WO2016204134A1 - Six-membered-heterocycle derivative - Google Patents

Six-membered-heterocycle derivative Download PDF

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Publication number
WO2016204134A1
WO2016204134A1 PCT/JP2016/067616 JP2016067616W WO2016204134A1 WO 2016204134 A1 WO2016204134 A1 WO 2016204134A1 JP 2016067616 W JP2016067616 W JP 2016067616W WO 2016204134 A1 WO2016204134 A1 WO 2016204134A1
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methoxy
chromeno
methyl
group
dioxo
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PCT/JP2016/067616
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French (fr)
Japanese (ja)
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篠塚　剛
秀紀 双木
雄一 落合
薫 松下
達矢 西
茂雄 山野井
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第一三共株式会社
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Publication of WO2016204134A1 publication Critical patent/WO2016204134A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/495—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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic 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
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • 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
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel compound having an action such as lowering blood sugar and useful as a therapeutic and / or prophylactic agent for diabetes and the like and a pharmacologically acceptable salt thereof.
  • the present invention includes diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), postprandial hyperglycemia, impaired glucose tolerance, diabetic neuropathy, diabetes containing the above compound or a pharmacologically acceptable salt thereof as an active ingredient Therapeutic and / or prevention for diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, hyperinsulinemia, etc.
  • the present invention relates to a drug (preferably a therapeutic and / or preventive for diabetes).
  • the present invention provides a composition for preventing or treating the above-mentioned disease containing the above compound or a pharmacologically acceptable salt thereof as an active ingredient, and the above-mentioned pharmaceutical composition for producing a medicament for preventing or treating the above-mentioned disease.
  • the present invention relates to the use of a compound, or a method for preventing or treating the above disease, wherein a pharmacologically effective amount of the above compound is administered to a mammal (preferably a human).
  • Diabetes is a disease whose main feature is chronic hyperglycemia, and develops due to an absolute or relative lack of insulin action. In clinical practice, it is roughly divided into insulin-dependent diabetes (type 1 diabetes) and non-insulin-dependent diabetes (type 2 diabetes).
  • diabetes treatment is basically diet therapy and exercise therapy.
  • a drug is administered. Therefore, there is a demand for safer and more effective drugs.
  • Patent Documents 1 and 2 disclose compounds having a partial structure partially in common with the compound of the present invention.
  • the present inventors have found that the compound represented by the formula (I) described below has excellent properties in terms of pharmacokinetics based on its specific chemical structure, resulting in extremely excellent blood glucose. It has an activity such as lowering, and has excellent physical properties as a pharmaceutical product such as stability, and is safe as a prophylactic / therapeutic agent for hyperglycemia, diabetes and pathologies or diseases related to those diseases.
  • the present invention was completed based on these findings.
  • the compound of the present invention has a hypoglycemic action and the like, such as diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), postprandial hyperglycemia, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetes Prevention, treatment for diseases such as retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, hyperinsulinemia, especially type 2 diabetes Useful as an agent.
  • diabetes type 1 diabetes, type 2 diabetes, gestational diabetes, etc.
  • postprandial hyperglycemia impaired glucose tolerance
  • diabetic neuropathy diabetic nephropathy
  • diabetes Prevention treatment for diseases such as retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, hyperinsulinemia, especially type 2 diabetes Useful as an agent.
  • a double line including a broken line represents a single bond or a double bond
  • R 1 represents a hydrogen atom, a C1-C3 alkyl group or a C3-C6 cycloalkyl group
  • R 2 represents a hydrogen atom or a C1-C3 alkyl group, or may combine with the C1-C3 alkyl group of R 1 to form a 3-6 membered saturated carbocycle
  • V represents —CH 2 — or —C ( ⁇ O) —
  • W is a phenyl group (the phenyl group may be substituted with the same or different 1-4 substituents selected from the substituent group ⁇ ), a biphenyl group (the biphenyl group is a substituent group) 5-10 containing the same or different 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted with the same or different 1-8 substituents selected from ⁇ )
  • a membered heteroarylphenyl group (the heteroarylphenyl group may
  • R 3 represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group
  • R 4 represents a hydrogen atom or a C1-C6 alkyl group, or may combine with the C1-C6 alkyl group of R 3 to form a 3-6 membered saturated carbocycle
  • R 5 represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group
  • R 6 represents a C2-C6 alkyl group or a C3-C6 cycloalkyl group
  • Z represents -CH 2- , -O- or -N (-R 7 )-
  • R 7 is a hydrogen atom, a C1-C6 alkyl group, a hydroxy C1-C3 alkyl group, a C1-C3 alkoxy C1-C3 alkyl group,
  • a C1-C3 alkyl group (the alkyl group may be substituted with one hydroxyl group), C3-C6 cycloalkyl group (the cycloalkyl group may be substituted with one C1-C3 alkyl group or carboxyl group), C1-C3 alkoxy group, carbamoyl group (the carbamoyl group is C1-C3 alkoxy) Selected from a C1-C3 alkylsulfonyl group, a C3-C6 cycloalkylsulfonyl group, or a hydroxy C1-C3 alkyl group optionally substituted by one group), nitrogen, oxygen and sulfur A 3-10 membered heterocyclyl group containing the same or different 1-4 heteroatoms, selected from nitrogen, oxygen and sulfur, or a 3-10 membered heterocyclylcarbonyl containing the same or different 1-4 heteroatoms A group, an amino group (the amino group may be
  • any one of the compounds selected from (1) to (7) above or a pharmacologically acceptable salt thereof (10) 6- ⁇ 3-[(3S, 10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7 , 8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid, 6- ⁇ 3-[(10R) -2-ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid, 6- ⁇ 3-[(10S) -2
  • the disease is diabetes, postprandial hyperglycemia, glucose intolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension , Edema, insulin resistance, unstable diabetes, insulinoma or hyperinsulinemia, or a pharmacologically acceptable salt thereof according to (23) above.
  • a double line including a broken line represents a single bond or a double bond
  • R 1 represents a hydrogen atom, a C1-C3 alkyl group or a C3-C6 cycloalkyl group
  • R 2 represents a hydrogen atom or a C1-C3 alkyl group, or may combine with the C1-C3 alkyl group of R 1 to form a 3-6 membered saturated carbocycle
  • V represents —CH 2 — or —C ( ⁇ O) —
  • W is a phenyl group (the phenyl group may be substituted with the same or different 1-4 substituents selected from the substituent group ⁇ ), a biphenyl group (the biphenyl group is a substituent group) 5-10 containing the same or different 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted with the same or different 1-8 substituents selected from ⁇ )
  • a membered heteroarylphenyl group (the heteroarylphenyl group may
  • R 3 represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group
  • R 4 represents a hydrogen atom or a C1-C6 alkyl group, or may combine with the C1-C6 alkyl group of R 3 to form a 3-6 membered saturated carbocycle
  • R 5 represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group
  • R 6 represents a C2-C6 alkyl group or a C3-C6 cycloalkyl group
  • Z represents -CH 2- , -O- or -N (-R 7 )-
  • R 7 represents a hydrogen atom, a C1-C6 alkyl group, a hydroxy C1-C3 alkyl group, a carboxy C1-C3 alkyl group, a C2-C6
  • a C1-C3 alkyl group (the alkyl group may be substituted with one hydroxyl group), C3-C6 cycloalkyl group (the cycloalkyl group may be substituted with one C1-C3 alkyl group or carboxyl group), C1-C3 alkoxy group, carbamoyl group (the carbamoyl group is C1-C3 alkoxy) Selected from a C1-C3 alkylsulfonyl group, a C3-C6 cycloalkylsulfonyl group, or a hydroxy C1-C3 alkyl group optionally substituted by one group), nitrogen, oxygen and sulfur A 3-10 membered heterocyclyl group containing the same or different 1-4 heteroatoms, selected from nitrogen, oxygen and sulfur, or a 3-10 membered heterocyclylcarbonyl containing the same or different 1-4 heteroatoms A group, an amino group (the amino group may be
  • the “C1-C3 alkyl group” is a linear or branched alkyl group having 1 to 3 carbon atoms, for example, a methyl, ethyl, n-propyl or isopropyl group. Can be mentioned.
  • a methyl group is preferable.
  • the “C1-C6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms.
  • the “C1-3 alkyl group” Listed groups or n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methyl Pentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3 Mention may be made of -dimethylbutyl or 2-ethylbutyl groups.
  • R 3 and R 4 are preferably a methyl group, a t-butyl group or an isopropyl group.
  • R 5 is preferably an isopropyl group.
  • R 7 is preferably a methyl group or an ethyl group.
  • examples of the “3-6 membered saturated carbocycle” include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
  • R 1 , R 2 , R 3 and R 4 are preferably cyclopropane or cyclobutane.
  • the “C2-C6 alkyl group” is a linear or branched alkyl group having 2 to 6 carbon atoms, such as ethyl, n-propyl, isopropyl, n-butyl.
  • R 6 is preferably an isopropyl group.
  • the “C3-C6 cycloalkyl group” is a 3- to 6-membered saturated cyclic hydrocarbon group, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
  • R 1 and R 3 are preferably a cyclopropyl group, and R 5 , R 6 , R 7 and the substituent group ⁇ are preferably a cyclopropyl group or a cyclobutyl group.
  • the “hydroxy C1-C3 alkyl group” is a group in which a hydroxyl group is substituted on the “C1-C3 alkyl group”, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl.
  • the substituent of R 7 and the “carbamoyl group” of the substituent group ⁇ is preferably a hydroxymethyl group or a 1-hydroxyethyl group.
  • the “C1-C3 alkoxy group” is a group in which the “C1-C3 alkyl group” is bonded to an oxygen atom, and has, for example, a carbon number such as methoxy, ethoxy, n-propoxy, isopropoxy group. Mention may be made of 1 to 3 straight-chain or branched alkoxy groups.
  • the substituent of the substituent group ⁇ and the substituent of the “carbamoyl group” in the substituent group ⁇ is preferably a methoxy or ethoxy group.
  • the “C1-C3 alkoxy C1-C3 alkyl group” is a group in which the “C1-C3 alkoxy group” is substituted on the “C1-C3 alkyl group”.
  • n-butoxymethyl, isobutoxy Methyl, s-butoxymethyl, tert-butoxymethyl, n-pentoxymethyl isopentoxymethyl, 2-methylbutoxymethyl, neopentoxymethyl, n-hexyloxymethyl, 4-methylpentoxymethyl, 3-methyl Pentoxymethyl, 2-methylpentoxymethyl, 3,3-dimethylbutoxymethyl, 2,2-dimethylbutoxymethyl, 1,1-dimethylbutoxymethyl, 1,2-dimethylbutoxymethyl, 1,3-dimethylbutoxymethyl 2,3-dimethylbutoxymethyl group
  • R 7 is preferably a methoxyethyl group.
  • the “C2-C6 alkenyl group” is a straight chain or branched alkenyl group having 2 to 6 carbon atoms containing one double bond, such as ethenyl, 1-propenyl, 2-propenyl.
  • C2-C6 alkynyl group is a straight chain or branched alkynyl group having 2 to 6 carbon atoms containing one triple bond, such as ethynyl, prop-2-yne-1 -Yl group may be mentioned.
  • R 7 is preferably a prop-2-yn-1-yl group.
  • the “3- to 10-membered heterocyclyl group containing 1-4 heteroatoms which are the same or different and selected from nitrogen, oxygen and sulfur” refers to 3 to 4 containing 1 to 4 nitrogen, oxygen or sulfur 10-membered heterocyclic group such as furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl (for example , 2-pyridylphenyl, 3-pyridylphenyl, 4-pyridylphenyl), aromatic heterocyclic groups such as pyridazinyl, pyrimidinyl, pyrazinyl and oxetanyl, morpholiny
  • the above “4- to 10-membered heterocyclic group” may be condensed with other cyclic groups, such as benzofuranyl, chromenyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolidinyl, isoquinolyl, quinolyl, Phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, isoindolinyl, 2,3-dihydro-1-benzofuranyl, 3,4-dihydro-1H-isochromenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4 -A tetrahydroisoquinolinyl group can be mentioned.
  • other cyclic groups such as benzofuranyl, chromenyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl,
  • Preferred examples of the substituent group ⁇ include triazolyl, tetrazolyl, morpholinyl, pyrrolidinyl, piperidinyl, and 5-oxo-4,5-dihydro-1,2,4-oxadiazolyl groups.
  • the “3- to 10-membered heterocyclic carbonyl group containing the same or different 1-4 heteroatoms selected from nitrogen, oxygen and sulfur” is selected from the above “nitrogen, oxygen and sulfur”
  • a morpholinylcarbonyl group is preferable.
  • the “5- to 10-membered heteroaryl group containing 1-4 heteroatoms which are the same or different from nitrogen, oxygen and sulfur” includes 1 to 4 nitrogen, oxygen or sulfur.
  • To 10-membered heteroaromatic group such as furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl , Pyridazinyl, pyrimidinyl and pyrazinyl groups.
  • the “5- to 10-membered heteroarylphenyl group containing 1-4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur” is selected from the above “nitrogen, oxygen and sulfur” ⁇ 5- to 10-membered heteroaryl group containing the same or different 1-4 heteroatoms '' is a group bonded to a phenyl group, such as furylphenyl, thienylphenyl, pyrrolylphenyl, azepinylphenyl, pyrazolylphenyl, Imidazolylphenyl, oxazolylphenyl, oxadiazolylphenyl, isoxazolylphenyl, thiazolylphenyl, isothiazolylphenyl, 1,2,3-oxadiazolylphenyl, triazolylphenyl, tetrazolylphenyl, Thiadiazolylphenyl, pyranylphenyl, 2-pyridylphenyl
  • the “C1-C3 alkylcarbonyl group” is a group in which the “C1-C3 alkyl group” is bonded to a carbonyl group.
  • a carbon such as acetyl, propionyl, n-propylcarbonyl, isopropylcarbonyl, etc.
  • examples thereof include a linear or branched alkoxycarbonyl group having a number of 1 to 3, and the substituent of the “amino group” in the substituent group ⁇ is preferably an acetyl or propionyl group.
  • the “C1-C3 alkylsulfonyl group” is a group to which the “C1-3 alkyl group” is bonded via a sulfonyl group, such as methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropane.
  • a sulfonyl group can be mentioned.
  • the substituent of the substituent group ⁇ “carbamoyl group” and the substituent of the “amino group” of the substituent group ⁇ are preferably a methanesulfonyl group.
  • the “C3-C6 cycloalkylsulfonyl group” is a group to which the “C3-C6 cycloalkyl” is bonded via a sulfonyl group, such as cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexyl.
  • a sulfonyl group can be mentioned.
  • the substituent of the substituent group ⁇ “carbamoyl group” is preferably a cyclopropylsulfonyl group.
  • the “carboxy C1-C3 alkyl group” is a group in which a carboxylic acid is bonded to the “C1-3 alkyl group”, and includes, for example, 1 to C carbon atoms such as ethanoic acid, propanoic acid, and butanoic acid.
  • R 7 and the substituent of the “amino group” in the substituent group ⁇ are preferably ethanoic acid.
  • the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and in the substituent group ⁇ , preferably a chlorine atom or a fluorine atom.
  • the “C1-C3 haloalkyl group” is a group obtained by substituting the “halogen atom” for the “C1-C3 alkyl group”.
  • the ⁇ C1-C3 haloalkyl group '' for example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, Examples include 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, and 2,2-dibromoethyl group.
  • R 7 is preferably a 2-fluoroethyl group. .
  • the “naphthyl group” is a 1-naphthyl group or a 2-naphthyl group, and W is preferably a 1-naphthyl group.
  • examples of the “biphenyl group” include 2-biphenyl, 3-biphenyl, and 4-biphenyl, and W is preferably 3-biphenyl.
  • the term “pharmacologically acceptable salt” refers to a case where a basic group such as an amino group is reacted with an acid, and a case where an acidic group such as a carboxyl group is present. By reacting with a base, it can be converted into a salt, so that salt is shown.
  • the salt based on the basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfuric acid.
  • Inorganic acid salts such as salts and phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate, aryl sulfones such as benzene sulfonate and p-toluene sulfonate Acid salt, acetate salt, malate salt, fumarate salt, succinate salt, citrate salt, ascorbate salt, tartrate salt, succinate salt, maleate salt, etc .; and glycine salt, lysine salt And amino acid salts such as arginine salt, ornithine salt, glutamate and aspartate.
  • it is a hydrohalide salt or an inorgan
  • the salt based on an acidic group is preferably an alkali metal salt such as a sodium salt, potassium salt or lithium salt, an alkaline earth metal salt such as a calcium salt or magnesium salt, an aluminum salt or an iron salt.
  • Metal salt such as ammonium salt, tert-butylamine salt, t-octylamine salt, diisopropylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglu Camine salt, 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 Salt, tris (hydro Shimechir
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof includes all isomers (keto-enol isomer, stereoisomer, etc.).
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has various isomers when an asymmetric carbon atom is present 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.
  • stereoisomers as described above can be obtained by isolating the synthesized compound according to the present invention, if desired, using a conventional optical resolution method or separation method.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may also contain an unnatural ratio of atomic isotopes at one or more of atoms constituting such a compound.
  • atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), and carbon-14 ( 14 C).
  • the compound may also be radiolabeled with a radioisotope such as, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is left in the air 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 pharmacologically acceptable salt thereof may absorb a certain other solvent and become a solvate, and such a solvate is also present. Included in the salts of the invention.
  • the present invention provides a compound that is metabolized in vivo and converted to a 6-membered heterocyclic derivative having the general formula (I) or a salt thereof (for example, the carboxylic acid moiety of the general formula (I) is esterified Derivatives etc.) are all included.
  • R 1 in the present invention is preferably a methyl group.
  • R 2 in the present invention is preferably a methyl group.
  • R 3 in the present invention is preferably a C1-C6 alkyl group, and more preferably a methyl group or an isopropyl group.
  • R 4 in the present invention is preferably a hydrogen atom or a methyl group.
  • R 5 in the present invention is preferably a C1-C6 alkyl group, and more preferably an isopropyl group.
  • R 6 in the present invention is preferably a C1-C6 alkyl group, and more preferably an isopropyl group.
  • R 7 in the present invention is preferably a hydrogen atom or a C1-C6 alkyl group, more preferably a hydrogen atom or a methyl group.
  • W is preferably a 5- to 10-membered heteroarylphenyl group containing 1-4 heteroatoms selected from nitrogen, oxygen and sulfur (the heteroarylphenyl group is a group of substituents). and may be substituted with the same or different 1-8 substituents selected from ⁇ ).
  • X in the present invention is preferably —CH ⁇ or —CH 2 —.
  • Z in the present invention is preferably —NR 7 —.
  • the substituent group ⁇ of the present invention is preferably a C3-C6 cycloalkyl group, a C1-C3 alkoxy group or a carboxyl group in the substituent of the phenyl group of W.
  • the substituent group ⁇ of the present invention is preferably a C1-C3 alkyl group, a C1-C3 alkoxy group or a carboxyl group in the substituent of the biphenyl group of W.
  • the substituent group ⁇ of the present invention is preferably a carbamoyl group in a substituent of a 5- to 10-membered heteroarylphenyl group containing 1-4 heteroatoms selected from nitrogen, oxygen and sulfur of W.
  • the carbamoyl group may be substituted with a C1-C3 alkylsulfonyl group, a C3-C6 cycloalkylsulfonyl group, or a hydroxy C1-C3 alkyl group, which may be substituted with a C1-C3 alkoxy group.
  • the general formula (I) of the present invention is preferably the following formula (Ia)
  • R 1 , R 2 , R 3 , R 4 , R 7 and W are as defined above] ].
  • the general formula (I) of the present invention is preferably the following general formula (II)
  • R 8 represents a carbamoyl group (the carbamoyl group may be substituted by one methylsulfonyl group) or a carboxyl group
  • R 1 , R 2 , R 3 , R 4 and R 7 are Synonymous with. More preferably, the following formula (III)
  • the compound having the general formula (I) of the present invention can be produced, for example, by the following method: Method A: Among the compounds having the general formula (I), V is —C ( ⁇ O) — (Ia) can be produced by carrying out Steps A-1 to A-3.
  • Method B Among the compounds having the general formula (I), the compound (Ib) in which V is —CH 2 — is subjected to the steps B-1 and B-2 after the steps A-1 and A-2. Can be manufactured.
  • W, X, Y, Z, R 1 , R 2 , R 3 , R 4 and R 5 have the same meaning as described above.
  • P 1 is not particularly limited as long as it is a protecting group used for protecting a carboxyl group.
  • P 2 is not particularly limited as long as it is a protecting group used for protecting a hydroxyl group, but benzyl group, trimethylsilyl group, triethylsilyl group, isopropyldimethylsilyl group, t-butyldimethylsilyl group A methyldiisopropylsilyl group, a methyldi-t-butylsilyl group or a triisopropylsilyl group is preferred.
  • Protecting and deprotecting hydroxyl groups, amino groups and carboxyl groups during the above steps and in the following description can be carried out by conventional methods in the field of synthetic organic chemistry.
  • the methods and protecting groups described in Green Watts, "Protective groups in organic synthesis 4th edition” (Wiley-Interscience, USA) can be mentioned, but are not limited thereto. Is not to be done.
  • Raw material compound (1), compound (2), and cocoon compound (4) are commercially available or can be synthesized by methods in accordance with literature.
  • This step is a step for producing the intermediate compound (3) by reacting the starting compound (1) with the compound (2) in the presence of a base in a solvent.
  • the solvent is preferably an ether or an amide, more preferably acetonitrile, tetrahydrofuran or N, N-dimethylformamide.
  • the base is preferably an organic base or an inorganic base, more preferably an amino acid, an amine, an alkali metal carbonate or an alkaline earth metal carbonate, and more preferably proline, pyrrolidine, or piperidine. Morpholine, triethylamine, diisopropylethylamine, cesium carbonate or potassium carbonate.
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to 60 ° C.
  • the reaction time is usually 0.5 to 72 hours, preferably 1 to 30 hours.
  • step A-2 may be directly performed without isolating the compound (3).
  • This step is a step for producing intermediate compound (5) by reacting compound (3) with compound (4) in the presence of a base in a solvent.
  • the solvent is preferably an ether or an amide, more preferably acetonitrile, tetrahydrofuran or N, N-dimethylformamide.
  • the base is preferably an organic base or an inorganic base, more preferably amines, alkali metal alkoxides, alkali metal carbonates or alkaline earth metal carbonates, and more preferably pyrrolidine, piperidine. , Morpholine, triethylamine, diisopropylethylamine, potassium t-butoxy, cesium carbonate or potassium carbonate.
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
  • the step A-3 may be directly performed without isolating the compound (5).
  • This step is a step of producing the target compound (Ia) by activating the enolic hydroxyl group of compound (5) in a solvent.
  • the enolic hydroxyl group activation method includes methanesulfonylation reaction, trifluoromethanesulfonyl
  • the reaction reagent or Mitsunobu reaction is used.
  • the solvent is preferably an ether, amide or halogenated hydrocarbon, more preferably tetrahydrofuran, N, N-dimethylformamide or dichloromethane.
  • the base is preferably an organic base or an alkaline earth metal carbonate, and more preferably triethylamine, diisopropylethylamine or cesium carbonate.
  • methanesulfonylation and trifluoromethanesulfonylating agent include methanesulfonyl chloride, methanesulfonic anhydride, N-phenylbis (trifluoromethanesulfonimide), and trifluoromethanesulfonic anhydride.
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
  • the solvent is preferably ethers, hydrocarbons or halogenated hydrocarbons, and more preferably tetrahydrofuran, toluene or dichloromethane.
  • the azo reagent is preferably diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, or 1,1 ′-(azodicarbonyl) dipiperidine.
  • the phosphine reagent is preferably triphenylphosphine, tributylphosphine, or tricyclohexylphosphine.
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
  • This step is a step for producing intermediate compound (6) by reacting compound (Ib) with a thiocarbonylating agent in a solvent.
  • the solvent is preferably ethers or hydrocarbons, more preferably tetrahydrofuran, 1,4-dioxane or toluene.
  • the thiocarbonylating agent is preferably Lawesson's reagent or diphosphorus pentasulfide.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
  • This step is a step for producing compound (Ib) by reacting intermediate compound (6) with a reducing agent in a solvent.
  • the solvent is preferably an ether or an alcohol, and more preferably tetrahydrofuran or ethanol.
  • the reducing agent is preferably a transition metal, a mixture of a reducing agent and a transition metal, and more preferably a mixture of Raney nickel, sodium borohydride and nickel chloride.
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
  • the target compound can also be produced by appropriately adding a step of introducing a substituent R 7 onto the nitrogen atom in any of the steps of Method A and Method B.
  • Introduction of the substituent R 7 onto the nitrogen atom is achieved, for example, by reacting a halide of R 7 (chloride, bromide, etc.) in the presence of a base in a solvent.
  • the solvent used is preferably an ether or an amide, more preferably tetrahydrofuran or N, N-dimethylformamide.
  • the base is preferably an inorganic base, more preferably an alkali metal hydride or alkaline earth metal hydride, and more preferably sodium hydride.
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
  • R 5 is not a hydrogen atom
  • a step of introducing the substituent R 5 onto the nitrogen atom according to the method of introducing the substituent R 7 is appropriately added in any of the methods A and B.
  • the target compound can also be produced.
  • the solvent is preferably ethers, halogenated hydrocarbons or alcohols, and more preferably tetrahydrofuran, dichloromethane, methanol or ethanol.
  • the base is preferably a metal hydroxide, and more preferably sodium hydroxide, lithium hydroxide, or potassium hydroxide.
  • the acid is preferably hydrochloric acid or trifluoroacetic acid.
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
  • the solvent is preferably a halogenated hydrocarbon, ether or amide, more preferably dichloromethane, tetrahydrofuran or N, N-dimethylformamide.
  • the condensing agent is preferably carbonyldiimidazole.
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
  • the solvent is preferably an ether or an amide, more preferably 1,4-dioxane or tetrahydrofuran.
  • the catalyst is, for example, a divalent palladium catalyst or a zero-valent palladium catalyst, and more preferably PdCl 2 (dppe), PdCl 2 (dppf), or PdCl 2 (Ph 3 P) 2 .
  • the reaction temperature is usually 0 ° C. to 150 ° C., preferably room temperature to 120 ° C.
  • the reaction time is usually 0.5 to 60 hours, preferably 1 to 48 hours.
  • the solvent is preferably an ether or an amide, more preferably 1,4-dioxane or tetrahydrofuran.
  • the catalyst is, for example, a divalent palladium catalyst or a zero-valent palladium catalyst, more preferably PdCl 2 (dppe), PdCl 2 (dppf), Pd (Ph 3 P) 4 or 2nd Generation X-Phos Precatalyst. It is.
  • the reaction temperature is usually 0 ° C. to 150 ° C., preferably room temperature to 120 ° C.
  • the reaction time is usually 0.5 to 60 hours, preferably 1 to 48 hours.
  • the target compound is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, washed with water, and the target compound is then contained.
  • the organic layer is separated, dried over anhydrous magnesium sulfate and the like, and then the solvent is distilled off.
  • the obtained target product can be obtained by a conventional method such as recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, such as adsorption column chromatography, distribution column chromatography, etc. Separation and purification by eluting with an appropriate eluent by combining a method using a synthetic adsorbent, a method using ion exchange chromatography, or a normal phase / reverse phase column chromatography method using silica gel or alkylated silica gel. can do.
  • the optically active substance can be separated and purified by a chiral column.
  • the 6-membered heterocyclic derivative having the general formula (I) of the present invention and a pharmacologically acceptable salt thereof are administered in various forms.
  • the administration form is not particularly limited, and is determined according to various preparation forms, patient age, sex and other conditions, the degree of disease, and the like.
  • tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions and capsules they are administered orally.
  • a normal replacement fluid such as glucose or amino acid
  • it is administered intramuscularly, intradermally, subcutaneously or intraperitoneally as necessary.
  • a suppository it is administered intrarectally. Oral administration is preferred.
  • compositions are prepared by using known adjuvants that can be generally used in the field of known pharmaceutical preparations such as excipients, binders, disintegrants, lubricants, solubilizers, flavoring agents, and coating agents according to conventional methods. It can be formulated.
  • conventionally known carriers can be widely used as carriers, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like.
  • carriers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like.
  • Form water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, agar powder, laminaran powder Sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and other disintegrants, sucrose, stearin, cacao butter, hydrogenated oil and other
  • the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets.
  • those conventionally known in this field can be widely used as carriers, for example, glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc and other excipients, gum arabic powder, Examples thereof include binders such as tragacanth powder, gelatin and ethanol, and disintegrants such as lamina lankanten.
  • conventionally known carriers can be widely used as carriers, such as polyethylene glycol, cacao butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides and the like. it can.
  • the solutions and suspensions are preferably sterilized and isotonic with blood, and in the form of these solutions, emulsions and suspensions, this is used as a diluent.
  • Any of those commonly used in the field can be used, and examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters.
  • a sufficient amount of sodium chloride, glucose, or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation.
  • Ordinary solubilizers, buffers, soothing agents, etc. may be added. It may be added.
  • colorants may be included.
  • preservatives may be included.
  • fragrances may be included.
  • flavors may be included.
  • sweeteners may be included.
  • the amount of the active ingredient compound contained in the pharmaceutical preparation is not particularly limited and is appropriately selected within a wide range, but is usually 1 to 70% by weight, preferably 1 to 30% by weight in the total composition. Is appropriate.
  • the dosage varies depending on symptoms, age, body weight, administration method, dosage form, etc., but is usually 0.001 mg / kg (preferably 0.01 mg / kg, more preferably 0.1 mg as a lower limit for adults per day) / mg), and 200 mg / kg (preferably 20 mg / kg, more preferably 10 mg / kg) as the upper limit can be administered once to several times.
  • the compound of the present invention can be used in combination with various therapeutic or prophylactic agents for the diseases for which the present invention is considered to be effective.
  • the combination may be administered simultaneously or separately in succession or at desired time intervals.
  • the simultaneous administration preparation may be a compounding agent or may be separately formulated.
  • antidiabetic agents that can be used in combination include insulin preparations, sulfonylureas, thiazolidines, biguanides, ⁇ -glucosidase inhibitors, fast-acting insulin secretagogues, GLP-1 receptor agonists, SGLT2 inhibitors And DPPIV inhibitors and the like.
  • the compound of the present invention which is a 6-membered heterocyclic derivative and a pharmacologically acceptable salt thereof, has an excellent hypoglycemic action, such as diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), postprandial hyperglycemia Impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, high It is useful as a therapeutic or prophylactic agent for diseases such as insulinemia. In addition, since it is low in toxicity and excellent in safety, it can be said that it is extremely useful as a medicine.
  • silica gel SK-85 230-400 mesh
  • silica gel SK-34 70-230 mesh
  • Fuji Silysia Chemical Chromatorex NH 200-350 mesh
  • Merck & Co., Inc. was used.
  • SP-1 Biotage's automated chromatography device
  • Yamazen's automated chromatography device Yamazen's automated chromatography device
  • Teledyne Isco's automated chromatography device CombiFlash Rf
  • Hexane represents n-hexane
  • THF represents tetrahydrofuran
  • DME represents 1,2-dimethoxyethane
  • DMA represents N, N-dimethylacetamide
  • DMF represents N, N-dimethylformamide
  • DBU represents 1,8-diazabicyclo [5.4.0] undec-7-ene
  • 2nd generation X-phos precatalyst is chloro (2-dicyclohexylphosphino-2 ', 4', 6'-triisopropyl-1,1'- Biphenyl) [2- (2′-amino-1,1′-biphenyl)] palladium (II)
  • WSC ⁇ HCl represents N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride
  • DMPU indicates 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone
  • the first peak was shown as a low polarity compound, and the second peak was shown as a high polarity compound.
  • Example 1 6- [4-Methoxy-2-methyl-3- (2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl) phenyl] -3-methylpyridine-2-carboxylic acid (1a) tert-butyl 6- ⁇ 3-[(4,4-dimethyl-2,6-dioxocyclohexylidene) methyl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxy Rate Known compounds tert-butyl 6- (3-formyl-4-methoxy-2-methylphenyl) -3-methylpyridine-2-carboxylate (1.40 g, 4.10 mmol) and L-proline (23.6 mg, 0.250) mmol) in acetonitrile (7.0 mL) was added dimedone (632 mg, 4.
  • reaction solution was stirred at room temperature for 30 minutes, methanesulfonyl chloride (125 ⁇ L, 1.62 mmol) was added, and the reaction solution was stirred at 50 ° C. for 1 hour. After cooling to room temperature, water and ethyl acetate were added to the reaction solution, and the precipitated crystals were filtered to obtain the title compound (111 mg, 18%).
  • Example 2 6- [4-Methoxy-2-methyl-3- (2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl) phenyl] -3-methylpyridine-2-carboxylic acid tert-butylamine salt (2a) tert-butyl 6- [3- (2-ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro -1H-chromeno [3,2-c] pyridin-10-yl) -4-methoxy-2-methylphenyl] -3-methylpyridine-2-carboxylate tert-butyl 6- [4 prepared in Example 1b -Methoxy-2-methyl-3- (3,3,7,7-tetramethyl-1,9-dioxo-2,
  • Example 4 6- ⁇ 4-Methoxy-2-methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9, 10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butylamine salt or 6- ⁇ 4-methoxy-2-methyl-3- [(10R) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c ] Pyridin-10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butylamine salt (4a) 6- ⁇ 4-Methoxy-2-methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1,9-d
  • Example 5 6- ⁇ 4-Methoxy-2-methyl-3- [3,3,7,7-tetramethyl-1,9-dioxo-2- (prop-2-en-1-yl) -2,3,4 , 6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butylamine salt (5a) tert-butyl 6- ⁇ 4-methoxy-2-methyl-3- [3,3,7,7-tetramethyl-1,9-dioxo-2- (prop-2-en-1-yl) -2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylate
  • Example 1b Tert-butyl 6- [4-methoxy-2-methyl-3- (3,3,7,
  • Methanesulfonamide (37.3 mg, 0.392 mmol) and DBU (54 ⁇ L, 0.362 mmol) were added to the reaction solution, and the reaction solution was stirred at room temperature for 3.5 hours.
  • a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (122 mg, 65%).
  • Example 7 6- ⁇ 4-Methoxy-2-methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9, 10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ -3-methyl lN- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt or 6- ⁇ 4-methoxy-2 -Methyl-3-[(10R) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [ 3,2-c] pyridin-10-yl] phenyl ⁇ -3-methyllN- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt (7a) 6- ⁇ 4-Methoxy-2-methyl-3
  • the reaction solution was stirred at 0 ° C. for 3 hours, water was added and the mixture was extracted twice with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude adduct.
  • Di-tert-butyl azodicarboxylate (1.99 g, 8.65 mmol) was added to a crude adduct and a solution of triphenylphosphine (2.27 g, 8.65 mmol) in THF (33 mL) at room temperature, and the reaction solution was stirred at room temperature for 1.5. Stir for hours.
  • tert-butyl 6- ⁇ 3-[(3S *, 10R *)-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4, 6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2methylphenyl ⁇ -3-methylpyridine-2-carboxylate (70.0 mg , 1.6%).
  • Example 10 6- ⁇ 4-Methoxy-2-methyl-3-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4, 6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid (10a) tert-butyl 6- ⁇ 4-methoxy-2-methyl-3-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl)- 2,3,4,6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylate in Example 9d Prepared tert-butyl 6- ⁇ 3-[(3S, 10S) -7,
  • Example 12 6- ⁇ 4-Methoxy-2-methyl-3-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4, 6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide in Example 10b
  • Example 13 6- [4-Methoxy-2-methyl-3- (2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [ 3,2-c] pyridine-3,1′-cyclobutane] -10-yl) phenyl] -3-methylpyridine-2-carboxylic acid (13a) 10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-6 , 7,8,10-Tetrahydrospiro [chromeno [3,2-c] pyridine-3,1'-cyclobutane] -1,9 (2H, 4H) -dione 2- [6-methoxy prepared in Example 9b -2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
  • Example 14 6- ⁇ 4-Methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,6,7,8, 9,10-Hexahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid (14a) tert-Butyl 6- ⁇ 3-[(10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,6,7,8,9,10- Hexahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylate tert-butyl 6- ⁇ prepared in Example 9d 3-[(3S, 10S) -7,7-dimethyl-1,9-dioxo
  • Example 15 6- ⁇ 4-methoxy-2-methyl-3-[(3R, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3, 6,7,8,9,10,10a-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid
  • 15a tert-butyl 6- ⁇ 3-[(3R, 10S, 10aR) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,6,7, 8,9,10,10a-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylate
  • Example 1a Prepared tert-butyl 6- ⁇ 3-
  • tert-butyl 6- ⁇ 3-[(3S, 10R) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6, 7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2methylphenyl ⁇ -3-methylpyridine-2-carboxylate (1.71 g, 14 %).
