.65-4.74 (1H, m), 5.11-5.20 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.08-7.19 (3H, m), 7.39 (1H, d, J = 7.3 Hz), 7.50 (1H, t, J = 7.3 Hz), 7.62 (1H, t, J = 7.3 Hz), 7.97 (1H, d , J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 618 (M + H) + .
　（実施例８７）
２－（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－Ｎ－メチル－２－オキソアセタミド (Example 87)
2- (4- {4-[(1-{[2- (Ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine-1 -Yl) -N-methyl-2-oxoacetamide
Figure JPOXMLDOC01-appb-C000127
Figure JPOXMLDOC01-appb-C000127
　実施例（８５ｂ）で得られた化合物（２５０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）懸濁液にジイソプロピルエチルアミン（０．２１０　ｍＬ）、メチルアミン塩酸塩（１３８　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（１１７　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（５５．５　ｍｇ）を加え、室温で１２時間攪拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／ジクロロメタン）で精製することで、標記化合物（１８５　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.26 (3H, t, J = 7.9 Hz), 1.60-1.81 (2H, m), 1.87-1.99 (2H, m), 2.12 (3H, s), 2.70-2.85 (2H, m), 2.89 (3H, d, J = 4.9 Hz), 3.10-3.26 (5H, m), 4.27 (2H, t, J = 7.9 Hz), 4.37 (2H, s), 4.65-4.72 (1H, m), 5.11-5.19 (1H, m), 6.77 (1H, d, J = 9.2 Hz), 6.81 (2H, d, J= 9.2 Hz), 7.20-7.22 (3H, m), 7.39 (1H, d, J = 7.3 Hz), 7.50 (1H, t, J= 7.3 Hz), 7.62 (1H, t, J = 7.3 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 604 (M+H)+。 To a suspension of the compound (250 mg) obtained in Example (85b) in N, N-dimethylformamide (5 mL) was added diisopropylethylamine (0.210 mL), methylamine hydrochloride (138 mg), 1-ethyl. -3- (3-Dimethylaminopropyl) carboximide hydrochloride (117 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (55.5 mg) was added, and room temperature was added. For 12 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, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol / dichloromethane) to give the title compound (185 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.9 Hz), 1.60-1.81 (2H, m), 1.87-1.99 (2H, m), 2.12 (3H, s), 2.70-2.85 (2H, m), 2.89 (3H, d, J = 4.9 Hz), 3.10-3.26 (5H, m), 4.27 (2H, t, J = 7.9 Hz), 4.37 (2H, s), 4.65 -4.72 (1H, m), 5.11-5.19 (1H, m), 6.77 (1H, d, J = 9.2 Hz), 6.81 (2H, d, J = 9.2 Hz), 7.20-7.22 (3H, m), 7.39 (1H, d, J = 7.3 Hz), 7.50 (1H, t, J = 7.3 Hz), 7.62 (1H, t, J = 7.3 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.03 ( (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 604 (M + H) + .
　（実施例８８）：実施例（８８ｄ）で合成
１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）ピペリジン－３－イル］フェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン Example 88: Synthesis in Example (88d) 1- (5- {4- [1- (1,4-dioxane-2-ylcarbonyl) piperidin-3-yl] phenoxy} -4-methyl-2 , 3-Dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000128
Figure JPOXMLDOC01-appb-C000128
（８８ａ）　ｔｅｒｔ－ブチル　５－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－カルボキシレート
　実施例（１ｂ）で得られた化合物（５００　ｍｇ）、１－ｔｅｒｔ－ブトキシカルボニル－５，６－ジヒドロ－２Ｈ－ピリジン－３－ボロン酸　ピナコールエステル（３７０　ｍｇ）の１，２－ジメトキシエタン（１２　ｍＬ）溶液に炭酸ナトリウム（３１７　ｍｇ）の水溶液（３　ｍＬ）を加え、室温で５分間撹拌した。次いで［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（８１．６　ｍｇ）を加え、マイクロウェーブ反応装置にて、１３０℃で１時間反応させた。反応液を室温に冷却後、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（２７２　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.49 (9H, s), 2.12 (3H, s), 2.24-2.34 (2H, br m), 3.12 (3H, s), 3.17-3.26 (2H, m), 3.49-3.59 (2H, br m), 4.19-4.34 (4H, m), 4.37 (2H, s), 6.11 (1H, br s), 6.76-6.88 (3H, m), 7.23-7.32 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.98 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz)。
（８８ｂ）　ｔｅｒｔ－ブチル　３－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－ピペリジン－１－カルボキシレート
　実施例（８８ａ）で得られた化合物（２７２　ｍｇ）をテトラヒドロフラン（３　ｍＬ）及び酢酸エチル（３　ｍＬ）に溶解し、７．５％パラジウム炭素（５４．５　ｍｇ）を加え、水素雰囲気下、室温で１８時間撹拌した。反応液に酢酸エチルを加え、不溶物をろ去し、減圧下で溶媒を留去することで標記化合物（２７９　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.46 (9H, s), 1.51-1.64 (2H, m), 1.71-1.78 (1H, br m), 1.89-2.02 (2H, m), 2.13 (3H, s), 2.56-2.79 (3H, br m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 4.05-4.18 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.74-6.88 (3H, m), 7.13 (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)。
（８８ｃ）　１－｛４－メチル－５－［４－（ピペリジン－３－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン塩酸塩
　実施例（８８ｂ）で得られた化合物（２７２　ｍｇ）のジクロロメタン（２　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（４　ｍＬ）を加え、室温で３時間攪拌した。反応液を減圧下濃縮後、酢酸エチルを加え不溶物をろ取した。得られた固体を減圧乾燥することで標記化合物（２７４　ｍｇ）を白色固体として得た。
MS(APCI) m/z: 505 (M+H)+。
（８８ｄ）　１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）ピペリジン－３－イル］フェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（８８ｃ）で得られた化合物（８０．０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液にトリエチルアミン（４１．０　μＬ）を加え、室温で５分間攪拌した。４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（６１．４　ｍｇ）及び１，４－ジオキサン－２－カルボン酸（２３．０　ｍｇ）を加え、室温で２０時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（７２．３　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.51-1.75 (2H, m), 1.78-1.92 (1H, m), 2.00-2.09 (1H, m), 2.12 (3H, d, J = 6.7 Hz), 2.47-2.82 (2H, m), 2.86-3.17 (4H, m), 3.17-3.25 (2H, m), 3.65-4.09 (7H, m), 4.23-4.41 (5H, m), 4.58-4.71 (1H, m), 6.74-6.89 (3H, m), 7.12 (2H, d, J = 8.5 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), 7.98 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).
MS(APCI) m/z: 619 (M+H)+。 (88a) tert-butyl 5- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} -3,6-Dihydropyridine-1 (2H) -carboxylate Compound (500 mg) obtained in Example (1b), 1-tert-butoxycarbonyl-5,6-dihydro-2H-pyridine-3-boronic acid An aqueous solution (3 mL) of sodium carbonate (317 mg) was added to a solution of pinacol ester (370 mg) in 1,2-dimethoxyethane (12 mL), followed by stirring at room temperature for 5 minutes. Next, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (81.6 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 (272 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.49 (9H, s), 2.12 (3H, s), 2.24-2.34 (2H, br m), 3.12 (3H, s), 3.17-3.26 (2H, m), 3.49-3.59 (2H, br m), 4.19-4.34 (4H, m), 4.37 (2H, s), 6.11 (1H, br s), 6.76-6.88 (3H, m), 7.23-7.32 ( 2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.98 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
(88b) tert-butyl 3- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} Piperidine-1-carboxylate The compound (272 mg) obtained in Example (88a) was dissolved in tetrahydrofuran (3 mL) and ethyl acetate (3 mL), and 7.5% palladium on carbon (54.5 mg). And stirred for 18 hours at room temperature under hydrogen atmosphere. Ethyl acetate was added to the reaction solution, the insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain the title compound (279 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.46 (9H, s), 1.51-1.64 (2H, m), 1.71-1.78 (1H, br m), 1.89-2.02 (2H, m), 2.13 ( 3H, s), 2.56-2.79 (3H, br m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 4.05-4.18 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.74-6.88 (3H, m), 7.13 (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).
(88c) 1- {4-Methyl-5- [4- (piperidin-3-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl Ethanone hydrochloride To a solution of the compound (272 mg) obtained in Example (88b) in dichloromethane (2 mL) was added 4N hydrochloric acid dioxane solution (4 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the insoluble material was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (274 mg) as a white solid.
MS (APCI) m / z: 505 (M + H) + .
(88d) 1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) piperidin-3-yl] phenoxy} -4-methyl-2,3-dihydro-1H-indole-1 -Yl) -2- [2- (methylsulfonyl) phenyl] ethanone To a solution of the compound obtained in Example (88c) (80.0 mg) in N, N-dimethylformamide (3 mL) was added triethylamine (41.0 μL) was added and stirred at room temperature for 5 minutes. 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (61.4 mg) and 1,4-dioxane-2-carboxylic acid (23.0 mg) was added and stirred at room temperature for 20 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 (72.3 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.51-1.75 (2H, m), 1.78-1.92 (1H, m), 2.00-2.09 (1H, m), 2.12 (3H, d, J = 6.7 Hz ), 2.47-2.82 (2H, m), 2.86-3.17 (4H, m), 3.17-3.25 (2H, m), 3.65-4.09 (7H, m), 4.23-4.41 (5H, m), 4.58-4.71 (1H, m), 6.74-6.89 (3H, m), 7.12 (2H, d, J = 8.5 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), 7.98 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).
MS (APCI) m / z: 619 (M + H) + .
　（実施例８９）
１－｛５－［４－（１－アセチルピペリジン－３－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン Example 89
1- {5- [4- (1-Acetylpiperidin-3-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl ] Ethanon
Figure JPOXMLDOC01-appb-C000129
Figure JPOXMLDOC01-appb-C000129
　実施例（８８ｃ）で得られた化合物（１５３　ｍｇ）のジクロロメタン（８　ｍＬ）溶液にトリエチルアミン（８６　μＬ）を加え、室温で５分間攪拌した。無水酢酸（３２．１　μＬ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１１８　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.49-1.72 (2H, m), 1.76-1.88 (1H, m), 2.00-2.09 (4H, m), 2.13 (3H, s), 2.47-2.70 (2H, m), 3.01-3.10 (1H, m), 3.12 (3H, s), 3.16-3.26 (2H, m), 3.79-3.89 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.64-4.78 (1H, m), 6.73-6.86 (3H, m), 7.13 (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), 7.98 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 547 (M+H)+。 Triethylamine (86 μL) was added to a solution of the compound (153 mg) obtained in Example (88c) in dichloromethane (8 mL), and the mixture was stirred at room temperature for 5 minutes. Acetic anhydride (32.1 μL) was added, and the mixture was stirred at room temperature for 18 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 (118 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.49-1.72 (2H, m), 1.76-1.88 (1H, m), 2.00-2.09 (4H, m), 2.13 (3H, s), 2.47-2.70 (2H, m), 3.01-3.10 (1H, m), 3.12 (3H, s), 3.16-3.26 (2H, m), 3.79-3.89 (1H, m), 4.29 (2H, t, J = 8.2 Hz ), 4.36 (2H, s), 4.64-4.78 (1H, m), 6.73-6.86 (3H, m), 7.13 (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), 7.98 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 547 (M + H) + .
　（実施例９０）：実施例（９０ｅ）で合成
１－（５－｛４－［１－（1，4－ジオキサン－２－イルカルボニル）ピロリジン－３－イル］フェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン Example 90: Synthesis in Example (90e) 1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) pyrrolidin-3-yl] phenoxy} -4-methyl-2 , 3-Dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000130
Figure JPOXMLDOC01-appb-C000130
（９０ａ）　２－［２－（メチルスルホニル）フェニル］－１－｛４－メチル－５－［４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝エタノン
　実施例（１ｂ）で得られた化合物（３００　ｍｇ）、ビス（ピナコラト）ジボロン（１６７　ｍｇ）、酢酸カリウム（１１７　ｍｇ）、ジメチルスルホキシド（２００　μＬ）の１，４－ジオキサン（１０　ｍＬ）溶液に［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（１４．７　ｍｇ）を加え、窒素雰囲気下、１００℃で５時間反応させた。反応液を室温に冷却後、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（２２２　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) 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), 6.74-7.02 (3H, m), 7.26-7.44 (2H, m), 7.49-7.55 (1H, m), 7.62 (1H, t, J = 7.9 Hz), 7.73 (1H, d, J = 8.5 Hz), 7.95-8.04 (1H, m), 8.07 (1H, d, J = 7.9 Hz)。
（９０ｂ）　ベンジル　３－｛［（トリフルオロメチル）スルホニル］オキシ｝－２，５－ジヒドロ－１Ｈ－ピロール－１－カルボンキシレート
　１－カルボベンジルオキシ－３－ピロリジノン（１．００　ｇ）のテトラヒドロフラン（５　ｍＬ）溶液を－７８℃に冷却し、ナトリウム　ビス（トリメチルシリル）アミド（１．６Ｍテトラヒドロフラン溶液、８．４４　ｍＬ）を滴下して加え、同温で１時間撹拌した。次いで、Ｎ－フェニルビス（トリフルオロメタンスルホンイミド）（１．７９　ｇ）のテトラヒドロフラン（１０　ｍＬ）溶液を滴下して加え、氷冷下で２時間撹拌した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（５９３　ｍｇ）を茶色油状物として得た。
1H-NMR (400 MHz, CDCl3) δ: 4.30 (4H, br m), 5.17 (2H, s), 5.73 (0.5H, s), 5.78 (0.5H, s), 7.26-7.45 (5H, m)。
（９０ｃ）　ベンジル　３－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－２，５－ジヒドロ－１Ｈ－ピロール－１－カルボンキシレート
　実施例（９０ａ）で得られた化合物（１００　ｍｇ）及び実施例（９０ｂ）で得られた化合物（８７．５　ｍｇ）の１，２－ジメトキシエタン（３　ｍＬ）溶液に炭酸ナトリウム（５８．０　ｍｇ）の水溶液（１　ｍＬ）を加え、室温で５分間撹拌した。次いで［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（１５．０　ｍｇ）を加え、マイクロウェーブ反応装置にて、１３０℃で４５分間反応させた。反応液を室温に冷却後、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（２６２　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.11 (3H, s), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 4.29 (2H, t, J = 8.5 Hz), 4.33-4.43 (4H, br m), 4.48-4.60 (2H, m), 5.20 (2H, s), 6.01 (0.5H, s), 6.05 (0.5H, s), 6.74-6.88 (3H, m), 7.25-7.44 (8H, m), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.99 (1H, d, J = 9.2 Hz), 8.08 (1H, d, J = 7.9 Hz).
（９０ｄ）　１－｛４－メチル－５－［４－（ピロリジン－３－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（９０ｃ）で得られた化合物（２６．２　ｍｇ）をエタノール（１．５　ｍＬ）及び酢酸エチル（１．５　ｍＬ）に溶解し、７．５％パラジウム炭素（５．５　ｍｇ）を加え水素雰囲気下、室温で１８時間撹拌した。反応液に酢酸エチルを加え、不溶物をろ去後、ろ液を減圧下で濃縮乾固することで標記化合物（１９．４　ｍｇ）を黄色油状物として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.78-1.97 (2H, m), 2.13 (3H, s), 2.18-2.38 (1H, m), 2.43-2.72 (2H, m), 3.06-3.26 (7H, m), 3.31-3.45 (1H, m), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.72-6.85 (3H, m), 7.10-7.20 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.58-7.65 (1H, m), 7.96 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz)。
（９０ｅ）　１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）ピロリジン－３－イル］フェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（９０ｄ）で得られた化合物（１９．４　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液に４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（１６．４　ｍｇ）及び１，４－ジオキサン－２－カルボン酸（６．２７　ｍｇ）を加え、室温で１５時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（５．８　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.88-2.09 (1H, m), 2.12 (3H, s), 2.20-2.40 (1H, m), 3.12 (3H, s), 3.16-3.25 (2H, m), 3.29-3.62 (3H, m), 3.66-4.02 (8H, m), 4.20-4.33 (3H, m), 4.37 (2H, s), 6.77 (1H, d, J = 8.5 Hz), 6.84 (2H, t, J = 8.5 Hz), 7.08-7.19 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.98 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 605 (M+H)+。 (90a) 2- [2- (Methylsulfonyl) phenyl] -1- {4-methyl-5- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ) Phenoxy] -2,3-dihydro-1H-indol-1-yl} ethanone Compound (300 mg) obtained in Example (1b), bis (pinacolato) diboron (167 mg), potassium acetate (117 mg) Then, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (14.7 mg) was added to a 1,4-dioxane (10 mL) solution of dimethyl sulfoxide (200 μL), and nitrogen was added. The reaction was performed at 100 ° C. for 5 hours in an atmosphere. 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 (222 mg) as a white 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), 6.74-7.02 (3H, m), 7.26-7.44 (2H, m), 7.49-7.55 (1H, m), 7.62 (1H, t, J = 7.9 Hz), 7.73 (1H, d, J = 8.5 Hz), 7.95-8.04 (1H, m), 8.07 (1H, d, J = 7.9 Hz).
(90b) Benzyl 3-{[(trifluoromethyl) sulfonyl] oxy} -2,5-dihydro-1H-pyrrole-1-carboxyloxylate 1-carbobenzyloxy-3-pyrrolidinone (1.00 g) in tetrahydrofuran The (5 mL) solution was cooled to −78 ° C., sodium bis (trimethylsilyl) amide (1.6 M tetrahydrofuran solution, 8.44 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hr. Next, a solution of N-phenylbis (trifluoromethanesulfonimide) (1.79 g) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred for 2 hours under ice cooling. 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 (593 mg) as a brown oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 4.30 (4H, br m), 5.17 (2H, s), 5.73 (0.5H, s), 5.78 (0.5H, s), 7.26-7.45 (5H, m).
(90c) Benzyl 3- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} -2 , 5-Dihydro-1H-pyrrole-1-carbonoxylate 1,2- of the compound (100 mg) obtained in Example (90a) and the compound (87.5 mg) obtained in Example (90b) An aqueous solution (1 mL) of sodium carbonate (58.0 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 (15.0 mg) was added and reacted at 130 ° C. for 45 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 (262 mg) as a white 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), 4.29 (2H, t, J = 8.5 Hz) , 4.33-4.43 (4H, br m), 4.48-4.60 (2H, m), 5.20 (2H, s), 6.01 (0.5H, s), 6.05 (0.5H, s), 6.74-6.88 (3H, m ), 7.25-7.44 (8H, m), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.99 (1H, d, J = 9.2 Hz), 8.08 (1H , d, J = 7.9 Hz).
(90d) 1- {4-Methyl-5- [4- (pyrrolidin-3-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl Ethanone The compound (26.2 mg) obtained in Example (90c) was dissolved in ethanol (1.5 mL) and ethyl acetate (1.5 mL), and 7.5% palladium on carbon (5.5 mg). ) And stirred for 18 hours at room temperature under hydrogen atmosphere. Ethyl acetate was added to the reaction mixture, the insoluble material was filtered off, and the filtrate was concentrated to dryness under reduced pressure to give the title compound (19.4 mg) as a yellow oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.78-1.97 (2H, m), 2.13 (3H, s), 2.18-2.38 (1H, m), 2.43-2.72 (2H, m), 3.06-3.26 (7H, m), 3.31-3.45 (1H, m), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.72-6.85 (3H, m), 7.10-7.20 (2H, m ), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.58-7.65 (1H, m), 7.96 (1H, d, J = 8.5 Hz), 8.07 (1H , d, J = 7.9 Hz).
(90e) 1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) pyrrolidin-3-yl] phenoxy} -4-methyl-2,3-dihydro-1H-indole-1 -Yl) -2- [2- (methylsulfonyl) phenyl] ethanone To a solution of the compound obtained in Example (90d) (19.4 mg) in N, N-dimethylformamide (3 mL) 4- (4 6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (16.4 mg) and 1,4-dioxane-2-carboxylic acid (6.27 mg) were added, Stir 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 (5.8 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.88-2.09 (1H, m), 2.12 (3H, s), 2.20-2.40 (1H, m), 3.12 (3H, s), 3.16-3.25 (2H , m), 3.29-3.62 (3H, m), 3.66-4.02 (8H, m), 4.20-4.33 (3H, m), 4.37 (2H, s), 6.77 (1H, d, J = 8.5 Hz), 6.84 (2H, t, J = 8.5 Hz), 7.08-7.19 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t , J = 7.6 Hz), 7.98 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 605 (M + H) + .
　（実施例９１）
１－｛５－［４－（１－アセチル－１，２，３，６－テトラヒドロピリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン (Example 91)
1- {5- [4- (1-acetyl-1,2,3,6-tetrahydropyridin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl}- 2- [2- (Methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000131
Figure JPOXMLDOC01-appb-C000131
　実施例（１ｂ）で得られた化合物（２００　ｍｇ）、１－［４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）－３，６－ジヒドロピリジン－１（２Ｈ）－イル］エタノン（１５０　ｍｇ）の１，２－ジメトキシエタン（６　ｍＬ）溶液に炭酸ナトリウム（１２７　ｍｇ）の水溶液（２　ｍＬ）を加え、室温で５分間撹拌した。次いで［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（３２．６　ｍｇ）を加え、マイクロウェーブ反応装置にて、１３０℃で１５分間反応させた。反応液を室温に冷却後、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（１２０　ｍｇ）を淡茶色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.12 (3H, s), 2.14 (1.5H, s), 2.17 (1.5H, s), 2.48-2.62 (2H, m), 3.02-3.19 (4H, m), 3.22 (2H, t, J = 8.2 Hz), 3.65 (1H, t, J = 5.8 Hz), 3.81 (1H, t, J = 5.8 Hz), 4.20-4.24 (2H, m), 4.29 (2H, t, J = 8.2 Hz), 4.37 (2H, s), 5.94 (0.5H, br s), 6.00 (0.5H, br s), 6.79 (1H, d, J = 9.2 Hz), 6.81-6.86 (2H, m), 7.25-7.31 (1H, m), 7.36 (1H, d, J = 7.9 Hz), 7.51-7.55 (1H, m), 7.60-7.64 (1H, m), 7.99 (1H, d, J = 9.2 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 545 (M+H)+。 Compound (200 mg) obtained in Example (1b), 1- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydropyridine An aqueous solution (2 mL) of sodium carbonate (127 mg) was added to a solution of -1 (2H) -yl] ethanone (150 mg) in 1,2-dimethoxyethane (6 mL), and the mixture was stirred at room temperature for 5 minutes. Next, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (32.6 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 (120 mg) as a pale brown solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.12 (3H, s), 2.14 (1.5H, s), 2.17 (1.5H, s), 2.48-2.62 (2H, m), 3.02-3.19 (4H , m), 3.22 (2H, t, J = 8.2 Hz), 3.65 (1H, t, J = 5.8 Hz), 3.81 (1H, t, J = 5.8 Hz), 4.20-4.24 (2H, m), 4.29 (2H, t, J = 8.2 Hz), 4.37 (2H, s), 5.94 (0.5H, br s), 6.00 (0.5H, br s), 6.79 (1H, d, J = 9.2 Hz), 6.81- 6.86 (2H, m), 7.25-7.31 (1H, m), 7.36 (1H, d, J = 7.9 Hz), 7.51-7.55 (1H, m), 7.60-7.64 (1H, m), 7.99 (1H, d, J = 9.2 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 545 (M + H) + .
　（実施例９２）：実施例（９２ｂ）で合成
２－メトキシ－１－［４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］エタノン Example 92: synthesized in Example (92b) 2-methoxy-1- [4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3- Dihydro-1H-indol-5-yl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] ethanone
Figure JPOXMLDOC01-appb-C000132
Figure JPOXMLDOC01-appb-C000132
（９２ａ）　２－［２－（メチルスルホニル）フェニル］－１－｛４－メチル－５－［４－（１，２，３，６－テトラヒドロピリジン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝エタノン塩酸塩
　実施例（１ｃ）で得られた化合物（２１９　ｍｇ）のジクロロメタン（２　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（４　ｍＬ）を加え、室温で３時間攪拌した。反応液を減圧下濃縮し、残渣を酢酸エチルで洗浄後ろ取、乾燥することで標記化合物（３２６　ｍｇ）を白色固体として得た。
MS(APCI) m/z: 503 (M+H)+。
（９２ｂ）　２－メトキシ－１－［４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］エタノン
　実施例（９２ａ）で得られた化合物（１５０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液にトリエチルアミン（７７．０　μＬ）を加え、室温で５分間攪拌した。次いで４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（１１５　ｍｇ）及びメトキシ酢酸（２６．０　μＬ）を加え、室温で４８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（６９．５　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.12 (3H, s), 2.49-2.60 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.2 Hz), 3.45 (3H, s), 3.68 (1H, t, J = 5.5 Hz), 3.83 (1H, t, J = 5.5 Hz), 4.09-4.20 (3H, m), 4.21-4.25 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.37 (2H, s), 5.93 (0.4H, br s), 5.99 (0.6H, br s), 6.79 (1H, d, J = 8.5 Hz), 6.84 (2H, d, J = 9.2 Hz), 7.24-7.32 (2H, m), 7.37 (1H, d, J = 7.9 Hz), 7.49-7.55 (1H, m), 7.60-7.64 (1H, m), 7.99 (1H, d, J = 9.2 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 575 (M+H)+。 (92a) 2- [2- (Methylsulfonyl) phenyl] -1- {4-methyl-5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenoxy] -2,3- Dihydro-1H-indol-1-yl} ethanone hydrochloride To a solution of the compound obtained in Example (1c) (219 mg) in dichloromethane (2 mL) was added 4N hydrochloric acid dioxane solution (4 mL), and at room temperature for 3 hours. Stir. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethyl acetate, collected after drying, and dried to obtain the title compound (326 mg) as a white solid.
MS (APCI) m / z: 503 (M + H) + .
(92b) 2-Methoxy-1- [4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) Oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] ethanone To a solution of the compound obtained in Example (92a) (150 mg) in N, N-dimethylformamide (3 mL), triethylamine (77. 0 μL) was added and stirred at room temperature for 5 minutes. Then 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (115 mg) and methoxyacetic acid (26.0 μL) were added, and the mixture was stirred at room temperature for 48 hours. Stir. 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 (69.5 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.12 (3H, s), 2.49-2.60 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.2 Hz), 3.45 ( 3H, s), 3.68 (1H, t, J = 5.5 Hz), 3.83 (1H, t, J = 5.5 Hz), 4.09-4.20 (3H, m), 4.21-4.25 (1H, m), 4.29 (2H , t, J = 8.2 Hz), 4.37 (2H, s), 5.93 (0.4H, br s), 5.99 (0.6H, br s), 6.79 (1H, d, J = 8.5 Hz), 6.84 (2H, d, J = 9.2 Hz), 7.24-7.32 (2H, m), 7.37 (1H, d, J = 7.9 Hz), 7.49-7.55 (1H, m), 7.60-7.64 (1H, m), 7.99 (1H , d, J = 9.2 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 575 (M + H) + .
　（実施例９３）
（２Ｓ）－２－ヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル）プロパン－１－オン (Example 93)
(2S) -2-Hydroxy-1- (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl ) Oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl) propan-1-one
Figure JPOXMLDOC01-appb-C000133
Figure JPOXMLDOC01-appb-C000133
　実施例（９２ａ）で得られた化合物（３００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にトリエチルアミン（２３０　μＬ）を加え、室温で５分間攪拌した。次いでＬ－乳酸（５７．１　μＬ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（１５９　ｍｇ）、１－ヒドロキシベンゾトリアゾール一水和物（８４．９　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１４６　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.36 (3H, dd, J = 14.6, 6.7 Hz), 2.12 (3H, s), 2.48-2.63 (2H, m), 3.11 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.56-3.65 (1H, m), 3.84-3.93 (1H, m), 3.98-4.15 (1H, m), 4.29 (3H, t, J = 8.5 Hz), 4.36 (2H, s), 4.44-4.61 (1H, m), 5.93 (0.5H, br s), 6.02 (0.5H, br s), 6.79 (1H, d, J = 8.5 Hz), 6.84 (2H, d, J = 9.2 Hz), 7.22-7.32 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.47-7.55 (1H, m), 7.57-7.65 (1H, m), 7.99 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 575 (M+H)+。 Triethylamine (230 μL) was added to a solution of the compound (300 mg) obtained in Example (92a) in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 5 minutes. Next, L-lactic acid (57.1 μL), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (159 mg) and 1-hydroxybenzotriazole monohydrate (84.9 mg) were added. And stirred at room temperature for 18 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 amino silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (146 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.36 (3H, dd, J = 14.6, 6.7 Hz), 2.12 (3H, s), 2.48-2.63 (2H, m), 3.11 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.56-3.65 (1H, m), 3.84-3.93 (1H, m), 3.98-4.15 (1H, m), 4.29 (3H, t, J = 8.5 Hz) , 4.36 (2H, s), 4.44-4.61 (1H, m), 5.93 (0.5H, br s), 6.02 (0.5H, br s), 6.79 (1H, d, J = 8.5 Hz), 6.84 (2H , d, J = 9.2 Hz), 7.22-7.32 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.47-7.55 (1H, m), 7.57-7.65 (1H, m), 7.99 ( 1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 575 (M + H) + .
　（実施例９４）：実施例（９４ｂ）で合成
３－ヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル）プロパン－１－オン Example 94: synthesized in Example (94b) 3-hydroxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3- Dihydro-1H-indol-5-yl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl) propan-1-one
Figure JPOXMLDOC01-appb-C000134
Figure JPOXMLDOC01-appb-C000134
（９４ａ）　１－［４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル）－３－（プロプ－２－エン－１－イルオキシ）プロパン－１－オン
　実施例（９２ａ）で得られた化合物（３００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（８　ｍＬ）溶液にトリエチルアミン（１５０　μＬ）を加え、室温で５分間攪拌した。次いで３－アリルオキシプロピオン酸（８１．７　μＬ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（２３０　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（６１．８　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.12 (3H, s), 2.47-2.58 (2H, m), 2.63-2.75 (2H, m), 3.13 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.69 (1H, t, J = 5.8 Hz), 3.77-3.85 (3H, m), 3.96-4.03 (2H, m), 4.09-4.15 (1H, m), 4.19-4.25 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 5.15-5.30 (2H, m), 5.85-5.99 (2H, m), 6.79 (1H, d, J = 8.5 Hz), 6.82-6.86 (2H, m), 7.21-7.31 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.50-7.54 (1H, m), 7.59-7.66 (1H, m), 7.95-8.04 (1H, m), 8.07 (1H, d, J = 7.9 Hz)。
（９４ｂ）　３－ヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル）プロパン－１－オン
　実施例（９４ａ）で得られた化合物（１６１　ｍｇ）のテトラヒドロフラン（３ ｍＬ）溶液に１，３－ジメチルバルビツール酸（８２．２　ｍｇ）、　テトラキス（トリフェニルホスフィン）パラジウム（０）（１５．２　ｍｇ）を加え、窒素雰囲気下、９０℃で５時間撹拌した。反応液を減圧下で濃縮し、得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン→メタノール／ジクロロメタン）で精製することで、標記化合物（１２４　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.12 (3H, s), 2.49-2.65 (4H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.43-3.52 (1H, m), 3.65 (1H, t, J = 5.8 Hz), 3.83 (1H, t, J = 5.8 Hz), 3.86-3.93 (2H, m), 4.07-4.12 (1H, m), 4.22-4.33 (3H, m), 4.37 (2H, s), 5.93 (0.5H, br s), 6.01 (0.5H, br s), 6.79 (1H, d, J = 9.2 Hz), 6.84 (2H, q, J = 8.5 Hz), 7.19-7.31 (2H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.60-7.64 (1H, m), 7.99 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 575 (M+H)+。 (94a) 1- [4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl) -3- (prop-2-en-1-yloxy) propan-1-one The compound obtained in Example (92a) (300 mg) in N, Triethylamine (150 μL) was added to an N-dimethylformamide (8 mL) solution, and the mixture was stirred at room temperature for 5 minutes. Then 3-allyloxypropionic acid (81.7 μL), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (230 mg) was added, Stir at room temperature for 18 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 (61.8 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.12 (3H, s), 2.47-2.58 (2H, m), 2.63-2.75 (2H, m), 3.13 (3H, s), 3.22 (2H, t , J = 8.5 Hz), 3.69 (1H, t, J = 5.8 Hz), 3.77-3.85 (3H, m), 3.96-4.03 (2H, m), 4.09-4.15 (1H, m), 4.19-4.25 ( 1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 5.15-5.30 (2H, m), 5.85-5.99 (2H, m), 6.79 (1H, d, J = 8.5 Hz), 6.82-6.86 (2H, m), 7.21-7.31 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.50-7.54 (1H, m), 7.59-7.66 (1H, m ), 7.95-8.04 (1H, m), 8.07 (1H, d, J = 7.9 Hz).
(94b) 3-hydroxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) Oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl) propan-1-one To a solution of the compound obtained in Example (94a) (161 mg) in tetrahydrofuran (3 mL) was added 1,3-dimethyl. Barbituric acid (82.2 mg) and tetrakis (triphenylphosphine) palladium (0) (15.2 mg) were added, and the mixture was stirred at 90 ° C. for 5 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by amino silica gel column chromatography (ethyl acetate / dichloromethane → methanol / dichloromethane) to give the title compound (124 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.12 (3H, s), 2.49-2.65 (4H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.43- 3.52 (1H, m), 3.65 (1H, t, J = 5.8 Hz), 3.83 (1H, t, J = 5.8 Hz), 3.86-3.93 (2H, m), 4.07-4.12 (1H, m), 4.22 -4.33 (3H, m), 4.37 (2H, s), 5.93 (0.5H, br s), 6.01 (0.5H, br s), 6.79 (1H, d, J = 9.2 Hz), 6.84 (2H, q , J = 8.5 Hz), 7.19-7.31 (2H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.60-7.64 (1H, m), 7.99 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 575 (M + H) + .
　（実施例９５）：実施例（９５ｂ）で合成
（２Ｓ）－２－ヒドロキシ－１－［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］プロパン－１－オン Example 95: Synthesis in Example (95b) (2S) -2-hydroxy-1- [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] Acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] propan-1-one
Figure JPOXMLDOC01-appb-C000135
Figure JPOXMLDOC01-appb-C000135
（９５ａ）　ｔｅｒｔ－ブチル　４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－カルボキシレート
　実施例（３ｂ）で得られた化合物（２６７　ｍｇ）の１，２－ジメトキシエタン（４　ｍＬ）、水（２　ｍＬ）溶液にｔｅｒｔ－ブチル　４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボラン－２－イル）－３，６－ジヒドロピリジン－１（２Ｈ）－カルボキシレート（１９３　ｍｇ）、［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）　ジクロロメタン錯体（４２．４　ｍｇ）、炭酸ナトリウム（１１０　ｍｇ）を加えてマイクロウェーブ照射下１２０℃で３０分撹拌した。室温まで冷却後、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、ろ過、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（３１９　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.50 (9H, s), 2.13 (3H, s), 2.22 (3H, s), 2.28-2.36 (2H, m), 3.12 (3H, s), 3.18-3.26 (2H, m), 3.56-3.64 (2H, m), 3.98-4.05 (2H, m), 4.25-4.32 (2H, m), 4.37 (2H, s), 5.46-5.59 (1H, m), 6.61-6.66 (1H, m), 6.68-6.71 (1H, m), 6.77-6.81 (1H, m), 6.95-6.99 (1H, m), 7.34-7.39 (1H, m), 7.49-7.56 (1H, m), 7.59-7.65 (1H, m), 7.96-8.00 (1H, m), 8.06-8.10 (1H, m)。
（９５ｂ）　（２Ｓ）－２－ヒドロキシ－１－［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］プロパン－１－オン
　実施例（９５ａ）で得られた化合物（６３２　ｍｇ）に４Ｎ塩酸ジオキサン溶液（１０　ｍＬ）を加えて室温で２時間撹拌した。反応液を減圧濃縮することで粗製の１－｛４－メチル－５－［３－メチル－４－（１，２，３，６－テトラヒドロピリジン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン塩酸塩を得た。 (95a) tert-butyl 4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) Oxy] phenyl} -3,6-dihydropyridine-1 (2H) -carboxylate solution of the compound obtained in Example (3b) (267 mg) in 1,2-dimethoxyethane (4 mL), water (2 mL) Tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate (193 mg), [ 1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (42.4 mg) and sodium carbonate (110 mg) were added, and It was stirred for 30 minutes over Bed irradiation under 120 ° C.. After cooling to room temperature, 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 (319 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.50 (9H, s), 2.13 (3H, s), 2.22 (3H, s), 2.28-2.36 (2H, m), 3.12 (3H, s), 3.18-3.26 (2H, m), 3.56-3.64 (2H, m), 3.98-4.05 (2H, m), 4.25-4.32 (2H, m), 4.37 (2H, s), 5.46-5.59 (1H, m ), 6.61-6.66 (1H, m), 6.68-6.71 (1H, m), 6.77-6.81 (1H, m), 6.95-6.99 (1H, m), 7.34-7.39 (1H, m), 7.49-7.56 (1H, m), 7.59-7.65 (1H, m), 7.96-8.00 (1H, m), 8.06-8.10 (1H, m).
(95b) (2S) -2-Hydroxy-1- [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro- 1H-Indol-5-yl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] propan-1-one 4N dioxane hydrochloride solution in the compound (632 mg) obtained in Example (95a) (10 mL) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give crude 1- {4-methyl-5- [3-methyl-4- (1,2,3,6-tetrahydropyridin-4-yl) phenoxy] -2,3-dihydro -1H-Indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone hydrochloride was obtained.
　得られた化合物（１４５　ｍｇ）のジクロロメタン（４　ｍＬ）溶液に８５％Ｌ－乳酸水溶液　（３３．３　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（１０１　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（３５．７　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１３７　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール／酢酸エチル）で精製することで標記化合物（５１．０　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.34-1.40 (3H, m), 2.13 (3H, s), 2.19-2.24 (3H, m), 2.35-2.44 (2H, m), 3.12 (3H, s), 3.18-3.26 (2H, m), 3.56-3.62 (1H, m), 3.89-3.95 (1H, m), 3.98-4.07 (1H, m), 4.17-4.33 (3H, m), 4.37 (2H, s), 4.48-4.56 (1H, m), 5.50-5.63 (1H, m), 6.62-6.67 (1H, m), 6.69-6.72 (1H, m), 6.76-6.81 (1H, m), 6.94-6.99 (1H, m), 7.34-7.39 (1H, m), 7.49-7.56 (1H, m), 7.59-7.65 (1H, m), 7.96-8.01 (1H, m), 8.05-8.10 (1H, m).
MS (APCI) m/z: 589 (M+H)+。 To a solution of the obtained compound (145 mg) in dichloromethane (4 mL), 85% L-lactic acid aqueous solution (33.3 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (101 mg) 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (35.7 mg) and N, N-diisopropylethylamine (0.137 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 (51.0 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.34-1.40 (3H, m), 2.13 (3H, s), 2.19-2.24 (3H, m), 2.35-2.44 (2H, m), 3.12 (3H , s), 3.18-3.26 (2H, m), 3.56-3.62 (1H, m), 3.89-3.95 (1H, m), 3.98-4.07 (1H, m), 4.17-4.33 (3H, m), 4.37 (2H, s), 4.48-4.56 (1H, m), 5.50-5.63 (1H, m), 6.62-6.67 (1H, m), 6.69-6.72 (1H, m), 6.76-6.81 (1H, m) , 6.94-6.99 (1H, m), 7.34-7.39 (1H, m), 7.49-7.56 (1H, m), 7.59-7.65 (1H, m), 7.96-8.01 (1H, m), 8.05-8.10 ( 1H, m).
MS (APCI) m / z: 589 (M + H) + .
　（実施例９６）：実施例（９６ｂ）で合成
（２Ｓ）－２,３－ジヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル）プロパン－１－オン Example 96: Synthesis in Example (96b) (2S) -2,3-dihydroxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl } -2,3-Dihydro-1H-indol-5-yl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl) propan-1-one
Figure JPOXMLDOC01-appb-C000136
Figure JPOXMLDOC01-appb-C000136
（９６ａ）　１－｛５－［４－（１－｛［（４Ｓ）－２，２－ジメチル－１，３－ジオキソラン－４－イル］カルボニル｝－１，２，３，６－テトラヒドロピリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（９２ａ）で得られた化合物（３００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（８　ｍＬ）溶液にトリエチルアミン（１５０　μＬ）を加え、室温で５分間攪拌した。次いで、文献記載の方法（Ｂｉｏｏｒｇａｎｉｃ　ａｎｄ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ　Ｌｅｔｔｅｒｓ，２００４，１４，３２３１）に従って合成した（４Ｓ）－２，２－ジメチル－１，３－ジオキソラン－４－カルボン酸（１００　ｍｇ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（２３１　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（２４２　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.38-1.45 (6H, m), 2.12 (3H, s), 2.48-2.64 (1H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.2 Hz), 3.62-3.75 (1H, m), 3.91-4.03 (1H, m), 4.09-4.22 (2H, m), 4.22-4.39 (5H, m), 4.40-4.51 (1H, m), 4.70-4.76 (1H, m), 5.96 (1H, br s), 6.00 (1H, br s), 6.79 (1H, d, J = 9.2 Hz), 6.84 (2H, d, J = 8.5 Hz), 7.22-7.32 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.0 Hz), 7.62 (1H, t, J = 7.0 Hz), 7.98 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz)。
（９６ｂ）　（２Ｓ）－２,３－ジヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル）プロパン－１－オン
　実施例（９６ａ）で得られた化合物（３２０　ｍｇ）のジクロロメタン（１　ｍＬ）と水（５００　μＬ）の混合溶液に４Ｎ塩酸ジオキサン溶液（２　ｍＬ）を加え、室温で２時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮することで、標記化合物（２５４　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.12 (3H, s), 2.48-2.66 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.59-3.73 (5H, m), 3.74-3.84 (1H, m), 4.02-4.17 (1H, m), 4.20-4.33 (3H, m), 4.37 (2H, s), 4.46-4.57 (1H, m), 5.93 (0.4H, br s), 6.00 (0.6H, br s), 6.76-6.90 (3H, m), 7.16-7.31 (2H, m), 7.37 (1H, d, J = 7.9 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.63 (1H, t, J = 7.6 Hz), 7.99 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 591 (M+H)+。 (96a) 1- {5- [4- (1-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] carbonyl} -1,2,3,6-tetrahydropyridine- 4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone Compound (300) obtained in Example (92a) mg) in N, N-dimethylformamide (8 mL) was added triethylamine (150 μL), and the mixture was stirred at room temperature for 5 minutes. Subsequently, (4S) -2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (100 mg), 4-(()) synthesized according to a method described in the literature (Bioorganic and Medicinal Chemistry Letters, 2004, 14, 3231). 4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (231 mg) was added, and the mixture was stirred at room temperature for 18 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 (242 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.38-1.45 (6H, m), 2.12 (3H, s), 2.48-2.64 (1H, m), 3.12 (3H, s), 3.22 (2H, t , J = 8.2 Hz), 3.62-3.75 (1H, m), 3.91-4.03 (1H, m), 4.09-4.22 (2H, m), 4.22-4.39 (5H, m), 4.40-4.51 (1H, m ), 4.70-4.76 (1H, m), 5.96 (1H, br s), 6.00 (1H, br s), 6.79 (1H, d, J = 9.2 Hz), 6.84 (2H, d, J = 8.5 Hz) , 7.22-7.32 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.0 Hz), 7.62 (1H, t, J = 7.0 Hz), 7.98 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
(96b) (2S) -2,3-dihydroxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H- Indol-5-yl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl) propan-1-one Compound (320 mg) obtained in Example (96a) with dichloromethane (1 mL) A 4N hydrochloric acid dioxane solution (2 mL) was added to a mixed solution of water (500 μL), and the mixture was stirred at room temperature for 2 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 to give the title compound (254 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.12 (3H, s), 2.48-2.66 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.59- 3.73 (5H, m), 3.74-3.84 (1H, m), 4.02-4.17 (1H, m), 4.20-4.33 (3H, m), 4.37 (2H, s), 4.46-4.57 (1H, m), 5.93 (0.4H, br s), 6.00 (0.6H, br s), 6.76-6.90 (3H, m), 7.16-7.31 (2H, m), 7.37 (1H, d, J = 7.9 Hz), 7.53 ( 1H, t, J = 7.6 Hz), 7.63 (1H, t, J = 7.6 Hz), 7.99 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 591 (M + H) + .
　（実施例９７）
２－ヒドロキシ－３－メトキシ－１－［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］プロパン－１－オン (Example 97)
2-hydroxy-3-methoxy-1- [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole -5-yl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] propan-1-one
Figure JPOXMLDOC01-appb-C000137
Figure JPOXMLDOC01-appb-C000137
　実施例（９５ｂ）で得られた１－｛４－メチル－５－［３－メチル－４－（１，２，３，６－テトラヒドロピリジン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン塩酸塩（２０５　ｍｇ）のジクロロメタン（４　ｍＬ）溶液に２－ヒドロキシ－３－メトキシプロパン酸（５３．４　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（９２．４　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（５６．８　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１９４　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（１６７　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.13 (3H, s), 2.22 (3H, s), 2.34-2.43 (2H, m), 3.12 (3H, s), 3.18-3.26 (2H, m), 3.40 (3H, s), 3.49-3.81 (3H, m), 3.89-4.16 (2H, m), 4.22-4.29 (3H, m), 4.37 (2H, s), 4.57-4.67 (1H, m), 5.49-5.62 (1H, m), 6.62-6.67 (1H, m), 6.68-6.72 (1H, m), 6.76-6.81 (1H, m), 6.93-6.99 (1H, m), 7.34-7.39 (1H, m), 7.49-7.56 (1H, m), 7.59-7.65 (1H, m), 7.96-8.01 (1H, m), 8.06-8.10 (1H, m).
MS (APCI) m/z: 619 (M+H)+。 1- {4-Methyl-5- [3-methyl-4- (1,2,3,6-tetrahydropyridin-4-yl) phenoxy] -2,3-dihydro- obtained in Example (95b) To a solution of 1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone hydrochloride (205 mg) in dichloromethane (4 mL) was added 2-hydroxy-3-methoxypropanoic acid (53.4 mg). 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (92.4 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (56.8) mg) and N, N-diisopropylethylamine (0.194 mL) were added, and the mixture 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 (167 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.13 (3H, s), 2.22 (3H, s), 2.34-2.43 (2H, m), 3.12 (3H, s), 3.18-3.26 (2H, m ), 3.40 (3H, s), 3.49-3.81 (3H, m), 3.89-4.16 (2H, m), 4.22-4.29 (3H, m), 4.37 (2H, s), 4.57-4.67 (1H, m ), 5.49-5.62 (1H, m), 6.62-6.67 (1H, m), 6.68-6.72 (1H, m), 6.76-6.81 (1H, m), 6.93-6.99 (1H, m), 7.34-7.39 (1H, m), 7.49-7.56 (1H, m), 7.59-7.65 (1H, m), 7.96-8.01 (1H, m), 8.06-8.10 (1H, m).
MS (APCI) m / z: 619 (M + H) + .
　（実施例９８）
１－｛５－［４－［１－（１，４－ジオキサン－２－イルカルボニル－１，２，３，６－テトラヒドロピリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン (Example 98)
1- {5- [4- [1- (1,4-Dioxane-2-ylcarbonyl-1,2,3,6-tetrahydropyridin-4-yl) phenoxy] -4-methyl-2,3-dihydro -1H-Indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000138
Figure JPOXMLDOC01-appb-C000138
　実施例（１ｂ）で得られた１－［５－（４－ブロモフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン（２．５　ｇ）及び実施例（１０３ｂ）で得られた化合物（１．９４　ｇ）の１，２－ジメトキシエタン（５０　ｍＬ）溶液に炭酸ナトリウム（１．５９　ｇ）の水溶液（１０　ｍＬ）を加え、室温で５分間撹拌した。次いで［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（４０８　ｍｇ）を加え、マイクロウェーブ反応装置にて、１３０℃で４５分間反応させた。反応液を室温に冷却後、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（１．９６　ｇ）を淡黄色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.12 (3H, s), 2.46-2.57 (1H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.62-3.99 (9H, m), 4.08-4.19 (1H, m), 4.23-4.41 (6H, m), 5.94 (0.5H, br s), 5.98 (0.5H, br s), 6.79 (1H, d, J = 8.5 Hz), 6.84 (2H, d, J = 8.5 Hz), 7.23-7.32 (2H, m), 7.37 (1H, d, J = 7.9 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.63 (1H, t, J = 7.6 Hz), 7.99 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 617 (M+H)+。 1- [5- (4-Bromophenoxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl obtained in Example (1b) A solution of sodium carbonate (1.59 g) in a solution of ethanone (2.5 g) and the compound (1.94 g) obtained in Example (103b) in 1,2-dimethoxyethane (50 mL) (10 mL) was added and stirred at room temperature for 5 minutes. Next, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (408 mg) was added and reacted at 130 ° C. for 45 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 (1.96 g) as a pale yellow solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.12 (3H, s), 2.46-2.57 (1H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.62- 3.99 (9H, m), 4.08-4.19 (1H, m), 4.23-4.41 (6H, m), 5.94 (0.5H, br s), 5.98 (0.5H, br s), 6.79 (1H, d, J = 8.5 Hz), 6.84 (2H, d, J = 8.5 Hz), 7.23-7.32 (2H, m), 7.37 (1H, d, J = 7.9 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.63 (1H, t, J = 7.6 Hz), 7.99 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 617 (M + H) + .
　（実施例９９）
Ｎ，Ｎ－ジメチル－２－［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］－２－オキソアセトアミド Example 99
N, N-dimethyl-2- [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole-5 -Yl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000139
Figure JPOXMLDOC01-appb-C000139
　実施例（１０２ｂ）で得られた化合物（２３２　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（４　ｍＬ）溶液にジメチルアミン塩酸塩（６４．３　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（１１３　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（６０．４　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１７２　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール／酢酸エチル）で精製することで標記化合物（１５２　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.12 (3H, s), 2.20-2.23 (3H, m), 2.37-2.46 (2H, m), 3.00-3.09 (6H, m), 3.12 (3H, s), 3.18-3.26 (2H, m), 3.57-3.63 (1H, m), 3.82-3.89 (1H, m), 4.02-4.07 (1H, m), 4.22-4.33 (3H, m), 4.37 (2H, s), 5.50-5.62 (1H, m), 6.62-6.67 (1H, m), 6.68-6.71 (1H, m), 6.76-6.81 (1H, m), 6.94-6.99 (1H, m), 7.34-7.39 (1H, m), 7.50-7.56 (1H, m), 7.59-7.65 (1H, m), 7.96-8.00 (1H, m), 8.06-8.10 (1H, m).
