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WO2016072402A1 - Dérivé d'amine cyclique - Google Patents

Dérivé d'amine cyclique 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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Prior art keywords
group
methyl
phenyl
compound
dihydro
Prior art date
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English (en)
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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Daiichi Sankyo Co Ltd
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Daiichi Sankyo Co Ltd
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Publication of WO2016072402A1 publication Critical patent/WO2016072402A1/fr
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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

La présente invention se rapporte à un composé ayant un effet exceptionnel d'inhibition des récepteurs γt orphelins liés aux récepteurs de l'acide rétinoique, ou un sel pharmacologiquement acceptable de celui-ci. L'invention concerne un composé représenté par la formule générale (I) (dans laquelle : R1 représente un groupe alkyle en C1 à C6, un groupe cycloalkyle en C3 à C6, ou un groupe phényle ; R2 représente un atome d'hydrogène, un atome d'halogène, un groupe alkyle en C1 à C6, ou similaire ; R3 représente un atome d'hydrogène, un groupe carboxyalkyle en C2 à C7, ou un groupe hydroxyle ; R4 représente un atome d'halogène ou un groupe alkyle en C1 à C6 ; R5 représente un atome d'hydrogène ou un groupe alkyle en C1 à C6 ; R6 représente un atome d'hydrogène, un atome d'halogène, ou un groupe alkyle en C1 à C6 ; Q1 représente un atome d'azote ou un groupe de formule =CH- ; Q2 représente un atome d'azote ou un groupe de formule =CH- ; un groupe de formule -U-T- représente un groupe de formule -CH2-CH2-, ou similaire ; Y représente un groupe méthylène ou un atome d'oxygène ; V représente un atome d'azote ou un groupe de formule =C(R7)- ; R7 représente un atome d'hydrogène, un atome d'halogène, un groupe alkyle en C1 à C6, ou similaire ; E représente un groupe pipéridin-1-yl, pipéridin-4-yl, ou 1,2,3,6-tétrahydropyridin-4-yl éventuellement substitué de façon indépendante par un à quatre groupes choisis dans le groupe de substituants A, ou similaire ; le groupe de substituants A comprend des groupes alkyle en C1 à C6, des groupes halogénure d'alkyle en C1 à C6, des groupes de formule -L-R8, et similaires ; L représente un groupe carbonyle, un groupe oxalyle, ou similaire ; R8 représente un groupe alkyle en C1 à C6, un groupe hydroxyalkyle en C1 à C6, un groupe monoalkylamino en C1 à C6, ou similaire) ; ou un sel pharmacologiquement acceptable de celui-ci.
PCT/JP2015/080982 2014-11-05 2015-11-04 Dérivé d'amine cyclique Ceased WO2016072402A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019151270A1 (fr) * 2018-01-31 2019-08-08 東レ株式会社 Dérivé d'amine cyclique et utilisation pharmaceutique associée
WO2023109918A1 (fr) * 2021-12-17 2023-06-22 中国科学院上海药物研究所 Composé hétérocyclique azoté, son procédé de préparation et son utilisation

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4844272A (fr) * 1971-10-05 1973-06-26
WO2013029338A1 (fr) * 2011-09-01 2013-03-07 Glaxo Group Limited Nouveaux composés
WO2013171729A2 (fr) * 2013-01-08 2013-11-21 Glenmark Pharmaceuticals S.A. Composés d'aryl- et hétéroarylamide en tant que modulateur de rorγt
WO2014086894A1 (fr) * 2012-12-06 2014-06-12 Glaxo Group Limited MODULATEURS DU RÉCEPTEUR GAMMA ORPHELIN ASSOCIÉ AU RÉTINOÏDE (RORγ) DESTINÉS AU TRAITEMENT DE MALADIES AUTO-IMMUNES ET INFLAMMATOIRES

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4844272A (fr) * 1971-10-05 1973-06-26
WO2013029338A1 (fr) * 2011-09-01 2013-03-07 Glaxo Group Limited Nouveaux composés
WO2014086894A1 (fr) * 2012-12-06 2014-06-12 Glaxo Group Limited MODULATEURS DU RÉCEPTEUR GAMMA ORPHELIN ASSOCIÉ AU RÉTINOÏDE (RORγ) DESTINÉS AU TRAITEMENT DE MALADIES AUTO-IMMUNES ET INFLAMMATOIRES
WO2013171729A2 (fr) * 2013-01-08 2013-11-21 Glenmark Pharmaceuticals S.A. Composés d'aryl- et hétéroarylamide en tant que modulateur de rorγt

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019151270A1 (fr) * 2018-01-31 2019-08-08 東レ株式会社 Dérivé d'amine cyclique et utilisation pharmaceutique associée
WO2023109918A1 (fr) * 2021-12-17 2023-06-22 中国科学院上海药物研究所 Composé hétérocyclique azoté, son procédé de préparation et son utilisation

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