  • Example 16 6- ⁇ 4-Methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,6,7,8, 9,10-Hexahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide 6- ⁇ 4 prepared in Example 14c -Methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,6,7,8,9,10- Hexahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid (200 mg, 0.359 mmol), carbonyldiimidazole (75.7 mg, 0.467 mmol), DMF
  • Example 17 6- ⁇ 3-[(3R, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide prepared in Example 11d 6- ⁇ 3-[(3R, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid (200 mg, 0.367 mmol), carbonyldiimidazole ( 77.4 mg,
  • Example 20 6- ⁇ 3-[(5S) -8,8-Dimethyl-4,6-dioxo-2- (propan-2-yl) -1,3,4,5,6,7,8,9-octahydro- 2H-chromeno [2,3-c] pyridin-5-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid (20a) tert-butyl 5- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -8,8- Dimethyl-4,6-dioxo-1,3,4,5,6,7,8,9-octahydro-2H-chromeno [2,3-c] pyridine-2-carboxylate 2-prepared in Example 9b [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2
  • reaction solution was stirred at room temperature for 2 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate; 3: 7) to obtain the title compound (687 mg, 76%).
  • Example 21 6- ⁇ 4-Methoxy-2-methyl-3-[(5S) -3,8,8-trimethyl-4,6-dioxo-2- (propan-2-yl) -3,5,6,7, 8,9-Hexahydro-4H-chromeno [2,3-d] pyrimidin-5-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid (21a) 5- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,8,8-trimethyl 2- (propan-2-yl) -5,7,8,9-tetrahydro-4H-chromeno [2,3-d] pyrimidine-4,6 (3H) -dione 2- [prepared in Example 9b 6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylid
  • Example 23 6- ⁇ 3-[(3S, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,6,7,8,9,10,10a- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid
  • Example 23a tert-butyl 6- ⁇ 3-[(3S, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,6,7,8, 9,10,10a-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylate by-product in Example 22d
  • Example 25 6- ⁇ 4-Methoxy-2-methyl-3-[(10R) -2,3,3,7,7-pentamethyl-1-oxo-2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid (25a) 10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3,7,7 -Tetramethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 2- [6-methoxy prepared in Example 9b -2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] -5,5-dimethylcycl
  • the aqueous layer was extracted 3 times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (132 mg, 93%).
  • Example 26 6- ⁇ 3-[(3S, 10R) -3-tert-butyl-2,7,7-trimethyl-1-oxo-2,3,4,6,7,8,9,10-octahydro-1H- Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid (26a) (3S, 10S) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) phenyl] -7,7-dimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione prepared in Example 9b 2- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2
  • Example 27 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-Butylamine salt (27a) (3R, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3- (propan-2-yl) -3,6,7,8,10,10a-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H)- Dione
  • Example 28 6- ⁇ 4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2, 3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine -2-carboxamide tert-butylamine salt
  • 28a 6- ⁇ 4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇
  • Example 30 6- [4-Methoxy-2-methyl-3- (3,3,7,7-tetramethyl-1,9-dioxo-4,6,7,8,9,10-hexahydro-1H, 3H-pyrano [4,3-b] chromen-10-yl) phenyl] pyridine-2-carboxylic acid (30a) tert-butyl 6- [4-methoxy-2-methyl-3- (3,3,7,7-tetra Methyl-1,9-dioxo-4,6,7,8,9,10-hexahydro-1H, 3H-pyrano [4,3-b] chromen-10-yl) phenyl] pyridine-2-carboxylate Examples 10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3,7 by-produced in 29a , 7-Tetramethyl-3,4,6,7,
  • Example 31 6- [4-Methoxy-2-methyl-3- (3,3,7,7-tetramethyl-1,9-dioxo-4,6,7,8,9,10-hexahydro-1H, 3H-pyrano [4,3-b] chromen-10-yl) phenyl] -N- (methylsulfonyl) pyridine-2-carboxamide 6- [4-methoxy-2-methyl-3- (3,3) prepared in Example 30 , 7,7-Tetramethyl-1,9-dioxo-4,6,7,8,9,10-hexahydro-1H, 3H-pyrano [4,3-b] chromen-10-yl) phenyl] pyridine- Using 2-carboxylic acid (50.0 mg, 0.0966 mmol), carbonyldiimidazole (18.8 mg, 0.116 mmol), DMF (1.0 mL), methanesulfonamide (11.9 mg, 0.126 mmol) and DBU (19 ⁇
  • Example 32 2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxy-6- (1H-pyrazol-1-yl) benzoic acid (32a) Ethyl 3-bromo-2- (bromomethyl) -6-methoxybenzoate Ethyl 3-bromo-6-methoxy-2-methylbenzoate (110 g, 404 mmol), 2,2'-azobis (isobutyronitrile ) (6.64 g, 40.4 mmol) and N-bromosuccinimide (79.2 g, 445 mmol) in carbon tetrachloride (500 mL) and acetonitrile (200 mL) were stirred at 80 ° C.
  • reaction solution was stirred at room temperature for 1 hour, 1 M hydrochloric acid (45 mL) was added, and the reaction solution was further stirred at room temperature for 5.5 hours.
  • Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized from hexane and ether to obtain the title compound (11.6 g, 75%).
  • Example 33 3-Methoxy-6- (1H-pyrazol-1-yl) -2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2 , 3,4,6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzoic acid (33a) (3S, 10S) -10- [6-Methoxy-2- ⁇ [(4-methoxybenzyl) oxy] methyl ⁇ -3- (1H-pyrazol-1-yl) phenyl] -7,7-dimethyl -3- (propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione prepared in Example 32h 2- [6-methoxy-2- ⁇ [(4-methoxybenzyl) oxy] methyl ⁇
  • Example 34 2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxy-6- (pyridin-2-yl) benzoic acid (34a) (3-Bromo-6-methoxy-2- ⁇ [(4-methoxybenzyl) oxy] methyl ⁇ phenyl) methanol Ethyl 3-bromo-6-methoxy-2- ⁇ [(4 -Methoxybenzyl) oxy] methyl ⁇ benzoate (974 mg, 2.38 mmol) in dichloromethane (10 mL) at -78 ° C was added diisobutylaluminum hydride (1.04 M toluene solution; 5.50 mL, 2.72 mmol), and the reaction solution was- The mixture was stirred at 78
  • Example 35 6- ⁇ 3-[(3S, 10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8, 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butylamine salt
  • 35a tert-butyl 6- ⁇ 3-[(3S, 10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4, 6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylate
  • Tert-butyl 6- ⁇ 3
  • Example 36 6- ⁇ 3-[(3S, 10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8, 9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide tert- Butylamine salt (36a) 6- ⁇ 3-[(3S, 10S) -2-Ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7 , 8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine
  • Example 37 6- ⁇ 3-[(10R) -2-ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butylamine salt
  • 37a 2-Ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3 , 7,7-Tetramethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 10- prepared in Example 25a [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-d
  • Example 38 6- ⁇ 3-[(10S) -2-Ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butylamine salt
  • 38a 6- ⁇ 3-[(10S) -2-Ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid benzyl 6- ⁇ 3- [(10S) -2-ethyl-3,3,7,7-tetramethyl-1,9-d
  • reaction solution was stirred at 0 ° C. for 1 hour 30 minutes, methanesulfonyl chloride (444 ⁇ L, 5.69 mmol) was added at 0 ° C., and the reaction solution was stirred at room temperature for 5 hours. A 10% aqueous citric acid solution was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain the title compound (2.62 g, 99%).
  • Example 40 6- ⁇ 3-[(10S) -2-Ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt (40a) 6- ⁇ 3-[(10S) -2-Ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide prepared in Example 38a 6- ⁇ 3-[(10S)
  • Example 41 6- ⁇ 4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3, 4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] phenyl ⁇ -3-methylpyridine-2 -Carboxylic acid tert-butylamine salt (41a) 6- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] spiro [2.5] octane-5, 7-dione 6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde prepared in Example
  • reaction solution was stirred at 0 ° C. for 3 hours, water was added and the mixture was extracted twice with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude adduct.
  • Example 42 6- ⁇ 4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3, 4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl] phenyl ⁇ -3-methylpyridine-2- Carboxylic acid tert-butylamine salt (42a) 7- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] spiro [3.5] nonane-6, 8-Dione 6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde (2.00 g, 7.
  • reaction solution was stirred at 0 ° C. for 3 hours, water was added and the mixture was extracted twice with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude adduct.
  • Example 43 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfonyl Pyridine-2-carboxamide tert-butylamine salt
  • 43a 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -2-Ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4 , 4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-me
  • Example 45 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,4a, 6,7,8,9, 10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butylamine salt (45a) (3S, 10S, 10aR) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) phenyl] -7,7-dimethyl-3,6,7,8,10,10a-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione
  • Example 9b 2- [6-Methoxy-2
  • reaction solution was stirred at 0 ° C. for 3 hours, water was added and the mixture was extracted twice with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude adduct.
  • Example 46 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,4a, 6,7,8,9, 10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide tert- Butylamine salt (46a) 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,4a, 6,7,8 , 9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfon
  • Example 48 6- ⁇ 4-Methoxy-2-methyl-3-[(10S) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10 -Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butylamine salt (48a) Benzyl 6- [4-methoxy-2-methyl-3- (3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10 -Octahydro-1H-chromeno [3,2-c] pyridin-10-yl) phenyl] -3-methylpyridine-2-carboxylate 10- [6-methoxy-2-methyl-3- prepared in Example 25a (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,
  • Example 49 2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxy-6- (6-methylpyridazin-3-yl) benzoic acid (49a) (3S, 10S) -3-tert-butyl-10- [6-methoxy-2- ⁇ [(4-methoxybenzyl) oxy] methyl ⁇ -3- (6-methylpyridazin-3-yl) phenyl ] -2,7,7-Trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione Prepared in Example 34f (3S, 10S) -3-tert-butyl-10- [6-methoxy-2- ⁇ [(3S,
  • Example 50 6-cyclopropyl-3-methoxy-2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6, 7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzoic acid (50a) 3-Cyclopropyl-6-methoxy-2- ⁇ [(4-methoxybenzyl) oxy] methyl ⁇ benzaldehyde 3-bromo-6-methoxy-2- ⁇ [(4-methoxybenzyl) prepared in Example 34b ) Oxy] methyl ⁇ benzaldehyde (10.0 g, 27.4 mmol), cyclopropaneboronic acid (4.70 g, 54.8 mmol), potassium carbonate (7.57 g, 54.8 mmol), bis (di-tert-butyl (4-dimethylaminophenyl) P
  • Example 51 2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -6-cyclopropyl-3-methoxybenzoic acid (51a) (3S, 10S) -3-tert-butyl-10- (3-cyclopropyl-6-methoxy-2- ⁇ [(4-methoxybenzyl) oxy] methyl ⁇ phenyl) -7,7-dimethyl- 3,4,6,7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 2- (3-cyclopropyl-6- prepared in Example 50b Methoxy-2- ⁇ [(4-methoxybenzyl) oxy] methyl ⁇ benzylidene) -5,5-dimethylcycl
  • Example 52 6-Cyclopropyl-3-methoxy-N- (methylsulfonyl) -2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2 , 3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzamide 6-cyclopropyl-3-methoxy-2 prepared in Example 50 g -[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl] benzoic acid (100 mg, 0.203 mmol) in dichloromethane (2.0 mL) at room temperature with pyridine (26 ⁇ L, 0.324 mmol) and
  • Example 53 2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -6-cyclopropyl-3-methoxy-N- (methylsulfonyl) benzamide 2-[(3S, 10S) -3-tert-butyl prepared in Example 51e -2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl]- 6-cyclopropyl-3-methoxybenzoic acid (30.0 mg, 0.0591 mmol), dichloromethane (0.9 mL), pyridine (11 ⁇ L, 0.130 mmol), cyanuric fluoride (10 ⁇ L, 0.118 m
  • Example 54 3-Methoxy-6- (pyridin-2-yl) -2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3 , 4,6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzoic acid (54a) (3S, 10S) -10- [6-Methoxy-2 - ⁇ [(4-Methoxybenzyl) oxy] methyl ⁇ -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3 -(Propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione prepared in Example 34d 2 -[6-Methoxy-2- ⁇ [(4
  • Example 55 3-Methoxy-2-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -6- (pyridin-2-yl) benzoic acid (55a) 10- [6-Methoxy-2- ⁇ [(4-methoxybenzyl) oxy] methyl ⁇ -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) Phenyl] -3,3,7,7-tetramethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 2- [6-Methoxy-2- ⁇ [(4-methoxybenzyl) oxy] methyl ⁇ -3- (4,4,5,5-tetramethyl-1,3,2-diox
  • Example 56 6- ⁇ 4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3, 4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl] phenyl ⁇ -3-methyl-N- ( Methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt
  • Example 57 6- ⁇ 4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2, 3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ -3,4-dimethylpyridine-2-carboxylic acid tert-Butylamine salt (57a) 3,4-Dimethylpyridine-2-carbonitrile 1-oxide 3,4-Dimethylpyridine-2-carbonitrile (30.0 g, 227 mmol), Oxone (101 g, 363 mmol) in methanol (150 mL) And the water (150 mL) solution was stirred at room temperature for 48 hours.
  • Example 58 6- ⁇ 4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2, 3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ pyridine-2-carboxylic acid tert-butylamine salt (58a) tert-butyl 6- ⁇ 4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propane-2 -Yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ pyridine-2-carboxylic
  • Example 59 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7, 8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butylamine salt (59a) tert-butyl 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4, 4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carbox
  • Example 60 6- ⁇ 4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2, 3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ -4-methylpyridine-2-carboxylic acid tert- Butylamine salt (60a) tert-butyl 6- ⁇ 4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propane-2 -Yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ -4-methylpyridine-2
  • Example 61 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8, 9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butylamine salt
  • 61a 2- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] cyclohexane-1,3-dione 6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde prepared in Example 9a (3.00 g, 10.9 mmol), acet
  • Example 62 4-Methoxy-6- ⁇ 4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl ) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ pyridine-2-carboxylic acid (62a) Ethyl 4-methoxy-6- ⁇ 4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propane -2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ pyridine-2-carboxylic acid
  • Example 63 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ pyridine-2-carboxylic acid tert-butylamine salt (63a) tert-butyl 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2, 3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylpheny
  • Example 64 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -3-cyclopropyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7,8,9 , 10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butylamine salt
  • 64a (6S) -6-cyclopropyl-3- ⁇ (S)-(4,4-dimethyl-2,6-dioxocyclohexyl) [6-methoxy-2-methyl-3- (4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] methyl ⁇ piperidine-2,4-dione 2- [6-Methoxy-2-methyl-3- (prepared in Example 9b) 4,4,5,5-te
  • Example 65 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6,8, 9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2 -Carboxylic acid tert-butylamine salt (65a) (3S, 4aS, 10S, 10aR) -2-ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) phenyl] -3- (propan-2-yl) -3,4,4a, 6,10,10a-hexahydrospiro [chromeno [3,2-c] pyridine-7,
  • Example 66 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7,8, 9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide tert-Butylamine salt 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3, prepared in Example 24b 4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine- A solution of
  • Methanesulfonamide (26.4 mg, 0.278 mmol) and DBU (42 ⁇ L, 0.278 mmol) were added to the reaction solution, and the reaction solution was stirred at room temperature for 1 day.
  • the reaction solution was concentrated, and the residue was crystallized from hexane and ethyl acetate to obtain the title compound (76.5 mg, 61%, 2 steps).
  • Example 72 6- ⁇ 4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3, 4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] phenyl ⁇ -3-methyl-N- (Methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt
  • 72a 6- ⁇ 4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2 , 3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-
  • Example 74 2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxy-6- (4-methyl-1H-pyrazol-1-yl) benzoic acid (74a) (3S, 10S) -3-tert-Butyl-10- [6-methoxy-2- ⁇ [(4-methoxybenzyl) oxy] methyl ⁇ -3- (4-methyl-1H-pyrazole-1- Yl) phenyl] -2,7,7-trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione
  • Example 34f (3S, 10S) -3-tert-butyl-10- [6-methoxy-2- ⁇ [(4
  • Example 76 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7,8, 9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ pyridine-2-carboxylic acid tert-butylamine salt
  • 76a tert-butyl 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ pyridine-2-carboxylate in Example 75a Prepared
  • reaction solution was stirred at 0 ° C. for 3 hours, water was added and the mixture was extracted twice with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude adduct.
  • Example 84 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2-ethyl-7,7-dimethyl-1,9-dioxo-2,3,4,4a, 6,7, 8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ pyridine-2-carboxylic acid tert-butylamine salt (84a) (3S, 4aS, 10S, 10aR) -3-tert-butyl-2-ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c] pyridine-1
  • Example 85 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2-ethyl-7,7-dimethyl-1,9-dioxo-2,3,4,4a, 6,7, 8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -4-methylpyridine-2-carboxylic acid (85a) tert-butyl 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2-ethyl-7,7-dimethyl-1,9-dioxo-2,3,4, 4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -4-methylpyridine-2- Carboxylate (3S
  • Example 86 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -4-methoxy-N- (methylsulfonyl ) Pyridine-2-carboxamide 6- ⁇ 3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propane-2) prepared in Example 82b -Yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-
  • the reaction solution was concentrated, and the concentrated residue was diluted with ethyl acetate.
  • the organic layer was washed twice with 5% aqueous citric acid solution and twice with saturated brine.
  • the organic layer was dried over anhydrous sodium sulfate and concentrated to give the crude title compound (21.5 g, 95%).
  • reaction solution was stirred at 0 ° C. for 3 hours, water was added and the mixture was extracted twice with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound as a mixture of diastereomers.
  • Example 88 2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxynaphthalene-1-carboxylic acid (88a) Ethyl 1-hydroxy-3-methoxynaphthalene-2-carboxylate Ethyl 1,3-dihydroxynaphthalene-2-carboxylate (3.00 g, 12.9 mmol), triphenylphosphine (5.25 g, 20.0 mmol) and methanol ( To a solution of 786 ⁇ L, 19.4 mmol) in THF (90 mL) was added diisopropyl azodicarboxylate (4.01 mL, 20.0 mmol) at 0 ° C., and the reaction solution was stirred at room temperature for 7 hours.
  • Example 89 6- ⁇ 3-[(3R, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H- Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ pyridine-2-carboxylic acid (89a) tert-butyl 6- ⁇ 3-[(3R, 10S) -3- tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ pyridine-2-carboxylate (3R, 10S) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4) prepared in Example 87d 4,5,5-
  • Example 90 6- ⁇ 3-[(3R, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H- Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -4-methylpyridine-2-carboxylic acid (90a) tert-butyl 6- ⁇ 3-[(3R, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9, 10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -4-methylpyridine-2-carboxylate prepared in Example 87d (3R, 10S ) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,
  • Example 94 6- ⁇ 3-[(3R, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H- Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt (94a) 6- ⁇ 3-[(3R, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro -1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide prepared in Example 87f 6 - ⁇ 3
  • Example 98 (3R, 10S) -10- ⁇ 3- [6- (Hydroxymethyl) -5-methylpyridin-2-yl] -6-methoxy-2-methylphenyl ⁇ -7,7-dimethyl-3- (propane- 2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione prepared in Example 11a (3R, 10S) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3- ( Propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (200 mg, 0.374 mmol), ( 6-chloro-3-methylpyridin-2-yl) m
  • Example 99 (10S) -10- ⁇ 3- [6- (Hydroxymethyl) -5-methylpyridin-2-yl] -6-methoxy-2-methylphenyl ⁇ -2,7,7-trimethyl-3- (propane- 2-yl) -6,7,8,10-tetrahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 6- ⁇ 4-methoxy-2-prepared in Example 14c Methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,6,7,8,9,10-hexahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid (357 mg, 0.641 mmol) and carbonyldiimidazole (135 mg, 0.834 mmol) in THF (7.0 mL
  • Example 100 6- ⁇ 3-[(3R, 10S) -3-tert-butyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2- c] Pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid (100a) (3R, 10S) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) phenyl] -3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -1,9 (2H, 8H) -dione prepared in Example 41a 6- [6-Methoxy-2-methyl-3- (4,4,5,5-te
  • Example 104 N- (Ethylsulfonyl) -6- ⁇ 4-methoxy-2-methyl-3-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ -3-methylpyridine-2-carboxamide in Example 10b The prepared 6- ⁇ 4-methoxy-2-methyl-3-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3, 4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid (300 mg, 0.537 mmol), Using carbonyld
  • Example 105 6- ⁇ 3-[(3S, 10S) -1,9-Dioxo-3- (propan-2-yl) -1,2,3,4,6,8,9,10-octahydrospiro [chromeno [ 3,2-c] pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butylamine salt (105a) tert-butyl 6- ⁇ 3-[(3S, 10S) -1,9-dioxo-3- (propan-2-yl) -1,2,3,4,6,8,9,10- Octahydrospiro [chromeno [3,2-c] pyridine-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylate
  • Example 77b (3S, 10S) -10- [
  • Example 10-7 6-Cyclopropyl-N- (cyclopropylsulfonyl) -3-methoxy-2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl)- 2,3,4,6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzamide 6-cyclopropyl-3-methoxy-prepared in Example 50 g 2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10-octahydro -1H-chromeno [3,2-c] pyridin-10-yl] benzoic acid (30.0 mg, 0.0608 mmol) in dichloromethane (0.6 mL) at 0 ° C.
  • Example 109 6-Cyclopropyl-N- (2-hydroxyethyl) -3-methoxy-2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzamide 6-cyclopropyl-3-methoxy prepared in Example 50g -2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzoic acid (40.0 mg, 0.0810 mmol) in dichloromethane (0.4 mL) at 0 ° C.
  • Example 110 6- ⁇ 4-Methoxy-2-methyl-3- [2,3,3-trimethyl-1,9-dioxo-7- (propan-2-yl) -2,3,4,6,7,8, 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid (110a) 2- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] -5- (propane-2- Yl) cyclohexane-1,3-dione 6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde prepared in Example 9a (2.00 g, 7.24 mmol), acetonitrile (10 mL), 5- (propan-2-yl)
  • Example 111 7-[(10S) -2-Ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [ 3,2-c] pyridin-10-yl] -2,4-dimethyl-1-benzofuran-5-carboxylic acid or 7-[(10R) -2-ethyl-3,3,7,7-tetramethyl -1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -2,4-dimethyl-1- Benzofuran-5-carboxylic acid (111a) Benzyl 7-[(10S) -2-ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H
  • Example 113 7-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -2,4-dimethyl-1-benzofuran-5-carboxylic acid (113a) Benzyl 7-[(4,4-dimethyl-2,6-dioxocyclohexylidene) methyl] -2,4-dimethyl-1-benzofuran-5-carboxylate The benzyl 7- prepared in Example 102b Dimedone (1.04 g, 7.42 mmol) in a solution of formyl-2,4-dimethyl-1-benzofuran-5-carboxylate (2.00 g, 6.49 mmol) and pyrrolidine (590 ⁇ L, 7.20 mmol) in toluene (20 mL) at
  • Example 115 6- ⁇ 3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-7,1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid or 6- ⁇ 3-[(10R)- 2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1 ' -Cyclobutane] -10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid (115a) 10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,
  • reaction solution was stirred at room temperature for 3 hours, 4 M hydrochloric acid (ethyl acetate solution, 61 mL, 244 mmol) was added to the reaction solution at 0 ° C., and the reaction solution was stirred at room temperature for 6 hours.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction twice with ethyl acetate, and then the organic layer was concentrated under reduced pressure. The concentrated residue was crystallized from hexane / ethyl acetate (2: 1) to obtain the title compound (7.38 g, 85%).
  • Example 116 6- ⁇ 3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-7,1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid or 6- ⁇ 3-[(10R)- 2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1 ' -Cyclobutane] -10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butyl 6- ⁇ 3-[(10S) -2-ethyl prepared in Example 115d
  • Example 117 6- ⁇ 3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid or 6- ⁇ 3-[(10R) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1 '-Cyclopropane] -10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid (117a) 10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,
  • Example 120 6- ⁇ 3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid or 6- ⁇ 3-[(10R) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1 '-Cyclopropane] -10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butyl 6- ⁇ 3-[(10S) -2 prepared in Example 117d -Ethyl-3,
  • Example 121 6- ⁇ 3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-7,1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide or 6- ⁇ 3 -[(10R) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] Pyridine-7,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide 6- ⁇ 3 prepared in Example 115
  • Example 122 6- ⁇ 3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-7,1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide or 6- ⁇ 3 -[(10R) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] Pyridine-7,1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide 6- ⁇ 3 prepared in Example 116
  • Example 123 6- ⁇ 3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide or 6- ⁇ 3-[(10R) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c ] Pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide 6-prepared in Example 117e ⁇ 3
  • Example 124 6- ⁇ 3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide or 6- ⁇ 3-[(10R) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c ] Pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide 6- ⁇ 3-[(10S) -2
  • Example 125 6- ⁇ 4-Methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-3,1'-cyclobutane] -10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid or 6- ⁇ 4-methoxy-2-methyl-3 -[(10R) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine- 3,1'-Cyclobutane] -10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid (125a) Benzyl 6- [4-methoxy-2-methyl-3- (2,7,7-trimethyl-1,9-dioxo
  • the reaction solution was stirred for 1 hour at room temperature, aqueous sodium thiosulfate solution was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to give the crude title compound.
  • reaction solution was stirred for 1 hour at 0 ° C., aqueous ammonium chloride solution was added, and the mixture was extracted twice with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (114 mg, 95%, 2 steps).
  • Example 12-7 3-[(3S, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -4-methoxybiphenyl-2-carboxylic acid (127a) (3S, 10S) -10- (1-Hydroxy-5-methoxy-1,3-dihydro-2,1-benzoxabolol-4-yl) -7,7-dimethyl-3- (propane -2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 2- [6 prepared in Example 34d -Methoxy-2- ⁇ [(4-methoxybenzyl) oxy] methyl ⁇ -3- (4,4,5,5-tetra
  • the reaction solution was stirred at 0 ° C. for 3 hours, water was added and the mixture was extracted twice with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude adduct.
  • ethyl acetate 20 mL
  • 4 M hydrochloric acid (1,4-dioxane solution; 2.0 mL
  • Example 130 6- ⁇ 4-Methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-3,1'-cyclopropane] -10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butylamine salt or 6- ⁇ 4-methoxy- 2-Methyl-3-[(10R) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2 -c] pyridine-3,1'-cyclopropane] -10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butylamine salt (130a) 10- [6-Methoxy-2-methyl-3- (4
  • reaction solution was stirred at room temperature for 5 hours, water (120 mL) was added to the reaction solution at 0 ° C., and the precipitated solid was collected by filtration to give an adduct.
  • N-phenylbis (trifluoromethanesulfonimide) (1.43 g, 4.00 mmol) was added to a DMF (18 mL) solution of the adduct and cesium carbonate (2.71 g, 8.33 mmol) at room temperature, and the reaction solution was stirred at room temperature for 24 hours. did.
  • Example 131 6- ⁇ 4-Methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-3,1'-cyclopropane] -10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butylamine salt or 6- ⁇ 4-methoxy- 2-Methyl-3-[(10R) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2 -c] pyridine-3,1'-cyclopropane] -10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butylamine salt (131a) 6- ⁇ 4-Methoxy-2-methyl-3-[(
  • Example 132 6- ⁇ 4-Methoxy-2-methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid or 6- ⁇ 4-methoxy-2-methyl-3 -[(10R) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine- 7,1'-Cyclobutane] -10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid (132a) 10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
  • Example 133 6- ⁇ 4-Methoxy-2-methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butylamine salt or 6- ⁇ 4-methoxy-2 -Methyl-3-[(10R) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2- c] Pyridine-7,1'-cyclobutane] -10-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butylamine salt (133a) 6- ⁇ 4-Methoxy-2-methyl-3-[(10S)

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Abstract

The present invention relates to a compound, or a pharmacologically acceptable salt thereof, that is represented by general formula (I) and that has excellent hypoglycemic action. [In the formula, double lines that include a broken line indicate a single bond or a double bond, R1 is a hydrogen atom, a C1-3 alkyl group, or the like, R2 is a hydrogen atom, a C1-3 alkyl group, or the like, R3 is a hydrogen atom, a C1-6 alkyl group, or the like, R4 is a hydrogen atom, a C1-6 alkyl group, or the like, R5 is a hydrogen atom or the like, R6 is a C2-6 alkyl group or the like, R7 is a hydrogen atom or the like, V is -CH2- or -C(=O)-, W is a phenyl group or the like that may be substituted with 1-4 identical or different substituents selected from substituent group α, substituent group α comprises C1-3 alkyl groups or the like, X is -CH=, -CH2-, -O-, or -N=, Y is -CR3R4-, -NR5- or -CR6=, and Z is -CH2-, -O-, or -NR7-, provided that when V is -C(=O)- and X and Z are -CH2-, Y is not -CR3R4-.]

Description

６員ヘテロ環誘導体6-membered heterocyclic derivatives
　本発明は、血糖低下等の作用を有し、糖尿病等の治療薬及び／又は予防薬として有用な新規な化合物及びその薬理上許容される塩に関する。 The present invention relates to a novel compound having an action such as lowering blood sugar and useful as a therapeutic and / or prophylactic agent for diabetes and the like and a pharmacologically acceptable salt thereof.
　本発明は、上記化合物又はその薬理上許容される塩を有効成分として含有する糖尿病（1型糖尿病、2型糖尿病、妊娠糖尿病等）、食後過血糖症、耐糖能障害、糖尿病性神経障害、糖尿病性腎症、糖尿病性網膜症、高脂血症、動脈硬化症、血栓性疾患、肥満、高血圧、浮腫、インスリン抵抗性、不安定糖尿病、インスリノーマ、高インスリン血症等の治療薬及び／又は予防薬（好適には糖尿病の治療薬及び／又は予防薬である）に関する。 The present invention includes diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), postprandial hyperglycemia, impaired glucose tolerance, diabetic neuropathy, diabetes containing the above compound or a pharmacologically acceptable salt thereof as an active ingredient Therapeutic and / or prevention for diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, hyperinsulinemia, etc. The present invention relates to a drug (preferably a therapeutic and / or preventive for diabetes).
　更に、本発明は、上記化合物又はその薬理上許容される塩を有効成分として含有する上記疾病の予防若しくは治療のための組成物、上記疾病の予防若しくは治療のための医薬を製造するための上記化合物の使用、又は上記化合物の薬理的な有効量を哺乳動物（好適には人間である）に投与する上記疾病の予防若しくは治療方法に関する。 Furthermore, the present invention provides a composition for preventing or treating the above-mentioned disease containing the above compound or a pharmacologically acceptable salt thereof as an active ingredient, and the above-mentioned pharmaceutical composition for producing a medicament for preventing or treating the above-mentioned disease. The present invention relates to the use of a compound, or a method for preventing or treating the above disease, wherein a pharmacologically effective amount of the above compound is administered to a mammal (preferably a human).
　糖尿病は、慢性的な高血糖を主徴とする疾患であり、インスリン作用の絶対的または相対的な不足により発症する。臨床においてはその特徴からインスリン依存性糖尿病（1型糖尿病）とインスリン非依存性糖尿病（2型糖尿病）に大別される。 Diabetes is a disease whose main feature is chronic hyperglycemia, and develops due to an absolute or relative lack of insulin action. In clinical practice, it is roughly divided into insulin-dependent diabetes (type 1 diabetes) and non-insulin-dependent diabetes (type 2 diabetes).
　現在、糖尿病の治療は基本的に食事療法と運動療法である。しかし、これらだけで血糖値をコントロールできなくなった場合、薬物が投与される。そこで、より安全で効果の高い薬剤が求められている。 Currently, diabetes treatment is basically diet therapy and exercise therapy. However, if the blood sugar level cannot be controlled by these alone, a drug is administered. Therefore, there is a demand for safer and more effective drugs.
　特許文献１及び２には、本発明の化合物と一部共通する部分構造を有する化合物が開示されている。 Patent Documents 1 and 2 disclose compounds having a partial structure partially in common with the compound of the present invention.
国際公開第2014/061764号パンフレットInternational Publication No. 2014/061764 Pamphlet 国際公開第2014/142127号パンフレット（対応する米国特許番号：US8975263）International Publication No. 2014/142127 Pamphlet (Corresponding US Patent Number: US8975263)
　本発明者らは、鋭意研究を重ねた結果、後記式(I)で表わされる化合物がその特異的な化学構造に基づいて、薬物動態面において優れた性質を有することで、非常に優れた血糖低下等の作用活性を有し、更に安定性等の医薬品としての物性においても優れた性質を有しており、高血糖症、糖尿病及びそれら疾病に関連する病態または疾患の予防・治療薬として安全でかつ有用な医薬となることを見出し、これらの知見に基づいて本発明を完成した。 As a result of extensive research, the present inventors have found that the compound represented by the formula (I) described below has excellent properties in terms of pharmacokinetics based on its specific chemical structure, resulting in extremely excellent blood glucose. It has an activity such as lowering, and has excellent physical properties as a pharmaceutical product such as stability, and is safe as a prophylactic / therapeutic agent for hyperglycemia, diabetes and pathologies or diseases related to those diseases The present invention was completed based on these findings.
　即ち、本発明の化合物は、血糖降下作用等を有し糖尿病（1型糖尿病、2型糖尿病、妊娠糖尿病等）、食後過血糖症、耐糖能障害、糖尿病性神経障害、糖尿病性腎症、糖尿病性網膜症、高脂血症、動脈硬化症、血栓性疾患、肥満、高血圧、浮腫、インスリン抵抗性、不安定糖尿病、インスリノーマ、高インスリン血症などの疾患、特に、2型糖尿病に対する予防・治療剤として有用である。 That is, the compound of the present invention has a hypoglycemic action and the like, such as diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), postprandial hyperglycemia, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetes Prevention, treatment for diseases such as retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, hyperinsulinemia, especially type 2 diabetes Useful as an agent.
　本発明は、
（１）下記一般式（I） The present invention
(1) The following general formula (I)
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
［式中、破線を含む二重線は、単結合又は二重結合を示し、
R1は、水素原子、C1-C3アルキル基又はC3-C6シクロアルキル基を示し、
R2は、水素原子若しくはC1-C3アルキル基を示すか又は、R1のC1-C3アルキル基と結合して 3-6員飽和炭素環を形成していてもよく、
Vは、-CH2-又は-C(=O)-を示し、
Wは、フェニル基（該フェニル基は、置換基群αより選択される同一または異なった1-4個の置換基で置換されていても良い）、ビフェニル基（該ビフェニル基は、置換基群αより選択される同一または異なった1-8個の置換基で置換されていても良い）、窒素、酸素及び硫黄から選択される同一若しくは異なった1-4個のヘテロ原子を含む5-10員ヘテロアリールフェニル基（該ヘテロアリールフェニル基は、置換基群αより選択される同一または異なった1-8個の置換基で置換されていても良い）、7-ベンゾフラニル基（該7-ベンゾフラニル基は、置換基群αより選択される同一または異なった1-4個の置換基で置換されていても良い）又は、ナフチル基（該ナフチル基は、置換基群αより選択される同一または異なった1-4個の置換基で置換されていても良い）を示し、
Xは、-CH=、-CH2-、-O- 又は -N=を示し、
Yは、  [In the formula, a double line including a broken line represents a single bond or a double bond,
R 1 represents a hydrogen atom, a C1-C3 alkyl group or a C3-C6 cycloalkyl group,
R 2 represents a hydrogen atom or a C1-C3 alkyl group, or may combine with the C1-C3 alkyl group of R 1 to form a 3-6 membered saturated carbocycle,
V represents —CH 2 — or —C (═O) —,
W is a phenyl group (the phenyl group may be substituted with the same or different 1-4 substituents selected from the substituent group α), a biphenyl group (the biphenyl group is a substituent group) 5-10 containing the same or different 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted with the same or different 1-8 substituents selected from α) A membered heteroarylphenyl group (the heteroarylphenyl group may be substituted with the same or different 1-8 substituents selected from the substituent group α), a 7-benzofuranyl group (the 7-benzofuranyl group) Group may be substituted with the same or different 1-4 substituents selected from substituent group α) or a naphthyl group (the naphthyl group is the same or selected from substituent group α) May be substituted with 1-4 different substituents )
X represents -CH =, -CH 2- , -O- or -N =,
Y is
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
、-N(-R5)-又は-C(-R6)=を示し、
R3は、水素原子、C1-C6アルキル基又はC3-C6シクロアルキル基を示し、
R4は、水素原子若しくはC1-C6アルキル基を示すか又は、R3のC1-C6アルキル基と結合して3-6員飽和炭素環を形成していてもよく、
R5は、水素原子、C1-C6 アルキル基又はC3-C6シクロアルキル基を示し、
R6は、C2-C6 アルキル基又はC3-C6シクロアルキル基を示し、
Zは、-CH2-、-O-又は-N(-R7)-を示し、
R7は、水素原子、C1-C6 アルキル基、ヒドロキシC1-C3アルキル基、C1-C3アルコキシC1-C3アルキル基、カルボキシC1-C3アルキル基、ハロC1-C3アルキル基、C2-C6アルケニル基、C2-C6 アルキニル基又はC3-C6シクロアルキル基を示す。
ただし、 V が-C(=O)-を示し、かつX及びZが-CH2-を示す場合、Yは , -N (-R 5 )-or -C (-R 6 ) =
R 3 represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group,
R 4 represents a hydrogen atom or a C1-C6 alkyl group, or may combine with the C1-C6 alkyl group of R 3 to form a 3-6 membered saturated carbocycle,
R 5 represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group,
R 6 represents a C2-C6 alkyl group or a C3-C6 cycloalkyl group,
Z represents -CH 2- , -O- or -N (-R 7 )-,
R 7 is a hydrogen atom, a C1-C6 alkyl group, a hydroxy C1-C3 alkyl group, a C1-C3 alkoxy C1-C3 alkyl group, a carboxy C1-C3 alkyl group, a halo C1-C3 alkyl group, a C2-C6 alkenyl group, C2-C6 represents an alkynyl group or a C3-C6 cycloalkyl group.