MS (APCI) m/z: 616 (M+H)+。 To a solution of the compound (232 mg) obtained in Example (102b) in N, N-dimethylformamide (4 mL) was added dimethylamine hydrochloride (64.3 mg), 1-ethyl-3- (3-dimethylaminopropyl). ) Carboximide hydrochloride (113 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (60.4 mg), N, N-diisopropylethylamine (0.172 mL) 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 (152 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.12 (3H, s), 2.20-2.23 (3H, m), 2.37-2.46 (2H, m), 3.00-3.09 (6H, m), 3.12 (3H , s), 3.18-3.26 (2H, m), 3.57-3.63 (1H, m), 3.82-3.89 (1H, m), 4.02-4.07 (1H, m), 4.22-4.33 (3H, m), 4.37 (2H, s), 5.50-5.62 (1H, m), 6.62-6.67 (1H, m), 6.68-6.71 (1H, m), 6.76-6.81 (1H, m), 6.94-6.99 (1H, m) , 7.34-7.39 (1H, m), 7.50-7.56 (1H, m), 7.59-7.65 (1H, m), 7.96-8.00 (1H, m), 8.06-8.10 (1H, m).
MS (APCI) m / z: 616 (M + H) + .
　（実施例１００）
Ｎ－エチル－２－［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］－２－オキソアセトアミド (Example 100)
N-ethyl-2- [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl ) Oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000140
Figure JPOXMLDOC01-appb-C000140
　実施例（１０２ｂ）で得られた化合物（１４７　ｍｇ）のジクロロメタン（４　ｍＬ）溶液にエチルアミン塩酸塩（４０．７　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（９５．７　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（３４．０　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１３１　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール／酢酸エチル）で精製することで標記化合物（８４．０　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (500 MHz, CDCl3) δ: 1.21 (3H, t, J = 7.1 Hz), 2.13 (3H, s), 2.21-2.24 (3H, m), 2.37-2.50 (2H, m), 3.12 (3H, s), 3.19-3.25 (2H, m), 3.32-3.39 (2H, m), 3.83-3.87 (1H, m), 4.19-4.23 (1H, m), 4.24-4.32 (3H, m), 4.36 (2H, s), 4.72-4.76 (1H, m), 5.52-5.59 (1H, m), 6.62-6.66 (1H, m), 6.68-6.71 (1H, m), 6.76-6.81 (1H, m), 6.94-6.98 (1H, m), 7.29-7.39 (2H, m), 7.50-7.54 (1H, m), 7.59-7.64 (1H, m), 7.96-8.00 (1H, m), 8.06-8.09 (1H, m).
MS (APCI) m/z: 616 (M+H)+。 To a solution of the compound (147 mg) obtained in Example (102b) in dichloromethane (4 mL) was added ethylamine hydrochloride (40.7 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride ( 95.7 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (34.0 mg) and N, N-diisopropylethylamine (0.131 mL) were added at room temperature. Stir with. 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 (84.0 mg) as a white amorphous solid.
1 H-NMR (500 MHz, CDCl 3 ) δ: 1.21 (3H, t, J = 7.1 Hz), 2.13 (3H, s), 2.21-2.24 (3H, m), 2.37-2.50 (2H, m), 3.12 (3H, s), 3.19-3.25 (2H, m), 3.32-3.39 (2H, m), 3.83-3.87 (1H, m), 4.19-4.23 (1H, m), 4.24-4.32 (3H, m ), 4.36 (2H, s), 4.72-4.76 (1H, m), 5.52-5.59 (1H, m), 6.62-6.66 (1H, m), 6.68-6.71 (1H, m), 6.76-6.81 (1H , m), 6.94-6.98 (1H, m), 7.29-7.39 (2H, m), 7.50-7.54 (1H, m), 7.59-7.64 (1H, m), 7.96-8.00 (1H, m), 8.06 -8.09 (1H, m).
MS (APCI) m / z: 616 (M + H) + .
　（実施例１０１）
Ｎ－（２－フルオロエチル）－２－［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］－２－オキソアセトアミド (Example 101)
N- (2-fluoroethyl) -2- [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H- Indol-5-yl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000141
Figure JPOXMLDOC01-appb-C000141
　実施例（１０２ｂ）で得られた化合物（１４７　ｍｇ）のジクロロメタン（４　ｍＬ）溶液に２－フルオロエチルアミン塩酸塩（４９．７　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（９５．７　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（３４．０　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１３１　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール／酢酸エチル）で精製することで標記化合物（９５．０　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.13 (3H, s), 2.23 (3H, s), 2.38-2.51 (2H, m), 3.13 (3H, s), 3.19-3.26 (2H, m), 3.58-3.72 (2H, m), 3.83-3.89 (1H, m), 4.20-4.33 (4H, m), 4.37 (2H, s), 4.47-4.52 (1H, m), 4.59-4.63 (1H, m), 4.70-4.74 (1H, m), 5.51-5.60 (1H, m), 6.62-6.67 (1H, m), 6.68-6.71 (1H, m), 6.77-6.81 (1H, m), 6.95-7.00 (1H, m), 7.34-7.39 (1H, m), 7.49-7.56 (1H, m), 7.57-7.72 (2H, m), 7.96-8.00 (1H, m), 8.06-8.10 (1H, m).
MS (APCI) m/z: 634 (M+H)+。 To a solution of the compound (147 mg) obtained in Example (102b) in dichloromethane (4 mL) was added 2-fluoroethylamine hydrochloride (49.7 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide. Hydrochloride (95.7 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (34.0 mg), N, N-diisopropylethylamine (0.131 mL) In addition, the mixture was 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 (95.0 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.13 (3H, s), 2.23 (3H, s), 2.38-2.51 (2H, m), 3.13 (3H, s), 3.19-3.26 (2H, m ), 3.58-3.72 (2H, m), 3.83-3.89 (1H, m), 4.20-4.33 (4H, m), 4.37 (2H, s), 4.47-4.52 (1H, m), 4.59-4.63 (1H , m), 4.70-4.74 (1H, m), 5.51-5.60 (1H, m), 6.62-6.67 (1H, m), 6.68-6.71 (1H, m), 6.77-6.81 (1H, m), 6.95 -7.00 (1H, m), 7.34-7.39 (1H, m), 7.49-7.56 (1H, m), 7.57-7.72 (2H, m), 7.96-8.00 (1H, m), 8.06-8.10 (1H, m).
MS (APCI) m / z: 634 (M + H) + .
　（実施例１０２）
　（実施例１０２－１）：実施例（１０２ａ）で合成
エチル　［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］（オキソ）アセテート (Example 102)
Example 102-1: Ethyl synthesized in Example (102a) [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3 -Dihydro-1H-indol-5-yl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] (oxo) acetate
Figure JPOXMLDOC01-appb-C000142
Figure JPOXMLDOC01-appb-C000142
　（実施例１０２－２）：実施例（１０２ｂ）で合成
［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］（オキソ）酢酸 Example 102-2: synthesized in Example (102b) [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3- Dihydro-1H-indol-5-yl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] (oxo) acetic acid
Figure JPOXMLDOC01-appb-C000143
Figure JPOXMLDOC01-appb-C000143
　（実施例１０２－３）：実施例（１０２ｃ）で合成
Ｎ－メチル－２－［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］－２－オキソアセトアミド Example 102-3: N-methyl-2- [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl) synthesized in Example (102c) } -2,3-Dihydro-1H-indol-5-yl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000144
Figure JPOXMLDOC01-appb-C000144
（１０２ａ）　エチル　［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］（オキソ）アセテート
　実施例（９５ｂ）で得られた１－｛４－メチル－５－［３－メチル－４－（１，２，３，６－テトラヒドロピリジン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン塩酸塩（４２５　ｍｇ）のジクロロメタン（１０　ｍＬ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．４０１　ｍＬ）溶液にエチル　クロロ（オキソ）アセテート（０．１１１　ｍＬ）を加えて室温で撹拌した。３０分後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（４６２　ｍｇ）を淡黄色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.36-1.42 (3H, m), 2.13 (3H, s), 2.22 (3H, s), 2.37-2.46 (2H, m), 3.12 (3H, s), 3.18-3.25 (2H, m), 3.60-3.64 (1H, m), 3.81-3.86 (1H, m), 4.07-4.11 (1H, m), 4.19-4.24 (1H, m), 4.26-4.33 (2H, m), 4.33-4.40 (4H, m), 5.49-5.61 (1H, m), 6.62-6.67 (1H, m), 6.68-6.71 (1H, m), 6.76-6.81 (1H, m), 6.94-6.99 (1H, m), 7.34-7.39 (1H, m), 7.50-7.55 (1H, m), 7.59-7.65 (1H, m), 7.96-8.01 (1H, m), 8.05-8.10 (1H, m)。
（１０２ｂ）　［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］（オキソ）酢酸
　実施例（１０２ａ）で得られた化合物（４６２　ｍｇ）１，４－ジオキサン（５　ｍＬ）溶液に１Ｎ水酸化ナトリウム水溶液（１．５　ｍＬ）を加えて室温で３時間撹拌した。１Ｎ塩酸水溶液で中和後、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、ろ過、減圧濃縮することで粗製の［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］（オキソ）酢酸を得た。
（１０２ｃ）　Ｎ－メチル－２－［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］－２－オキソアセトアミド
　実施例（１０２ｂ）で得られた化合物（１４７　ｍｇ）のジクロロメタン（４　ｍＬ）溶液にメチルアミン塩酸塩（３３．７　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（９５．７　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（３４．０　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１３１　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール／酢酸エチル）で精製することで標記化合物（３８．０　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.13 (3H, s), 2.19-2.25 (3H, m), 2.37-2.51 (2H, m), 2.90 (3H, d, J = 5.1 Hz), 3.12 (3H, s), 3.18-3.26 (2H, m), 3.82-3.87 (1H, m), 4.18-4.33 (4H, m), 4.37 (2H, s), 4.72-4.76 (1H, m), 5.51-5.64 (1H, m), 6.61-6.67 (1H, m), 6.68-6.72 (1H, m), 6.76-6.81 (1H, m), 6.94-6.99 (1H, m), 7.30-7.40 (2H, m), 7.49-7.56 (1H, m), 7.59-7.65 (1H, m), 7.96-8.01 (1H, m), 8.05-8.10 (1H, m).
MS (APCI) m/z: 602 (M+H)+。 (102a) Ethyl [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy ] Phenyl} -3,6-dihydropyridin-1 (2H) -yl] (oxo) acetate 1- {4-Methyl-5- [3-methyl-4- (1,2) obtained in Example (95b) , 3,6-Tetrahydropyridin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone hydrochloride (425 mg) in dichloromethane Ethyl chloro (oxo) acetate (0.111 mL) was added to a solution of (10 mL) and N, N-diisopropylethylamine (0.401 mL), and the mixture was stirred at room temperature. After 30 minutes, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (462 mg) as a pale yellow amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.36-1.42 (3H, m), 2.13 (3H, s), 2.22 (3H, s), 2.37-2.46 (2H, m), 3.12 (3H, s ), 3.18-3.25 (2H, m), 3.60-3.64 (1H, m), 3.81-3.86 (1H, m), 4.07-4.11 (1H, m), 4.19-4.24 (1H, m), 4.26-4.33 (2H, m), 4.33-4.40 (4H, m), 5.49-5.61 (1H, m), 6.62-6.67 (1H, m), 6.68-6.71 (1H, m), 6.76-6.81 (1H, m) , 6.94-6.99 (1H, m), 7.34-7.39 (1H, m), 7.50-7.55 (1H, m), 7.59-7.65 (1H, m), 7.96-8.01 (1H, m), 8.05-8.10 ( 1H, m).
(102b) [4- {2-Methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] Phenyl} -3,6-dihydropyridin-1 (2H) -yl] (oxo) acetic acid A solution of the compound obtained in Example (102a) (462 mg) and 1,4-dioxane (5 mL) in 1N aqueous sodium hydroxide solution (1.5 mL) was added and stirred at room temperature for 3 hours. The mixture was neutralized with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl}- 2,3-Dihydro-1H-indol-5-yl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] (oxo) acetic acid was obtained.
(102c) N-methyl-2- [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole- 5-yl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] -2-oxoacetamide To a solution of the compound obtained in Example (102b) (147 mg) in dichloromethane (4 mL) Amine hydrochloride (33.7 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (95.7 mg), 3H-1,2,3-triazolo [4,5-b] Pyridin-3-ol (34.0 mg) and N, N-diisopropylethylamine (0.131 mL) were added, and the mixture was 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 (38.0 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.13 (3H, s), 2.19-2.25 (3H, m), 2.37-2.51 (2H, m), 2.90 (3H, d, J = 5.1 Hz), 3.12 (3H, s), 3.18-3.26 (2H, m), 3.82-3.87 (1H, m), 4.18-4.33 (4H, m), 4.37 (2H, s), 4.72-4.76 (1H, m), 5.51-5.64 (1H, m), 6.61-6.67 (1H, m), 6.68-6.72 (1H, m), 6.76-6.81 (1H, m), 6.94-6.99 (1H, m), 7.30-7.40 (2H , m), 7.49-7.56 (1H, m), 7.59-7.65 (1H, m), 7.96-8.01 (1H, m), 8.05-8.10 (1H, m).
MS (APCI) m / z: 602 (M + H) + .
　（実施例１０３）：実施例（１０３ｄ）で合成
１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）ピペリジン－４－イル］ベンジル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン Example 103: Synthesis in Example (103d) 1- (5- {4- [1- (1,4-dioxane-2-ylcarbonyl) piperidin-4-yl] benzyl} -4-methyl-2 , 3-Dihydro-1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000145
Figure JPOXMLDOC01-appb-C000145
（１０３ａ）　ｔｅｒｔ－ブチル　５－（４－ブロモベンジル）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　ｔｅｒｔ－ブチル　４－メチル－５－（４，４，５，５－テトラメチル－１，３，２－ジオキサボラン－２－イル）－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート（９００　ｍｇ）の１，２－ジメトキシエタン（１２　ｍＬ）、水（６　ｍＬ）溶液に１－ブロモ－４－（クロロメチル）ベンゼン（６１８　ｍｇ）、テトラキス（トリフェニルホスフィン）パラジウム（０）（１４５　ｍｇ）、炭酸ナトリウム（６６４　ｍｇ）を加えて１００℃で１０時間撹拌した。室温まで冷却した後、酢酸エチルで抽出し、有機層を水及び飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、ろ過、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（５２４　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.52-1.59 (9H, m), 2.04 (3H, s), 2.94-3.03 (2H, m), 3.89 (2H, s), 3.91-4.04 (2H, m), 6.87-7.01 (3H, m), 7.32-7.39 (2H, m), 7.54-7.75 (1H, m)。
（１０３ｂ）　１，４－ジオキサン－２－イル［４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボラン－２－イル）－３，６－ジヒドロピリジン－１（２Ｈ）－イル］メタノン
　１，４－ジオキサン－２－カルボン酸（１．０２　ｇ）のジクロロメタン（３０　ｍＬ）溶液に４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボラン－２－イル）－１，２，３，６－テトラヒドロピリジン塩酸塩（１．７３　ｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（２．０２　ｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（０．９５８　ｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（３．６８　ｍＬ）を加えて室温で撹拌した。１２時間後、水を加えてジクロロメタンで抽出した。無水硫酸ナトリウムで乾燥後、ろ過、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（１．７８　ｇ）を無色油状物として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.22-1.28 (12H, m), 2.21-2.40 (2H, m), 3.44-4.36 (11H, m), 6.41-6.55 (1H, m)。
（１０３ｃ）　ｔｅｒｔ－ブチル　５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）－１，２，３，６－テトラヒドロピリジン－４－イル］ベンジル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　実施例（１０３ａ）で得られた化合物（４５３　ｍｇ）の１，２－ジメトキシエタン（８　ｍＬ）、水（４　ｍＬ）溶液に実施例（１０３ｂ）で得られた化合物（５４５　ｍｇ）、テトラキス（トリフェニルホスフィン）パラジウム（０）（６５．１　ｍｇ）、炭酸ナトリウム（２３９　ｍｇ）を加えて１００℃で１０時間撹拌した。室温まで冷却した後、酢酸エチルで抽出し、有機層を水及び飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、ろ過、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（５６１　ｍｇ）をアモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.45-1.61 (9H, m), 2.06 (3H, s), 2.47-2.71 (2H, m), 2.95-3.04 (2H, m), 3.62-4.40 (15H, m), 5.96-6.06 (1H, m), 6.92-7.04 (1H, m), 7.06-7.13 (2H, m), 7.22-7.24 (2H, m), 7.60-7.75 (1H, m)。
（１０３ｄ）　１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）ピペリジン－４－イル］ベンジル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（１０３ｃ）で得られた化合物（５６０　ｍｇ）の酢酸エチル（１０　ｍＬ）溶液に７．５％パラジウム炭素（５０．０　ｍｇ）を加えて水素雰囲気下室温で１２時間撹拌した。反応液をセライトろ過後、減圧濃縮することで粗製のｔｅｒｔ－ブチル　５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）ピペリジン－４－イル］ベンジル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート（５３４　ｍｇ）を得た。 (103a) tert-butyl 5- (4-bromobenzyl) -4-methyl-2,3-dihydro-1H-indole-1-carboxylate tert-butyl 4-methyl-5- (4,4,5,5 -Tetramethyl-1,3,2-dioxaboran-2-yl) -2,3-dihydro-1H-indole-1-carboxylate (900 mg) 1,2-dimethoxyethane (12 mL), water (6 1-bromo-4- (chloromethyl) benzene (618 mg), tetrakis (triphenylphosphine) palladium (0) (145 mg) and sodium carbonate (664 mg) were added to the solution, and the mixture was stirred at 100 ° C. for 10 hours. did. After cooling to room temperature, 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 (524 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.52-1.59 (9H, m), 2.04 (3H, s), 2.94-3.03 (2H, m), 3.89 (2H, s), 3.91-4.04 (2H m), 6.87-7.01 (3H, m), 7.32-7.39 (2H, m), 7.54-7.75 (1H, m).
(103b) 1,4-Dioxane-2-yl [4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) -3,6-dihydropyridine-1 (2H) -Yl] methanone To a solution of 1,4-dioxane-2-carboxylic acid (1.02 g) in dichloromethane (30 mL) was added 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane- 2-yl) -1,2,3,6-tetrahydropyridine hydrochloride (1.73 g), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (2.02 g), 3H— 1,2,3-Triazolo [4,5-b] pyridin-3-ol (0.958 g) and N, N-diisopropylethylamine (3.68 mL) were added and stirred at room temperature. After 12 hours, water was added and extracted with dichloromethane. 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 (1.78 g) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.22-1.28 (12H, m), 2.21-2.40 (2H, m), 3.44-4.36 (11H, m), 6.41-6.55 (1H, m).
(103c) tert-butyl 5- {4- [1- (1,4-dioxane-2-ylcarbonyl) -1,2,3,6-tetrahydropyridin-4-yl] benzyl} -4-methyl-2 , 3-Dihydro-1H-indole-1-carboxylate Example (103b) in a solution of the compound (453 mg) obtained in Example (103a) in 1,2-dimethoxyethane (8 mL) and water (4 mL). The compound (545 mg) obtained in (4), tetrakis (triphenylphosphine) palladium (0) (65.1 mg), and sodium carbonate (239 mg) were added, and the mixture was stirred at 100 ° C. for 10 hours. After cooling to room temperature, 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 (561 mg) as an amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.45-1.61 (9H, m), 2.06 (3H, s), 2.47-2.71 (2H, m), 2.95-3.04 (2H, m), 3.62-4.40 (15H, m), 5.96-6.06 (1H, m), 6.92-7.04 (1H, m), 7.06-7.13 (2H, m), 7.22-7.24 (2H, m), 7.60-7.75 (1H, m) .
(103d) 1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) piperidin-4-yl] benzyl} -4-methyl-2,3-dihydro-1H-indole-1 -Yl) -2- [2- (methylsulfonyl) phenyl] ethanone 7.5% palladium on carbon (50.0 mg) was added to a solution of the compound obtained in Example (103c) (560 mg) in ethyl acetate (10 mL). ) And stirred at room temperature under a hydrogen atmosphere for 12 hours. The reaction mixture was filtered through celite, and concentrated under reduced pressure to give crude tert-butyl 5- {4- [1- (1,4-dioxane-2-ylcarbonyl) piperidin-4-yl] benzyl} -4-methyl- 2,3-Dihydro-1H-indole-1-carboxylate (534 mg) was obtained.
　得られた化合物（５２８　ｍｇ）のジクロロメタン溶液（１０　ｍＬ）にトリフルオロ酢酸（２．５　ｍＬ）を加えて室温で撹拌した。３時間後、飽和重曹水で中和し、ジクロロメタンで抽出した。有機層を無水硫酸ナトリウムで乾燥後、ろ過、減圧濃縮することで粗製の１，４－ジオキサン－２－イル（４－｛４－［（４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）メチル］フェニル｝ピペリジン－１－イル）メタノンを得た。 Trifluoroacetic acid (2.5 mL) was added to a dichloromethane solution (10 mL) of the obtained compound (528 mg) and stirred at room temperature. After 3 hours, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 1,4-dioxane-2-yl (4- {4-[(4-methyl-2,3-dihydro-1H-indole- 5-yl) methyl] phenyl} piperidin-1-yl) methanone was obtained.
　得られた化合物（１９５　ｍｇ）のジクロロメタン（５　ｍＬ）溶液に［２－（メチルスルホニル）フェニル］酢酸（ＣＡＳ番号１４２３３６－２０－７）（１１９　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（１３３　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（６３．１　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．２４２　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム）で精製することで標記化合物（２４３　ｍｇ）を白色固体として得た。
1H-NMR (500 MHz, CDCl3) δ: 1.54-1.74 (2H, m), 1.83-1.95 (2H, m), 2.09-2.16 (3H, m), 2.58-2.76 (2H, m), 3.00-3.22 (5H, m), 3.62-3.95 (8H, m), 4.08-4.15 (2H, m), 4.20-4.27 (2H, m), 4.27-4.38 (3H, m), 4.66-4.74 (1H, m), 6.96-7.01 (1H, m), 7.03-7.12 (4H, m), 7.34-7.38 (1H, m), 7.49-7.55 (1H, m), 7.58-7.64 (1H, m), 7.93-7.98 (1H, m), 8.05-8.10 (1H, m).
MS (APCI) m/z: 617 (M+H)+。 To a solution of the obtained compound (195 mg) in dichloromethane (5 mL), [2- (methylsulfonyl) phenyl] acetic acid (CAS No. 142336-20-7) (119 mg), 1-ethyl-3- (3-dimethyl Aminopropyl) carboximide hydrochloride (133 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (63.1 mg), N, N-diisopropylethylamine (0.242) mL) was 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 (ethyl acetate / chloroform) to obtain the title compound (243 mg) as a white solid.
1 H-NMR (500 MHz, CDCl 3 ) δ: 1.54-1.74 (2H, m), 1.83-1.95 (2H, m), 2.09-2.16 (3H, m), 2.58-2.76 (2H, m), 3.00 -3.22 (5H, m), 3.62-3.95 (8H, m), 4.08-4.15 (2H, m), 4.20-4.27 (2H, m), 4.27-4.38 (3H, m), 4.66-4.74 (1H, m), 6.96-7.01 (1H, m), 7.03-7.12 (4H, m), 7.34-7.38 (1H, m), 7.49-7.55 (1H, m), 7.58-7.64 (1H, m), 7.93- 7.98 (1H, m), 8.05-8.10 (1H, m).
MS (APCI) m / z: 617 (M + H) + .
　（実施例１０４）
１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）ピペリジン－４－イル］ベンジル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（エチルスルホニル）フェニル］エタノン (Example 104)
1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) piperidin-4-yl] benzyl} -4-methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (Ethylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000146
Figure JPOXMLDOC01-appb-C000146
　実施例（１０３ｄ）で得られた１，４－ジオキサン－２－イル（４－｛４－［（４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）メチル］フェニル｝ピペリジン－１－イル）メタノン（２００　ｍｇ）のジクロロメタン（５　ｍＬ）溶液に［２－（エチルスルホニル）フェニル］酢酸（ＣＡＳ番号１３６３１７９－４７－８）（１３０　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（１３７　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（６４．７　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．２４９　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム）で精製することで標記化合物（２５６　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (500 MHz, CDCl3) δ: 1.21-1.28 (3H, m), 1.52-1.75 (2H, m), 1.83-1.94 (2H, m), 2.09-2.16 (4H, m), 2.58-2.76 (2H, m), 3.00-3.24 (4H, m), 3.66-3.97 (8H, m), 4.07-4.15 (1H, m), 4.19-4.25 (2H, m), 4.28-4.39 (3H, m), 4.66-4.74 (1H, m), 6.97-7.01 (1H, m), 7.03-7.12 (4H, m), 7.37-7.41 (1H, m), 7.47-7.53 (1H, m), 7.59-7.64 (1H, m), 7.93-7.97 (1H, m), 8.01-8.05 (1H, m).
MS (APCI) m/z: 631 (M+H)+。 1,4-Dioxan-2-yl (4- {4-[(4-methyl-2,3-dihydro-1H-indol-5-yl) methyl] phenyl} piperidine- obtained in Example (103d) To a solution of 1-yl) methanone (200 mg) in dichloromethane (5 mL), [2- (ethylsulfonyl) phenyl] acetic acid (CAS No. 1363179-47-8) (130 mg), 1-ethyl-3- (3- Dimethylaminopropyl) carboximide hydrochloride (137 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (64.7 mg), N, N-diisopropylethylamine (0. (249 mL) was 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 (ethyl acetate / chloroform) to obtain the title compound (256 mg) as a white amorphous solid.
1 H-NMR (500 MHz, CDCl 3 ) δ: 1.21-1.28 (3H, m), 1.52-1.75 (2H, m), 1.83-1.94 (2H, m), 2.09-2.16 (4H, m), 2.58 -2.76 (2H, m), 3.00-3.24 (4H, m), 3.66-3.97 (8H, m), 4.07-4.15 (1H, m), 4.19-4.25 (2H, m), 4.28-4.39 (3H, m), 4.66-4.74 (1H, m), 6.97-7.01 (1H, m), 7.03-7.12 (4H, m), 7.37-7.41 (1H, m), 7.47-7.53 (1H, m), 7.59- 7.64 (1H, m), 7.93-7.97 (1H, m), 8.01-8.05 (1H, m).
MS (APCI) m / z: 631 (M + H) + .
　（実施例１０５）：実施例（１０５ｄ）で合成
１－｛５－［４－（４－アセチルピペラジン－１－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン Example 105: synthesized in Example (105d) 1- {5- [4- (4-acetylpiperazin-1-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indole-1- Yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000147
Figure JPOXMLDOC01-appb-C000147
（１０５ａ）　ｔｅｒｔ－ブチル　５－（４－｛４－［（ベンジルオキシ）カルボニル］ピペラジン－１－イル｝フェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　ベンジル　４－（４－ブロモフェニル）ピペラジン－１－カルボキシレート（ＣＡＳ番号１１５０２７１－３３－２）（２　ｇ）の１，４－ジオキサン溶液にｔｅｒｔ－ブチル　５－ヒドロキシ－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート（１．３３　ｇ）、ヨウ化銅（Ｉ）（２０３　ｍｇ）、Ｎ，Ｎ－ジメチルグリシン（２１９　ｍｇ）及び炭酸セシウム（３．４７　ｇ）を加え、１００℃で１２時間撹拌した。反応液を室温まで冷却し、セライトろ過した。ろ液を減圧下で濃縮し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（７７３　ｍｇ）をアモルファス固体として得た。
1H-NMR (500 MHz, CDCl3) δ: 1.51-1.59 (9H, m), 2.09 (3H, s), 2.98-3.09 (6H, m), 3.63-3.69 (4H, m), 3.96-4.07 (2H, m), 5.16 (2H, s), 6.67-6.77 (1H, m), 6.77-6.89 (4H, m), 7.18-7.27 (1H, m), 7.29-7.40 (4H, m), 7.58-7.68 (1H, m)。
（１０５ｂ）　ベンジル　４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペラジン－１－カルボキシレート
　実施例（１０５ａ）で得られた化合物（７７０　ｍｇ）に４Ｎ塩酸ジオキサン溶液（５　ｍＬ）を加え、室温で撹拌した。３時間後、反応液を濃縮することで粗製のベンジル　４－｛４－［（４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペラジン－１－カルボキシレート塩酸塩を得た。 (105a) tert-butyl 5- (4- {4-[(benzyloxy) carbonyl] piperazin-1-yl} phenoxy) -4-methyl-2,3-dihydro-1H-indole-1-carboxylate benzyl 4 To a 1,4-dioxane solution of-(4-bromophenyl) piperazine-1-carboxylate (CAS No. 1150271-33-2) (2 g) in tert-butyl 5-hydroxy-4-methyl-2,3-dihydro -1H-indole-1-carboxylate (1.33 g), copper (I) iodide (203 mg), N, N-dimethylglycine (219 mg) and cesium carbonate (3.47 g) were added. Stir at 12 ° C. for 12 hours. The reaction was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (773 mg) as an amorphous solid.
1 H-NMR (500 MHz, CDCl 3 ) δ: 1.51-1.59 (9H, m), 2.09 (3H, s), 2.98-3.09 (6H, m), 3.63-3.69 (4H, m), 3.96-4.07 (2H, m), 5.16 (2H, s), 6.67-6.77 (1H, m), 6.77-6.89 (4H, m), 7.18-7.27 (1H, m), 7.29-7.40 (4H, m), 7.58 -7.68 (1H, m).
(105b) Benzyl 4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperazine- 1-Carboxylate 4N Hydrochloric acid dioxane solution (5 mL) was added to the compound (770 mg) obtained in Example (105a), and the mixture was stirred at room temperature. After 3 hours, the reaction mixture was concentrated to give crude benzyl 4- {4-[(4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperazine-1-carboxylate hydrochloride Salt was obtained.
　得られた化合物のジクロロメタン溶液に［２－（メチルスルホニル）フェニル］酢酸（ＣＡＳ番号１４２３３６－２０－７）（３３２　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（４０５　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（１９２　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．７３７　ｍＬ）を加えて室温で撹拌した。１２時間後、水を加えて酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥後、ろ過、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（５２０　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.14 (3H, s), 2.99-3.12 (7H, m), 3.16-3.24 (2H, m), 3.62-3.69 (4H, m), 4.24-4.30 (2H, m), 4.36 (2H, s), 5.16 (2H, s), 6.67-6.72 (1H, m), 6.80-6.90 (4H, m), 7.30-7.40 (6H, m), 7.48-7.55 (1H, m), 7.58-7.64 (1H, m), 7.91-7.96 (1H, m), 8.04-8.09 (1H, m)。
（１０５ｃ）　１－｛４－メチル－５－［４－（ピペラジン－１－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（１０５ｂ）で得られた化合物（２００　ｍｇ）のメタノール（８　ｍＬ）、ジクロロメタン（４　ｍＬ）、酢酸（０．４　ｍＬ）溶液に７．５％パラジウム炭素（１００　ｍｇ）を加えて水素雰囲気下、室温で撹拌した。５時間後、反応液をセライトろ過、減圧濃縮した。残渣をアミノシリカゲルクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（１２５　ｍｇ）を無色油状物として得た。
MS (APCI) m/z: 506 (M+H)+。
（１０５ｄ）　１－｛５－［４－（４－アセチルピペラジン－１－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（１０５ｃ）で合成した化合物（７０．０　ｍｇ）のピリジン（０．８　ｍＬ）溶液に無水酢酸（０．０６５　ｍＬ）を加えて室温で撹拌した。２時間後、水を加えて酢酸エチルで抽出した。有機層を塩酸で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム）で精製することで標記化合物（６６　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.14 (3H, s), 2.15 (3H, s), 3.03-3.13 (7H, m), 3.18-3.24 (2H, m), 3.59-3.64 (2H, m), 3.74-3.79 (2H, m), 4.25-4.30 (2H, m), 4.36 (2H, s), 6.69-6.73 (1H, m), 6.82-6.91 (4H, m), 7.34-7.38 (1H, m), 7.49-7.55 (1H, m), 7.59-7.64 (1H, m), 7.92-7.96 (1H, m), 8.05-8.09 (1H, m).
MS (APCI) m/z: 548 (M+H)+。 To the dichloromethane solution of the obtained compound, [2- (methylsulfonyl) phenyl] acetic acid (CAS No. 142336-20-7) (332 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride ( 405 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (192 mg) and N, N-diisopropylethylamine (0.737 mL) were added and stirred at room temperature. After 12 hours, water was added and extracted with ethyl acetate. The organic layer was dried over 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 (520 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.14 (3H, s), 2.99-3.12 (7H, m), 3.16-3.24 (2H, m), 3.62-3.69 (4H, m), 4.24-4.30 (2H, m), 4.36 (2H, s), 5.16 (2H, s), 6.67-6.72 (1H, m), 6.80-6.90 (4H, m), 7.30-7.40 (6H, m), 7.48-7.55 (1H, m), 7.58-7.64 (1H, m), 7.91-7.96 (1H, m), 8.04-8.09 (1H, m).
(105c) 1- {4-Methyl-5- [4- (piperazin-1-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl Ethanone 7.5% palladium on carbon (100 mg) was added to a solution of the compound (200 mg) obtained in Example (105b) in methanol (8 mL), dichloromethane (4 mL), and acetic acid (0.4 mL). And stirred at room temperature under a hydrogen atmosphere. After 5 hours, the reaction solution was filtered through Celite and concentrated under reduced pressure. The residue was purified by amino silica gel chromatography (ethyl acetate / hexane) to give the title compound (125 mg) as a colorless oil.
MS (APCI) m / z: 506 (M + H) + .
(105d) 1- {5- [4- (4-Acetylpiperazin-1-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methyl (Sulfonyl) phenyl] ethanone Acetic anhydride (0.065 mL) was added to a solution of the compound synthesized in Example (105c) (70.0 mg) in pyridine (0.8 mL) and stirred at room temperature. After 2 hours, water was added and extracted with ethyl acetate. The organic layer was washed with hydrochloric acid, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / chloroform) to obtain the title compound (66 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.14 (3H, s), 2.15 (3H, s), 3.03-3.13 (7H, m), 3.18-3.24 (2H, m), 3.59-3.64 (2H , m), 3.74-3.79 (2H, m), 4.25-4.30 (2H, m), 4.36 (2H, s), 6.69-6.73 (1H, m), 6.82-6.91 (4H, m), 7.34-7.38 (1H, m), 7.49-7.55 (1H, m), 7.59-7.64 (1H, m), 7.92-7.96 (1H, m), 8.05-8.09 (1H, m).
MS (APCI) m / z: 548 (M + H) + .
　（実施例１０６）
１－（５－｛４－［４－（１，４－ジオキサン－２－イルカルボニル）ピペラジン－１－イル］フェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン (Example 106)
1- (5- {4- [4- (1,4-Dioxane-2-ylcarbonyl) piperazin-1-yl] phenoxy} -4-methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- (Methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000148
Figure JPOXMLDOC01-appb-C000148
　実施例（１０５ｃ）で得られた化合物（５０．０　ｍｇ）のジクロロメタン（２　ｍＬ）溶液に１，４－ジオキサン－２－カルボン酸（ＣＡＳ番号８９３６４－４１－０）（１５　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（２８　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（０．０５２　ｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．０５１６　ｍＬ）を加えて室温で終夜撹拌した。反応液を濃縮後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム）で精製することで標記化合物（５６．０　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.15 (3H, s), 2.99-3.15 (7H, m), 3.17-3.25 (2H, m), 3.60-3.90 (9H, m), 3.92-3.98 (1H, m), 4.24-4.34 (3H, m), 4.36 (2H, s), 6.68-6.73 (1H, m), 6.81-6.91 (4H, m), 7.34-7.39 (1H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.92-7.97 (1H, m), 8.05-8.10 (1H, m).
MS (APCI) m/z: 620 (M+H)+。 To a solution of the compound (50.0 mg) obtained in Example (105c) in dichloromethane (2 mL) was added 1,4-dioxane-2-carboxylic acid (CAS number 89364-41-0) (15 mg), 1- Ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (28 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (0.052 g), N, N-diisopropylethylamine (0.0516 mL) was added and stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / chloroform) to give the title compound (56.0 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.15 (3H, s), 2.99-3.15 (7H, m), 3.17-3.25 (2H, m), 3.60-3.90 (9H, m), 3.92-3.98 (1H, m), 4.24-4.34 (3H, m), 4.36 (2H, s), 6.68-6.73 (1H, m), 6.81-6.91 (4H, m), 7.34-7.39 (1H, m), 7.49 -7.55 (1H, m), 7.59-7.65 (1H, m), 7.92-7.97 (1H, m), 8.05-8.10 (1H, m).
MS (APCI) m / z: 620 (M + H) + .
　（実施例１０７）
　（実施例１０７－１）：実施例（１０７ａ）で合成
２－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２,３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペラジン－１－イル）－２－オキソエチル アセテート (Example 107)
Example 107-1: Synthesis in Example (107a) 2- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro- 1H-Indol-5-yl) oxy] phenyl} piperazin-1-yl) -2-oxoethyl acetate
Figure JPOXMLDOC01-appb-C000149
Figure JPOXMLDOC01-appb-C000149
　（実施例１０７－２）：実施例（１０７ｂ）で合成
２－ヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペラジン－１－イル）エタノン Example 107-2: synthesized in Example (107b) 2-hydroxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2, 3-Dihydro-1H-indol-5-yl) oxy] phenyl} piperazin-1-yl) ethanone
Figure JPOXMLDOC01-appb-C000150
Figure JPOXMLDOC01-appb-C000150
（１０７ａ）　２－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２,３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペラジン－１－イル）－２－オキソエチル アセテート
　実施例（１０５ｃ）で得られた化合物（２１０　ｍｇ）のジクロロメタン（４　ｍＬ）溶液に（アセチルオキシ）酢酸（ＣＡＳ番号１３８３１－３０－６）（５８．０　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（１１９　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（５６．０　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１６１　ｍＬ）を加えて室温で終夜撹拌した。反応液を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム）で精製することで標記化合物（１９２　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.14 (3H, s), 2.20 (3H, s), 3.03-3.14 (7H, m), 3.17-3.25 (2H, m), 3.51-3.58 (2H, m), 3.73-3.81 (2H, m), 4.24-4.31 (2H, m), 4.36 (2H, s), 4.77 (2H, s), 6.68-6.74 (1H, m), 6.81-6.91 (4H, m), 7.33-7.38 (1H, m), 7.48-7.55 (1H, m), 7.58-7.65 (1H, m), 7.91-7.97 (1H, m), 8.04-8.10 (1H, m)。
（１０７ｂ）　２－ヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペラジン－１－イル）エタノン
　実施例（１０７ａ）で得られた化合物（１８８　ｍｇ）のメタノール（２　ｍＬ）溶液に炭酸カリウム（２１４　ｍｇ）を加えて室温で５時間撹拌した。反応液を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム）で精製することで標記化合物（１３９　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.14 (3H, s), 3.06-3.13 (7H, m), 3.18-3.25 (2H, m), 3.40-3.46 (2H, m), 3.60-3.65 (1H, m), 3.80-3.86 (2H, m), 4.20-4.23 (2H, m), 4.25-4.31 (2H, m), 4.36 (2H, s), 6.69-6.73 (1H, m), 6.82-6.92 (4H, m), 7.34-7.39 (1H, m), 7.59-7.65 (1H, m), 7.59-7.65 (1H, m), 7.93-7.97 (1H, m), 8.05-8.10 (1H, m).
MS (APCI) m/z: 564 (M+H)+。 (107a) 2- (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} Piperazin-1-yl) -2-oxoethyl acetate To a solution of the compound (210 mg) obtained in Example (105c) in dichloromethane (4 mL) was added (acetyloxy) acetic acid (CAS No.13831-30-6) (58. 0 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (119 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (56. 0 mg) and N, N-diisopropylethylamine (0.161 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / chloroform) to obtain the title compound (192 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.14 (3H, s), 2.20 (3H, s), 3.03-3.14 (7H, m), 3.17-3.25 (2H, m), 3.51-3.58 (2H , m), 3.73-3.81 (2H, m), 4.24-4.31 (2H, m), 4.36 (2H, s), 4.77 (2H, s), 6.68-6.74 (1H, m), 6.81-6.91 (4H , m), 7.33-7.38 (1H, m), 7.48-7.55 (1H, m), 7.58-7.65 (1H, m), 7.91-7.97 (1H, m), 8.04-8.10 (1H, m).
(107b) 2-hydroxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) Oxy] phenyl} piperazin-1-yl) ethanone To a solution of the compound obtained in Example (107a) (188 mg) in methanol (2 mL) was added potassium carbonate (214 mg), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (methanol / chloroform) to obtain the title compound (139 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.14 (3H, s), 3.06-3.13 (7H, m), 3.18-3.25 (2H, m), 3.40-3.46 (2H, m), 3.60-3.65 (1H, m), 3.80-3.86 (2H, m), 4.20-4.23 (2H, m), 4.25-4.31 (2H, m), 4.36 (2H, s), 6.69-6.73 (1H, m), 6.82 -6.92 (4H, m), 7.34-7.39 (1H, m), 7.59-7.65 (1H, m), 7.59-7.65 (1H, m), 7.93-7.97 (1H, m), 8.05-8.10 (1H, m).
MS (APCI) m / z: 564 (M + H) + .
　（実施例１０８）：実施例（１０８ｂ）で合成
１－｛５－［４－（４－｛［（２Ｓ）－４，４－ジフルオロピロリジン－２－イル］カルボニル｝ピペラジン－１－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン塩酸塩 Example 108: Synthesis in Example (108b) 1- {5- [4- (4-{[(2S) -4,4-difluoropyrrolidin-2-yl] carbonyl} piperazin-1-yl) phenoxy ] -4-Methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone hydrochloride
Figure JPOXMLDOC01-appb-C000151
Figure JPOXMLDOC01-appb-C000151
（１０８ａ）　ｔｅｒｔ－ブチル　（２Ｓ）－４，４－ジフルオロ－２－［（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペラジン－１－イル）カルボニル］ピロリジン－１－カルボキシレート
　実施例（１０５ｃ）で得られた化合物（２９９　ｍｇ）にジクロロメタン（４　ｍＬ）、１－（ｔｅｒｔ－ブトキシカルボニル）－４，４－ジフルオロ－Ｌ－プロリン（ＣＡＳ番号２０３８６６－１５－３）（１７８　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（１７０　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（８０．５　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．３０９　ｍＬ）を加えて室温で終夜撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム）で精製することで標記化合物（４０７　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.59 (9H, s), 2.15 (3H, s), 2.29-2.50 (1H, m), 2.58-2.76 (1H, m), 3.00-3.27 (8H, m), 3.57-3.68 (2H, m), 3.72-4.02 (4H, m), 4.23-4.32 (2H, m), 4.36 (2H, s), 4.75-4.82 (1H, m), 4.87-4.95 (1H, m), 6.68-6.73 (1H, m), 6.81-6.91 (4H, m), 7.33-7.38 (1H, m), 7.49-7.55 (1H, m), 7.58-7.65 (1H, m), 7.91-7.97 (1H, m), 8.04-8.09 (1H, m)。
（１０８ｂ）　１－｛５－［４－（４－｛［（２Ｓ）－４，４－ジフルオロピロリジン－２－イル］カルボニル｝ピペラジン－１－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン塩酸塩
　実施例（１０８ａ）で得られた化合物（４０２　ｍｇ）の１，４－ジオキサン（３　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（５　ｍＬ）を加え、室温で撹拌した。３時間後、反応液を減圧濃縮した。残渣にアセトンを添加し、析出した固体をろ取、乾燥することで標記化合物（３４５　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CD3OD) δ: 2.09 (3H, s), 2.66-2.81 (1H, m), 3.09-3.16 (4H, m), 3.17-3.31 (3H, m), 3.59-3.78 (4H, m), 3.77-4.22 (6H, m), 4.31-4.40 (4H, m), 5.12-5.21 (1H, m), 6.73-6.79 (1H, m), 6.97-7.04 (2H, m), 7.45-7.51 (1H, m), 7.55-7.63 (3H, m), 7.65-7.72 (1H, m), 7.91-7.97 (1H, m), 8.03-8.08 (1H, m).
MS (APCI) m/z: 639 (M+H)+。 (108a) tert-butyl (2S) -4,4-difluoro-2-[(4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3- Dihydro-1H-indol-5-yl) oxy] phenyl} piperazin-1-yl) carbonyl] pyrrolidine-1-carboxylate The compound (299 mg) obtained in Example (105c) was added to dichloromethane (4 mL), 1 -(Tert-butoxycarbonyl) -4,4-difluoro-L-proline (CAS No. 203866-15-3) (178 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (170 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (80.5 mg), N, N-diisopropyl Was stirred overnight at room temperature by addition of ethylamine (0.309 mL). The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / chloroform) to obtain the title compound (407 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.59 (9H, s), 2.15 (3H, s), 2.29-2.50 (1H, m), 2.58-2.76 (1H, m), 3.00-3.27 (8H , m), 3.57-3.68 (2H, m), 3.72-4.02 (4H, m), 4.23-4.32 (2H, m), 4.36 (2H, s), 4.75-4.82 (1H, m), 4.87-4.95 (1H, m), 6.68-6.73 (1H, m), 6.81-6.91 (4H, m), 7.33-7.38 (1H, m), 7.49-7.55 (1H, m), 7.58-7.65 (1H, m) , 7.91-7.97 (1H, m), 8.04-8.09 (1H, m).
(108b) 1- {5- [4- (4-{[(2S) -4,4-Difluoropyrrolidin-2-yl] carbonyl} piperazin-1-yl) phenoxy] -4-methyl-2,3- Dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone hydrochloride A solution of the compound obtained in Example (108a) (402 mg) in 1,4-dioxane (3 mL) Was added 4N dioxane hydrochloride solution (5 mL) and stirred at room temperature. After 3 hours, the reaction solution was concentrated under reduced pressure. Acetone was added to the residue, and the precipitated solid was collected by filtration and dried to obtain the title compound (345 mg) as a white solid.
1 H-NMR (400 MHz, CD 3 OD) δ: 2.09 (3H, s), 2.66-2.81 (1H, m), 3.09-3.16 (4H, m), 3.17-3.31 (3H, m), 3.59- 3.78 (4H, m), 3.77-4.22 (6H, m), 4.31-4.40 (4H, m), 5.12-5.21 (1H, m), 6.73-6.79 (1H, m), 6.97-7.04 (2H, m ), 7.45-7.51 (1H, m), 7.55-7.63 (3H, m), 7.65-7.72 (1H, m), 7.91-7.97 (1H, m), 8.03-8.08 (1H, m).
MS (APCI) m / z: 639 (M + H) + .
　（実施例１０９）
１－｛５－［４－（４－｛［（２Ｓ）－１－アセチル－４，４－ジフルオロピロリジン－２－イル］カルボニル｝ピペラジン－１－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン (Example 109)
1- {5- [4- (4-{[(2S) -1-acetyl-4,4-difluoropyrrolidin-2-yl] carbonyl} piperazin-1-yl) phenoxy] -4-methyl-2,3 -Dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000152
Figure JPOXMLDOC01-appb-C000152
　実施例（１０８ｂ）で得られた化合物（８４．０　ｍｇ）のピリジン（１　ｍＬ）溶液に無水酢酸（０．０５９　ｍＬ）を加えて室温で２時間撹拌した。反応液に水を加えた後、酢酸エチルで抽出した。有機層を塩酸で洗浄した後、無水硫酸ナトリウムで乾燥し、ろ過、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム）で精製することで標記化合物（６７．０　ｍｇ）を白色固体として得た。
1H-NMR (500 MHz, CDCl3) δ: 2.09 (3H, s), 2.15 (3H, s), 2.42-2.56 (1H, m), 2.59-2.71 (1H, m), 3.03-3.15 (6H, m), 3.15-3.29 (3H, m), 3.61-3.72 (2H, m), 3.83-3.97 (3H, m), 4.01-4.13 (1H, m), 4.24-4.31 (2H, m), 4.36 (2H, s), 5.04-5.11 (1H, m), 6.68-6.72 (1H, m), 6.81-6.91 (4H, m), 7.34-7.38 (1H, m), 7.49-7.54 (1H, m), 7.59-7.64 (1H, m), 7.92-7.97 (1H, m), 8.05-8.09 (1H, m).
MS (APCI) m/z: 681 (M+H)+。 Acetic anhydride (0.059 mL) was added to a solution of the compound (84.0 mg) obtained in Example (108b) in pyridine (1 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with hydrochloric acid, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / chloroform) to obtain the title compound (67.0 mg) as a white solid.
1 H-NMR (500 MHz, CDCl 3 ) δ: 2.09 (3H, s), 2.15 (3H, s), 2.42-2.56 (1H, m), 2.59-2.71 (1H, m), 3.03-3.15 (6H , m), 3.15-3.29 (3H, m), 3.61-3.72 (2H, m), 3.83-3.97 (3H, m), 4.01-4.13 (1H, m), 4.24-4.31 (2H, m), 4.36 (2H, s), 5.04-5.11 (1H, m), 6.68-6.72 (1H, m), 6.81-6.91 (4H, m), 7.34-7.38 (1H, m), 7.49-7.54 (1H, m) , 7.59-7.64 (1H, m), 7.92-7.97 (1H, m), 8.05-8.09 (1H, m).
MS (APCI) m / z: 681 (M + H) + .
　（実施例１１０）
１－｛５－［４－（４－｛［（２Ｓ）－４，４－ジフルオロ－１－メチルピロリジン－２－イル］カルボニル｝ピペラジン－１－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン (Example 110)
1- {5- [4- (4-{[(2S) -4,4-difluoro-1-methylpyrrolidin-2-yl] carbonyl} piperazin-1-yl) phenoxy] -4-methyl-2,3 -Dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000153
Figure JPOXMLDOC01-appb-C000153
　実施例（１０８ｂ）で得られた化合物（１４３　ｍｇ）のメタノール（２　ｍＬ）溶液にホルムアルデヒド液（３７％）（０．３　ｍＬ）、７．５％パラジウム炭素（２０．０　ｍｇ）、１２Ｎ塩酸（０．１０　ｍＬ）、を加えて水素雰囲気下１０時間撹拌した。反応液をセライトでろ過し、減圧濃縮した。残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム）で精製することで標記化合物（７３．０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.15 (3H, s), 2.39 (3H, s), 2.44-2.61 (1H, m), 2.63-2.77 (1H, m), 2.99-3.17 (8H, m), 3.17-3.25 (2H, m), 3.46-3.58 (2H, m), 3.68-3.81 (2H, m), 3.82-3.94 (2H, m), 4.23-4.32 (2H, m), 4.36 (2H, s), 6.68-6.73 (1H, m), 6.81-6.93 (4H, m), 7.33-7.39 (1H, m), 7.49-7.56 (1H, m), 7.59-7.66 (1H, m), 7.92-7.97 (1H, m), 8.05-8.11 (1H, m).