However, when V represents -C (= O)-and X and Z represent -CH 2- , Y is
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
ではない。
＜置換基群α＞
C1-C3アルキル基（該アルキル基は、水酸基で1個置換されていてもよい）、
C3-C6シクロアルキル基（該シクロアルキル基は、C1-C3アルキル基又はカルボキシル基で1個置換されていてもよい）、C1-C3アルコキシ基、カルバモイル基（該カルバモイル基は、C1-C3アルコキシ基で1個置換されていてもよいC1-C3アルキルスルホニル基、C3-C6シクロアルキルスルホニル基又は、ヒドロキシC1-C3アルキル基で1個置換されていてもよい）、窒素、酸素及び硫黄から選択される同一若しくは異なった1-4個のヘテロ原子を含む3-10員ヘテロシクリル基、窒素、酸素及び硫黄から選択される同一若しくは異なった1-4個のヘテロ原子を含む3-10員ヘテロシクリルカルボニル基、アミノ基（該アミノ基は、C1-C3アルキルスルホニル基、C1-C3アルキルカルボニル基又はカルボキシC1-C3アルキル基で1個置換されていてもよい）、ハロゲン原子、カルボキシル基、水酸基及びシアノ基］で表される化合物又はその薬理上許容される塩、
（２）R1が、C1-C3アルキル基であり、R2が、C1-C3アルキル基であるか又は、R1のC1-C3アルキル基と結合して 3-6員飽和炭素環を形成していてもよい、上記（１）に記載の化合物若しくはその薬理上許容される塩、
（３）R3が、C1-C6アルキル基であり、R4が、C1-C6アルキル基であるか又は、R3のC1-C6アルキル基と結合して3-6員飽和炭素環を形成していてもよい、上記（１）又は（２）に記載の化合物若しくはその薬理上許容される塩、
（４）Zが、-N(-R7)-であり、Xが、-CH=又は-CH2-である、上記（１）乃至（３）から選択されるいずれか１つに記載の化合物又はその薬理上許容される塩、
（５）
　Zが、-N(-R7)-であり、Yが、 is not.
<Substituent group α>
A C1-C3 alkyl group (the alkyl group may be substituted with one hydroxyl group),
C3-C6 cycloalkyl group (the cycloalkyl group may be substituted with one C1-C3 alkyl group or carboxyl group), C1-C3 alkoxy group, carbamoyl group (the carbamoyl group is C1-C3 alkoxy) Selected from a C1-C3 alkylsulfonyl group, a C3-C6 cycloalkylsulfonyl group, or a hydroxy C1-C3 alkyl group optionally substituted by one group), nitrogen, oxygen and sulfur A 3-10 membered heterocyclyl group containing the same or different 1-4 heteroatoms, selected from nitrogen, oxygen and sulfur, or a 3-10 membered heterocyclylcarbonyl containing the same or different 1-4 heteroatoms A group, an amino group (the amino group may be substituted by a C1-C3 alkylsulfonyl group, a C1-C3 alkylcarbonyl group or a carboxy C1-C3 alkyl group), a halogen atom, a carboxy Group, a hydroxyl group and a compound represented by the cyano group] or a pharmacologically acceptable salt thereof,
(2) R 1 is a C1-C3 alkyl group and R 2 is a C1-C3 alkyl group or is bonded to the C1-C3 alkyl group of R 1 to form a 3-6 membered saturated carbocycle A compound or a pharmacologically acceptable salt thereof according to (1), which may be
(3) R 3 is a C1-C6 alkyl group and R 4 is a C1-C6 alkyl group or is bonded to a C1-C6 alkyl group of R 3 to form a 3-6 membered saturated carbocycle A compound or a pharmacologically acceptable salt thereof according to (1) or (2), which may be
(4) The device according to any one of (1) to (3), wherein Z is —N (—R 7 ) —, and X is —CH═ or —CH 2 —. A compound or a pharmacologically acceptable salt thereof,
(5)
Z is -N (-R 7 )-and Y is
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
であり、Xが、-CH2-である、上記（１）乃至（４）から選択されるいずれか１つに記載の化合物又はその薬理上許容される塩、
（６）R7が、C1-C6 アルキル基である、上記（１）乃至（５）から選択されるいずれか１つに記載の化合物又はその薬理上許容される塩、
（７）R7が、メチル基又はエチル基である、上記（１）乃至（５）から選択されるいずれか１つに記載の化合物又はその薬理上許容される塩、
（８）Wが、窒素、酸素及び硫黄から選択される同一若しくは異なった1-4個のヘテロ原子を含む5-10員ヘテロアリールフェニル基（該ヘテロアリールフェニル基は、置換基群αより選択される同一または異なった1-8個の置換基で置換されていても良い）である、上記（１）乃至（７）から選択されるいずれか１つに記載の化合物又はその薬理上許容される塩、
（９）Wが、ピリジルフェニル基（該ピリジルフェニル基は、C1-C3アルキル基、C1-C3アルコキシ基及びカルボキシル基から選ばれる3～4個の置換基で置換されていても良い）である、上記（１）乃至（７）から選択されるいずれか１つに記載の化合物又はその薬理上許容される塩、
（１０）6-{3-[(3S,10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、
6-{3-[(10R)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、6-{3-[(10S)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、
6-{4-メトキシ-2-メチル-3-[(3S,10S)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、6-{3-[(3S,10S)-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、又は、
6-{4-メトキシ-2-メチル-3-[(10S)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,6,8,9,10-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、
（１１）6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、
6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、
6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、
6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、
（１２）6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、
6-{4-メトキシ-2-メチル-3-[(10R)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、
6-{3-[(10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、6-{3-[(10R)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、
6-{3-[(10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、又は、6-{3-[(10R)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、
（１３）6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、
6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロブタン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロブタン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、
6-{4-メトキシ-2-メチル-3-[(10'S)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸、6-{4-メトキシ-2-メチル-3-[(10'R)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸、
6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、
6-{4-メトキシ-2-メチル-3-[(10'S)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸、6-{4-メトキシ-2-メチル-3-[(10'R)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸、
6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、又は、6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、
（１４）6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルl-N-(メチルスルホニル)ピリジン-2-カルボキサミド、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルl-N-(メチルスルホニル)ピリジン-2-カルボキサミド、6-{3-[(3R,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、6-{4-メトキシ-2-メチル-3-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド、6-{3-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、6-{3-[(10S)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド、6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド、又は、6-{3-[(3S,10S)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、
（１５）6-{3-[(3S,10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド、6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド、6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド、6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド、6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド、6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド、又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド、
（１６）上記（１０）乃至（１５）のいずれか１つに記載の化合物又はその薬理上許容される塩、
（１６－１）上記（１０）乃至（１５）のいずれか１つに記載の化合物のtert-ブチルアミン塩、
（１７）上記（１）乃至（１６－１）のいずれか１つに記載の化合物又はその薬理上許容される塩を有効成分として含有する血糖降下剤、
（１８）上記（１）乃至（１６－１）のいずれか１つに記載の化合物又はその薬理上許容される塩を有効成分として含有する医薬、
（１９）糖尿病、食後過血糖症、耐糖能障害、糖尿病性神経障害、糖尿病性腎症、糖尿病性網膜症、高脂血症、動脈硬化症、血栓性疾患、肥満、高血圧、浮腫、インスリン抵抗性、不安定糖尿病、インスリノーマ又は高インスリン血症の治療若しくは予防のための、上記（１８）に記載の医薬、
（１９－１）糖尿病、食後過血糖症又は耐糖能障害の治療若しくは予防のための、上記（１８）に記載の医薬、
（１９－２）2型糖尿病の治療又は予防のための、上記（１８）に記載の医薬、
（２０）2型糖尿病の治療のための、上記（１８）に記載の医薬、
（２１）医薬組成物を製造するための、上記（１）乃至（１５）から選択されるいずれか１つに記載された化合物又はその薬理上許容される塩の使用、
（２１－１）2型糖尿病の治療のための医薬組成物を製造するための、上記（１）乃至（１５）から選択されるいずれか１つに記載された化合物又はその薬理上許容される塩の使用、
（２２）上記（１）乃至（１５）から選択されるいずれか１つに記載された化合物又はその薬理上許容される塩の薬理的な有効量を温血動物に投与することを含む、2型糖尿病の治療又は予防方法、
（２３）疾患の治療若しくは予防のための方法における使用のための、請求項（１）乃至（１５）から選択されるいずれか１つに記載された化合物又はその薬理上許容される塩。
（２３－１）疾患が、糖尿病、食後過血糖症、耐糖能障害、糖尿病性神経障害、糖尿病性腎症、糖尿病性網膜症、高脂血症、動脈硬化症、血栓性疾患、肥満、高血圧、浮腫、インスリン抵抗性、不安定糖尿病、インスリノーマ又は高インスリン血症である、上記（２３）に記載された化合物又はその薬理上許容される塩。
（２３－２）疾患が、2型糖尿病である、上記（２３）に記載された化合物又はその薬理上許容される塩。
（２４）下記一般式（I） And the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof, wherein X is —CH 2 —
(6) The compound according to any one of (1) to (5) or a pharmacologically acceptable salt thereof, wherein R 7 is a C1-C6 alkyl group,
(7) The compound according to any one of (1) to (5) or a pharmacologically acceptable salt thereof, wherein R 7 is a methyl group or an ethyl group,
(8) W is a 5- to 10-membered heteroarylphenyl group containing 1-4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur (the heteroarylphenyl group is selected from the substituent group α) Which may be substituted with the same or different 1-8 substituents), or a pharmacologically acceptable compound thereof according to any one selected from (1) to (7) above Salt,
(9) W is a pyridylphenyl group (the pyridylphenyl group may be substituted with 3 to 4 substituents selected from a C1-C3 alkyl group, a C1-C3 alkoxy group and a carboxyl group). Any one of the compounds selected from (1) to (7) above or a pharmacologically acceptable salt thereof,
(10) 6- {3-[(3S, 10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7 , 8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid,
6- {3-[(10R) -2-ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid, 6- {3-[(10S) -2-ethyl- 3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl ] -4-Methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid,
6- {4-Methoxy-2-methyl-3-[(3S, 10S) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,6, 8,9,10-Octahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid, 6- {3 -[(3S, 10S) -1,9-dioxo-3- (propan-2-yl) -1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2- c] pyridine-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid, 6- {4-methoxy-2-methyl-3 -[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine- 7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid, 6- {4-methoxy-2-methyl-3-[(10R) -2,3,3-trimethyl -1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl } -3-Methylpyridi -2-carboxylic acid, or
6- {4-Methoxy-2-methyl-3-[(10S) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,6,8,9,10- Hexahydrospiro [chromeno [3,2-c] pyridine-7,1′-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid,
(11) 6- {3-[(10S) -2-ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid, 6- {3-[(10R ) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7, 1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid,
6- {3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] Pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid, 6- {3-[(10R)- 2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1 ' -Cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid,
6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid, 6- {4-methoxy-2-methyl-3 -[(10R) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine- 7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid,
6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2-methyl- 3-[(10R) -2,3,3-Trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine -7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid,
(12) 6- {4-Methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10 -Octahydrospiro [chromeno [3,2-c] pyridine-3,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid,
6- {4-Methoxy-2-methyl-3-[(10R) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-3,1′-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid,
6- {3-[(10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-3,1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid, 6- {3-[(10R) -2 -Ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-3,1'- Cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid,
6- {3-[(10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-3,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid or 6- {3-[(10R ) -2-Ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-3, 1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid,
(13) 6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H- Dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine -2-carboxylic acid, 6- {3-[(10'R) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro -2'H-dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridin-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid,
6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H-dispiro [cyclobutane -1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclobutane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid Acid, 6- {3-[(10'R) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H -Dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclobutane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine -2-carboxylic acid,
6- {4-Methoxy-2-methyl-3-[(10'S) -2'-methyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro -2'H-Disspiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3 ', 1''-cyclopropane]-10'-yl] phenyl} -3-methylpyridine-2- Carboxylic acid, 6- {4-methoxy-2-methyl-3-[(10'R) -2'-methyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9' , 10'-Hexahydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3 ', 1''-cyclopropane]-10'-yl] phenyl} -3- Methylpyridine-2-carboxylic acid,
6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H-dispiro [cyclobutane -1,7'-chromeno [3,2-c] pyridine-3 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2- Carboxylic acid, 6- {3-[(10'R) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2 ' H-Disspiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl} -3- Methylpyridine-2-carboxylic acid,
6- {4-Methoxy-2-methyl-3-[(10'S) -2'-methyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro -2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] phenyl} -3-methylpyridine-2 -Carboxylic acid, 6- {4-methoxy-2-methyl-3-[(10'R) -2'-methyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9 ', 10'-Hexahydro-2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclopropane] -10'-yl] phenyl}- 3-methylpyridine-2-carboxylic acid,
6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H-dispiro [cyclo Propane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2 -Carboxylic acid or 6- {3-[(10'R) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro -2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl } -3-Methylpyridine-2-carboxylic acid,
(14) 6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8 , 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid, 6- {4-methoxy-2-methyl-3- [ (10R) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] Pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid, 6- {4-methoxy-2-methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1 , 9-Dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methyllN- (methylsulfonyl ) Pyridine-2-carboxamide, 6- {4-methoxy-2-methyl-3-[(10R) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6 , 7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methyllN- (methylsulfonyl) pyridine-2-carboxamide, 6- {3- [(3R, 10S) -7,7-Di Methyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridine-10- Yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid, 6- {4-methoxy-2-methyl-3-[(3S, 10S) -2,7,7-trimethyl -1,9-Dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl ] Phenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide, 6- {3-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9- Dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl Pyridine-2-carboxylic acid, 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6,8,9,10,10a-decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] phenyl} -3-Methylpyridine- 2-carboxylic acid, 6- {3-[(10S) -2-ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9, 10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide, 6- { 4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a , 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl] phenyl} -3-methyl-N- (methylsulfonyl) Pyridine-2-carboxamide or 6- {3-[(3S, 10S) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,6, 8,9,10-Octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2 -carboxylic acid,
(15) 6- {3-[(3S, 10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7 , 8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2- Carboxamide, 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7, 8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2 -Carboxamide, 6- {3-[(10S) -2-ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide, 6 -{3-[(10R) -2-ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2 -c] Pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide, 6- {4-methoxy-2 -Methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2- c] Pyridine-7,1'-cyclobutane] -10-yl] phenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide, 6- {4-methoxy-2-methyl-3-[( 10R) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1 '-Cyclobutane] -10-yl] phenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide, 6- {4-methoxy-2-methyl-3-[(10S) -2,3, 3-Trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10 -Yl] phenyl} -3-methyl-N- (methylsulfonyl) pyridine-2- Ruboxamide or 6- {4-methoxy-2-methyl-3-[(10R) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9, 10-octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] phenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide,
(16) The compound according to any one of (10) to (15) above or a pharmacologically acceptable salt thereof,
(16-1) a tert-butylamine salt of the compound according to any one of (10) to (15) above,
(17) A hypoglycemic agent comprising the compound according to any one of (1) to (16-1) above or a pharmacologically acceptable salt thereof as an active ingredient,
(18) A pharmaceutical comprising the compound according to any one of (1) to (16-1) or a pharmacologically acceptable salt thereof as an active ingredient,
(19) Diabetes, postprandial hyperglycemia, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance The medicament according to (18) above for the treatment or prevention of sex, unstable diabetes, insulinoma or hyperinsulinemia,
(19-1) The medicament according to the above (18) for the treatment or prevention of diabetes, postprandial hyperglycemia or impaired glucose tolerance,
(19-2) The medicament according to (18) above for the treatment or prevention of type 2 diabetes,
(20) The medicament according to (18) above for the treatment of type 2 diabetes,
(21) Use of the compound described in any one of (1) to (15) or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition,
(21-1) A compound described in any one of (1) to (15) or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition for the treatment of type 2 diabetes The use of salt,
(22) comprising administering to a warm-blooded animal a pharmacologically effective amount of the compound described in any one of (1) to (15) above or a pharmacologically acceptable salt thereof, Treatment or prevention of type 2 diabetes,
(23) The compound or a pharmaceutically acceptable salt thereof according to any one of claims (1) to (15) for use in a method for treatment or prevention of a disease.
(23-1) The disease is diabetes, postprandial hyperglycemia, glucose intolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension , Edema, insulin resistance, unstable diabetes, insulinoma or hyperinsulinemia, or a pharmacologically acceptable salt thereof according to (23) above.
(23-2) The compound or pharmacologically acceptable salt thereof described in (23) above, wherein the disease is type 2 diabetes.
(24) The following general formula (I)
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
［式中、破線を含む二重線は、単結合又は二重結合を示し、
R1は、水素原子、C1-C3アルキル基又はC3-C6シクロアルキル基を示し、
R2は、水素原子若しくはC1-C3アルキル基を示すか又は、R1のC1-C3アルキル基と結合して 3-6員飽和炭素環を形成していてもよく、
Vは、-CH2-又は-C(=O)-を示し、
Wは、フェニル基（該フェニル基は、置換基群αより選択される同一または異なった1-4個の置換基で置換されていても良い）、ビフェニル基（該ビフェニル基は、置換基群αより選択される同一または異なった1-8個の置換基で置換されていても良い）、窒素、酸素及び硫黄から選択される同一若しくは異なった1-4個のヘテロ原子を含む5-10員ヘテロアリールフェニル基（該ヘテロアリールフェニル基は、置換基群αより選択される同一または異なった1-8個の置換基で置換されていても良い）、7-ベンゾフラニル基（該7-ベンゾフラニル基は、置換基群αより選択される同一または異なった1-4個の置換基で置換されていても良い）又は、ナフチル基（該ナフチル基は、置換基群αより選択される同一または異なった1-4個の置換基で置換されていても良い）を示し、
Xは、-CH=、-CH2-、-O- 又は -N=を示し、
Yは、 [In the formula, a double line including a broken line represents a single bond or a double bond,
R 1 represents a hydrogen atom, a C1-C3 alkyl group or a C3-C6 cycloalkyl group,
R 2 represents a hydrogen atom or a C1-C3 alkyl group, or may combine with the C1-C3 alkyl group of R 1 to form a 3-6 membered saturated carbocycle,
V represents —CH 2 — or —C (═O) —,
W is a phenyl group (the phenyl group may be substituted with the same or different 1-4 substituents selected from the substituent group α), a biphenyl group (the biphenyl group is a substituent group) 5-10 containing the same or different 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted with the same or different 1-8 substituents selected from α) A membered heteroarylphenyl group (the heteroarylphenyl group may be substituted with the same or different 1-8 substituents selected from the substituent group α), a 7-benzofuranyl group (the 7-benzofuranyl group) Group may be substituted with the same or different 1-4 substituents selected from substituent group α) or a naphthyl group (the naphthyl group is the same or selected from substituent group α) May be substituted with 1-4 different substituents )
X represents -CH =, -CH 2- , -O- or -N =,
Y is
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
、-N(-R5)-又は-C(-R6)=を示し、
R3は、水素原子、C1-C6アルキル基又はC3-C6シクロアルキル基を示し、
R4は、水素原子若しくはC1-C6アルキル基を示すか又は、R3のC1-C6アルキル基と結合して3-6員飽和炭素環を形成していてもよく、
R5は、水素原子、C1-C6 アルキル基又はC3-C6シクロアルキル基を示し、
R6は、C2-C6 アルキル基又はC3-C6シクロアルキル基を示し、
Zは、-CH2-、-O-又は-N(-R7)-を示し、
R7は、水素原子、C1-C6 アルキル基、ヒドロキシC1-C3アルキル基、カルボキシC1-C3アルキル基、C2-C6アルケニル基、C2-C6 アルキニル基又はC3-C6シクロアルキル基を示す。
ただし、 V が-C(=O)-を示し、かつX及びZが-CH2-を示す場合、Yは , -N (-R 5 )-or -C (-R 6 ) =
R 3 represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group,
R 4 represents a hydrogen atom or a C1-C6 alkyl group, or may combine with the C1-C6 alkyl group of R 3 to form a 3-6 membered saturated carbocycle,
R 5 represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group,
R 6 represents a C2-C6 alkyl group or a C3-C6 cycloalkyl group,
Z represents -CH 2- , -O- or -N (-R 7 )-,
R 7 represents a hydrogen atom, a C1-C6 alkyl group, a hydroxy C1-C3 alkyl group, a carboxy C1-C3 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group or a C3-C6 cycloalkyl group.
However, when V represents -C (= O)-and X and Z represent -CH 2- , Y is
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
ではない。
＜置換基群α＞
C1-C3アルキル基（該アルキル基は、水酸基で1個置換されていてもよい）、
C3-C6シクロアルキル基（該シクロアルキル基は、C1-C3アルキル基又はカルボキシル基で1個置換されていてもよい）、C1-C3アルコキシ基、カルバモイル基（該カルバモイル基は、C1-C3アルコキシ基で1個置換されていてもよいC1-C3アルキルスルホニル基、C3-C6シクロアルキルスルホニル基又は、ヒドロキシC1-C3アルキル基で1個置換されていてもよい）、窒素、酸素及び硫黄から選択される同一若しくは異なった1-4個のヘテロ原子を含む3-10員ヘテロシクリル基、窒素、酸素及び硫黄から選択される同一若しくは異なった1-4個のヘテロ原子を含む3-10員ヘテロシクリルカルボニル基、アミノ基（該アミノ基は、C1-C3アルキルスルホニル基、C1-C3アルキルカルボニル基又はカルボキシC1-C3アルキル基で1個置換されていてもよい）、ハロゲン原子、カルボキシル基、水酸基及びシアノ基］で表される化合物又はその薬理上許容される塩である。 is not.
<Substituent group α>
A C1-C3 alkyl group (the alkyl group may be substituted with one hydroxyl group),
C3-C6 cycloalkyl group (the cycloalkyl group may be substituted with one C1-C3 alkyl group or carboxyl group), C1-C3 alkoxy group, carbamoyl group (the carbamoyl group is C1-C3 alkoxy) Selected from a C1-C3 alkylsulfonyl group, a C3-C6 cycloalkylsulfonyl group, or a hydroxy C1-C3 alkyl group optionally substituted by one group), nitrogen, oxygen and sulfur A 3-10 membered heterocyclyl group containing the same or different 1-4 heteroatoms, selected from nitrogen, oxygen and sulfur, or a 3-10 membered heterocyclylcarbonyl containing the same or different 1-4 heteroatoms A group, an amino group (the amino group may be substituted by a C1-C3 alkylsulfonyl group, a C1-C3 alkylcarbonyl group or a carboxy C1-C3 alkyl group), a halogen atom, a carboxy Group, a hydroxyl group and a compound represented by the cyano group] or a pharmacologically acceptable salt thereof.
　本発明において、「C1-C3アルキル基」とは、炭素原子を1個乃至3個有する直鎖状又は分枝鎖状のアルキル基であり、例えば、メチル、エチル、n-プロピル若しくはイソプロピル基を挙げることができる。R1、R 2、R3、R4、置換基群α及び置換基群αの「C3-C6シクロアルキル基」の置換基においては、好適にはメチル基である。 In the present invention, the “C1-C3 alkyl group” is a linear or branched alkyl group having 1 to 3 carbon atoms, for example, a methyl, ethyl, n-propyl or isopropyl group. Can be mentioned. In the substituents of R 1 , R 2 , R 3 , R 4 , the substituent group α, and the “C3-C6 cycloalkyl group” of the substituent group α, a methyl group is preferable.
　本発明において、「C1-C6アルキル基」とは、炭素原子を1個乃至6個有する直鎖状又は分枝鎖状のアルキル基であり、例えば、前記「C1-3アルキル基」の例として挙げた基又は、n-ブチル、イソブチル、s-ブチル、tert-ブチル、n-ペンチル、イソペンチル、2-メチルブチル、ネオペンチル、1-エチルプロピル、n-ヘキシル、イソヘキシル、4-メチルペンチル、3-メチルペンチル、2-メチルペンチル、1-メチルペンチル、3,3-ジメチルブチル、2,2-ジメチルブチル、1,1-ジメチルブチル、1,2-ジメチルブチル、1,3-ジメチルブチル、2,3-ジメチルブチル若しくは2-エチルブチル基を挙げることができる。R3及びR4においては、好適にはメチル基、t-ブチル基又はイソプロピル基である。 R5においては、好適にはイソプロピル基である。 R7においては、好適にはメチル基又はエチル基である。 In the present invention, the “C1-C6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms. For example, as an example of the “C1-3 alkyl group”, Listed groups or n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methyl Pentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3 Mention may be made of -dimethylbutyl or 2-ethylbutyl groups. R 3 and R 4 are preferably a methyl group, a t-butyl group or an isopropyl group. R 5 is preferably an isopropyl group. R 7 is preferably a methyl group or an ethyl group.
　本発明において、「3-6員飽和炭素環」とは、例えば、シクロプロパン、シクロブタン、シクロペンタン、シクロヘキサンを挙げることができる。R1、R 2、R3及びR4においては、好適には、シクロプロパン又はシクロブタンである。 In the present invention, examples of the “3-6 membered saturated carbocycle” include cyclopropane, cyclobutane, cyclopentane, and cyclohexane. R 1 , R 2 , R 3 and R 4 are preferably cyclopropane or cyclobutane.
　本発明において、「C2-C6アルキル基」とは、炭素原子を2個乃至6個有する直鎖状又は分枝鎖状のアルキル基であり、例えば、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、s-ブチル、tert-ブチル、n-ペンチル、イソペンチル、2-メチルブチル、ネオペンチル、1-エチルプロピル、n-ヘキシル、イソヘキシル、4-メチルペンチル、3-メチルペンチル、2-メチルペンチル、1-メチルペンチル、3,3-ジメチルブチル、2,2-ジメチルブチル、1,1-ジメチルブチル、1,2-ジメチルブチル、1,3-ジメチルブチル、2,3-ジメチルブチル若しくは2-エチルブチル基を挙げることができる。R6においては、好適にはイソプロピル基である。 In the present invention, the “C2-C6 alkyl group” is a linear or branched alkyl group having 2 to 6 carbon atoms, such as ethyl, n-propyl, isopropyl, n-butyl. , Isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1 -Methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl groups Can be mentioned. R 6 is preferably an isopropyl group.
　本発明において、「C3-C6シクロアルキル基」とは、3乃至6員飽和環状炭化水素基であり、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル基を挙げることができる。R1、R3においては、好適には、シクロプロピル基であり、R5、R6、R7及び置換基群αにおいては、好適にはシクロプロピル基又はシクロブチル基である。 In the present invention, the “C3-C6 cycloalkyl group” is a 3- to 6-membered saturated cyclic hydrocarbon group, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. R 1 and R 3 are preferably a cyclopropyl group, and R 5 , R 6 , R 7 and the substituent group α are preferably a cyclopropyl group or a cyclobutyl group.
　本発明において、「ヒドロキシC1-C3アルキル基」とは前記「C1-C3アルキル基」に水酸基が置換した基であり、例えば、ヒドロキシメチル、1-ヒドロキシエチル、2-ヒドロキシエチル、3-ヒドロキシプロピル基を挙げることができ、R7及び置換基群αの「カルバモイル基」の置換基においては、好適にはヒドロキシメチル基又は1-ヒドロキシエチル基である。 In the present invention, the “hydroxy C1-C3 alkyl group” is a group in which a hydroxyl group is substituted on the “C1-C3 alkyl group”, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl. The substituent of R 7 and the “carbamoyl group” of the substituent group α is preferably a hydroxymethyl group or a 1-hydroxyethyl group.
　本発明において、「C1-C3アルコキシ基」とは、前記「C1-C3アルキル基」が酸素原子に結合した基であり、例えば、メトキシ、エトキシ、n-プロポキシ、イソプロポキシ基のような炭素数1乃至3個の直鎖又は分枝鎖アルコキシ基を挙げることができる。置換基群α、置換基群αの「カルバモイル基」の置換基の置換基においては、好適にはメトキシ又はエトキシ基である。 In the present invention, the “C1-C3 alkoxy group” is a group in which the “C1-C3 alkyl group” is bonded to an oxygen atom, and has, for example, a carbon number such as methoxy, ethoxy, n-propoxy, isopropoxy group. Mention may be made of 1 to 3 straight-chain or branched alkoxy groups. The substituent of the substituent group α and the substituent of the “carbamoyl group” in the substituent group α is preferably a methoxy or ethoxy group.
　本発明において、「C1-C3アルコキシC1-C3アルキル基」とは前記「C1-C3アルキル基」に前記「C1-C3アルコキシ基」が置換した基であり、例えば、n-ブトキシメチル、イソブトキシメチル、s-ブトキシメチル、tert-ブトキシメチル、n-ペントキシメチル、イソペントキシメチル、2-メチルブトキシメチル、ネオペントキシメチル、n-ヘキシルオキシメチル、4-メチルペントキシメチル、3-メチルペントキシメチル、2-メチルペントキシメチル、3,3-ジメチルブトキシメチル、2,2-ジメチルブトキシメチル、1,1-ジメチルブトキシメチル、1,2-ジメチルブトキシメチル、1,3-ジメチルブトキシメチル、2,3-ジメチルブトキシメチル基を挙げることができ、R7においては、好適にはメトキシエチル基である。 In the present invention, the “C1-C3 alkoxy C1-C3 alkyl group” is a group in which the “C1-C3 alkoxy group” is substituted on the “C1-C3 alkyl group”. For example, n-butoxymethyl, isobutoxy Methyl, s-butoxymethyl, tert-butoxymethyl, n-pentoxymethyl, isopentoxymethyl, 2-methylbutoxymethyl, neopentoxymethyl, n-hexyloxymethyl, 4-methylpentoxymethyl, 3-methyl Pentoxymethyl, 2-methylpentoxymethyl, 3,3-dimethylbutoxymethyl, 2,2-dimethylbutoxymethyl, 1,1-dimethylbutoxymethyl, 1,2-dimethylbutoxymethyl, 1,3-dimethylbutoxymethyl 2,3-dimethylbutoxymethyl group, and R 7 is preferably a methoxyethyl group.
　本発明において、「C2-C6アルケニル基」とは、2重結合を一つ含む炭素数2乃至6個の直鎖又は分枝鎖アルケニル基であり、例えば、エテニル、1-プロペニル、2-プロペニル、1-メチル-2-プロペニル、1-メチル-1-プロペニル、2-メチル-1-プロペニル、2-メチル-2-プロペニル、2-エチル-2-プロペニル、1-ブテニル、2-ブテニル、1-メチル-2-ブテニル、1-メチル-1-ブテニル、3-メチル-2-ブテニル、1-エチル-2-ブテニル、3-ブテニル、1-メチル-3-ブテニル、2-メチル-3-ブテニル、1-エチル-3-ブテニル、1-ペンテニル、2-ペンテニル、1-メチル-2-ペンテニル、2-メチル-2-ペンテニル、3-ペンテニル、1-メチル-3-ペンテニル、2-メチル-3-ペンテニル、4-ペンテニル、1-メチル-4-ペンテニル、2-メチル-4-ペンテニル、1-ヘキセニル、2-ヘキセニル、3-ヘキセニル、4-ヘキセニル、5-ヘキセニル基を挙げることができる。R7においては、好適には、1-プロペニル基である。 In the present invention, the “C2-C6 alkenyl group” is a straight chain or branched alkenyl group having 2 to 6 carbon atoms containing one double bond, such as ethenyl, 1-propenyl, 2-propenyl. 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1 -Methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3 -Pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hex It can be mentioned Seniru group. R 7 is preferably a 1-propenyl group.
　本発明において、「C2-C6アルキニル基」とは、3重結合を一つ含む炭素数2乃至6個の直鎖又は分枝鎖アルキニル基であり、例えば、エチニル、プロパ-2-イン-1-イル基を挙げることができる。R7においては、好適には、プロパ-2-イン-1-イル基である。 In the present invention, the “C2-C6 alkynyl group” is a straight chain or branched alkynyl group having 2 to 6 carbon atoms containing one triple bond, such as ethynyl, prop-2-yne-1 -Yl group may be mentioned. R 7 is preferably a prop-2-yn-1-yl group.
　本発明において、「窒素、酸素及び硫黄から選択される同一若しくは異なった1-4個のヘテロ原子を含む3-10員ヘテロシクリル基」とは、窒素、酸素又は硫黄を1乃至4個含む3乃至10員複素環基であり、例えばフリル、チエニル、ピロリル、アゼピニル、ピラゾリル、イミダゾリル、オキサゾリル、オキサジアゾリル、イソキサゾリル、チアゾリル、イソチアゾリル、1,2,3-オキサジアゾリル、トリアゾリル、テトラゾリル、チアジアゾリル、ピラニル、 ピリジル（例えば、2-ピリジルフェニル、3-ピリジルフェニル、4-ピリジルフェニル）、ピリダジニル、ピリミジニル、ピラジニルのような芳香族複素環基及びオキセタニル、モルホリニル、チオモルホリニル、ピロリジニル、ピロリニル、イミダゾリジニル、イミダゾリニル、ピラゾリジニル、ピラゾリニル、ピペリジニル、ピペラジニル、テトラヒドロフラニル、テトラヒドロピラニル、5-オキソ-4,5-ジヒドロ-1,2,4-オキサジアゾリルのようなこれらの基に対応する、部分若しくは完全還元型の基を挙げることができる。尚、上記「4乃至10員複素環基」は、他の環式基と縮環していてもよく、例えば、ベンゾフラニル、クロメニル、インドリジニル、イソインドリル、インドリル、インダゾリル、プリニル、キノリジニル、イソキノリル、キノリル、フタラジニル、ナフチリジニル、キノキサリニル、キナゾリニル、イソインドリニル、2,3-ジヒドロ-1-ベンゾフラニル、3,4-ジヒドロ-1H-イソクロメニル、1,2,3,4-テトラヒドロキノリニル、1,2,3,4-テトラヒドロイソキノリニル基を挙げることができる。置換基群αにおいては、好適には、トリアゾリル、テトラゾリル、モルホリニル、ピロリジニル、ピペリジニル、5-オキソ-4,5-ジヒドロ-1,2,4-オキサジアゾリル基を挙げることがでる。 In the present invention, the “3- to 10-membered heterocyclyl group containing 1-4 heteroatoms which are the same or different and selected from nitrogen, oxygen and sulfur” refers to 3 to 4 containing 1 to 4 nitrogen, oxygen or sulfur 10-membered heterocyclic group such as furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl (for example , 2-pyridylphenyl, 3-pyridylphenyl, 4-pyridylphenyl), aromatic heterocyclic groups such as pyridazinyl, pyrimidinyl, pyrazinyl and oxetanyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl List partially or fully reduced groups corresponding to these groups such as pyrazolinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, 5-oxo-4,5-dihydro-1,2,4-oxadiazolyl Can do. The above “4- to 10-membered heterocyclic group” may be condensed with other cyclic groups, such as benzofuranyl, chromenyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolidinyl, isoquinolyl, quinolyl, Phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, isoindolinyl, 2,3-dihydro-1-benzofuranyl, 3,4-dihydro-1H-isochromenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4 -A tetrahydroisoquinolinyl group can be mentioned. Preferred examples of the substituent group α include triazolyl, tetrazolyl, morpholinyl, pyrrolidinyl, piperidinyl, and 5-oxo-4,5-dihydro-1,2,4-oxadiazolyl groups.