MS (APCI) m/z: 653 (M+H)+。 A solution of the compound (143 mg) obtained in Example (108b) in methanol (2 mL) was added to formaldehyde solution (37%) (0.3 mL), 7.5% palladium carbon (20.0 mg), 12N hydrochloric acid. (0.10 mL) was added and stirred under a hydrogen atmosphere for 10 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (ethyl acetate / chloroform) to obtain the title compound (73.0 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.15 (3H, s), 2.39 (3H, s), 2.44-2.61 (1H, m), 2.63-2.77 (1H, m), 2.99-3.17 (8H , m), 3.17-3.25 (2H, m), 3.46-3.58 (2H, m), 3.68-3.81 (2H, m), 3.82-3.94 (2H, m), 4.23-4.32 (2H, m), 4.36 (2H, s), 6.68-6.73 (1H, m), 6.81-6.93 (4H, m), 7.33-7.39 (1H, m), 7.49-7.56 (1H, m), 7.59-7.66 (1H, m) , 7.92-7.97 (1H, m), 8.05-8.11 (1H, m).
MS (APCI) m / z: 653 (M + H) + .
　（実施例１１１）：実施例（１１１ｂ）で合成
１－｛５－［４－（４－アセチルピペラジン－１－イル）－３－メチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン Example 111: Synthesis in Example (111b) 1- {5- [4- (4-acetylpiperazin-1-yl) -3-methylphenoxy] -4-methyl-2,3-dihydro-1H- Indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000154
Figure JPOXMLDOC01-appb-C000154
（１１１ａ）　ｔｅｒｔ－ブチル　４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペラジン－１－カルボキシレート
　実施例（３ｂ）で合成した化合物（２００　ｍｇ）のトルエン溶液にｔｅｒｔ－ブチル　ピペラジン－１－カルボキシレート（８６．０　ｍｇ）、ジシクロヘキシル［２’，４’，６’－トリ（プロパン－２－イル）ビフェニル－２－イル］ホスファン（１８．０　ｍｇ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（１７．０　ｍｇ）、ナトリウム　ｔｅｒｔ－ブトキシド（１１２　ｍｇ）を加えて１００℃で１０時間撹拌した。室温に冷却後、ろ過、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）によって精製することで標記化合物（１２２　ｍｇ）を淡黄色固体として得た。
MS (APCI) m/z: 620 (M+H)+。
（１１１ｂ）　１－｛５－［４－（４－アセチルピペラジン－１－イル）－３－メチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（１１１ａ）で得られた化合物（１２０　ｍｇ）のジクロロメタン（１　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（１．５　ｍＬ）を加え室温で撹拌した。２時間後、減圧濃縮することで粗製の１－｛４－メチル－５－［３－メチル－４－（ピペラジン－１－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン塩酸塩を固体として得た。 (111a) tert-butyl 4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) Oxy] phenyl} piperazine-1-carboxylate To a toluene solution of the compound synthesized in Example (3b) (200 mg), tert-butyl piperazine-1-carboxylate (86.0 mg), dicyclohexyl [2 ′, 4 ′ , 6′-tri (propan-2-yl) biphenyl-2-yl] phosphane (18.0 mg), tris (dibenzylideneacetone) dipalladium (0) (17.0 mg), sodium tert-butoxide (112 mg) and the mixture was stirred at 100 ° C. for 10 hours. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (122 mg) as a pale yellow solid.
MS (APCI) m / z: 620 (M + H) + .
(111b) 1- {5- [4- (4-Acetylpiperazin-1-yl) -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 (111a) (120 mg) in dichloromethane (1 mL) was added 4N hydrochloric acid dioxane solution (1.5 mL), and the mixture was stirred at room temperature. After 2 hours, crude 1- {4-methyl-5- [3-methyl-4- (piperazin-1-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl was concentrated by concentration under reduced pressure. } -2- [2- (Methylsulfonyl) phenyl] ethanone hydrochloride was obtained as a solid.
　得られた化合物のジクロロメタン（１　ｍＬ）溶液にピリジン（１　ｍＬ）、無水酢酸（０．０９１　ｍＬ）を加えて室温で２時間撹拌した。水を加えてクロロホルムで抽出した後、有機層を塩酸で洗浄し、硫酸ナトリウムで乾燥し、ろ過、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム）によって精製することで標記化合物（８５．０　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.14 (6H, s), 2.28 (3H, s), 2.78-2.88 (4H, m), 3.12 (3H, s), 3.17-3.25 (2H, m), 3.56-3.62 (2H, m), 3.70-3.78 (2H, m), 4.24-4.32 (2H, m), 4.36 (2H, s), 6.64-6.70 (1H, m), 6.71-6.77 (2H, m), 6.88-6.92 (1H, m), 7.34-7.38 (1H, m), 7.49-7.55 (1H, m), 7.58-7.65 (1H, m), 7.93-7.98 (1H, m), 8.05-8.09 (1H, m).
MS (APCI) m/z: 562 (M+H)+。 To a solution of the obtained compound in dichloromethane (1 mL), pyridine (1 mL) and acetic anhydride (0.091 mL) were added and stirred at room temperature for 2 hours. After adding water and extracting with chloroform, the organic layer was washed with hydrochloric acid, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / chloroform) to obtain the title compound (85.0 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.14 (6H, s), 2.28 (3H, s), 2.78-2.88 (4H, m), 3.12 (3H, s), 3.17-3.25 (2H, m ), 3.56-3.62 (2H, m), 3.70-3.78 (2H, m), 4.24-4.32 (2H, m), 4.36 (2H, s), 6.64-6.70 (1H, m), 6.71-6.77 (2H , m), 6.88-6.92 (1H, m), 7.34-7.38 (1H, m), 7.49-7.55 (1H, m), 7.58-7.65 (1H, m), 7.93-7.98 (1H, m), 8.05 -8.09 (1H, m).
MS (APCI) m / z: 562 (M + H) + .
　（実施例１１２）：実施例（１１２ｂ）で合成
１－｛５－［４－（４－アセチルピペラジン－１－イル）－３－メチルフェノキシ］４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン Example 112: synthesized in Example (112b) 1- {5- [4- (4-acetylpiperazin-1-yl) -3-methylphenoxy] 4-methyl-2,3-dihydro-1H-indole -1-yl} -2- [2- (ethylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000155
Figure JPOXMLDOC01-appb-C000155
（１１２ａ）　ｔｅｒｔ－ブチル　４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］－２－メチルフェニル｝ピペラジン－１－カルボキシレート
　実施例（１ｂ）と同様の手法により合成した１－［５－（４－ブロモフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（エチルスルホニル）フェニル］エタノン（５４８　ｍｇ）にｔｅｒｔ－ブチル　ピペラジン－１－カルボキシレート（２３１　ｍｇ）、ナトリウム　ｔｅｒｔ－ブトキシド（２９８　ｍｇ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（４７．０　ｍｇ）、２－（ジシクロヘキシルホスフィノ）－２’，４’，６’－トリイソプロピル－１，１’－ビフェニル（４９．０　ｍｇ）、トルエン（５　ｍＬ）を加えて１００℃で１０時間撹拌した。室温まで冷却後、ろ過及び減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（３２８　ｍｇ）を淡黄色油状物として得た。
MS (APCI) m/z: 634 (M+H)+。
（１１２ｂ）　１－｛５－［４－（４－アセチルピペラジン－１－イル）－３－メチルフェノキシ］４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン
　実施例（１１２ａ）で得られた化合物（３２７　ｍｇ）のジクロロメタン溶液に４Ｎ塩酸ジオキサン溶液（４　ｍＬ）を加えて室温で撹拌した。３時間後、減圧濃縮することで粗製の２－［２－（エチルスルホニル）フェニル］－１－｛４－メチル－５－［３－メチル－４－（ピペラジン－１－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝エタノン塩酸塩を淡黄色固体として得た。 (112a) tert-butyl 4- {4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -2 -Methylphenyl} piperazine-1-carboxylate 1- [5- (4-Bromophenoxy) -4-methyl-2,3-dihydro-1H-indole-1- synthesized by the same method as in Example (1b) Yl] -2- [2- (ethylsulfonyl) phenyl] ethanone (548 mg) to tert-butyl piperazine-1-carboxylate (231 mg), sodium tert-butoxide (298 mg), tris (dibenzylideneacetone) di Palladium (0) (47.0 mg), 2- (dicyclohexylphosphino) -2 ′, 4 ′, 6′-triisopropyl 1,1'-biphenyl (49.0 mg), and stirred for 10 hours at 100 ° C. with toluene (5 mL). After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (328 mg) as a pale yellow oil.
MS (APCI) m / z: 634 (M + H) + .
(112b) 1- {5- [4- (4-Acetylpiperazin-1-yl) -3-methylphenoxy] 4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2 -(Ethylsulfonyl) phenyl] ethanone To a dichloromethane solution of the compound (327 mg) obtained in Example (112a) was added 4N hydrochloric acid dioxane solution (4 mL), and the mixture was stirred at room temperature. After 3 hours, crude 2- [2- (ethylsulfonyl) phenyl] -1- {4-methyl-5- [3-methyl-4- (piperazin-1-yl) phenoxy] -2 was concentrated by concentration under reduced pressure. , 3-Dihydro-1H-indol-1-yl} ethanone hydrochloride was obtained as a pale yellow solid.
　得られた化合物にジクロロメタン（２　ｍＬ）、ピリジン（２　ｍＬ）、無水酢酸（０．２４３　ｍＬ）を加えて室温で３時間撹拌した。反応液を直接シリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム）によって精製することで標記化合物（２２５　ｍｇ）を白色固体として得た。
1H-NMR (500 MHz, CDCl3) δ: 1.26 (3H, t, J= 7.6 Hz), 2.12-2.15 (6H, m), 2.28 (3H, s), 2.79-2.88 (4H, m), 3.17-3.24 (4H, m), 3.56-3.61 (2H, m), 3.71-3.78 (2H, m), 4.24-4.30 (2H, m), 4.37 (2H, s), 6.64-6.69 (1H, m), 6.71-6.76 (2H, m), 6.88-6.92 (1H, m), 7.37-7.41 (1H, m), 7.48-7.53 (1H, m), 7.59-7.64 (1H, m), 7.93-7.97 (1H, m), 8.00-8.04 (1H, m).
MS (APCI) m/z: 576 (M+H)+。 Dichloromethane (2 mL), pyridine (2 mL), and acetic anhydride (0.243 mL) were added to the obtained compound, and the mixture was stirred at room temperature for 3 hours. The reaction solution was directly purified by silica gel column chromatography (ethyl acetate / chloroform) to obtain the title compound (225 mg) as a white solid.
1 H-NMR (500 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.6 Hz), 2.12-2.15 (6H, m), 2.28 (3H, s), 2.79-2.88 (4H, m), 3.17-3.24 (4H, m), 3.56-3.61 (2H, m), 3.71-3.78 (2H, m), 4.24-4.30 (2H, m), 4.37 (2H, s), 6.64-6.69 (1H, m ), 6.71-6.76 (2H, m), 6.88-6.92 (1H, m), 7.37-7.41 (1H, m), 7.48-7.53 (1H, m), 7.59-7.64 (1H, m), 7.93-7.97 (1H, m), 8.00-8.04 (1H, m).
MS (APCI) m / z: 576 (M + H) + .
　（実施例１１３）：実施例（１１３ｂ）で合成
１－｛５－［４－（４－アセチルピペラジン－１－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン Example 113: Synthesis in Example (113b) 1- {5- [4- (4-acetylpiperazin-1-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indole-1- Yl} -2- [2- (ethylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000156
Figure JPOXMLDOC01-appb-C000156
（１１３ａ）　ｔｅｒｔ－ブチル　５－［４－（４－アセチルピペラジン－１－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　実施例（１０５ａ）で得られた化合物（４３３　ｍｇ）をメタノール（６　ｍＬ）、ジクロロメタン（３　ｍＬ）及び酢酸（０．３　ｍＬ）に溶解し、７．５％パラジウム炭素を加え、水素雰囲気下、室温で撹拌した。７時間後、反応液をセライトろ過し、ろ液を減圧濃縮することで粗製のｔｅｒｔ－ブチル　４－メチル－５－［４－（ピペラジン－１－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレートを淡橙色油状物として得た。得られた化合物のジクロロメタン（５　ｍＬ）溶液にピリジン（３　ｍＬ）、無水酢酸（０．７５２　ｍＬ）を加えて室温で３時間撹拌した。反応液を直接シリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム）で精製することで標記化合物（３０２　ｍｇ）を白色固体として得た。
MS (APCI) m/z: 452 (M+H)+。
（１１３ｂ）　１－｛５－［４－（４－アセチルピペラジン－１－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン
　実施例（１１３ａ）で得られた化合物（３００　ｍｇ）のジクロロメタン（２　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（２　ｍＬ）を加えて室温で撹拌した。３時間後、減圧濃縮することで粗製の１－（４－｛４－［（４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）エタノン塩酸塩を得た。 (113a) tert-butyl 5- [4- (4-acetylpiperazin-1-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indole-1-carboxylate obtained in Example (105a) The compound (433 mg) was dissolved in methanol (6 mL), dichloromethane (3 mL) and acetic acid (0.3 mL), 7.5% palladium carbon was added, and the mixture was stirred at room temperature under a hydrogen atmosphere. After 7 hours, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to give crude tert-butyl 4-methyl-5- [4- (piperazin-1-yl) phenoxy] -2,3-dihydro-1H. -Indole-1-carboxylate was obtained as a pale orange oil. Pyridine (3 mL) and acetic anhydride (0.752 mL) were added to a dichloromethane (5 mL) solution of the obtained compound, and the mixture was stirred at room temperature for 3 hours. The reaction solution was directly purified by silica gel column chromatography (ethyl acetate / chloroform) to obtain the title compound (302 mg) as a white solid.
MS (APCI) m / z: 452 (M + H) + .
(113b) 1- {5- [4- (4-Acetylpiperazin-1-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (ethyl (Sulfonyl) phenyl] ethanone To a solution of the compound (300 mg) obtained in Example (113a) in dichloromethane (2 mL) was added 4N dioxane hydrochloride solution (2 mL), and the mixture was stirred at room temperature. After 3 hours, crude 1- (4- {4-[(4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) ethanone was concentrated by concentration under reduced pressure. The hydrochloride salt was obtained.
　得られた化合物にジクロロメタン（４　ｍＬ）、［２－（エチルスルホニル）フェニル］酢酸（ＣＡＳ番号１３６３１７９－４７－８）（１８２　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（１９１　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（９０　ｍｇ）、ジイソプロピルエチルアミン（０．３４７　ｍＬ）を加えて室温で１２時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム）で精製することで標記化合物（１８５　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.23-1.28 (3H, m), 2.12-2.16 (6H, m), 3.02-3.12 (4H, m), 3.16-3.25 (4H, m), 3.58-3.64 (2H, m), 3.74-3.80 (2H, m), 4.23-4.30 (2H, m), 4.37 (2H, s), 6.68-6.73 (1H, m), 6.81-6.91 (4H, m), 7.37-7.42 (1H, m), 7.47-7.53 (1H, m), 7.59-7.65 (1H, m), 7.92-7.96 (1H, m), 8.01-8.05 (1H, m).
MS (APCI) m/z: 562 (M+H)+。 Dichloromethane (4 mL), [2- (ethylsulfonyl) phenyl] acetic acid (CAS number 1363179-47-8) (182 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide were obtained. Hydrochloric acid salt (191 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (90 mg) and diisopropylethylamine (0.347 mL) were added and stirred at room temperature for 12 hours. . The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / chloroform) to obtain the title compound (185 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.23-1.28 (3H, m), 2.12-2.16 (6H, m), 3.02-3.12 (4H, m), 3.16-3.25 (4H, m), 3.58 -3.64 (2H, m), 3.74-3.80 (2H, m), 4.23-4.30 (2H, m), 4.37 (2H, s), 6.68-6.73 (1H, m), 6.81-6.91 (4H, m) , 7.37-7.42 (1H, m), 7.47-7.53 (1H, m), 7.59-7.65 (1H, m), 7.92-7.96 (1H, m), 8.01-8.05 (1H, m).
MS (APCI) m / z: 562 (M + H) + .
　（実施例１１４）：実施例（１１４ｄ）で合成
１－（５－｛［６－（４－アセチルピペラジン－１－イル）ピリジン－３－イル］オキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン Example 114: Synthesis in Example 114d 1- (5-{[6- (4-acetylpiperazin-1-yl) pyridin-3-yl] oxy} -4-methyl-2,3-dihydro -1H-indol-1-yl) -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000157
Figure JPOXMLDOC01-appb-C000157
（１１４ａ）　ｔｅｒｔ－ブチル　４－（５－ブロモピリジン－２－イル）ピペラジン－１－カルボキシレート
　ｔｅｒｔ－ブチル　ピペラジン－１－カルボキシレート（２．４０　ｇ）と２，５－ジブロモピリジン（３．１０　ｇ）のトルエン（３５　ｍＬ）溶液にトリス（ジベンジリデンアセトン）ジパラジウム（０）（０．６０　ｇ）、４，５－ビス（ジフェニルホスフィノ）－９，９－ジメチルキサンテン（１．１０　ｇ）、ナトリウム　ｔｅｒｔ－ブトキシド（３．８０　ｇ）を加えて１００℃で１０時間撹拌した。室温まで冷却後、セライトろ過し、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（１．３２　ｇ）を黄色固体として得た。
（１１４ｂ）　１－［４－（５－ブロモピリジン－２－イル）ピペラジン－１－イル］エタノン
　実施例（１１４ａ）で得られた化合物（６３０　ｍｇ）のジクロロメタン（２　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（４　ｍＬ）を加えて室温で撹拌した。３時間後、減圧濃縮することで粗製の１－（５－ブロモピリジン－２－イル）ピペラジン二塩酸塩を得た。 (114a) tert-butyl 4- (5-bromopyridin-2-yl) piperazine-1-carboxylate tert-butyl piperazine-1-carboxylate (2.40 g) and 2,5-dibromopyridine (3.10) g) in a toluene (35 mL) solution of tris (dibenzylideneacetone) dipalladium (0) (0.60 g), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (1.10 g) ) And sodium tert-butoxide (3.80 g) were added, and the mixture was stirred at 100 ° C. for 10 hours. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.32 g) as a yellow solid.
(114b) 1- [4- (5-Bromopyridin-2-yl) piperazin-1-yl] ethanone To a solution of the compound obtained in Example (114a) (630 mg) in dichloromethane (2 mL) was added 4N dioxane hydrochloride. Solution (4 mL) was added and stirred at room temperature. After 3 hours, crude 1- (5-bromopyridin-2-yl) piperazine dihydrochloride was obtained by concentration under reduced pressure.
　得られた化合物にジクロロメタン（４　ｍＬ）、トリエチルアミン（１．２８　ｍＬ）、無水酢酸（０．５２２　ｍＬ）を加えて室温で撹拌した。３時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム）で精製することで標記化合物（５２０　ｍｇ）を淡黄色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.15 (3H, s), 3.45-3.50 (2H, m), 3.55-3.64 (4H, m), 3.71-3.77 (2H, m), 6.55-6.60 (1H, m), 7.55-7.60 (1H, m), 8.20-8.23 (1H, m)。
（１１４ｃ）　ｔｅｒｔ－ブチル　５－｛［６－（４－アセチルピペラジン－１－イル）ピリジン－３－イル］オキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　実施例（１１４ｂ）で得られた化合物（７５０　ｍｇ）の１，４－ジオキサン（１０　ｍＬ）溶液にｔｅｒｔ－ブチル ５－ヒドロキシ－４－メチル－２,３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート（７８９　ｍｇ）、ヨウ化銅（Ｉ）（１００　ｍｇ）、Ｎ，Ｎ－ジメチルグリシン（１０８　ｍｇ）、炭酸セシウム（１．７２　ｇ）を加えて１００℃で１２時間撹拌した。室温まで冷却後、セライトろ過し、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム）で精製することで標記化合物と原料との混合物（４３１　ｍｇ）を淡黄色固体として得た。
MS (APCI) m/z: 453 (M+H)+。
（１１４ｄ）　１－（５－｛［６－（４－アセチルピペラジン－１－イル）ピリジン－３－イル］オキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（１１４ｃ）で得られた化合物（４３１　ｍｇ）のジクロロメタン（２　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（４　ｍＬ）を加え、室温で撹拌した。３時間後、反応液を濃縮することで粗製の１－（４－｛５－［（４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］ピリジン－２－イル｝ピペラジン－１－イル）エタノン二塩酸塩を得た。 Dichloromethane (4 mL), triethylamine (1.28 mL), and acetic anhydride (0.522 mL) were added to the obtained compound, and the mixture was stirred at room temperature. After 3 hours, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / chloroform) to obtain the title compound (520 mg) as a pale yellow solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.15 (3H, s), 3.45-3.50 (2H, m), 3.55-3.64 (4H, m), 3.71-3.77 (2H, m), 6.55-6.60 (1H, m), 7.55-7.60 (1H, m), 8.20-8.23 (1H, m).
(114c) tert-butyl 5-{[6- (4-acetylpiperazin-1-yl) pyridin-3-yl] oxy} -4-methyl-2,3-dihydro-1H-indole-1-carboxylate To a solution of the compound (750 mg) obtained in Example (114b) in 1,4-dioxane (10 mL), tert-butyl 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylate (789 mg), copper (I) iodide (100 mg), N, N-dimethylglycine (108 mg) and cesium carbonate (1.72 g) were added, and the mixture was stirred at 100 ° C. for 12 hours. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / chloroform) to obtain a mixture (431 mg) of the title compound and the raw material as a pale yellow solid.
MS (APCI) m / z: 453 (M + H) + .
(114d) 1- (5-{[6- (4-Acetylpiperazin-1-yl) pyridin-3-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 (114c) (431 mg) in dichloromethane (2 mL) was added 4N hydrochloric acid dioxane solution (4 mL), and the mixture was stirred at room temperature. After 3 hours, the reaction solution was concentrated to give crude 1- (4- {5-[(4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] pyridin-2-yl} piperazine. -1-yl) ethanone dihydrochloride was obtained.
　得られた化合物のジクロロメタン（４　ｍＬ）溶液に［２－（メチルスルホニル）フェニル］酢酸（ＣＡＳ番号１４２３３６－２０－７）（０．２２０　ｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（０．２７０　ｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（０．１３０　ｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．６６０　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム）で精製することで標記化合物（０．１４２　ｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.15 (3H, s), 2.18 (3H, s), 3.10 (3H, s), 3.18-3.25 (2H, m), 3.39-3.45 (2H, m), 3.51-3.62 (4H, m), 3.72-3.79 (2H, m), 4.24-4.32 (2H, m), 4.35 (2H, s), 6.61-6.67 (2H, m), 7.13-7.18 (1H, m), 7.33-7.39 (1H, m), 7.48-7.55 (1H, m), 7.58-7.65 (1H, m), 7.90-7.98 (2H, m), 8.05-8.10 (1H, m).
MS (APCI) m/z: 549 (M+H)+。 To a solution of the obtained compound in dichloromethane (4 mL), [2- (methylsulfonyl) phenyl] acetic acid (CAS number 142336-20-7) (0.220 g), 1-ethyl-3- (3-dimethylaminopropyl) was added. ) Carboximide hydrochloride (0.270 g), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (0.130 g), N, N-diisopropylethylamine (0.660) mL) was 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 (ethyl acetate / chloroform) to obtain the title compound (0.142 g) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.15 (3H, s), 2.18 (3H, s), 3.10 (3H, s), 3.18-3.25 (2H, m), 3.39-3.45 (2H, m ), 3.51-3.62 (4H, m), 3.72-3.79 (2H, m), 4.24-4.32 (2H, m), 4.35 (2H, s), 6.61-6.67 (2H, m), 7.13-7.18 (1H , m), 7.33-7.39 (1H, m), 7.48-7.55 (1H, m), 7.58-7.65 (1H, m), 7.90-7.98 (2H, m), 8.05-8.10 (1H, m).
MS (APCI) m / z: 549 (M + H) + .
　（実施例１１５）
　（実施例１１５－１）：実施例（１１５ａ）で合成
エチル　（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペラジン－１－イル）（オキソ）アセテート (Example 115)
Example 115-1: Ethyl (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H) synthesized in Example (115a) -Indol-5-yl) oxy] phenyl} piperazin-1-yl) (oxo) acetate
Figure JPOXMLDOC01-appb-C000158
Figure JPOXMLDOC01-appb-C000158
　（実施例１１５－２）：実施例（１１５ｂ）で合成
（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペラジン－１－イル）（オキソ）酢酸 Example 115-2: synthesized in Example (115b) (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H- Indol-5-yl) oxy] phenyl} piperazin-1-yl) (oxo) acetic acid
Figure JPOXMLDOC01-appb-C000159
Figure JPOXMLDOC01-appb-C000159
（１１５ａ）　エチル　（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペラジン－１－イル）（オキソ）アセテート
　実施例（１０５ｂ）で得られた化合物（６８０　ｍｇ）のメタノール（４　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（２　ｍＬ）、７．５％パラジウム炭素（５０．０　ｍｇ）を加えて水素雰囲気下室温で撹拌した。４時間後、セライトろ過しろ液を減圧濃縮することで粗製の１－｛４－メチル－５－［４－（ピペラジン－１－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン塩酸塩を得た。 (115a) ethyl (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperazine 1-yl) (oxo) acetate A solution of the compound obtained in Example (105b) (680 mg) in methanol (4 mL) was added to a 4N hydrochloric acid dioxane solution (2 mL), 7.5% palladium carbon (50.0). mg) was added and stirred at room temperature under a hydrogen atmosphere. After 4 hours, the mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give crude 1- {4-methyl-5- [4- (piperazin-1-yl) phenoxy] -2,3-dihydro-1H-indole-1- IL} -2- [2- (methylsulfonyl) phenyl] ethanone hydrochloride was obtained.
　得られた化合物（１５２　ｍｇ）にジクロロメタン（３　ｍＬ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１４７　ｍＬ）、エチル　クロロ（オキソ）アセテート（０．０４３６　ｍＬ）を０℃で加えて室温まで昇温した。室温で３時間撹拌後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（６９．０　ｍｇ）をアモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.38 (3H, t, J = 7.2 Hz), 2.14 (3H, s), 3.09-3.15 (7H, m), 3.18-3.25 (2H, m), 3.57-3.63 (2H, m), 3.77-3.82 (2H, m), 4.25-4.31 (2H, m), 4.32-4.39 (4H, m), 6.69-6.73 (1H, m), 6.81-6.91 (4H, m), 7.34-7.39 (1H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.93-7.97 (1H, m), 8.05-8.10 (1H, m).
MS (APCI) m/z: 606 (M+H)+。
（１１５ｂ）　（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペラジン－１－イル）（オキソ）酢酸
　実施例（１１５ａ）で得られた化合物（６７．０　ｍｇ）の１，４－ジオキサン（１　ｍＬ）溶液に１Ｎ水酸化ナトリウム水溶液（１　ｍＬ）を加えて室温で撹拌した。５時間後、１Ｎ塩酸水溶液で中和し、析出した固体をろ取し、水とクロロホルムで洗い、乾燥することで標記化合物（４３．０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, DMSO-d6) δ: 2.06 (3H, s), 2.47-2.53 (2H, m), 3.13-3.28 (7H, m), 3.55-3.74 (4H, m), 4.22-4.35 (4H, m), 6.68-6.73 (1H, m), 6.80-6.86 (2H, m), 7.09-7.22 (2H, m), 7.45-7.50 (1H, m), 7.54-7.61 (1H, m), 7.68-7.70 (1H, m), 7.80-7.85 (1H, m), 7.93-7.99 (1H, m)。 Dichloromethane (3 mL), N, N-diisopropylethylamine (0.147 mL), ethyl chloro (oxo) acetate (0.0436 mL) were added to the obtained compound (152 mg) at 0 ° C., and the mixture was warmed to room temperature. did. The mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (69.0 mg) as an amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.38 (3H, t, J = 7.2 Hz), 2.14 (3H, s), 3.09-3.15 (7H, m), 3.18-3.25 (2H, m), 3.57-3.63 (2H, m), 3.77-3.82 (2H, m), 4.25-4.31 (2H, m), 4.32-4.39 (4H, m), 6.69-6.73 (1H, m), 6.81-6.91 (4H , m), 7.34-7.39 (1H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.93-7.97 (1H, m), 8.05-8.10 (1H, m).
MS (APCI) m / z: 606 (M + H) + .
(115b) (4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperazine- 1-yl) (oxo) acetic acid To a solution of the compound (67.0 mg) obtained in Example (115a) in 1,4-dioxane (1 mL) was added 1N aqueous sodium hydroxide solution (1 mL) at room temperature. Stir. After 5 hours, the mixture was neutralized with 1N aqueous hydrochloric acid, and the precipitated solid was collected by filtration, washed with water and chloroform, and dried to obtain the title compound (43.0 mg) as a white solid.
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 2.06 (3H, s), 2.47-2.53 (2H, m), 3.13-3.28 (7H, m), 3.55-3.74 (4H, m), 4.22 -4.35 (4H, m), 6.68-6.73 (1H, m), 6.80-6.86 (2H, m), 7.09-7.22 (2H, m), 7.45-7.50 (1H, m), 7.54-7.61 (1H, m), 7.68-7.70 (1H, m), 7.80-7.85 (1H, m), 7.93-7.99 (1H, m).
　（実施例１１６）：実施例（１１６ｄ）で合成
１－｛５－［４－（４－アセチルピペラジン－１－イル）－３－フルオロフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン Example 116: Synthesis in Example (116d) 1- {5- [4- (4-acetylpiperazin-1-yl) -3-fluorophenoxy] -4-methyl-2,3-dihydro-1H- Indol-1-yl} -2- [2- (ethylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000160
Figure JPOXMLDOC01-appb-C000160
（１１６ａ）　ｔｅｒｔ－ブチル ４－（４－ブロモ－２－フルオロフェニル）ピペラジン－１－カルボキシレート
　４－ブロモ－２－フルオロ－１－ヨードベンゼン（２．００　ｇ）のトルエン（１５　ｍＬ）溶液にｔｅｒｔ－ブチル　ピペラジン－１－カルボキシレート（１．２４　ｇ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（３０４　ｍｇ）、（±）－２，２’－ビス（ジフェニルホスフィノ）－１，１’－ビナフチル（４１３　ｍｇ）、ナトリウム　ｔｅｒｔ－ブトキシド（１．２８　ｇ）を加えて１００℃で撹拌した。１０時間後、室温まで冷却した。セライトろ過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（５４２　ｍｇ）を淡黄色油状物として得た。
MS (APCI) m/z: 359 (M+H)+。
（１１６ｂ）　１－［４－（４－ブロモ－２－フルオロフェニル）ピペラジン－１－イル］エタノン
　実施例（１１６ａ）で得られた化合物（５４２　ｍｇ）のジクロロメタン（２　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（２　ｍＬ）を加え、室温で撹拌した。５時間後、反応液を濃縮することで粗製の１－（４－ブロモ－２－フルオロフェニル）ピペラジン塩酸塩を得た。 (116a) tert-butyl 4- (4-bromo-2-fluorophenyl) piperazine-1-carboxylate 4-bromo-2-fluoro-1-iodobenzene (2.00 g) in a toluene (15 mL) solution tert-Butyl piperazine-1-carboxylate (1.24 g), tris (dibenzylideneacetone) dipalladium (0) (304 mg), (±) -2,2′-bis (diphenylphosphino) -1, 1′-binaphthyl (413 mg) and sodium tert-butoxide (1.28 g) were added, and the mixture was stirred at 100 ° C. After 10 hours, it was cooled to room temperature. After filtration through Celite, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (542 mg) as a pale yellow oil.
MS (APCI) m / z: 359 (M + H) + .
(116b) 1- [4- (4-Bromo-2-fluorophenyl) piperazin-1-yl] ethanone To a solution of the compound (542 mg) obtained in Example (116a) in dichloromethane (2 mL) was added 4N dioxane hydrochloride. Solution (2 mL) was added and stirred at room temperature. After 5 hours, the reaction solution was concentrated to obtain crude 1- (4-bromo-2-fluorophenyl) piperazine hydrochloride.
　得られた化合物をジクロロメタン（３　ｍＬ）とピリジン（３　ｍＬ）に溶解し、無水酢酸（１．４　ｍＬ）を加えて室温で撹拌した。３時間後、反応液を減圧濃縮した得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム）で精製することで標記化合物（４０７　ｍｇ）を淡黄色固体として得た。
（１１６ｃ）　ｔｅｒｔ－ブチル　５－［４－（４－アセチルピペラジン－１－イル）－３－フルオロフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　実施例（１１６ｂ）で得られた化合物（４０７　ｍｇ）の１，４－ジオキサン（１５　ｍＬ）溶液にｔｅｒｔ－ブチル　５－ヒドロキシ－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート（６７３　ｍｇ）、ヨウ化銅（Ｉ）（５１．０　ｍｇ）、Ｎ，Ｎ－ジメチルグリシン（５５　ｍｇ）、炭酸セシウム（８８０　ｍｇ）を加えて１００℃で１２時間撹拌した。室温まで冷却後、セライトろ過、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム）で精製することで原料と標記化合物の約１対１の混合物（４２８　ｍｇ）を茶色油状物として得た。
MS (APCI) m/z: 470 (M+H)+。
（１１６ｄ）　１－｛５－［４－（４－アセチルピペラジン－１－イル）－３－フルオロフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン
　実施例（１１６ｃ）で得られた化合物（４２８　ｍｇ）のジクロロメタン（３　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（４　ｍＬ）を加え、室温で撹拌した。３時間後、反応液を濃縮することで粗製の１－（４－｛２－フルオロ－４－［（４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペラジン－１－イル）エタノン塩酸塩を得た。 The obtained compound was dissolved in dichloromethane (3 mL) and pyridine (3 mL), acetic anhydride (1.4 mL) was added, and the mixture was stirred at room temperature. After 3 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol / chloroform) to obtain the title compound (407 mg) as a pale yellow solid.
(116c) tert-butyl 5- [4- (4-acetylpiperazin-1-yl) -3-fluorophenoxy] -4-methyl-2,3-dihydro-1H-indole-1-carboxylate Example (116b) ) In a solution of the compound obtained in (407 mg) in 1,4-dioxane (15 mL) and tert-butyl 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylate (673 mg). ), Copper (I) iodide (51.0 mg), N, N-dimethylglycine (55 mg) and cesium carbonate (880 mg) were added, and the mixture was stirred at 100 ° C. for 12 hours. After cooling to room temperature, the mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / chloroform) to obtain an approximately 1: 1 mixture (428 mg) of the raw material and the title compound as a brown oil.
MS (APCI) m / z: 470 (M + H) + .
(116d) 1- {5- [4- (4-Acetylpiperazin-1-yl) -3-fluorophenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [ 2- (Ethylsulfonyl) phenyl] ethanone To a solution of the compound (428 mg) obtained in Example (116c) in dichloromethane (3 mL) was added 4N hydrochloric acid dioxane solution (4 mL), and the mixture was stirred at room temperature. After 3 hours, the reaction solution was concentrated to give crude 1- (4- {2-fluoro-4-[(4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperazine. -1-yl) ethanone hydrochloride was obtained.
　得られた化合物のジクロロメタン（６　ｍＬ）溶液に［２－（エチルスルホニル）フェニル］酢酸（ＣＡＳ番号１３６３１７９－４７－８）（２５０　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（２６２　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（１２４　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．４７６　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム）で精製することで標記化合物（４６．０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.23-1.29 (3H, m), 2.11 (3H, s), 2.13 (3H, s), 2.94-3.03 (4H, m), 3.16-3.25 (4H, m), 3.59-3.64 (2H, m), 3.75-3.80 (2H, m), 4.24-4.31 (2H, m), 4.37 (2H, s), 6.57-6.65 (2H, m), 6.75-6.80 (1H, m), 6.82-6.89 (1H, m), 7.37-7.42 (1H, m), 7.48-7.54 (1H, m), 7.59-7.66 (1H, m), 7.96-8.00 (1H, m), 8.01-8.06 (1H, m)。 To a solution of the obtained compound in dichloromethane (6 mL), [2- (ethylsulfonyl) phenyl] acetic acid (CAS number 1363179-47-8) (250 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboxyl Imide hydrochloride (262 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (124 mg), N, N-diisopropylethylamine (0.476 mL) were added, and room temperature was added. Stir with. After 12 hours, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / chloroform) to obtain the title compound (46.0 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.23-1.29 (3H, m), 2.11 (3H, s), 2.13 (3H, s), 2.94-3.03 (4H, m), 3.16-3.25 (4H , m), 3.59-3.64 (2H, m), 3.75-3.80 (2H, m), 4.24-4.31 (2H, m), 4.37 (2H, s), 6.57-6.65 (2H, m), 6.75-6.80 (1H, m), 6.82-6.89 (1H, m), 7.37-7.42 (1H, m), 7.48-7.54 (1H, m), 7.59-7.66 (1H, m), 7.96-8.00 (1H, m) , 8.01-8.06 (1H, m).
　（実施例１１７）：実施例（１１７ｃ）で合成
１－｛５－［４－（４－アセチルピペラジン－１－イル）－３－メトキシフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン Example 117: synthesized in Example (117c) 1- {5- [4- (4-acetylpiperazin-1-yl) -3-methoxyphenoxy] -4-methyl-2,3-dihydro-1H- Indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000161
Figure JPOXMLDOC01-appb-C000161
（１１７ａ）　ｔｅｒｔ－ブチル　５－（４－ブロモ－３－メトキシフェノキシ）－４－メチルｌ－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　１－ブロモ－４－ヨード－２－メトキシベンゼン（ＣＡＳ番号７５５０２７－１８－０）（２　ｇ）の１，４－ジオキサン（３０　ｍＬ）溶液にｔｅｒｔ－ブチル ５－ヒドロキシ－４－メチル－２,３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート（１．９１　ｇ）、ヨウ化銅（Ｉ）（２４３　ｍｇ）、Ｎ，Ｎ－ジメチルグリシン（２６３　ｍｇ）、炭酸セシウム（４．１６　ｇ）を加えて１００℃で１２時間撹拌した。室温まで冷却後、セライトろ過し、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（１．４２　ｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.48-1.64 (9H, m), 2.05 (3H, s), 2.98-3.07 (2H, m), 3.83 (3H, s), 3.97-4.11 (2H, m), 6.22-6.27 (1H, m), 6.51-6.58 (1H, m), 6.76-6.86 (1H, m), 7.33-7.38 (1H, m), 7.63-7.76 (1H, m)。 (117a) tert-butyl 5- (4-bromo-3-methoxyphenoxy) -4-methyl l-2,3-dihydro-1H-indole-1-carboxylate 1-bromo-4-iodo-2-methoxybenzene (CAS No. 755027-18-0) (2 g) in 1,4-dioxane (30 mL) in tert-butyl 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylate (1.91 g), copper (I) iodide (243 mg), N, N-dimethylglycine (263 mg) and cesium carbonate (4.16 g) were added, and the mixture was stirred at 100 ° C. for 12 hours. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.42 g) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48-1.64 (9H, m), 2.05 (3H, s), 2.98-3.07 (2H, m), 3.83 (3H, s), 3.97-4.11 (2H m), 6.22-6.27 (1H, m), 6.51-6.58 (1H, m), 6.76-6.86 (1H, m), 7.33-7.38 (1H, m), 7.63-7.76 (1H, m).
　（１１７ｂ）　ｔｅｒｔ－ブチル　５－［４－（４－アセチルピペラジン－１－イル）－３－メトキシフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　実施例（１１７ａ）で得られた化合物（４００　ｍｇ）のトルエン（２　ｍＬ）溶液に１－（ピペラジン－１－イル）エタノン（ＣＡＳ　１３８８９－９８－０）（１７７　ｍｇ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（４２．０　ｍｇ）、（±）－２，２’－ビス（ジフェニルホスフィノ）－１，１’－ビナフチル（５７．０　ｍｇ）、ナトリウム　ｔｅｒｔ－ブトキシド（２２１　ｍｇ）を加えて１００℃で１０時間撹拌した。室温まで冷却後、セライトろ過し、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム）で精製することで標記化合物（２３２　ｍｇ）を淡黄色油状物として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.51-1.62 (9H, m), 2.09 (3H, s), 2.13 (3H, s), 2.92-3.06 (6H, m), 3.60-3.66 (2H, m), 3.76-3.85 (5H, m), 3.97-4.09 (2H, m), 6.27-6.32 (1H, m), 6.54-6.59 (1H, m), 6.71-6.73 (2H, m), 7.60-7.74 (1H, m)。
（１１７ｃ）　１－｛５－［４－（４－アセチルピペラジン－１－イル）－３－メトキシフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（１１７ｂ）で得られた化合物（２１０　ｍｇ）のジクロロメタン（２　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（４　ｍＬ）を加えて室温で撹拌した。１時間後、減圧濃縮することで粗製の１－（４－｛２－メトキシ－４－［（４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペラジン－１－イル）エタノン塩酸塩を得た。 (117b) tert-Butyl 5- [4- (4-acetylpiperazin-1-yl) -3-methoxyphenoxy] -4-methyl-2,3-dihydro-1H-indole-1-carboxylate Example (117a) ) In a toluene (2 mL) solution of the compound (400 mg) obtained in 1) was added 1- (piperazin-1-yl) ethanone (CAS 13889-98-0) (177 mg), tris (dibenzylideneacetone) dipalladium ( 0) (42.0 mg), (±) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (57.0 mg), sodium tert-butoxide (221 mg) and 100 Stir at 0 ° C. for 10 hours. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / chloroform) to give the title compound (232 mg) as a pale yellow oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.51-1.62 (9H, m), 2.09 (3H, s), 2.13 (3H, s), 2.92-3.06 (6H, m), 3.60-3.66 (2H , m), 3.76-3.85 (5H, m), 3.97-4.09 (2H, m), 6.27-6.32 (1H, m), 6.54-6.59 (1H, m), 6.71-6.73 (2H, m), 7.60 -7.74 (1H, m).
(117c) 1- {5- [4- (4-Acetylpiperazin-1-yl) -3-methoxyphenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [ 2- (Methylsulfonyl) phenyl] ethanone To a solution of the compound (210 mg) obtained in Example (117b) in dichloromethane (2 mL) was added 4N hydrochloric acid dioxane solution (4 mL), and the mixture was stirred at room temperature. After 1 hour, crude 1- (4- {2-methoxy-4-[(4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperazine-1 was concentrated by concentration under reduced pressure. -Yl) Ethanone hydrochloride was obtained.
　得られた化合物にジクロロメタン（４　ｍＬ）、［２－（メチルスルホニル）フェニル］酢酸（ＣＡＳ番号１４２３３６－２０－７）（１１２　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（１２５　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（５９．０　ｍｇ）、ジイソプロピルエチルアミン（０．２２８　ｍＬ）を加えて室温で１２時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム）で精製することで標記化合物（２０５　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (500 MHz, CDCl3) δ: 2.13 (3H, s), 2.14 (3H, s), 2.93-3.01 (4H, m), 3.12 (3H, s), 3.19-3.24 (2H, m), 3.60-3.65 (2H, m), 3.76-3.81 (2H, m), 3.83 (3H, s), 4.26-4.31 (2H, m), 4.36 (2H, s), 6.30-6.36 (1H, m), 6.55-6.59 (1H, m), 6.73-6.81 (2H, m), 7.34-7.39 (1H, m), 7.50-7.55 (1H, m), 7.59-7.65 (1H, m), 7.94-7.99 (1H, m), 8.05-8.10 (1H, m).
MS (APCI) m/z: 578 (M+H)+。 Dichloromethane (4 mL), [2- (methylsulfonyl) phenyl] acetic acid (CAS No. 142336-20-7) (112 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide Hydrochloric acid salt (125 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (59.0 mg) and diisopropylethylamine (0.228 mL) were added, and the mixture was stirred at room temperature for 12 hours. Stir. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / chloroform) to obtain the title compound (205 mg) as a white amorphous solid.
1 H-NMR (500 MHz, CDCl 3 ) δ: 2.13 (3H, s), 2.14 (3H, s), 2.93-3.01 (4H, m), 3.12 (3H, s), 3.19-3.24 (2H, m ), 3.60-3.65 (2H, m), 3.76-3.81 (2H, m), 3.83 (3H, s), 4.26-4.31 (2H, m), 4.36 (2H, s), 6.30-6.36 (1H, m ), 6.55-6.59 (1H, m), 6.73-6.81 (2H, m), 7.34-7.39 (1H, m), 7.50-7.55 (1H, m), 7.59-7.65 (1H, m), 7.94-7.99 (1H, m), 8.05-8.10 (1H, m).
MS (APCI) m / z: 578 (M + H) + .
　（実施例１１８）
　（実施例１１８－１）：実施例（１１８ｃ）で合成
１－｛５－［４－（１－アセチル－１，２，３，６－テトラヒドロピリジン－４－イル）フェノキシ］－４－フルオロ－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン (Example 118)
Example 118-1: Synthesis in Example 118c) 1- {5- [4- (1-acetyl-1,2,3,6-tetrahydropyridin-4-yl) phenoxy] -4-fluoro- 2,3-Dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000162
Figure JPOXMLDOC01-appb-C000162
　（実施例１１８－２）：実施例（１１８ｄ）で合成
１－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－フルオロ－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン Example 118-2: Synthesis in Example (118d) 1- {5- [4- (1-acetylpiperidin-4-yl) phenoxy] -4-fluoro-2,3-dihydro-1H-indole- 1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000163
Figure JPOXMLDOC01-appb-C000163
（１１８ａ）　ｔｅｒｔ－ブチル　５－（４－ブロモフェノキシ）－４－フルオロ－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　ｔｅｒｔ－ブチル　５－ヒドロキシ－４－フルオロ－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート（５００　ｍｇ）及び１－ブロモ－４－ヨードベンゼン（６７０　ｍｇ）のジオキサン（１２　ｍＬ）溶液にヨウ化銅（Ｉ）（７５．２　ｍｇ）、Ｎ，Ｎ－ジメチルグリシン（８１．４　ｍｇ）、炭酸セシウム（１．２９　ｇ）を加え、９０℃で５時間攪拌した。反応液に飽和塩化アンモニウム水溶液（１０　ｍＬ）、飽和炭酸水素ナトリウム水溶液（５　ｍＬ）を加え、酢酸エチルを加えて抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することにより、標記化合物（２５４　ｍｇ）を無色油状物として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.56 (9H, s), 3.14 (2H, t, J = 8.9 Hz), 4.01-4.10 (2H, m), 6.81 (2H, d, J = 8.5 Hz), 6.85-6.96 (1H, m), 7.38 (2H, d, J = 8.5 Hz), 7.50-7.66 (1H, br m)。
（１１８ｂ）　１－［５－（４－ブロモフェノキシ）－４－フルオロ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（１１８ａ）で得られた化合物（２５４　ｍｇ）のジクロロメタン（１　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（２　ｍＬ）を加え、室温で１８時間攪拌した。反応液を減圧下濃縮し、減圧乾燥することで、粗製の５－（４－ブロモフェノキシ）－４－フルオロ－２，３－ジヒドロ－１Ｈ－インドール塩酸塩（２０２　ｍｇ）を白色固体で得た。 (118a) tert-butyl 5- (4-bromophenoxy) -4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl 5-hydroxy-4-fluoro-2,3-dihydro- To a solution of 1H-indole-1-carboxylate (500 mg) and 1-bromo-4-iodobenzene (670 mg) in dioxane (12 mL) was added copper (I) iodide (75.2 mg), N, N— Dimethylglycine (81.4 mg) and cesium carbonate (1.29 g) were added, and the mixture was stirred at 90 ° C. for 5 hours. A saturated aqueous ammonium chloride solution (10 mL) and a saturated aqueous sodium hydrogen carbonate solution (5 mL) were added to the reaction solution, followed by extraction 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 (254 mg) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.56 (9H, s), 3.14 (2H, t, J = 8.9 Hz), 4.01-4.10 (2H, m), 6.81 (2H, d, J = 8.5 Hz), 6.85-6.96 (1H, m), 7.38 (2H, d, J = 8.5 Hz), 7.50-7.66 (1H, br m).
(118b) 1- [5- (4-Bromophenoxy) -4-fluoro-2,3-dihydro-1H-indol-1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone Example (118a) 4N hydrochloric acid dioxane solution (2 mL) was added to a dichloromethane (1 mL) solution of the compound (254 mg) obtained in (1) and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and dried under reduced pressure to obtain crude 5- (4-bromophenoxy) -4-fluoro-2,3-dihydro-1H-indole hydrochloride (202 mg) as a white solid. .
　得られた化合物（２０２　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にトリエチルアミン（１６０　μＬ）を加え、室温で５分間攪拌した。４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（２４４　ｍｇ）及び[２－（メチルスルホニル）フェニル]酢酸（ＣＡＳ番号１４２３３６－２０－７）（１５１　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することにより、標記化合物（２５５　ｍｇ）を無色油状物として得た。
1H-NMR (400 MHz, CDCl3) δ: 3.12 (3H, s), 3.33 (2H, t, J = 8.5 Hz), 4.27-4.39 (4H, m), 6.83 (2H, d, J = 8.5 Hz), 6.91 (1H, t, J = 8.2 Hz), 7.35 (1H, d, J = 7.3 Hz), 7.40 (2H, d, J = 8.5 Hz), 7.50-7.65 (2H, m), 7.90 (1H, d, J = 9.2 Hz), 8.07 (1H, d, J = 9.2 Hz)。
（１１８ｃ）　１－｛５－［４－（１－アセチル－１，２，３，６－テトラヒドロピリジン－４－イル）フェノキシ］－４－フルオロ－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（１１８ｂ）で得られた化合物（１５５　ｍｇ）、１－［４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）－３，６－ジヒドロピリジン－１（２Ｈ）－イル］エタノン（１１５　ｍｇ）の１，２－ジメトキシエタン（１０　ｍＬ）溶液及び炭酸ナトリウム（９７．７　ｍｇ）の水溶液（２　ｍＬ）を加え、室温で５分間撹拌した。［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（１０．０　ｍｇ）を加え、マイクロウェーブ反応装置にて、１３０℃で１５分間反応させた。反応液を室温に冷却後、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１３５　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.15 (3H, d, J = 11.6 Hz), 2.47-2.59 (2H, m), 3.12 (3H, s), 3.34 (2H, t, J = 8.2 Hz), 3.66 (1H, t, J = 5.8 Hz), 3.81 (1H, t, J = 5.8 Hz), 4.08-4.15 (1H, m), 4.19-4.24 (1H, br m), 4.29-4.37 (4H, m), 5.94 (0.5H, br s), 6.02 (0.5H, br s), 6.88-6.96 (3H, m), 7.29-7.37 (3H, m), 7.50-7.56 (1H, m), 7.59-7.67 (1H, m), 7.90 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz)。
（１１８ｄ）　１－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－フルオロ－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（１１８ｃ）で得られた化合物（１３５　ｍｇ）をメタノール（３　ｍＬ）及び酢酸エチル（２　ｍＬ）に溶解させ、窒素雰囲気下、室温で撹拌した。７．５％パラジウム炭素（２７．２　ｍｇ）を加え、水素雰囲気下、室温で１８時間撹拌した。不溶物をろ去し、溶媒を減圧下、留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１２９　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.50-1.64 (2H, m), 1.80-1.93 (2H, m), 2.13 (3H, s), 2.54-2.73 (2H, m), 3.08-3.22 (4H, m), 3.33 (2H, t, J = 8.2 Hz), 3.87-3.98 (1H, m), 4.27-4.39 (4H, m), 4.72-4.83 (1H, m), 6.85-6.93 (3H, m), 7.12 (2H, d, J = 8.5 Hz), 7.35 (1H, d, J = 7.3 Hz), 7.54 (1H, t, J = 7.0 Hz), 7.63 (1H, t, J = 7.0 Hz), 7.88 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).
MS(APCI) m/z: 551 (M+H)+。 Triethylamine (160 μL) was added to a solution of the obtained compound (202 mg) in N, N-dimethylformamide (5 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 (244 mg) and [2- (methylsulfonyl) phenyl] acetic acid (CAS No. 142336-20) -7) (151 mg) was added, and the mixture was stirred at room temperature for 18 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 / hexane) to give the title compound (255 mg) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.12 (3H, s), 3.33 (2H, t, J = 8.5 Hz), 4.27-4.39 (4H, m), 6.83 (2H, d, J = 8.5 Hz), 6.91 (1H, t, J = 8.2 Hz), 7.35 (1H, d, J = 7.3 Hz), 7.40 (2H, d, J = 8.5 Hz), 7.50-7.65 (2H, m), 7.90 ( 1H, d, J = 9.2 Hz), 8.07 (1H, d, J = 9.2 Hz).
(118c) 1- {5- [4- (1-acetyl-1,2,3,6-tetrahydropyridin-4-yl) phenoxy] -4-fluoro-2,3-dihydro-1H-indole-1- Yl} -2- [2- (methylsulfonyl) phenyl] ethanone Compound (155 mg) obtained in Example (118b), 1- [4- (4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl) -3,6-dihydropyridin-1 (2H) -yl] ethanone (115 mg) in 1,2-dimethoxyethane (10 mL) and sodium carbonate (97.7 mg) Aqueous solution (2 mL) was added and stirred at room temperature for 5 minutes. [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (10.0 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 / dichloromethane) to give the title compound (135 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.15 (3H, d, J = 11.6 Hz), 2.47-2.59 (2H, m), 3.12 (3H, s), 3.34 (2H, t, J = 8.2 Hz), 3.66 (1H, t, J = 5.8 Hz), 3.81 (1H, t, J = 5.8 Hz), 4.08-4.15 (1H, m), 4.19-4.24 (1H, br m), 4.29-4.37 ( 4H, m), 5.94 (0.5H, br s), 6.02 (0.5H, br s), 6.88-6.96 (3H, m), 7.29-7.37 (3H, m), 7.50-7.56 (1H, m), 7.59-7.67 (1H, m), 7.90 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).
(118d) 1- {5- [4- (1-Acetylpiperidin-4-yl) phenoxy] -4-fluoro-2,3-dihydro-1H-indol-1-yl} -2- [2- (methyl (Sulfonyl) phenyl] ethanone The compound (135 mg) obtained in Example (118c) was dissolved in methanol (3 mL) and ethyl acetate (2 mL) and stirred at room temperature under a nitrogen atmosphere. 7.5% palladium carbon (27.2 mg) was added, and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. Insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (129 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.50-1.64 (2H, m), 1.80-1.93 (2H, m), 2.13 (3H, s), 2.54-2.73 (2H, m), 3.08-3.22 (4H, m), 3.33 (2H, t, J = 8.2 Hz), 3.87-3.98 (1H, m), 4.27-4.39 (4H, m), 4.72-4.83 (1H, m), 6.85-6.93 (3H , m), 7.12 (2H, d, J = 8.5 Hz), 7.35 (1H, d, J = 7.3 Hz), 7.54 (1H, t, J = 7.0 Hz), 7.63 (1H, t, J = 7.0 Hz) ), 7.88 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).
MS (APCI) m / z: 551 (M + H) + .
　（実施例１１９）：実施例（１１９ｃ）で合成
１－アセチル－４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－３－オン Example 119: Synthesis in Example (119c) 1-acetyl-4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H -Indol-5-yl) oxy] phenyl} piperidin-3-one
Figure JPOXMLDOC01-appb-C000164
Figure JPOXMLDOC01-appb-C000164
（１１９ａ）　ｔｅｒｔ－ブチル　３－ヒドロキシ－４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－カルボキシレート
　実施例（１ｃ）で得られた化合物（５００　ｍｇ）のテトラヒドロフラン（２０　ｍＬ）溶液にボラン－テトラヒドロフラン錯体（１Ｍテトラヒドロフラン溶液、１．６６　ｍＬ）を加え、室温で１８時間撹拌した。反応液を０℃に冷却し、５Ｎ水酸化ナトリウム水溶液（４９７　μＬ）を加え、２０分間撹拌した。さらに３０％過酸化水素水（２３５　μＬ）を加え、５０℃で６時間撹拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（３３９　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.48 (9H, s), 1.53-1.83 (4H, m), 2.13 (3H, s), 2.45-2.52 (1H, m), 2.56-2.83 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.58-3.68 (1H, br m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.79 (1H, d, J = 9.2 Hz), 6.85 (2H, d, J = 8.5 Hz), 7.16 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.47-7.55 (1H, m), 7.58-7.66 (1H, m), 7.98 (1H, d, J = 9.2 Hz), 8.07 (1H, d, J = 7.3 Hz)。
（１１９ｂ）　ｔｅｒｔ－ブチル　４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３－オキソピペリジン－１－カルボキシレート
　オキザリルクロリド（３５．９　μＬ）のジクロロメタン（６　ｍＬ）溶液を窒素雰囲気下、－７８℃に冷却し、ジメチルスルホキシド　（５９．４　μＬ）を滴下して加え、１５分間撹拌した。反応液に実施例（１１９ａ）で得られた化合物（２００　ｍｇ）のジクロロメタン（４　ｍＬ）溶液を滴下して加え、－７８℃で１５分間撹拌した。トリエチルアミン（１７８　μＬ）を加え、室温で２時間撹拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（１３８　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.48 (9H, s), 2.10-2.36 (5H, m), 3.13 (3H, s), 3.21 (2H, t, J = 8.5 Hz), 3.43-3.55 (1H, br m), 3.57-3.65 (1H, m), 3.88-4.13 (2H, br m), 4.21-4.31 (3H, m), 4.36 (2H, s), 6.80 (1H, d, J = 8.5 Hz), 6.85 (2H, d, J = 8.5 Hz), 7.03 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.50-7.54 (1H, m), 7.59-7.67 (1H, m), 7.98 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz)。
（１１９ｃ）　１－アセチル－４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－３－オン
　実施例（１１９ｂ）で得られた化合物（１０４　ｍｇ）のジクロロメタン（１　ｍＬ）溶液に４Ｎ塩酸のジオキサン溶液（２　ｍＬ）を加え、室温で１８時間攪拌した。反応液を減圧下濃縮し、減圧乾燥することで、粗製の４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－３－オン塩酸塩（９３．５　ｍｇ）を白色固体で得た。 (119a) tert-butyl 3-hydroxy-4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) Oxy] phenyl} piperidine-1-carboxylate To a solution of the compound obtained in Example (1c) (500 mg) in tetrahydrofuran (20 mL) was added borane-tetrahydrofuran complex (1M tetrahydrofuran solution, 1.66 mL) at room temperature. For 18 hours. The reaction mixture was cooled to 0 ° C., 5N aqueous sodium hydroxide solution (497 μL) was added, and the mixture was stirred for 20 min. Further, 30% hydrogen peroxide (235 μL) was added, and the mixture was stirred at 50 ° C. for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 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 (339 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48 (9H, s), 1.53-1.83 (4H, m), 2.13 (3H, s), 2.45-2.52 (1H, m), 2.56-2.83 (2H , m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.58-3.68 (1H, br m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s ), 6.79 (1H, d, J = 9.2 Hz), 6.85 (2H, d, J = 8.5 Hz), 7.16 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.47-7.55 (1H, m), 7.58-7.66 (1H, m), 7.98 (1H, d, J = 9.2 Hz), 8.07 (1H, d, J = 7.3 Hz).
(119b) tert-butyl 4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} A solution of -3-oxopiperidine-1-carboxylate oxalyl chloride (35.9 μL) in dichloromethane (6 mL) was cooled to −78 ° C. under a nitrogen atmosphere, and dimethyl sulfoxide (59.4 μL) was added dropwise. Added and stirred for 15 minutes. To the reaction solution was added dropwise a solution of the compound (200 mg) obtained in Example (119a) in dichloromethane (4 mL), and the mixture was stirred at −78 ° C. for 15 minutes. Triethylamine (178 μL) was added and stirred at room temperature for 2 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 / hexane) to give the title compound (138 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48 (9H, s), 2.10-2.36 (5H, m), 3.13 (3H, s), 3.21 (2H, t, J = 8.5 Hz), 3.43- 3.55 (1H, br m), 3.57-3.65 (1H, m), 3.88-4.13 (2H, br m), 4.21-4.31 (3H, m), 4.36 (2H, s), 6.80 (1H, d, J = 8.5 Hz), 6.85 (2H, d, J = 8.5 Hz), 7.03 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.50-7.54 (1H, m), 7.59-7.67 (1H, m), 7.98 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).
(119c) 1-acetyl-4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl } Piperidin-3-one To a solution of the compound obtained in Example (119b) (104 mg) in dichloromethane (1 mL) was added 4N hydrochloric acid in dioxane (2 mL), and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure and dried under reduced pressure to give crude 4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H- Indol-5-yl) oxy] phenyl} piperidin-3-one hydrochloride (93.5 mg) was obtained as a white solid.
　得られた化合物（９３．５　ｍｇ）のジクロロメタン（５　ｍＬ）溶液にトリエチルアミン（７０　μＬ）を加え、室温で５分間攪拌した。無水酢酸（１５．９　μＬ）を加え、室温で４時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。
得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（７９．９　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.12 (3H, s), 2.16 (3H, d, J = 18.3 Hz), 2.20-2.44 (1H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.46-3.54 (1H, m), 3.60-3.68 (2H, m), 3.83-3.93 (1H, m), 4.26 (4H, td, J = 17.1, 7.3 Hz), 4.36 (2H, s), 6.80 (1H, d, J = 8.5 Hz), 6.85 (2H, d, J = 8.5 Hz), 7.02 (2H, t, 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), 7.98 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 561 (M+H)+。 Triethylamine (70 μL) was added to a dichloromethane (5 mL) solution of the obtained compound (93.5 mg), and the mixture was stirred at room temperature for 5 minutes. Acetic anhydride (15.9 μL) was added, and the mixture was stirred at room temperature for 4 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 (79.9 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.12 (3H, s), 2.16 (3H, d, J = 18.3 Hz), 2.20-2.44 (1H, m), 3.12 (3H, s), 3.22 ( 2H, t, J = 8.5 Hz), 3.46-3.54 (1H, m), 3.60-3.68 (2H, m), 3.83-3.93 (1H, m), 4.26 (4H, td, J = 17.1, 7.3 Hz) , 4.36 (2H, s), 6.80 (1H, d, J = 8.5 Hz), 6.85 (2H, d, J = 8.5 Hz), 7.02 (2H, t, 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), 7.98 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = (7.9 Hz).
MS (APCI) m / z: 561 (M + H) + .
　（実施例１２０）
１－（５－｛４－［１－アセチル－３－ヒドロキシピペリジン－４－イル］フェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン (Example 120)
1- (5- {4- [1-acetyl-3-hydroxypiperidin-4-yl] phenoxy} -4-methyl-2,3-dihydro-1H-indol-1-yl) -2- [2- ( Methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000165
Figure JPOXMLDOC01-appb-C000165
　実施例（１１９ｃ）で得られた化合物（２０．０　ｍｇ）のメタノール（２　ｍＬ）溶液に水素化ホウ素ナトリウム（２．７　ｍｇ）を加え、４０分間加熱還流した。反応液に水を加えて減圧下で濃縮し、残渣を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１９．９　ｍｇ）を薄桃色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.60-1.75 (2H, m), 1.79-1.92 (1H, m), 2.13 (3H, s), 2.15 (3H, d, J = 7.3 Hz), 2.51-2.62 (1H, m), 2.91-3.02 (1H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.2 Hz), 3.57-3.67 (1H, br m), 3.79-4.07 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.37 (2H, s), 4.68-4.95 (1H, m), 6.79 (1H, d, J = 8.5 Hz), 6.84-6.89 (2H, m), 7.15 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.99 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 563 (M+H)+。 Sodium borohydride (2.7 mg) was added to a solution of the compound (20.0 mg) obtained in Example (119c) in methanol (2 mL), and the mixture was heated to reflux for 40 minutes. Water was added to the reaction mixture, and the mixture was concentrated under reduced pressure. 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 / dichloromethane) to give the title compound (19.9 mg) as a pale pink solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.60-1.75 (2H, m), 1.79-1.92 (1H, m), 2.13 (3H, s), 2.15 (3H, d, J = 7.3 Hz), 2.51-2.62 (1H, m), 2.91-3.02 (1H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.2 Hz), 3.57-3.67 (1H, br m), 3.79-4.07 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.37 (2H, s), 4.68-4.95 (1H, m), 6.79 (1H, d, J = 8.5 Hz), 6.84-6.89 ( 2H, m), 7.15 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.99 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 563 (M + H) + .
　（実施例１２１）：実施例（１２１ｃ）で合成
１－メチル－４－｛４［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－２－オン Example 121: Synthesis in Example (121c) 1-methyl-4- {4 [(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H- Indol-5-yl) oxy] phenyl} piperidin-2-one
Figure JPOXMLDOC01-appb-C000166
Figure JPOXMLDOC01-appb-C000166
（１２１ａ）　ｔｅｒｔ－ブチル　４－メチル－５－［４－（１－メチル－２－オキソ－１，２－ジヒドロピリジン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　実施例（１ａ）で得られた化合物（２００　ｍｇ）、文献記載の方法（ＷＯ２００９／７４８１２）で合成した１－メチル－４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）ピリジン－２（１Ｈ）－オン（２９１　ｍｇ）の１，２－ジメトキシエタン（６　ｍＬ）溶液及び炭酸ナトリウム（１５７　ｍｇ）の水溶液（２　ｍＬ）を加え、室温で５分間撹拌した。［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（１６．２　ｍｇ）を加え、マイクロウェーブ反応装置にて、１３０℃で１５分間反応させた。反応液を室温に冷却後、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（１０４　ｍｇ）を茶色油状物として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.57 (9H, s), 2.07 (3H, s), 3.04 (2H, t, J = 8.9 Hz), 3.57 (3H, s), 3.95-4.09 (2H, br m), 6.41 (1H, d, J = 7.0 Hz), 6.75 (1H, s), 6.78-6.87 (1H, m), 6.91 (2H, d, J = 8.5 Hz), 7.31 (1H, d, J = 7.0 Hz), 7.50 (2H, t, J = 8.5 Hz), 7.70 (1H, br s)。
（１２１ｂ）　ｔｅｒｔ－ブチル　４－メチル－５－［４－（１－メチル－２－オキソピペリジン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　実施例（１２１ａ）で得られた化合物（２０．０　ｍｇ）のメタノール（２　ｍＬ）溶液に２０％水酸化パラジウム炭素（３．０　ｍｇ）を加え、水素雰囲気下、室温で２４時間撹拌した。不溶物をろ去し、減圧下で溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで標記化合物（１６．０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.57 (9H, s), 1.86-1.97 (1H, m), 2.05-2.11 (4H, m), 2.39-2.51 (1H, m), 2.63-2.75 (1H, m), 2.95-3.07 (6H, m), 3.27-3.44 (2H, m), 3.98-4.07 (2H, br m), 6.74-6.84 (3H, m), 7.04-7.12 (2H, m), 7.56-7.74 (1H, br m)。
（１２１ｃ）　１－メチル－４－｛４［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－２－オン
　実施例（１２１ｂ）で得られた化合物（１３３　ｍｇ）のジクロロメタン（１　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（２　ｍＬ）を加え、室温で１８時間攪拌した。反応液を減圧下濃縮し、得られた固体をろ取し、酢酸エチルで洗浄し、乾燥することで粗製の１－メチル－４－｛４－［（４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－２－オン塩酸塩（１５４　ｍｇ）を桃色固体として得た。 (121a) tert-butyl 4-methyl-5- [4- (1-methyl-2-oxo-1,2-dihydropyridin-4-yl) phenoxy] -2,3-dihydro-1H-indole-1-carboxy Rate The compound (200 mg) obtained in Example (1a), 1-methyl-4- (4,4,5,5-tetramethyl-1,3, synthesized by the method described in the literature (WO2009 / 74812) 2-Dioxaborolan-2-yl) pyridin-2 (1H) -one (291 mg) in 1,2-dimethoxyethane (6 mL) and an aqueous solution (2 mL) of sodium carbonate (157 mg) were added at room temperature. Stir for 5 minutes. [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (16.2 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 (104 mg) as a brown oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.57 (9H, s), 2.07 (3H, s), 3.04 (2H, t, J = 8.9 Hz), 3.57 (3H, s), 3.95-4.09 ( 2H, br m), 6.41 (1H, d, J = 7.0 Hz), 6.75 (1H, s), 6.78-6.87 (1H, m), 6.91 (2H, d, J = 8.5 Hz), 7.31 (1H, d, J = 7.0 Hz), 7.50 (2H, t, J = 8.5 Hz), 7.70 (1H, br s).
(121b) tert-butyl 4-methyl-5- [4- (1-methyl-2-oxopiperidin-4-yl) phenoxy] -2,3-dihydro-1H-indole-1-carboxylate Example (121a) 20% palladium hydroxide carbon (3.0 mg) was added to a methanol (2 mL) solution of the compound obtained in (20.0 mg) and stirred at room temperature for 24 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (16.0 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.57 (9H, s), 1.86-1.97 (1H, m), 2.05-2.11 (4H, m), 2.39-2.51 (1H, m), 2.63-2.75 (1H, m), 2.95-3.07 (6H, m), 3.27-3.44 (2H, m), 3.98-4.07 (2H, br m), 6.74-6.84 (3H, m), 7.04-7.12 (2H, m ), 7.56-7.74 (1H, br m).
(121c) 1-methyl-4- {4 [(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} Piperidin-2-one To a solution of the compound (133 mg) obtained in Example (121b) in dichloromethane (1 mL) was added 4N hydrochloric acid dioxane solution (2 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the resulting solid was collected by filtration, washed with ethyl acetate, and dried to give crude 1-methyl-4- {4-[(4-methyl-2,3-dihydro- 1H-Indol-5-yl) oxy] phenyl} piperidin-2-one hydrochloride (154 mg) was obtained as a pink solid.
　得られた化合物（１１４　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液にトリエチルアミン（１３０　μＬ）を加え、室温で５分間攪拌した。４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（１２６　ｍｇ）及び[２－（メチルスルホニル）フェニル]酢酸（ＣＡＳ番号１４２３３６－２０－７）（７８．６　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１４８　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.88-2.02 (1H, m), 2.07-2.16 (4H, m), 2.40-2.51 (1H, m), 2.65-2.75 (1H, m), 2.98 (3H, s), 3.01-3.13 (4H, m), 3.22 (2H, t, J = 8.2 Hz), 3.30-3.44 (2H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 6.78 (1H, d, J = 8.5 Hz), 6.84 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 9.2 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), 7.98 (1H, d, J = 9.2 Hz), 8.07 (1H, d, J = 7.3 Hz).
MS(APCI) m/z: 533 (M+H)+。 Triethylamine (130 μL) was added to a solution of the obtained compound (114 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- (methylsulfonyl) phenyl] acetic acid (CAS No. 142336-20) -7) (78.6 mg) was added, and the mixture was stirred at room temperature for 18 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 amino silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (148 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.88-2.02 (1H, m), 2.07-2.16 (4H, m), 2.40-2.51 (1H, m), 2.65-2.75 (1H, m), 2.98 (3H, s), 3.01-3.13 (4H, m), 3.22 (2H, t, J = 8.2 Hz), 3.30-3.44 (2H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 ( 2H, s), 6.78 (1H, d, J = 8.5 Hz), 6.84 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 9.2 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), 7.98 (1H, d, J = 9.2 Hz), 8.07 (1H, d, J = 7.3 Hz) .
MS (APCI) m / z: 533 (M + H) + .
　（実施例１２２）：実施例（１２２ｂ）で合成
Ｎ－（１－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピロリジン－３－イル）アセトアミド Example 122: Synthesis in Example (122b) N- (1- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H- Indol-5-yl) oxy] phenyl} pyrrolidin-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000167
Figure JPOXMLDOC01-appb-C000167
（１２２ａ）　ｔｅｒｔ－ブチル　５－｛４－［３－（アセチルアミノ）ピロリジン－１－イル］フェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　実施例（１ａ）で得られた化合物（６００　ｍｇ）、Ｎ－（ピロリジン－３－イル）アセトアミド（２４７　ｍｇ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（６８．０　ｍｇ）、（±）－２，２’－ビス（ジフェニルホスフィノ）－１，１’－ビナフチル（９２．４　ｍｇ）、ナトリウム　ｔｅｒｔ－ブトキシド（４２８　ｍｇ）、トルエン（４　ｍＬ）の混合物を１００℃で１０時間撹拌した。室温まで冷却後、ろ過、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム）で精製することで標記化合物（２４０　ｍｇ）を橙色アモルファス固体として得た。
MS (APCI) m/z: 452 (M+H)+。
（１２２ｂ）　Ｎ－（１－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピロリジン－３－イル）アセトアミド
　実施例（１２２ａ）で得られた化合物（２４０　ｍｇ）のジクロロメタン（２　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（３　ｍＬ）を加えて室温で撹拌した。３時間後、減圧濃縮することで粗製のＮ－（１－｛４－［（４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピロリジン－３－イル）アセトアミド塩酸塩を得た。 (122a) tert-butyl 5- {4- [3- (acetylamino) pyrrolidin-1-yl] phenoxy} -4-methyl-2,3-dihydro-1H-indole-1-carboxylate Example (1a) (600 mg), N- (pyrrolidin-3-yl) acetamide (247 mg), tris (dibenzylideneacetone) dipalladium (0) (68.0 mg), (±) -2,2 A mixture of '-bis (diphenylphosphino) -1,1'-binaphthyl (92.4 mg), sodium tert-butoxide (428 mg) and toluene (4 mL) was stirred at 100 ° C. for 10 hours. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / chloroform) to obtain the title compound (240 mg) as an orange amorphous solid.
MS (APCI) m / z: 452 (M + H) + .
(122b) N- (1- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} Pyrrolidin-3-yl) acetamide To a solution of the compound (240 mg) obtained in Example (122a) in dichloromethane (2 mL) was added 4N dioxane hydrochloride solution (3 mL), and the mixture was stirred at room temperature. After 3 hours, crude N- (1- {4-[(4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl} pyrrolidin-3-yl) acetamide was concentrated by concentration under reduced pressure. The hydrochloride salt was obtained.
　得られた化合物にジクロロメタン（４　ｍＬ）、［２－（メチルスルホニル）フェニル］酢酸（ＣＡＳ番号１４２３３６－２０－７）（１３７　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（１５３　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（７２．３　ｍｇ）、ジイソプロピルエチルアミン（０．２７７　ｍＬ）を加えて室温で１２時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（メタノール／酢酸エチル）で精製することで標記化合物（１４２　ｍｇ）を茶色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.98 (3H, s), 2.19 (3H, s), 2.24-2.36 (1H, m), 3.10 (3H, s), 3.15-3.32 (4H, m), 3.40-3.53 (2H, m), 4.23-4.30 (2H, m), 4.35 (2H, s), 4.59-4.68 (1H, m), 5.64-5.72 (1H, m), 6.49-6.56 (2H, m), 6.59-6.64 (1H, m), 6.83-6.89 (2H, m), 7.33-7.38 (1H, m), 7.48-7.55 (1H, m), 7.58-7.64 (1H, m), 7.88-7.93 (1H, m), 8.05-8.09 (1H, m).
MS (APCI) m/z: 548 (M+H)+。 Dichloromethane (4 mL), [2- (methylsulfonyl) phenyl] acetic acid (CAS No. 142336-20-7) (137 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide were obtained. Hydrochloric acid salt (153 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (72.3 mg), diisopropylethylamine (0.277 mL) were added, and the mixture was stirred at room temperature for 12 hours. Stir. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (142 mg) as a brown solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.98 (3H, s), 2.19 (3H, s), 2.24-2.36 (1H, m), 3.10 (3H, s), 3.15-3.32 (4H, m ), 3.40-3.53 (2H, m), 4.23-4.30 (2H, m), 4.35 (2H, s), 4.59-4.68 (1H, m), 5.64-5.72 (1H, m), 6.49-6.56 (2H , m), 6.59-6.64 (1H, m), 6.83-6.89 (2H, m), 7.33-7.38 (1H, m), 7.48-7.55 (1H, m), 7.58-7.64 (1H, m), 7.88 -7.93 (1H, m), 8.05-8.09 (1H, m).
MS (APCI) m / z: 548 (M + H) + .
　（実施例１２３）：実施例（１２３ｂ）で合成
１－｛５－［４－（１，４－ジオキサ－８－アザスピロ［４．５］デカ－８－イル）フェノキシ］－４－メチルｌ－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン Example 123: Synthesis in Example (123b) 1- {5- [4- (1,4-dioxa-8-azaspiro [4.5] dec-8-yl) phenoxy] -4-methyl 1- 2,3-Dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000168
Figure JPOXMLDOC01-appb-C000168
（１２３ａ）　ｔｅｒｔ－ブチル　５－［４－（１，４－ジオキサ－８－アザスピロ［４．５］デカ－８－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　実施例（１ａ）で得られた化合物（１　ｇ）、１，４－ジオキサ－８－アザスピロ［４．５］デカン（５３１　ｍｇ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（１１３　ｍｇ）、２－（ジシクロヘキシルホスフィノ）－２’，４’，６’－トリイソプロピル－１，１’－ビフェニル（１１８　ｍｇ）、ナトリウム　ｔｅｒｔ－ブトキシド（５９４　ｍｇ）、トルエン（５　ｍＬ）の混合物を１００℃で１０時間撹拌した。室温まで冷却後、ろ過、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（９４５　ｍｇ）を淡黄色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.55 (9H, s), 1.82-1.90 (4H, m), 2.09 (3H, s), 2.97-3.07 (2H, m), 3.17-3.27 (4H, m), 3.94-4.08 (6H, m), 6.66-6.83 (3H, m), 6.86-6.93 (2H, m), 7.57-7.72 (1H, m)。
（１２３ｂ）　１－｛５－［４－（１，４－ジオキサ－８－アザスピロ［４．５］デカ－８－イル）フェノキシ］－４－メチルｌ－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（１２３ａ）で得られた化合物（２６３　ｍｇ）のアセトン（３　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（３　ｍＬ）を加えて室温で撹拌した。３時間後、減圧濃縮することで粗製の８－｛４－［（４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－１，４－ジオキサ－８－アザスピロ［４．５］デカン塩酸塩を得た。 (123a) tert-butyl 5- [4- (1,4-dioxa-8-azaspiro [4.5] dec-8-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indole-1 -Carboxylate Compound (1 g) obtained in Example (1a), 1,4-dioxa-8-azaspiro [4.5] decane (531 mg), tris (dibenzylideneacetone) dipalladium (0) ( 113 mg), 2- (dicyclohexylphosphino) -2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl (118 mg), sodium tert-butoxide (594 mg), toluene (5 mL) The mixture was stirred at 100 ° C. for 10 hours. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (945 mg) as a pale yellow amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.55 (9H, s), 1.82-1.90 (4H, m), 2.09 (3H, s), 2.97-3.07 (2H, m), 3.17-3.27 (4H m), 3.94-4.08 (6H, m), 6.66-6.83 (3H, m), 6.86-6.93 (2H, m), 7.57-7.72 (1H, m).
(123b) 1- {5- [4- (1,4-Dioxa-8-azaspiro [4.5] dec-8-yl) phenoxy] -4-methyl l-2,3-dihydro-1H-indole- 1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone To a solution of the compound (263 mg) obtained in Example (123a) in acetone (3 mL) was added 4N dioxane hydrochloride solution (3 mL). Stir at room temperature. After 3 hours, crude 8- {4-[(4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl} -1,4-dioxa-8-azaspiro was concentrated by concentration under reduced pressure. [4.5] Decane hydrochloride was obtained.
　得られた化合物のジクロロメタン（５　ｍＬ）溶液に［２－（メチルスルホニル）フェニル］酢酸（ＣＡＳ番号１４２３３６－２０－７）（２４１　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（２１６　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（７６．６　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．２９４　ｍＬ）を加えて室温で撹拌した。１２時間後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（３０５　ｍｇ）を淡黄色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.85-1.86 (4H, m), 2.15 (3H, s), 3.11 (3H, s), 3.18-3.26 (6H, m), 3.99 (4H, s), 4.23-4.31 (2H, m), 4.36 (2H, s), 6.70 (1H, d, J = 8.3 Hz), 6.79-6.84 (2H, m), 6.87-6.92 (2H, m), 7.34-7.38 (1H, m), 7.49-7.54 (1H, m), 7.59-7.64 (1H, m), 7.91-7.95 (1H, m), 8.05-8.09 (1H, m).
MS (APCI) m/z: 563 (M+H)+。 To a solution of the obtained compound in dichloromethane (5 mL), [2- (methylsulfonyl) phenyl] acetic acid (CAS number 142336-20-7) (241 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboxyl Imide hydrochloride (216 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (76.6 mg), N, N-diisopropylethylamine (0.294 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 (ethyl acetate / hexane) to give the title compound (305 mg) as a pale yellow amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.85-1.86 (4H, m), 2.15 (3H, s), 3.11 (3H, s), 3.18-3.26 (6H, m), 3.99 (4H, s ), 4.23-4.31 (2H, m), 4.36 (2H, s), 6.70 (1H, d, J = 8.3 Hz), 6.79-6.84 (2H, m), 6.87-6.92 (2H, m), 7.34- 7.38 (1H, m), 7.49-7.54 (1H, m), 7.59-7.64 (1H, m), 7.91-7.95 (1H, m), 8.05-8.09 (1H, m).
MS (APCI) m / z: 563 (M + H) + .
　（実施例１２４）
１－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－４－オン (Example 124)
1- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-4-one
Figure JPOXMLDOC01-appb-C000169
Figure JPOXMLDOC01-appb-C000169
　実施例（１２３ｂ）で得られた化合物（３０２　ｍｇ）のアセトン（８　ｍＬ）溶液に３５％塩酸（８　ｍＬ）を加えて外温８０℃で３時間撹拌した。室温まで冷却後、減圧濃縮した。残渣をジクロロメタンで抽出した後、有機層を無水硫酸ナトリウムで乾燥した。ろ過、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（１９１　ｍｇ）を黄色アモルファス固体として得た。
MS (APCI) m/z: 519 (M+H)+。 35% hydrochloric acid (8 mL) was added to a solution of the compound (302 mg) obtained in Example (123b) in acetone (8 mL), and the mixture was stirred at an external temperature of 80 ° C. for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was extracted with dichloromethane, and the organic layer was 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 (191 mg) as a yellow amorphous solid.
MS (APCI) m / z: 519 (M + H) + .
　（実施例１２５）
１－｛５－［４－（４－ヒドロキシピペリジン－１－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン (Example 125)
1- {5- [4- (4-Hydroxypiperidin-1-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl ] Ethanon
Figure JPOXMLDOC01-appb-C000170
Figure JPOXMLDOC01-appb-C000170
　実施例１２４で得られた化合物（１９１　ｍｇ）のメタノール（３　ｍＬ）、テトラヒドロフラン（１．５　ｍＬ）溶液に水素化ホウ素ナトリウム（２７．９　ｍｇ）を０℃で加えた。０℃で１時間撹拌した後、１Ｎ塩酸水溶液を加えた。減圧濃縮により有機溶媒を留去した後、ジクロロメタンで抽出した。有機層を無水硫酸ナトリウムで乾燥後、ろ過、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール／酢酸エチル）で精製することで標記化合物（１４３　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.66-1.76 (2H, m), 1.97-2.05 (2H, m), 2.15 (3H, s), 2.80-2.89 (2H, m), 3.11 (3H, s), 3.17-3.24 (2H, m), 3.40-3.48 (2H, m), 3.78-3.87 (1H, m), 4.24-4.31 (2H, m), 4.36 (2H, s), 6.67-6.72 (1H, m), 6.79-6.84 (2H, m), 6.86-6.92 (2H, m), 7.34-7.38 (1H, m), 7.48-7.54 (1H, m), 7.58-7.64 (1H, m), 7.90-7.95 (1H, m), 8.05-8.09 (1H, m).
MS (APCI) m/z: 521 (M+H)+。 To a solution of the compound obtained in Example 124 (191 mg) in methanol (3 mL) and tetrahydrofuran (1.5 mL), sodium borohydride (27.9 mg) was added at 0 ° C. After stirring at 0 ° C. for 1 hour, 1N aqueous hydrochloric acid solution was added. The organic solvent was distilled off by concentration under reduced pressure, followed by extraction 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 (methanol / ethyl acetate) to give the title compound (143 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.66-1.76 (2H, m), 1.97-2.05 (2H, m), 2.15 (3H, s), 2.80-2.89 (2H, m), 3.11 (3H , s), 3.17-3.24 (2H, m), 3.40-3.48 (2H, m), 3.78-3.87 (1H, m), 4.24-4.31 (2H, m), 4.36 (2H, s), 6.67-6.72 (1H, m), 6.79-6.84 (2H, m), 6.86-6.92 (2H, m), 7.34-7.38 (1H, m), 7.48-7.54 (1H, m), 7.58-7.64 (1H, m) , 7.90-7.95 (1H, m), 8.05-8.09 (1H, m).
MS (APCI) m / z: 521 (M + H) + .
　（実施例１２６）
４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］－２－メチルフェニル｝－１－メチルピペラジン－２－オン (Example 126)
4- {4-[(1-{[2- (Ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] -2-methylphenyl} -1 -Methylpiperazin-2-one
Figure JPOXMLDOC01-appb-C000171
Figure JPOXMLDOC01-appb-C000171
　実施例（１ｂ）と同様の手法により合成した１－［５－（４－ブロモフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（エチルスルホニル）フェニル］エタノン（５００　ｍｇ）、１－メチルピペラジン－２－オン（１３０　ｍｇ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（４３．３　ｍｇ）、（±）－２，２’－ビス（ジフェニルホスフィノ）－１，１’－ビナフチル（５８．９　ｍｇ）、ナトリウム　ｔｅｒｔ－ブトキシド（２７３　ｍｇ）、トルエン（５　ｍＬ）の混合物を１００℃で１０時間撹拌した。室温まで冷却後、ろ過、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム）で精製することで標記化合物（５３．０　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.26 (3H, t, J = 7.2 Hz), 2.13 (3H, s), 2.26 (3H, s), 3.03 (3H, s), 3.11-3.26 (6H, m), 3.39-3.44 (2H, m), 3.56 (2H, s), 4.24-4.31 (2H, m), 4.37 (2H, s), 6.65-6.71 (1H, m), 6.73-6.78 (2H, m), 6.89-6.94 (1H, m), 7.37-7.43 (1H, m), 7.47-7.55 (1H, m), 7.60-7.66 (1H, m), 7.94-7.99 (1H, m), 8.01-8.06 (1H, m).
MS (APCI) m/z: 562 (M+H)+。 1- [5- (4-Bromophenoxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2- [2- (ethyl) synthesized by the same method as in Example (1b) (Sulfonyl) phenyl] ethanone (500 mg), 1-methylpiperazin-2-one (130 mg), tris (dibenzylideneacetone) dipalladium (0) (43.3 mg), (±) -2,2′- A mixture of bis (diphenylphosphino) -1,1′-binaphthyl (58.9 mg), sodium tert-butoxide (273 mg) and toluene (5 mL) was stirred at 100 ° C. for 10 hours. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / chloroform) to obtain the title compound (53.0 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.2 Hz), 2.13 (3H, s), 2.26 (3H, s), 3.03 (3H, s), 3.11-3.26 ( 6H, m), 3.39-3.44 (2H, m), 3.56 (2H, s), 4.24-4.31 (2H, m), 4.37 (2H, s), 6.65-6.71 (1H, m), 6.73-6.78 ( 2H, m), 6.89-6.94 (1H, m), 7.37-7.43 (1H, m), 7.47-7.55 (1H, m), 7.60-7.66 (1H, m), 7.94-7.99 (1H, m), 8.01-8.06 (1H, m).
MS (APCI) m / z: 562 (M + H) + .
　（実施例１２７）：実施例（１２７ｃ）で合成
４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝モルホリン－３－オン Example 127: Synthesis in Example (127c) 4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole-5 -Yl) oxy] phenyl} morpholin-3-one
Figure JPOXMLDOC01-appb-C000172
Figure JPOXMLDOC01-appb-C000172
（１２７ａ）　ｔｅｒｔ－ブチル　４－メチル－５－［４－（３－オキソモルホリン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　ｔｅｒｔ－ブチル　５－ヒドロキシ－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボン酸（１．００　ｇ）及び４－（４－ブロモフェニル）モルホリン－３－オン（１．１３　ｇ）のジオキサン（１５　ｍＬ）溶液にヨウ化銅（Ｉ）（１５２　ｍｇ）、Ｎ，Ｎ－ジメチルグリシン（１６６　ｍｇ）、炭酸セシウム（２．６１　ｇ）を加え、１００℃で１２時間攪拌した。放冷後、反応液に飽和塩化アンモニウム水溶液、飽和炭酸水素ナトリウム水溶液を順次加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）にて精製することにより、標記化合物を含む混合物（８８０　ｍｇ）を淡赤色固体として得た。
MS(APCI) m/z: 425 (M+H)+。
（１２７ｂ）　４－｛４－［（４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝モルホリン－３－オン　トリフルオロ酢酸塩
　実施例（１２７ａ）で得られた混合物（３６５　ｍｇ）をジクロロメタン（５　ｍＬ）に溶解し、室温にてトリフルオロ酢酸を加え、同温にて３時間攪拌した。反応液を減圧下濃縮し、減圧下、乾燥することで、粗製の標記化合物（３７０　ｍｇ）を茶褐色油状物として得た。本化合物はそのまま次工程に用いた。
（１２７ｃ）　４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝モルホリン－３－オン
　実施例（１２７ｂ）で得られた化合物（１９５　ｍｇ）のジオキサン（８　ｍＬ）溶液にジイソプロピルエチルアミン（０．２０６　ｍＬ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（１５０　ｍｇ）及び[２－（メチルスルホニル）フェニル]酢酸（１０９　ｍｇ）を加え、室温で２４時間攪拌した。水を加え酢酸エチルで３回抽出し、合わせた有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／ジクロロメタン）にて精製することにより、標記化合物を含む混合物（１３５　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.11 (3H, s), 3.12 (3H, s), 3.17-3.27 (2H, m), 3.70-3.75 (2H, m), 3.99-4.05 (2H, m), 4.24-4.39 (6H, m), 6.81 (1H, d, J= 8.5 Hz), 6.89 (2H, dd, J = 8.5, 2.1 Hz), 7.18-7.24 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.49-7.55 (1H, m), 7.58-7.65 (1H, m), 7.96-8.02 (1H, m), 8.07 (1H, d, J = 7.9 Hz).
MS(APCI) m/z: 521 (M+H)+。 (127a) tert-butyl 4-methyl-5- [4- (3-oxomorpholin-4-yl) phenoxy] -2,3-dihydro-1H-indole-1-carboxylate tert-butyl 5-hydroxy-4 A solution of methyl-2,3-dihydro-1H-indole-1-carboxylic acid (1.00 g) and 4- (4-bromophenyl) morpholin-3-one (1.13 g) in dioxane (15 mL) To the mixture were added copper (I) iodide (152 mg), N, N-dimethylglycine (166 mg) and cesium carbonate (2.61 g), and the mixture was stirred at 100 ° C. for 12 hours. After allowing to cool, a saturated aqueous ammonium chloride solution and a saturated aqueous sodium hydrogen carbonate solution were sequentially added to the reaction solution, 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 a mixture (880 mg) containing the title compound as a pale red solid.
MS (APCI) m / z: 425 (M + H) + .
(127b) 4- {4-[(4-Methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl} morpholin-3-one trifluoroacetate obtained in Example (127a) The mixture (365 mg) was dissolved in dichloromethane (5 mL), trifluoroacetic acid was added at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was concentrated under reduced pressure and dried under reduced pressure to give the crude title compound (370 mg) as a brown oil. This compound was directly used in the next step.
(127c) 4- {4-[(4-Methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} morpholine-3 -On A solution of the compound obtained in Example (127b) (195 mg) in dioxane (8 mL) was added diisopropylethylamine (0.206 mL), 4- (4,6-dimethoxy-1,3,5-triazine- 2-yl) -4-methylmorpholinium chloride (150 mg) and [2- (methylsulfonyl) phenyl] acetic acid (109 mg) were added, and the mixture was stirred at room temperature for 24 hours. Water was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (methanol / dichloromethane) to give a mixture (135 mg) containing the title compound as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.11 (3H, s), 3.12 (3H, s), 3.17-3.27 (2H, m), 3.70-3.75 (2H, m), 3.99-4.05 (2H , m), 4.24-4.39 (6H, m), 6.81 (1H, d, J = 8.5 Hz), 6.89 (2H, dd, J = 8.5, 2.1 Hz), 7.18-7.24 (2H, m), 7.36 ( 1H, d, J = 7.9 Hz), 7.49-7.55 (1H, m), 7.58-7.65 (1H, m), 7.96-8.02 (1H, m), 8.07 (1H, d, J = 7.9 Hz).
MS (APCI) m / z: 521 (M + H) + .
　（実施例１２８）
４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝モルホリン－３－オン (Example 128)
4- {4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl} morpholin-3-one
Figure JPOXMLDOC01-appb-C000173
Figure JPOXMLDOC01-appb-C000173
　実施例（１２７ｂ）で得られた化合物（１１０　ｍｇ）のジオキサン（８　ｍＬ）溶液にジイソプロピルエチルアミン（０．１１６　ｍＬ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（８５．１　ｍｇ）及び[２－（エチルスルホニル）フェニル]酢酸（ＣＡＳ番号１３６３１７９－４７－８）（６３．０　ｍｇ）を加え、室温で２４時間攪拌した。水を加え酢酸エチルで３回抽出し、合わせた有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／ジクロロメタン）にて精製することにより、標記化合物を含む混合物（１３６　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.28 (3H, t, J = 7.9 Hz), 2.12 (3H, s), 3.16-3.26 (4H, m), 3.69-3.80 (2H, m), 3.99-4.07 (2H, m), 4.21-4.44 (6H, m), 6.81 (1H, d, J = 8.5 Hz), 6.89 (2H, d, J = 8.5 Hz), 7.15-7.30 (2H, m), 7.37-7.43 (1H, m), 7.48-7.54 (1H, m), 7.59-7.66 (1H, m), 7.96-8.05 (2H, m).
MS(APCI) m/z: 535 (M+H)+。 To a solution of the compound (110 mg) obtained in Example (127b) in dioxane (8 mL) was added diisopropylethylamine (0.116 mL), 4- (4,6-dimethoxy-1,3,5-triazine-2- Yl) -4-methylmorpholinium chloride (85.1 mg) and [2- (ethylsulfonyl) phenyl] acetic acid (CAS No. 1363179-47-8) (63.0 mg) were added and stirred at room temperature for 24 hours. did. Water was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (methanol / dichloromethane) to give a mixture (136 mg) containing the title compound as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.28 (3H, t, J = 7.9 Hz), 2.12 (3H, s), 3.16-3.26 (4H, m), 3.69-3.80 (2H, m), 3.99-4.07 (2H, m), 4.21-4.44 (6H, m), 6.81 (1H, d, J = 8.5 Hz), 6.89 (2H, d, J = 8.5 Hz), 7.15-7.30 (2H, m) , 7.37-7.43 (1H, m), 7.48-7.54 (1H, m), 7.59-7.66 (1H, m), 7.96-8.05 (2H, m).
MS (APCI) m / z: 535 (M + H) + .
　（実施例１２９）：実施例（１２９ｃ）で合成
１－｛４－メチル－５－［４－（モルホリン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル）｝－２－［２－（メチルスルホニル）フェニル］エタノン Example 129: synthesized in Example (129c) 1- {4-methyl-5- [4- (morpholin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl)} -2- [2- (Methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000174
Figure JPOXMLDOC01-appb-C000174
（１２９ａ）　ｔｅｒｔ－ブチル　４－メチル－５－［４－（３－モルホリン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　ｔｅｒｔ－ブチル　５－ヒドロキシ－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボン酸（１．００　ｇ）及び４－（４－ブロモフェニル）モルホリン（１．４６　ｇ）のジオキサン（１５　ｍＬ）溶液にヨウ化銅（Ｉ）（１５３　ｍｇ）、Ｎ，Ｎ－ジメチルグリシン（１６６　ｍｇ）、炭酸セシウム（２．６１　ｇ）を加え、９０℃で２５時間攪拌した。放冷後、酢酸エチルを加え３０分間攪拌後、不溶物をろ去した。溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）にて精製することにより、標記化合物を含む混合物（１２５　ｍｇ）を茶褐色アモルファス固体として得た。
MS(APCI) m/z: 411 (M+H)+。
（１２９ｂ）　４－メチル－５－［４－（モルホリン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール　トリフルオロ酢酸塩
　実施例（１２９ａ）で得られた混合物（３７０　ｍｇ）をジクロロメタン（５　ｍＬ）に溶解し、室温にてトリフルオロ酢酸（８　ｍＬ）を加え、同温にて３時間攪拌した。反応液を減圧下濃縮し、減圧下、乾燥することで、粗製の標記化合物（３８５　ｍｇ）を茶褐色油状物として得た。本化合物はそのまま次工程に用いた。
（１２９ｃ）　１－｛４－メチル－５－［４－（モルホリン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル）｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（１２９ｂ）で得られた化合物（１６５　ｍｇ）のジオキサン（８　ｍＬ）溶液にジイソプロピルエチルアミン（０．１８０　ｍＬ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（１３２　ｍｇ）及び[２－（メチルスルホニル）フェニル]酢酸（ＣＡＳ番号１４２３３６－２０－７）（９１．６　ｍｇ）を加え、室温で４８時間攪拌した。水を加え酢酸エチルで３回抽出し、合わせた有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリムで乾燥し、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）にて精製することにより、標記化合物（２１．０　ｍｇ）を褐色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.15 (3H, s), 3.04-3.24 (7H, m), 3.82-3.89 (6H, m), 4.28 (2H, t, J = 7.9 Hz), 4.36 (2H, s), 6.69 (1H, d, J = 8.5 Hz), 6.79-6.89 (4H, m), 7.36 (1H, d, J = 7.9 Hz), 7.51 (1H, t, J = 7.3 Hz), 7.59-7.64 (1H, m), 7.93 (1H, d, J= 8.5 Hz), 8.05-8.09 (1H, m).
MS(APCI) m/z: 507 (M+H)+。 (129a) tert-butyl 4-methyl-5- [4- (3-morpholin-4-yl) phenoxy] -2,3-dihydro-1H-indole-1-carboxylate tert-butyl 5-hydroxy-4- To a solution of methyl-2,3-dihydro-1H-indole-1-carboxylic acid (1.00 g) and 4- (4-bromophenyl) morpholine (1.46 g) in dioxane (15 mL) was added copper iodide (15 mL). I) (153 mg), N, N-dimethylglycine (166 mg) and cesium carbonate (2.61 g) were added, and the mixture was stirred at 90 ° C. for 25 hours. After allowing to cool, ethyl acetate was added, and the mixture was stirred for 30 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give a mixture (125 mg) containing the title compound as a brown amorphous solid.
MS (APCI) m / z: 411 (M + H) + .
(129b) 4-methyl-5- [4- (morpholin-4-yl) phenoxy] -2,3-dihydro-1H-indole trifluoroacetate The mixture (370 mg) obtained in Example (129a) Dissolved in dichloromethane (5 mL), trifluoroacetic acid (8 mL) was added at room temperature, and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and dried under reduced pressure to give the crude title compound (385 mg) as a brown oil. This compound was directly used in the next step.
(129c) 1- {4-Methyl-5- [4- (morpholin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl)}-2- [2- (methylsulfonyl) Phenyl] ethanone To a solution of the compound obtained in Example (129b) (165 mg) in dioxane (8 mL) was added diisopropylethylamine (0.180 mL), 4- (4,6-dimethoxy-1,3,5-triazine. -2-yl) -4-methylmorpholinium chloride (132 mg) and [2- (methylsulfonyl) phenyl] acetic acid (CAS No. 142336-20-7) (91.6 mg) were added and the mixture was stirred at room temperature for 48 hours. Stir. Water was added and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (21.0 mg) as a brown amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.15 (3H, s), 3.04-3.24 (7H, m), 3.82-3.89 (6H, m), 4.28 (2H, t, J = 7.9 Hz), 4.36 (2H, s), 6.69 (1H, d, J = 8.5 Hz), 6.79-6.89 (4H, m), 7.36 (1H, d, J = 7.9 Hz), 7.51 (1H, t, J = 7.3 Hz ), 7.59-7.64 (1H, m), 7.93 (1H, d, J = 8.5 Hz), 8.05-8.09 (1H, m).
MS (APCI) m / z: 507 (M + H) + .