　本発明において、「窒素、酸素及び硫黄から選択される同一若しくは異なった1-4個のヘテロ原子を含む3-10員複素環カルボニル基」とは、前記「窒素、酸素及び硫黄から選択される同一若しくは異なった1-4個のヘテロ原子を含む3-10員複素環基」がカルボニル基に結合した基であり例えばピリジルカルボニル、オキセタニルカルボニル、モルホリニルカルボニル、ピペリジニルカルボニル及びテトラヒドロフラニルカルボニル基を挙げることができる。置換基群αにおいては、好適には、モルホリニルカルボニル基である。 In the present invention, the “3- to 10-membered heterocyclic carbonyl group containing the same or different 1-4 heteroatoms selected from nitrogen, oxygen and sulfur” is selected from the above “nitrogen, oxygen and sulfur” A 3-10 membered heterocyclic group containing 1-4 heteroatoms which are the same or different "is a group bonded to a carbonyl group, such as pyridylcarbonyl, oxetanylcarbonyl, morpholinylcarbonyl, piperidinylcarbonyl and tetrahydrofuranylcarbonyl The group can be mentioned. In the substituent group α, a morpholinylcarbonyl group is preferable.
　本発明において、「窒素、酸素及び硫黄から選択される同一若しくは異なった1-4個のヘテロ原子を含む5-10員ヘテロアリール基」とは、窒素、酸素又は硫黄を1乃至4個含む5乃至10員複素芳香環基であり、例えばフリル、チエニル、ピロリル、アゼピニル、ピラゾリル、イミダゾリル、オキサゾリル、オキサジアゾリル、イソキサゾリル、チアゾリル、イソチアゾリル、1,2,3-オキサジアゾリル、トリアゾリル、テトラゾリル、チアジアゾリル、ピラニル、 ピリジル、ピリダジニル、ピリミジニル、ピラジニル基を挙げることができる。 In the present invention, the “5- to 10-membered heteroaryl group containing 1-4 heteroatoms which are the same or different from nitrogen, oxygen and sulfur” includes 1 to 4 nitrogen, oxygen or sulfur. To 10-membered heteroaromatic group such as furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl , Pyridazinyl, pyrimidinyl and pyrazinyl groups.
　本発明において、「窒素、酸素及び硫黄から選択される同一若しくは異なった1-4個のヘテロ原子を含む5-10員ヘテロアリールフェニル基」とは、前記「窒素、酸素及び硫黄から選択される同一若しくは異なった1-4個のヘテロ原子を含む5-10員ヘテロアリール基」がフェニル基に結合した基であり、例えばフリルフェニル、チエニルフェニル、ピロリルフェニル、アゼピニルフェニル、ピラゾリルフェニル、イミダゾリルフェニル、オキサゾリルフェニル、オキサジアゾリルフェニル、イソキサゾリルフェニル、チアゾリルフェニル、イソチアゾリルフェニル、1,2,3-オキサジアゾリルフェニル、トリアゾリルフェニル、テトラゾリルフェニル、チアジアゾリルフェニル、ピラニルフェニル、2-ピリジルフェニル 、3-ピリジルフェニル、4-ピリジルフェニル、ピリダジニルフェニル、ピリミジニルフェニル、ピラジニルフェニル基を挙げることができる。Wにおいて好適には、2-ピリジルフェニル基である。 In the present invention, the “5- to 10-membered heteroarylphenyl group containing 1-4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur” is selected from the above “nitrogen, oxygen and sulfur” `` 5- to 10-membered heteroaryl group containing the same or different 1-4 heteroatoms '' is a group bonded to a phenyl group, such as furylphenyl, thienylphenyl, pyrrolylphenyl, azepinylphenyl, pyrazolylphenyl, Imidazolylphenyl, oxazolylphenyl, oxadiazolylphenyl, isoxazolylphenyl, thiazolylphenyl, isothiazolylphenyl, 1,2,3-oxadiazolylphenyl, triazolylphenyl, tetrazolylphenyl, Thiadiazolylphenyl, pyranylphenyl, 2-pyridylphenyl, 3-pyridylphenyl, 4-pyridyl Mention may be made of phenyl, pyridazinylphenyl, pyrimidinylphenyl and pyrazinylphenyl groups. In W, a 2-pyridylphenyl group is preferred.
　本発明において、「C1-C3アルキルカルボニル基」とは、前記「C1-C3アルキル基」がカルボニル基に結合した基であり、例えば、アセチル、プロピオニル、n-プロピルカルボニル、イソプロピルカルボニルのような炭素数1乃至3個の直鎖又は分枝鎖アルコキシカルボニル基を挙げることができ、置換基群αの「アミノ基」の置換基においては、好適にはアセチル又はプロピオニル基である。 In the present invention, the “C1-C3 alkylcarbonyl group” is a group in which the “C1-C3 alkyl group” is bonded to a carbonyl group. For example, a carbon such as acetyl, propionyl, n-propylcarbonyl, isopropylcarbonyl, etc. Examples thereof include a linear or branched alkoxycarbonyl group having a number of 1 to 3, and the substituent of the “amino group” in the substituent group α is preferably an acetyl or propionyl group.
　本発明において、「C1-C3アルキルスルホニル基」とは、前記「C1-3アルキル基」がスルホニル基を介して結合する基であり、例えば、メタンスルホニル、エタンスルホニル、n-プロパンスルホニル、イソプロパンスルホニル基を挙げることができる。置換基群α「カルバモイル基」の置換基並びに置換基群αの「アミノ基」の置換基においては、好適にはメタンスルホニル基である。 In the present invention, the “C1-C3 alkylsulfonyl group” is a group to which the “C1-3 alkyl group” is bonded via a sulfonyl group, such as methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropane. A sulfonyl group can be mentioned. The substituent of the substituent group α “carbamoyl group” and the substituent of the “amino group” of the substituent group α are preferably a methanesulfonyl group.
　本発明において、「C3-C6シクロアルキルスルホニル基」とは、前記「C3-C6シクロアルキル」がスルホニル基を介して結合する基であり、例えば、シクロプロピルスルホニル、シクロブチルスルホニル、シクロペンチルスルホニル、シクロヘキシルスルホニル基を挙げることができる。置換基群α「カルバモイル基」の置換基においては、好適にはシクロプロピルスルホニル基である。 In the present invention, the “C3-C6 cycloalkylsulfonyl group” is a group to which the “C3-C6 cycloalkyl” is bonded via a sulfonyl group, such as cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexyl. A sulfonyl group can be mentioned. The substituent of the substituent group α “carbamoyl group” is preferably a cyclopropylsulfonyl group.
　本発明において、「カルボキシC1-C3アルキル基」とは、カルボン酸が前記「C1-3アルキル基」に結合した基であり、例えば、エタン酸、プロパン酸、ブタン酸のような炭素数1乃至3個の直鎖又は分枝鎖アルコキシカルボニル基を挙げることができ、R7及び置換基群αの「アミノ基」の置換基においては、好適にはエタン酸である。 In the present invention, the “carboxy C1-C3 alkyl group” is a group in which a carboxylic acid is bonded to the “C1-3 alkyl group”, and includes, for example, 1 to C carbon atoms such as ethanoic acid, propanoic acid, and butanoic acid. There can be mentioned three straight-chain or branched alkoxycarbonyl groups, and R 7 and the substituent of the “amino group” in the substituent group α are preferably ethanoic acid.
　本発明において、「ハロゲン原子」とは、弗素原子、塩素原子、臭素原子又は沃素原子であり、置換基群αにおいては、好適には、塩素原子又は弗素原子である。 In the present invention, the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and in the substituent group α, preferably a chlorine atom or a fluorine atom.
　本発明において、「C1-C3ハロアルキル基」とは、それぞれ前記「C1-C3アルキル基」に前記「ハロゲン原子」が置換した基である。「C1-C3ハロアルキル基」としては、例えば、トリフルオロメチル、トリクロロメチル、ジフルオロメチル、ジクロロメチル、ジブロモメチル、フルオロメチル、2,2,2-トリフルオロエチル、2,2,2-トリクロロエチル、2-ブロモエチル、2-クロロエチル、2-フルオロエチル、2-ヨードエチル、3-クロロプロピル、2,2-ジブロモエチル基を挙げることができ、R7においては、好適には2-フルオロエチル基である。 In the present invention, the “C1-C3 haloalkyl group” is a group obtained by substituting the “halogen atom” for the “C1-C3 alkyl group”. As the `` C1-C3 haloalkyl group '', for example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, Examples include 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, and 2,2-dibromoethyl group. R 7 is preferably a 2-fluoroethyl group. .
　本発明において、「ナフチル基」とは、1-ナフチル基又は2-ナフチル基であり、Wにおいて好適には、1-ナフチル基である。 In the present invention, the “naphthyl group” is a 1-naphthyl group or a 2-naphthyl group, and W is preferably a 1-naphthyl group.
　本発明において、「ビフェニル基」とは2-ビフェニル、3-ビフェニル、4-ビフェニルが挙げられ、Wにおいて好適には、好適には3-ビフェニルである。 In the present invention, examples of the “biphenyl group” include 2-biphenyl, 3-biphenyl, and 4-biphenyl, and W is preferably 3-biphenyl.
　本発明において、「薬理上許容される塩」とは、アミノ基のような塩基性の基を有する場合には酸と反応させることにより、又、カルボキシル基のような酸性基を有する場合には塩基と反応させることにより、塩にすることができるので、その塩を示す。 In the present invention, the term “pharmacologically acceptable salt” refers to a case where a basic group such as an amino group is reacted with an acid, and a case where an acidic group such as a carboxyl group is present. By reacting with a base, it can be converted into a salt, so that salt is shown.
　塩基性基に基づく塩としては、好適には、弗化水素酸塩、塩酸塩、臭化水素酸塩、沃化水素酸塩のようなハロゲン化水素酸塩、硝酸塩、過塩素酸塩、硫酸塩、燐酸塩等の無機酸塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩のような低級アルカンスルホン酸塩、ベンゼンスルホン酸塩、p-トルエンスルホン酸塩のようなアリールスルホン酸塩、酢酸塩、りんご酸塩、フマ－ル酸塩、コハク酸塩、クエン酸塩、アスコルビン酸塩、酒石酸塩、蓚酸塩、マレイン酸塩等の有機酸塩；及び、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩を挙げることができる。好適には、ハロゲン化水素酸塩又は無機酸塩である。 The salt based on the basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfuric acid. Inorganic acid salts such as salts and phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate, aryl sulfones such as benzene sulfonate and p-toluene sulfonate Acid salt, acetate salt, malate salt, fumarate salt, succinate salt, citrate salt, ascorbate salt, tartrate salt, succinate salt, maleate salt, etc .; and glycine salt, lysine salt And amino acid salts such as arginine salt, ornithine salt, glutamate and aspartate. Preferably, it is a hydrohalide salt or an inorganic acid salt.
　一方、酸性基に基づく塩としては、好適には、ナトリウム塩、カリウム塩、リチウム塩のようなアルカリ金属塩、カルシウム塩、マグネシウム塩のようなアルカリ土類金属塩、アルミニウム塩、鉄塩等の金属塩；アンモニウム塩のような無機塩、tert-ブチルアミン塩、t-オクチルアミン塩、ジイソプロピルアミン塩、ジベンジルアミン塩、モルホリン塩、グルコサミン塩、フェニルグリシンアルキルエステル塩、エチレンジアミン塩、N-メチルグルカミン塩、グアニジン塩、ジエチルアミン塩、トリエチルアミン塩、ジシクロヘキシルアミン塩、N,N’-ジベンジルエチレンジアミン塩、クロロプロカイン塩、プロカイン塩、ジエタノ－ルアミン塩、N-ベンジルフェネチルアミン塩、ピペラジン塩、テトラメチルアンモニウム塩、トリス（ヒドロキシメチル）アミノメタン塩のような有機塩等のアミン塩；及び、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩を挙げることができる。更に好適には、マグネシウム塩、カルシウム塩、ジイソプロピルアミン塩及びtert-ブチルアミン塩をあげることができ、特に好適には、tert-ブチルアミン塩をあげることができる。 On the other hand, the salt based on an acidic group is preferably an alkali metal salt such as a sodium salt, potassium salt or lithium salt, an alkaline earth metal salt such as a calcium salt or magnesium salt, an aluminum salt or an iron salt. Metal salt; inorganic salt such as ammonium salt, tert-butylamine salt, t-octylamine salt, diisopropylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglu Camine salt, 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 Salt, tris (hydro Shimechiru) amine salts of organic salts such as aminomethane salts; and include glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts, amino acid salts such as aspartate. More preferred are magnesium salts, calcium salts, diisopropylamine salts and tert-butylamine salts, and particularly preferred are tert-butylamine salts.
　本発明の一般式(I)で表される化合物又はその薬理上許容される塩は、全ての異性体（ケト－エノール異性体、立体異性体等）を包含する。 The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof includes all isomers (keto-enol isomer, stereoisomer, etc.).
　本発明の一般式(I)で表される化合物又はその薬理上許容される塩は、その分子内に不斉炭素原子が存在する場合、種々の異性体を有する。本発明の化合物においては、これらの異性体およびこれらの異性体の混合物がすべて単一の式、即ち一般式(I)で示されている。従って、本発明はこれらの異性体およびこれらの異性体の任意の割合の混合物をもすべて含むものである。 The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has various isomers when an asymmetric carbon atom is present in the molecule. In the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers in an arbitrary ratio.
　上記のような立体異性体は、合成した本発明に係る化合物を所望により通常の光学分割法又は分離法を用いて単離することにより得ることができる。 The stereoisomers as described above can be obtained by isolating the synthesized compound according to the present invention, if desired, using a conventional optical resolution method or separation method.
　本発明の一般式(I)で表される化合物又はその薬理上許容される塩は、このような化合物を構成する原子の1以上に、原子同位体の非天然割合も含有し得る。原子同位体としては、例えば、重水素(2H)、トリチウム(3H)、ヨウ素－125(125I)又は炭素－14(14C)などが挙げられる。また、前記化合物は、例えば、トリチウム(3H)、ヨウ素－125(125I)又は炭素－14(14C)などの放射性同位体で放射性標識され得る。放射性標識された化合物は、治療又は予防剤、研究試薬、例えば、アッセイ試薬、及び診断剤、例えば、インビボ画像診断剤として有用である。本発明の化合物の全ての同位体変異種は、放射性であると否とを問わず、本発明の範囲に包含されるものとする。 The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may also contain an unnatural ratio of atomic isotopes at one or more of atoms constituting such a compound. Examples of atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), and carbon-14 ( 14 C). The compound may also be radiolabeled with a radioisotope such as, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
　本発明の一般式(I)で表される化合物又はその薬理上許容される塩は、大気中に放置したり、又は、再結晶をすることにより、水分を吸収し、吸着水が付いたり、水和物となる場合があり、そのような水和物も本発明の塩に包含される。 The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is left in the air or recrystallized to absorb moisture and adsorb water. It may become a hydrate, and such a hydrate is also included in the salt of the present invention.
　本発明の一般式(I)で表される化合物又はその薬理上許容される塩は、他のある種の溶媒を吸収し、溶媒和物となる場合があり、そのような溶媒和物も本発明の塩に包含される。 The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may absorb a certain other solvent and become a solvate, and such a solvate is also present. Included in the salts of the invention.
　更に本発明は、生体内において代謝されて前記一般式(I)を有する６員ヘテロ環誘導体又はその塩に変換される化合物（例えば、前記一般式(I)のカルボン酸部分がエステル化された誘導体等）もすべて含むものである。 Furthermore, the present invention provides a compound that is metabolized in vivo and converted to a 6-membered heterocyclic derivative having the general formula (I) or a salt thereof (for example, the carboxylic acid moiety of the general formula (I) is esterified Derivatives etc.) are all included.
　本発明のR1は好適には、メチル基である。 R 1 in the present invention is preferably a methyl group.
　本発明のR2は好適には、メチル基である。 R 2 in the present invention is preferably a methyl group.
　本発明のR3は好適には、C1-C6アルキル基であり、さらに好適にはメチル基又はイソプロピル基である。 R 3 in the present invention is preferably a C1-C6 alkyl group, and more preferably a methyl group or an isopropyl group.
　本発明のR4は好適には、水素原子又はメチル基である。 R 4 in the present invention is preferably a hydrogen atom or a methyl group.
　本発明のR5は好適には、C1-C6アルキル基であり、さらに好適は、イソプロピル基である。 R 5 in the present invention is preferably a C1-C6 alkyl group, and more preferably an isopropyl group.
　本発明のR6は好適には、C1-C6アルキル基であり、さらに好適にはイソプロピル基である。 R 6 in the present invention is preferably a C1-C6 alkyl group, and more preferably an isopropyl group.
　本発明のR7は好適には、水素原子又はC1-C6アルキル基であり、さらに好適には水素原子又はメチル基である。 R 7 in the present invention is preferably a hydrogen atom or a C1-C6 alkyl group, more preferably a hydrogen atom or a methyl group.
　本発明のVは好適には、-C(=O)-である。 V in the present invention is preferably -C (= O)-.
　本発明のWは好適には、窒素、酸素及び硫黄から選択される同一若しくは異なった1-4個のヘテロ原子を含む5-10員ヘテロアリールフェニル基（該ヘテロアリールフェニル基は、置換基群αより選択される同一または異なった1-8個の置換基で置換されていても良い）である。 In the present invention, W is preferably a 5- to 10-membered heteroarylphenyl group containing 1-4 heteroatoms selected from nitrogen, oxygen and sulfur (the heteroarylphenyl group is a group of substituents). and may be substituted with the same or different 1-8 substituents selected from α).
　本発明のXは好適には、-CH=又は-CH2-である。 X in the present invention is preferably —CH═ or —CH 2 —.
　本発明のYは好適には、-CR3R4-又は-CR6=である。 Y of the present invention is preferably —CR 3 R 4 — or —CR 6 =.
　本発明のZは好適には、-NR7-である。 Z in the present invention is preferably —NR 7 —.
　本発明の置換基群αは、Wのフェニル基の置換基において好適には、C3-C6シクロアルキル基、C1-C3アルコキシ基又はカルボキシル基である。 The substituent group α of the present invention is preferably a C3-C6 cycloalkyl group, a C1-C3 alkoxy group or a carboxyl group in the substituent of the phenyl group of W.
　本発明の置換基群αは、Wのビフェニル基の置換基において好適には、C1-C3アルキル基、C1-C3アルコキシ基又はカルボキシル基である。 The substituent group α of the present invention is preferably a C1-C3 alkyl group, a C1-C3 alkoxy group or a carboxyl group in the substituent of the biphenyl group of W.
　本発明の置換基群αはWの窒素、酸素及び硫黄から選択される同一若しくは異なった1-4個のヘテロ原子を含む5-10員ヘテロアリールフェニル基の置換基において好適には、カルバモイル基（該カルバモイル基は、C1-C3アルコキシ基で1個置換されていてもよいC1-C3アルキルスルホニル基、C3-C6シクロアルキルスルホニル基又は、ヒドロキシC1-C3アルキル基で1個置換されていてもよい）、C1-C3アルキル基、C1-C3アルコキシ基又はカルボキシル基である。 The substituent group α of the present invention is preferably a carbamoyl group in a substituent of a 5- to 10-membered heteroarylphenyl group containing 1-4 heteroatoms selected from nitrogen, oxygen and sulfur of W. (The carbamoyl group may be substituted with a C1-C3 alkylsulfonyl group, a C3-C6 cycloalkylsulfonyl group, or a hydroxy C1-C3 alkyl group, which may be substituted with a C1-C3 alkoxy group. C1-C3 alkyl group, C1-C3 alkoxy group or carboxyl group.
　本発明の一般式(I)は好適には、以下の式（Ia） The general formula (I) of the present invention is preferably the following formula (Ia)
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
[式中、R1、R2、R3、R4、R7及びWは前記と同義を示す。]であり、更に好適には以下の式（Ib） [Wherein, R 1 , R 2 , R 3 , R 4 , R 7 and W are as defined above] More preferably, the following formula (Ib)
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
[式中、R1、R2、R3、R4、R7及びWは前記と同義を示す。]である。 [Wherein, R 1 , R 2 , R 3 , R 4 , R 7 and W are as defined above] ].
　本発明の一般式(I)は、また、好適には、下記一般式（II） The general formula (I) of the present invention is preferably the following general formula (II)
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
[式中、R8はカルバモイル基（該カルバモイル基は、メチルスルホニル基で1個置換されていてもよい）又はカルボキシル基を示し、R1、R2、R3、R4及びR7は前記と同義を示す。]であり、更に好適には以下の式（III） [Wherein R 8 represents a carbamoyl group (the carbamoyl group may be substituted by one methylsulfonyl group) or a carboxyl group, and R 1 , R 2 , R 3 , R 4 and R 7 are Synonymous with. More preferably, the following formula (III)
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
[式中、R3、R4及びR7は前記と同義を示す。]である。 [Wherein R 3 , R 4 and R 7 have the same meaning as described above. ].
　本発明の一般式(I)を有する化合物は、例えば、以下の方法により製造することができる
　Ａ法：一般式(I)を有する化合物のうち、Vが-C(=O)-である化合物（Ia）はA-1～3工程を実施することにより製造することができる。 The compound having the general formula (I) of the present invention can be produced, for example, by the following method: Method A: Among the compounds having the general formula (I), V is —C (═O) — (Ia) can be produced by carrying out Steps A-1 to A-3.
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
　Ｂ法：一般式(I)を有する化合物のうち、Vが-CH2-である化合物（Ib）はA-1及びA-2工程の後、B-1及びB-2工程を実施することで製造することができる。 Method B: Among the compounds having the general formula (I), the compound (Ib) in which V is —CH 2 — is subjected to the steps B-1 and B-2 after the steps A-1 and A-2. Can be manufactured.
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
　上記式中及び以下の記載においてW、X、Y、Z、R1、R2、R3、R4及びR5は、前述したものと同意義を示す。 In the above formula and the following description, W, X, Y, Z, R 1 , R 2 , R 3 , R 4 and R 5 have the same meaning as described above.
　上記式中及び以下の記載において、P1はカルボキシル基の保護に用いられる保護基であれば、特に限定はない。 In the above formula and the following description, P 1 is not particularly limited as long as it is a protecting group used for protecting a carboxyl group.
　上記式中及び以下の記載において、P2は水酸基の保護に用いられる保護基であれば特に限定はないが、ベンジル基、トリメチルシリル基、トリエチルシリル基、イソプロピルジメチルシリル基、t-ブチルジメチルシリル基、メチルジイソプロピルシリル基、メチルジ-t－ブチルシリル基又はトリイソプロピルシリル基が好適である。 In the above formula and the following description, P 2 is not particularly limited as long as it is a protecting group used for protecting a hydroxyl group, but benzyl group, trimethylsilyl group, triethylsilyl group, isopropyldimethylsilyl group, t-butyldimethylsilyl group A methyldiisopropylsilyl group, a methyldi-t-butylsilyl group or a triisopropylsilyl group is preferred.
　上記工程中及び以下の記載において、水酸基、アミノ基及びカルボキシル基の保護、脱保護は、有機合成化学の分野の常法によりおこなうことができる。例えば、グリーン・ワッツ著、「プロテクティブ　グループス　イン　オーガニック　シンセシス第4版(Protective groups in organic synthesis )」（米国、Wiley-Interscience社）に記載の方法や保護基を挙げることができるが、これに限定されるものではない。 Protecting and deprotecting hydroxyl groups, amino groups and carboxyl groups during the above steps and in the following description can be carried out by conventional methods in the field of synthetic organic chemistry. For example, the methods and protecting groups described in Green Watts, "Protective groups in organic synthesis 4th edition" (Wiley-Interscience, USA) can be mentioned, but are not limited thereto. Is not to be done.
　原料化合物(1),化合物(2), 化合物(4)は市販、もしくは文献に則った方法で合成することができる。 Raw material compound (1), compound (2), and cocoon compound (4) are commercially available or can be synthesized by methods in accordance with literature.
　以下、各工程につき、説明する。
（A法）
（第A-1工程）
　本工程は溶媒中、塩基の存在下、原料化合物(1)を化合物(2)と反応させることにより中間体化合物(3)を製造する工程である。 Hereinafter, each step will be described.
(Method A)
(Process A-1)
This step is a step for producing the intermediate compound (3) by reacting the starting compound (1) with the compound (2) in the presence of a base in a solvent.
　溶媒としては、好適には、エーテル類又はアミド類であり、より好適にはアセトニトリル、テトラヒドロフラン又はN,N-ジメチルホルムアミドである。 The solvent is preferably an ether or an amide, more preferably acetonitrile, tetrahydrofuran or N, N-dimethylformamide.
　塩基としては、好適には、有機塩基又は無機塩基であり、より好適には、アミノ酸、アミン類、アルカリ金属炭酸塩又はアルカリ土類金属炭酸塩であり、より好適には、プロリン、ピロリジン、ピペリジン、モルホリン、トリエチルアミンン、ジイソプロピルエチルアミン、炭酸セシウム又は炭酸カリウムである。 The base is preferably an organic base or an inorganic base, more preferably an amino acid, an amine, an alkali metal carbonate or an alkaline earth metal carbonate, and more preferably proline, pyrrolidine, or piperidine. Morpholine, triethylamine, diisopropylethylamine, cesium carbonate or potassium carbonate.
　反応温度は、通常、0℃乃至100℃であり、好適には0℃乃至60℃である。 The reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to 60 ° C.
　反応時間は、通常、0.5時間乃至72時間であり、好適には1時間乃至30時間である。 The reaction time is usually 0.5 to 72 hours, preferably 1 to 30 hours.
　なお、化合物(3)を単離せずに、直接第A-2工程を実施してもよい。 In addition, the step A-2 may be directly performed without isolating the compound (3).
（第A-2工程）
　本工程は溶媒中、塩基の存在下、化合物(3)を化合物(4)と反応させることにより中間体化合物(5)を製造する工程である。 (Process A-2)
This step is a step for producing intermediate compound (5) by reacting compound (3) with compound (4) in the presence of a base in a solvent.
　溶媒としては、好適には、エーテル類又はアミド類であり、より好適にはアセトニトリル、テトラヒドロフラン又はN,N-ジメチルホルムアミドである。 The solvent is preferably an ether or an amide, more preferably acetonitrile, tetrahydrofuran or N, N-dimethylformamide.
　塩基としては、好適には、有機塩基又は無機塩基であり、より好適には、アミン類、アルカリ金属アルコキシド、アルカリ金属炭酸塩又はアルカリ土類金属炭酸塩であり、より好適には、ピロリジン、ピペリジン、モルホリン、トリエチルアミン、ジイソプロピルエチルアミン、t-ブトキシカリウム、炭酸セシウム又は炭酸カリウムである。 The base is preferably an organic base or an inorganic base, more preferably amines, alkali metal alkoxides, alkali metal carbonates or alkaline earth metal carbonates, and more preferably pyrrolidine, piperidine. , Morpholine, triethylamine, diisopropylethylamine, potassium t-butoxy, cesium carbonate or potassium carbonate.
　反応温度は、通常、0℃乃至100℃であり、好適には0℃乃至室温である。 The reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
　反応時間は、通常、0.5時間乃至48時間であり、好適には1時間乃至30時間である。
なお、化合物(5)を単離せずに、直接第A-3工程を実施してもよい。 The reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
The step A-3 may be directly performed without isolating the compound (5).
（第A-3工程）
　本工程は溶媒中、化合物(5)のエノール性水酸基を活性化することにより目的化合物（Ia）を製造する工程であり、エノール性水酸基の活性化の方法としてはメタンスルホニル化反応、トリフルオロメタンスルホニル化反応試薬又は光延反応が用いられる。
（メタンスルホニル化又はトリフルオロメタンスルホニル化反応を用いる場合）
　溶媒としては、好適には、エーテル類、アミド類又はハロゲン化炭化水素類であり、より好適にはテトラヒドロフラン、N,N-ジメチルホルムアミド又はジクロロメタンである。 (Process A-3)
This step is a step of producing the target compound (Ia) by activating the enolic hydroxyl group of compound (5) in a solvent. The enolic hydroxyl group activation method includes methanesulfonylation reaction, trifluoromethanesulfonyl The reaction reagent or Mitsunobu reaction is used.
(When methanesulfonylation or trifluoromethanesulfonylation reaction is used)
The solvent is preferably an ether, amide or halogenated hydrocarbon, more preferably tetrahydrofuran, N, N-dimethylformamide or dichloromethane.
　塩基としては、好適には、有機塩基又はアルカリ土類金属炭酸塩であり、より好適には、トリエチルアミンン、ジイソプロピルエチルアミン又は炭酸セシウムである。 The base is preferably an organic base or an alkaline earth metal carbonate, and more preferably triethylamine, diisopropylethylamine or cesium carbonate.
　メタンスルホニル化、トリフルオロメタンスルホニル化剤としては、好適には、メタンスルホニルクロリド、メタンスルホン酸無水物、N-フェニルビス(トリフルオロメタンスルホンイミド)、トリフルオロメタンスルホン酸無水物である。 Preferred examples of the methanesulfonylation and trifluoromethanesulfonylating agent include methanesulfonyl chloride, methanesulfonic anhydride, N-phenylbis (trifluoromethanesulfonimide), and trifluoromethanesulfonic anhydride.
　反応温度は、通常、0℃乃至100℃であり、好適には0℃乃至室温である。 The reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
　反応時間は、通常、0.5時間乃至48時間であり、好適には1時間乃至30時間である。 The reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
（光延反応を用いる場合）
　溶媒としては、好適には、エーテル類、炭化水素類又はハロゲン化炭化水素類であり、より好適にはテトラヒドロフラン、トルエン又はジクロロメタンである。 (When Mitsunobu reaction is used)
The solvent is preferably ethers, hydrocarbons or halogenated hydrocarbons, and more preferably tetrahydrofuran, toluene or dichloromethane.
　アゾ試薬としては、好適には、ジエチルアゾジカルボキシレート、ジイソプロピルアゾジカルボキシレート、ジ-tert-ブチルアゾジカルボキシレート、1,1'-(アゾジカルボニル)ジピペリジンである。 The azo reagent is preferably diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, or 1,1 ′-(azodicarbonyl) dipiperidine.
　ホスフィン試薬としては、好適には、トリフェニルホスフィン、トリブチルホスフィン、トリシクロヘキシルホスフィンある。 The phosphine reagent is preferably triphenylphosphine, tributylphosphine, or tricyclohexylphosphine.
　反応温度は、通常、0℃乃至100℃であり、好適には0℃乃至室温である。 The reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
　反応時間は、通常、0.5時間乃至48時間であり、好適には1時間乃至30時間である。 The reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
（B法）
（第B-1工程）
　本工程は、溶媒中、化合物（Ib）をチオカルボニル化剤と反応させることにより中間体化合物(6)を製造する工程である。 (Method B)
(Process B-1)
This step is a step for producing intermediate compound (6) by reacting compound (Ib) with a thiocarbonylating agent in a solvent.
　溶媒はとしては、好適には、エーテル類又は炭化水素類であり、より好適にはテトラヒドロフラン、1,4-ジオキサン又はトルエンである。 The solvent is preferably ethers or hydrocarbons, more preferably tetrahydrofuran, 1,4-dioxane or toluene.
　チオカルボニル化剤は、好適には、ローソン試薬、五硫化二燐である。 The thiocarbonylating agent is preferably Lawesson's reagent or diphosphorus pentasulfide.
　反応温度は、通常、0℃乃至200℃であり、好適には0℃乃至100℃である。 The reaction temperature is usually 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
　反応時間は、通常、0.5時間乃至48時間であり、好適には1時間乃至30時間である。 The reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
（第B-2工程）
　本工程は溶媒中、中間体化合物(6)を還元剤と反応させることにより化合物(Ib)を製造する工程である。 (Process B-2)
This step is a step for producing compound (Ib) by reacting intermediate compound (6) with a reducing agent in a solvent.
　溶媒としては、好適には、エーテル類又はアルコール類であり、より好適にはテトラヒドロフラン又はエタノールである。 The solvent is preferably an ether or an alcohol, and more preferably tetrahydrofuran or ethanol.
　還元剤は、好適には、遷移金属、還元剤と遷移金属の混合物であり、より好適には、ラネーニッケル、水素化ホウ素ナトリウムと塩化ニッケルの混合物である。 The reducing agent is preferably a transition metal, a mixture of a reducing agent and a transition metal, and more preferably a mixture of Raney nickel, sodium borohydride and nickel chloride.
　反応温度は、通常、0℃乃至100℃であり、好適には0℃乃至室温である。 The reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
　反応時間は、通常、0.5時間乃至48時間であり、好適には1時間乃至30時間である。 The reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
　R7が水素原子でない場合には、窒素原子上に置換基R7を導入する工程を、Ａ法及びＢ法のいずれの工程中に適宜追加することにより、目的化合物を製造することもできる。窒素原子上への置換基R7の導入は、例えば、溶媒中、塩基存在下、R7のハロゲン化物（塩化物、臭素化物等）を反応させることにより達成される。 When R 7 is not a hydrogen atom, the target compound can also be produced by appropriately adding a step of introducing a substituent R 7 onto the nitrogen atom in any of the steps of Method A and Method B. Introduction of the substituent R 7 onto the nitrogen atom is achieved, for example, by reacting a halide of R 7 (chloride, bromide, etc.) in the presence of a base in a solvent.
　使用される溶媒は、好適には、エーテル類又はアミド類であり、より好適にはテトラヒドロフラン又はN,N-ジメチルホルムアミドである。 The solvent used is preferably an ether or an amide, more preferably tetrahydrofuran or N, N-dimethylformamide.
　塩基は、好適には、無機塩基であり、より好適には、アルカリ金属水素化物又はアルカリ土類金属水素化物であり、より好適には、水素化ナトリウムである。 The base is preferably an inorganic base, more preferably an alkali metal hydride or alkaline earth metal hydride, and more preferably sodium hydride.
　反応温度は、通常、0℃乃至100℃であり、好適には0℃乃至室温である。 The reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
　反応時間は、通常、0.5時間乃至48時間であり、好適には1時間乃至30時間である。 The reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
　R5が水素原子でない場合には、上記置換基R7を導入する方法に準じた窒素原子上に置換基R5を導入する工程を、Ａ法及びＢ法のいずれの工程中に適宜追加することにより、目的化合物を製造することもできる。 When R 5 is not a hydrogen atom, a step of introducing the substituent R 5 onto the nitrogen atom according to the method of introducing the substituent R 7 is appropriately added in any of the methods A and B. Thus, the target compound can also be produced.
　さらに、以下に記載の置換基の変換を、上記工程中適宜おこなってもよい。 Furthermore, the substituents described below may be appropriately converted during the above steps.
　＜エステルの加水分解＞
　本変換は溶媒中、エステルを塩基もしくは酸と反応させることにより行われる。 <Ester hydrolysis>
This conversion is carried out by reacting an ester with a base or acid in a solvent.
　溶媒は、好適には、エーテル類、ハロゲン化炭化水素類又はアルコール類であり、より好適にはテトラヒドロフラン、ジクロロメタン、メタノール又はエタノールである。 The solvent is preferably ethers, halogenated hydrocarbons or alcohols, and more preferably tetrahydrofuran, dichloromethane, methanol or ethanol.
　塩基は、好適には、金属水酸化物であり、より好適には、水酸化ナトリウム、水酸化リチウム、水酸化カリウムである。 The base is preferably a metal hydroxide, and more preferably sodium hydroxide, lithium hydroxide, or potassium hydroxide.
　酸は、好適には、塩酸又はトリフルオロ酢酸である。 The acid is preferably hydrochloric acid or trifluoroacetic acid.
　反応温度は、通常、0℃乃至100℃であり、好適には0℃乃至室温である。 The reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
　反応時間は、通常、0.5時間乃至48時間であり、好適には1時間乃至30時間である。 The reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
　＜アシルスルホンアミドの合成＞
　本合成は溶媒中、縮合剤の存在下、カルボン酸をスルホンアミドと反応させることにより行われる。 <Synthesis of acylsulfonamide>
This synthesis is performed by reacting a carboxylic acid with a sulfonamide in a solvent in the presence of a condensing agent.
　溶媒は、好適には、ハロゲン化炭化水素類、エーテル類又はアミド類であり、より好適にはジクロロメタン、テトラヒドロフラン又はN,N-ジメチルホルムアミドである。 The solvent is preferably a halogenated hydrocarbon, ether or amide, more preferably dichloromethane, tetrahydrofuran or N, N-dimethylformamide.