　（実施例１３０）：実施例（１３０ｃ）で合成
１－｛５－［（１’－アセチル－１’，２’，３’，６’－テトラヒドロ－２，４’－ビピリジン－５－イル）オキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン Example 130: Synthesis in Example (130c) 1- {5-[(1′-acetyl-1 ′, 2 ′, 3 ′, 6′-tetrahydro-2,4′-bipyridin-5-yl) Oxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (ethylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000175
Figure JPOXMLDOC01-appb-C000175
（１３０ａ）　ｔｅｒｔ－ブチル　５－［（６－ブロモピリジン－３－イル）オキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　ｔｅｒｔ－ブチル　５－ヒドロキシ－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート（１　ｇ）及び２－ブロモ－５－フルオロピリジン（０．７７７　ｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液に炭酸セシウム（３．９２　ｇ）を加え、マイクロウェーブ反応装置にて１５０℃で７０分間反応させた。反応液を減圧下濃縮し、シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（０．５８０　ｇ）を白色固体として得た。
MS (APCI) m/z: 405 (M+H)+。
（１３０ｂ）　１－｛５－［（６－ブロモピリジン－３－イル）オキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン
　実施例（１３０ａ）で得られた化合物（４００　ｍｇ）をジクロロメタン（１０　ｍＬ）に溶解し、室温で４Ｎ塩酸ジオキサン溶液（４．０　ｍＬ）を加え４時間攪拌した。反応液を濃縮し、粗製の５－［（６－ブロモピリジン－３－イル）オキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール塩酸塩（３３５　ｍｇ）を得た。 (130a) tert-butyl 5-[(6-bromopyridin-3-yl) oxy] -4-methyl-2,3-dihydro-1H-indole-1-carboxylate tert-butyl 5-hydroxy-4-methyl -2,3-dihydro-1H-indole-1-carboxylate (1 g) and 2-bromo-5-fluoropyridine (0.777 g) in N, N-dimethylformamide (5 mL) in cesium carbonate (5 mL) 3.92 g) was added and reacted in a microwave reactor at 150 ° C. for 70 minutes. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.580 g) as a white solid.
MS (APCI) m / z: 405 (M + H) + .
(130b) 1- {5-[(6-Bromopyridin-3-yl) oxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (ethylsulfonyl) Phenyl] ethanone The compound (400 mg) obtained in Example (130a) was dissolved in dichloromethane (10 mL), 4N hydrochloric acid dioxane solution (4.0 mL) was added at room temperature, and the mixture was stirred for 4 hours. The reaction mixture was concentrated to give crude 5-[(6-bromopyridin-3-yl) oxy] -4-methyl-2,3-dihydro-1H-indole hydrochloride (335 mg).
　得られた化合物（３３５　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液に４－メチルモルホリン（０．２１６　ｍＬ）を加え室温で２０分間攪拌した。次いで、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（３５３　ｍｇ）及び[２－（エチルスルホニル）フェニル]酢酸（ＣＡＳ番号１３６３１７９－４７－８）（２６９　ｍｇ）を加え、さらに室温で３時間攪拌した。反応液を減圧下濃縮し、シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（４００　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.27 (3H, t, J = 7.3 Hz), 2.10 (3H, s), 3.17-3.25 (4H, m), 4.29 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.79 (1H, d, J= 9.1 Hz), 7.03 (1H, dd, J = 8.5, 3.0 Hz), 7.34-7.41 (2H, m), 7.49-7.54 (1H, m), 7.60-7.65 (1H, m), 7.99-8.07 (3H, m).
MS (APCI) m/z: 515 (M+H)+。
（１３０ｃ）　１－｛５－［（１’－アセチル－１’，２’，３’，６’－テトラヒドロ－２，４’－ビピリジン－５－イル）オキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン
　（実施例１３０ｂ）で得られた化合物（１００　ｍｇ）、１－［４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）－３，６－ジヒドロピリジン－１（２Ｈ）－イル］エタノン（７３．１　ｍｇ）の１，２－ジメトキシエタン（２　ｍＬ）溶液に炭酸ナトリウム（６１．７　ｍｇ）水溶液（１　ｍＬ）及び［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（１５．８　ｍｇ）を加え、マイクロウェーブ反応装置にて、１００℃で１５分間反応させた。反応液を室温に冷却後、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／ジクロロメタン）で精製することで、標記化合物（７０．０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.26 (3H, t, J = 7.3 Hz), 2.12 (3H, s), 2.14 (3H x 1/2, s), 2.17 (3H x 1/2, s), 2.58-2.74 (2H, br m), 3.16-3.25 (2H, m), 3.66 (1H, t, J = 5.8 Hz), 3.83 (1H, t, J = 5.8 Hz), 4.09-4.20 (2H, m), 4.24-4.32 (4H, m), 4.37 (2H, s), 6.44-6.55 (1H, br m), 6.79 (1H, d, J = 8.5 Hz), 7.07-7.13 (1H, m), 7.28-7.34 (1H, m), 7.40 (1H, d, J= 7.9 Hz), 7.51 (1H, t, J = 7.6 Hz), 7.63 (1H, t, J = 7.6 Hz), 7.98-8.05 (2H, m), 8.26-8.28 (1H, m).
MS (APCI) m/z: 560 (M+H)+。 4-Methylmorpholine (0.216 mL) was added to a solution of the obtained compound (335 mg) in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 20 minutes. Then 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (353 mg) and [2- (ethylsulfonyl) phenyl] acetic acid (CAS No. 1363179) -47-8) (269 mg) was added, and the mixture was further stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (400 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.10 (3H, s), 3.17-3.25 (4H, m), 4.29 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.79 (1H, d, J = 9.1 Hz), 7.03 (1H, dd, J = 8.5, 3.0 Hz), 7.34-7.41 (2H, m), 7.49-7.54 (1H , m), 7.60-7.65 (1H, m), 7.99-8.07 (3H, m).
MS (APCI) m / z: 515 (M + H) + .
(130c) 1- {5-[(1′-acetyl-1 ′, 2 ′, 3 ′, 6′-tetrahydro-2,4′-bipyridin-5-yl) oxy] -4-methyl-2,3 -Dihydro-1H-indol-1-yl} -2- [2- (ethylsulfonyl) phenyl] ethanone Compound obtained in Example 130b (100 mg), 1- [4- (4,4,5 , 5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydropyridin-1 (2H) -yl] ethanone (73.1 mg) in 1,2-dimethoxyethane (2 mL) To the solution was added an aqueous solution (1 mL) of sodium carbonate (61.7 mg) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (15.8 mg), and a microwave reactor was added. In It was allowed to react for 15 minutes at 100 ° C.. 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 (methanol / dichloromethane) to give the title compound (70.0 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 2.12 (3H, s), 2.14 (3H x 1/2, s), 2.17 (3H x 1/2 , s), 2.58-2.74 (2H, br m), 3.16-3.25 (2H, m), 3.66 (1H, t, J = 5.8 Hz), 3.83 (1H, t, J = 5.8 Hz), 4.09-4.20 (2H, m), 4.24-4.32 (4H, m), 4.37 (2H, s), 6.44-6.55 (1H, br m), 6.79 (1H, d, J = 8.5 Hz), 7.07-7.13 (1H, m), 7.28-7.34 (1H, m), 7.40 (1H, d, J = 7.9 Hz), 7.51 (1H, t, J = 7.6 Hz), 7.63 (1H, t, J = 7.6 Hz), 7.98- 8.05 (2H, m), 8.26-8.28 (1H, m).
MS (APCI) m / z: 560 (M + H) + .
　（実施例１３１）
１－（５－｛［６－（１－アセチルピペリジン－４－イル）ピリジン－３－イル］オキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（エチルスルホニル）フェニル］エタノン (Example 131)
1- (5-{[6- (1-acetylpiperidin-4-yl) pyridin-3-yl] oxy} -4-methyl-2,3-dihydro-1H-indol-1-yl) -2- [ 2- (Ethylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000176
Figure JPOXMLDOC01-appb-C000176
　実施例（１３０ｃ）で得られた化合物（５４．０　ｍｇ）をジクロロメタン（５　ｍＬ）及びメタノール（５　ｍＬ）に溶解し、７．５％パラジウム炭素（３０．０　ｍｇ）を加え、水素雰囲気下室温にて３０分間攪拌した。不溶物をろ去し、ろ液を減圧下濃縮して標記化合物（５２．０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.26 (3H, t, J = 7.3 Hz), 1.62-1.79 (2H, m), 1.89-2.03 (2H, m), 2.12 (6H, s), 2.61-2.71 (1H, m), 2.85-2.95 (1H, br m), 3.15-3.25 (5H, m), 3.94 (1H, d, J = 13.4 Hz), 4.28 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 4.76 (1H, d, J = 13.4 Hz), 6.77 (1H, d, J = 8.5 Hz), 7.02-7.10 (2H, m), 7.39 (1H, d, J = 7.6 Hz), 7.51 (1H, t, J = 7.6 Hz), 7.63 (1H, t, J = 7.6 Hz), 8.01 (2H, dd, J = 15.6, 8.2 Hz), 8.25 (1H, d, J = 2.4 Hz).
MS (APCI) m/z: 562 (M+H)+。 The compound (54.0 mg) obtained in Example (130c) was dissolved in dichloromethane (5 mL) and methanol (5 mL), 7.5% palladium carbon (30.0 mg) was added, and hydrogen atmosphere was added. Stir at room temperature for 30 minutes. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (52.0 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.62-1.79 (2H, m), 1.89-2.03 (2H, m), 2.12 (6H, s), 2.61-2.71 (1H, m), 2.85-2.95 (1H, br m), 3.15-3.25 (5H, m), 3.94 (1H, d, J = 13.4 Hz), 4.28 (2H, t, J = 8.5 Hz ), 4.37 (2H, s), 4.76 (1H, d, J = 13.4 Hz), 6.77 (1H, d, J = 8.5 Hz), 7.02-7.10 (2H, m), 7.39 (1H, d, J = 7.6 Hz), 7.51 (1H, t, J = 7.6 Hz), 7.63 (1H, t, J = 7.6 Hz), 8.01 (2H, dd, J = 15.6, 8.2 Hz), 8.25 (1H, d, J = 2.4 Hz).
MS (APCI) m / z: 562 (M + H) + .
　（実施例１３２）：実施例（１３２ｂ）で合成
１－｛５－［（１’－アセチル－１’，２’，３’，６’－テトラヒドロ－２，４’－ビピリジン－５－イル）オキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン Example 132: Synthesis in Example (132b) 1- {5-[(1′-acetyl-1 ′, 2 ′, 3 ′, 6′-tetrahydro-2,4′-bipyridin-5-yl) Oxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000177
Figure JPOXMLDOC01-appb-C000177
（１３２ａ）　１－｛５－［（６－ブロモピリジン－３－イル）オキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　（１３０ｂ）で得られた粗製の５－［（６－ブロモピリジン－３－イル）オキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール塩酸塩（４００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液に４－メチルモルホリン（０．２３３　ｍＬ）を加え室温で２０分間攪拌した。次いで、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（３８１　ｍｇ）及び[２－（メチルスルホニル）フェニル]酢酸（ＣＡＳ番号１４２３３６－２０－７）（２７２　ｍｇ）を加え、さらに室温で３時間攪拌した。反応液を減圧下濃縮し、シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（４６０　ｍｇ）を白色固体として得た。
MS (APCI) m/z: 501 (M+H)+。
（１３２ｂ）　１－｛５－［（１’－アセチル－１’，２’，３’，６’－テトラヒドロ－２，４’－ビピリジン－５－イル）オキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　（１３２ａ）で得られた化合物（１９０　ｍｇ）及び１－［４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）－３，６－ジヒドロピリジン－１（２Ｈ）－イル］エタノン（１４３　ｍｇ）の１，２－ジメトキシエタン（２　ｍＬ）溶液に炭酸ナトリウム（１２１　ｍｇ）水溶液（０．５　ｍＬ）及び［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（３１．０　ｍｇ）を加え、マイクロウェーブ反応装置にて、１００℃で１５分間反応させた。反応液を室温に冷却後、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１００　ｍｇ）を淡黄色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.12 (3H, s), 2.14 (3H x 1/2, s), 2.17 (3H x 1/2, s), 2.58-2.75 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.2 Hz), 3.66 (1H, t, J = 5.8 Hz), 3.83 (1H, t, J = 5.8 Hz), 4.15-4.20 (1H, br m), 4.25-4.33 (3H, m), 4.37 (2H, s), 6.44-6.54 (1H, m), 6.79 (1H, d, J = 8.5 Hz), 7.10 (1H, dd, J = 8.5, 2.4 Hz), 7.28-7.39 (2H, m), 7.53 (1H, t, J = 7.3 Hz), 7.63 (1H, t, J = 7.3 Hz), 8.00 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz), 8.28 (1H, dd, J = 7.9, 2.4 Hz).
MS (APCI) m/z: 546 (M+H)+。 (132a) 1- {5-[(6-Bromopyridin-3-yl) oxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) The crude 5-[(6-bromopyridin-3-yl) oxy] -4-methyl-2,3-dihydro-1H-indole hydrochloride (400 mg) N, obtained with phenyl] ethanone (130b), 4-Methylmorpholine (0.233 mL) was added to an N-dimethylformamide (5 mL) solution, and the mixture was stirred at room temperature for 20 minutes. Then 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (381 mg) and [2- (methylsulfonyl) phenyl] acetic acid (CAS No. 142336) -20-7) (272 mg) was added, and the mixture was further stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (460 mg) as a white solid.
MS (APCI) m / z: 501 (M + H) + .
(132b) 1- {5-[(1′-acetyl-1 ′, 2 ′, 3 ′, 6′-tetrahydro-2,4′-bipyridin-5-yl) oxy] -4-methyl-2,3 -Dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone (132 mg) (190 mg) and 1- [4- (4,4,5,5) -Tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydropyridin-1 (2H) -yl] ethanone (143 mg) in 1,2-dimethoxyethane (2 mL) in sodium carbonate (121 mg) aqueous solution (0.5 mL) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (31.0 mg) were added, and in a microwave reactor, 00 was allowed to react for 15 minutes at ° C.. 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 (100 mg) as a pale yellow solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.12 (3H, s), 2.14 (3H x 1/2, s), 2.17 (3H x 1/2, s), 2.58-2.75 (2H, m) , 3.12 (3H, s), 3.22 (2H, t, J = 8.2 Hz), 3.66 (1H, t, J = 5.8 Hz), 3.83 (1H, t, J = 5.8 Hz), 4.15-4.20 (1H, br m), 4.25-4.33 (3H, m), 4.37 (2H, s), 6.44-6.54 (1H, m), 6.79 (1H, d, J = 8.5 Hz), 7.10 (1H, dd, J = 8.5 , 2.4 Hz), 7.28-7.39 (2H, m), 7.53 (1H, t, J = 7.3 Hz), 7.63 (1H, t, J = 7.3 Hz), 8.00 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz), 8.28 (1H, dd, J = 7.9, 2.4 Hz).
MS (APCI) m / z: 546 (M + H) + .
　（実施例１３３）
１－（５－｛［６－（１－アセチルピペリジン－４－イル）ピリジン－３－イル］オキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［２－（メチルスルホニル）フェニル］エタノン (Example 133)
1- (5-{[6- (1-acetylpiperidin-4-yl) pyridin-3-yl] oxy} -4-methyl-2,3-dihydro-1H-indol-1-yl) -2- [ 2- (Methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000178
Figure JPOXMLDOC01-appb-C000178
　実施例（１３２ｂ）で得られた化合物（３０．０　ｍｇ）をジクロロメタン（５　ｍＬ）及びメタノール（５　ｍＬ）に溶解し、７．５％パラジウム炭素（１０．０　ｍｇ）を加え、水素雰囲気下室温にて２時間攪拌した。不溶物をろ去し、ろ液を減圧下濃縮して標記化合物（２５．０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.67-1.81 (2H, m), 1.90-2.03 (2H, m), 2.12 (3H, s), 2.13 (3H, s), 2.46-2.53 (1H, m), 2.62-2.71 (1H, m), 3.12 (3H, s), 3.17-3.25 (3H, m), 3.87-3.97 (2H, m), 4.30 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.76 (1H, d, J = 8.5 Hz), 7.02-7.10 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.50-7.55 (1H, m), 7.59-7.65 (1H, m), 7.99 (1H, d, J = 8.5 Hz), 8.05-8.09 (1H, m), 8.26 (1H, d, J = 2.4 Hz).
MS (APCI) m/z: 548 (M+H)+。 The compound (30.0 mg) obtained in Example (132b) was dissolved in dichloromethane (5 mL) and methanol (5 mL), 7.5% palladium carbon (10.0 mg) was added, and hydrogen atmosphere was added. Stir at room temperature for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (25.0 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.67-1.81 (2H, m), 1.90-2.03 (2H, m), 2.12 (3H, s), 2.13 (3H, s), 2.46-2.53 (1H , m), 2.62-2.71 (1H, m), 3.12 (3H, s), 3.17-3.25 (3H, m), 3.87-3.97 (2H, m), 4.30 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.76 (1H, d, J = 8.5 Hz), 7.02-7.10 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.50-7.55 (1H, m), 7.59 -7.65 (1H, m), 7.99 (1H, d, J = 8.5 Hz), 8.05-8.09 (1H, m), 8.26 (1H, d, J = 2.4 Hz).
MS (APCI) m / z: 548 (M + H) + .
　（実施例１３４）
１－［５－（４－｛１－［（２Ｒ）－１，４－ジオキサン－２－イルカルボニル］ピペリジン－４－イル｝フェノキシ）－４－メチル－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン (Example 134)
1- [5- (4- {1-[(2R) -1,4-dioxan-2-ylcarbonyl] piperidin-4-yl} phenoxy) -4-methyl-1H-indol-1-yl] -2 -[2- (Methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000179
Figure JPOXMLDOC01-appb-C000179
　実施例（１ｇ－２）として得られた化合物（１５０　ｍｇ）のクロロホルム（１０　ｍＬ）溶液に酸化マンガン（ＩＶ）（６３２　ｍｇ）を加え、３６時間加熱還流した。反応液にクロロホルムを加え、セライトろ過を行い、減圧下にて濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（２３．１　ｍｇ）を黄色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.54-1.74 (2H, m), 1.84-1.96 (2H, m), 2.39 (3H, s), 2.58-2.78 (2H, m), 3.00-3.21 (4H, m), 3.63-3.99 (6H, m), 4.06-4.16 (1H, br m), 4.28-4.38 (1H, br m), 4.65-4.75 (1H, br m), 4.88 (2H, s), 6.76 (1H, d, J = 3.7 Hz), 6.81 (2H, d, J = 8.5 Hz), 6.97 (1H, d, J = 9.2 Hz), 7.06-7.12 (2H, m), 7.40 (1H, d, J = 6.7 Hz), 7.55-7.61 (1H, m), 7.62-7.68 (2H, m), 8.10-8.13 (1H, m), 8.21 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 617 (M+H)+。 Manganese (IV) oxide (632 mg) was added to a solution of the compound (150 mg) obtained in Example (1g-2) in chloroform (10 mL), and the mixture was heated to reflux for 36 hours. Chloroform was added to the reaction solution, filtered through celite, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (23.1 mg) as a yellow solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.54-1.74 (2H, m), 1.84-1.96 (2H, m), 2.39 (3H, s), 2.58-2.78 (2H, m), 3.00-3.21 (4H, m), 3.63-3.99 (6H, m), 4.06-4.16 (1H, br m), 4.28-4.38 (1H, br m), 4.65-4.75 (1H, br m), 4.88 (2H, s ), 6.76 (1H, d, J = 3.7 Hz), 6.81 (2H, d, J = 8.5 Hz), 6.97 (1H, d, J = 9.2 Hz), 7.06-7.12 (2H, m), 7.40 (1H , d, J = 6.7 Hz), 7.55-7.61 (1H, m), 7.62-7.68 (2H, m), 8.10-8.13 (1H, m), 8.21 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 617 (M + H) + .
　（実施例１３５）
１－［５－（４－｛１－［（２Ｓ）－１，４－ジオキサン－２－イルカルボニル］ピペリジン－４－イル｝フェノキシ）－４－メチル－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン (Example 135)
1- [5- (4- {1-[(2S) -1,4-dioxane-2-ylcarbonyl] piperidin-4-yl} phenoxy) -4-methyl-1H-indol-1-yl] -2 -[2- (Methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000180
Figure JPOXMLDOC01-appb-C000180
　実施例（１ｇ－１）として得られた化合物（３００　ｍｇ）のクロロホルム（１０　ｍＬ）溶液に２，３－ジクロロ－５，６－ジシアノ－１，４－ベンゾキノン（２３１　ｍｇ）を加え、６時間加熱還流した。反応液にクロロホルムを加え、セライトろ過を行い、減圧下にて濃縮した。残渣に水を加え、酢酸エチルで抽出した。有機層を水で２回および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（９０．３　ｍｇ）を淡褐色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.52-1.73 (2H, m), 1.82-1.95 (2H, m), 2.39 (3H, s), 2.57-2.76 (2H, m), 3.04-3.24 (4H, m), 3.65-4.00 (6H, m), 4.07-4.18 (1H, br m), 4.27-4.37 (1H, br m), 4.68-4.75 (1H, br m), 4.89 (2H, s), 6.77 (1H, d, J = 3.7 Hz), 6.79-6.84 (2H, m), 6.97 (1H, d, J = 9.2 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.37-7.44 (1H, m), 7.55-7.62 (1H, m), 7.63-7.69 (2H, m), 8.09-8.15 (1H, m), 8.22 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 617 (M+H)+。 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (231 mg) was added to a chloroform (10 mL) solution of the compound (300 mg) obtained as Example (1g-1) for 6 hours. Heated to reflux. Chloroform was added to the reaction solution, filtered through celite, and concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed twice 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 (90.3 mg) as a light brown solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.52-1.73 (2H, m), 1.82-1.95 (2H, m), 2.39 (3H, s), 2.57-2.76 (2H, m), 3.04-3.24 (4H, m), 3.65-4.00 (6H, m), 4.07-4.18 (1H, br m), 4.27-4.37 (1H, br m), 4.68-4.75 (1H, br m), 4.89 (2H, s ), 6.77 (1H, d, J = 3.7 Hz), 6.79-6.84 (2H, m), 6.97 (1H, d, J = 9.2 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.37-7.44 (1H, m), 7.55-7.62 (1H, m), 7.63-7.69 (2H, m), 8.09-8.15 (1H, m), 8.22 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 617 (M + H) + .
　（実施例１３６）
（２Ｓ）－２－ヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）プロパン－１－オン (Example 136)
(2S) -2-hydroxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -1H-indol-5-yl) oxy] phenyl} piperidine -1-yl) propan-1-one
Figure JPOXMLDOC01-appb-C000181
Figure JPOXMLDOC01-appb-C000181
　実施例１０で得られた化合物（７２．８　ｍｇ）のクロロホルム（５　ｍＬ）溶液に２，３－ジクロロ－５，６－ジシアノ－１，４－ベンゾキノン（６０．２　ｍｇ）を加え、７５℃で６時間撹拌した。反応液を室温に冷却後、水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１４．７　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.35 (3H, dd, J = 13.4, 6.7 Hz), 1.57-1.70 (2H, m), 1.88-1.97 (2H, m), 2.39 (3H, s), 2.67-2.80 (2H, m), 3.08-3.18 (4H, m), 3.77-3.86 (1H, m), 3.90-3.98 (1H, br m), 4.44-4.54 (1H, br m), 4.71-4.82 (1H, br m), 4.88 (2H, s), 6.77 (1H, d, J = 4.3 Hz), 6.82 (2H, d, J = 7.3 Hz), 6.97 (1H, d, J = 8.5 Hz), 7.05-7.13 (2H, m), 7.41 (1H, d, J = 7.3 Hz), 7.54-7.60 (1H, m), 7.62-7.69 (2H, m), 8.11 (1H, t, J = 4.3 Hz), 8.22 (1H, d, J = 8.5 Hz).
MS(APCI) m/z: 575 (M+H)+。 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (60.2 mg) was added to a chloroform (5 mL) solution of the compound (72.8 mg) obtained in Example 10 at 75 ° C. For 6 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 / dichloromethane) to give the title compound (14.7 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.35 (3H, dd, J = 13.4, 6.7 Hz), 1.57-1.70 (2H, m), 1.88-1.97 (2H, m), 2.39 (3H, s ), 2.67-2.80 (2H, m), 3.08-3.18 (4H, m), 3.77-3.86 (1H, m), 3.90-3.98 (1H, br m), 4.44-4.54 (1H, br m), 4.71 -4.82 (1H, br m), 4.88 (2H, s), 6.77 (1H, d, J = 4.3 Hz), 6.82 (2H, d, J = 7.3 Hz), 6.97 (1H, d, J = 8.5 Hz) ), 7.05-7.13 (2H, m), 7.41 (1H, d, J = 7.3 Hz), 7.54-7.60 (1H, m), 7.62-7.69 (2H, m), 8.11 (1H, t, J = 4.3 Hz), 8.22 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 575 (M + H) + .
　（実施例１３７）：実施例（１３７ｂ）で合成
１－｛５－［４－（１－｛［（２Ｓ，４Ｓ）－４－フルオロ－１－メチルピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン Example 137: Synthesis in Example (137b) 1- {5- [4- (1-{[(2S, 4S) -4-fluoro-1-methylpyrrolidin-2-yl] carbonyl} piperidine-4 -Yl) phenoxy] -4-methyl-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000182
Figure JPOXMLDOC01-appb-C000182
（１３７ａ）　ｔｅｒｔ－ブチル　（２Ｓ，４Ｓ）－４－フルオロ－２－［（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）カルボニル］ピロリジン－１－カルボキシレート
　実施例（１３９ｂ）で得られた化合物（３００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（８　ｍＬ）溶液にトリエチルアミン（１５０　μＬ）を加え、室温で５分間攪拌した。４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（２３１　ｍｇ）及びＮ－ｔｅｒｔ－ブトキシカルボニル－ｃｉｓ－４－フルオロ－Ｌ－プロリン（１５８　ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（３５０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.48 (9H, s), 1.53-1.66 (2H, m), 1.81-1.97 (2H, m), 2.15-2.33 (1H, m), 2.39 (3H, s), 2.42-2.78 (3H, m), 3.07-3.25 (4H, m), 3.71-3.98 (3H, m), 4.62-4.83 (2H, m), 4.89 (2H, s), 5.15 (0.5H, br s), 5.30 (0.5H, br s), 6.77 (1H, d, J = 3.7 Hz), 6.81 (2H, d, J = 7.9 Hz), 6.98 (1H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.41 (1H, d, J = 7.9 Hz), 7.58 (1H, t, J = 7.6 Hz), 7.62-7.69 (2H, m), 8.12 (1H, d, J = 7.9 Hz), 8.22 (1H, d, J = 9.2 Hz)。
（１３７ｂ）　１－｛５－［４－（１－｛［（２Ｓ，４Ｓ）－４－フルオロ－１－メチルピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（１３７ａ）で得られた化合物（３５０　ｍｇ）のジクロロメタン（５　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（１０　ｍＬ）を加え、室温で１０時間撹拌した。減圧下にて溶媒を留去し、析出した固体を酢酸エチルで洗浄することで、粗製の１－｛５－［４－（１－｛［（２Ｓ，４Ｓ）－４－フルオロピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン塩酸塩（３３４　ｍｇ）を薄桃色固体として得た。 (137a) tert-butyl (2S, 4S) -4-fluoro-2-[(4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -1H-indole- 5-yl) oxy] phenyl} piperidin-1-yl) carbonyl] pyrrolidine-1-carboxylate Triethylamine was added to a solution of the compound obtained in Example (139b) (300 mg) in N, N-dimethylformamide (8 mL). (150 μL) was added and stirred at room temperature for 5 minutes. 4- (4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (231 mg) and N-tert-butoxycarbonyl-cis-4-fluoro-L-proline (158 mg) was added and stirred at room temperature for 18 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 (350 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48 (9H, s), 1.53-1.66 (2H, m), 1.81-1.97 (2H, m), 2.15-2.33 (1H, m), 2.39 (3H , s), 2.42-2.78 (3H, m), 3.07-3.25 (4H, m), 3.71-3.98 (3H, m), 4.62-4.83 (2H, m), 4.89 (2H, s), 5.15 (0.5 H, br s), 5.30 (0.5H, br s), 6.77 (1H, d, J = 3.7 Hz), 6.81 (2H, d, J = 7.9 Hz), 6.98 (1H, d, J = 8.5 Hz) , 7.10 (2H, d, J = 8.5 Hz), 7.41 (1H, d, J = 7.9 Hz), 7.58 (1H, t, J = 7.6 Hz), 7.62-7.69 (2H, m), 8.12 (1H, d, J = 7.9 Hz), 8.22 (1H, d, J = 9.2 Hz).
(137b) 1- {5- [4- (1-{[(2S, 4S) -4-Fluoro-1-methylpyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl- 1H-Indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone To a solution of the compound obtained in Example (137a) (350 mg) in dichloromethane (5 mL) was added 4N hydrochloric acid in dioxane (10 mL). ) And stirred at room temperature for 10 hours. The solvent was distilled off under reduced pressure, and the precipitated solid was washed with ethyl acetate, whereby crude 1- {5- [4- (1-{[(2S, 4S) -4-fluoropyrrolidine-2- Yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone hydrochloride (334 mg) as a pale pink solid It was.
　得られた化合物（３３４　ｍｇ）のテトラヒドロフラン（６　ｍＬ）とメタノール（２　ｍＬ）の混合溶液に酢酸（１７５　μＬ）、３７％ホルムアルデヒド液（５７　μＬ）、ナトリウムトリアセトキシボロヒドリド（１６２　ｍｇ）を加え、室温で１８時間撹拌した。反応液を減圧下で濃縮し、飽和炭酸水素ナトリウム（１０　ｍＬ）を加えて酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（２４０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.48-1.67 (2H, m), 1.83-1.95 (2H, m), 2.09-2.32 (2H, m), 2.39 (6H, s), 2.48-2.77 (3H, m), 2.96-3.17 (5H, m), 3.32-3.44 (1H, m), 4.50-4.60 (0.5H, br m), 4.63-4.72 (0.5H, br m), 4.76-4.84 (1H, br m), 4.88 (2H, s), 5.07 (0.5H, br s), 5.22 (0.5H, br s), 6.76 (1H, d, J = 3.7 Hz), 6.81 (2H, d, J = 8.5 Hz), 6.97 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 9.2 Hz), 7.40 (1H, d, J = 8.5 Hz), 7.55-7.60 (1H, m), 7.63-7.68 (2H, m), 8.10-8.13 (1H, m), 8.21 (1H, d, J = 9.2 Hz).
MS(APCI) m/z: 632 (M+H)+。 Acetic acid (175 μL), 37% formaldehyde solution (57 μL) and sodium triacetoxyborohydride (162 mg) were added to a mixed solution of the obtained compound (334 mg) in tetrahydrofuran (6 mL) and methanol (2 mL). And stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, saturated sodium hydrogen carbonate (10 mL) 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 amino silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (240 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48-1.67 (2H, m), 1.83-1.95 (2H, m), 2.09-2.32 (2H, m), 2.39 (6H, s), 2.48-2.77 (3H, m), 2.96-3.17 (5H, m), 3.32-3.44 (1H, m), 4.50-4.60 (0.5H, br m), 4.63-4.72 (0.5H, br m), 4.76-4.84 ( 1H, br m), 4.88 (2H, s), 5.07 (0.5H, br s), 5.22 (0.5H, br s), 6.76 (1H, d, J = 3.7 Hz), 6.81 (2H, d, J = 8.5 Hz), 6.97 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 9.2 Hz), 7.40 (1H, d, J = 8.5 Hz), 7.55-7.60 (1H, m), 7.63-7.68 (2H, m), 8.10-8.13 (1H, m), 8.21 (1H, d, J = 9.2 Hz).
MS (APCI) m / z: 632 (M + H) + .
　（実施例１３８）：実施例（１３８ｂ）で合成
（２Ｓ）－２,３－ジヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）プロパン－１－オン Example 138: Synthesis in Example (138b) (2S) -2,3-dihydroxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl } -1H-Indol-5-yl) oxy] phenyl} piperidin-1-yl) propan-1-one
Figure JPOXMLDOC01-appb-C000183
Figure JPOXMLDOC01-appb-C000183
（１３８ａ）　１－｛５－［４－（１－｛［（４Ｓ）－２，２－ジメチル－１，３－ジオキソラン－４－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（１３９ｂ）で得られた化合物（３２０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（８　ｍＬ）溶液にトリエチルアミン（１５０　μＬ）を加え、室温で５分間攪拌した。文献記載の方法（Ｂｉｏｏｒｇａｎｉｃ　ａｎｄ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ　Ｌｅｔｔｅｒｓ，２００４，１４，３２３１）に従って合成した（４Ｓ）－２，２－ジメチル－１，３－ジオキソラン－４－カルボン酸（１００　ｍｇ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（２３１　ｍｇ）を順次加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（３２０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.39-1.46 (6H, m), 1.50-1.75 (2H, m), 1.85-1.96 (2H, m), 2.39 (3H, s), 2.64-2.76 (2H, m), 3.01-3.22 (4H, m), 3.73 (0.5H, t, J = 4.9 Hz), 3.85 (0.5H, t, J = 4.9 Hz), 4.20-4.33 (1H, m), 4.39-4.52 (1H, m), 4.67-4.77 (2H, m), 4.88 (2H, s), 6.76 (1H, d, J = 3.7 Hz), 6.82 (2H, d, J = 8.5 Hz), 6.97 (1H, d, J = 9.2 Hz), 7.09 (2H, d, J = 7.3 Hz), 7.40 (1H, d, J = 7.3 Hz), 7.55-7.60 (1H, m), 7.63-7.68 (2H, m), 8.11 (1H, d, J = 9.2 Hz), 8.21 (1H, d, J = 9.2 Hz)。
（１３８ｂ）　（２Ｓ）－２，３－ジヒドロキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）プロパン－１－オン
　実施例（１３８ａ）で得られた化合物（３５０　ｍｇ）のジクロロメタン（１　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（２　ｍＬ）を加え、室温で２．５時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下で濃縮することで、標記化合物（２５５　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.59-1.71 (2H, m), 1.88-2.00 (2H, m), 2.38 (3H, s), 2.69-2.83 (2H, m), 3.12 (3H, s), 3.13-3.23 (1H, m), 3.56-3.66 (1H, m), 3.72-3.81 (1H, m), 3.83-3.94 (1H, m), 4.50 (1H, br s), 4.69-4.78 (1H, br m), 4.88 (2H, s), 6.76 (1H, d, J = 4.0 Hz), 6.82 (2H, d, J = 8.5 Hz), 6.97 (1H, d, J = 9.2 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.40 (1H, d, J = 7.6 Hz), 7.58 (1H, t, J = 7.6 Hz), 7.63-7.68 (2H, m), 8.11 (1H, d, J = 4.0 Hz), 8.22 (1H, d, J = 9.2 Hz).
MS(APCI) m/z: 591 (M+H)+。 (138a) 1- {5- [4- (1-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl -1H-Indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone Triethylamine was added to a solution of the compound obtained in Example (139b) (320 mg) in N, N-dimethylformamide (8 mL). (150 μL) was added and stirred at room temperature for 5 minutes. (4S) -2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (100 mg), 4- (4,4) synthesized according to a method described in the literature (Bioorganic and Medicinal Chemistry Letters, 2004, 14, 3231). 6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (231 mg) was sequentially added, and the mixture was stirred at room temperature for 18 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 (320 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.39-1.46 (6H, m), 1.50-1.75 (2H, m), 1.85-1.96 (2H, m), 2.39 (3H, s), 2.64-2.76 (2H, m), 3.01-3.22 (4H, m), 3.73 (0.5H, t, J = 4.9 Hz), 3.85 (0.5H, t, J = 4.9 Hz), 4.20-4.33 (1H, m), 4.39-4.52 (1H, m), 4.67-4.77 (2H, m), 4.88 (2H, s), 6.76 (1H, d, J = 3.7 Hz), 6.82 (2H, d, J = 8.5 Hz), 6.97 (1H, d, J = 9.2 Hz), 7.09 (2H, d, J = 7.3 Hz), 7.40 (1H, d, J = 7.3 Hz), 7.55-7.60 (1H, m), 7.63-7.68 (2H, m), 8.11 (1H, d, J = 9.2 Hz), 8.21 (1H, d, J = 9.2 Hz).
(138b) (2S) -2,3-dihydroxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -1H-indol-5-yl) Oxy] phenyl} piperidin-1-yl) propan-1-one To a solution of the compound obtained in Example (138a) (350 mg) in dichloromethane (1 mL) was added 4N hydrochloric acid dioxane solution (2 mL) at room temperature. Stir for 2.5 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 to give the title compound (255 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.59-1.71 (2H, m), 1.88-2.00 (2H, m), 2.38 (3H, s), 2.69-2.83 (2H, m), 3.12 (3H , s), 3.13-3.23 (1H, m), 3.56-3.66 (1H, m), 3.72-3.81 (1H, m), 3.83-3.94 (1H, m), 4.50 (1H, br s), 4.69- 4.78 (1H, br m), 4.88 (2H, s), 6.76 (1H, d, J = 4.0 Hz), 6.82 (2H, d, J = 8.5 Hz), 6.97 (1H, d, J = 9.2 Hz) , 7.09 (2H, d, J = 8.5 Hz), 7.40 (1H, d, J = 7.6 Hz), 7.58 (1H, t, J = 7.6 Hz), 7.63-7.68 (2H, m), 8.11 (1H, d, J = 4.0 Hz), 8.22 (1H, d, J = 9.2 Hz).
MS (APCI) m / z: 591 (M + H) + .
　（実施例１３９）：実施例（１３９ｄ）で合成
１－｛５－［４－（１－｛［（２Ｓ）－４，４－ジフルオロピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン塩酸塩 Example 139: Synthesis in Example (139d) 1- {5- [4- (1-{[(2S) -4,4-difluoropyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy ] -4-Methyl-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone hydrochloride
Figure JPOXMLDOC01-appb-C000184
Figure JPOXMLDOC01-appb-C000184
（１３９ａ）　ｔｅｒｔ－ブチル　４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－カルボキシレート
　実施例（１ｄ）で得られた化合物（１５０　ｍｇ）のジクロロメタン（１０　ｍＬ）溶液に２，３－ジクロロ－５，６－ジシアノ－１，４－ベンゾキノン（８４．５　ｍｇ）を加え、１５時間加熱還流した。反応液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（６０．０　ｍｇ）を淡褐色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.48 (9H, s), 1.57-1.64 (2H, m), 1.76-1.84 (2H, br m), 2.39 (3H, s), 2.54-2.65 (1H, br m), 2.71-2.85 (2H, br m), 3.13 (3H, s), 4.08-4.32 (2H, br m), 4.89 (2H, s), 6.75-6.83 (3H, m), 6.98 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.40 (1H, d, J = 7.3 Hz), 7.55-7.67 (3H, m), 8.11 (1H, d, J = 7.9 Hz), 8.21 (1H, d, J = 9.2 Hz)。
（１３９ｂ）　１－｛４－メチル－５－［４－（ピペリジン－４－イル）フェノキシ］－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン塩酸塩
　実施例（１３９ａ）で得られた化合物（５８．０　ｍｇ）のジクロロメタン（３　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（２　ｍＬ）を加え、室温で４時間攪拌した。反応液を減圧下濃縮し、乾燥することで標記化合物（５０．０　ｍｇ）を白色固体として得た。
MS (APCI) m/z: 503 (M+H)+。
（１３９ｃ）　ｔｅｒｔ－ブチル　（２Ｓ）－４，４－ジフルオロ－２－［（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）カルボニル］ピロリジン－１－カルボキシレート
　実施例（１３９ｂ）で得られた化合物（４８．０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（２．５　ｍＬ）溶液に４－メチルモルホリン（１８．０　ｍｇ）を加え、室温で２０分間攪拌した。次いでＮ－ｔｅｒｔ－ブトキシカルボニル－４，４－ジフルオロ－Ｌ－プロリン（２６．８　ｍｇ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（３２．０　ｍｇ）を加え、室温で３．５時間攪拌した。反応液を減圧下で濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（６５．０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.47 (9H, s), 1.53-1.64 (4H, m), 1.82-2.01 (2H, m), 2.39 (3H, s), 2.59-2.80 (3H, m), 3.13 (3H, s), 3.15-3.31 (1H, br m), 3.80-4.03 (3H, m), 4.68-4.84 (1H, m), 4.89 (2H, s), 6.75-6.85 (3H, m), 6.97 (1H, d, J= 8.5 Hz), 7.02-7.13 (2H, m), 7.41 (1H, d, J = 6.7 Hz), 7.55-7.69 (3H, m), 8.09-8.14 (1H, m), 8.22 (1H, d, J = 8.5 Hz)。
（１３９ｄ）　１－｛５－［４－（１－｛［（２Ｓ）－４，４－ジフルオロピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン塩酸塩
　実施例（１３９ｃ）で得られた化合物（５５．０　ｍｇ）をジクロロメタン（３　ｍＬ）に溶解し、４Ｎ塩酸ジオキサン溶液（１　ｍＬ）を加え室温にて２時間攪拌した。反応液を減圧下濃縮後、乾燥し標記化合物（４５．０　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.43-1.76 (5H, br m), 1.83-2.09 (2H, m), 2.38 (3H, s), 2.43-2.59 (1H, m), 2.70-2.91 (2H, m), 3.12 (3H, s), 3.73-4.05 (3H, br m), 4.57-4.73 (1H, m), 4.88 (2H, s), 6.74-6.85 (3H, m), 6.97 (1H, d, J = 9.2 Hz), 7.04-7.15 (2H, br m), 7.40 (1H, d, J= 7.3 Hz), 7.55-7.69 (3H, m), 8.11 (1H, d, J = 7.9 Hz), 8.22 (1H, d, J= 9.2 Hz).
MS (APCI) m/z: 636 (M+H)+。 (139a) tert-butyl 4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -1H-indol-5-yl) oxy] phenyl} piperidine-1-carboxylate 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (84.5 mg) was added to a solution of the compound (150 mg) obtained in Example (1d) in dichloromethane (10 mL), and the mixture was added for 15 hours. Heated to reflux. 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 (60.0 mg) as a pale brown solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48 (9H, s), 1.57-1.64 (2H, m), 1.76-1.84 (2H, br m), 2.39 (3H, s), 2.54-2.65 ( 1H, br m), 2.71-2.85 (2H, br m), 3.13 (3H, s), 4.08-4.32 (2H, br m), 4.89 (2H, s), 6.75-6.83 (3H, m), 6.98 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.40 (1H, d, J = 7.3 Hz), 7.55-7.67 (3H, m), 8.11 (1H, d, J = 7.9 Hz), 8.21 (1H, d, J = 9.2 Hz).
(139b) 1- {4-Methyl-5- [4- (piperidin-4-yl) phenoxy] -1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone hydrochloride Examples To a solution of the compound obtained in (139a) (58.0 mg) in dichloromethane (3 mL) was added 4N hydrochloric acid dioxane solution (2 mL), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure and dried to obtain the title compound (50.0 mg) as a white solid.
MS (APCI) m / z: 503 (M + H) + .
(139c) tert-butyl (2S) -4,4-difluoro-2-[(4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -1H-indole- 5-yl) oxy] phenyl} piperidin-1-yl) carbonyl] pyrrolidine-1-carboxylate N, N-dimethylformamide (2.5 mL) of the compound obtained in Example (139b) (48.0 mg) ) 4-Methylmorpholine (18.0 mg) was added to the solution and stirred at room temperature for 20 minutes. N-tert-butoxycarbonyl-4,4-difluoro-L-proline (26.8 mg), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmol Holinium chloride (32.0 mg) was added, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (65.0 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.47 (9H, s), 1.53-1.64 (4H, m), 1.82-2.01 (2H, m), 2.39 (3H, s), 2.59-2.80 (3H , m), 3.13 (3H, s), 3.15-3.31 (1H, br m), 3.80-4.03 (3H, m), 4.68-4.84 (1H, m), 4.89 (2H, s), 6.75-6.85 ( 3H, m), 6.97 (1H, d, J = 8.5 Hz), 7.02-7.13 (2H, m), 7.41 (1H, d, J = 6.7 Hz), 7.55-7.69 (3H, m), 8.09-8.14 (1H, m), 8.22 (1H, d, J = 8.5 Hz).
(139d) 1- {5- [4- (1-{[(2S) -4,4-Difluoropyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl-1H-indole- 1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone hydrochloride The compound (55.0 mg) obtained in Example (139c) was dissolved in dichloromethane (3 mL), and 4N hydrochloric acid dioxane solution ( 1 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried to give the title compound (45.0 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.43-1.76 (5H, br m), 1.83-2.09 (2H, m), 2.38 (3H, s), 2.43-2.59 (1H, m), 2.70- 2.91 (2H, m), 3.12 (3H, s), 3.73-4.05 (3H, br m), 4.57-4.73 (1H, m), 4.88 (2H, s), 6.74-6.85 (3H, m), 6.97 (1H, d, J = 9.2 Hz), 7.04-7.15 (2H, br m), 7.40 (1H, d, J = 7.3 Hz), 7.55-7.69 (3H, m), 8.11 (1H, d, J = 7.9 Hz), 8.22 (1H, d, J = 9.2 Hz).
MS (APCI) m / z: 636 (M + H) + .
　（実施例１４０）
１－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－メチル－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン (Example 140)
1- {5- [4- (1-Acetylpiperidin-4-yl) phenoxy] -4-methyl-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000185
Figure JPOXMLDOC01-appb-C000185
　実施例（１３９ｂ）で得られた化合物（５０．０　ｍｇ）のジクロロメタン（３　ｍＬ）溶液に４－メチルモルホリン（２０　μＬ）を加え、室温で２０分間攪拌した。無水酢酸（１０．５　μＬ）を加え、室温で２時間攪拌した。反応液を減圧下で濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（５０．０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.48-1.69 (2H, m), 1.82-1.95 (2H, m), 2.13 (3H, s), 2.39 (3H, s), 2.57-2.75 (2H, m), 3.12 (3H, s), 3.16-3.24 (1H, m), 3.88-3.97 (1H, br m), 4.73-4.83 (1H, br m), 4.88 (2H, s), 6.75-6.85 (3H, m), 6.97 (1H, d, J= 9.2 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.40 (1H, d, J = 7.9 Hz), 7.55-7.69 (3H, m), 8.11 (1H, d, J= 7.9 Hz), 8.21 (1H, d, J = 9.2 Hz).
MS (APCI) m/z 545 (M+H)+。 4-Methylmorpholine (20 μL) was added to a solution of the compound (50.0 mg) obtained in Example (139b) in dichloromethane (3 mL), and the mixture was stirred at room temperature for 20 minutes. Acetic anhydride (10.5 μL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (50.0 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48-1.69 (2H, m), 1.82-1.95 (2H, m), 2.13 (3H, s), 2.39 (3H, s), 2.57-2.75 (2H , m), 3.12 (3H, s), 3.16-3.24 (1H, m), 3.88-3.97 (1H, br m), 4.73-4.83 (1H, br m), 4.88 (2H, s), 6.75-6.85 (3H, m), 6.97 (1H, d, J = 9.2 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.40 (1H, d, J = 7.9 Hz), 7.55-7.69 (3H, m) , 8.11 (1H, d, J = 7.9 Hz), 8.21 (1H, d, J = 9.2 Hz).
MS (APCI) m / z 545 (M + H) + .
　（実施例１４１）：実施例（１４１ｃ）で合成
１－｛５－［４－（１－アセチルピペリジン－４－イル）－３－メチルフェノキシ］－４－メチル－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン Example 141: Synthesis in Example (141c) 1- {5- [4- (1-Acetylpiperidin-4-yl) -3-methylphenoxy] -4-methyl-1H-indol-1-yl} -2- [2- (Methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000186
Figure JPOXMLDOC01-appb-C000186
（１４１ａ）　ｔｅｒｔ－ブチル　４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－カルボキシレート
　実施例（８ａ）で得られた化合物（３．５０　ｇ）のジクロロメタン（５０　ｍＬ）溶液に２，３－ジクロロ－５，６－ジシアノ－１，４－ベンゾキノン（１．９５　ｇ）を加え、３時間加熱還流した。ジクロロメタン（２５　ｍＬ）を加え５分間攪拌後、不溶物をろ去し反応液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製し、得られた固体をさらにメタノールで洗浄後、ろ取することで標記化合物（３．１０　ｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.48 (9H, s), 1.51-1.65 (2H, m), 1.67-1.79 (2H, m), 2.29 (3H, s), 2.39 (3H, s), 2.71-2.89 (3H, m), 3.12 (3H, s), 4.24 (2H, br s), 4.89 (2H, s), 6.64-6.70 (2H, m), 6.77 (1H, d, J = 3.7 Hz), 6.97 (1H, d, J = 8.5 Hz), 7.05 (1H, d, J = 8.5 Hz), 7.41 (1H, d, J = 7.9 Hz), 7.55-7.61 (1H, m), 7.62-7.68 (2H, m), 8.12 (1H, d, J= 7.9 Hz), 8.21 (1H, d, J = 8.5 Hz)。
（１４１ｂ）　１－｛４－メチル－５－［３－メチル－４－（ピペリジン－４－イル）フェノキシ］－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン塩酸塩
　実施例（１４１ａ）で得られた化合物（３．４０　ｇ）のジクロロメタン（３０　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（２０　ｍＬ）を加え、室温にて４時間攪拌した。溶媒を減圧下留去し、乾燥することにより標記化合物（３．３０　ｇ）を得た。
MS (APCI) m/z: 517 (M+H)+。
（１４１ｃ）　１－｛５－［４－（１－アセチルピペリジン－４－イル）－３－メチルフェノキシ］－４－メチル－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン
　実施例（１４１ｂ）で得た化合物（３．１０　ｇ）のジクロロメタン（５０　ｍＬ）溶液に４－メチルモルホリン（１．２　ｍＬ）を加え、室温で３０分間攪拌した。無水酢酸（０．６４０　ｍＬ）を加え、室温で４時間攪拌した。反応液を減圧下で濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製後、エタノールで洗浄することにより標記化合物（２．５０　ｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.55-1.61 (2H, m), 1.74-1.86 (2H, m), 2.13 (3H, s), 2.29 (3H, s), 2.39 (3H, s), 2.57-2.67 (1H, m), 2.83-2.93 (1H, m), 3.13 (3H, s), 3.15-3.22 (1H, m), 3.94 (1H, d, J = 12.8 Hz), 4.79 (1H, d, J = 12.8 Hz), 4.88 (2H, s), 6.64-6.71 (2H, m), 6.75-6.79 (1H, m), 6.95-7.05 (2H, m), 7.40 (1H, d, J = 7.3 Hz), 7.55-7.61 (1H, m), 7.62-7.68 (2H, m), 8.09-8.14 (1H, m), 8.21 (1H, d, J = 8.5 Hz).
MS (APCI) m/z: 559 (M+H)+。 (141a) tert-butyl 4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -1H-indol-5-yl) oxy] phenyl} piperidine- 1-Carboxylate To a solution of the compound (3.50 g) obtained in Example (8a) in dichloromethane (50 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.95 g). ) And heated to reflux for 3 hours. Dichloromethane (25 mL) was added, and the mixture was stirred for 5 min, insoluble material was filtered off, and the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the obtained solid was further washed with methanol and collected by filtration to give the title compound (3.10 g) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48 (9H, s), 1.51-1.65 (2H, m), 1.67-1.79 (2H, m), 2.29 (3H, s), 2.39 (3H, s ), 2.71-2.89 (3H, m), 3.12 (3H, s), 4.24 (2H, br s), 4.89 (2H, s), 6.64-6.70 (2H, m), 6.77 (1H, d, J = 3.7 Hz), 6.97 (1H, d, J = 8.5 Hz), 7.05 (1H, d, J = 8.5 Hz), 7.41 (1H, d, J = 7.9 Hz), 7.55-7.61 (1H, m), 7.62 -7.68 (2H, m), 8.12 (1H, d, J = 7.9 Hz), 8.21 (1H, d, J = 8.5 Hz).
(141b) 1- {4-Methyl-5- [3-methyl-4- (piperidin-4-yl) phenoxy] -1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone Hydrochloric acid salt To a solution of the compound (3.40 g) obtained in Example (141a) in dichloromethane (30 mL) was added 4N hydrochloric acid dioxane solution (20 mL), and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure and dried to obtain the title compound (3.30 g).
MS (APCI) m / z: 517 (M + H) + .
(141c) 1- {5- [4- (1-Acetylpiperidin-4-yl) -3-methylphenoxy] -4-methyl-1H-indol-1-yl} -2- [2- (methylsulfonyl) Phenyl] ethanone To a solution of the compound (3.10 g) obtained in Example (141b) in dichloromethane (50 mL) was added 4-methylmorpholine (1.2 mL), and the mixture was stirred at room temperature for 30 minutes. Acetic anhydride (0.640 mL) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) and then washed with ethanol to give the title compound (2.50 g) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.55-1.61 (2H, m), 1.74-1.86 (2H, m), 2.13 (3H, s), 2.29 (3H, s), 2.39 (3H, s ), 2.57-2.67 (1H, m), 2.83-2.93 (1H, m), 3.13 (3H, s), 3.15-3.22 (1H, m), 3.94 (1H, d, J = 12.8 Hz), 4.79 ( 1H, d, J = 12.8 Hz), 4.88 (2H, s), 6.64-6.71 (2H, m), 6.75-6.79 (1H, m), 6.95-7.05 (2H, m), 7.40 (1H, d, J = 7.3 Hz), 7.55-7.61 (1H, m), 7.62-7.68 (2H, m), 8.09-8.14 (1H, m), 8.21 (1H, d, J = 8.5 Hz).
MS (APCI) m / z: 559 (M + H) + .
　（実施例１４２）：実施例（１４２ｃ）で合成
１－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－メチル－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン Example 142: Synthesis in Example (142c) 1- {5- [4- (1-acetylpiperidin-4-yl) phenoxy] -4-methyl-1H-indol-1-yl} -2- [ 2- (Ethylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000187
Figure JPOXMLDOC01-appb-C000187
（１４２ａ）　ｔｅｒｔ－ブチル　４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－カルボキシレート
　実施例（２ｃ）で得られた化合物（４００　ｍｇ）のジクロロメタン（１５　ｍＬ）溶液に２，３－ジクロロ－５，６－ジシアノ－１，４－ベンゾキノン（３６５　ｍｇ）を１時間おきに５回に分けて加え、５時間加熱還流した。放冷後、ジクロロメタンを加え、不溶物をろ去し反応液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製し、得られた固体をさらにメタノールで洗浄後、ろ取することで標記化合物（１１０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.29 (3H, t, J = 7.3 Hz), 1.47 (9H, s), 1.51-1.64 (2H, m), 1.75-1.85 (2H, m), 2.39 (3H, s), 2.54-2.65 (1H, br m), 2.71-2.85 (2H, br m), 3.20 (2H, q, J = 7.3 Hz), 4.23 (2H, br s), 4.89 (2H, s), 6.73-6.83 (3H, m), 6.98 (1H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.43 (1H, d, J = 7.9 Hz), 7.56 (1H, t, J = 7.9 Hz), 7.62-7.68 (2H, m), 8.07 (1H, d, J = 7.9 Hz), 8.21 (1H, d, J = 8.5 Hz)。
（１４２ｂ）　２－［２－（エチルスルホニル）フェニル］－１－｛４－メチル－５－［４－（ピペリジン－４－イル）フェノキシ］－１Ｈ－インドール－１－イル｝エタノン塩酸塩
　実施例（１４２ａ）で得られた化合物（１１０　ｍｇ）をジクロロメタン（５　ｍＬ）に溶解し、４Ｎ塩酸ジオキサン溶液（２　ｍＬ）を室温にて３時間攪拌した。溶媒を減圧下留去し、乾燥することにより標記化合物（１００　ｍｇ）を得た。
MS (APCI) m/z: 517 (M+H)+。
（１４２ｃ）　１－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－メチル－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン
　実施例（１４２ｂ）で得られた化合物（１００　ｍｇ）をジクロロメタン（１０　ｍＬ）に溶解し、４－メチルモルホリン（０．０４０　ｍＬ）を加え室温で３０分間攪拌した。次いで、無水酢酸（０．０２１　ｍＬ）を加えさらに室温で３時間攪拌した。反応液を減圧下で濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することにより標記化合物（９０．０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.24-1.31 (3H, m), 1.52-1.65 (2H, br m), 1.82-1.93 (2H, m), 2.13 (3H, s), 2.39 (3H, s), 2.56-2.74 (2H, m), 3.10-3.24 (3H, m), 3.88-3.96 (1H, m), 4.74-4.81 (1H, m), 4.89 (2H, s), 6.74-6.84 (3H, m), 6.96-7.00 (1H, m), 7.06-7.11 (2H, m), 7.41-7.45 (1H, m), 7.53-7.59 (1H, m), 7.63-7.68 (2H, m), 8.05-8.09 (1H, m), 8.22 (1H, d, J = 9.2 Hz).
MS (APCI) m/z: 559 (M+H)+。 (142a) tert-butyl 4- {4-[(1-{[2- (ethylsulfonyl) phenyl] acetyl} -4-methyl-1H-indol-5-yl) oxy] phenyl} piperidine-1-carboxylate To a solution of the compound (400 mg) obtained in Example (2c) in dichloromethane (15 mL), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (365 mg) was added 5 times every 1 hour. The mixture was added in portions and heated to reflux for 5 hours. After allowing to cool, dichloromethane was added, insolubles were removed by filtration, and the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the obtained solid was further washed with methanol and collected by filtration 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), 1.47 (9H, s), 1.51-1.64 (2H, m), 1.75-1.85 (2H, m), 2.39 (3H, s), 2.54-2.65 (1H, br m), 2.71-2.85 (2H, br m), 3.20 (2H, q, J = 7.3 Hz), 4.23 (2H, br s), 4.89 (2H , s), 6.73-6.83 (3H, m), 6.98 (1H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.43 (1H, d, J = 7.9 Hz), 7.56 (1H, t, J = 7.9 Hz), 7.62-7.68 (2H, m), 8.07 (1H, d, J = 7.9 Hz), 8.21 (1H, d, J = 8.5 Hz).
(142b) 2- [2- (Ethylsulfonyl) phenyl] -1- {4-methyl-5- [4- (piperidin-4-yl) phenoxy] -1H-indol-1-yl} ethanone hydrochloride Examples The compound (110 mg) obtained in (142a) was dissolved in dichloromethane (5 mL), and 4N hydrochloric acid dioxane solution (2 mL) was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure and dried to obtain the title compound (100 mg).
MS (APCI) m / z: 517 (M + H) + .
(142c) 1- {5- [4- (1-acetylpiperidin-4-yl) phenoxy] -4-methyl-1H-indol-1-yl} -2- [2- (ethylsulfonyl) phenyl] ethanone The compound (100 mg) obtained in Example (142b) was dissolved in dichloromethane (10 mL), 4-methylmorpholine (0.040 mL) was added, and the mixture was stirred at room temperature for 30 min. Next, acetic anhydride (0.021 mL) was added, and the mixture was further stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (90.0 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.24-1.31 (3H, m), 1.52-1.65 (2H, br m), 1.82-1.93 (2H, m), 2.13 (3H, s), 2.39 ( 3H, s), 2.56-2.74 (2H, m), 3.10-3.24 (3H, m), 3.88-3.96 (1H, m), 4.74-4.81 (1H, m), 4.89 (2H, s), 6.74- 6.84 (3H, m), 6.96-7.00 (1H, m), 7.06-7.11 (2H, m), 7.41-7.45 (1H, m), 7.53-7.59 (1H, m), 7.63-7.68 (2H, m ), 8.05-8.09 (1H, m), 8.22 (1H, d, J = 9.2 Hz).
MS (APCI) m / z: 559 (M + H) + .
　（実施例１４３）
１－｛５－［４－（１－｛［（２Ｓ）－１－アセチル－４，４－ジフルオロピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン (Example 143)
1- {5- [4- (1-{[(2S) -1-acetyl-4,4-difluoropyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl-1H-indole -1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone
Figure JPOXMLDOC01-appb-C000188
Figure JPOXMLDOC01-appb-C000188
　実施例（１３９ｄ）で得られた化合物（３０．０　ｍｇ）のジクロロメタン（２　ｍＬ）溶液に４－メチルモルホリン（９．８１　μＬ）を加え、室温で２０分間攪拌した。次いで、無水酢酸（５．０６　μＬ）を加え、同温にて２時間攪拌した。溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することにより標記化合物（３０．０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.51-1.60 (4H, m), 1.82-2.02 (2H, br m), 2.10 (3H, s), 2.39 (3H, s), 2.40-2.53 (1H, br m), 2.60-2.79 (2H, br m), 3.13 (3H, s), 3.14-3.39 (1H, br m), 3.88-4.09 (2H, br m), 4.66-4.76 (1H, m), 4.89 (2H, s), 5.05-5.14 (1H, m), 6.75-6.85 (3H, m), 6.97 (1H, d, J = 8.5 Hz), 7.06-7.15 (2H, m), 7.41 (1H, d, J = 6.7 Hz), 7.58 (1H, t, J = 7.6 Hz), 7.62-7.67 (2H, m), 8.09-8.14 (1H, m), 8.21 (1H, d, J = 9.2 Hz).
MS (APCI) m/z: 678 (M+H)+。 4-Methylmorpholine (9.81 μL) was added to a solution of the compound (30.0 mg) obtained in Example (139d) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 20 minutes. Subsequently, acetic anhydride (5.06 μL) was added, and the mixture was stirred at the same temperature for 2 hours. 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 (30.0 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.51-1.60 (4H, m), 1.82-2.02 (2H, br m), 2.10 (3H, s), 2.39 (3H, s), 2.40-2.53 ( 1H, br m), 2.60-2.79 (2H, br m), 3.13 (3H, s), 3.14-3.39 (1H, br m), 3.88-4.09 (2H, br m), 4.66-4.76 (1H, m ), 4.89 (2H, s), 5.05-5.14 (1H, m), 6.75-6.85 (3H, m), 6.97 (1H, d, J = 8.5 Hz), 7.06-7.15 (2H, m), 7.41 ( 1H, d, J = 6.7 Hz), 7.58 (1H, t, J = 7.6 Hz), 7.62-7.67 (2H, m), 8.09-8.14 (1H, m), 8.21 (1H, d, J = 9.2 Hz ).
MS (APCI) m / z: 678 (M + H) + .
　（実施例１４４）
２－［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］－２－オキソアセトアミド (Example 144)
2- [4- {2-Methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl } -3,6-Dihydropyridin-1 (2H) -yl] -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000189
Figure JPOXMLDOC01-appb-C000189
　実施例（１０２ｂ）で得られた化合物（２００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３　ｍＬ）溶液に塩化アンモニウム（５４．５　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（９７．７　ｍｇ）、ＨＯＢｔ・Ｈ２Ｏ（５２．０　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１４８　ｍＬ）を加えて室温で撹拌した。１２時間後、反応液をシリカゲルカラムクロマトグラフィー（メタノール／酢酸エチル）で精製することで標記化合物（１４４　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.13 (3H, s), 2.23 (3H, s), 2.37-2.51 (2H, m), 3.12 (3H, s), 3.18-3.26 (2H, m), 3.82-3.88 (1H, m), 4.16-4.24 (2H, m), 4.25-4.33 (2H, m), 4.37 (2H, s), 4.65-4.69 (1H, m), 5.52-5.60 (2H, m), 6.62-6.66 (1H, m), 6.68-6.72 (1H, m), 6.76-6.81 (1H, m), 6.95-6.99 (1H, m), 7.01-7.17 (1H, m), 7.34-7.39 (1H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.96-8.01 (1H, m), 8.05-8.10 (1H, m).
MS (APCI) m/z: 588 (M+H)+。 A solution of the compound obtained in Example (102b) (200 mg) in N, N-dimethylformamide (3 mL) was added ammonium chloride (54.5 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboxyl. Imide hydrochloride (97.7 mg), HOBt · H 2 O (52.0 mg), and N, N-diisopropylethylamine (0.148 mL) were added, and the mixture was stirred at room temperature. After 12 hours, the reaction solution was purified by silica gel column chromatography (methanol / ethyl acetate) to obtain the title compound (144 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.13 (3H, s), 2.23 (3H, s), 2.37-2.51 (2H, m), 3.12 (3H, s), 3.18-3.26 (2H, m ), 3.82-3.88 (1H, m), 4.16-4.24 (2H, m), 4.25-4.33 (2H, m), 4.37 (2H, s), 4.65-4.69 (1H, m), 5.52-5.60 (2H , m), 6.62-6.66 (1H, m), 6.68-6.72 (1H, m), 6.76-6.81 (1H, m), 6.95-6.99 (1H, m), 7.01-7.17 (1H, m), 7.34 -7.39 (1H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.96-8.01 (1H, m), 8.05-8.10 (1H, m).
MS (APCI) m / z: 588 (M + H) + .
　（実施例１４５）：実施例（１４５ｅ）で合成
１－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン Example 145: Synthesis in Example (145e) 1- {5- [4- (1-acetylpiperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indole-1- Yl} -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone
Figure JPOXMLDOC01-appb-C000190
Figure JPOXMLDOC01-appb-C000190
（１４５ａ）　［３－（メチルスルホニル）ピリジン－２－イル］プロパン二酸ジエチルエステル
　２－クロロ－３－（メチルスルホニル）ピリジン（０．３００　ｇ）、ヨウ化銅（Ｉ）（０．１４９　ｇ）、マロン酸ジエチル（０．４７６　ｍＬ）、炭酸セシウム（１．５３　ｇ）及びピコリン酸（０．１９３　ｇ）を１，４－ジオキサン（７．５　ｍＬ）に懸濁し、１００℃で７時間攪拌した。反応液を室温で終夜静置した後、１００℃で４時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加えて酢酸エチルで抽出した後、有機層を飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥させ、減圧下で濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（０．０９１　ｇ）を淡黄色油状物として得た。
1H-NMR (400 MHz, CDCl3) 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)。
（１４５ｂ）　［３－（メチルスルホニル）ピリジン－２－イル］酢酸
　実施例（１４５ａ）で得られた化合物（０．０５３３　ｇ）をメタノール（１．５　ｍＬ）に溶解し、２Ｎ水酸化ナトリウム水溶液（０．７５　ｍＬ）を加えた後、５０℃で２時間３０分攪拌した。反応液を室温で終夜静置した後、１Ｎ塩酸を加えて中和させた。反応液をジクロロメタン／エタノール（１９：１）混合溶液で３回抽出し、有機層を硫酸ナトリウムで乾燥させた。有機層を減圧下で濃縮することで標記化合物（０．０３２２　ｇ）を黄色油状物として得た。
1H-NMR (400 MHz, CDCl3) 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)。
（１４５ｃ）　ｔｅｒｔ－ブチル　４－｛４－［（４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－カルボキシレート
　実施例（１ｄ）で得られた化合物（３００　ｍｇ）のエタノール（３．５　ｍＬ）、水（１．５　ｍＬ）混合物に水酸化カリウム（１．６７　ｇ）を加えて９０℃で１．５時間撹拌した。室温まで冷却後、水を加えて酢酸エチルで抽出した。有機層を水、重曹水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、ろ過、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（１２４　ｍｇ）を無色油状物として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.48 (9H, s), 1.51-1.65 (2H, m), 1.75-1.84 (2H, m), 2.04-2.07 (4H, m), 2.51-2.63 (1H, m), 2.71-2.85 (2H, m), 2.96-3.03 (2H, m), 3.58-3.64 (2H, m), 4.15-4.32 (2H, m), 6.45-6.49 (1H, m), 6.65-6.70 (1H, m), 6.76-6.81 (2H, m), 7.04-7.10 (2H, m)。
（１４５ｄ）　ｔｅｒｔ－ブチル　４－｛４－［（４－メチル－１－｛［３－（メチルスルホニル）ピリジン－２－イル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－カルボキシレート
　実施例（１４５ｃ）で得られた化合物（１２４　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（２　ｍＬ）溶液に実施例（１４５ｂ）で得られた化合物（７２．０　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（８７．３　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（４１．３　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１０６　ｍＬ）を加えて室温で撹拌した。１２時間後、反応液をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製した後、さらにアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（１１８　ｍｇ）をアモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.48 (9H, s), 1.51-1.65 (2H, m), 1.76-1.84 (2H, m), 2.13 (3H, s), 2.55-2.65 (1H, m), 2.71-2.85 (2H, m), 3.19-3.28 (5H, m), 4.15-4.38 (4H, m), 4.61 (2H, s), 6.74-6.84 (3H, m), 7.07-7.14 (2H, m), 7.45-7.50 (1H, m), 7.91-7.96 (1H, m), 8.34-8.39 (1H, m), 8.78-8.82 (1H, m)。
（１４５ｅ）　１－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン
　実施例（１４５ｄ）で得られた化合物（１１７　ｍｇ）のジクロロメタン（１．５　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（１．５　ｍＬ）を加えて室温で撹拌した。３時間後、減圧濃縮することで粗製の１－｛４－メチル－５－［４－（ピペリジン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－ｙｌ］エタノン二塩酸塩（１１５　ｍｇ）を得た。 (145a) [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) were suspended in 1,4-dioxane (7.5 mL), and the mixture was suspended at 100 ° C. for 7 hours. Stir. 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).
(145b) [3- (Methylsulfonyl) pyridin-2-yl] acetic acid The compound (0.0533 g) obtained in Example (145a) 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 solution, 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).
(145c) tert-butyl 4- {4-[(4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine-1-carboxylate obtained in example (1d) Potassium hydroxide (1.67 g) was added to a mixture of the compound (300 mg) in ethanol (3.5 mL) and water (1.5 mL), and the mixture was stirred at 90 ° C. for 1.5 hours. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water, aqueous sodium bicarbonate and saturated brine, 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 (124 mg) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48 (9H, s), 1.51-1.65 (2H, m), 1.75-1.84 (2H, m), 2.04-2.07 (4H, m), 2.51-2.63 (1H, m), 2.71-2.85 (2H, m), 2.96-3.03 (2H, m), 3.58-3.64 (2H, m), 4.15-4.32 (2H, m), 6.45-6.49 (1H, m) , 6.65-6.70 (1H, m), 6.76-6.81 (2H, m), 7.04-7.10 (2H, m).
(145d) tert-butyl 4- {4-[(4-methyl-1-{[3- (methylsulfonyl) pyridin-2-yl] acetyl} -2,3-dihydro-1H-indol-5-yl) Oxy] phenyl} piperidine-1-carboxylate The compound (72.) obtained in Example (145b) in a solution of the compound (124 mg) obtained in Example (145c) in N, N-dimethylformamide (2 mL). 0 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (87.3 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol ( 41.3 mg) and N, N-diisopropylethylamine (0.106 mL) were added and stirred at room temperature. After 12 hours, the reaction solution was purified by silica gel column chromatography (ethyl acetate / hexane), and further purified by amino silica gel column chromatography (ethyl acetate / hexane) to give the title compound (118 mg) as an amorphous solid. It was.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48 (9H, s), 1.51-1.65 (2H, m), 1.76-1.84 (2H, m), 2.13 (3H, s), 2.55-2.65 (1H , m), 2.71-2.85 (2H, m), 3.19-3.28 (5H, m), 4.15-4.38 (4H, m), 4.61 (2H, s), 6.74-6.84 (3H, m), 7.07-7.14 (2H, m), 7.45-7.50 (1H, m), 7.91-7.96 (1H, m), 8.34-8.39 (1H, m), 8.78-8.82 (1H, m).
(145e) 1- {5- [4- (1-Acetylpiperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (methyl (Sulfonyl) pyridin-2-yl] ethanone To a solution of the compound (117 mg) obtained in Example (145d) in dichloromethane (1.5 mL) was added 4N hydrochloric acid dioxane solution (1.5 mL), and the mixture was stirred at room temperature. . After 3 hours, crude 1- {4-methyl-5- [4- (piperidin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl} -2- [3- (Methylsulfonyl) pyridine-2-yl] ethanone dihydrochloride (115 mg) was obtained.
　得られた化合物（１１５　ｍｇ）のジクロロメタン（４　ｍＬ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１２１　ｍＬ）溶液に無水酢酸（０．０２８２　ｍＬ）を加えて室温で１時間撹拌した。反応液を濃縮後、残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム）で精製することで標記化合物（９８．０　ｍｇ）を白色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.82-1.93 (2H, m), 2.11-2.15 (6H, m), 2.55-2.75 (3H, m), 3.10-3.28 (7H, m), 3.88-3.96 (1H, m), 4.31-4.38 (2H, m), 4.61 (2H, s), 4.73-4.82 (1H, m), 6.73-6.85 (3H, m), 7.06-7.12 (2H, m), 7.44-7.50 (1H, m), 7.92-7.96 (1H, m), 8.34-8.38 (1H, m), 8.78-8.81 (1H, m).
MS (APCI) m/z: 548 (M+H)+。 Acetic anhydride (0.0282 mL) was added to a solution of the obtained compound (115 mg) in dichloromethane (4 mL) and N, N-diisopropylethylamine (0.121 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (methanol / chloroform) to give the title compound (98.0 mg) as a white amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.82-1.93 (2H, m), 2.11-2.15 (6H, m), 2.55-2.75 (3H, m), 3.10-3.28 (7H, m), 3.88 -3.96 (1H, m), 4.31-4.38 (2H, m), 4.61 (2H, s), 4.73-4.82 (1H, m), 6.73-6.85 (3H, m), 7.06-7.12 (2H, m) , 7.44-7.50 (1H, m), 7.92-7.96 (1H, m), 8.34-8.38 (1H, m), 8.78-8.81 (1H, m).
MS (APCI) m / z: 548 (M + H) + .
　（実施例１４６）：実施例（１４６ｃ）で合成
１－｛５－［４－（１－アセチル－１，２，３，６－テトラヒドロピリジン－４－イル）－２，５－ジメチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン Example 146: Synthesis in Example (146c) 1- {5- [4- (1-acetyl-1,2,3,6-tetrahydropyridin-4-yl) -2,5-dimethylphenoxy]- 4-Methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone
Figure JPOXMLDOC01-appb-C000191
Figure JPOXMLDOC01-appb-C000191
（１４６ａ）　１－［５－（４－ブロモ－２，５－ジメチルフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン
　実施例（２４ａ）で得られた化合物（６８３　ｍｇ）のジクロロメタン（３　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（６　ｍＬ）を加えて室温で３時間撹拌した。反応液を減圧濃縮後、酢酸エチルに懸濁させ、ろ取することで、５－（４－ブロモ－２，５－ジメチルフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール塩酸塩（５１９　ｍｇ）を淡灰色固体として得た。 (146a) 1- [5- (4-Bromo-2,5-dimethylphenoxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2- [3- (methylsulfonyl) pyridine -2-yl] ethanone To a solution of compound (683 mg) obtained in Example (24a) in dichloromethane (3 mL) was added 4N hydrochloric acid dioxane solution (6 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution is concentrated under reduced pressure, suspended in ethyl acetate, and collected by filtration to give 5- (4-bromo-2,5-dimethylphenoxy) -4-methyl-2,3-dihydro-1H-indole hydrochloride. (519 mg) was obtained as a light gray solid.
　得られた化合物（５１８　ｍｇ）のジクロロメタン（８　ｍＬ）、Ｎ，Ｎ－ジメチルホルムアミド（３　ｍＬ）の溶液に実施例（１４５ｂ）で得られた化合物（３２４　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（４０４　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（１９１　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．７３４　ｍＬ）を加えて室温で撹拌した。１２時間後、反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（５９７　ｍｇ）を白色固体として得た。
1H-NMR (500 MHz, CDCl3) δ: 2.13 (3H, s), 2.22-2.25 (6H, m), 3.19-3.28 (5H, m), 4.31-4.37 (2H, m), 4.61 (2H, s), 6.49 (1H, s), 6.60 (1H, d, J = 8.8 Hz), 7.36 (1H, s), 7.45-7.49 (1H, m), 7.89-7.93 (1H, m), 8.34-8.38 (1H, m), 8.78-8.81 (1H, m).
MS (APCI) m/z: 530 (M+H)+。
（１４６ｂ）　ｔｅｒｔ－ブチル　４－｛２，５－ジメチル－４－［（４－メチル－１－｛［３－（メチルスルホニル）ピリジン－２－イル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－カルボキシレート
　実施例（１４６ａ）で得られた化合物（５６５　ｍｇ）、ｔｅｒｔ－ブチル　４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）－３，６－ジヒドロピリジン－１（２Ｈ）－カルボキシレート（３９６　ｍｇ）、［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）　ジクロライド　ジクロロメタン　錯体（８７．１　ｍｇ）、炭酸ナトリウム（２２６　ｍｇ）、ジメトキシエタン（８　ｍＬ）、水（４　ｍＬ）の混合物をマイクロウェーブ照射下、１２０℃で３０分撹拌した。室温まで冷却後、水を加えて酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（６７２　ｍｇ）を橙色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.50 (9H, s), 2.11-2.19 (6H, m), 2.23 (3H, s), 2.27-2.37 (2H, m), 3.20-3.28 (5H, m), 3.57-3.64 (2H, m), 3.98-4.05 (2H, m), 4.30-4.37 (2H, m), 4.61 (2H, s), 5.47-5.57 (1H, m), 6.45 (1H, s), 6.59-6.64 (1H, m), 6.93 (1H, s), 7.44-7.50 (1H, m), 7.88-7.93 (1H, m), 8.33-8.38 (1H, m), 8.77-8.81 (1H, m)。
（１４６ｃ）　１－｛５－［４－（１－アセチル－１，２，３，６－テトラヒドロピリジン－４－イル）－２，５－ジメチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン
　実施例（１４６ｂ）で得られた化合物（６７２　ｍｇ）のジクロロメタン（３　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（６　ｍＬ）を加えて室温で４時間撹拌した。酢酸エチルを加えて懸濁した後、ろ取することで、１－｛５－［２，５－ジメチル－４－（１，２，３，６－テトラヒドロピリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン二塩酸塩（６３５　ｍｇ）を白色固体として得た。 To a solution of the obtained compound (518 mg) in dichloromethane (8 mL) and N, N-dimethylformamide (3 mL), the compound (324 mg) obtained in Example (145b), 1-ethyl-3- ( 3-dimethylaminopropyl) carboximide hydrochloride (404 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (191 mg), N, N-diisopropylethylamine (0. 734 mL) was added and stirred at room temperature. After 12 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (597 mg) as a white solid.
1 H-NMR (500 MHz, CDCl 3 ) δ: 2.13 (3H, s), 2.22-2.25 (6H, m), 3.19-3.28 (5H, m), 4.31-4.37 (2H, m), 4.61 (2H , s), 6.49 (1H, s), 6.60 (1H, d, J = 8.8 Hz), 7.36 (1H, s), 7.45-7.49 (1H, m), 7.89-7.93 (1H, m), 8.34- 8.38 (1H, m), 8.78-8.81 (1H, m).
MS (APCI) m / z: 530 (M + H) + .
(146b) tert-butyl 4- {2,5-dimethyl-4-[(4-methyl-1-{[3- (methylsulfonyl) pyridin-2-yl] acetyl} -2,3-dihydro-1H- Indol-5-yl) oxy] phenyl} -3,6-dihydropyridine-1 (2H) -carboxylate Compound (565 mg) obtained in Example (146a), tert-butyl 4- (4,4,5 , 5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate (396 mg), [1,1′-bis (diphenylphosphino) ferrocene ] Palladium (II) dichloride dichloromethane complex (87.1 mg), sodium carbonate (226 mg), dimethoxyethane (8 mL), water (4 mL) The mixture under microwave irradiation, the mixture was stirred for 30 minutes at 120 ° C.. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, 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 (672 mg) as an orange amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.50 (9H, s), 2.11-2.19 (6H, m), 2.23 (3H, s), 2.27-2.37 (2H, m), 3.20-3.28 (5H , m), 3.57-3.64 (2H, m), 3.98-4.05 (2H, m), 4.30-4.37 (2H, m), 4.61 (2H, s), 5.47-5.57 (1H, m), 6.45 (1H , s), 6.59-6.64 (1H, m), 6.93 (1H, s), 7.44-7.50 (1H, m), 7.88-7.93 (1H, m), 8.33-8.38 (1H, m), 8.77-8.81 (1H, m).
(146c) 1- {5- [4- (1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl) -2,5-dimethylphenoxy] -4-methyl-2,3-dihydro- 1H-Indol-1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone 4N dioxane hydrochloride in a solution of the compound obtained in Example (146b) (672 mg) in dichloromethane (3 mL) The solution (6 mL) was added and stirred at room temperature for 4 hours. 1- {5- [2,5-Dimethyl-4- (1,2,3,6-tetrahydropyridin-4-yl) phenoxy] -4 is obtained by suspending by adding ethyl acetate and filtering. -Methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone dihydrochloride (635 mg) was obtained as a white solid.
　得られた化合物（３３５　ｍｇ）のジクロロメタン（６　ｍＬ）、Ｎ，Ｎ－ジイソプロピルアミン（０．３８６　ｍＬ）溶液に無水酢酸（０．０７８６　ｍＬ）を加えて室温で２時間撹拌した。反応液を減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム）で精製することで標記化合物（２８１　ｍｇ）を白色固体として得た。
1H-NMR (500 MHz, CDCl3) δ: 2.12-2.18 (9H, m), 2.23 (3H, s), 2.32-2.42 (2H, m), 3.21-3.28 (5H, m), 3.61-3.66 (1H, m), 3.76-3.82 (1H, m), 4.06-4.11 (1H, m), 4.17-4.22 (1H, m), 4.31-4.37 (2H, m), 4.61 (2H, s), 5.51-5.61 (1H, m), 6.45 (1H, s), 6.59-6.64 (1H, m), 6.92 (1H, s), 7.45-7.49 (1H, m), 7.89-7.93 (1H, m), 8.34-8.38 (1H, m), 8.77-8.82 (1H, m).
MS (APCI) m/z: 574 (M+H)+。 Acetic anhydride (0.0786 mL) was added to a solution of the obtained compound (335 mg) in dichloromethane (6 mL) and N, N-diisopropylamine (0.386 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform) to give the title compound (281 mg) as a white solid.
1 H-NMR (500 MHz, CDCl 3 ) δ: 2.12-2.18 (9H, m), 2.23 (3H, s), 2.32-2.42 (2H, m), 3.21-3.28 (5H, m), 3.61-3.66 (1H, m), 3.76-3.82 (1H, m), 4.06-4.11 (1H, m), 4.17-4.22 (1H, m), 4.31-4.37 (2H, m), 4.61 (2H, s), 5.51 -5.61 (1H, m), 6.45 (1H, s), 6.59-6.64 (1H, m), 6.92 (1H, s), 7.45-7.49 (1H, m), 7.89-7.93 (1H, m), 8.34 -8.38 (1H, m), 8.77-8.82 (1H, m).
MS (APCI) m / z: 574 (M + H) + .
　（実施例１４７）：実施例（１４７ｄ）で合成
１－｛５－［４－（１－アセチルピペリジン－４－イル）－２，５－ジメチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン Example 147: Synthesis in Example (147d) 1- {5- [4- (1-acetylpiperidin-4-yl) -2,5-dimethylphenoxy] -4-methyl-2,3-dihydro- 1H-Indol-1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone
Figure JPOXMLDOC01-appb-C000192
Figure JPOXMLDOC01-appb-C000192
（１４７ａ）　１－［４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）－３，６－ジヒドロピリジン－１（２Ｈ）－イル］エタノン
　４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）－１，２，３，６－テトラヒドロピリジン塩酸塩（１．００　ｇ）、ジクロロメタン（１５　ｍＬ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（１．０６　ｍＬ）の混合物に無水酢酸（０．４６２　ｍＬ）を加えて室温で撹拌した。２時間後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（４８５　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.27 (12H, s), 2.07-2.14 (3H, m), 2.21-2.32 (2H, m), 3.44-3.49 (1H, m), 3.60-3.65 (1H, m), 3.98-4.02 (1H, m), 4.10-4.14 (1H, m), 6.40-6.56 (1H, m)。
（１４７ｂ）　ｔｅｒｔ－ブチル　５－［４－（１－アセチル－１，２，３，６－テトラヒドロピリジン－４－イル）－２，５－ジメチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　実施例（１４７ａ）で得られた化合物（２００　ｍｇ）、実施例（２４ａ）で得られた化合物（３６２　ｍｇ）、［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）　ジクロライド　ジクロロメタン錯体（６５．０　ｍｇ）、炭酸ナトリウム（１６９　ｍｇ）、ジメトキシエタン（８　ｍＬ）、水（４　ｍＬ）の混合物をマイクロウェーブ照射下、１２０℃で３０分撹拌した。室温まで冷却後、水を加えて酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（１７０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.51-1.61 (9H, m), 2.07-2.19 (9H, m), 2.26 (3H, s), 2.31-2.43 (2H, m), 3.00-3.08 (2H, m), 3.61-3.66 (1H, m), 3.76-3.82 (1H, m), 3.97-4.11 (3H, m), 4.17-4.22 (1H, m), 5.51-5.61 (1H, m), 6.35-6.45 (1H, m), 6.59-6.74 (1H, m), 6.92 (1H, s), 7.56-7.74 (1H, m)。
（１４７ｃ）　ｔｅｒｔ－ブチル　５－［４－（１－アセチルピペリジン－４－イル）－２，５－ジメチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　実施例（１４７ｂ）で得られた化合物（１６５　ｍｇ）のジクロロメタン（２　ｍＬ）、メタノール（３　ｍＬ）溶液に１０％パラジウム炭素（３０．０　ｍｇ）を加えて水素雰囲気下室温で撹拌した。１０時間後、セライトろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで標記化合物（１２４　ｍｇ）を無色油状物として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.50-1.69 (11H, m), 1.74-1.87 (2H, m), 2.10 (3H, s), 2.15 (3H, s), 2.20 (3H, s), 2.25 (3H, s), 2.56-2.67 (1H, m), 2.80-2.91 (1H, m), 2.99-3.08 (2H, m), 3.12-3.22 (1H, m), 3.90-4.09 (3H, m), 4.76-4.84 (1H, m), 6.34-6.48 (1H, m), 6.52-6.73 (1H, m), 6.96 (1H, s), 7.61-7.64 (1H, m)。
（１４７ｄ）　１－｛５－［４－（１－アセチルピペリジン－４－イル）－２，５－ジメチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン
　実施例（１４７ｃ）で得られた化合物（１２４　ｍｇ）のジクロロメタン（１　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（２　ｍＬ）を加えて室温で撹拌した。３時間後、酢酸エチルを加えて懸濁させ、ろ取することで、１－（４－｛２，５－ジメチル－４－［（４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）エタノン塩酸塩（１０２　ｍｇ）を得た。 (147a) 1- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydropyridin-1 (2H) -yl] ethanone 4- ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2,3,6-tetrahydropyridine hydrochloride (1.00 g), dichloromethane (15 mL), N , N-diisopropylethylamine (1.06 mL) was added acetic anhydride (0.462 mL) and stirred at room temperature. After 2 hours, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (485 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.27 (12H, s), 2.07-2.14 (3H, m), 2.21-2.32 (2H, m), 3.44-3.49 (1H, m), 3.60-3.65 (1H, m), 3.98-4.02 (1H, m), 4.10-4.14 (1H, m), 6.40-6.56 (1H, m).
(147b) tert-butyl 5- [4- (1-acetyl-1,2,3,6-tetrahydropyridin-4-yl) -2,5-dimethylphenoxy] -4-methyl-2,3-dihydro- 1H-indole-1-carboxylate Compound (200 mg) obtained in Example (147a), Compound (362 mg) obtained in Example (24a), [1,1′-bis (diphenylphosphino) Ferrocene] palladium (II) dichloride Dichloromethane complex (65.0 mg), sodium carbonate (169 mg), dimethoxyethane (8 mL), water (4 mL) were stirred at 120 ° C. for 30 minutes under microwave irradiation. . After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, 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 (170 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.51-1.61 (9H, m), 2.07-2.19 (9H, m), 2.26 (3H, s), 2.31-2.43 (2H, m), 3.00-3.08 (2H, m), 3.61-3.66 (1H, m), 3.76-3.82 (1H, m), 3.97-4.11 (3H, m), 4.17-4.22 (1H, m), 5.51-5.61 (1H, m) 6.35-6.45 (1H, m), 6.59-6.74 (1H, m), 6.92 (1H, s), 7.56-7.74 (1H, m).
(147c) tert-butyl 5- [4- (1-acetylpiperidin-4-yl) -2,5-dimethylphenoxy] -4-methyl-2,3-dihydro-1H-indole-1-carboxylate Examples To a solution of the compound obtained in (147b) (165 mg) in dichloromethane (2 mL) and methanol (3 mL) was added 10% palladium carbon (30.0 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere. After 10 hours, the mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (124 mg) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.50-1.69 (11H, m), 1.74-1.87 (2H, m), 2.10 (3H, s), 2.15 (3H, s), 2.20 (3H, s ), 2.25 (3H, s), 2.56-2.67 (1H, m), 2.80-2.91 (1H, m), 2.99-3.08 (2H, m), 3.12-3.22 (1H, m), 3.90-4.09 (3H m), 4.76-4.84 (1H, m), 6.34-6.48 (1H, m), 6.52-6.73 (1H, m), 6.96 (1H, s), 7.61-7.64 (1H, m).
(147d) 1- {5- [4- (1-Acetylpiperidin-4-yl) -2,5-dimethylphenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2 -[3- (Methylsulfonyl) pyridin-2-yl] ethanone To a solution of the compound (124 mg) obtained in Example (147c) in dichloromethane (1 mL) was added 4N hydrochloric acid dioxane solution (2 mL) at room temperature. Stir. After 3 hours, ethyl acetate was added to suspend, and the mixture was collected by filtration to give 1- (4- {2,5-dimethyl-4-[(4-methyl-2,3-dihydro-1H-indole-5 -Yl) oxy] phenyl} piperidin-1-yl) ethanone hydrochloride (102 mg) was obtained.
　得られた化合物（１０２　ｍｇ）、[３－（メチルスルホニル）ピリジン－２－イル]酢酸ナトリウム（７０．０　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（７０．７　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（３３．５　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１２８　ｍＬ）、Ｎ，Ｎ－ジメチルホルムアミド（２　ｍＬ）、ジクロロメタン（２　ｍＬ）の混合物を室温で撹拌した。１２時間後、反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム）で精製することで標記化合物（８３．０　ｍｇ）を白色固体として得た。
1H-NMR (500 MHz, CDCl3) δ: 1.55-1.68 (2H, m), 1.75-1.86 (2H, m), 2.14 (3H, s), 2.17 (3H, s), 2.21 (3H, s), 2.22 (3H, s), 2.57-2.66 (1H, m), 2.81-2.91 (1H, m), 3.12-3.28 (6H, m), 3.91-3.98 (1H, m), 4.31-4.37 (2H, m), 4.61 (2H, s), 4.76-4.84 (1H, m), 6.46 (1H, s), 6.55-6.59 (1H, m), 6.97 (1H, s), 7.45-7.50 (1H, m), 7.87-7.92 (1H, m), 8.34-8.38 (1H, m), 8.78-8.81 (1H, m).
MS (APCI) m/z: 576 (M+H)+。 The obtained compound (102 mg), [3- (methylsulfonyl) pyridin-2-yl] acetate sodium (70.0 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (70 .7 mg), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (33.5 mg), N, N-diisopropylethylamine (0.128 mL), N, N— A mixture of dimethylformamide (2 mL) and dichloromethane (2 mL) was stirred at room temperature. After 12 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform) to obtain the title compound (83.0 mg) as a white solid.
1 H-NMR (500 MHz, CDCl 3 ) δ: 1.55-1.68 (2H, m), 1.75-1.86 (2H, m), 2.14 (3H, s), 2.17 (3H, s), 2.21 (3H, s ), 2.22 (3H, s), 2.57-2.66 (1H, m), 2.81-2.91 (1H, m), 3.12-3.28 (6H, m), 3.91-3.98 (1H, m), 4.31-4.37 (2H , m), 4.61 (2H, s), 4.76-4.84 (1H, m), 6.46 (1H, s), 6.55-6.59 (1H, m), 6.97 (1H, s), 7.45-7.50 (1H, m ), 7.87-7.92 (1H, m), 8.34-8.38 (1H, m), 8.78-8.81 (1H, m).
MS (APCI) m / z: 576 (M + H) + .
　（実施例１４８）：実施例（１４８ｃ）で合成
１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）ピペリジン－４－イル］フェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン Example 148: Synthesis in Example (148c) 1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) piperidin-4-yl] phenoxy} -4-methyl-2 , 3-Dihydro-1H-indol-1-yl) -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone
Figure JPOXMLDOC01-appb-C000193
Figure JPOXMLDOC01-appb-C000193
（１４８ａ）　ｔｅｒｔ－ブチル　４－｛４－［（４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－カルボキシレート
　実施例（１ｄ）で得られた化合物（５００　ｍｇ）をエタノール（６　ｍＬ）及び水（２　ｍＬ）に溶解させ、水酸化カリウム（４６４　ｍｇ）を添加した。反応液を９０℃にて４時間攪拌した後、室温に冷却し、反応液を水で希釈した。水層をジクロロメタンで３回抽出し、合わせた有機層を硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（３０１　ｍｇ）を無色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.48 (9H, s), 1.50-1.65 (2H, m), 1.77-1.82 (2H, m), 2.00-2.10 (3H, m), 2.53-2.63 (1H, m), 2.72-2.84 (2H, m), 2.99 (2H, t, J= 8.5 Hz), 3.61 (2H, t, J = 8.5 Hz), 4.14-4.30 (2H, m), 6.47 (1H, d, J= 8.5 Hz), 6.67 (1H, d, J = 8.5 Hz), 6.78 (2H, d, J = 8.5 Hz), 7.07 (2H, d, J = 8.5 Hz)。
（１４８ｂ）　ｔｅｒｔ－ブチル　４－｛４－［（４－メチル－１－｛［３－（メチルスルホニル）ピリジン－２－イル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－カルボキシレート
　実施例（１４８ａ）で得られた化合物（１５０　ｍｇ）及び［３－（メチルスルホニル）ピリジン－２－イル］酢酸ナトリウム塩（１０５　ｍｇ）のジメチルホルムアミド（５　ｍＬ）溶液に４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリウム　クロリド（１５２　ｍｇ）を加え、室温で１５時間攪拌した。反応液を減圧下濃縮し、残渣をカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（１９３　ｍｇ）を淡黄色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.61-1.44 (11H, m), 1.76-1.83 (2H, m), 2.13 (3H, s), 2.55-2.64 (1H, m), 2.73-2.83 (2H, m), 3.20-3.28 (5H, m), 4.11-4.36 (4H, m), 4.61 (2H, s), 6.74-6.83 (3H, m), 7.10 (2H, d, J = 9.1 Hz), 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.94 (1H, d, J = 9.1 Hz), 8.36 (1H, dd, J = 8.2, 1.5 Hz), 8.80 (1H, dd, J = 4.9, 1.8 Hz).
MS (APCI) m/z: 606 (M+H)+。
（１４８ｃ）　１－（５－｛４－［１－（１，４－ジオキサン－２－イルカルボニル）ピペリジン－４－イル］フェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン
　実施例（１４８ｂ）で得られた化合物（６０．０　ｍｇ）のジクロロメタン（２　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（２　ｍＬ）を加え、室温で攪拌した。２時間攪拌後、反応液を濃縮することで、粗製の１－｛４－メチル－５－［４－（ピペリジン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン塩酸塩を得た。 (148a) tert-butyl 4- {4-[(4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine-1-carboxylate obtained in example (1d) The compound (500 mg) was dissolved in ethanol (6 mL) and water (2 mL), and potassium hydroxide (464 mg) was added. The reaction solution was stirred at 90 ° C. for 4 hours, then cooled to room temperature, and the reaction solution was diluted with water. The aqueous layer was extracted 3 times with dichloromethane, and the combined organic layer was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (301 mg) as a colorless amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48 (9H, s), 1.50-1.65 (2H, m), 1.77-1.82 (2H, m), 2.00-2.10 (3H, m), 2.53-2.63 (1H, m), 2.72-2.84 (2H, m), 2.99 (2H, t, J = 8.5 Hz), 3.61 (2H, t, J = 8.5 Hz), 4.14-4.30 (2H, m), 6.47 ( 1H, d, J = 8.5 Hz), 6.67 (1H, d, J = 8.5 Hz), 6.78 (2H, d, J = 8.5 Hz), 7.07 (2H, d, J = 8.5 Hz).
(148b) tert-butyl 4- {4-[(4-methyl-1-{[3- (methylsulfonyl) pyridin-2-yl] acetyl} -2,3-dihydro-1H-indol-5-yl) Oxy] phenyl} piperidine-1-carboxylate Compound (150 mg) obtained in Example (148a) and [3- (methylsulfonyl) pyridin-2-yl] acetic acid sodium salt (105 mg) in dimethylformamide (5 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholium chloride (152 mg) was added to the solution, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (193 mg) as a pale yellow amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.61-1.44 (11H, m), 1.76-1.83 (2H, m), 2.13 (3H, s), 2.55-2.64 (1H, m), 2.73-2.83 (2H, m), 3.20-3.28 (5H, m), 4.11-4.36 (4H, m), 4.61 (2H, s), 6.74-6.83 (3H, m), 7.10 (2H, d, J = 9.1 Hz ), 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.94 (1H, d, J = 9.1 Hz), 8.36 (1H, dd, J = 8.2, 1.5 Hz), 8.80 (1H, dd, J = (4.9, 1.8 Hz).
MS (APCI) m / z: 606 (M + H) + .
(148c) 1- (5- {4- [1- (1,4-Dioxane-2-ylcarbonyl) piperidin-4-yl] phenoxy} -4-methyl-2,3-dihydro-1H-indole-1 -Yl) -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone A solution of the compound (60.0 mg) obtained in Example (148b) in dichloromethane (2 mL) in 4N dioxane hydrochloride solution (2 mL) was added and stirred at room temperature. After stirring for 2 hours, the reaction mixture was concentrated to give crude 1- {4-methyl-5- [4- (piperidin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl. } -2- [3- (Methylsulfonyl) pyridin-2-yl] ethanone hydrochloride was obtained.
　得られた化合物のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にＮ－メチルモルホリン（０．０４３６　ｍＬ）を加え、室温で１時間１５分攪拌した。反応液に４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（４１．１　ｍｇ）及び１，４－ジオキサン－２－カルボン酸（２６．２　ｍｇ）を加え、室温で２０時間攪拌した。反応液を減圧下濃縮し、残渣をカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（６５．８　ｍｇ）を淡黄色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.65-1.76 (2H, m), 1.95-1.84 (2H, m), 2.14 (3H, s), 2.59-2.77 (2H, m), 3.03-3.29 (6H, m), 3.65-3.97 (6H, m), 4.07-4.16 (1H, m), 4.28-4.38 (3H, m), 4.61 (2H, s), 4.67-4.75 (1H, m), 6.74-6.83 (3H, m), 7.07-7.12 (2H, m), 7.48 (1H, dd, J = 8.5, 4.9 Hz), 7.94 (1H, d, J = 8.5 Hz), 8.34-8.38 (1H, m), 8.78-8.81 (1H, m).
MS (APCI) m/z: 620 (M+H)+。 N-methylmorpholine (0.0436 mL) was added to a solution of the obtained compound in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 1 hour and 15 minutes. To the reaction mixture was added 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (41.1 mg) and 1,4-dioxane-2-carboxylic acid ( 26.2 mg) was added and stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (65.8 mg) as a pale yellow amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.65-1.76 (2H, m), 1.95-1.84 (2H, m), 2.14 (3H, s), 2.59-2.77 (2H, m), 3.03-3.29 (6H, m), 3.65-3.97 (6H, m), 4.07-4.16 (1H, m), 4.28-4.38 (3H, m), 4.61 (2H, s), 4.67-4.75 (1H, m), 6.74 -6.83 (3H, m), 7.07-7.12 (2H, m), 7.48 (1H, dd, J = 8.5, 4.9 Hz), 7.94 (1H, d, J = 8.5 Hz), 8.34-8.38 (1H, m ), 8.78-8.81 (1H, m).
MS (APCI) m / z: 620 (M + H) + .
　（実施例１４９）：実施例（１４９ｂ）で合成
１－｛５－［４－（１－｛［（２Ｓ）－４，４－ジフルオロピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン Example 149: Synthesis in Example (149b) 1- {5- [4- (1-{[(2S) -4,4-difluoropyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy ] -4-Methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone
Figure JPOXMLDOC01-appb-C000194
Figure JPOXMLDOC01-appb-C000194
（１４９ａ）　ｔｅｒｔ－ブチル　（２Ｓ）－４，４－ジフルオロ－２－［（４－｛４－［（４－メチル－１－｛［３－（メチルスルホニル）ピリジン－２－イル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）カルボニル］ピロリジン－１－カルボキシレート
　実施例（１４８ｂ）で得られた化合物（６０．０　ｍｇ）のジクロロメタン（２　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（２　ｍＬ）を加え、室温で攪拌した。２時間攪拌後、反応液を濃縮することで、粗製の１－｛４－メチル－５－［４－（ピペリジン－４－イル）フェノキシ］－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン塩酸塩を得た。 (149a) tert-butyl (2S) -4,4-difluoro-2-[(4- {4-[(4-methyl-1-{[3- (methylsulfonyl) pyridin-2-yl] acetyl}- 2,3-Dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) carbonyl] pyrrolidine-1-carboxylate Dichloromethane of the compound (60.0 mg) obtained in Example (148b) (2 mL) To the solution was added 4N dioxane hydrochloride solution (2 mL), and the mixture was stirred at room temperature. After stirring for 2 hours, the reaction mixture was concentrated to give crude 1- {4-methyl-5- [4- (piperidin-4-yl) phenoxy] -2,3-dihydro-1H-indol-1-yl. } -2- [3- (Methylsulfonyl) pyridin-2-yl] ethanone hydrochloride was obtained.