　縮合剤は、好適には、カルボニルジイミダゾールである。 The condensing agent is preferably carbonyldiimidazole.
　反応温度は、通常、0℃乃至100℃であり、好適には0℃乃至室温である。 The reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
　反応時間は、通常、0.5時間乃至48時間であり、好適には1時間乃至30時間である。 The reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
　＜宮浦ボレーション＞
　本反応は溶媒中、触媒の存在下、ハロゲン化合物をビス(ピナコラト)ジボロンと反応させることにより行われる。 <Miyaura Boration>
This reaction is carried out by reacting a halogen compound with bis (pinacolato) diboron in a solvent in the presence of a catalyst.
　溶媒は、好適には、エーテル類又はアミド類であり、より好適には1,4-ジオキサン又はテトラヒドロフランである。 The solvent is preferably an ether or an amide, more preferably 1,4-dioxane or tetrahydrofuran.
　触媒は、例えば、2価のパラジウム触媒又は0価のパラジウム触媒であり、より好適には、PdCl2(dppe)、PdCl2(dppf)又はPdCl2(Ph3P)2である。 The catalyst is, for example, a divalent palladium catalyst or a zero-valent palladium catalyst, and more preferably PdCl 2 (dppe), PdCl 2 (dppf), or PdCl 2 (Ph 3 P) 2 .
　反応温度は、通常、0℃乃至150℃であり、好適には室温乃至120℃である。 The reaction temperature is usually 0 ° C. to 150 ° C., preferably room temperature to 120 ° C.
　反応時間は、通常、0.5時間乃至60時間であり、好適には1時間乃至48時間である。 The reaction time is usually 0.5 to 60 hours, preferably 1 to 48 hours.
　＜鈴木カップリング＞
　本反応は溶媒中、触媒の存在下、ボロン酸誘導体をハロゲン化合物と反応させることにより行われる。 <Suzuki coupling>
This reaction is performed by reacting a boronic acid derivative with a halogen compound in a solvent in the presence of a catalyst.
　溶媒は、好適には、エーテル類又はアミド類であり、より好適には1,4-ジオキサン又はテトラヒドロフランである。 The solvent is preferably an ether or an amide, more preferably 1,4-dioxane or tetrahydrofuran.
　触媒は、例えば、2価のパラジウム触媒又は0価のパラジウム触媒であり、より好適には、PdCl2(dppe)、PdCl2(dppf)、Pd(Ph3P)4又は2nd Generation X-Phos Precatalystである。 The catalyst is, for example, a divalent palladium catalyst or a zero-valent palladium catalyst, more preferably PdCl 2 (dppe), PdCl 2 (dppf), Pd (Ph 3 P) 4 or 2nd Generation X-Phos Precatalyst. It is.
　反応温度は、通常、0℃乃至150℃であり、好適には室温乃至120℃である。 The reaction temperature is usually 0 ° C. to 150 ° C., preferably room temperature to 120 ° C.
　反応時間は、通常、0.5時間乃至60時間であり、好適には1時間乃至48時間である。 The reaction time is usually 0.5 to 60 hours, preferably 1 to 48 hours.
　上記各工程の反応終了後、目的化合物は常法に従って、反応混合物から採取される。例えば、反応混合物を適宜中和し、又、不溶物が存在する場合には濾過により除去した後、水と酢酸エチルのような混和しない有機溶媒を加え、水等で洗浄後、目的化合物を含む有機層を分離し、無水硫酸マグネシウム等で乾燥後、溶剤を留去することによって得られる。 After completion of each step, the target compound is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, washed with water, and the target compound is then contained. The organic layer is separated, dried over anhydrous magnesium sulfate and the like, and then the solvent is distilled off.
　得られた目的物は必要ならば常法、例えば再結晶、再沈殿、又は、通常、有機化合物の分離精製に慣用されている方法、例えば、吸着カラムクロマトグラフィー法、分配カラムクロマトグラフィー法等の合成吸着剤を使用する方法、イオン交換クロマトグラフィーを使用する方法、又は、シリカゲル若しくはアルキル化シリカゲルによる順相・逆相カラムクロマトグラフィー法を適宜組み合わせ、適切な溶離剤で溶出することによって分離、精製することができる。 If necessary, the obtained target product can be obtained by a conventional method such as recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, such as adsorption column chromatography, distribution column chromatography, etc. Separation and purification by eluting with an appropriate eluent by combining a method using a synthetic adsorbent, a method using ion exchange chromatography, or a normal phase / reverse phase column chromatography method using silica gel or alkylated silica gel. can do.
　さらに、必要に応じて、キラルカラムにより光学活性体の分離、精製を行なうこともできる。 Furthermore, if necessary, the optically active substance can be separated and purified by a chiral column.
　本発明の前記一般式(I)を有する６員ヘテロ環誘導体、その薬理上許容される塩は、種々の形態で投与される。その投与形態としては特に限定はなく、各種製剤形態、患者の年齢、性別その他の条件、疾患の程度等に応じて決定される。例えば錠剤、丸剤、散剤、顆粒剤、シロップ剤、液剤、懸濁剤、乳剤およびカプセル剤の場合には経口投与される。また注射剤の場合には単独であるいはぶどう糖、アミノ酸等の通常の補液と混合して静脈内投与され、更には必要に応じて単独で筋肉内、皮内、皮下もしくは腹腔内投与される。坐剤の場合には直腸内投与される。好適には経口投与である。 The 6-membered heterocyclic derivative having the general formula (I) of the present invention and a pharmacologically acceptable salt thereof are administered in various forms. The administration form is not particularly limited, and is determined according to various preparation forms, patient age, sex and other conditions, the degree of disease, and the like. For example, in the case of tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions and capsules, they are administered orally. In the case of an injection, it is administered intravenously alone or mixed with a normal replacement fluid such as glucose or amino acid, and further administered alone intramuscularly, intradermally, subcutaneously or intraperitoneally as necessary. In the case of a suppository, it is administered intrarectally. Oral administration is preferred.
　これらの各種製剤は、常法に従って主薬に賦形剤、結合剤、崩壊剤、潤沢剤、溶解剤、矯味矯臭、コーティング剤等既知の医薬製剤分野において通常使用しうる既知の補助剤を用いて製剤化することができる。 These various preparations are prepared by using known adjuvants that can be generally used in the field of known pharmaceutical preparations such as excipients, binders, disintegrants, lubricants, solubilizers, flavoring agents, and coating agents according to conventional methods. It can be formulated.
　錠剤の形態に成形するに際しては、担体としてこの分野で従来公知のものを広く使用でき、例えば乳糖、白糖、塩化ナトリウム、ぶどう糖、尿素、澱粉、炭酸カルシウム、カオリン、結晶セルロース、ケイ酸等の賦形剤、水、エタノール、プロパノール、単シロップ、ぶどう糖液、澱粉液、ゼラチン溶液、カルボキシメチルセルロース、セラック、メチルセルロース、リン酸カリウム、ポリビニルピロリドン等の結合剤、乾燥澱粉、アルギン酸ナトリウム、カンテン末、ラミナラン末、炭酸水素ナトリウム、炭酸カルシウム、ポリオキシエチレンソルビタン脂肪酸エステル類、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、澱粉、乳糖等の崩壊剤、白糖、ステアリン、カカオバター、水素添加油等の崩壊抑制剤、第４級アンモニウム塩基、ラウリル硫酸ナトリウム等の吸収促進剤、グリセリン、澱粉等の保湿剤、澱粉、乳糖、カオリン、ベントナイト、コロイド状ケイ酸等の吸着剤、精製タルク、ステアリン酸塩、硼酸末、ポリエチレングリコール等の滑沢剤等が例示できる。更に錠剤は必要に応じ通常の剤皮を施した錠剤、例えば糖衣錠、ゼラチン被包錠、腸溶被錠、フィルムコーティング錠あるいは二重錠、多層錠とすることができる。 In molding into tablets, conventionally known carriers can be widely used as carriers, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like. Form, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, agar powder, laminaran powder Sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and other disintegrants, sucrose, stearin, cacao butter, hydrogenated oil and other disintegration inhibitors, Class Ammoni Absorption accelerators such as mud base, sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, purified talc, stearate, boric acid powder, polyethylene glycol, etc. Examples of these lubricants can be given. Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets.
　丸剤の形態に成形するに際しては、担体としてこの分野で従来公知のものを広く使用でき、例えばぶどう糖、乳糖、澱粉、カカオ脂、硬化植物油、カオリン、タルク等の賦形剤、アラビアゴム末、トラガント末、ゼラチン、エタノール等の結合剤、ラミナランカンテン等の崩壊剤等が例示できる。 In molding into the form of pills, those conventionally known in this field can be widely used as carriers, for example, glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc and other excipients, gum arabic powder, Examples thereof include binders such as tragacanth powder, gelatin and ethanol, and disintegrants such as lamina lankanten.
　坐剤の形態に成形するに際しては、担体としてこの分野で従来公知のものを広く使用でき、例えばポリエチレングリコール、カカオ脂、高級アルコール、高級アルコールのエステル類、ゼラチン、半合成グリセライド等を挙げることができる。 In molding into the form of suppository, conventionally known carriers can be widely used as carriers, such as polyethylene glycol, cacao butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides and the like. it can.
　注射剤として調製される場合には、液剤および懸濁剤は殺菌され、且つ血液と等張であるのが好ましく、これら液剤、乳剤および懸濁剤の形態に成形するに際しては、希釈剤としてこの分野において慣用されているものを全て使用でき、例えば水、エチルアルコール、プロピレングリコール、エトキシ化イソステアリルアルコール、ポリオキシ化イソステアリルアルコール、ポリオキシエチレンソルビタン脂肪酸エステル類等を挙げることができる。なお、この場合、等張性の溶液を調製するに十分な量の食塩、ぶどう糖、あるいはグリセリンを医薬製剤中に含有せしめてもよく、また通常の溶解補助剤、緩衝剤、無痛化剤等を添加してもよい。 When prepared as injections, the solutions and suspensions are preferably sterilized and isotonic with blood, and in the form of these solutions, emulsions and suspensions, this is used as a diluent. Any of those commonly used in the field can be used, and examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of sodium chloride, glucose, or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation. Ordinary solubilizers, buffers, soothing agents, etc. may be added. It may be added.
　更に必要に応じて着色剤、保存剤、香料、風味剤、甘味剤等や他の医薬品を含有せしめてもよい。 Furthermore, if necessary, colorants, preservatives, fragrances, flavors, sweeteners, and other pharmaceuticals may be included.
　上記医薬製剤中に含まれる有効成分化合物の量は、特に限定されず広範囲に適宜選択されるが、通常全組成物中1～70重量％、好ましくは1～30重量％含まれる量とするのが適当である。 The amount of the active ingredient compound contained in the pharmaceutical preparation is not particularly limited and is appropriately selected within a wide range, but is usually 1 to 70% by weight, preferably 1 to 30% by weight in the total composition. Is appropriate.
　その投与量は、症状、年令、体重、投与方法および剤型等によって異なるが、通常は成人に対して１日、下限として0.001mg/kg（好ましくは0.01mg/kg、更に好ましくは0.1mg/kg）であり、上限として200mg/kg（好ましくは20mg/kg、更に好ましくは10mg/kg）を1回ないし数回投与することができる。 The dosage varies depending on symptoms, age, body weight, administration method, dosage form, etc., but is usually 0.001 mg / kg (preferably 0.01 mg / kg, more preferably 0.1 mg as a lower limit for adults per day) / mg), and 200 mg / kg (preferably 20 mg / kg, more preferably 10 mg / kg) as the upper limit can be administered once to several times.
　本発明の化合物は、前述の本発明が有効と考えられる疾患の種々の治療又は予防剤と併用することができる。当該併用は、同時投与或いは別個に連続して若しくは所望の時間間隔をおいて投与してもよい。同時投与製剤は、配合剤であっても別個に製剤化されていてもよい。併用することができる糖尿病治療薬としては、例えば、インスリン製剤、スルホニルウレア剤、チアゾリジン系薬剤、ビグアナイド系薬剤、α-グルコシダーゼ阻害剤、速効型インスリン分泌促進薬、GLP-1受容体作動薬、SGLT2阻害剤等、DPPIV阻害薬等が挙げられる。 The compound of the present invention can be used in combination with various therapeutic or prophylactic agents for the diseases for which the present invention is considered to be effective. The combination may be administered simultaneously or separately in succession or at desired time intervals. The simultaneous administration preparation may be a compounding agent or may be separately formulated. Examples of antidiabetic agents that can be used in combination include insulin preparations, sulfonylureas, thiazolidines, biguanides, α-glucosidase inhibitors, fast-acting insulin secretagogues, GLP-1 receptor agonists, SGLT2 inhibitors And DPPIV inhibitors and the like.
　本発明の化合物である、６員ヘテロ環誘導体及びその薬理上許容される塩は、優れた血糖降下作用を有し、糖尿病（1型糖尿病、2型糖尿病、妊娠糖尿病等）、食後過血糖症、耐糖能障害、糖尿病性神経障害、糖尿病性腎症、糖尿病性網膜症、高脂血症、動脈硬化症、血栓性疾患、肥満、高血圧、浮腫、インスリン抵抗性、不安定糖尿病、インスリノーマ、高インスリン血症などの疾患等の治療薬または予防薬として有用である。また、毒性が低く、安全性に優れることから、医薬として極めて有用であるといえる。 The compound of the present invention, which is a 6-membered heterocyclic derivative and a pharmacologically acceptable salt thereof, has an excellent hypoglycemic action, such as diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), postprandial hyperglycemia Impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, high It is useful as a therapeutic or prophylactic agent for diseases such as insulinemia. In addition, since it is low in toxicity and excellent in safety, it can be said that it is extremely useful as a medicine.
　次に実施例等をあげて本発明を更に詳細に説明するが、本発明はこれらに限定されるものではない。 Next, the present invention will be described in more detail with reference to examples and the like, but the present invention is not limited thereto.
　実施例のカラム用シリカゲルはメルク社製のシリカゲルSK-85(230～400メッシュ)、シリカゲルSK-34(70～230メッシュ)もしくは富士シリシア化学　Chromatorex NH (200-350メッシュ)を用いた。通常のカラムクロマトグラフィーの他に、Biotage社の自動クロマトグラフィー装置（SP-1)、山善社の自動クロマトグラフィー装置（Parallel Frac FR-260）、テレダインイスコ社の自動クロマトグラフィー装置（CombiFlash Rf）を適宜使用した。尚、実施例で用いる略号は、次のような意義を有する。
mg：ミリグラム，g：グラム，mL：ミリリットル，MHz：メガヘルツ。 As the silica gel for the column of Examples, silica gel SK-85 (230-400 mesh), silica gel SK-34 (70-230 mesh) or Fuji Silysia Chemical Chromatorex NH (200-350 mesh) manufactured by Merck & Co., Inc. was used. In addition to conventional column chromatography, Biotage's automated chromatography device (SP-1), Yamazen's automated chromatography device (Parallel Frac FR-260), Teledyne Isco's automated chromatography device (CombiFlash Rf) Were used as appropriate. The abbreviations used in the examples have the following significance.
mg: milligram, g: gram, mL: milliliter, MHz: megahertz.
　以下の実施例において、核磁気共鳴（以下、1H NMR)スペクトルは、テトラメチルシランを標準物質として、ケミカルシフト値をδ値(ppm)にて記載した。分裂パターンは一重線をs、二重線をd、三重線をt、四重線をq、多重線をmで示した。質量分析（以下、MS)は、FAB(Fast Atom Bombardment)法、EI(Electron Ionization)法、APCI(Atmospheric Pressure Chemical Ionization)法もしくはESI（Electron Spray Ionization)法で行った。 In the following examples, nuclear magnetic resonance (hereinafter, 1 H NMR) spectra are described with chemical shift values as δ values (ppm) using tetramethylsilane as a standard substance. The splitting pattern is indicated by s for single lines, d for double lines, t for triple lines, q for quadruple lines, and m for multiple lines. Mass spectrometry (hereinafter referred to as MS) was carried out by FAB (Fast Atom Bombardment) method, EI (Electron Ionization) method, APCI (Atmospheric Pressure Chemical Ionization) method or ESI (Electron Spray Ionization) method.
　ヘキサンは、n-ヘキサンを示し、THFはテトラヒドロフランを示し、DME は1,2-ジメトキシエタンを示し、DMA はN,N-ジメチルアセトアミドを示し、DMFはN,N-ジメチルホルムアミドを示し、DBUは1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エンを示し、2nd generation X-phos precatalystはクロロ(2-ジシクロヘキシルホスフィノ-2',4',6'-トリイソプロピル-1,1'-ビフェニル)[2-(2'-アミノ-1,1'-ビフェニル)]パラジウム(II)を示し、WSC・HClはN-(3-ジメチルアミノプロピル)-N′-エチルカルボジイミド塩酸塩を示し、DMPUは1,3-ジメチル-3,4,5,6-テトラヒドロ-2(1H)-ピリミジノンを示し、WSC・HClはN-(3-ジメチルアミノプロピル)-N′-エチルカルボジイミド塩酸塩を示し、DMPUは1,3-ジメチル-3,4,5,6-テトラヒドロ-2(1H)-ピリミジノンを示す。 Hexane represents n-hexane, THF represents tetrahydrofuran, DME represents 1,2-dimethoxyethane, DMA represents N, N-dimethylacetamide, DMF represents N, N-dimethylformamide, DBU represents 1,8-diazabicyclo [5.4.0] undec-7-ene, 2nd generation X-phos precatalyst is chloro (2-dicyclohexylphosphino-2 ', 4', 6'-triisopropyl-1,1'- Biphenyl) [2- (2′-amino-1,1′-biphenyl)] palladium (II), WSC · HCl represents N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride, DMPU indicates 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone, WSC · HCl indicates N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride DMPU represents 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone.
　化合物中及び化合物名称中のアスタリスク(*)は、化合物がラセミ体であることを示す。 An asterisk (*) in the compound and in the compound name indicates that the compound is a racemate.
　以下の実施例中のキラルカラムによる光学分割では、第一ピークを低極性化合物、第二ピークを高極性化合物として示した。 In the optical resolution using the chiral column in the following examples, the first peak was shown as a low polarity compound, and the second peak was shown as a high polarity compound.
(実施例1)
　6-[4-メトキシ-2-メチル-3-(2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)フェニル]-3-メチルピリジン-2-カルボン酸
(1a) tert-ブチル　6-{3-[(4,4-ジメチル-2,6-ジオキソシクロヘキシリデン)メチル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　公知化合物であるtert-ブチル　6-(3-ホルミル-4-メトキシ-2-メチルフェニル)-3-メチルピリジン-2-カルボキシレート(1.40 g, 4.10 mmol)及びL-プロリン(23.6 mg, 0.250 mmol)のアセトニトリル(7.0 mL)溶液に60℃でジメドン(632 mg, 4.51 mmol)を加え、反応溶液を60℃で2.5時間攪拌した。室温まで冷却後、反応溶液に飽和炭酸水素ナトリウム水溶液を加えて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をジイソプロピルエーテル及びヘキサンで結晶化し、標記化合物(1.82 g, 96％)を得た。
1H-NMR(500MHz, CDCl3):δ ppm: 1.13 (6H, s), 1.63 (9H, s), 2.27 (3H, s), 2.51 (3H, s), 2.55 (2H, s), 2.62 (2H, m), 3.76 (3H, s), 6.79 (1H, d, J = 8.5 Hz), 7.37 (1H, d, J = 7.8 Hz), 7.54 (1H, d, J = 8.5 Hz), 7.58 (1H, d, J = 8.1 Hz), 7.93 (1H, s).
(1b) tert-ブチル　6-[4-メトキシ-2-メチル-3-(3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)フェニル]-3-メチルピリジン-2-カルボキシレート
　実施例1aで製造したtert-ブチル6-{3-[(4,4-ジメチル-2,6-ジオキソシクロヘキシリデン)メチル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(500 mg, 1.08 mmol)及び6,6-ジメチルピペリジン-2,4-ジオン(167 mg, 1.19 mmol)のDMF (5.4 mL)溶液に室温で炭酸セシウム(1.05 g, 3.24 mmol)を加えた。反応溶液を室温で30分攪拌後、メタンスルホニルクロリド(125 μL, 1.62 mmol)を加え、反応溶液を50℃で1時間攪拌した。室温まで冷却後、反応溶液に水及び酢酸エチルを加えて、析出した結晶をろ過し、標記化合物(111 mg, 18%)を得た。
1H-NMR(500MHz, CDCl3):δ ppm: 0.96 (3H, s), 1.09 (3H, s), 1.19 (3H, s), 1.29 (3H, s), 1.63 (9H, s), 2.14 (1H, d, J = 16.4 Hz), 2.22 (1H, d, J = 16.6 Hz), 2.33 (2H, d, J = 18.3 Hz), 2.45 (1H, d, J = 17.8 Hz), 2.49 (3H, s), 2.64 (1H, d, J = 16.6 Hz), 2.83 (3H, s), 3.73 (3H, s), 5.01 (1H, s), 5.16 (1H, s), 6.69 (1H, d, J = 8.8 Hz), 7.26 (1H, d, J = 8.3 Hz), 7.37 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.1 Hz).
(1c) tert-ブチル　6-[4-メトキシ-2-メチル-3-(2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)フェニル]-3-メチルピリジン-2-カルボキシレート
　実施例1bで製造したtert-ブチル　6-[4-メトキシ-2-メチル-3-(3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)フェニル]-3-メチルピリジン-2-カルボキシレート(110 mg, 0.187 mmol)、ヨウ化メチル(117 mg, 1.87 mmol)のDMF (1.0 mL)溶液に0℃で水素化ナトリウム(60%, 9.0 mg, 0.225 mmol)を加えた。反応溶液を1時間室温で攪拌後、水を加えて酢酸エチルで2回抽出した。有機層を水及び飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をジイソプロピルエーテルより結晶化し、標記化合物(63.0 mg, 56%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.96 (3H, s), 1.09 (3H, s), 1.11 (3H, s), 1.35 (3H, s), 1.64 (9H, s), 2.13 (1H, d, J = 16.4 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.31 (1H, d, J = 16.8 Hz), 2.33 (1H, d, J = 17.6 Hz), 2.45 (1H, d, J = 17.6 Hz), 2.49 (3H, s), 2.64 (1H, dd, J = 2.0, 16.8 Hz), 2.80 (3H, s), 2.86 (3H, s), 3.72 (3H, s), 5.18 (1H, s), 6.68 (1H, d, J = 8.6 Hz), 7.26 (1H, d, J = 7.0 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.53 (1H, d, J = 8.2 Hz).
(1d) 6-[4-メトキシ-2-メチル-3-(2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)フェニル]-3-メチルピリジン-2-カルボン酸
　実施例1cで製造したtert-ブチル　6-[4-メトキシ-2-メチル-3-(2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)フェニル]-3-メチルピリジン-2-カルボキシレート(63.0 mg, 0.105 mmol)のジクロロメタン(3.0 mL)溶液に室温でトリフルオロ酢酸(3.0 mL)を加え、反応溶液を室温で14時間攪拌した。反応溶液を濃縮後、残渣をエーテル及びヘキサンより結晶化し、標記化合物(40.9 mg, 72%)を得た。 (Example 1)
6- [4-Methoxy-2-methyl-3- (2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl) phenyl] -3-methylpyridine-2-carboxylic acid
(1a) tert-butyl 6- {3-[(4,4-dimethyl-2,6-dioxocyclohexylidene) methyl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxy Rate Known compounds tert-butyl 6- (3-formyl-4-methoxy-2-methylphenyl) -3-methylpyridine-2-carboxylate (1.40 g, 4.10 mmol) and L-proline (23.6 mg, 0.250) mmol) in acetonitrile (7.0 mL) was added dimedone (632 mg, 4.51 mmol) at 60 ° C., and the reaction solution was stirred at 60 ° C. for 2.5 hours. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was crystallized from diisopropyl ether and hexane to obtain the title compound (1.82 g, 96%).
1 H-NMR (500 MHz, CDCl 3 ): δ ppm: 1.13 (6H, s), 1.63 (9H, s), 2.27 (3H, s), 2.51 (3H, s), 2.55 (2H, s), 2.62 (2H, m), 3.76 (3H, s), 6.79 (1H, d, J = 8.5 Hz), 7.37 (1H, d, J = 7.8 Hz), 7.54 (1H, d, J = 8.5 Hz), 7.58 (1H, d, J = 8.1 Hz), 7.93 (1H, s).
(1b) tert-butyl 6- [4-methoxy-2-methyl-3- (3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9 , 10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl) phenyl] -3-methylpyridine-2-carboxylate tert-butyl 6- {3-[(4 , 4-Dimethyl-2,6-dioxocyclohexylidene) methyl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (500 mg, 1.08 mmol) and 6,6-dimethyl Cesium carbonate (1.05 g, 3.24 mmol) was added to a DMF (5.4 mL) solution of piperidine-2,4-dione (167 mg, 1.19 mmol) at room temperature. The reaction solution was stirred at room temperature for 30 minutes, methanesulfonyl chloride (125 μL, 1.62 mmol) was added, and the reaction solution was stirred at 50 ° C. for 1 hour. After cooling to room temperature, water and ethyl acetate were added to the reaction solution, and the precipitated crystals were filtered to obtain the title compound (111 mg, 18%).
1 H-NMR (500 MHz, CDCl 3 ): δ ppm: 0.96 (3H, s), 1.09 (3H, s), 1.19 (3H, s), 1.29 (3H, s), 1.63 (9H, s), 2.14 (1H, d, J = 16.4 Hz), 2.22 (1H, d, J = 16.6 Hz), 2.33 (2H, d, J = 18.3 Hz), 2.45 (1H, d, J = 17.8 Hz), 2.49 (3H , s), 2.64 (1H, d, J = 16.6 Hz), 2.83 (3H, s), 3.73 (3H, s), 5.01 (1H, s), 5.16 (1H, s), 6.69 (1H, d, J = 8.8 Hz), 7.26 (1H, d, J = 8.3 Hz), 7.37 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.1 Hz).
(1c) tert-butyl 6- [4-methoxy-2-methyl-3- (2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8, 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl) phenyl] -3-methylpyridine-2-carboxylate tert-butyl 6- [4-methoxy- prepared in Example 1b 2-Methyl-3- (3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2- c] Pyridin-10-yl) phenyl] -3-methylpyridine-2-carboxylate (110 mg, 0.187 mmol), methyl iodide (117 mg, 1.87 mmol) in DMF (1.0 mL) at 0 ° C. Sodium chloride (60%, 9.0 mg, 0.225 mmol) was added. The reaction solution was stirred for 1 hour at room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was crystallized from diisopropyl ether to obtain the title compound (63.0 mg, 56%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.96 (3H, s), 1.09 (3H, s), 1.11 (3H, s), 1.35 (3H, s), 1.64 (9H, s), 2.13 (1H, d, J = 16.4 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.31 (1H, d, J = 16.8 Hz), 2.33 (1H, d, J = 17.6 Hz), 2.45 (1H , d, J = 17.6 Hz), 2.49 (3H, s), 2.64 (1H, dd, J = 2.0, 16.8 Hz), 2.80 (3H, s), 2.86 (3H, s), 3.72 (3H, s) , 5.18 (1H, s), 6.68 (1H, d, J = 8.6 Hz), 7.26 (1H, d, J = 7.0 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.53 (1H, d, J = 8.2 Hz).
(1d) 6- [4-Methoxy-2-methyl-3- (2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10 -Octahydro-1H-chromeno [3,2-c] pyridin-10-yl) phenyl] -3-methylpyridine-2-carboxylic acid tert-butyl 6- [4-methoxy-2-methyl prepared in Example 1c -3- (2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] To a solution of (pyridin-10-yl) phenyl] -3-methylpyridine-2-carboxylate (63.0 mg, 0.105 mmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (3.0 mL) at room temperature, and the reaction solution was stirred at room temperature. Stir for 14 hours. The reaction solution was concentrated, and the residue was crystallized from ether and hexane to obtain the title compound (40.9 mg, 72%).
(実施例2)
　6-[4-メトキシ-2-メチル-3-(2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)フェニル]-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(2a) tert-ブチル　6-[3-(2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート
　実施例1bで製造したtert-ブチル　6-[4-メトキシ-2-メチル-3-(3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)フェニル]-3-メチルピリジン-2-カルボキシレート(300 mg, 0.511 mmol)及びヨウ化エチル(848 μL, 5.11 mmol)のDMF (10 mL)溶液に0℃で水素化ナトリウム(60%, 40.9 mg, 1.02 mmol)を加えた。反応溶液を3時間室温で攪拌後、水を加えて酢酸エチルで2回抽出した。有機層を水及び飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 2:8)で精製し、標記化合物(178 mg, 57%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.95 (3H, s), 1.08 (3H, s), 1.08 (3H, t, J = 3.9 Hz), 1.12 (3H, s), 1.40 (3H, s), 1.63 (9H, s), 2.13 (1H, dd, J = 1.2, 16.4 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.27 (1H, d, J = 16.8 Hz), 2.33 (1H, dd, J = 0.8, 17.2 Hz), 2.44 (1H, d, J = 17.6 Hz), 2.49 (3H, s), 2.67 (1H, dd, J = 1.6, 17.2 Hz), 2.87 (3H, s), 3.01 (1H, dq, J = 7.0, 14.1 Hz), 3.56 (1H, dq, J = 7.0, 14.5 Hz), 3.72 (3H, s), 5.21 (1H, s), 6.68 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 7.8 Hz).
(2b) 6-[4-メトキシ-2-メチル-3-(2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)フェニル]-3-メチルピリジン-2-カルボン酸
　実施例2aで製造したtert-ブチル　6-[3-(2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート(178 mg, 0.290 mmol)のジクロロメタン(3.0 mL)溶液に室温でトリフルオロ酢酸(1.0 mL)を加え、反応溶液を4時間室温で攪拌した。反応溶液を濃縮し、粗製の標記化合物を得た。
(2c) 6-[4-メトキシ-2-メチル-3-(2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)フェニル]-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例2bで製造した粗製の6-[4-メトキシ-2-メチル-3-(2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)フェニル]-3-メチルピリジン-2-カルボン酸のエタノール(5.0 mL)溶液にtert-ブチルアミン(46 μL, 0.435 mmol)を加え、室温で1時間攪拌した。反応溶液を濃縮後、残渣をヘキサン及びアセトンより結晶化し、標記化合物(80.0 mg, 44%, 2 steps)を得た。 (Example 2)
6- [4-Methoxy-2-methyl-3- (2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl) phenyl] -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(2a) tert-butyl 6- [3- (2-ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro -1H-chromeno [3,2-c] pyridin-10-yl) -4-methoxy-2-methylphenyl] -3-methylpyridine-2-carboxylate tert-butyl 6- [4 prepared in Example 1b -Methoxy-2-methyl-3- (3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3 , 2-c] pyridin-10-yl) phenyl] -3-methylpyridine-2-carboxylate (300 mg, 0.511 mmol) and ethyl iodide (848 μL, 5.11 mmol) in DMF (10 mL) solution. Sodium hydride (60%, 40.9 mg, 1.02 mmol) was added at ° C. The reaction solution was stirred for 3 hours at room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 2: 8) to obtain the title compound (178 mg, 57%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.95 (3H, s), 1.08 (3H, s), 1.08 (3H, t, J = 3.9 Hz), 1.12 (3H, s), 1.40 (3H , s), 1.63 (9H, s), 2.13 (1H, dd, J = 1.2, 16.4 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.27 (1H, d, J = 16.8 Hz), 2.33 (1H, dd, J = 0.8, 17.2 Hz), 2.44 (1H, d, J = 17.6 Hz), 2.49 (3H, s), 2.67 (1H, dd, J = 1.6, 17.2 Hz), 2.87 (3H, s), 3.01 (1H, dq, J = 7.0, 14.1 Hz), 3.56 (1H, dq, J = 7.0, 14.5 Hz), 3.72 (3H, s), 5.21 (1H, s), 6.68 (1H, d , J = 8.6 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 7.8 Hz).
(2b) 6- [4-Methoxy-2-methyl-3- (2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10 -Octahydro-1H-chromeno [3,2-c] pyridin-10-yl) phenyl] -3-methylpyridine-2-carboxylic acid tert-butyl 6- [3- (2-ethyl-) prepared in Example 2a 3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl ) -4-Methoxy-2-methylphenyl] -3-methylpyridine-2-carboxylate (178 mg, 0.290 mmol) in dichloromethane (3.0 mL) at room temperature was added trifluoroacetic acid (1.0 mL), and the reaction solution Was stirred at room temperature for 4 hours. The reaction solution was concentrated to give the crude title compound.
(2c) 6- [4-Methoxy-2-methyl-3- (2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10 -Octahydro-1H-chromeno [3,2-c] pyridin-10-yl) phenyl] -3-methylpyridine-2-carboxylic acid tert-butylamine salt Crude 6- [4-methoxy-] prepared in Example 2b 2-Methyl-3- (2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2 To a solution of -c] pyridin-10-yl) phenyl] -3-methylpyridine-2-carboxylic acid in ethanol (5.0 mL) was added tert-butylamine (46 μL, 0.435 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was crystallized from hexane and acetone to obtain the title compound (80.0 mg, 44%, 2 steps).
(実施例3)
　6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　t-ブチルアミン塩もしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　t-ブチルアミン塩
(3a) tert-ブチル　6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート及びtert-ブチル　6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例1cで製造したtert-ブチル　6-[4-メトキシ-2-メチル-3-(2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)フェニル]-3-メチルピリジン-2-カルボキシレート(225 mg)をChiral flash IA(ダイセル化学工業; ヘキサン/エタノール；4:6)により光学分割し、高極性化合物(103 mg)及び低極性化合物(110 mg)を得た。
(3b) 6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸もしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例3aで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレートもしくはtert-ブチル　6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(低極性化合物;110 mg, 0.183 mmol)、ジクロロメタン(4.0 mL)及びトリフルオロ酢酸(4.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(67.3 mg, 68%)を得た。
MS(ESI/APCI)m/z: 545[M+H]+.
(3c) 6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩もしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例3bで製造した6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸もしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(133 mg, 0.244 mmol)のエタノール(2.0 mL)溶液にtert-ブチルアミン(52 μL, 0.491 mmol)を加え、反応溶液を室温で2時間攪拌した。反応溶液を濃縮後、残渣をヘキサン及び酢酸エチルより結晶化し、標記化合物(107 mg, 71%)を得た。 (Example 3)
6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9, 10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid t-butylamine salt or 6- {4-methoxy-2-methyl-3- [(10R) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c ] Pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid t-butylamine salt
(3a) tert-butyl 6- {4-methoxy-2-methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6, 7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylate and tert-butyl 6- {4-methoxy-2 -Methyl-3-[(10R) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [ 3,2-c] Pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylate tert-butyl 6- [4-methoxy-2-methyl-3- (2,3) prepared in Example 1c , 3,7,7-Pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl) phenyl ] -3-Methylpyridine-2-carboxylate (225 mg) was optically resolved with Chiral flash IA (Daicel Chemical Industries; Hexane / Ethanol; 4: 6) to obtain a high polar compound (103 mg) and a low polar compound (110 mg).
(3b) 6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8 , 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2-methyl-3- [ (10R) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] Pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butyl 6- {4-methoxy-2-methyl-3-[(10S) -2,3,3 prepared in Example 3a , 7,7-Pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl}- 3-methylpyridine-2-carboxylate or tert-butyl 6- {4-methoxy-2-methyl-3-[(10R) -2,3,3,7,7-pentamethyl-1,9-dioxo-2 , 3,4,6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylate (low polarity Compound; 110 mg, 0.183 mmol), dichloromethane (4.0 mL) and trifluoroacetic acid (4.0 mL) were used for the reaction and workup according to Example 1d to give the title compound (67.3 mg, 68%) Got.
MS (ESI / APCI) m / z: 545 [M + H] +.
(3c) 6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8 , 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt or 6- {4-methoxy-2-methyl -3-[(10R) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3, 2-c] Pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt 6- {4-methoxy-2-methyl-3-[(10S)-prepared in Example 3b 2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridine-10- Yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2-methyl-3-[(10R) -2,3,3,7,7-pentamethyl-1,9-dioxo -2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid (133 m g, 0.244 mmol) in ethanol (2.0 mL) was added tert-butylamine (52 μL, 0.491 mmol), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was crystallized from hexane and ethyl acetate to obtain the title compound (107 mg, 71%).