　得られた化合物のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にＮ－メチルモルホリン（０．０４３６　ｍＬ）を加え、室温で２時間攪拌した。反応液に４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（４１．１　ｍｇ）及び１－（ｔｅｒｔ－ブチルカルボニル）－４，４－ジフルオロ－Ｌ－プロリン（４９．８　ｍｇ）を加え、室温で１８時間攪拌した。反応液を減圧下濃縮し、残渣をカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（１００　ｍｇ）を淡茶色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.41-1.52 (11H, m), 1.83-1.99 (2H, m), 2.13 (3H, s), 2.29-2.47 (1H, m), 2.57-2.79 (4H, m), 3.19-3.28 (5H, m), 3.81-4.00 (4H, m), 4.34 (2H, t, J = 8.5 Hz), 4.62 (2H, s), 4.68-4.84 (1H, m), 6.73-6.85 (3H, m), 7.04-7.14 (2H, m), 7.48 (1H, dd, J = 7.9, 4.9 Hz), 7.94 (1H, d, J = 8.5 Hz), 8.36 (1H, dd, J = 7.9, 1.8 Hz), 8.80 (1H, dd, J = 4.9, 1.8 Hz).
MS (APCI) m/z: 739 (M+H)+。
（１４９ｂ）　１－｛５－［４－（１－｛［（２Ｓ）－４，４－ジフルオロピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン
　実施例（１４９ａ）で得られた化合物（７３．２　ｍｇ）のジクロロメタン（２　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（２　ｍＬ）を加え、室温で攪拌した。２時間４５分攪拌後、反応液を濃縮し、残渣に飽和炭酸水素ナトリウム水溶液を添加した。得られた混合溶液をジクロロメタンで３回抽出し、合わせた有機層を硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残渣をＮＨカラムクロマトグラフィー（ジクロロメタン）で精製することで、標記化合物（５４．５　ｍｇ）を無色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.57-1.68 (2H, m), 1.87-1.98 (2H, m), 2.13 (3H, s), 2.21-2.35 (1H, m), 2.46-2.60 (1H, m), 2.66-2.79 (2H, m), 3.06-3.29 (7H, m), 3.39-3.50 (1H, m), 3.84-3.92 (1H, m), 4.16-4.25 (1H, m), 4.34 (2H, t, J = 8.5 Hz), 4.61 (2H, s), 4.74-4.78 (1H, m), 6.74-6.87 (3H, m), 7.06-7.13 (2H, m), 7.48 (1H, dd, J= 7.9, 4.9 Hz), 7.94 (1H, d, J= 8.5 Hz), 8.36 (1H, dd, J = 7.9, 1.8 Hz), 8.80 (1H, dd, J = 4.9, 1.8 Hz).
MS (APCI) m/z: 639 (M+H)+。 N-methylmorpholine (0.0436 mL) was added to a solution of the obtained compound in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (41.1 mg) and 1- (tert-butylcarbonyl) -4, 4-Difluoro-L-proline (49.8 mg) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (100 mg) as a light brown amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.41-1.52 (11H, m), 1.83-1.99 (2H, m), 2.13 (3H, s), 2.29-2.47 (1H, m), 2.57-2.79 (4H, m), 3.19-3.28 (5H, m), 3.81-4.00 (4H, m), 4.34 (2H, t, J = 8.5 Hz), 4.62 (2H, s), 4.68-4.84 (1H, m ), 6.73-6.85 (3H, m), 7.04-7.14 (2H, m), 7.48 (1H, dd, J = 7.9, 4.9 Hz), 7.94 (1H, d, J = 8.5 Hz), 8.36 (1H, dd, J = 7.9, 1.8 Hz), 8.80 (1H, dd, J = 4.9, 1.8 Hz).
MS (APCI) m / z: 739 (M + H) + .
(149b) 1- {5- [4- (1-{[(2S) -4,4-Difluoropyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl-2,3- Dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone A solution of the compound (73.2 mg) obtained in Example (149a) in dichloromethane (2 mL) To the mixture was added 4N dioxane hydrochloride solution (2 mL), and the mixture was stirred at room temperature. After stirring for 2 hours and 45 minutes, the reaction solution was concentrated, and a saturated aqueous sodium hydrogen carbonate solution was added to the residue. The obtained mixed solution was extracted three times with dichloromethane, and the combined organic layer was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by NH column chromatography (dichloromethane) to give the title compound (54.5 mg) as a colorless amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.57-1.68 (2H, m), 1.87-1.98 (2H, m), 2.13 (3H, s), 2.21-2.35 (1H, m), 2.46-2.60 (1H, m), 2.66-2.79 (2H, m), 3.06-3.29 (7H, m), 3.39-3.50 (1H, m), 3.84-3.92 (1H, m), 4.16-4.25 (1H, m) , 4.34 (2H, t, J = 8.5 Hz), 4.61 (2H, s), 4.74-4.78 (1H, m), 6.74-6.87 (3H, m), 7.06-7.13 (2H, m), 7.48 (1H , dd, J = 7.9, 4.9 Hz), 7.94 (1H, d, J = 8.5 Hz), 8.36 (1H, dd, J = 7.9, 1.8 Hz), 8.80 (1H, dd, J = 4.9, 1.8 Hz) .
MS (APCI) m / z: 639 (M + H) + .
　（実施例１５０）
１－｛５－［４－（１－｛［（２Ｓ）－４，４－ジフルオロ－１－メチルピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン (Example 150)
1- {5- [4- (1-{[(2S) -4,4-difluoro-1-methylpyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl-2,3 -Dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone
Figure JPOXMLDOC01-appb-C000195
Figure JPOXMLDOC01-appb-C000195
　実施例（１４９ｂ）で得られた化合物（５０．０　ｍｇ）のメタノール（４　ｍＬ）溶液に、３７％ホルムアルデヒド溶液（０．２　ｍＬ）、７．５％パラジウム炭素（５０．０　ｍｇ）及び４Ｎ塩酸ジオキサン溶液（０．１　ｍＬ）を加え、水素雰囲気下、室温で１３時間攪拌した。ろ過により触媒を除いた後、ろ液を減圧下濃縮した。得られた残渣に飽和炭酸水素ナトリウム水溶液を添加し、ジクロロメタンで３回抽出を行った。合わせた有機層を硫酸ナトリウムで乾燥後、減圧下溶媒を留去し、得られた残渣ををカラムクロマトグラフィー（酢酸エチル／ジクロロメタン→メタノール／酢酸エチル）で精製することで、標記化合物（１０．０　ｍｇ）を白色アモルファス固体として得た。
MS (APCI) m/z: 653 (M+H)+。 To a solution of the compound (50.0 mg) obtained in Example (149b) in methanol (4 mL) was added 37% formaldehyde solution (0.2 mL), 7.5% palladium carbon (50.0 mg) and 4N. A dioxane hydrochloride solution (0.1 mL) was added, and the mixture was stirred at room temperature for 13 hours under a hydrogen atmosphere. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and extraction was performed 3 times with dichloromethane. The combined organic layers were dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate / dichloromethane → methanol / ethyl acetate) to give the title compound (10. 0 mg) was obtained as a white amorphous solid.
MS (APCI) m / z: 653 (M + H) + .
　（実施例１５１）：実施例（１５１ｄ）で合成
１－｛５－［４－（１－アセチル－１，２，３，６－テトラヒドロピリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－４－イル］エタノン (Example 151): synthesized in Example (151d) 1- {5- [4- (1-acetyl-1,2,3,6-tetrahydropyridin-4-yl) phenoxy] -4-methyl-2, 3-Dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) pyridin-4-yl] ethanone
Figure JPOXMLDOC01-appb-C000196
Figure JPOXMLDOC01-appb-C000196
（１５１ａ）　エチル　［３－（メチルスルホニル）ピリジン－４－イル］アセテート
　エチル　（３－ブロモピリジン－４－イル）アセテート（ＣＡＳ番号５１０５４－９９－０）（３００　ｍｇ）のジメチルスルホキシド（２　ｍＬ）溶液にメタンスルフィン酸ナトリウム（２５１　ｍｇ）、Ｌ－プロリンナトリウム塩（３３７　ｍｇ）、ヨウ化銅（２３４　ｍｇ）を加えてマイクロウェーブ照射下１１０℃で１時間撹拌した。室温まで冷却後、反応液を直接シリカゲルカラムクロマトグラフィーを用いて精製することで標記化合物（６６．０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.28-1.33 (3H, m), 3.20 (3H, s), 4.18-4.25 (4H, m), 7.30-7.34 (1H, m), 8.77-8.81 (1H, m), 9.21 (1H, s)。
（１５１ｂ）　［３－（メチルスルホニル）ピリジン－４－イル］酢酸ナトリウム
　実施例（１５１ａ）で得られた化合物（６６．０　ｍｇ）の１，４－ジオキサン（２　ｍＬ）溶液に１Ｎ水酸化ナトリウム水溶液（０．２７１　ｍＬ）を加えて室温で撹拌した。４時間後、減圧濃縮することで粗製の［３－（メチルスルホニル）ピリジン－４－イル］酢酸ナトリウム（６８．０　ｍｇ）を得た。
（１５１ｃ）　１－［５－（４－ブロモフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［３－（メチルスルホニル）ピリジン－４－イル］エタノン
　実施例（１ａ）で得られた化合物（１．１６　ｇ）に４Ｎ塩酸ジオキサン溶液（１０　ｍＬ）を加えて室温で３時間撹拌した。減圧濃縮し、析出した固体を酢酸エチルに懸濁させ、ろ取することで５－（４－ブロモフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール塩酸塩（９１１　ｍｇ）を得た。 (151a) Ethyl [3- (methylsulfonyl) pyridin-4-yl] acetate Ethyl (3-bromopyridin-4-yl) acetate (CAS number 51054-99-0) (300 mg) in dimethyl sulfoxide (2 mL) To the solution were added sodium methanesulfinate (251 mg), L-proline sodium salt (337 mg) and copper iodide (234 mg), and the mixture was stirred at 110 ° C. for 1 hour under microwave irradiation. After cooling to room temperature, the reaction solution was directly purified using silica gel column chromatography to obtain the title compound (66.0 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.28-1.33 (3H, m), 3.20 (3H, s), 4.18-4.25 (4H, m), 7.30-7.34 (1H, m), 8.77-8.81 (1H, m), 9.21 (1H, s).
(151b) [3- (Methylsulfonyl) pyridin-4-yl] acetate 1N sodium hydroxide was added to a solution of the compound obtained in Example (151a) (66.0 mg) in 1,4-dioxane (2 mL). Aqueous solution (0.271 mL) was added and stirred at room temperature. After 4 hours, crude [3- (methylsulfonyl) pyridin-4-yl] acetate (68.0 mg) was obtained by concentration under reduced pressure.
(151c) 1- [5- (4-Bromophenoxy) -4-methyl-2,3-dihydro-1H-indol-1-yl] -2- [3- (methylsulfonyl) pyridin-4-yl] ethanone 4N Hydrochloric acid dioxane solution (10 mL) was added to the compound (1.16 g) obtained in Example (1a), and the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, the precipitated solid was suspended in ethyl acetate and collected by filtration to obtain 5- (4-bromophenoxy) -4-methyl-2,3-dihydro-1H-indole hydrochloride (911 mg). It was.
　得られた化合物（９７．７　ｍｇ）、実施例（１５１ｂ）で得られた化合物（６８．０　ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボキシイミド塩酸塩（８２．４　ｍｇ）、３Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジン－３－オール（３９．０　ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１５０　ｍＬ）、Ｎ，Ｎ－ジメチルホルムアミド（２　ｍＬ）の混合物を室温で撹拌した。１２時間後、反応液をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム）で精製することで標記化合物と４－メチル－３－（メチルスルホニル）ピリジンとの混合物（６１．０　ｍｇ）を淡黄色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.10 (3H, s), 3.18-3.27 (5H, m), 4.26-4.31 (2H, m), 4.34 (2H, s), 6.73-6.80 (3H, m), 7.28-7.40 (3H, m), 7.93-7.96 (1H, m), 8.79-8.82 (1H, m), 9.20 (1H, s)。
（１５１ｄ）　１－｛５－［４－（１－アセチル－１，２，３，６－テトラヒドロピリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－４－イル］エタノン
　実施例（１４７ａ）で得られた化合物（６１．１　ｍｇ）と実施例（１５１ｃ）で得られた化合物（６１．０　ｍｇ）、［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）　ジクロライド　ジクロロメタン錯体（９．９３　ｍｇ）、炭酸ナトリウム（２５．８　ｍｇ）、ジメトキシエタン（３　ｍＬ）、水（１．５　ｍＬ）の混合物をマイクロウェーブ照射下、１２０℃で３０分撹拌した。室温まで冷却後、水を加えて酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム）で精製することで標記化合物（２７．０　ｍｇ）を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.11-2.18 (6H, m), 2.47-2.60 (2H, m), 3.19 (3H, s), 3.20-3.28 (2H, m), 3.63-3.68 (1H, m), 3.78-3.84 (1H, m), 4.10-4.14 (1H, m), 4.20-4.25 (1H, m), 4.25-4.32 (2H, m), 4.34 (2H, s), 5.92-6.02 (1H, m), 6.77-6.87 (3H, m), 7.24-7.32 (3H, m), 7.92-7.97 (1H, m), 8.78-8.82 (1H, m), 9.20 (1H, s).
MS (APCI) m/z: 546 (M+H)+。 The obtained compound (97.7 mg), the compound obtained in Example (151b) (68.0 mg), 1-ethyl-3- (3-dimethylaminopropyl) carboximide hydrochloride (82.4 mg) ), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (39.0 mg), N, N-diisopropylethylamine (0.150 mL), N, N-dimethylformamide ( (2 mL) was stirred at room temperature. After 12 hours, the reaction solution was purified by silica gel column chromatography (methanol / chloroform) to obtain a mixture (61.0 mg) of the title compound and 4-methyl-3- (methylsulfonyl) pyridine as a pale yellow solid. It was.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.10 (3H, s), 3.18-3.27 (5H, m), 4.26-4.31 (2H, m), 4.34 (2H, s), 6.73-6.80 (3H m), 7.28-7.40 (3H, m), 7.93-7.96 (1H, m), 8.79-8.82 (1H, m), 9.20 (1H, s).
(151d) 1- {5- [4- (1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indole-1- Yl} -2- [3- (methylsulfonyl) pyridin-4-yl] ethanone The compound (61.1 mg) obtained in Example (147a) and the compound (61.0) obtained in Example (151c) mg), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (9.93 mg), sodium carbonate (25.8 mg), dimethoxyethane (3 mL), water (1 0.5 mL) was stirred for 30 minutes at 120 ° C. under microwave irradiation. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform) to obtain the title compound (27.0 mg) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.11-2.18 (6H, m), 2.47-2.60 (2H, m), 3.19 (3H, s), 3.20-3.28 (2H, m), 3.63-3.68 (1H, m), 3.78-3.84 (1H, m), 4.10-4.14 (1H, m), 4.20-4.25 (1H, m), 4.25-4.32 (2H, m), 4.34 (2H, s), 5.92 -6.02 (1H, m), 6.77-6.87 (3H, m), 7.24-7.32 (3H, m), 7.92-7.97 (1H, m), 8.78-8.82 (1H, m), 9.20 (1H, s) .
MS (APCI) m / z: 546 (M + H) + .
　（実施例１５２）
１－｛５－［２，５－ジメチル－４－（１－｛［（２Ｓ）－１－メチルピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン (Example 152)
1- {5- [2,5-dimethyl-4- (1-{[(2S) -1-methylpyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl-2,3 -Dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone
Figure JPOXMLDOC01-appb-C000197
Figure JPOXMLDOC01-appb-C000197
　実施例（１５８ｅ）で得られた化合物（１００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にＮ－メチルモルホリン（０．０７２５　ｍＬ）を加え、室温で４０分間攪拌した。反応液に４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（６８．４　ｍｇ）及び１－メチル－Ｌ－プロリン（４２．６　ｍｇ）を加え、室温で２時間３０分攪拌した。反応液を減圧下濃縮し、残渣をカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（４９．２　ｍｇ）を黄色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.00-1.75 (5H, m), 2.16-2.24 (12H, m), 2.35-2.42 (3H, m), 2.58-2.68 (1H, m), 2.81-2.93 (1H, m), 3.03-3.29 (9H, m), 4.20-4.38 (3H, m), 4.61 (2H, s), 4.80-4.90 (1H, m), 6.46 (1H, s), 6.57 (1H, d, J = 8.5 Hz), 6.94-6.99 (1H, m), 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.89 (1H, d, J = 8.5 Hz), 8.34-8.37 (1H, m), 8.79 (1H, dd, J = 4.9, 1.8 Hz).
MS (APCI) m/z: 645 (M+H)+。 N-methylmorpholine (0.0725 mL) was added to a solution of the compound (100 mg) obtained in Example (158e) in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 40 minutes. To the reaction solution, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (68.4 mg) and 1-methyl-L-proline (42.6) were added. mg) was added, and the mixture was stirred at room temperature for 2 hours and 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / dichloromethane) to give the title compound (49.2 mg) as a yellow amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.00-1.75 (5H, m), 2.16-2.24 (12H, m), 2.35-2.42 (3H, m), 2.58-2.68 (1H, m), 2.81 -2.93 (1H, m), 3.03-3.29 (9H, m), 4.20-4.38 (3H, m), 4.61 (2H, s), 4.80-4.90 (1H, m), 6.46 (1H, s), 6.57 (1H, d, J = 8.5 Hz), 6.94-6.99 (1H, m), 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.89 (1H, d, J = 8.5 Hz), 8.34-8.37 ( 1H, m), 8.79 (1H, dd, J = 4.9, 1.8 Hz).
MS (APCI) m / z: 645 (M + H) + .
　（実施例１５３）
１－［５－（２，５－ジメチル－４－｛１－［（１－メチル－１Ｈ－イミダゾール－５－イル）カルボニル］ピペリジン－４－イル｝フェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン (Example 153)
1- [5- (2,5-Dimethyl-4- {1-[(1-methyl-1H-imidazol-5-yl) carbonyl] piperidin-4-yl} phenoxy) -4-methyl-2,3- Dihydro-1H-indol-1-yl] -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone
Figure JPOXMLDOC01-appb-C000198
Figure JPOXMLDOC01-appb-C000198
　実施例（１５８ｅ）で得られた化合物（７０．０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にＮ－メチルモルホリン（０．０５０７　ｍＬ）を加え、室温で２５分間攪拌した。反応液に４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（４７．９　ｍｇ）及び１－メチル－１Ｈ－イミダゾール－５－カルボン酸（２１．８　ｍｇ）を加え、室温で７０分間攪拌した。反応液を減圧下濃縮し、残渣をＮＨカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（５１．８　ｍｇ）を無色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.63-1.77 (2H, m), 1.81-1.93 (2H, m), 2.13-2.30 (10H, m), 2.83-3.31 (8H, m), 3.84 (3H, s), 4.34 (2H, t, J = 8.5 Hz), 4.51-4.80 (3H, m), 6.46 (1H, s), 6.58 (1H, d, J = 8.5 Hz), 7.00 (1H, s), 7.25 (1H, s), 7.43-7.54 (2H, m), 7.89 (1H, d, J = 8.5 Hz), 8.32-8.38 (1H, m), 8.77-8.81 (1H, m).
MS (APCI) m/z: 642 (M+H)+。 N-methylmorpholine (0.0507 mL) was added to a solution of the compound (70.0 mg) obtained in Example (158e) in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 25 minutes. To the reaction solution, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (47.9 mg) and 1-methyl-1H-imidazole-5-carboxylic acid were added. Acid (21.8 mg) was added and stirred at room temperature for 70 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH column chromatography (ethyl acetate / dichloromethane) to give the title compound (51.8 mg) as a colorless amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.63-1.77 (2H, m), 1.81-1.93 (2H, m), 2.13-2.30 (10H, m), 2.83-3.31 (8H, m), 3.84 (3H, s), 4.34 (2H, t, J = 8.5 Hz), 4.51-4.80 (3H, m), 6.46 (1H, s), 6.58 (1H, d, J = 8.5 Hz), 7.00 (1H, s), 7.25 (1H, s), 7.43-7.54 (2H, m), 7.89 (1H, d, J = 8.5 Hz), 8.32-8.38 (1H, m), 8.77-8.81 (1H, m).
MS (APCI) m / z: 642 (M + H) + .
　（実施例１５４）：実施例（１５４ｂ）で合成
１－｛５－［４－（１－｛［（２Ｓ，４Ｒ）－４－フルオロピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）－２，５－ジメチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン Example 154: Synthesis in Example (154b) 1- {5- [4- (1-{[(2S, 4R) -4-fluoropyrrolidin-2-yl] carbonyl} piperidin-4-yl)- 2,5-Dimethylphenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone
Figure JPOXMLDOC01-appb-C000199
Figure JPOXMLDOC01-appb-C000199
（１５４ａ）　ｔｅｒｔ－ブチル　（２Ｓ，４Ｒ）－２－［（４－｛２，５－ジメチル－４－［（４－メチル－１－｛［３－（メチルスルホニル）ピリジン－２－イル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）カルボニルｌ］－４－フルオロピロリジン－１－カルボキシレート
　実施例（１５８ｅ）で得られた化合物（２００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にＮ－メチルモルホリン（０．１４５　ｍＬ）を加え、室温で２０分間攪拌した。反応液に４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（１３７　ｍｇ）及び１－（ｔｅｒｔ－ブチルカルボニル）－４－フルオロ－Ｌ－プロリン（１１５　ｍｇ）を加え、室温で３時間２０分攪拌した。反応液を減圧下濃縮し、残渣をカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（１８８　ｍｇ）を無色アモルファス固体として得た。
MS (APCI) m/z: 749 (M+H)+。
（１５４ｂ）　１－｛５－［４－（１－｛［（２Ｓ，４Ｒ）－４－フルオロピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）－２，５－ジメチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン
　実施例（１５４ａ）で得られた化合物（１８８　ｍｇ）のジクロロメタン（３　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（２　ｍＬ）を加え、室温で攪拌した。４５分攪拌後、反応液を濃縮し、残渣に飽和炭酸水素ナトリウム水溶液を添加した。得られた混合溶液をジクロロメタンで３回抽出し、合わせた有機層を硫酸ナトリウムで乾燥後、減圧下溶媒を留去することで、標記化合物（１３８　ｍｇ）を淡黄色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.54-1.97 (4H, m), 2.13-2.27 (10H, m), 2.32-2.45 (1H, m), 2.65-2.76 (1H, m), 2.85-2.95 (1H, m), 3.11-3.29 (7H, m), 3.33-3.49 (1H, m), 4.01-4.09 (1H, m), 4.19-4.27 (1H, m), 4.34 (2H, t, J= 8.5 Hz), 4.61 (2H, s), 4.76-4.83 (1H, m), 5.20-5.40 (1H, m), 6.47-6.44 (1H, m), 6.58 (1H, d, J = 8.5 Hz), 6.96 (1H, d, J = 8.5 Hz), 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.89 (1H, d, J = 8.5 Hz), 8.34-8.38 (1H, m), 8.79 (1H, dd, J = 4.9, 1.8 Hz).
MS (APCI) m/z: 649 (M+H)+。 (154a) tert-butyl (2S, 4R) -2-[(4- {2,5-dimethyl-4-[(4-methyl-1-{[3- (methylsulfonyl) pyridin-2-yl] acetyl } -2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) carbonyl l] -4-fluoropyrrolidine-1-carboxylate Compound obtained in Example (158e) ( 200 mg) of N, N-dimethylformamide (5 mL) was added with N-methylmorpholine (0.145 mL), and the mixture was stirred at room temperature for 20 minutes. 4- (4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (137 mg) and 1- (tert-butylcarbonyl) -4-fluoro- were added to the reaction solution. L-proline (115 mg) was added, and the mixture was stirred at room temperature for 3 hours and 20 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (188 mg) as a colorless amorphous solid.
MS (APCI) m / z: 749 (M + H) + .
(154b) 1- {5- [4- (1-{[(2S, 4R) -4-fluoropyrrolidin-2-yl] carbonyl} piperidin-4-yl) -2,5-dimethylphenoxy] -4- Methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone Compound (188 mg) obtained in Example (154a) in dichloromethane ( 3N solution was added 4N dioxane hydrochloride solution (2 mL) and stirred at room temperature. After stirring for 45 minutes, the reaction solution was concentrated, and a saturated aqueous sodium hydrogen carbonate solution was added to the residue. The obtained mixed solution was extracted three times with dichloromethane, and the combined organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (138 mg) as a pale yellow solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.54-1.97 (4H, m), 2.13-2.27 (10H, m), 2.32-2.45 (1H, m), 2.65-2.76 (1H, m), 2.85 -2.95 (1H, m), 3.11-3.29 (7H, m), 3.33-3.49 (1H, m), 4.01-4.09 (1H, m), 4.19-4.27 (1H, m), 4.34 (2H, t, J = 8.5 Hz), 4.61 (2H, s), 4.76-4.83 (1H, m), 5.20-5.40 (1H, m), 6.47-6.44 (1H, m), 6.58 (1H, d, J = 8.5 Hz ), 6.96 (1H, d, J = 8.5 Hz), 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.89 (1H, d, J = 8.5 Hz), 8.34-8.38 (1H, m), 8.79 (1H, dd, J = 4.9, 1.8 Hz).
MS (APCI) m / z: 649 (M + H) + .
　（実施例１５５）
１－｛５－［４－（１－｛［（２Ｓ，４Ｒ）－４－フルオロ－１－メチルピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）－２，５－ジメチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン (Example 155)
1- {5- [4- (1-{[(2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl] carbonyl} piperidin-4-yl) -2,5-dimethylphenoxy] -4 -Methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone
Figure JPOXMLDOC01-appb-C000200
Figure JPOXMLDOC01-appb-C000200
　実施例（１５４ｂ）で得られた化合物（１２９　ｍｇ）のメタノール（６　ｍＬ）溶液に、３７％ホルムアルデヒド溶液（０．２　ｍＬ）、７．５％パラジウム炭素（５０．０　ｍｇ）及び４Ｎ塩酸ジオキサン溶液（０．２　ｍＬ）を加え、水素雰囲気下、室温で１９時間攪拌した。ろ過により触媒を除いた後、ろ液を減圧下濃縮した。得られた残渣に飽和炭酸水素ナトリウム水溶液を添加し、ジクロロメタンで３回抽出を行った。合わせた有機層を硫酸ナトリウムで乾燥後、減圧下溶媒を留去し、得られた残渣ををカラムクロマトグラフィー（酢酸エチル／ジクロロメタン→メタノール／酢酸エチル）で精製することで、標記化合物（１４．３　ｍｇ）を淡黄色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.77-1.91 (4H, m), 2.09-2.30 (10H, m), 2.41-2.49 (3H, m), 2.58-2.71 (2H, m), 2.83-2.95 (1H, m), 3.06-3.28 (7H, m), 3.59-3.72 (2H, m), 4.16-4.24 (1H, m), 4.34 (2H, t, J = 8.5 Hz), 4.61 (2H, s), 4.78-4.88 (1H, m), 5.16-5.36 (1H, m), 6.42-6.50 (1H, m), 6.58 (1H, d, J = 8.5 Hz), 6.92-7.00 (1H, m), 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.89 (1H, d, J = 8.5 Hz), 8.36 (1H, dd, J = 8.2, 1.8 Hz), 8.79 (1H, dd, J = 4.9, 1.8 Hz).
MS (APCI) m/z: 663 (M+H)+。 To a solution of the compound (129 mg) obtained in Example (154b) in methanol (6 mL), 37% formaldehyde solution (0.2 mL), 7.5% palladium on carbon (50.0 mg) and 4N dioxane hydrochloride. The solution (0.2 mL) was added, and the mixture was stirred at room temperature for 19 hours under a hydrogen atmosphere. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and extraction was performed 3 times with dichloromethane. The combined organic layers were dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate / dichloromethane → methanol / ethyl acetate) to give the title compound (14. 3 mg) was obtained as a pale yellow amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.77-1.91 (4H, m), 2.09-2.30 (10H, m), 2.41-2.49 (3H, m), 2.58-2.71 (2H, m), 2.83 -2.95 (1H, m), 3.06-3.28 (7H, m), 3.59-3.72 (2H, m), 4.16-4.24 (1H, m), 4.34 (2H, t, J = 8.5 Hz), 4.61 (2H , s), 4.78-4.88 (1H, m), 5.16-5.36 (1H, m), 6.42-6.50 (1H, m), 6.58 (1H, d, J = 8.5 Hz), 6.92-7.00 (1H, m ), 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.89 (1H, d, J = 8.5 Hz), 8.36 (1H, dd, J = 8.2, 1.8 Hz), 8.79 (1H, dd, J = (4.9, 1.8 Hz).
MS (APCI) m / z: 663 (M + H) + .
　（実施例１５６）：実施例（１５６ｂ）で合成
１－｛５－［４－（１－｛［（２Ｓ）－４，４－ジフルオロピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）－２，５－ジメチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン Example 156: Synthesis in Example (156b) 1- {5- [4- (1-{[(2S) -4,4-difluoropyrrolidin-2-yl] carbonyl} piperidin-4-yl)- 2,5-Dimethylphenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone
Figure JPOXMLDOC01-appb-C000201
Figure JPOXMLDOC01-appb-C000201
（１５６ａ）　ｔｅｒｔ－ブチル　（２Ｓ）－２－［（４－｛２，５－ジメチル－４－［（４－メチル－１－｛［３－（メチルスルホニル）ピリジン－２－イル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）カルボニル］－４，４－ジフルオロピロリジン－１－カルボキシレート
　実施例（１５８ｅ）で得られた化合物（２００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にＮ－メチルモルホリン（０．１４５　ｍＬ）を加え、室温で３５分間攪拌した。反応液に４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（１３７　ｍｇ）及び１－（ｔｅｒｔ－ブチルカルボニル）－４，４－ジフルオロ－Ｌ－プロリン（９９．４　ｍｇ）を加え、室温で１５時間３０分攪拌した。反応液を減圧下濃縮し、残渣をカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（２３６　ｍｇ）を淡黄色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.41-1.62 (11H, m), 1.69-1.94 (2H, m), 2.14-2.25 (9H, m), 2.31-2.51 (1H, m), 2.62-2.95 (3H, m), 3.15-3.28 (6H, m), 3.84-3.99 (3H, m), 4.34 (2H, t, J = 8.2 Hz), 4.61 (2H, s), 4.73-4.97 (2H, m), 6.43-6.48 (1H, m), 6.58 (1H, d, J= 8.5 Hz), 6.86-7.05 (1H, m), 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.89 (1H, d, J = 8.5 Hz), 8.36 (1H, dd, J = 7.9, 1.8 Hz), 8.79 (1H, dd, J = 4.9, 1.8 Hz).
MS (APCI) m/z: 767 (M+H)+。
（１５６ｂ）　１－｛５－［４－（１－｛［（２Ｓ）－４，４－ジフルオロピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）－２，５－ジメチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン
　実施例（１５６ａ）で得られた化合物（２３４　ｍｇ）のジクロロメタン（３　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（３　ｍＬ）を加え、室温で攪拌した。４０分間攪拌後、反応液を濃縮し、残渣に飽和炭酸水素ナトリウム水溶液を添加した。得られた混合溶液をメタノール／ジクロロメタン（５／９５）で３回抽出し、合わせた有機層を硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残渣をＮＨカラムクロマトグラフィー（メタノール／ジクロロメタン）で精製することで、標記化合物（１７９　ｍｇ）を淡黄色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.60-1.71 (2H, m), 1.79-1.91 (2H, m), 2.12-2.37 (10H, m), 2.48-2.61 (1H, m), 2.66-2.76 (1H, m), 2.94-2.84 (1H, m), 3.06-3.28 (7H, m), 3.40-3.51 (1H, m), 3.83-3.94 (1H, m), 4.17-4.24 (1H, m), 4.34 (2H, t, J = 8.2 Hz), 4.61 (2H, s), 4.75-4.83 (1H, m), 6.42-6.47 (1H, m), 6.58 (1H, d, J = 8.5 Hz), 6.95 (1H, s), 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.89 (1H, d, J = 8.5 Hz), 8.34-8.37 (1H, m), 8.79 (1H, dd, J= 4.9, 1.8 Hz).
MS (APCI) m/z: 667 (M+H)+。 (156a) tert-butyl (2S) -2-[(4- {2,5-dimethyl-4-[(4-methyl-1-{[3- (methylsulfonyl) pyridin-2-yl] acetyl}- 2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidin-1-yl) carbonyl] -4,4-difluoropyrrolidine-1-carboxylate Compound (200) obtained in Example (158e) mg) in N, N-dimethylformamide (5 mL) was added N-methylmorpholine (0.145 mL), and the mixture was stirred at room temperature for 35 minutes. To the reaction solution was added 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (137 mg) and 1- (tert-butylcarbonyl) -4,4- Difluoro-L-proline (99.4 mg) was added, 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 column chromatography (ethyl acetate / hexane) to give the title compound (236 mg) as a pale yellow amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.41-1.62 (11H, m), 1.69-1.94 (2H, m), 2.14-2.25 (9H, m), 2.31-2.51 (1H, m), 2.62 -2.95 (3H, m), 3.15-3.28 (6H, m), 3.84-3.99 (3H, m), 4.34 (2H, t, J = 8.2 Hz), 4.61 (2H, s), 4.73-4.97 (2H , m), 6.43-6.48 (1H, m), 6.58 (1H, d, J = 8.5 Hz), 6.86-7.05 (1H, m), 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.89 ( 1H, d, J = 8.5 Hz), 8.36 (1H, dd, J = 7.9, 1.8 Hz), 8.79 (1H, dd, J = 4.9, 1.8 Hz).
MS (APCI) m / z: 767 (M + H) + .
(156b) 1- {5- [4- (1-{[(2S) -4,4-difluoropyrrolidin-2-yl] carbonyl} piperidin-4-yl) -2,5-dimethylphenoxy] -4- Methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone Compound (234 mg) obtained in Example (156a) in dichloromethane ( 3N solution was added 4N dioxane hydrochloride solution (3 mL) and stirred at room temperature. After stirring for 40 minutes, the reaction solution was concentrated, and a saturated aqueous sodium hydrogen carbonate solution was added to the residue. The obtained mixed solution was extracted three times with methanol / dichloromethane (5/95), and the combined organic layer was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by NH column chromatography (methanol / dichloromethane) to give the title compound (179 mg) as a pale yellow solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.60-1.71 (2H, m), 1.79-1.91 (2H, m), 2.12-2.37 (10H, m), 2.48-2.61 (1H, m), 2.66 -2.76 (1H, m), 2.94-2.84 (1H, m), 3.06-3.28 (7H, m), 3.40-3.51 (1H, m), 3.83-3.94 (1H, m), 4.17-4.24 (1H, m), 4.34 (2H, t, J = 8.2 Hz), 4.61 (2H, s), 4.75-4.83 (1H, m), 6.42-6.47 (1H, m), 6.58 (1H, d, J = 8.5 Hz) ), 6.95 (1H, s), 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.89 (1H, d, J = 8.5 Hz), 8.34-8.37 (1H, m), 8.79 (1H, dd, J = 4.9, 1.8 Hz).
MS (APCI) m / z: 667 (M + H) + .
　（実施例１５７）
１－｛５－［４－（１－｛［（２Ｓ）－４，４－ジフルオロ－１－メチルピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）－２，５－ジメチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン (Example 157)
1- {5- [4- (1-{[(2S) -4,4-difluoro-1-methylpyrrolidin-2-yl] carbonyl} piperidin-4-yl) -2,5-dimethylphenoxy] -4 -Methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone
Figure JPOXMLDOC01-appb-C000202
Figure JPOXMLDOC01-appb-C000202
　実施例（１５６ｂ）で得られた化合物（１７９　ｍｇ）のメタノール（７　ｍＬ）溶液に、３７％ホルムアルデヒド溶液（０．２　ｍＬ）、７．５％パラジウム炭素（５０．０　ｍｇ）及び４Ｎ塩酸ジオキサン溶液（０．４　ｍＬ）を加え、水素雰囲気下、室温で１２時間攪拌した。ろ過により触媒を除いた後、ろ液を減圧下濃縮した。得られた残渣に飽和炭酸水素ナトリウム水溶液を添加し、ジクロロメタンで３回抽出を行った。合わせた有機層を硫酸ナトリウムで乾燥後、減圧下溶媒を留去し、得られた残渣ををカラムクロマトグラフィー（酢酸エチル／ヘキサン→メタノール／酢酸エチル）で精製することで、標記化合物（９１．９　ｍｇ）を淡黄色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.68-1.57 (2H, m), 1.79-1.90 (2H, m), 2.11-2.27 (9H, m), 2.39-2.47 (3H, m), 2.47-2.59 (2H, m), 2.63-2.80 (2H, m), 2.84-2.94 (1H, m), 3.05-3.19 (1H, m), 3.21-3.28 (5H, m), 3.50-3.62 (2H, m), 4.19-4.38 (3H, m), 4.61 (2H, s), 4.80-4.87 (1H, m), 6.42-6.49 (1H, m), 6.57 (1H, d, J = 8.5 Hz), 6.95 (1H, s), 7.45-7.50 (1H, m), 7.89 (1H, d, J = 8.5 Hz), 8.34-8.39 (1H, m), 8.78-8.81 (1H, m).
MS (APCI) m/z: 681 (M+H)+。 To a solution of the compound (179 mg) obtained in Example (156b) in methanol (7 mL) was added 37% formaldehyde solution (0.2 mL), 7.5% palladium carbon (50.0 mg) and 4N dioxane hydrochloride. The solution (0.4 mL) was added, and the mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and extraction was performed 3 times with dichloromethane. The combined organic layer was dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate / hexane → methanol / ethyl acetate) to give the title compound (91. 9 mg) was obtained as a pale yellow amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.68-1.57 (2H, m), 1.79-1.90 (2H, m), 2.11-2.27 (9H, m), 2.39-2.47 (3H, m), 2.47 -2.59 (2H, m), 2.63-2.80 (2H, m), 2.84-2.94 (1H, m), 3.05-3.19 (1H, m), 3.21-3.28 (5H, m), 3.50-3.62 (2H, m), 4.19-4.38 (3H, m), 4.61 (2H, s), 4.80-4.87 (1H, m), 6.42-6.49 (1H, m), 6.57 (1H, d, J = 8.5 Hz), 6.95 (1H, s), 7.45-7.50 (1H, m), 7.89 (1H, d, J = 8.5 Hz), 8.34-8.39 (1H, m), 8.78-8.81 (1H, m).
MS (APCI) m / z: 681 (M + H) + .
　（実施例１５８）：実施例（１５８ｆ）で合成
１－（４－｛２，５－ジメチル－４－［（４－メチル－１－｛［３－（メチルスルホニル）ピリジン－２－イル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシフェニル｝ピペリジン－１－イル）－２－メトキシエタノン Example 158: Synthesis in Example (158f) 1- (4- {2,5-dimethyl-4-[(4-methyl-1-{[3- (methylsulfonyl) pyridin-2-yl] acetyl } -2,3-dihydro-1H-indol-5-yl) oxyphenyl} piperidin-1-yl) -2-methoxyethanone
Figure JPOXMLDOC01-appb-C000203
Figure JPOXMLDOC01-appb-C000203
（１５８ａ）　ベンジル　５－（４－ブロモ－２，５－ジメチルフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　実施例（２４ａ）で得られた化合物（１５．０　ｇ）のジクロロメタン（３０　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（３０　ｍＬ）を加え、室温で攪拌した。２時間攪拌後、反応液を濃縮することで、粗製の５－（４－ブロモ－２，５－ジメチルフェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール塩酸塩（１２．８　ｇ）を得た。 (158a) Benzyl 5- (4-bromo-2,5-dimethylphenoxy) -4-methyl-2,3-dihydro-1H-indole-1-carboxylate Compound (15.) obtained in Example (24a) To a solution of 0 g) in dichloromethane (30 mL) was added 4N hydrochloric acid dioxane solution (30 mL), and the mixture was stirred at room temperature. After stirring for 2 hours, the reaction mixture was concentrated to give crude 5- (4-bromo-2,5-dimethylphenoxy) -4-methyl-2,3-dihydro-1H-indole hydrochloride (12.8 g). )
　得られた化合物（５．００　ｇ）のテトラヒドロフラン（７５　ｍＬ）溶液に、クロロギ酸ベンジル（５．８１　ｍＬ）及び飽和炭酸水素ナトリウム水溶液（７５　ｍＬ）を加え、室温で攪拌した。４時間３０分後、反応混合物に水を加え、酢酸エチルで３回抽出を行い、合わせた有機層を硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残渣をジクロロメタンに溶解させ、ヘキサンを添加した。析出した固体をろ取し、乾燥させることで、標記化合物（５．７７　ｇ）を無色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.08 (3H, s), 2.26-2.21 (6H, m), 3.07 (2H, t, J= 8.5 Hz), 4.12 (2H, t, J = 8.5 Hz), 5.20-5.35 (2H, m), 6.44 (1H, s), 6.52-6.72 (1H, m), 7.21-7.45 (6H, m), 7.65-7.71 (1H, m).
MS (APCI) m/z: 466 (M+H)+。
（１５８ｂ）　ベンジル　５－｛４－［１－（ｔｅｒｔ－ブトキシカルボニル）－１，２，３，６－テトラヒドロピリジン－４－イル］－２，５－ジメチルフェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－カルボキシレート
　実施例（１５８ａ）で合成した化合物（２．００　ｇ）、ｔｅｒｔ－ブチル　４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）－３，６－ジヒドロピリジン－１（２Ｈ）－カルボキシレート（１．５９　ｇ）及びテトラキストリフェニルホスフィンパラジウム（２４８　ｍｇ）の１，２－ジメトキシエタン（１００　ｍＬ）溶液に、リン酸三カリウム（２．７３　ｇ）の水溶液（１０　ｍＬ）を加え、９０℃で１６時間攪拌した。室温に冷却後、有機層を硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することで、標記化合物（１．９３　ｇ）を無色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.50 (9H, s), 2.08-2.16 (6H, m), 2.24 (3H, s), 2.29-2.37 (2H, m), 3.08 (2H, t, J = 8.5 Hz), 3.54-3.65 (2H, m), 4.02 (2H, s), 4.12 (2H, t, J = 8.5 Hz), 5.21-5.34 (2H, m), 5.48-5.57 (1H, m), 6.40 (1H, s), 6.53-6.73 (1H, m), 6.92 (1H, s), 7.19-7.45 (5H, m), 7.64-7.71 (1H, m)。
（１５８ｃ）　ｔｅｒｔ－ブチル　４－｛２，５－ジメチル－４－［（４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－カルボキシレート
　実施例（１５８ｂ）で得られた化合物（１．９２　ｇ）のメタノール（６０　ｍＬ）溶液に１０％パラジウム炭素（１００　ｍｇ）を加え、水素雰囲気下、室温で１０時間１５分攪拌した。ろ過で触媒を除去した後、反応液を減圧下濃縮することで、粗製の標記化合物（１．４９　ｇ）を無色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.50-1.48 (9H, m), 1.57-1.76 (4H, m), 2.12 (3H, s), 2.19 (3H, s), 2.24 (3H, s), 2.69-2.86 (3H, m), 3.08 (2H, t, J= 8.2 Hz), 3.72 (2H, t, J = 8.2 Hz), 4.14-4.36 (2H, m), 6.41 (1H, s), 6.57 (1H, d, J = 8.5 Hz), 6.71 (1H, d, J= 8.5 Hz), 6.98 (1H, s).
MS (APCI) m/z: 437 (M+H)+。
（１５８ｄ）　ｔｅｒｔ－ブチル　４－｛２，５－ジメチル－４－［（４－メチル－１－｛［３－（メチルスルホニル）ピリジン－２－イル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－カルボキシレート
　実施例（１５８ｃ）で得られた化合物（７００　ｍｇ）及び［３－（メチルスルホニル）ピリジン－２－イル］酢酸ナトリウム塩（４５６　ｍｇ）のジメチルホルムアミド（１０　ｍＬ）溶液に４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリウム　クロリド（６６６　ｍｇ）を加え、室温で１７時間３０分攪拌した。反応液を減圧下濃縮し、残渣をカラムクロマトグラフィー（酢酸エチル／ジクロロメタン）で精製することで、標記化合物（１．０３　ｇ）を黄色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.49 (9H, s), 1.60-1.76 (4H, m), 2.17 (3H, s), 2.20 (3H, s), 2.22 (3H, s), 2.70-2.85 (3H, m), 3.20-3.29 (5H, m), 4.18-4.38 (4H, m), 4.61 (2H, s), 6.45 (1H, s), 6.57 (1H, d, J = 8.5 Hz), 6.99 (1H, s), 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.89 (1H, d, J = 8.5 Hz), 8.35 (1H, dd, J = 7.9, 1.8 Hz), 8.79 (1H, dd, J = 4.9, 1.8 Hz)。
（１５８ｅ）　１－｛５－［２，５－ジメチル－４－（ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン塩酸塩
　実施例（１５８ｄ）で得られた化合物（１．０２　ｇ）のジクロロメタン（１０　ｍＬ）溶液に４Ｎ塩酸ジオキサン溶液（１０　ｍＬ）を加え、室温で攪拌した。２時間攪拌後、反応液を濃縮することで、粗製の標記化合物（１．０３　ｇ）を得た。
MS (APCI) m/z: 534 (M+H)+。
（１５８ｆ）　１－（４－｛２，５－ジメチル－４－［（４－メチル－１－｛［３－（メチルスルホニル）ピリジン－２－イル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシフェニル｝ピペリジン－１－イル）－２－メトキシエタノン
　実施例（１５８ｅ）で得られた化合物（１００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にＮ－メチルモルホリン（０．０７２５　ｍＬ）を加え、室温で５５分間攪拌した。反応液に４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（６８．４　ｍｇ）及びメトキシ酢酸（１９．３　ｍｇ）を加え、室温で１４時間攪拌した。反応液を減圧下濃縮し、残渣をカラムクロマトグラフィー（酢酸エチル／ヘキサン→メタノール／酢酸エチル）で精製することで、標記化合物（８８．８　ｍｇ）を淡黄色アモルファス固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.62-1.70 (2H, m), 1.78-1.85 (2H, m), 2.17 (3H, s), 2.19-2.26 (6H, m), 2.63-2.72 (1H, m), 2.83-2.92 (1H, m), 3.06-3.19 (1H, m), 3.20-3.29 (5H, m), 3.44-3.53 (3H, m), 3.96-4.23 (3H, m), 4.34 (2H, t, J = 8.2 Hz), 4.61 (2H, s), 4.73-4.81 (1H, m), 6.45 (1H, s), 6.57 (1H, d, J = 8.5 Hz), 6.96 (1H, s), 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.89 (1H, d, J = 8.5 Hz), 8.33-8.38 (1H, m), 8.77-8.82 (1H, m).
MS (APCI) m/z: 606 (M+H)+。 To a solution of the obtained compound (5.00 g) in tetrahydrofuran (75 mL), benzyl chloroformate (5.81 mL) and saturated aqueous sodium hydrogen carbonate solution (75 mL) were added, and the mixture was stirred at room temperature. After 4 hours and 30 minutes, water was added to the reaction mixture, extraction was performed three times with ethyl acetate, the combined organic layers were dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in dichloromethane and hexane was added. The precipitated solid was collected by filtration and dried to obtain the title compound (5.77 g) as a colorless solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.08 (3H, s), 2.26-2.21 (6H, m), 3.07 (2H, t, J = 8.5 Hz), 4.12 (2H, t, J = 8.5 Hz), 5.20-5.35 (2H, m), 6.44 (1H, s), 6.52-6.72 (1H, m), 7.21-7.45 (6H, m), 7.65-7.71 (1H, m).
MS (APCI) m / z: 466 (M + H) + .
(158b) Benzyl 5- {4- [1- (tert-butoxycarbonyl) -1,2,3,6-tetrahydropyridin-4-yl] -2,5-dimethylphenoxy} -4-methyl-2,3 -Dihydro-1H-indole-1-carboxylate Compound (2.00 g) synthesized in Example (158a), tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2- To a solution of dioxaborolan-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate (1.59 g) and tetrakistriphenylphosphine palladium (248 mg) in 1,2-dimethoxyethane (100 mL), An aqueous solution (10 mL) of tripotassium phosphate (2.73 g) was added, and the mixture was stirred at 90 ° C. for 16 hours. After cooling to room temperature, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (1.93 g) as a colorless solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.50 (9H, s), 2.08-2.16 (6H, m), 2.24 (3H, s), 2.29-2.37 (2H, m), 3.08 (2H, t , J = 8.5 Hz), 3.54-3.65 (2H, m), 4.02 (2H, s), 4.12 (2H, t, J = 8.5 Hz), 5.21-5.34 (2H, m), 5.48-5.57 (1H, m), 6.40 (1H, s), 6.53-6.73 (1H, m), 6.92 (1H, s), 7.19-7.45 (5H, m), 7.64-7.71 (1H, m).
(158c) tert-butyl 4- {2,5-dimethyl-4-[(4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine-1-carboxylate Examples ( To a solution of the compound (1.92 g) obtained in 158b) in methanol (60 mL) was added 10% palladium carbon (100 mg), and the mixture was stirred at room temperature for 10 hours and 15 minutes in a hydrogen atmosphere. After removing the catalyst by filtration, the reaction solution was concentrated under reduced pressure to obtain the crude title compound (1.49 g) as a colorless amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.50-1.48 (9H, m), 1.57-1.76 (4H, m), 2.12 (3H, s), 2.19 (3H, s), 2.24 (3H, s ), 2.69-2.86 (3H, m), 3.08 (2H, t, J = 8.2 Hz), 3.72 (2H, t, J = 8.2 Hz), 4.14-4.36 (2H, m), 6.41 (1H, s) , 6.57 (1H, d, J = 8.5 Hz), 6.71 (1H, d, J = 8.5 Hz), 6.98 (1H, s).
MS (APCI) m / z: 437 (M + H) + .
(158d) tert-butyl 4- {2,5-dimethyl-4-[(4-methyl-1-{[3- (methylsulfonyl) pyridin-2-yl] acetyl} -2,3-dihydro-1H- Indol-5-yl) oxy] phenyl} piperidine-1-carboxylate Compound (700 mg) obtained in Example (158c) and [3- (methylsulfonyl) pyridin-2-yl] acetic acid sodium salt (456 mg) ) In dimethylformamide (10 mL) was added 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholium chloride (666 mg) for 17 hours at room temperature. Stir for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / dichloromethane) to give the title compound (1.03 g) as a yellow amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.49 (9H, s), 1.60-1.76 (4H, m), 2.17 (3H, s), 2.20 (3H, s), 2.22 (3H, s), 2.70-2.85 (3H, m), 3.20-3.29 (5H, m), 4.18-4.38 (4H, m), 4.61 (2H, s), 6.45 (1H, s), 6.57 (1H, d, J = 8.5 Hz), 6.99 (1H, s), 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.89 (1H, d, J = 8.5 Hz), 8.35 (1H, dd, J = 7.9, 1.8 Hz), 8.79 (1H, dd, J = 4.9, 1.8 Hz).
(158e) 1- {5- [2,5-Dimethyl-4- (piperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [3 -(Methylsulfonyl) pyridin-2-yl] ethanone hydrochloride To a solution of the compound obtained in Example (158d) (1.02 g) in dichloromethane (10 mL) was added 4N hydrochloric acid dioxane solution (10 mL) at room temperature. And stirred. After stirring for 2 hours, the reaction solution was concentrated to obtain the crude title compound (1.03 g).
MS (APCI) m / z: 534 (M + H) + .
(158f) 1- (4- {2,5-dimethyl-4-[(4-methyl-1-{[3- (methylsulfonyl) pyridin-2-yl] acetyl} -2,3-dihydro-1H- Indol-5-yl) oxyphenyl} piperidin-1-yl) -2-methoxyethanone To a solution of the compound obtained in Example (158e) (100 mg) in N, N-dimethylformamide (5 mL), N- Methylmorpholine (0.0725 mL) was added and stirred at room temperature for 55 minutes. 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (68.4 mg) and methoxyacetic acid (19.3 mg) were added to the reaction mixture, Stir at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane → methanol / ethyl acetate) to obtain the title compound (88.8 mg) as a pale yellow amorphous solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.62-1.70 (2H, m), 1.78-1.85 (2H, m), 2.17 (3H, s), 2.19-2.26 (6H, m), 2.63-2.72 (1H, m), 2.83-2.92 (1H, m), 3.06-3.19 (1H, m), 3.20-3.29 (5H, m), 3.44-3.53 (3H, m), 3.96-4.23 (3H, m) , 4.34 (2H, t, J = 8.2 Hz), 4.61 (2H, s), 4.73-4.81 (1H, m), 6.45 (1H, s), 6.57 (1H, d, J = 8.5 Hz), 6.96 ( 1H, s), 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.89 (1H, d, J = 8.5 Hz), 8.33-8.38 (1H, m), 8.77-8.82 (1H, m).
MS (APCI) m / z: 606 (M + H) + .
　（実施例１５９）
１－（５－｛４－［１－（１Ｈ－イミダゾール－５－イルカルボニル）ピペリジン－４－イル］－２，５－ジメチルフェノキシ｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン (Example 159)
1- (5- {4- [1- (1H-imidazol-5-ylcarbonyl) piperidin-4-yl] -2,5-dimethylphenoxy} -4-methyl-2,3-dihydro-1H-indole- 1-yl) -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone
Figure JPOXMLDOC01-appb-C000204
Figure JPOXMLDOC01-appb-C000204
　実施例（１５８ｅ）で得られた化合物（８０．０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５　ｍＬ）溶液にＮ－メチルモルホリン（０．０５８０　ｍＬ）を加え、室温で６０分間攪拌した。反応液に４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（５４．７　ｍｇ）及び４－イミダゾールカルボン酸（２２．２　ｍｇ）を加え、室温で２０時間攪拌した。反応液を減圧下濃縮し、残渣をＮＨカラムクロマトグラフィー（酢酸エチル／ジクロロメタン→メタノール／酢酸エチル）で精製することで、標記化合物（３２．７　ｍｇ）を無色固体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.68-1.94 (4H, m), 2.13-2.29 (10H, m), 2.79-3.31 (8H, m), 4.34 (2H, t, J = 8.5 Hz), 4.55-4.89 (3H, m), 6.46 (1H, s), 6.58 (1H, d, J = 9.1 Hz), 6.95-7.06 (1H, m), 7.38-7.50 (2H, m), 7.62-7.75 (2H, m), 7.89 (1H, d, J = 8.5 Hz), 8.36 (1H, dd, J = 7.9, 1.2 Hz), 8.79 (1H, dd, J = 4.9, 1.2 Hz).
MS (APCI) m/z: 628 (M+H)+。 N-methylmorpholine (0.0580 mL) was added to a solution of the compound (80.0 mg) obtained in Example (158e) in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 60 minutes. 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (54.7 mg) and 4-imidazolecarboxylic acid (22.2 mg) were added to the reaction solution. And stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH column chromatography (ethyl acetate / dichloromethane → methanol / ethyl acetate) to obtain the title compound (32.7 mg) as a colorless solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.68-1.94 (4H, m), 2.13-2.29 (10H, m), 2.79-3.31 (8H, m), 4.34 (2H, t, J = 8.5 Hz ), 4.55-4.89 (3H, m), 6.46 (1H, s), 6.58 (1H, d, J = 9.1 Hz), 6.95-7.06 (1H, m), 7.38-7.50 (2H, m), 7.62- 7.75 (2H, m), 7.89 (1H, d, J = 8.5 Hz), 8.36 (1H, dd, J = 7.9, 1.2 Hz), 8.79 (1H, dd, J = 4.9, 1.2 Hz).
MS (APCI) m / z: 628 (M + H) + .
　（試験例１）
RORγt遺伝子導入細胞のIL-17産生に対する阻害効果
（１）RORγt遺伝子導入細胞の作製
　マウス（Mus musculus）RORgamma t 蛋白質の全長アミノ酸配列をコードするmRNAの塩基配列（GenBank Accession Number AF163668: http://www.metalife.com/Genbank/5679306）を基に全長蛋白質をコードするmRNAのcDNAをPCR法により取得した。得られたcDNAは、発現ベクターであるpUNOベクター（InvivoGen社）に挿入し、マウスRORγt発現ベクターを構築した。構築したマウスRORγt発現ベクターは、EL4細胞（マウスTリンパ腫細胞株）に導入し、選択培地（DMEM培地にウシ胎児血清、Blasticidin S、ペニシリン、ストレプトマイシンを添加したもの）で培養することでRORγt遺伝子導入細胞を取得した。
（２）IL-17産生阻害作用の評価
　試験化合物のIL-17産生阻害作用は、前述のRORγt遺伝子導入細胞をphorbol 12-Myristate 13-acetate（PMA）とionomycinで刺激した際のIL-17産生で測定した。すなわち、RORγt遺伝子導入細胞を前述の選択培地にて調製し、1穴当たり75000個ずつ96穴平底プレート（Corning社）内に分注した。このとき、種々の濃度の試験化合物を同時に添加した。5%CO2濃度のインキュベーター中で37℃にて1時間培養した後、PMAを終濃度25ng/mL、ionomycinを終濃度125ng/mL、各穴に添加し合計100μLで5%CO2濃度のインキュベーター中で37℃にて20時間培養した。その後、培養上清を回収し、上清中のマウスIL-17濃度を、HTRFマウスIL-17キット（Cisbio社）を用いて、EnVison（パーキンエルマー社）にて時間分解蛍光として測定した。試験化合物によるIL-17産生阻害作用については、試験化合物存在下のIL-17産生量に対して試験化合物濃度を片対数プロットしたグラフから、試験化合物非存在下のIL-17産生量の50%に相当するIL-17産生量の試験化合物濃度をIC50値として算出した。IL-17産生阻害作用の結果を表１に示す。
（表１）
――――――――――――――――――――――――――――――――――
　　実施例　IC50値(nM)　　　実施例　IC50値(nM)　　　実施例　IC50値(nM)
――――――――――――――――――――――――――――――――――
　　１－１　　５１．２　　　１－３　３８５　　　　１－５　　５７．２
　　１－６　　４６．１　　　２　　　１４．７　　　３－２　　３１．２
　　４－２　　１７　　　　　５　　　５０．１　　　６　　　　１６．１
　　７　　　　１２．１　　　８　　　２７．５　　　９　　　　１８
　１０　　　１２７　　　　１１－２　１９１　　　１２　　　　３４．５
　１３　　　１３７　　　　１４　　　１２．９　　１５　　　　１９．３
　１６　　　　４５．１　　１７　　１０３　　　　１８　　　　１０．４
　１９　　　　８５．９　　２０　　　６２．９　　２１　　　　７１．５
　２２－２　　５０．２　　２３－２　３４．７　　２４－２　　５０．６
　２５　　　　９１　　　　２６　　　７９．５　　２７　　　　９３．２
　２８　　　１１４　　　　２９　　１４５　　　　３０－２　　８４．２
　３１－１　　６５．２　　３１－２　３１．９　　３１－３　　１７
　３２　　　　９３．８　　３３－１　４９．７　　３３－２　　４４．２
　３４　　　１３８　　　　３５　　１１７　　　　３６　　　１８６
　３７－１　　２８．１　　３７－２　４０．５　　３８　　　１９１
　３９－２　　５４　　　　４０　　　２９　　　　４１　　　１２７
　４２－１　　５６．６　　４２－２　４９．６　　４３　　　２１２
　４４－１　　６１．２　　４４－２　５９．３　　４５－１　　３６
　４５－２　　４８．５　　４６　　　７２．９　　４７　　　　２３．６
　４８　　　　５４．３　　４９　　　９１．３　　５０　　　３０９
　５１－２　１１９　　　　５２　　　２２．６　　５３　　　　１４．７
　５４　　　２７２　　　　５５　　１８１　　　　５６　　　１３５
　５７　　　１１１　　　　５８　　　７６．４　　５９　　　６１３
　６０　　　２０５　　　　６１　　１４２　　　　６２　＞３０００
　６３　　　１２８　　　　６４－１　２１４　　　６４－２　３７０
　６５　　　　５９．４　　６６　　１１７　　　　６７　　　　３２
　６８　　　　４４．１　　６９　　　４０．１　　７０　　　　４６．８
　７１　　　　３６．１　　７２　　　４０．１　　７３　　　　２４．７
　７４　　　　５８．９　　７５　　　５９．１　　７６　　　１８８
　７７　　　　７８．１　　７８　　　１２．７　　７９　　３１４０
　８０－２　２２５０　　　８１－３　５０．２　　８２　　　　１９．４
　８３　　　　１５．７　　８４　　　１１．７　　８５－３　　１６．４
　８６　　　　１１　　　　８７　　　　７．８　　８８　　　　２７．２
　８９　　　　４８．７　　９０　　１５７　　　　９１　　　　５０．７
　９２　　　　２８．２　　９３　　　７２　　　　９４　　　　６１．２
　９５　　　　１４．９　　９６　　　９７．１　　９７　　　　１６．９
　９８　　　　３４．８　　９９　　　２７　　　１００　　　　１３．６
１０１　　　　２２．７　１０２－３　２０．７　１０３　　　２０２
１０４　　　　７０　　　１０５　　　８４．５　１０６　　　１１６
１０７－２　１５４　　　１０８　　１８１　　　１０９　　　３７２
１１０　　　１１０　　　１１１　　　３１．９　１１２　　　　　５．２
１１３　　　　１６．６　１１４　　２７２　　　１１５－２　１５７０
１１６　　　　１０．３　１１７　　　５２．６　１１８－２　１１７０
１１９　　１６１０　　　１２０　１４４０　　　１２１　　　１２３
１２２　　　２０１　　　１２３　　　６７．４　１２４　　　　４６．５
１２５　　　　５８．９　１２６　　　１９．７　１２７　　１５９７
１２８　　　２０１　　　１２９　　　８０．７　１３０　　　　２７．９
１３１　　　１５１　　　１３２　　２４５　　　１３３　　　５８８
１３４　　　　８７　　　１３５　　１４４　　　１３６　　　２６６
１３７　　　　６１．４　１３８　　１８９　　　１３９　　　　３９
１４０　　　１１３　　　１４１　　　３８．４　１４２　　　　２５
１４３　　　　３５．９　１４４　　　１１．５　１４５　　　　１７．４
１４６　　　　１６．２　１４７　　　２１．２　１４８　　　　３６．１
１４９　　　　３３．１　１５０　　　１５．６　１５１　　　　４８．８
１５２　　　　５．４１　１５３　　　１１．７　１５４　　　　２２．７
１５５　　　　１９．１　１５６　　　２４．１　１５７　　　　１６．７
１５８　　　　５６．６　１５９　　　３８
―――――――――――――――――――――――――――――――――。 (Test Example 1)
Inhibitory effects on IL-17 production of RORγt gene-introduced cells (1) Preparation of RORγt gene-introduced cells The nucleotide sequence of mRNA encoding the full-length amino acid sequence of mouse (Mus musculus) RORgamma t protein (GenBank Accession Number AF163668: http: // Based on www.metalife.com/Genbank/5679306), 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 75000 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)
――――――――――――――――――――――――――――――――――
1-1 51.2 1-3 385 1-5 57.2
1-6 46.1 2 14.7 3-2 31.2
4-2 17 5 50.1 6 16.1
7 12.1 8 27.5 9 18
10 127 11-2 191 12 34.5
13 137 14 12.9 15 19.3
16 45.1 17 103 18 10.4
19 85.9 20 62.9 21 71.5
22-2 50.2 23-2 34.7 24-2 50.6
25 91 26 79.5 27 93.2
28 114 29 145 30-2 84.2
31-1 65.2 31-2 31.9 31-3 17
32 93.8 33-1 49.7 33-2 44.2
34 138 35 117 36 186
37-1 28.1 37-2 40.5 38 191
39-2 54 40 29 41 127
42-1 56.6 42-2 49.6 43 212
44-1 61.2 44-2 59.3 45-1 36
45-2 48.5 46 72.9 47 23.6
48 54.3 49 91.3 50 309
51-2 119 52 22.6 53 14.7
54 272 55 181 56 135
57 111 58 76.4 59 613
60 205 61 142 62> 3000
63 128 64-1 214 64-2 370
65 59.4 66 117 67 32
68 44.1 69 40.1 70 46.8
71 36.1 72 40.1 73 24.7
74 58.9 75 59.1 76 188
77 78.1 78 12.7 79 3140
80-2 2250 81-3 50.2 82 19.4
83 15.7 84 11.7 85-3 16.4
86 11 87 7.8 88 27.2
89 48.7 90 157 91 50.7
92 28.2 93 72 94 61.2
95 14.9 96 97.1 97 16.9
98 34.8 99 27 100 13.6
101 22.7 102-3 20.7 103 202
104 70 105 84.5 106 116
107-2 154 108 181 109 372
110 110 111 31.9 112 5.2
113 16.6 114 272 115-2 1570
116 10.3 117 52.6 118-2 1170
119 1610 120 1440 121 123
122 201 123 67.4 124 46.5
125 58.9 126 19.7 127 1597
128 201 129 80.7 130 27.9
131 151 132 245 133 588
134 87 135 144 136 266
137 61.4 138 189 139 39
140 113 141 38.4 142 25
143 35.9 144 11.5 145 17.4
146 16.2 147 21.2 148 36.1
149 33.1 150 15.6 151 48.8
152 5.41 153 11.7 154 22.7
155 19.1 156 24.1 157 16.7
158 56.6 159 38
―――――――――――――――――――――――――――――――――
　本試験において、本発明の化合物は、優れたIL-17産生阻害作用を示した。従って、乾癬、乾癬性関節炎、強直性脊椎炎、多発性硬化症、関節リウマチ、炎症性腸疾患（クローン病や潰瘍性大腸炎など）、シェーグレン症候群、全身性エリテマトーデス、慢性閉塞性肺疾患（COPD）、アトピー性皮膚炎、喘息、一型糖尿病、移植片対宿主病（GvHD）、円形脱毛症、白斑、川崎病、ベーチェット病、糸球体腎炎、心筋症、再生不良性貧血、橋本病、強皮症、巨細胞性動脈炎、接触性皮膚炎、視神経炎などの自己免疫疾患又はIL-17の産生が病態発症に関与している大腸癌の治療剤及び／又は予防剤として有用である。 In this test, the compound of the present invention showed an excellent IL-17 production inhibitory action. Therefore, psoriasis, psoriatic arthritis, ankylosing spondylitis, 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 (COPD) ), Atopic dermatitis, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, strong It is useful as a therapeutic and / or prophylactic agent for colorectal cancer in which autoimmune diseases such as dermatosis, giant cell arteritis, contact dermatitis, optic neuritis or IL-17 production is involved in the pathogenesis of the disease.
　（試験例２）
IL-23誘導性マウス乾癬様皮膚炎モデルに対する阻害効果
　IL-23誘導性マウス乾癬様皮膚炎モデルはIL-17に依存していることが知られている（The Journal of Immunology, 186, 1495-1502(2011)）（The Journal of Immunology, 186, 4481-4489(2011)）。 (Test Example 2)
Inhibitory effect on IL-23-induced mouse psoriasis-like dermatitis model IL-23-induced mouse psoriasis-like dermatitis model is known to be dependent on IL-17 (The Journal of Immunology, 186, 1495- 1502 (2011)) (The Journal of Immunology, 186, 4481-4489 (2011)).
　実験にはBALB/cマウス（日本チャールス・リバー社）の7週令以降の雄性マウスを5～10匹使用した。Day 0から3まで、マウス片耳へマウスIL-23（R&D Systems社、phosphate buffered salineで50 μg/mLに調製） を1 μg/匹で麻酔下1日1回連日皮内投与して皮膚炎を誘発した（The Journal of Experimental Medicine, 203, 2577-2587(2006)）（Nature, 445, 648-651(2007)）。対照群にはbovine serum albumin（Sigma社、phosphate buffered salineで50 μg/mLに調製）を1 μg/匹で同様に皮内投与した。皮膚炎の評価は、マウスIL-23最終投与24時間後（day4）にシックネスゲージを用いて測定した耳介の厚みから、day 0のIL-23投与開始前の耳介の厚みを差し引いた耳介肥厚を指標とした。試験化合物は0.5%メチルセルロース溶液または9～10% Kollidon（登録商標） VA64溶液に懸濁した。試験化合物または溶媒は、day 0から3まで1日2回経口投与した。試験化合物による皮膚炎阻害効果については、下記の式に従って阻害率（％）として算出した。皮膚炎阻害効果の結果は表２に示す。
阻害率（％）＝１００×（溶媒投与時の耳介肥厚―試験化合物投与時の耳介肥厚）/（溶媒投与時の耳介肥厚―対照群の耳介肥厚）
（表２）
―――――――――――――――――――――――――
　実施例　　ｎ数　　投与量　         　阻害率(％)　　
―――――――――――――――――――――――――
　　　５　　　５　　100mg/kg（b.i.d）  ８２
―――――――――――――――――――――――――
　上述のように本発明の化合物は、皮膚炎阻害効果を有し、乾癬に有効であることが示された。 For the experiment, 5 to 10 male mice from 7 weeks old of BALB / c mice (Charles River Japan) were used. From day 0 to 3, mouse IL-23 (R & D Systems, adjusted to 50 μg / mL with phosphate buffered saline) was administered intradermally once daily under anesthesia at 1 μg / animal to the ear of the mouse. Induced (The Journal of Experimental Medicine, 203, 2577-2587 (2006)) (Nature, 445, 648-651 (2007)). In the control group, bovine serum albumin (Sigma, adjusted to 50 μg / mL with phosphate buffered saline) was similarly administered intradermally at 1 μg / animal. Evaluation of dermatitis was performed by subtracting the thickness of the auricle before starting IL-23 administration on day 0 from the thickness of the auricle measured using a thickness gauge 24 hours after the last dose of mouse IL-23 (day 4). Thickness was used as an index. Test compounds were suspended in 0.5% methylcellulose solution or 9-10% Kollidon® VA64 solution. The test compound or solvent was orally administered twice a day from day 0 to 3. About the dermatitis inhibitory effect by a test compound, it calculated as an inhibition rate (%) according to the following formula. The results of the dermatitis inhibitory effect are shown in Table 2.
Inhibition rate (%) = 100 × (Auricular thickening at the time of solvent administration−Auricular thickening at the time of test compound administration) / (Auricular thickening at the time of solvent administration−Auricular thickening in the control group)
(Table 2)
―――――――――――――――――――――――――
Example n number Dose Inhibition rate (%)
―――――――――――――――――――――――――
5 5 100mg / kg (bid) 82
―――――――――――――――――――――――――
As described above, the compound of the present invention has a dermatitis inhibitory effect and has been shown to be effective for psoriasis.
　製剤例１：カプセル剤
実施例１－１又は２の化合物　　５０ｍｇ
乳糖　　　　　　　　　　　　１２８ｍｇ
トウモロコシデンプン　　　　　７０ｍｇ
ステアリン酸マグネシウム　　　　２ｍｇ
－－－－－－－－－－－－－－－－－
　　　　　　　　　　　　　　２５０ｍｇ
上記処方の粉末を混合し、６０メッシュのふるいを通した後、この粉末を２５０ｍｇのゼラチンカプセルに入れ、カプセル剤とする。 Formulation Example 1: Capsule 50 mg of the compound of Example 1-1 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.
　製剤例２：錠剤
実施例１－１又は２の化合物　　５０ｍｇ
乳糖　　　　　　　　　　　　１２６ｍｇ
トウモロコシデンプン　　　　　２３ｍｇ
ステアリン酸マグネシウム　　　　１ｍｇ
－－－－－－－－－－－－－－－－－
　　　　　　　　　　　　　　２００ｍｇ
上記処方の粉末を混合し、トウモロコシデンプン糊を用いて造粒、乾燥した後、打錠機により打錠して、１錠２００ｍｇの錠剤とする。この錠剤は必要に応じて糖衣を施すことができる。 Formulation Example 2: Tablet Example 1-1 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.
　本発明の一般式（Ｉ）で表される化合物若しくはその同位体標識化合物又はそれらの薬学上許容される塩は、優れたレチノイン酸受容体関連オーファン受容体γｔ阻害作用およびIL-17産生抑制作用を有し、医薬として有用である。
  The compound represented by the general formula (I) of the present invention or an isotope-labeled compound thereof or a pharmaceutically acceptable salt thereof has an excellent retinoic acid receptor-related orphan receptor γt inhibitory action and IL-17 production suppression. It has an action and is useful as a medicine.

Claims (45)

  1. 　一般式（Ｉ）
    Figure JPOXMLDOC01-appb-C000001
    ［式中、
    　Ｒ１は、Ｃ１－Ｃ６アルキル基、Ｃ３－Ｃ６シクロアルキル基又はフェニル基を示し、
    　Ｒ２は、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基又はＣ１－Ｃ６アルコキシ基を示し、
    　Ｒ３は、水素原子、Ｃ２－Ｃ７カルボキシアルキル基又は水酸基を示し、
    　Ｒ４は、ハロゲン原子又はＣ１－Ｃ６アルキル基を示し、
    　Ｒ５は、水素原子又はＣ１－Ｃ６アルキル基を示し、
    　Ｒ６は、水素原子、ハロゲン原子又はＣ１－Ｃ６アルキル基を示し、
    　Ｑ１は、窒素原子又は式＝ＣＨ－で表される基を示し、
    　Ｑ２は、窒素原子又は式＝ＣＨ－で表される基を示し、
    　式－Ｕ－Ｔ－で表される基は、式－ＣＨ２－ＣＨ２－で表される基又は式－ＣＨ＝ＣＨ－で表される基を示し、
    　Ｙは、メチレン基又は酸素原子を示し、
    　Ｖは、窒素原子又は式＝Ｃ（Ｒ７）－で表される基を示し、
    　Ｒ７は、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ３－Ｃ６シクロアルキル基、Ｃ２－Ｃ６アルケニル基、Ｃ１－Ｃ６アルコキシ基、Ｃ１－Ｃ６ハロゲン化アルコキシ基、（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルキル）基、（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルコキシ）基、Ｃ２－Ｃ７アルキルカルボニル基、テトラヒドロフリル基又はオキセチルオキシ基を示し、
    　Ｅは、置換基群Ａから選択される基で独立に１乃至４個置換されていてもよいピペリジン－１－イル基、ピペリジン－３－イル基、ピペリジン－４－イル基、１，２，３，６－テトラヒドロピリジン－４－イル基、ピペラジン－１－イル基、モルホリン－４－イル基、ピロリジン－１－イル基又はピロリジン－３－イル基を示し、
    　置換基群Ａは、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６ハロゲン化アルキル基、Ｃ１－Ｃ６ヒドロキシアルキル基、（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルキル）基、カルボキシメチル基、水酸基、モノ－Ｃ２－Ｃ７アルキルカルボニルアミノ基、オキソ基、オキセタン－３－イル基、（１，４－ジオキサン－２－イル）メチル基、Ｅのメチレン部位に２位で結合してスピロ構造を構築する１，３－ジオキソラン及び式－Ｌ－Ｒ８で表される基からなる群を示し、
    　Ｌは、カルボニル基、オキサリル基又はスルホニル基を示し、
    　Ｒ８は、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６ヒドロキシアルキル基、Ｃ１－Ｃ６ジヒドロキシアルキル基、（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルキル）基、ジ（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルキル）基、（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６ヒドロキシアルキル）基、Ｃ３－Ｃ６ヒドロキシシクロアルキル基、Ｃ１－Ｃ６シアノアルキル基、Ｃ１－Ｃ６アルコキシ基、水酸基、アミノ基、モノ－Ｃ１－Ｃ６アルキルアミノ基、モノ－Ｃ１－Ｃ６ハロゲン化アルキルアミノ基、ジ－（Ｃ１－Ｃ６アルキル）アミノ基、（Ｃ２－Ｃ７アルキルカルボニルオキシ）－（Ｃ１－Ｃ６アルキル）基、（モノ－Ｃ３－Ｃ６シクロアルキルアミノ）－（Ｃ１－Ｃ６アルキル）基、（Ｃ２－Ｃ７ヒドロキシアルキルカルボニルオキシ）－（Ｃ１－Ｃ６アルキル）基、（モノ－Ｃ１－Ｃ６ヒドロキシアルキルアミノ）－（Ｃ１－Ｃ６アルキル）基、テトラヒドロキシシクロヘキシル基、テトラヒドロフラン－２－イル基、テトラヒドロフラン－３－イル基、オキセタン－２－イル基、オキセタン－３－イル基、１，４－ジオキサン－２－イル基、アゼチジン－１－イル基、モルホリン－４－イル基、（モルホリン－４－イル）メチル基、Ｃ１－Ｃ６アルキル基で独立に１又は２個置換されていてもよいピロール－２－イル基、Ｃ１－Ｃ６アルキル基で独立に１又は２個置換されていてもよいモルホリン－２－イル基、Ｃ１－Ｃ６アルキル基で独立に１又は２個置換されていてもよいイミダゾール－５－イル基又はハロゲン原子、Ｃ１－Ｃ６アルキル基、水酸基、Ｃ１－Ｃ６ヒドロキシアルキル基、Ｃ２－Ｃ７アルキルカルボニル基及びオキソ基から選択される基で独立に１乃至５個置換されていてもよいピロリジン－２－イル基を示す。］で表される化合物又はその薬学上許容される塩。     Formula (I)
    Figure JPOXMLDOC01-appb-C000001
    [Where:
    R 1 represents a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group or a phenyl group,
    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,
    R 4 represents a halogen atom or a C 1 -C 6 alkyl group,
    R 5 represents a hydrogen atom or a C 1 -C 6 alkyl group,
    R 6 represents a hydrogen atom, a halogen atom or a C 1 -C 6 alkyl group,
    Q 1 represents a nitrogen atom or a group represented by the formula = CH-
    Q 2 represents a nitrogen atom or a group represented by the formula = CH-
    The group represented by the formula —UT— represents a group represented by the formula —CH 2 —CH 2 — or a group represented by the formula —CH═CH—.
    Y represents a methylene group or an oxygen atom,
    V represents a nitrogen atom or a group represented by the formula = C (R 7 )-
    R 7 represents a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a C 2 -C 6 alkenyl group, a C 1 -C 6 alkoxy group, or a C 1 -C 6 halogenated group. An alkoxy group, a (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, a (C 1 -C 6 alkoxy)-(C 1 -C 6 alkoxy) group, a C 2 -C 7 alkylcarbonyl group, Represents a tetrahydrofuryl group or an oxetyloxy group,
    E represents a piperidin-1-yl group, a piperidin-3-yl group, a piperidin-4-yl group, 1, 2, 2, which may be independently substituted with 1 to 4 groups independently selected from the substituent group A; Represents a 3,6-tetrahydropyridin-4-yl group, piperazin-1-yl group, morpholin-4-yl group, pyrrolidin-1-yl group or pyrrolidin-3-yl group;
    Substituent group A includes a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 hydroxyalkyl group, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) Group, carboxymethyl group, hydroxyl group, mono-C 2 -C 7 alkylcarbonylamino group, oxo group, oxetan-3-yl group, (1,4-dioxane-2-yl) methyl group, 2 in the methylene moiety of E A group consisting of 1,3-dioxolane and a group represented by the formula -LR 8 , which are bonded at a position to form a spiro structure;
    L represents a carbonyl group, an oxalyl group or a sulfonyl group,
    R 8 is a C 1 -C 6 alkyl group, a C 1 -C 6 hydroxyalkyl group, a C 1 -C 6 dihydroxyalkyl group, a (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, a di (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, (C 1 -C 6 alkoxy)-(C 1 -C 6 hydroxyalkyl) group, C 3 -C 6 hydroxycycloalkyl group, C 1- C 6 cyanoalkyl group, C 1 -C 6 alkoxy group, hydroxyl group, amino group, mono-C 1 -C 6 alkylamino group, mono-C 1 -C 6 halogenated alkylamino group, di- (C 1 -C 6 alkyl) amino group, (C 2 -C 7 alkylcarbonyloxy)-(C 1 -C 6 alkyl) group, (mono-C 3 -C 6 cycloalkylamino)-(C 1 -C 6 alkyl) group, (C 2 C 7 hydroxyalkyl carbonyloxy) - (C 1 -C 6 alkyl) group, (mono -C 1 -C 6 hydroxyalkyl amino) - (C 1 -C 6 alkyl) group, tetra-hydroxycyclohexyl group, tetrahydrofuran-2 Yl group, tetrahydrofuran-3-yl group, oxetan-2-yl group, oxetane-3-yl group, 1,4-dioxane-2-yl group, azetidin-1-yl group, morpholin-4-yl group, Morpholin-4-yl) methyl group, C 1 -C 6 alkyl group independently 1 or 2 optionally substituted pyrrol-2-yl group, C 1 -C 6 alkyl group 1 or 2 independently optionally substituted morpholin-2-yl group, C 1 -C 6 alkyl which may be one or two substituted independently by a group imidazol-5-yl group or a halo Emissions atom, C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 hydroxyalkyl group, be C 2 -C 7 are one to five substituents from the alkyl group and oxo group independently a group selected A good pyrrolidin-2-yl group is indicated. Or a pharmaceutically acceptable salt thereof.
  2. 　請求項１において、Ｒ１が、メチル基又はエチル基である化合物又はその薬学上許容される塩。 The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is a methyl group or an ethyl group.
  3. 　請求項１又は２において、Ｒ２が、水素原子である化合物又はその薬学上許容される塩。 According to claim 1 or 2, a salt in which R 2 is acceptable compound or a pharmaceutically hydrogen atom.
  4. 　請求項１乃至３から選択されるいずれか一項において、Ｒ３が、水素原子である化合物又はその薬学上許容される塩。 The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 , wherein R 3 is a hydrogen atom.
  5. 　請求項１乃至４から選択されるいずれか一項において、Ｒ４が、メチル基である化合物又はその薬学上許容される塩。 The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 4 is a methyl group.
  6. 　請求項１乃至５から選択されるいずれか一項において、Ｒ５が、水素原子又はメチル基である化合物又はその薬学上許容される塩。 The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 , wherein R 5 is a hydrogen atom or a methyl group.
  7. 　請求項１乃至６から選択されるいずれか一項において、Ｒ６が、水素原子である化合物又はその薬学上許容される塩。 The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 , wherein R 6 is a hydrogen atom.
  8. 　請求項１乃至７から選択されるいずれか一項において、Ｑ１が、式＝ＣＨ－で表される基である化合物又はその薬学上許容される塩。 The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein Q 1 is a group represented by the formula = CH-.
  9. 　請求項１乃至８から選択されるいずれか一項において、Ｑ２が、式＝ＣＨ－で表される基である化合物又はその薬学上許容される塩。 The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein Q 2 is a group represented by the formula = CH-.
  10. 　請求項１乃至９から選択されるいずれか一項において、式－Ｕ－Ｔ－で表される基が、式－ＣＨ２－ＣＨ２－で表される基である化合物又はその薬学上許容される塩。 10. The compound according to any one of claims 1 to 9, wherein the group represented by the formula —UT— is a group represented by the formula —CH 2 —CH 2 — or a pharmaceutically acceptable salt thereof. Salt.
  11. 　請求項１乃至１０から選択されるいずれか一項において、Ｙが、酸素原子である化合物又はその薬学上許容される塩。 The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein Y is an oxygen atom.
  12. 　請求項１乃至１１から選択されるいずれか一項において、Ｖが、式＝Ｃ（Ｒ７）－で表される基である化合物又はその薬学上許容される塩。 The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein V is a group represented by the formula = C (R 7 )-.
  13. 　請求項１乃至１２から選択されるいずれか一項において、Ｒ７が、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基又はＣ１－Ｃ６アルコキシ基である化合物又はその薬学上許容される塩。 The compound or pharmaceutically acceptable compound thereof according to any one of claims 1 to 12, wherein R 7 is a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group. salt.
  14. 　請求項１乃至１２から選択されるいずれか一項において、Ｒ７が、水素原子又はメチル基である化合物又はその薬学上許容される塩。 The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R 7 is a hydrogen atom or a methyl group.
  15. 　請求項１乃至１１から選択されるいずれか一項において、Ｖが、窒素原子である化合物又はその薬学上許容される塩。 The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein V is a nitrogen atom.
  16. 　請求項１乃至１５から選択されるいずれか一項において、Ｅが、式－Ｌ－Ｒ８で表される基で１個置換されているピペリジン－４－イル基、１，２，３，６－テトラヒドロピリジン－４－イル基又はピペラジン－１－イル基である化合物又はその薬学上許容される塩。 The piperidin-4-yl group substituted with one group represented by the formula -LR 8 , 1, 2, 3, 6 according to any one of claims 1 to 15 A compound which is a tetrahydropyridin-4-yl group or a piperazin-1-yl group or a pharmaceutically acceptable salt thereof.
  17. 　請求項１乃至１５から選択されるいずれか一項において、Ｅが、式－Ｌ－Ｒ８で表される基で１位が置換されているピペリジン－４－イル基又は１，２，３，６－テトラヒドロピリジン－４－イル基である化合物又はその薬学上許容される塩。 The piperidin-4-yl group or 1,2,3, wherein E is substituted at the 1-position with a group represented by the formula -LR 8 . A compound which is a 6-tetrahydropyridin-4-yl group or a pharmaceutically acceptable salt thereof.
  18. 　請求項１乃至１５から選択されるいずれか一項において、置換基群Ａが、式－Ｌ－Ｒ８で表される基である化合物又はその薬学上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein the substituent group A is a group represented by the formula -LR 8 .
  19. 　請求項１乃至１８から選択されるいずれか一項において、Ｌが、カルボニル基又はオキサリル基である化合物又はその薬学上許容される塩。 The compound or pharmaceutically acceptable salt thereof, wherein L is a carbonyl group or an oxalyl group according to any one of claims 1 to 18.
  20. 　請求項１乃至１９から選択されるいずれか一項において、Ｒ８が、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６ヒドロキシアルキル基、（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルキル）基、アミノ基、モノ－Ｃ１－Ｃ６アルキルアミノ基、モノ－Ｃ１－Ｃ６ハロゲン化アルキルアミノ基、ジ－（Ｃ１－Ｃ６アルキル）アミノ基、モルホリン－２－イル基又はハロゲン原子及びＣ１－Ｃ６アルキル基から選択される基で独立に１乃至３個置換されているピロリジン－２－イル基である化合物又はその薬学上許容される塩。 20. The compound according to any one of claims 1 to 19, wherein R 8 is a C 1 -C 6 alkyl group, a C 1 -C 6 hydroxyalkyl group, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, amino group, mono-C 1 -C 6 alkylamino group, mono-C 1 -C 6 halogenated alkylamino group, di- (C 1 -C 6 alkyl) amino group, morpholin-2-yl Or a pharmaceutically acceptable salt thereof, which is a pyrrolidin-2-yl group which is independently substituted with 1 to 3 groups independently selected from a group or a halogen atom and a C 1 -C 6 alkyl group.
  21. 　請求項１乃至１９から選択されるいずれか一項において、Ｒ８が、メチル基、１－ヒドロキシエチル基、メトキシメチル基、メチルアミノ基、エチルアミノ基、２，２―ジフルオロエチルアミノ基、モルホリン－２－イル基又は４，４―ジフルオロ－１－メチルピロリジン－２－イル基である化合物又はその薬学上許容される塩。 20. The compound according to any one of claims 1 to 19, wherein R 8 is a methyl group, 1-hydroxyethyl group, methoxymethyl group, methylamino group, ethylamino group, 2,2-difluoroethylamino group, morpholine. A compound which is a -2-yl group or a 4,4-difluoro-1-methylpyrrolidin-2-yl group or a pharmaceutically acceptable salt thereof.
  22. 　１－［５－（４－｛１－［（２Ｓ）－１，４－ジオキサン－２－イルカルボニル］ピペリジン－４－イル｝フェノキシ）－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル］－２－［２－（メチルスルホニル）フェニル］エタノン、
    １－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン、
    ｔｅｒｔ－ブチル　４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－カルボキシレート、
    ２－メトキシ－１－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）エタノン、
    １－｛５－［４－（１－｛［（２Ｓ）－４，４－ジフルオロ－１－メチルピロリジン－２－イル］カルボニル｝ピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン、
    Ｎ－（２，２－ジフルオロエチル）－２－（４－｛４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－２－オキソアセトアミド、
    ２－（４－｛４－［（１－｛［２－（エチルスルホニル）フェニル］アセチル｝－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝ピペリジン－１－イル）－Ｎ－メチル－２－オキソアセタミド、
    （２Ｓ）－２－ヒドロキシ－１－［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］プロパン－１－オン、
    Ｎ－エチル－２－［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］－２－オキソアセトアミド、
    Ｎ－メチル－２－［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］－２－オキソアセトアミド、
    １－｛５－［４－（４－アセチルピペラジン－１－イル）－３－メチルフェノキシ］４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン、
    １－｛５－［（１’－アセチル－１’，２’，３’，６’－テトラヒドロ－２，４’－ビピリジン－５－イル）オキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン、
    １－｛５－［４－（１－アセチルピペリジン－４－イル）－３－メチルフェノキシ］－４－メチル－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン、
    １－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－メチル－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン、
    １－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン、又は、
    １－｛５－［４－（１－アセチル－１，２，３，６－テトラヒドロピリジン－４－イル）－２，５－ジメチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン
    である化合物又はその薬学上許容される塩。     1- [5- (4- {1-[(2S) -1,4-dioxane-2-ylcarbonyl] piperidin-4-yl} phenoxy) -4-methyl-2,3-dihydro-1H-indole- 1-yl] -2- [2- (methylsulfonyl) phenyl] ethanone,
    1- {5- [4- (1-acetylpiperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl ] Ethanon,
    tert-Butyl 4- {2-Methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl } Piperidine-1-carboxylate,
    2-methoxy-1- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) oxy] phenyl } Piperidin-1-yl) ethanone,
    1- {5- [4- (1-{[(2S) -4,4-difluoro-1-methylpyrrolidin-2-yl] carbonyl} piperidin-4-yl) phenoxy] -4-methyl-2,3 -Dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone,
    N- (2,2-difluoroethyl) -2- (4- {4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole- 5-yl) oxy] phenyl} piperidin-1-yl) -2-oxoacetamide,
    2- (4- {4-[(1-{[2- (Ethylsulfonyl) phenyl] acetyl} -4-methyl-2,3-dihydro-1H-indol-5-yl) oxy] phenyl} piperidine-1 -Yl) -N-methyl-2-oxoacetamide,
    (2S) -2-hydroxy-1- [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole -5-yl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] propan-1-one,
    N-ethyl-2- [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl ) Oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] -2-oxoacetamide,
    N-methyl-2- [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl ) Oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] -2-oxoacetamide,
    1- {5- [4- (4-Acetylpiperazin-1-yl) -3-methylphenoxy] 4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (ethyl Sulfonyl) phenyl] ethanone,
    1- {5-[(1′-acetyl-1 ′, 2 ′, 3 ′, 6′-tetrahydro-2,4′-bipyridin-5-yl) oxy] -4-methyl-2,3-dihydro- 1H-indol-1-yl} -2- [2- (ethylsulfonyl) phenyl] ethanone,
    1- {5- [4- (1-Acetylpiperidin-4-yl) -3-methylphenoxy] -4-methyl-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone ,
    1- {5- [4- (1-acetylpiperidin-4-yl) phenoxy] -4-methyl-1H-indol-1-yl} -2- [2- (ethylsulfonyl) phenyl] ethanone,
    1- {5- [4- (1-acetylpiperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) pyridine -2-yl] ethanone, or
    1- {5- [4- (1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl) -2,5-dimethylphenoxy] -4-methyl-2,3-dihydro-1H-indole -1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone or a pharmaceutically acceptable salt thereof.
  23. 　１－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン、又はその薬学上許容される塩。 1- {5- [4- (1-acetylpiperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl ] Ethanone or a pharmaceutically acceptable salt thereof.
  24. （２Ｓ）－２－ヒドロキシ－１－［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］プロパン－１－オン、又はその薬学上許容される塩。 (2S) -2-hydroxy-1- [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indole -5-yl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] propan-1-one, or a pharmaceutically acceptable salt thereof.
  25. Ｎ－メチル－２－［４－｛２－メチル－４－［（４－メチル－１－｛［２－（メチルスルホニル）フェニル］アセチル｝－２，３－ジヒドロ－１Ｈ－インドール－５－イル）オキシ］フェニル｝－３，６－ジヒドロピリジン－１（２Ｈ）－イル］－２－オキソアセトアミド、又はその薬学上許容される塩。 N-methyl-2- [4- {2-methyl-4-[(4-methyl-1-{[2- (methylsulfonyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl ) Oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] -2-oxoacetamide, or a pharmaceutically acceptable salt thereof.
  26. １－｛５－［４－（１－アセチルピペリジン－４－イル）－３－メチルフェノキシ］－４－メチル－１Ｈ－インドール－１－イル｝－２－［２－（メチルスルホニル）フェニル］エタノン、又はその薬学上許容される塩。 1- {5- [4- (1-Acetylpiperidin-4-yl) -3-methylphenoxy] -4-methyl-1H-indol-1-yl} -2- [2- (methylsulfonyl) phenyl] ethanone Or a pharmaceutically acceptable salt thereof.
  27. １－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－メチル－１Ｈ－インドール－１－イル｝－２－［２－（エチルスルホニル）フェニル］エタノン、又はその薬学上許容される塩。 1- {5- [4- (1-Acetylpiperidin-4-yl) phenoxy] -4-methyl-1H-indol-1-yl} -2- [2- (ethylsulfonyl) phenyl] ethanone or its pharmacy Top acceptable salt.
  28. １－｛５－［４－（１－アセチルピペリジン－４－イル）フェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン、又はその薬学上許容される塩。 1- {5- [4- (1-acetylpiperidin-4-yl) phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [3- (methylsulfonyl) pyridine -2-yl] ethanone or a pharmaceutically acceptable salt thereof.
  29. １－｛５－［４－（１－アセチル－１，２，３，６－テトラヒドロピリジン－４－イル）－２，５－ジメチルフェノキシ］－４－メチル－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝－２－［３－（メチルスルホニル）ピリジン－２－イル］エタノン、又はその薬学上許容される塩。 1- {5- [4- (1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl) -2,5-dimethylphenoxy] -4-methyl-2,3-dihydro-1H-indole -1-yl} -2- [3- (methylsulfonyl) pyridin-2-yl] ethanone, or a pharmaceutically acceptable salt thereof.
  30. 　請求項１乃至２９から選択されるいずれか一項に記載された化合物又はその薬学上許容される塩を有効成分として含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof as an active ingredient.
  31. 　医薬組成物が、レチノイン酸受容体関連オーファン受容体γｔ阻害作用により、治療及び／又は予防される疾病の治療及び／又は予防のためのものである請求項３０に記載の医薬組成物。 The pharmaceutical composition according to claim 30, wherein the pharmaceutical composition is for the treatment and / or prevention of a disease which is treated and / or prevented by an retinoic acid receptor-related orphan receptor γt inhibitory action.
  32. 　医薬組成物が、Ｔｈ１７細胞分化の抑制及び／又はＩＬ－１７産生の抑制により、症状の治療、改善、軽減及び／又は予防がなされる疾病の治療及び／又は予防のためのものである請求項３０に記載の医薬組成物。 The pharmaceutical composition is for the treatment and / or prevention of diseases in which symptoms are treated, ameliorated, reduced and / or prevented by inhibiting Th17 cell differentiation and / or inhibiting IL-17 production. 30. The pharmaceutical composition according to 30.
  33. 　医薬組成物が、乾癬、乾癬性関節炎、強直性脊椎炎、多発性硬化症、関節リウマチ、炎症性腸疾患、シェーグレン症候群、全身性エリテマトーデス、慢性閉塞性肺疾患（COPD）、アトピー性皮膚炎、喘息、一型糖尿病、移植片対宿主病（GvHD）、円形脱毛症、白斑、川崎病、ベーチェット病、糸球体腎炎、心筋症、再生不良性貧血、橋本病、強皮症、巨細胞性動脈炎、接触性皮膚炎、視神経炎又は大腸癌の治療及び／又は予防のためのものである請求項３０に記載の医薬組成物。 The pharmaceutical composition is psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, Asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell artery The pharmaceutical composition according to claim 30, which is used for the treatment and / or prevention of inflammation, contact dermatitis, optic neuritis or colorectal cancer.
  34. 　医薬組成物が、乾癬又は乾癬性関節炎の治療及び／又は予防のためのものである請求項３０に記載の医薬組成物。 The pharmaceutical composition according to claim 30, wherein the pharmaceutical composition is for the treatment and / or prevention of psoriasis or psoriatic arthritis.
  35. 　請求項１乃至２９から選択されるいずれか一項に記載された化合物又はその薬学上許容される塩を有効成分として含有するレチノイン酸受容体関連オーファン受容体γｔ阻害剤。 A retinoic acid receptor-related orphan receptor γt inhibitor containing the compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof as an active ingredient.
  36. 　医薬組成物を製造するための、請求項１乃至２９から選択されるいずれか一項に記載された化合物又はその薬学上許容される塩の使用。 Use of the compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof for producing a pharmaceutical composition.
  37. 　医薬組成物が乾癬、乾癬性関節炎、強直性脊椎炎、多発性硬化症、関節リウマチ、炎症性腸疾患、シェーグレン症候群、全身性エリテマトーデス、慢性閉塞性肺疾患（COPD）、アトピー性皮膚炎、喘息、一型糖尿病、移植片対宿主病（GvHD）、円形脱毛症、白斑、川崎病、ベーチェット病、糸球体腎炎、心筋症、再生不良性貧血、橋本病、強皮症、巨細胞性動脈炎、接触性皮膚炎、視神経炎又は大腸癌の治療及び／又は予防のための組成物である請求項３６に記載の使用。 The pharmaceutical composition is psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma Type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis The use according to claim 36, which is a composition for the treatment and / or prevention of contact dermatitis, optic neuritis or colon cancer.
  38. 　医薬組成物が乾癬又は乾癬性関節炎の治療及び／又は予防のための組成物である請求項３６に記載の使用。 The use according to claim 36, wherein the pharmaceutical composition is a composition for treating and / or preventing psoriasis or psoriatic arthritis.
  39. 　レチノイン酸受容体関連オーファン受容体γｔ阻害作用により治療及び／又は予防される疾病の治療及び／又は予防の方法における使用のための請求項１乃至２９から選択されるいずれか一項に記載された化合物又はその薬学上許容される塩。 30. A method according to any one of claims 1 to 29 for use in a method for the treatment and / or prevention of diseases which are treated and / or prevented by retinoic acid receptor-related orphan receptor γt inhibitory action. Or a pharmaceutically acceptable salt thereof.
  40. 　乾癬、乾癬性関節炎、強直性脊椎炎、多発性硬化症、関節リウマチ、炎症性腸疾患、シェーグレン症候群、全身性エリテマトーデス、慢性閉塞性肺疾患（COPD）、アトピー性皮膚炎、喘息、一型糖尿病、移植片対宿主病（GvHD）、円形脱毛症、白斑、川崎病、ベーチェット病、糸球体腎炎、心筋症、再生不良性貧血、橋本病、強皮症、巨細胞性動脈炎、接触性皮膚炎、視神経炎又は大腸癌の治療及び／又は予防の方法における使用のための請求項１乃至２９から選択されるいずれか一項に記載された化合物又はその薬学上許容される塩。 Psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type 1 diabetes , Graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact skin 30. A compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof for use in a method for the treatment and / or prevention of inflammation, optic neuritis or colon cancer.
  41. 　請求項１乃至２９から選択されるいずれか一項に記載された化合物又はその薬学上許容される塩の薬理的な有効量を温血動物に投与する疾病の治療及び／又は予防方法。 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 29 or a pharmaceutically acceptable salt thereof.
  42. 　疾病が、レチノイン酸受容体関連オーファン受容体γｔ阻害作用により治療及び／又は予防されるものである請求項４１に記載の方法。 42. The method according to claim 41, wherein the disease is treated and / or prevented by an retinoic acid receptor-related orphan receptor γt inhibitory action.
  43. 　疾病が乾癬、乾癬性関節炎、強直性脊椎炎、多発性硬化症、関節リウマチ、炎症性腸疾患、シェーグレン症候群、全身性エリテマトーデス、慢性閉塞性肺疾患（COPD）、アトピー性皮膚炎、喘息、一型糖尿病、移植片対宿主病（GvHD）、円形脱毛症、白斑、川崎病、ベーチェット病、糸球体腎炎、心筋症、再生不良性貧血、橋本病、強皮症、巨細胞性動脈炎、接触性皮膚炎、視神経炎又は大腸癌である請求項４１に記載の方法。 The disease is psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, one Type diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact 42. The method according to claim 41, wherein the disease is dermatitis, optic neuritis or colon cancer.
  44. 　疾病が乾癬又は乾癬性関節炎である請求項４１に記載の方法。 42. The method according to claim 41, wherein the disease is psoriasis or psoriatic arthritis.
  45. 　温血動物がヒトである請求項４１乃至４４から選択されるいずれか一項に記載の方法。
          45. The method according to any one of claims 41 to 44, wherein the warm-blooded animal is a human.
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WO2023109918A1 (en) * 2021-12-17 2023-06-22 中国科学院上海药物研究所 Nitrogenous heterocyclic compound, and preparation method therefor and use thereof

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WO2019151270A1 (en) * 2018-01-31 2019-08-08 東レ株式会社 Cyclic amine derivative and pharmaceutical use thereof
WO2023109918A1 (en) * 2021-12-17 2023-06-22 中国科学院上海药物研究所 Nitrogenous heterocyclic compound, and preparation method therefor and use thereof

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