(実施例4)
　6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩もしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(4a) 6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸もしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例3aで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレートもしくはtert-ブチル　6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(高極性化合物;103 mg, 0.171 mmol)、ジクロロメタン(4.0 mL)及びトリフルオロ酢酸(4.0 mL) を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(64.0 mg, 69%)を得た。
MS(ESI/APCI)m/z: 545[M+H]+.
(4b) 6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩もしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例4aで製造した6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸もしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(92.1 mg, 0.169 mmol)、エタノール(2.0 mL)及びtert-ブチルアミン(36 μL, 0.338 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(170.4 mg, 67%)を得た。 (Example 4)
6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9, 10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt or 6- {4-methoxy-2-methyl-3- [(10R) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c ] Pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(4a) 6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8 , 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2-methyl-3- [ (10R) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] Pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butyl 6- {4-methoxy-2-methyl-3-[(10S) -2,3,3 prepared in Example 3a , 7,7-Pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl}- 3-methylpyridine-2-carboxylate or tert-butyl 6- {4-methoxy-2-methyl-3-[(10R) -2,3,3,7,7-pentamethyl-1,9-dioxo-2 , 3,4,6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylate (high polarity Compound; 103 mg, 0.171 mmol), dichloromethane (4.0 mL) and trifluoroacetic acid (4.0 mL) were used to carry out the reaction and post-treatment according to Example 1d to give the title compound (64.0 mg, 69%) Got.
MS (ESI / APCI) m / z: 545 [M + H] +.
(4b) 6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8 , 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt or 6- {4-methoxy-2-methyl -3-[(10R) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3, 2-c] Pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt 6- {4-methoxy-2-methyl-3-[(10S)-prepared in Example 4a 2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridine-10- Yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2-methyl-3-[(10R) -2,3,3,7,7-pentamethyl-1,9-dioxo -2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid (92.1 mg, 0.169 mmol), ethanol (2.0 mL) and tert-butylamine (36 μL, 0.338 mmol) were used for the reaction and post-treatment according to Example 3c to give the title compound (170.4 mg, 67%). Obtained.
(実施例5)
　6-{4-メトキシ-2-メチル-3-[3,3,7,7-テトラメチル-1,9-ジオキソ-2-(プロパ-2-エン-1-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(5a) tert-ブチル　6-{4-メトキシ-2-メチル-3-[3,3,7,7-テトラメチル-1,9-ジオキソ-2-(プロパ-2-エン-1-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例1bで製造したtert-ブチル　6-[4-メトキシ-2-メチル-3-(3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)フェニル]-3-メチルピリジン-2-カルボキシレート(3.00 g, 5.11 mmol)、ヨウ化アリル(2.33 mL, 25.6 mmol)、DMF (102 mL)及び水素化ナトリウム(60%, 409 mg, 10.2 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(1.92 g, 60%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.96 (3H, s), 1.09 (3H, s), 1.11 (3H, s), 1.36 (3H, s), 1.64 (9H, s), 2.13 (1H, d, J = 16.4 Hz), 2.22 (1H, d, J = 16.0 Hz), 2.27 (1H, d, J = 16.8 Hz), 2.34 (1H, d, J = 17.6 Hz), 2.45 (1H, d, J = 17.6 Hz), 2.49 (3H, s), 2.72 (1H, dd, J = 1.6, 16.8 Hz), 2.86 (3H, s), 3.63 (1H, dd, J = 5.1, 16.4 Hz), 3.72 (3H, s), 4.21 (1H, dd, J = 5.1, 16.4 Hz), 5.02-5.10 (2H, m), 5.22 (1H, s), 5.77-5.86 (1H, m), 6.69 (1H, d, J = 8.6 Hz), 7.29 (1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 8.2 Hz), 7.52 (1H, d, J = 8.2 Hz).
(5b) 6-{4-メトキシ-2-メチル-3-[3,3,7,7-テトラメチル-1,9-ジオキソ-2-(プロパ-2-エン-1-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例5aで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[3,3,7,7-テトラメチル-1,9-ジオキソ-2-(プロパ-2-エン-1-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(104 mg, 0.166 mmol)、ジクロロメタン(2.0 mL)及びトリフルオロ酢酸(2.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(90.4 mg, 95%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.97 (3H, s), 1.11 (3H, s), 1.17 (3H, s), 1.38 (3H, s), 2.15 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.32 (1H, d, J = 16.8 Hz), 2.36 (1H, d, J = 16.0 Hz), 2.48 (1H, d, J = 17.2 Hz), 2.74 (1H, d, J = 17.2 Hz), 2.80 (3H, s), 2.89 (3H, s), 3.64 (1H, d, J = 17.2 Hz), 3.76 (3H, s), 4.22 (1H, d, J = 14.5 Hz), 5.03-5.10 (2H, m), 5.21 (1H, s), 5.74-5.84 (1H, m), 6.73 (1H, d, J = 8.2 Hz), 7.21 (1H, d, J = 8.6 Hz), 7.58 (1H, d, J = 7.4 Hz), 7.69 (1H, d, J = 7.0 Hz).
(5c) 6-{4-メトキシ-2-メチル-3-[3,3,7,7-テトラメチル-1,9-ジオキソ-2-(プロパ-2-エン-1-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例5bで製造した6-{4-メトキシ-2-メチル-3-[3,3,7,7-テトラメチル-1,9-ジオキソ-2-(プロパ-2-エン-1-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(90.4 mg, 0.158 mmol)、エタノール(2.0 mL)及びtert-ブチルアミン(33 μL, 0.317 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(56.9 mg, 56%)を得た。 (Example 5)
6- {4-Methoxy-2-methyl-3- [3,3,7,7-tetramethyl-1,9-dioxo-2- (prop-2-en-1-yl) -2,3,4 , 6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(5a) tert-butyl 6- {4-methoxy-2-methyl-3- [3,3,7,7-tetramethyl-1,9-dioxo-2- (prop-2-en-1-yl) -2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylate Example 1b Tert-butyl 6- [4-methoxy-2-methyl-3- (3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9 , 10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl) phenyl] -3-methylpyridine-2-carboxylate (3.00 g, 5.11 mmol), allyl iodide (2.33 mL, 25.6 mmol) ), DMF (102 mL) and sodium hydride (60%, 409 mg, 10.2 mmol), the title compound (1.92 g, 60%) was obtained by carrying out the reaction and post-treatment according to Example 2a. It was.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.96 (3H, s), 1.09 (3H, s), 1.11 (3H, s), 1.36 (3H, s), 1.64 (9H, s), 2.13 (1H, d, J = 16.4 Hz), 2.22 (1H, d, J = 16.0 Hz), 2.27 (1H, d, J = 16.8 Hz), 2.34 (1H, d, J = 17.6 Hz), 2.45 (1H , d, J = 17.6 Hz), 2.49 (3H, s), 2.72 (1H, dd, J = 1.6, 16.8 Hz), 2.86 (3H, s), 3.63 (1H, dd, J = 5.1, 16.4 Hz) , 3.72 (3H, s), 4.21 (1H, dd, J = 5.1, 16.4 Hz), 5.02-5.10 (2H, m), 5.22 (1H, s), 5.77-5.86 (1H, m), 6.69 (1H , d, J = 8.6 Hz), 7.29 (1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 8.2 Hz), 7.52 (1H, d, J = 8.2 Hz).
(5b) 6- {4-Methoxy-2-methyl-3- [3,3,7,7-tetramethyl-1,9-dioxo-2- (prop-2-en-1-yl) -2, 3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid prepared in Example 5a tert-butyl 6- {4-methoxy-2-methyl-3- [3,3,7,7-tetramethyl-1,9-dioxo-2- (prop-2-en-1-yl) -2, 3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylate (104 mg, 0.166 mmol ), Dichloromethane (2.0 mL) and trifluoroacetic acid (2.0 mL) were reacted and worked up according to Example 1d to obtain the title compound (90.4 mg, 95%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.97 (3H, s), 1.11 (3H, s), 1.17 (3H, s), 1.38 (3H, s), 2.15 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.32 (1H, d, J = 16.8 Hz), 2.36 (1H, d, J = 16.0 Hz), 2.48 (1H, d, J = 17.2 Hz ), 2.74 (1H, d, J = 17.2 Hz), 2.80 (3H, s), 2.89 (3H, s), 3.64 (1H, d, J = 17.2 Hz), 3.76 (3H, s), 4.22 (1H , d, J = 14.5 Hz), 5.03-5.10 (2H, m), 5.21 (1H, s), 5.74-5.84 (1H, m), 6.73 (1H, d, J = 8.2 Hz), 7.21 (1H, d, J = 8.6 Hz), 7.58 (1H, d, J = 7.4 Hz), 7.69 (1H, d, J = 7.0 Hz).
(5c) 6- {4-Methoxy-2-methyl-3- [3,3,7,7-tetramethyl-1,9-dioxo-2- (prop-2-en-1-yl) -2, 3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt Examples 6- {4-Methoxy-2-methyl-3- [3,3,7,7-tetramethyl-1,9-dioxo-2- (prop-2-en-1-yl) -2 prepared in 5b , 3,4,6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid (90.4 mg, 0.158 mmol), ethanol (2.0 mL) and tert-butylamine (33 μL, 0.317 mmol) were used for the reaction and post-treatment according to Example 3c to obtain the title compound (56.9 mg, 56%).
(実施例6)
　6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルl-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩もしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルl-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
(6a) 6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルl-N-(メチルスルホニル)ピリジン-2-カルボキサミドもしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルl-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例3bで製造した6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸もしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(164 mg, 0.302 mmol)及びカルボニルジイミダゾール(63.6 mg, 0.392 mmol)のDMF (1.5 mL)溶液を室温で1時間攪拌した。反応溶液にメタンスルホンアミド(37.3 mg, 0.392 mmol)及びDBU (54 μL, 0.362 mmol)を加え、反応溶液を室温で3.5時間攪拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで2回抽出した。有機層を水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル)で精製し、標記化合物(122 mg, 65%)を得た。
(6b) 6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルl-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩もしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルl-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
　実施例6aで製造した6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルl-N-(メチルスルホニル)ピリジン-2-カルボキサミドもしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルl-N-(メチルスルホニル)ピリジン-2-カルボキサミド(122 mg, 0.196 mmol)、エタノール(2.0 mL)及びtert-ブチルアミン(41 μL, 0.392 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(86.0 mg, 63%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.96 (9H, s), 1.11 (3H, s), 1.18 (3H, s), 1.26 (3H, s), 1.35 (3H, s), 2.12 (1H, d, J = 17.2 Hz), 2.26 (1H, d, J = 16.8 Hz), 2.37 (1H, d, J = 17.6 Hz), 2.40 (1H, d, J = 17.2 Hz), 2.50 (1H, d, J = 18.4 Hz), 2.61 (1H, d, J = 18.0 Hz), 2.69 (3H, s), 2.77 (3H, s), 2.81 (3H, s), 3.28 (3H, s), 3.74 (3H, s), 5.07 (1H, s), 6.70 (1H, d, J = 8.6 Hz), 7.11 (1H, d, J = 8.6 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.61 (1H, d, J = 8.2 Hz). (Example 6)
6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9, 10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methyl lN- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt or 6- {4-methoxy-2 -Methyl-3-[(10R) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [ 3,2-c] pyridin-10-yl] phenyl} -3-methyllN- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt
(6a) 6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8 , 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methyllN- (methylsulfonyl) pyridine-2-carboxamide or 6- {4-methoxy-2- Methyl-3-[(10R) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3 , 2-c] pyridin-10-yl] phenyl} -3-methyl lN- (methylsulfonyl) pyridine-2-carboxamide 6- {4-methoxy-2-methyl-3-[(10S ) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridine- 10-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2-methyl-3-[(10R) -2,3,3,7,7-pentamethyl-1,9 -Dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-ca Bon acid (164 mg, 0.302 mmol) and carbonyl diimidazole (63.6 mg, 0.392 mmol) and DMF (1.5 mL) solution was stirred at room temperature for 1 h. Methanesulfonamide (37.3 mg, 0.392 mmol) and DBU (54 μL, 0.362 mmol) were added to the reaction solution, and the reaction solution was stirred at room temperature for 3.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (122 mg, 65%).
(6b) 6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8 , 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methyllN- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt or 6- {4- Methoxy-2-methyl-3-[(10R) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methyl lN- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt 6- {4-methoxy-2 prepared in Example 6a -Methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [ 3,2-c] pyridin-10-yl] phenyl} -3-methyl lN- (methylsulfonyl) pyridine-2-carboxamide or 6- {4-methoxy-2-methyl-3-[(10R) -2, 3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1 H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methyl lN- (methylsulfonyl) pyridine-2-carboxamide (122 mg, 0.196 mmol), ethanol (2.0 mL) and tert-butylamine (41 μL, 0.392 mmol) was used for the reaction and post-treatment according to Example 3c to obtain the title compound (86.0 mg, 63%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.96 (9H, s), 1.11 (3H, s), 1.18 (3H, s), 1.26 (3H, s), 1.35 (3H, s), 2.12 (1H, d, J = 17.2 Hz), 2.26 (1H, d, J = 16.8 Hz), 2.37 (1H, d, J = 17.6 Hz), 2.40 (1H, d, J = 17.2 Hz), 2.50 (1H , d, J = 18.4 Hz), 2.61 (1H, d, J = 18.0 Hz), 2.69 (3H, s), 2.77 (3H, s), 2.81 (3H, s), 3.28 (3H, s), 3.74 (3H, s), 5.07 (1H, s), 6.70 (1H, d, J = 8.6 Hz), 7.11 (1H, d, J = 8.6 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.61 (1H, d, J = 8.2 Hz).
(実施例7)
　6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルl-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩もしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルl-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
(7a) 6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルl-N-(メチルスルホニル)ピリジン-2-カルボキサミドもしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルl-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例4aで製造した6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸もしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(126 mg, 0.231 mmol)、カルボニルジイミダゾール(48.7 mg, 0.300 mmol)、DMF (1.2 mL)、メタンスルホンアミド(28.6 mg, 0.301 mmol)及びDBU (42 μL, 0.278 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(130 mg, 91%)を得た。
(7b) 6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルl-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩もしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルl-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
　実施例7aで製造した6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルl-N-(メチルスルホニル)ピリジン-2-カルボキサミドもしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルl-N-(メチルスルホニル)ピリジン-2-カルボキサミド(130 mg, 0.209 mmol)、エタノール(2.0 mL)及びtert-ブチルアミン(44 μL, 0.418 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(107 mg, 74%)を得た。 (Example 7)
6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9, 10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methyl lN- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt or 6- {4-methoxy-2 -Methyl-3-[(10R) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [ 3,2-c] pyridin-10-yl] phenyl} -3-methyllN- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt
(7a) 6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8 , 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methyllN- (methylsulfonyl) pyridine-2-carboxamide or 6- {4-methoxy-2- Methyl-3-[(10R) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3 , 2-c] pyridin-10-yl] phenyl} -3-methyl lN- (methylsulfonyl) pyridine-2-carboxamide 6- {4-methoxy-2-methyl-3-[(10S ) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridine- 10-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2-methyl-3-[(10R) -2,3,3,7,7-pentamethyl-1,9 -Dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-ca Conducted using boric acid (126 mg, 0.231 mmol), carbonyldiimidazole (48.7 mg, 0.300 mmol), DMF (1.2 mL), methanesulfonamide (28.6 mg, 0.301 mmol) and DBU (42 μL, 0.278 mmol) The title compound (130 mg, 91%) was obtained by carrying out the reaction and post-treatment according to Example 6a.
(7b) 6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8 , 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methyllN- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt or 6- {4- Methoxy-2-methyl-3-[(10R) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methyl lN- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt 6- {4-methoxy-2 prepared in Example 7a -Methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [ 3,2-c] pyridin-10-yl] phenyl} -3-methyl lN- (methylsulfonyl) pyridine-2-carboxamide or 6- {4-methoxy-2-methyl-3-[(10R) -2, 3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1 H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methyllN- (methylsulfonyl) pyridine-2-carboxamide (130 mg, 0.209 mmol), ethanol (2.0 mL) and tert-butylamine (44 μL, 0.418 mmol) was used for the reaction and post-treatment according to Example 3c to obtain the title compound (107 mg, 74%).
(実施例8)
　6-{3-[(3R*,10S*,10aR*)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,6,7,8,9,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
(8a) tert-ブチル　6-{3-[(3R*,10S*,10aR*)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,6,7,8,9,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例1aで製造したtert-ブチル6-{3-[(4,4-ジメチル-2,6-ジオキソシクロヘキシリデン)メチル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(3.34 g, 7.21 mmol)及び公知化合物である6-(プロパン-2-イル)ピペリジン-2,4-ジオン(1.23 g, 7.93 mmol)のDMF (33 mL)溶液に0℃で炭酸セシウム(5.87 g, 18.0 mmol)を加えた。反応溶液を0℃で3時間攪拌後、水を加えて酢酸エチルで2回抽出、有機層を水で洗浄した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮し、粗製の付加物を得た。粗製の付加物及びトリフェニルホスフィン(2.27 g, 8.65 mmol)のTHF (33 mL)溶液に室温でジ-tert-ブチルアゾジカルボキシレート(1.99 g, 8.65 mmol)を加え、反応溶液を室温で1.5時間攪拌した。反応溶液を濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 1:2)で精製し、標記化合物(280 mg, 6.5%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.90 (3H, d, J = 7.0 Hz), 0.91 (3H, d, J = 6.7 Hz), 0.98 (3H, s), 1.07 (3H, s), 1.64 (9H, s), 1.78-1.85 (1H, m), 2.05 (1H, dd, J = 1.2, 16.4 Hz), 2.14 (1H, d, J = 16.4 Hz), 2.33 (1H, d, J = 18.0 Hz), 2.42 (1H, dd, J = 2.4, 17.6 Hz), 2.49 (3H, s), 2.66 (3H, s), 3.75 (3H, s), 3.82-3.86 (1H, m), 3.97-4.01 (1H, m), 4.45 (1H, dd, J = 1.6, 8.2 Hz), 5.46-5.48 (1H, m), 5.92 (1H, s), 6.72 (1H, d, J = 8.6 Hz), 7.30 (1H, d, J = 8.6 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.2 Hz).
　また、副生したtert-ブチル　6-{3-[(3S*,10S*)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2メチルフェニル}-3-メチルピリジン-2-カルボキシレート(553 mg, 13%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.87 (3H, d, J = 6.7 Hz), 0.90 (3H, d, J = 6.7 Hz), 0.94 (3H, s), 1.09 (3H, s), 1.63 (9H, s), 1.67-1.75 (1H, m), 2.12 (1H, dd, J = 1.2, 16.4 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.33 (1H, dd, J = 1.2, 17.2 Hz), 2.45 (1H, d, J = 17.6 Hz), 2.49-2.53 (1H, m), 2.49 (3H, s), 2.64 (1H, ddd, J = 1.6, 6.3, 16.8 Hz), 2.83 (3H, s), 3.23 (1H, dq, J = 2.7, 7.0 Hz), 3.70 (3H, s), 5.10 (1H, s), 5.36 (1H, d, J = 2.4 Hz), 6.68 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.38 (1H, d, J = 8.2 Hz), 7.52 (1H, d, J = 7.4 Hz).
　また、副生したtert-ブチル　6-{3-[(3S*,10R*)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2メチルフェニル}-3-メチルピリジン-2-カルボキシレート(70.0 mg, 1.6%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.95-0.97 (9H, m), 1.09 (3H, s), 1.63 (9H, s), 1.70-1.77 (1H, m), 2.14 (1H, d, J = 16.4 Hz), 2.21 (1H, d, J = 16.0 Hz), 2.32-2.52 (4H, m), 2.49 (3H, s), 2.84 (3H, s), 3.26-3.32 (1H, m), 3.74 (3H, s), 5.06 (1H, s), 5.16 (1H, s), 6.72 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 7.4 Hz), 7.36 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.2 Hz).
(8b) 6-{3-[(3R*,10S*,10aR*)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,6,7,8,9,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例8aで製造したtert-ブチル　6-{3-[(3R*,10S*,10aR*)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,6,7,8,9,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(70.0 mg, 0.116 mmol)、ジクロロメタン(4.0 mL)及びトリフルオロ酢酸(2.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(42.8 mg, 68%)を得た。 (Example 8)
6- {3-[(3R *, 10S *, 10aR *)-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,6,7,8,9 , 10,10a-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid
(8a) tert-butyl 6- {3-[(3R *, 10S *, 10aR *)-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,6 , 7,8,9,10,10a-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate Tert-butyl 6- {3-[(4,4-dimethyl-2,6-dioxocyclohexylidene) methyl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2 prepared in Example 1a -Carboxylate (3.34 g, 7.21 mmol) and the known compound 6- (propan-2-yl) piperidine-2,4-dione (1.23 g, 7.93 mmol) in DMF (33 mL) at 0 ° C Cesium (5.87 g, 18.0 mmol) was added. The reaction solution was stirred at 0 ° C. for 3 hours, water was added and the mixture was extracted twice with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude adduct. Di-tert-butyl azodicarboxylate (1.99 g, 8.65 mmol) was added to a crude adduct and a solution of triphenylphosphine (2.27 g, 8.65 mmol) in THF (33 mL) at room temperature, and the reaction solution was stirred at room temperature for 1.5. Stir for hours. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 1: 2) to obtain the title compound (280 mg, 6.5%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.90 (3H, d, J = 7.0 Hz), 0.91 (3H, d, J = 6.7 Hz), 0.98 (3H, s), 1.07 (3H, s ), 1.64 (9H, s), 1.78-1.85 (1H, m), 2.05 (1H, dd, J = 1.2, 16.4 Hz), 2.14 (1H, d, J = 16.4 Hz), 2.33 (1H, d, J = 18.0 Hz), 2.42 (1H, dd, J = 2.4, 17.6 Hz), 2.49 (3H, s), 2.66 (3H, s), 3.75 (3H, s), 3.82-3.86 (1H, m), 3.97-4.01 (1H, m), 4.45 (1H, dd, J = 1.6, 8.2 Hz), 5.46-5.48 (1H, m), 5.92 (1H, s), 6.72 (1H, d, J = 8.6 Hz) , 7.30 (1H, d, J = 8.6 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.2 Hz).
The by-product tert-butyl 6- {3-[(3S *, 10S *)-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4, 6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2methylphenyl} -3-methylpyridine-2-carboxylate (553 mg , 13%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.87 (3H, d, J = 6.7 Hz), 0.90 (3H, d, J = 6.7 Hz), 0.94 (3H, s), 1.09 (3H, s ), 1.63 (9H, s), 1.67-1.75 (1H, m), 2.12 (1H, dd, J = 1.2, 16.4 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.33 (1H, dd, J = 1.2, 17.2 Hz), 2.45 (1H, d, J = 17.6 Hz), 2.49-2.53 (1H, m), 2.49 (3H, s), 2.64 (1H, ddd, J = 1.6, 6.3, 16.8 Hz ), 2.83 (3H, s), 3.23 (1H, dq, J = 2.7, 7.0 Hz), 3.70 (3H, s), 5.10 (1H, s), 5.36 (1H, d, J = 2.4 Hz), 6.68 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.38 (1H, d, J = 8.2 Hz), 7.52 (1H, d, J = 7.4 Hz).
Further, tert-butyl 6- {3-[(3S *, 10R *)-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4, 6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2methylphenyl} -3-methylpyridine-2-carboxylate (70.0 mg , 1.6%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.95-0.97 (9H, m), 1.09 (3H, s), 1.63 (9H, s), 1.70-1.77 (1H, m), 2.14 (1H, d, J = 16.4 Hz), 2.21 (1H, d, J = 16.0 Hz), 2.32-2.52 (4H, m), 2.49 (3H, s), 2.84 (3H, s), 3.26-3.32 (1H, m ), 3.74 (3H, s), 5.06 (1H, s), 5.16 (1H, s), 6.72 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 7.4 Hz), 7.36 (1H , d, J = 7.8 Hz), 7.52 (1H, d, J = 8.2 Hz).
(8b) 6- {3-[(3R *, 10S *, 10aR *)-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,6,7, 8,9,10,10a-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid In Example 8a Prepared tert-butyl 6- {3-[(3R *, 10S *, 10aR *)-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,6, 7,8,9,10,10a-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (70.0 mg, 0.116 mmol), dichloromethane (4.0 mL) and trifluoroacetic acid (2.0 mL) were used for the reaction and post-treatment according to Example 1d to obtain the title compound (42.8 mg, 68%).
(実施例9)
　6-{3-[(3S,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
(9a) 6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンズアルデヒド
　窒素雰囲気下、3-ブロモ-6-メトキシ-2-メチルベンズアルデヒド(26.5 g, 116 mmol)、ビス(ピナコラト)ジボロン(31.8 g, 121 mmol)及び酢酸カリウム(35.1 g, 347 mmol)の1,4-ジオキサン(265mL)懸濁液にビス(トリフェニルホスフィン)パラジウム(II)ジクロリド(4.14 g, 5.78 mmol)を加え、加熱還流下で6時間攪拌した。室温まで冷却後、反応液に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 8:1)で精製し、標記化合物(22.0g, 69％)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 1.34 (12H, s), 2.77 (3H, s), 3.90 (3H, s), 6.81 (1H, d, J = 8.2 Hz), 7.90 (1H, d, J = 8.2 Hz), 10.64 (1H, s).
(9b) 2-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン
　実施例9aで製造した6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンズアルデヒド(1.00 g, 3.62 mmol)及びピロリジン(30 μL, 0.362 mmol)のDMF (3.6 mL)溶液に80℃でジメドン(507 mg, 3.62 mmol)を加え、反応溶液を80℃で20分間攪拌した。室温まで冷却後、反応溶液に1 M塩酸(5 mL)及びエーテル(5 mL)を加えて、反応溶液を室温でさらに30分間攪拌した。反応溶液をエーテルで抽出後、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 7:3)で精製し、標記化合物(860 mg, 60％)を得た。 (Example 9)
6- {3-[(3S, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid
(9a) 6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde 3-bromo-6-methoxy- under nitrogen atmosphere To a suspension of 2-methylbenzaldehyde (26.5 g, 116 mmol), bis (pinacolato) diboron (31.8 g, 121 mmol) and potassium acetate (35.1 g, 347 mmol) in 1,4-dioxane (265 mL) Phenylphosphine) palladium (II) dichloride (4.14 g, 5.78 mmol) was added, and the mixture was stirred for 6 hours under reflux with heating. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate; 8: 1) to obtain the title compound (22.0 g, 69%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.34 (12H, s), 2.77 (3H, s), 3.90 (3H, s), 6.81 (1H, d, J = 8.2 Hz), 7.90 (1H , d, J = 8.2 Hz), 10.64 (1H, s).
(9b) 2- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] -5,5-dimethylcyclohexane- 1,3-dione 6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde (1.00 g, prepared in Example 9a) 3.62 mmol) and pyrrolidine (30 μL, 0.362 mmol) in DMF (3.6 mL) were added dimedone (507 mg, 3.62 mmol) at 80 ° C., and the reaction solution was stirred at 80 ° C. for 20 minutes. After cooling to room temperature, 1 M hydrochloric acid (5 mL) and ether (5 mL) were added to the reaction solution, and the reaction solution was further stirred at room temperature for 30 minutes. The reaction solution was extracted with ether, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate; 7: 3) to obtain the title compound (860 mg, 60%).
1H-NMR(500MHz, CDCl3):δ ppm: 1.12 (6H, s), 1.32 (12H, s), 2.44 (3H, s), 2.52 (2H, s) 2.60 (2H, s), 3.74 (3H, s), 6.69 (1H, d, J = 8.5 Hz), 7.78 (1H, d, J = 8.5 Hz), 7.95 (1H, s).
(9c) (3S,10S)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例9bで製造した2-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン(1.50 g, 3.80 mmol)及び公知化合物である(6S)-6-(プロパン-2-イル)ピペリジン-2,4-ジオン(Marin, J. et al, J. Org. Chem. (2004), 69(1), 130-141; 0.64 g, 4.10 mmol)のDMF (15 mL)溶液に室温で炭酸セシウム(3.10 g, 9.40 mmol)を加えた。反応溶液を室温で2時間攪拌後、N-フェニルビス(トリフルオロメタンスルホンイミド) (1.60 g, 4.50 mmol)を加え、反応溶液を室温で49時間攪拌した。反応溶液に水を加えて酢酸エチルで2回抽出後、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 1:1)で精製し、標記化合物(836 mg, 41%)を得た。 1 H-NMR (500 MHz, CDCl 3 ): δ ppm: 1.12 (6H, s), 1.32 (12H, s), 2.44 (3H, s), 2.52 (2H, s) 2.60 (2H, s), 3.74 ( 3H, s), 6.69 (1H, d, J = 8.5 Hz), 7.78 (1H, d, J = 8.5 Hz), 7.95 (1H, s).
(9c) (3S, 10S) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7 , 7-Dimethyl-3- (propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 2- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] -5,5-dimethyl prepared in Example 9b Cyclohexane-1,3-dione (1.50 g, 3.80 mmol) and the known compound (6S) -6- (propan-2-yl) piperidine-2,4-dione (Marin, J. et al, J. Org Chem. (2004), 69 (1), 130-141; 0.64 g, 4.10 mmol) in DMF (15 mL) was added cesium carbonate (3.10 g, 9.40 mmol) at room temperature. The reaction solution was stirred at room temperature for 2 hours, N-phenylbis (trifluoromethanesulfonimide) (1.60 g, 4.50 mmol) was added, and the reaction solution was stirred at room temperature for 49 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 1: 1) to obtain the title compound (836 mg, 41%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.82 (3H, d, J = 6.7 Hz), 0.88 (3H, d, J = 7.0 Hz), 0.91 (3H, s), 1.08 (3H, s), 1.30 (12H, s), 1.63-1.72 (1H, m), 2.10 (1H, dd, J = 1.2, 16.0 Hz), 2.20 (1H, d, J = 16.4 Hz), 2.31 (1H, dd, J = 1.2, 17.6 Hz), 2.43 (1H, dd, J = 0.8, 16.4 Hz), 2.47 (1H, dd, J = 6.7, 16.8 Hz), 2.63 (1H, ddd, J = 1.6, 7.0, 17.2 Hz), 3.10 (3H, s), 3.21 (1H, qd, J = 2.7, 7.0 Hz), 3.67 (3H, s), 5.11 (1H, s), 5.40 (1H, d, J = 2.0 Hz), 6.57 (1H, d, J = 8.6 Hz), 7.57 (1H, d, J = 8.6 Hz).
また、副生した(3S,10R)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(458 mg, 23%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.93-0.94 (6H, m), 0.95 (3H, s), 1.08 (3H, s), 1.30 (12H, s), 1.68-1.76 (1H, m), 2.11 (1H, d, J = 16.0 Hz), 2.20 (1H, d, J = 16.4 Hz), 2.30-2.50 (4H, m), 3.12 (3H, s), 3.25 (1H, dt, J = 5.1, 13.3 Hz), 3.70 (3H, s), 5.11 (1H, s), 5.19 (1H, s), 6.60 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 8.6 Hz).
(9d) tert-ブチル　6-{3-[(3S,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例9cで製造した(3S,10S)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(625 mg, 1.17 mmol)、公知化合物であるtert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(266 mg, 1.17 mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0) (67.4 mg, 0.0584 mmol)及び炭酸ナトリウム(371 mg, 3.50 mmol)のDME (12.5 mL)及び水(5.4 mL)混合溶液を90℃で6時間攪拌した。室温まで冷却後、反応溶液に水を加えて酢酸エチルで2回抽出後、有機層を水及び飽和食塩水で順次洗浄、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル; 1:2)で精製し、標記化合物(701 mg, 87%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.82 (3H, d, J = 6.7 Hz), 0.88 (3H, d, J = 7.0 Hz), 0.91 (3H, s), 1.08 (3H, s ), 1.30 (12H, s), 1.63-1.72 (1H, m), 2.10 (1H, dd, J = 1.2, 16.0 Hz), 2.20 (1H, d, J = 16.4 Hz), 2.31 (1H, dd, J = 1.2, 17.6 Hz), 2.43 (1H, dd, J = 0.8, 16.4 Hz), 2.47 (1H, dd, J = 6.7, 16.8 Hz), 2.63 (1H, ddd, J = 1.6, 7.0, 17.2 Hz ), 3.10 (3H, s), 3.21 (1H, qd, J = 2.7, 7.0 Hz), 3.67 (3H, s), 5.11 (1H, s), 5.40 (1H, d, J = 2.0 Hz), 6.57 (1H, d, J = 8.6 Hz), 7.57 (1H, d, J = 8.6 Hz).
In addition, by-product (3S, 10R) -10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) phenyl] -7,7-Dimethyl-3- (propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H)- Dione (458 mg, 23%) was obtained.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.93-0.94 (6H, m), 0.95 (3H, s), 1.08 (3H, s), 1.30 (12H, s), 1.68-1.76 (1H, m), 2.11 (1H, d, J = 16.0 Hz), 2.20 (1H, d, J = 16.4 Hz), 2.30-2.50 (4H, m), 3.12 (3H, s), 3.25 (1H, dt, J = 5.1, 13.3 Hz), 3.70 (3H, s), 5.11 (1H, s), 5.19 (1H, s), 6.60 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 8.6 Hz ).
(9d) tert-butyl 6- {3-[(3S, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7, 8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2methylphenyl} -3-methylpyridine-2-carboxylate Prepared in Example 9c ( 3S, 10S) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl -3- (propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (625 mg, 1.17 mmol), known compounds tert-butyl 6-chloro-3-methylpyridine-2-carboxylate (266 mg, 1.17 mmol), tetrakis (triphenylphosphine) palladium (0) (67.4 mg, 0.0584 mmol) and carbonic acid A mixed solution of sodium (371 mg, 3.50 mmol) in DME (12.5 mL) and water (5.4 mL) was stirred at 90 ° C. for 6 hours. After cooling to room temperature, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (hexane / ethyl acetate; 1: 2) to obtain the title compound (701 mg, 87%).
(9e) 6-{3-[(3S,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例9dで製造したtert-ブチル　6-{3-[(3S,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2メチルフェニル}-3-メチルピリジン-2-カルボキシレート(50.0 mg, 0.0832 mmol)、ジクロロメタン(3.0 mL)及びトリフルオロ酢酸(1.5 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(34.3 mg, 76%)を得た。 (9e) 6- {3-[(3S, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9 , 10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butyl prepared in Example 9d 6- {3-[(3S, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2methylphenyl} -3-methylpyridine-2-carboxylate (50.0 mg, 0.0832 mmol), dichloromethane (3.0 mL) And trifluoroacetic acid (1.5 mL) was used for the reaction and post-treatment according to Example 1d to obtain the title compound (34.3 mg, 76%).
(実施例10)
　6-{4-メトキシ-2-メチル-3-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
(10a) tert-ブチル　6-{4-メトキシ-2-メチル-3-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例9dで製造したtert-ブチル　6-{3-[(3S,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2メチルフェニル}-3-メチルピリジン-2-カルボキシレート(357 mg, 0.594 mmol)、ヨウ化メチル(370 μL, 5.94 mmol)、DMF (7.1 mL)及び水素化ナトリウム(63%, 24.9　mg, 0.654 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(286 mg, 78%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.84 (3H, d, J = 7.0 Hz), 0.86 (3H, d, J = 7.0 Hz), 0.95 (3H, s), 1.09 (3H, s), 1.64 (9H, s), 1.92-2.00 (1H, m), 2.12 (1H, dd, J = 1.2, 16.0 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.32 (1H, dd, J = 1.2, 17.2 Hz), 2.43 (1H, dd, J = 1.2, 3.9 Hz), 2.47 (1H, dd, J = 1.2, 4.3 Hz), 2.49 (3H, s), 2.86 (1H, ddd, J = 2.0, 7.8, 17.2 Hz), 2.87 (3H, s), 2.94 (3H, s), 3.07 (1H, dt, J = 1.2, 6.7 Hz), 3.68 (3H, s), 5.21 (1H, s), 6.65 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.2 Hz), 7.40 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.6 Hz).
(10b) 6-{4-メトキシ-2-メチル-3-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例10aで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(282 mg, 0.459 mmol)、ジクロロメタン(6.0 mL)及びトリフルオロ酢酸(3.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(237 mg, 92%)を得た。 (Example 10)
6- {4-Methoxy-2-methyl-3-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4, 6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid
(10a) tert-butyl 6- {4-methoxy-2-methyl-3-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl)- 2,3,4,6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylate in Example 9d Prepared tert-butyl 6- {3-[(3S, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8 , 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2methylphenyl} -3-methylpyridine-2-carboxylate (357 mg, 0.594 mmol), The title compound was obtained by carrying out the reaction and post-treatment according to Example 2a using methyl iodide (370 μL, 5.94 mmol), DMF (7.1 mL) and sodium hydride (63%, 24.9 mg, 0.654 mmol). (286 mg, 78%) was obtained.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.84 (3H, d, J = 7.0 Hz), 0.86 (3H, d, J = 7.0 Hz), 0.95 (3H, s), 1.09 (3H, s ), 1.64 (9H, s), 1.92-2.00 (1H, m), 2.12 (1H, dd, J = 1.2, 16.0 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.32 (1H, dd, J = 1.2, 17.2 Hz), 2.43 (1H, dd, J = 1.2, 3.9 Hz), 2.47 (1H, dd, J = 1.2, 4.3 Hz), 2.49 (3H, s), 2.86 (1H, ddd, J = 2.0, 7.8, 17.2 Hz), 2.87 (3H, s), 2.94 (3H, s), 3.07 (1H, dt, J = 1.2, 6.7 Hz), 3.68 (3H, s), 5.21 (1H, s) , 6.65 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.2 Hz), 7.40 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.6 Hz).
(10b) 6- {4-Methoxy-2-methyl-3-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3 , 4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert prepared in Example 10a -Butyl 6- {4-methoxy-2-methyl-3-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3, 4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylate (282 mg, 0.459 mmol), The title compound (237 mg, 92%) was obtained by performing reaction and post-treatment according to Example 1d using dichloromethane (6.0 mL) and trifluoroacetic acid (3.0 mL).
(実施例11)
　6-{3-[(3R,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(11a) (3R,10S)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例9bで製造した2-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン(1.50 g, 3.80 mmol)、公知化合物である(6R)-6-(プロパン-2-イル)ピペリジン-2,4-ジオン(Marin, J. et al, J. Org. Chem. (2004), 69(1), 130-141;0.64 g, 4.10 mmol)、DMF (15 mL)、炭酸セシウム(3.10 g, 9.40 mmol)及びN-フェニルビス(トリフルオロメタンメタンスルホンイミド) (1.60 g, 4.50 mmol)を用い、実施例9cに準じて反応及び後処理を行うことにより、標記化合物(252 mg, 12%)を得た。 (Example 11)
6- {3-[(3R, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(11a) (3R, 10S) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7 , 7-Dimethyl-3- (propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 2- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] -5,5-dimethyl prepared in Example 9b Cyclohexane-1,3-dione (1.50 g, 3.80 mmol), a known compound (6R) -6- (propan-2-yl) piperidine-2,4-dione (Marin, J. et al, J. Org Chem. (2004), 69 (1), 130-141; 0.64 g, 4.10 mmol), DMF (15 mL), cesium carbonate (3.10 g, 9.40 mmol) and N-phenylbis (trifluoromethanemethanesulfonimide) (1.60 g, 4.50 mmol) was used for the reaction and post-treatment according to Example 9c to obtain the title compound (252 mg, 12%).
　また、副生した(3R,10R)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(657 mg, 33%)を得た。
(11b) tert-ブチル　6-{3-[(3R,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例11aで製造した(3R,10S)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(231 mg, 0.431 mmol)、公知化合物であるtert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(98.2 mg, 0.431 mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0) (24.9 mg, 0.0216 mmol)、炭酸ナトリウム(137 mg, 1.29 mmol)、DME (4.6 mL)及び水(2.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(211 mg, 81%)を得た。
(11c) 6-{3-[(3R,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例11bで製造したtert-ブチル　6-{3-[(3R,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2メチルフェニル}-3-メチルピリジン-2-カルボキシレート(98.3 mg, 0.164 mmol)、ジクロロメタン(4.0 mL)及びトリフルオロ酢酸(2.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(73.0 mg, 82%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.96 (3H, d, J = 6.7 Hz), 0.96 (3H, d, J = 6.7 Hz), 0.99 (3H, s), 1.11 (3H, s), 1.71-1.79 (1H, m), 2.16 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.35-2.54 (4H, m), 2.80 (3H, s), 2.86 (3H, s), 3.28-3.34 (1H, m), 3.77 (3H, s), 5.16 (1H, s), 5.19 (1H, s), 6.75 (1H, d, J = 8.6 Hz), 7.19 (1H, d, J = 8.6 Hz), 7.56 (1H, d, J = 7.8 Hz), 7.70 (1H, d, J = 7.8 Hz).
MS(ESI/APCI)m/z: 545[M+H]+.
(11d) 6-{3-[(3R,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例11cで製造した6-{3-[(3R,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(200 mg, 0.367 mmol)、エタノール(2.0 mL)及びtert-ブチルアミン(77 μL, 0.734 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(169 mg, 75%)を得た。 In addition, by-product (3R, 10R) -10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) phenyl] -7,7-Dimethyl-3- (propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H)- Dione (657 mg, 33%) was obtained.
(11b) tert-butyl 6- {3-[(3R, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7, 8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2methylphenyl} -3-methylpyridine-2-carboxylate Prepared in Example 11a ( 3R, 10S) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl -3- (propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (231 mg, 0.431 mmol), known compounds tert-butyl 6-chloro-3-methylpyridine-2-carboxylate (98.2 mg, 0.431 mmol), tetrakis (triphenylphosphine) palladium (0) (24.9 mg, 0.0216 mmol), carbonic acid The title compound (211 mg, 81%) was obtained by performing reaction and post-treatment according to Example 9d using sodium (137 mg, 1.29 mmol), DME (4.6 mL) and water (2.0 mL). .
(11c) 6- {3-[(3R, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9 , 10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butyl prepared in Example 11b 6- {3-[(3R, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2methylphenyl} -3-methylpyridine-2-carboxylate (98.3 mg, 0.164 mmol), dichloromethane (4.0 mL) And trifluoroacetic acid (2.0 mL) was used for the reaction and post-treatment according to Example 1d to obtain the title compound (73.0 mg, 82%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.96 (3H, d, J = 6.7 Hz), 0.96 (3H, d, J = 6.7 Hz), 0.99 (3H, s), 1.11 (3H, s ), 1.71-1.79 (1H, m), 2.16 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.35-2.54 (4H, m), 2.80 (3H, s) , 2.86 (3H, s), 3.28-3.34 (1H, m), 3.77 (3H, s), 5.16 (1H, s), 5.19 (1H, s), 6.75 (1H, d, J = 8.6 Hz), 7.19 (1H, d, J = 8.6 Hz), 7.56 (1H, d, J = 7.8 Hz), 7.70 (1H, d, J = 7.8 Hz).
MS (ESI / APCI) m / z: 545 [M + H] +.
(11d) 6- {3-[(3R, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9 , 10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt Prepared in Example 11c 6- {3-[(3R, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10 -Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid (200 mg, 0.367 mmol), ethanol (2.0 mL) and tert-butylamine (77 μL, 0.734 mmol) were used for the reaction and post-treatment according to Example 3c to obtain the title compound (169 mg, 75%).
(実施例12)
　6-{4-メトキシ-2-メチル-3-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例10bで製造した6-{4-メトキシ-2-メチル-3-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(127 mg, 0.227 mmol)、カルボニルジイミダゾール(47.9 mg, 0.296 mmol)、DMF (2.6 mL)、メタンスルホンアミド(28.1 mg, 0.295 mmol)及びDBU (44 μL, 0.295 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(73.0 mg, 52%)を得た。 (Example 12)
6- {4-Methoxy-2-methyl-3-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4, 6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide in Example 10b The prepared 6- {4-methoxy-2-methyl-3-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3, 4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid (127 mg, 0.227 mmol), Using carbonyldiimidazole (47.9 mg, 0.296 mmol), DMF (2.6 mL), methanesulfonamide (28.1 mg, 0.295 mmol) and DBU (44 μL, 0.295 mmol), the reaction and workup were carried out according to Example 6a. This gave the title compound (73.0 mg, 52%).
(実施例13)
　6-[4-メトキシ-2-メチル-3-(2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル)フェニル]-3-メチルピリジン-2-カルボン酸
(13a) 10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-6,7,8,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-1,9(2H,4H)-ジオン
　実施例9bで製造した2-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン(1.00 g, 2.51 mmol)、公知化合物である5-アザスピロ[3.5]ノナン-6,8-ジオン(423 mg, 2.76 mmol)、DMF (10 mL)、炭酸セシウム(2.05 g, 6.28 mmol)及びN-フェニルビス(トリフルオロメタンスルホンイミド) (1.08 g, 3.01 mmol)を用い、実施例9cに準じて反応及び後処理を行うことにより、標記化合物(887 mg, 66%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.92 (3H, s), 1.08 (3H, s), 1.30 (12H, s), 1.70-1.87 (3H, m), 2.00-2.14 (4H, m), 2.20 (1H, d, J = 16.4 Hz), 2.31 (1H, dd, J = 1.2, 17.6 Hz), 2.44 (1H, dd, J = 0.8, 17.2 Hz), 2.66 (1H, d, J = 16.8 Hz), 2.71 (1H, d, J = 17.2 Hz), 3.10 (3H, s), 3.69 (3H, s), 5.15 (1H, s), 5.57 (1H, s), 6.57 (1H, d, J = 8.2 Hz), 7.58 (1H, d, J = 8.2 Hz).
(13b) tert-ブチル　6-[3-(7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート
　実施例13aで製造した10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-6,7,8,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-1,9(2H,4H)-ジオン(652 mg, 1.22 mmol)、公知化合物であるtert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(278 mg, 1.22 mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0) (70.6 mg, 0.0611 mmol)、炭酸ナトリウム(389 mg, 3.67 mmol)、DME (13 mL)及び水(5.7 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(732 mg, 43%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.96 (3H, s), 1.10 (3H, s), 1.63 (9H, s), 1.73-1.90 (3H, m), 2.04-2.15 (4H, m), 2.21 (1H, d, J = 16.4 Hz), 2.34 (1H, dd, J = 1.2, 17.2 Hz), 2.46 (1H, d, J = 20.0 Hz), 2.49 (3H, s), 2.71 (2H, s), 2.83 (3H, s), 3.72 (3H, s), 5.13 (1H, s), 5.45 (1H, s), 6.68 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 8.6 Hz), 7.37 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.2 Hz).
(13c) tert-ブチル　6-[4-メトキシ-2-メチル-3-(2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル)フェニル]-3-メチルピリジン-2-カルボキシレート
　実施例13bで製造したtert-ブチル　6-[3-(7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート(222 mg, 0.371 mmol)、ヨウ化メチル(231 μL, 3.71 mmol)、DMF (4.0 mL)及び水素化ナトリウム(63%, 15.5 mg, 0.408 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(163 mg, 72%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.96 (3H, s), 1.10 (3H, s), 1.64 (9H, s), 1.75-1.95 (4H, m), 2.02-2.07 (1H, m), 2.13 (1H, dd, J = 1.2, 16.0 Hz), 2.22 (1H, d, J = 16.0 Hz), 2.34 (1H, dd, J = 1.2, 17.2 Hz), 2.46 (1H, dd, J = 0.8, 17.6 Hz), 2.49 (3H, s), 2.63-2.71 (1H, m), 2.72 (1H, d, J = 16.8 Hz), 2.77 (1H, d, J = 16.4 Hz), 2.85 (3H, s), 2.94 (3H, s), 3.72 (3H, s), 5.16 (1H, s), 6.87 (1H, d, J = 8.6 Hz), 7.25 (1H, d, J = 8.2 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 7.8 Hz).
(13d) 6-[4-メトキシ-2-メチル-3-(2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル)フェニル]-3-メチルピリジン-2-カルボン酸
　実施例13cで製造したtert-ブチル　6-[4-メトキシ-2-メチル-3-(2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル)フェニル]-3-メチルピリジン-2-カルボキシレート(157 mg, 0.256 mmol)、ジクロロメタン(4.0 mL)及びトリフルオロ酢酸(2.0 mL) を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(143 mg, 78%)を得た。 (Example 13)
6- [4-Methoxy-2-methyl-3- (2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [ 3,2-c] pyridine-3,1′-cyclobutane] -10-yl) phenyl] -3-methylpyridine-2-carboxylic acid
(13a) 10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-6 , 7,8,10-Tetrahydrospiro [chromeno [3,2-c] pyridine-3,1'-cyclobutane] -1,9 (2H, 4H) -dione 2- [6-methoxy prepared in Example 9b -2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] -5,5-dimethylcyclohexane-1,3-dione (1.00 g, 2.51 mmol), 5-azaspiro [3.5] nonane-6,8-dione (423 mg, 2.76 mmol), DMF (10 mL), cesium carbonate (2.05 g, 6.28 mmol) and N-phenylbis ( Using trifluoromethanesulfonimide) (1.08 g, 3.01 mmol), the reaction and post-treatment were performed according to Example 9c to obtain the title compound (887 mg, 66%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.92 (3H, s), 1.08 (3H, s), 1.30 (12H, s), 1.70-1.87 (3H, m), 2.00-2.14 (4H, m), 2.20 (1H, d, J = 16.4 Hz), 2.31 (1H, dd, J = 1.2, 17.6 Hz), 2.44 (1H, dd, J = 0.8, 17.2 Hz), 2.66 (1H, d, J = 16.8 Hz), 2.71 (1H, d, J = 17.2 Hz), 3.10 (3H, s), 3.69 (3H, s), 5.15 (1H, s), 5.57 (1H, s), 6.57 (1H, d , J = 8.2 Hz), 7.58 (1H, d, J = 8.2 Hz).
(13b) tert-butyl 6- [3- (7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2- c] Pyridine-3,1′-cyclobutane] -10-yl) -4-methoxy-2-methylphenyl] -3-methylpyridine-2-carboxylate 10- [6-Methoxy-2 prepared in Example 13a -Methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-6,7,8,10-tetrahydrospiro [chromeno [3,2-c] pyridine-3,1'-cyclobutane] -1,9 (2H, 4H) -dione (652 mg, 1.22 mmol), a known compound tert-butyl 6-chloro-3-methylpyridine 2-carboxylate (278 mg, 1.22 mmol), tetrakis (triphenylphosphine) palladium (0) (70.6 mg, 0.0611 mmol), sodium carbonate (389 mg, 3.67 mmol), DME (13 mL) and water (5.7 The title compound (732 mg, 43%) was obtained by carrying out the reaction and post-treatment according to Example 9d.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.96 (3H, s), 1.10 (3H, s), 1.63 (9H, s), 1.73-1.90 (3H, m), 2.04-2.15 (4H, m), 2.21 (1H, d, J = 16.4 Hz), 2.34 (1H, dd, J = 1.2, 17.2 Hz), 2.46 (1H, d, J = 20.0 Hz), 2.49 (3H, s), 2.71 ( 2H, s), 2.83 (3H, s), 3.72 (3H, s), 5.13 (1H, s), 5.45 (1H, s), 6.68 (1H, d, J = 8.6 Hz), 7.27 (1H, d , J = 8.6 Hz), 7.37 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.2 Hz).
(13c) tert-butyl 6- [4-methoxy-2-methyl-3- (2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10- Octahydrospiro [chromeno [3,2-c] pyridine-3,1′-cyclobutane] -10-yl) phenyl] -3-methylpyridine-2-carboxylate tert-butyl 6- [prepared in Example 13b 3- (7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-3,1'- Cyclobutane] -10-yl) -4-methoxy-2-methylphenyl] -3-methylpyridine-2-carboxylate (222 mg, 0.371 mmol), methyl iodide (231 μL, 3.71 mmol), DMF (4.0 mL ) And sodium hydride (63%, 15.5 mg, 0.408 mmol), and the reaction and post-treatment were performed according to Example 2a to obtain the title compound (163 mg, 72%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.96 (3H, s), 1.10 (3H, s), 1.64 (9H, s), 1.75-1.95 (4H, m), 2.02-2.07 (1H, m), 2.13 (1H, dd, J = 1.2, 16.0 Hz), 2.22 (1H, d, J = 16.0 Hz), 2.34 (1H, dd, J = 1.2, 17.2 Hz), 2.46 (1H, dd, J = 0.8, 17.6 Hz), 2.49 (3H, s), 2.63-2.71 (1H, m), 2.72 (1H, d, J = 16.8 Hz), 2.77 (1H, d, J = 16.4 Hz), 2.85 (3H , s), 2.94 (3H, s), 3.72 (3H, s), 5.16 (1H, s), 6.87 (1H, d, J = 8.6 Hz), 7.25 (1H, d, J = 8.2 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 7.8 Hz).
(13d) 6- [4-Methoxy-2-methyl-3- (2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [Chromeno [3,2-c] pyridine-3,1'-cyclobutane] -10-yl) phenyl] -3-methylpyridine-2-carboxylic acid tert-butyl 6- [4-methoxy prepared in Example 13c -2-Methyl-3- (2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] Pyridine-3,1'-cyclobutane] -10-yl) phenyl] -3-methylpyridine-2-carboxylate (157 mg, 0.256 mmol), dichloromethane (4.0 mL) and trifluoroacetic acid (2.0 mL) The title compound (143 mg, 78%) was obtained by carrying out the reaction and post-treatment according to Example 1d.
(実施例14)
　6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,6,7,8,9,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
(14a) tert-ブチル　6-{3-[(10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,6,7,8,9,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
実施例9dで製造したtert-ブチル　6-{3-[(3S,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2メチルフェニル}-3-メチルピリジン-2-カルボキシレート(4.73 g, 7.87 mmol)及び2,3-ジクロロ-5,6-ジシアノ-1,4-ベンゾキノン(2.14 g, 9.45 mmol)のトルエン(95 mL)溶液を60℃で3時間攪拌した。室温まで冷却後、反応溶液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 1:1)で精製し、標記化合物(3.32 g, 70%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.96 (3H, s), 1.06 (3H, d, J = 7.0 Hz), 1.09 (3H, s), 1.09 (3H, d, J = 7.0 Hz), 1.63 (9H, s), 2.14 (1H, d, J = 16.0 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.38 (1H, d, J = 16.4 Hz), 2.47 (1H, d, J = 14.5 Hz), 2.49 (3H, s), 2.49-2.57 (1H, m), 2.90 (3H, s), 3.59 (3H, s), 5.21 (1H, s), 5.78 (1H, s), 6.63 (1H, d, J = 8.6 Hz), 7.23 (1H, d, J = 8.2 Hz), 7.33 (1H, d, J = 7.8 Hz), 7.50 (1H, d, J = 7.8 Hz).
(14b) tert-ブチル6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,6,7,8,9,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例14aで製造したtert-ブチル　6-{3-[(10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,6,7,8,9,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(2.30 g, 3.84 mmol)、ヨウ化メチル(359 μL, 5.76 mmol)及び炭酸セシウム(1.88 g, 5.76 mmol)のDMF (46 mL)溶液を0℃で5時間攪拌した。反応溶液に水を加え、酢酸エチルで抽出した。有機層を水で洗浄、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 9:1)で精製し、標記化合物(1.62 g, 69%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.96 (3H, s), 1.10 (3H, s), 1.25 (3H, d, J = 6.7 Hz), 1.26 (3H, d, J = 6.7 Hz), 1.64 (9H, s), 2.14 (1H, dd, J = 0.8, 16.0 Hz), 2.22 (1H, d, J = 16.0 Hz), 2.40 (1H, dd, J = 0.8, 18.0 Hz), 2.50 (1H, dd, J = 1.2, 17.6 Hz), 2.50 (3H, s), 2.95 (3H, s), 2.95-3.02 (1H, m), 3.45 (3H, s), 3.62 (3H, s), 5.27 (1H, s), 5.91 (1H, s), 6.67 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 8.6 Hz), 7.42 (1H, d, J = 7.8 Hz), 7.53 (1H, d, J = 8.6 Hz).
(14c) 6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,6,7,8,9,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例14bで製造したtert-ブチル6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,6,7,8,9,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(1.62 g, 2.64 mmol)、ジクロロメタン(32 mL)及びトリフルオロ酢酸(16 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(1.02 g, 69%)を得た。 (Example 14)
6- {4-Methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,6,7,8, 9,10-Hexahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid
(14a) tert-Butyl 6- {3-[(10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,6,7,8,9,10- Hexahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate tert-butyl 6- {prepared in Example 9d 3-[(3S, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2methylphenyl} -3-methylpyridine-2-carboxylate (4.73 g, 7.87 mmol) and 2,3-dichloro-5, A solution of 6-dicyano-1,4-benzoquinone (2.14 g, 9.45 mmol) in toluene (95 mL) was stirred at 60 ° C. for 3 hours. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 1: 1) to obtain the title compound (3.32 g, 70%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.96 (3H, s), 1.06 (3H, d, J = 7.0 Hz), 1.09 (3H, s), 1.09 (3H, d, J = 7.0 Hz ), 1.63 (9H, s), 2.14 (1H, d, J = 16.0 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.38 (1H, d, J = 16.4 Hz), 2.47 (1H, d , J = 14.5 Hz), 2.49 (3H, s), 2.49-2.57 (1H, m), 2.90 (3H, s), 3.59 (3H, s), 5.21 (1H, s), 5.78 (1H, s) , 6.63 (1H, d, J = 8.6 Hz), 7.23 (1H, d, J = 8.2 Hz), 7.33 (1H, d, J = 7.8 Hz), 7.50 (1H, d, J = 7.8 Hz).
(14b) tert-butyl 6- {4-methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2, 6,7,8,9,10-Hexahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylate tert-Butyl prepared in Example 14a 6 -{3-[(10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,6,7,8,9,10-hexahydro-1H-chromeno [3 , 2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (2.30 g, 3.84 mmol), methyl iodide (359 μL, 5.76 mmol) and A solution of cesium carbonate (1.88 g, 5.76 mmol) in DMF (46 mL) was stirred at 0 ° C. for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 9: 1) to obtain the title compound (1.62 g, 69%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.96 (3H, s), 1.10 (3H, s), 1.25 (3H, d, J = 6.7 Hz), 1.26 (3H, d, J = 6.7 Hz ), 1.64 (9H, s), 2.14 (1H, dd, J = 0.8, 16.0 Hz), 2.22 (1H, d, J = 16.0 Hz), 2.40 (1H, dd, J = 0.8, 18.0 Hz), 2.50 (1H, dd, J = 1.2, 17.6 Hz), 2.50 (3H, s), 2.95 (3H, s), 2.95-3.02 (1H, m), 3.45 (3H, s), 3.62 (3H, s), 5.27 (1H, s), 5.91 (1H, s), 6.67 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 8.6 Hz), 7.42 (1H, d, J = 7.8 Hz), 7.53 (1H, d, J = 8.6 Hz).
(14c) 6- {4-Methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,6,7 , 8,9,10-Hexahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butyl 6- {4 prepared in Example 14b -Methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,6,7,8,9,10- Hexahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylate (1.62 g, 2.64 mmol), dichloromethane (32 mL) and trifluoroacetic acid (16 mL) The title compound (1.02 g, 69%) was obtained by performing the reaction and post-treatment according to Example 1d.
(実施例15)
　6-{4-メトキシ-2-メチル-3-[(3R,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,6,7,8,9,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
(15a) tert-ブチル　6-{3-[(3R,10S,10aR)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,6,7,8,9,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例1aで製造したtert-ブチル6-{3-[(4,4-ジメチル-2,6-ジオキソシクロヘキシリデン)メチル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(9.50 g, 20.0 mmol)及び公知化合物である(6S)-6-(プロパン-2-イル)ピペリジン-2,4-ジオン(3.50 g, 23.0 mmol)のDMF (95 mL)溶液に0℃で炭酸セシウム(17.0 g, 51.0 mmol)を加えた。反応溶液を0℃で40分間攪拌後、クエン酸(9.80 g, 51.0 mmol)及び水を加えて酢酸エチルで2回抽出後、有機層を水で洗浄した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮し、粗製の付加物を得た。粗製の付加物及びトリフェニルホスフィン(6.50 g, 25.0 mmol)のTHF (95 mL)溶液に0℃ででジ-tert-ブチルアゾジカルボキシレート(5.70 g, 25.0 mmol)を加え、反応溶液を0℃で4.5時間攪拌した。反応溶液を濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 1:2)で精製し、標記化合物(2.54 g, 21%)を得た。 (Example 15)
6- {4-methoxy-2-methyl-3-[(3R, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3, 6,7,8,9,10,10a-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid
(15a) tert-butyl 6- {3-[(3R, 10S, 10aR) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,6,7, 8,9,10,10a-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate Example 1a Prepared tert-butyl 6- {3-[(4,4-dimethyl-2,6-dioxocyclohexylidene) methyl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (9.50 g, 20.0 mmol) and a known compound (6S) -6- (propan-2-yl) piperidine-2,4-dione (3.50 g, 23.0 mmol) in DMF (95 mL) at 0 ° C. Cesium carbonate (17.0 g, 51.0 mmol) was added. The reaction solution was stirred at 0 ° C. for 40 minutes, citric acid (9.80 g, 51.0 mmol) and water were added, and the mixture was extracted twice with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude adduct. Di-tert-butylazodicarboxylate (5.70 g, 25.0 mmol) was added to the crude adduct and triphenylphosphine (6.50 g, 25.0 mmol) in THF (95 mL) at 0 ° C. Stir at 4.5 ° C. for 4.5 hours. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 1: 2) to obtain the title compound (2.54 g, 21%).
　また、副生したtert-ブチル　6-{3-[(3S,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2メチルフェニル}-3-メチルピリジン-2-カルボキシレート(4.73 g, 38%)を得た。 In addition, by-product tert-butyl 6- {3-[(3S, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6, 7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2methylphenyl} -3-methylpyridine-2-carboxylate (4.73 g, 38 %).
　また、副生したtert-ブチル　6-{3-[(3S,10R)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2メチルフェニル}-3-メチルピリジン-2-カルボキシレート(1.71 g, 14%)を得た。
(15b) tert-ブチル　6-{4-メトキシ-2-メチル-3-[(3R,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,6,7,8,9,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例15aで製造したtert-ブチル　6-{3-[(3R,10S,10aR)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,6,7,8,9,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(2.54 g, 4.23 mmol)、ヨウ化メチル(2.63 mL, 42.3 mmol)、DMF (25 mL)及び水素化ナトリウム(63%, 193 mg, 5.07 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物( 2.54 g, 98%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.75 (3H, d, J = 6.7 Hz), 0.94 (3H, s), 0.99 (3H, d, J = 7.0 Hz), 1.06 (3H, s), 1.63 (9H, s), 2.04 (1H, dd, J = 1.6, 16.4 Hz), 2.13 (1H, d, J = 16.4 Hz), 2.15-2.22 (1H, m), 2.32 (1H, d, J = 17.6 Hz), 2.42 (1H, dd, J = 2.4, 17.6 Hz), 2.49 (3H, s), 2.78 (3H, s), 2.93 (3H, s), 3.74 (3H, s), 3.74-3.77 (1H, m), 3.87-3.90 (1H, m), 4.60 (1H, dd, J = 1.6, 7.0 Hz), 5.48 (1H, dd, J = 2.7, 5.1 Hz), 6.70 (1H, d, J = 8.6 Hz), 7.29 (1H, d, J = 8.6 Hz), 7.42 (1H, d, J = 7.8 Hz), 7.51 (1H, d, J = 7.8 Hz).
(15c) 6-{4-メトキシ-2-メチル-3-[(3R,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,6,7,8,9,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例15bで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[(3R,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,6,7,8,9,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(2.40 g, 3.90 mmol)、ジクロロメタン(48 mL)及びトリフルオロ酢酸(24 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(882 mg, 40%)を得た。 Further, tert-butyl 6- {3-[(3S, 10R) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6, 7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2methylphenyl} -3-methylpyridine-2-carboxylate (1.71 g, 14 %).
(15b) tert-butyl 6- {4-methoxy-2-methyl-3-[(3R, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl ) -2,3,6,7,8,9,10,10a-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylate Tert-butyl 6- {3-[(3R, 10S, 10aR) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,6,7 prepared in 15a , 8,9,10,10a-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (2.54 g , 4.23 mmol), methyl iodide (2.63 mL, 42.3 mmol), DMF (25 mL) and sodium hydride (63%, 193 mg, 5.07 mmol), followed by reaction and workup according to Example 2a. This gave the title compound (2.54 g, 98%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.75 (3H, d, J = 6.7 Hz), 0.94 (3H, s), 0.99 (3H, d, J = 7.0 Hz), 1.06 (3H, s ), 1.63 (9H, s), 2.04 (1H, dd, J = 1.6, 16.4 Hz), 2.13 (1H, d, J = 16.4 Hz), 2.15-2.22 (1H, m), 2.32 (1H, d, J = 17.6 Hz), 2.42 (1H, dd, J = 2.4, 17.6 Hz), 2.49 (3H, s), 2.78 (3H, s), 2.93 (3H, s), 3.74 (3H, s), 3.74- 3.77 (1H, m), 3.87-3.90 (1H, m), 4.60 (1H, dd, J = 1.6, 7.0 Hz), 5.48 (1H, dd, J = 2.7, 5.1 Hz), 6.70 (1H, d, J = 8.6 Hz), 7.29 (1H, d, J = 8.6 Hz), 7.42 (1H, d, J = 7.8 Hz), 7.51 (1H, d, J = 7.8 Hz).
(15c) 6- {4-Methoxy-2-methyl-3-[(3R, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2 , 3,6,7,8,9,10,10a-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid Prepared in Example 15b Tert-butyl 6- {4-methoxy-2-methyl-3-[(3R, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl)- 2,3,6,7,8,9,10,10a-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylate (2.40 g, 3.90 mmol), dichloromethane (48 mL), and trifluoroacetic acid (24 mL) were used, and the reaction and workup were performed according to Example 1d to obtain the title compound (882 mg, 40%).
(実施例16)
　6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,6,7,8,9,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例14cで製造した6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,6,7,8,9,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(200 mg, 0.359 mmol)、カルボニルジイミダゾール(75.7 mg, 0.467 mmol)、DMF (4.0 mL)、メタンスルホンアミド(44.4 mg, 0.467 mmol)及びDBU (70 μL, 0.467 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(177 mg, 78%)を得た。 (Example 16)
6- {4-Methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,6,7,8, 9,10-Hexahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide 6- {4 prepared in Example 14c -Methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,6,7,8,9,10- Hexahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid (200 mg, 0.359 mmol), carbonyldiimidazole (75.7 mg, 0.467 mmol), DMF (4.0 mL), methanesulfonamide (44.4 mg, 0.467 mmol) and DBU (70 μL, 0.467 mmol) were used for the reaction and workup according to Example 6a to give the title compound (177 mg, 78% )
(実施例17)
　6-{3-[(3R,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例11dで製造した6-{3-[(3R,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(200 mg, 0.367 mmol)、カルボニルジイミダゾール(77.4 mg, 0.477 mmol)、DMF (4.0 mL)、メタンスルホンアミド(45.4 mg, 0.477 mmol)及びDBU (71 μL, 0.477 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(194 mg, 85%)を得た。 (Example 17)
6- {3-[(3R, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide prepared in Example 11d 6- {3-[(3R, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid (200 mg, 0.367 mmol), carbonyldiimidazole ( 77.4 mg, 0.477 mmol), DMF (4.0 mL), methanesulfonamide (45.4 mg, 0.477 mmol) and DBU (71 μL, 0.477 mmol) were used, and the reaction and workup were carried out according to Example 6a. The title compound (194 mg, 85%) was obtained.
(実施例18)
　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　水素雰囲気下、実施例15cで製造した6-{4-メトキシ-2-メチル-3-[(3R,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,6,7,8,9,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(303 mg, 0.542 mmol)及びパラジウム炭素(10%, 303 mg)のTHF/メタノール(1:1, 12 mL)懸濁液を7時間攪拌した。反応溶液をろ過(セライト)し、ろ液を減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ジクロロメタン/メタノール; 4:1)で精製し、標記化合物(152 mg, 50%)を得た。 (Example 18)
6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2, 3,4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid Hydrogen atmosphere Below, 6- {4-methoxy-2-methyl-3-[(3R, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propane-2) prepared in Example 15c -Yl) -2,3,6,7,8,9,10,10a-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid A suspension of (303 mg, 0.542 mmol) and palladium on carbon (10%, 303 mg) in THF / methanol (1: 1, 12 mL) was stirred for 7 hours. The reaction solution was filtered (celite), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol; 4: 1) to obtain the title compound (152 mg, 50%).
(実施例19)
　6-{4-メトキシ-2-メチル-3-[3,8,8-トリメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]フェニル}ピリジン-2-カルボン酸
(19a) ベンジル　6-ブロモピリジン-2-カルボキシレート
　6-ブロモピリジン-2-カルボン酸(13.9 g, 68.8 mmol)、ベンジルブロミド(11.8 g, 68.8 mmol)及び炭酸カリウム(11.4 g, 82.6 mmol)アセトニトリル(100 mL)溶液を80℃で5時間攪拌した。室温まで冷却後、反応溶液に水を加えてトルエンで抽出後、有機層を水で2回洗浄、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をヘキサンより結晶化し、標記化合物(14.4 g, 72%)を得た。
1H-NMR (500MHz, CDCl3) ):δ ppm: 5.45 (2H, s), 7.33-7.40 (3H, m), 7.47 (2H, d, J = 7.6 Hz), 7.66-7.70 (2H, m), 8.07 (1H, dd, J = 2.2, 6.4 Hz).
(19b) ベンジル　6-(3-ホルミル-4-メトキシ-2-メチル-フェニル)ピリジン-2-カルボキシレート
　窒素雰囲気下、実施例19aで製造したベンジル　6-ブロモピリジン-2-カルボキシレート(3.81 g, 13.0 mmol)、実施例9aで製造した6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボラン-2-イル)ベンズアルデヒド(3.00 g, 10.9 mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0) (1.26 g, 1.09 mmol)及び炭酸ナトリウム(3.45 g, 32.6 mmol)のDME (20 mL)及び水(10 mL)混合溶液を100℃で5時間攪拌した。室温まで冷却後、反応溶液に水を加えてトルエンで抽出後、有機層を水で2回洗浄、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をエタノール及びトルエンから再結晶し、標記化合物(2.17 g, 55%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 2.52 (3H, s), 3.95 (3H, s), 5.46 (2H, s), 6.94 (1H, d, J = 8.6 Hz), 7.34-7.41 (3H, m), 7.48-7.52 (3H, m), 7.61 (1H, d, J = 8.6 Hz), 7.87 (1H, t, J = 7.8 Hz), 8.09 (1H, dd, J = 0.8, 7.8 Hz), 10.69 (1H, s).
(19c) ベンジル 6-{3-[(4,4-ジメチル-2,6-ジオキソシクロヘキシリデン)メチル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボキシレート
　実施例19bで製造したベンジル　6-(3-ホルミル-4-メトキシ-2-メチル-フェニル)ピリジン-2-カルボキシレート(3.00 g, 8.30 mmol)のアセトニトリル(30 mL)溶液に60℃でジメドン(1.28 g, 9.13 mmol)及びD-プロリン(47.8 mg, 0.415 mmol)を加え、反応溶液を60℃で2時間攪拌した。室温まで冷却後、反応溶液に飽和炭酸水素ナトリウム水溶液を加えて、酢酸エチルで2回抽出後、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮後、ヘキサン及びジクロロメタンより再結晶し、標記化合物(3.29 g, 82%)を得た。
1H-NMR(500MHz, CDCl3):δ ppm: 1.13 (6H, s), 2.25 (3H, s), 2.56 (2H, s) 2.62 (2H, s), 3.77 (3H, s), 5.46 (2H, s), 6.81 (1H, d, J = 8.5 Hz), 7.32-7.41 (4H, m), 7.49 (2H, d, J = 7.3 Hz), 7.57 (1H, dd, J = 1.0, 7.8 Hz), 7.85 (1H, t, J = 7.8 Hz), 7.93 (1H, s), 8.06 (1H, dd, J = 1.0, 7.8 Hz).
(19d) ベンジル6-{3-[8,8-ジメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボキシレート
　実施例19cで製造したベンジル 6-{3-[(4,4-ジメチル-2,6-ジオキソシクロヘキシリデン)メチル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボキシレート(300 mg, 0.620 mmol)、6-ヒドロキシ-2-(プロパン-2-イル)ピリミジン-4(3H)-オン(105 mg, 0.682 mmol)、DMF (3.0 mL)、炭酸セシウム(505 mg, 1.55 mmol)及びメタンスルホニルクロリド(58 μL, 0.774 mmol)を用い、実施例1bに準じて反応及び後処理を行うことにより、標記化合物(266 mg, 69%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.98 (3H, s), 1.11 (3H, s), 1.16 (6H, d, J = 7.0 Hz), 2.16 (1H, d, J = 16.0 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.49 (1H, d, J = 17.6 Hz), 2.57 (1H, d, J = 18.0 Hz), 2.70-2.78 (1H, m), 2.85 (3H, s), 3.68 (3H, s), 5.28 (1H, s), 5.43 (1H, d, J = 12.5 Hz), 5.47 (1H, d, J = 12.5 Hz), 6.71 (1H, d, J = 8.2 Hz), 7.29-7.40 (4H, m), 7.49-7.53 (3H, m), 7.80 (1H, t, J = 7.8 Hz), 8.04 (1H, dd, J = 1.2, 7.8 Hz), 13.05 (1H, brs).
(19e) ベンジル6-{4-メトキシ-2-メチル-3-[3,8,8-トリメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]フェニル}ピリジン-2-カルボキシレート
　実施例19dで製造したベンジル6-{3-[8,8-ジメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボキシレート(166 mg, 0.268 mmol)、ヨウ化メチル(50 μL, 0.804 mmol)、DMF (1.5 mL)及び炭酸セシウム(262 mg, 0.804 mmol)を用い、実施例14bに準じて反応及び後処理を行うことにより、標記化合物(124 mg, 73%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.99 (3H, s), 1.11 (3H, s), 1.29 (3H, d, J = 6.7 Hz), 1.30 (3H, d, J = 7.0 Hz), 2.17 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 16.0 Hz), 2.52 (1H, d, J = 18.0 Hz), 2.59 (1H, d, J = 17.2 Hz), 2.77 (3H, s), 2.97-3.03 (1H, m), 3.63 (3H, s), 3.82 (3H, s), 5.32 (1H, s), 5.47 (2H, s), 6.69 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.34-7.41 (3H, m), 7.51 (2H, d, J = 7.8 Hz), 7.57 (1H, dd, J = 1.2, 8.6 Hz), 7.84 (1H, t, J = 7.8 Hz), 8.06 (1H, dd, J = 0.8, 7.4 Hz).
(19f) 6-{4-メトキシ-2-メチル-3-[3,8,8-トリメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]フェニル}ピリジン-2-カルボン酸
　実施例19eで製造したベンジル6-{4-メトキシ-2-メチル-3-[3,8,8-トリメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]フェニル}ピリジン-2-カルボキシレート(119 mg, 0.188 mmol)、水酸化パラジウム炭素(20%, 23.8 mg)及びエタノール(2.0 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(85.0 mg, 83%)を得た。 (Example 19)
6- {4-Methoxy-2-methyl-3- [3,8,8-trimethyl-4,6-dioxo-2- (propan-2-yl) -3,5,6,7,8,9- Hexahydro-4H-chromeno [2,3-d] pyrimidin-5-yl] phenyl} pyridine-2-carboxylic acid
(19a) Benzyl 6-bromopyridine-2-carboxylate 6-bromopyridine-2-carboxylic acid (13.9 g, 68.8 mmol), benzyl bromide (11.8 g, 68.8 mmol) and potassium carbonate (11.4 g, 82.6 mmol) acetonitrile The (100 mL) solution was stirred at 80 ° C. for 5 hours. After cooling to room temperature, water was added to the reaction solution, extracted with toluene, and the organic layer was washed twice with water and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was crystallized from hexane to obtain the title compound (14.4 g, 72%).
1 H-NMR (500 MHz, CDCl 3 )): δ ppm: 5.45 (2H, s), 7.33-7.40 (3H, m), 7.47 (2H, d, J = 7.6 Hz), 7.66-7.70 (2H, m ), 8.07 (1H, dd, J = 2.2, 6.4 Hz).
(19b) Benzyl 6- (3-formyl-4-methoxy-2-methyl-phenyl) pyridine-2-carboxylate benzyl 6-bromopyridine-2-carboxylate prepared in Example 19a (3.81 g under nitrogen atmosphere) , 13.0 mmol), 6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) benzaldehyde prepared in Example 9a (3.00 g, 10.9 mmol), tetrakis (triphenylphosphine) palladium (0) (1.26 g, 1.09 mmol) and sodium carbonate (3.45 g, 32.6 mmol) in DME (20 mL) and water (10 mL) Stir for hours. After cooling to room temperature, water was added to the reaction solution, extracted with toluene, and the organic layer was washed twice with water and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was recrystallized from ethanol and toluene to obtain the title compound (2.17 g, 55%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 2.52 (3H, s), 3.95 (3H, s), 5.46 (2H, s), 6.94 (1H, d, J = 8.6 Hz), 7.34-7.41 (3H, m), 7.48-7.52 (3H, m), 7.61 (1H, d, J = 8.6 Hz), 7.87 (1H, t, J = 7.8 Hz), 8.09 (1H, dd, J = 0.8, 7.8 Hz), 10.69 (1H, s).
(19c) Benzyl 6- {3-[(4,4-dimethyl-2,6-dioxocyclohexylidene) methyl] -4-methoxy-2-methylphenyl} pyridine-2-carboxylate prepared in Example 19b Dimedone (1.28 g, 9.13 mmol) at 60 ° C. in a solution of benzyl 6- (3-formyl-4-methoxy-2-methyl-phenyl) pyridine-2-carboxylate (3.00 g, 8.30 mmol) in acetonitrile (30 mL) ) And D-proline (47.8 mg, 0.415 mmol) were added, and the reaction solution was stirred at 60 ° C. for 2 hours. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction twice with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from hexane and dichloromethane to obtain the title compound (3.29 g, 82%).
1 H-NMR (500 MHz, CDCl 3 ): δ ppm: 1.13 (6H, s), 2.25 (3H, s), 2.56 (2H, s) 2.62 (2H, s), 3.77 (3H, s), 5.46 ( 2H, s), 6.81 (1H, d, J = 8.5 Hz), 7.32-7.41 (4H, m), 7.49 (2H, d, J = 7.3 Hz), 7.57 (1H, dd, J = 1.0, 7.8 Hz ), 7.85 (1H, t, J = 7.8 Hz), 7.93 (1H, s), 8.06 (1H, dd, J = 1.0, 7.8 Hz).
(19d) Benzyl 6- {3- [8,8-dimethyl-4,6-dioxo-2- (propan-2-yl) -3,5,6,7,8,9-hexahydro-4H-chromeno [ 2,3-d] pyrimidin-5-yl] -4-methoxy-2-methylphenyl} pyridine-2-carboxylate benzyl 6- {3-[(4,4-dimethyl-2, prepared in Example 19c 6-Dioxocyclohexylidene) methyl] -4-methoxy-2-methylphenyl} pyridine-2-carboxylate (300 mg, 0.620 mmol), 6-hydroxy-2- (propan-2-yl) pyrimidine-4 (3H) -one (105 mg, 0.682 mmol), DMF (3.0 mL), cesium carbonate (505 mg, 1.55 mmol) and methanesulfonyl chloride (58 μL, 0.774 mmol) were used according to Example 1b. The title compound (266 mg, 69%) was obtained by post-treatment.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.98 (3H, s), 1.11 (3H, s), 1.16 (6H, d, J = 7.0 Hz), 2.16 (1H, d, J = 16.0 Hz ), 2.24 (1H, d, J = 16.4 Hz), 2.49 (1H, d, J = 17.6 Hz), 2.57 (1H, d, J = 18.0 Hz), 2.70-2.78 (1H, m), 2.85 (3H , s), 3.68 (3H, s), 5.28 (1H, s), 5.43 (1H, d, J = 12.5 Hz), 5.47 (1H, d, J = 12.5 Hz), 6.71 (1H, d, J = 8.2 Hz), 7.29-7.40 (4H, m), 7.49-7.53 (3H, m), 7.80 (1H, t, J = 7.8 Hz), 8.04 (1H, dd, J = 1.2, 7.8 Hz), 13.05 ( 1H, brs).
(19e) Benzyl 6- {4-methoxy-2-methyl-3- [3,8,8-trimethyl-4,6-dioxo-2- (propan-2-yl) -3,5,6,7, 8,9-Hexahydro-4H-chromeno [2,3-d] pyrimidin-5-yl] phenyl} pyridine-2-carboxylate benzyl 6- {3- [8,8-dimethyl-4 prepared in Example 19d , 6-Dioxo-2- (propan-2-yl) -3,5,6,7,8,9-hexahydro-4H-chromeno [2,3-d] pyrimidin-5-yl] -4-methoxy- Example using 2-methylphenyl} pyridine-2-carboxylate (166 mg, 0.268 mmol), methyl iodide (50 μL, 0.804 mmol), DMF (1.5 mL) and cesium carbonate (262 mg, 0.804 mmol) The title compound (124 mg, 73%) was obtained by carrying out the reaction and post-treatment according to 14b.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.99 (3H, s), 1.11 (3H, s), 1.29 (3H, d, J = 6.7 Hz), 1.30 (3H, d, J = 7.0 Hz ), 2.17 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 16.0 Hz), 2.52 (1H, d, J = 18.0 Hz), 2.59 (1H, d, J = 17.2 Hz), 2.77 (3H, s), 2.97-3.03 (1H, m), 3.63 (3H, s), 3.82 (3H, s), 5.32 (1H, s), 5.47 (2H, s), 6.69 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.34-7.41 (3H, m), 7.51 (2H, d, J = 7.8 Hz), 7.57 (1H, dd, J = 1.2, 8.6 Hz), 7.84 (1H, t, J = 7.8 Hz), 8.06 (1H, dd, J = 0.8, 7.4 Hz).
(19f) 6- {4-Methoxy-2-methyl-3- [3,8,8-trimethyl-4,6-dioxo-2- (propan-2-yl) -3,5,6,7,8 , 9-Hexahydro-4H-chromeno [2,3-d] pyrimidin-5-yl] phenyl} pyridine-2-carboxylic acid benzyl 6- {4-methoxy-2-methyl-3- [prepared in Example 19e 3,8,8-trimethyl-4,6-dioxo-2- (propan-2-yl) -3,5,6,7,8,9-hexahydro-4H-chromeno [2,3-d] pyrimidine- 5-yl] phenyl} pyridine-2-carboxylate (119 mg, 0.188 mmol), palladium hydroxide on carbon (20%, 23.8 mg) and ethanol (2.0 mL), reaction and workup according to Example 18. To give the title compound (85.0 mg, 83%).
(実施例20)
　6-{3-[(5S)-8,8-ジメチル-4,6-ジオキソ-2-(プロパン-2-イル)-1,3,4,5,6,7,8,9-オクタヒドロ-2H-クロメノ[2,3-c]ピリジン-5-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
(20a) tert-ブチル　5-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-8,8-ジメチル-4,6-ジオキソ-1,3,4,5,6,7,8,9-オクタヒドロ-2H-クロメノ[2,3-c]ピリジン-2-カルボキシレート
　実施例9bで製造した2-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン(1.00 g, 2.51 mmol)及び公知化合物であるtert-ブチル　3,5-ジオキソピペリジン-1-カルボキシレート(633 mg, 2.76 mmol)、DMF (13 mL)、炭酸セシウム(2.05 g, 6.28 mmol)及びメタンスルホニルクロリド(235 μL, 3.01 mmol)を用い、実施例1bに準じて反応及び後処理を行うことにより、標記化合物(846 mg, 57%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.94 (3H, s), 1.09 (3H, s), 1.32 (12H, s), 1.42 (9H, s), 2.13 (1H, d, J = 16.4 Hz), 2.20 (1H, d, J = 16.4 Hz), 2.39 (1H, d, J = 18.0 Hz), 2.47 (1H, d, J = 16.8 Hz), 3.13 (3H, s), 3.68 (3H, s), 3.70-3.76 (1H, m), 3.95-4.00 (1H, m), 4.24 (1H, d, J = 17.6 Hz), 4.65-4.69 (1H, m), 5.13 (1H, s), 6.60 (1H, d, J = 8.2 Hz), 7.60 (1H, d, J = 8.2 Hz).
(20b) 5-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-8,8-ジメチル-5,7,8,9-テトラヒドロ-2H-クロメノ[2,3-c]ピリジン-4,6(1H,3H)-ジオン　塩酸塩
　実施例20aで製造したtert-ブチル　5-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-8,8-ジメチル-4,6-ジオキソ-1,3,4,5,6,7,8,9-オクタヒドロ-2H-クロメノ[2,3-c]ピリジン-2-カルボキシレート(727 mg, 1.22 mmol)及び4 M塩酸(酢酸エチル溶液, 3.6 mL)の酢酸エチル(3.6 mL)溶液を室温で16時間攪拌した。反応溶液を濃縮し、標記化合物(649 mg, 99%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.92 (3H, s), 1.10 (3H, s), 1.30 (12H, s), 2.13 (1H, d, J = 16.4 Hz), 2.21 (1H, d, J = 16.8 Hz), 2.39 (1H, d, J = 18.0 Hz), 2.50 (1H, d, J = 17.6 Hz), 3.08 (3H, s), 3.54-3.56 (1H, m), 3.67-3.73 (1H, m), 3.70 (3H, s), 3.80-3.83 (1H, m), 4.08-7.13 (1H, m), 5.10 (1H, s), 6.59 (1H, d, J = 8.6 Hz), 7.58 (1H, d, J = 8.2 Hz).
(20c) 5-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-8,8-ジメチル-2-(プロパン-2-イル)-5,7,8,9-テトラヒドロ-2H-クロメノ[2,3-c]ピリジン-4,6(1H,3H)-ジオン
　実施例20bで製造した5-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-8,8-ジメチル-5,7,8,9-テトラヒドロ-2H-クロメノ[2,3-c]ピリジン-4,6(1H,3H)-ジオン　塩酸塩(680 mg, 1.28 mmol)及びアセトン(0.565 mL, 7.70 mmol)のジクロロメタン(10 mL)溶液に0℃でナトリウム　トリアセトキシボロハイドライド(1.09 g, 5.13 mmol)及び酢酸(80 μL, 1.41 mmol)を加えた。反応溶液を室温で2時間攪拌後、反応溶液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで2回抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 3:7)で精製し、標記化合物(687 mg, 76％)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.94 (3H, s), 1.04 (3H, d, J = 6.3 Hz), 1.06 (3H, d, J = 6.7 Hz), 1.08 (3H, s), 1.31 (12H, s), 2.12 (1H, d, J = 16.0 Hz), 2.19 (1H, d, J = 16.4 Hz), 2.35 (1H, d, J = 16.8 Hz), 2.43 (1H, d, J = 17.2 Hz), 2.75-2.81 (1H, m), 3.04-3.17 (2H, m), 3.12 (3H, s), 3.38 (1H, d, J = 17.2 Hz), 3.50 (1H, dd, J = 1.6, 16.8 Hz), 3.69 (3H, s), 5.08 (1H, s), 6.60 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 8.2 Hz).
(20d) (5S)-5-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-8,8-ジメチル-2-(プロパン-2-イル)-5,7,8,9-テトラヒドロ-2H-クロメノ[2,3-c]ピリジン-4,6(1H,3H)-ジオン
　実施例20cで製造した5-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-8,8-ジメチル-2-(プロパン-2-イル)-5,7,8,9-テトラヒドロ-2H-クロメノ[2,3-c]ピリジン-4,6(1H,3H)-ジオン(290 mg)をChiral flash IA(ダイセル化学工業; ヘキサン/エタノール；2:8)により光学分割し、高極性化合物(100 mg)及び低極性化合物(90 mg)を得た。
(20e) ベンジル　6-クロロ-3-メチルピリジン-2-カルボキシレート
　6-クロロ-3-メチルピリジン-2-カルボン酸(5.00 g, 29.1 mmol)、ベンジルブロミド(3.46 mL, 29.1 mmol)及び炭酸セシウム(11.4 g, 35.0 mmol)のDMF (25 mL)溶液を80℃で3時間攪拌した。室温まで冷却後、反応溶液に水を加え、トルエンで2回抽出した。有機層を水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 4:1)で精製し、標記化合物(6.66 g, 87％)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 2.50 (3H, s), 5.43 (2H, s), 7.32-7.40 (4H, m), 7.47 (2H, dd, J = 1.6, 8.2 Hz), 7.56 (1H, dd, J = 0.8, 8.2 Hz).
(20f) ベンジル　6-{3-[(5S)-8,8-ジメチル-4,6-ジオキソ-2-(プロパン-2-イル)-1,3,4,5,6,7,8,9-オクタヒドロ-2H-クロメノ[2,3-c]ピリジン-5-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例20dで製造した(5S)-5-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-8,8-ジメチル-2-(プロパン-2-イル)-5,7,8,9-テトラヒドロ-2H-クロメノ[2,3-c]ピリジン-4,6(1H,3H)-ジオン(高極性化合物; 100 mg, 0.187 mmol)、実施例20eで製造したベンジル　6-クロロ-3-メチルピリジン-2-カルボキシレート(58.6 mg, 0.224 mmol)、2nd Generation X-Phos Precatalyst (14.7 mg, 0.0187 mmol)、リン酸カリウム(63.4 mg, 0.299 mmol)、THF (0.4 mL)及び水(0.8 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(73.0 mg, 62%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.97 (3H, s), 1.06 (3H, d, J = 6.3 Hz), 1.08 (3H, d, J = 6.7 Hz), 1.09 (3H, s), 2.14 (1H, d, J = 16.0 Hz), 2.20 (1H, d, J = 15.6 Hz), 2.37 (1H, d, J = 15.6 Hz), 2.45 (1H, d, J = 15.6 Hz), 2.52 (3H, s), 2.75-2.81 (1H, m), 2.86 (3H, s), 3.09 (1H, d, J = 17.6 Hz), 3.17 (1H, d, J = 14.8 Hz), 3.40 (1H, d, J = 17.6 Hz), 3.53 (1H, d, J = 15.3 Hz), 3.73 (3H, s), 5.44 (1H, s), 6.72 (1H, d, J = 9.0 Hz), 7.26-7.39 (4H, m), 7.43 (1H, d, J = 8.2 Hz), 7.51 (2H, dd, J = 2.7, 10.2 Hz), 7.57 (1H, d, J = 8.2 Hz).
(20g) 6-{3-[(5S)-8,8-ジメチル-4,6-ジオキソ-2-(プロパン-2-イル)-1,3,4,5,6,7,8,9-オクタヒドロ-2H-クロメノ[2,3-c]ピリジン-5-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例20fで製造したベンジル　6-{3-[(5S)-8,8-ジメチル-4,6-ジオキソ-2-(プロパン-2-イル)-1,3,4,5,6,7,8,9-オクタヒドロ-2H-クロメノ[2,3-c]ピリジン-5-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(72.0 mg, 0.113 mmol)、水酸化パラジウム炭素(20%, 14.4 mg)及びエタノール(2.2 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(52.1 mg, 84%)を得た。 (Example 20)
6- {3-[(5S) -8,8-Dimethyl-4,6-dioxo-2- (propan-2-yl) -1,3,4,5,6,7,8,9-octahydro- 2H-chromeno [2,3-c] pyridin-5-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid
(20a) tert-butyl 5- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -8,8- Dimethyl-4,6-dioxo-1,3,4,5,6,7,8,9-octahydro-2H-chromeno [2,3-c] pyridine-2-carboxylate 2-prepared in Example 9b [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] -5,5-dimethylcyclohexane-1,3-dione (1.00 g, 2.51 mmol) and known compounds tert-butyl 3,5-dioxopiperidine-1-carboxylate (633 mg, 2.76 mmol), DMF (13 mL), cesium carbonate (2.05 g, 6.28 mmol) And methanesulfonyl chloride (235 μL, 3.01 mmol) were used for the reaction and post-treatment according to Example 1b to obtain the title compound (846 mg, 57%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.94 (3H, s), 1.09 (3H, s), 1.32 (12H, s), 1.42 (9H, s), 2.13 (1H, d, J = 16.4 Hz), 2.20 (1H, d, J = 16.4 Hz), 2.39 (1H, d, J = 18.0 Hz), 2.47 (1H, d, J = 16.8 Hz), 3.13 (3H, s), 3.68 (3H , s), 3.70-3.76 (1H, m), 3.95-4.00 (1H, m), 4.24 (1H, d, J = 17.6 Hz), 4.65-4.69 (1H, m), 5.13 (1H, s), 6.60 (1H, d, J = 8.2 Hz), 7.60 (1H, d, J = 8.2 Hz).
(20b) 5- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -8,8-dimethyl-5 , 7,8,9-Tetrahydro-2H-chromeno [2,3-c] pyridine-4,6 (1H, 3H) -dione hydrochloride tert-butyl 5- [6-methoxy-2 prepared in Example 20a -Methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -8,8-dimethyl-4,6-dioxo-1,3,4, Ethyl acetate with 5,6,7,8,9-octahydro-2H-chromeno [2,3-c] pyridine-2-carboxylate (727 mg, 1.22 mmol) and 4 M hydrochloric acid (ethyl acetate solution, 3.6 mL) The solution (3.6 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated to obtain the title compound (649 mg, 99%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.92 (3H, s), 1.10 (3H, s), 1.30 (12H, s), 2.13 (1H, d, J = 16.4 Hz), 2.21 (1H , d, J = 16.8 Hz), 2.39 (1H, d, J = 18.0 Hz), 2.50 (1H, d, J = 17.6 Hz), 3.08 (3H, s), 3.54-3.56 (1H, m), 3.67 -3.73 (1H, m), 3.70 (3H, s), 3.80-3.83 (1H, m), 4.08-7.13 (1H, m), 5.10 (1H, s), 6.59 (1H, d, J = 8.6 Hz ), 7.58 (1H, d, J = 8.2 Hz).
(20c) 5- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -8,8-dimethyl-2 -(Propan-2-yl) -5,7,8,9-tetrahydro-2H-chromeno [2,3-c] pyridine-4,6 (1H, 3H) -dione 5- [prepared in Example 20b 6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -8,8-dimethyl-5,7,8,9 -Tetrahydro-2H-chromeno [2,3-c] pyridine-4,6 (1H, 3H) -dione Hydrochloride (680 mg, 1.28 mmol) and acetone (0.565 mL, 7.70 mmol) in dichloromethane (10 mL) To the mixture was added sodium triacetoxyborohydride (1.09 g, 5.13 mmol) and acetic acid (80 μL, 1.41 mmol) at 0 ° C. The reaction solution was stirred at room temperature for 2 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate; 3: 7) to obtain the title compound (687 mg, 76%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.94 (3H, s), 1.04 (3H, d, J = 6.3 Hz), 1.06 (3H, d, J = 6.7 Hz), 1.08 (3H, s ), 1.31 (12H, s), 2.12 (1H, d, J = 16.0 Hz), 2.19 (1H, d, J = 16.4 Hz), 2.35 (1H, d, J = 16.8 Hz), 2.43 (1H, d , J = 17.2 Hz), 2.75-2.81 (1H, m), 3.04-3.17 (2H, m), 3.12 (3H, s), 3.38 (1H, d, J = 17.2 Hz), 3.50 (1H, dd, J = 1.6, 16.8 Hz), 3.69 (3H, s), 5.08 (1H, s), 6.60 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 8.2 Hz).
(20d) (5S) -5- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -8,8 -Dimethyl-2- (propan-2-yl) -5,7,8,9-tetrahydro-2H-chromeno [2,3-c] pyridine-4,6 (1H, 3H) -dione Prepared in Example 20c 5- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -8,8-dimethyl-2- ( Propan-2-yl) -5,7,8,9-tetrahydro-2H-chromeno [2,3-c] pyridine-4,6 (1H, 3H) -dione (290 mg) was converted to Chiral flash IA (Daicel Chemistry). Industrial resolution; hexane / ethanol; 2: 8) was optically resolved to obtain a highly polar compound (100 mg) and a less polar compound (90 mg).
(20e) Benzyl 6-chloro-3-methylpyridine-2-carboxylate 6-chloro-3-methylpyridine-2-carboxylic acid (5.00 g, 29.1 mmol), benzyl bromide (3.46 mL, 29.1 mmol) and cesium carbonate A solution of (11.4 g, 35.0 mmol) in DMF (25 mL) was stirred at 80 ° C. for 3 hours. After cooling to room temperature, water was added to the reaction solution and extracted twice with toluene. The organic layer was washed with water and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 4: 1) to obtain the title compound (6.66 g, 87%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 2.50 (3H, s), 5.43 (2H, s), 7.32-7.40 (4H, m), 7.47 (2H, dd, J = 1.6, 8.2 Hz) , 7.56 (1H, dd, J = 0.8, 8.2 Hz).
(20f) Benzyl 6- {3-[(5S) -8,8-dimethyl-4,6-dioxo-2- (propan-2-yl) -1,3,4,5,6,7,8, 9-Octahydro-2H-chromeno [2,3-c] pyridin-5-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (5S)-prepared in Example 20d 5- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -8,8-dimethyl-2- (propane -2-yl) -5,7,8,9-tetrahydro-2H-chromeno [2,3-c] pyridine-4,6 (1H, 3H) -dione (high polarity compound; 100 mg, 0.187 mmol), Benzyl 6-chloro-3-methylpyridine-2-carboxylate prepared in Example 20e (58.6 mg, 0.224 mmol), 2nd Generation X-Phos Precatalyst (14.7 mg, 0.0187 mmol), potassium phosphate (63.4 mg, 0.299) mmol), THF (0.4 mL) and water (0.8 mL) were used for the reaction and post-treatment according to Example 9d to obtain the title compound (73.0 mg, 62%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.97 (3H, s), 1.06 (3H, d, J = 6.3 Hz), 1.08 (3H, d, J = 6.7 Hz), 1.09 (3H, s ), 2.14 (1H, d, J = 16.0 Hz), 2.20 (1H, d, J = 15.6 Hz), 2.37 (1H, d, J = 15.6 Hz), 2.45 (1H, d, J = 15.6 Hz), 2.52 (3H, s), 2.75-2.81 (1H, m), 2.86 (3H, s), 3.09 (1H, d, J = 17.6 Hz), 3.17 (1H, d, J = 14.8 Hz), 3.40 (1H , d, J = 17.6 Hz), 3.53 (1H, d, J = 15.3 Hz), 3.73 (3H, s), 5.44 (1H, s), 6.72 (1H, d, J = 9.0 Hz), 7.26-7.39 (4H, m), 7.43 (1H, d, J = 8.2 Hz), 7.51 (2H, dd, J = 2.7, 10.2 Hz), 7.57 (1H, d, J = 8.2 Hz).
(20g) 6- {3-[(5S) -8,8-Dimethyl-4,6-dioxo-2- (propan-2-yl) -1,3,4,5,6,7,8,9 -Octahydro-2H-chromeno [2,3-c] pyridin-5-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid benzyl 6- {3 prepared in Example 20f -[(5S) -8,8-Dimethyl-4,6-dioxo-2- (propan-2-yl) -1,3,4,5,6,7,8,9-octahydro-2H-chromeno [ 2,3-c] pyridin-5-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (72.0 mg, 0.113 mmol), palladium hydroxide on carbon (20%, 14.4 mg ) And ethanol (2.2 mL) were used for the reaction and post-treatment according to Example 18 to obtain the title compound (52.1 mg, 84%).
(実施例21)
　6-{4-メトキシ-2-メチル-3-[(5S)-3,8,8-トリメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]フェニル}-3-メチルピリジン-2-カルボン酸
(21a) 5-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,8,8-トリメチル-2-(プロパン-2-イル)-5,7,8,9-テトラヒドロ-4H-クロメノ[2,3-d]ピリミジン-4,6(3H)-ジオン
実施例9bで製造した2-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン(700 mg, 1.76 mmol)及び6-ヒドロキシ-2-(プロパン-2-イル)ピリミジン-4(3H)-オン(298 mg, 1.93 mmol)のDMF (7.0 mL)溶液に室温で炭酸セシウム(2.29 g, 7.03 mmol)を加えた。反応溶液を室温で2時間攪拌後、0℃でメタンスルホニルクロリド(164 μL, 2.11 mmol)のDMF (2.0 mL)溶液を加え、反応溶液を室温で19時間攪拌した。反応溶液に0℃でヨウ化メチル(328 μL, 5.27 mmol)を加え、室温で5時間攪拌した。反応溶液に水を加えて酢酸エチルで2回抽出後、有機層を水で2回洗浄、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をヘキサン/ジクロロメタン; 3:1)で結晶化し、標記化合物(565 mg, 59%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.95 (3H, s), 1.09 (3H, s), 1.29 (3H, d, J = 7.0 Hz), 1.31 (12H, s), 1.32 (3H, d, J = 6.3 Hz), 2.13 (1H, d, J = 16.4 Hz), 2.22 (1H, d, J = 16.0 Hz), 2.48 (1H, d, J = 17.6 Hz), 2.56 (1H, d, J = 16.4 Hz), 3.05-3.12 (1H, m), 3.17 (3H, s), 3.47 (3H, s), 3.64 (3H, s), 5.33 (1H, s), 6.58 (1H, d, J = 8.6 Hz), 7.60 (1H, d, J = 8.6 Hz).
(21b) ベンジル　6-{4-メトキシ-2-メチル-3-[3,8,8-トリメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例21aで製造した5-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,8,8-トリメチル-2-(プロパン-2-イル)-5,7,8,9-テトラヒドロ-4H-クロメノ[2,3-d]ピリミジン-4,6(3H)-ジオン(250 mg, 0.456 mmol)、実施例20eで製造したベンジル　6-クロロ-3-メチルピリジン-2-カルボキシレート(143 mg, 0.547 mmol)、2nd Generation X-Phos Precatalyst (17.9 mg, 0.0228 mmol)、リン酸カリウム(145 mg, 0.684 mmol)、THF (2.5 mL)及び水(2.5 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(207 mg, 70%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.99 (3H, s), 1.11 (3H, s), 1.31 (3H, d, J = 6.7 Hz), 1.34 (3H, d, J = 6.7 Hz), 2.16 (1H, d, J = 16.4 Hz), 2.23 (1H, d, J = 16.0 Hz), 2.51 (1H, d, J = 17.6 Hz), 2.53 (3H, s), 2.59 (1H, d, J = 16.8 Hz), 2.91 (3H, s), 3.07-3.14 (1H, m), 3.48 (3H, s), 3.68 (3H, s), 5.32 (1H, s), 5.44 (2H, s), 6.70 (1H, d, J = 8.6 Hz), 7.28-7.40 (4H, m), 7.46 (1H, d, J = 8.2 Hz), 7.51 (2H, d, J = 7.0 Hz), 7.57 (1H, d,J = 8.2 Hz).
(21c) ベンジル　6-{4-メトキシ-2-メチル-3-[(5S)-3,8,8-トリメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例21bで製造したベンジル　6-{4-メトキシ-2-メチル-3-[3,8,8-トリメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(208 mg)をChiral flash IA(エタノール)により光学分割し、高極性化合物(90.5 mg)及び低極性化合物(101 mg)を得た。
(21d) 6-{4-メトキシ-2-メチル-3-[(5S)-3,8,8-トリメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例21cで製造したベンジル　6-{4-メトキシ-2-メチル-3-[(5S)-3,8,8-トリメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(高極性化合物; 100 mg, 0.154 mmol)、水酸化パラジウム炭素(20%, 20.0 mg)及びエタノール(2.0 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(51.6 mg, 60%)を得た。 (Example 21)
6- {4-Methoxy-2-methyl-3-[(5S) -3,8,8-trimethyl-4,6-dioxo-2- (propan-2-yl) -3,5,6,7, 8,9-Hexahydro-4H-chromeno [2,3-d] pyrimidin-5-yl] phenyl} -3-methylpyridine-2-carboxylic acid
(21a) 5- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,8,8-trimethyl 2- (propan-2-yl) -5,7,8,9-tetrahydro-4H-chromeno [2,3-d] pyrimidine-4,6 (3H) -dione 2- [prepared in Example 9b 6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] -5,5-dimethylcyclohexane-1,3-dione ( 700 mg, 1.76 mmol) and 6-hydroxy-2- (propan-2-yl) pyrimidin-4 (3H) -one (298 mg, 1.93 mmol) in DMF (7.0 mL) at room temperature with cesium carbonate (2.29 g , 7.03 mmol). After the reaction solution was stirred at room temperature for 2 hours, a solution of methanesulfonyl chloride (164 μL, 2.11 mmol) in DMF (2.0 mL) was added at 0 ° C., and the reaction solution was stirred at room temperature for 19 hours. Methyl iodide (328 μL, 5.27 mmol) was added to the reaction solution at 0 ° C., and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with water and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was crystallized from hexane / dichloromethane; 3: 1) to obtain the title compound (565 mg, 59%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.95 (3H, s), 1.09 (3H, s), 1.29 (3H, d, J = 7.0 Hz), 1.31 (12H, s), 1.32 (3H , d, J = 6.3 Hz), 2.13 (1H, d, J = 16.4 Hz), 2.22 (1H, d, J = 16.0 Hz), 2.48 (1H, d, J = 17.6 Hz), 2.56 (1H, d , J = 16.4 Hz), 3.05-3.12 (1H, m), 3.17 (3H, s), 3.47 (3H, s), 3.64 (3H, s), 5.33 (1H, s), 6.58 (1H, d, J = 8.6 Hz), 7.60 (1H, d, J = 8.6 Hz).
(21b) Benzyl 6- {4-methoxy-2-methyl-3- [3,8,8-trimethyl-4,6-dioxo-2- (propan-2-yl) -3,5,6,7, 8,9-Hexahydro-4H-chromeno [2,3-d] pyrimidin-5-yl] phenyl} -3-methylpyridine-2-carboxylate 5- [6-methoxy-2-methyl prepared in Example 21a -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,8,8-trimethyl-2- (propan-2-yl) -5, 7,8,9-Tetrahydro-4H-chromeno [2,3-d] pyrimidine-4,6 (3H) -dione (250 mg, 0.456 mmol), benzyl 6-chloro-3-methyl prepared in Example 20e Pyridine-2-carboxylate (143 mg, 0.547 mmol), 2nd Generation X-Phos Precatalyst (17.9 mg, 0.0228 mmol), potassium phosphate (145 mg, 0.684 mmol), THF (2.5 mL) and water (2.5 mL) The title compound (207 mg, 70%) was obtained by carrying out the reaction and post-treatment according to Example 9d.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.99 (3H, s), 1.11 (3H, s), 1.31 (3H, d, J = 6.7 Hz), 1.34 (3H, d, J = 6.7 Hz ), 2.16 (1H, d, J = 16.4 Hz), 2.23 (1H, d, J = 16.0 Hz), 2.51 (1H, d, J = 17.6 Hz), 2.53 (3H, s), 2.59 (1H, d , J = 16.8 Hz), 2.91 (3H, s), 3.07-3.14 (1H, m), 3.48 (3H, s), 3.68 (3H, s), 5.32 (1H, s), 5.44 (2H, s) , 6.70 (1H, d, J = 8.6 Hz), 7.28-7.40 (4H, m), 7.46 (1H, d, J = 8.2 Hz), 7.51 (2H, d, J = 7.0 Hz), 7.57 (1H, d, J = 8.2 Hz).
(21c) Benzyl 6- {4-methoxy-2-methyl-3-[(5S) -3,8,8-trimethyl-4,6-dioxo-2- (propan-2-yl) -3,5, 6,7,8,9-Hexahydro-4H-chromeno [2,3-d] pyrimidin-5-yl] phenyl} -3-methylpyridine-2-carboxylate benzyl 6- {4- prepared in Example 21b Methoxy-2-methyl-3- [3,8,8-trimethyl-4,6-dioxo-2- (propan-2-yl) -3,5,6,7,8,9-hexahydro-4H-chromeno [2,3-d] pyrimidin-5-yl] phenyl} -3-methylpyridine-2-carboxylate (208 mg) was optically resolved with Chiral flash IA (ethanol) to obtain high polar compounds (90.5 mg) and low Polar compound (101 mg) was obtained.
(21d) 6- {4-Methoxy-2-methyl-3-[(5S) -3,8,8-trimethyl-4,6-dioxo-2- (propan-2-yl) -3,5,6 , 7,8,9-Hexahydro-4H-chromeno [2,3-d] pyrimidin-5-yl] phenyl} -3-methylpyridine-2-carboxylic acid benzyl 6- {4-methoxy prepared in Example 21c -2-Methyl-3-[(5S) -3,8,8-trimethyl-4,6-dioxo-2- (propan-2-yl) -3,5,6,7,8,9-hexahydro- 4H-chromeno [2,3-d] pyrimidin-5-yl] phenyl} -3-methylpyridine-2-carboxylate (high polarity compound; 100 mg, 0.154 mmol), palladium hydroxide on carbon (20%, 20.0 mg ) And ethanol (2.0 mL) were used for the reaction and post-treatment according to Example 18 to obtain the title compound (51.6 mg, 60%).
(実施例22)
　6-{3-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
(22a) メチル　(3S)-3-[(3-エトキシ-3-オキソプロパノイル)アミノ]-4,4-ジメチルペンタノエート
　メチル　(3S)-3-アミノ-4,4-ジメチルペンタノエート塩酸塩(13.5 g, 68.7 mmol)及びトリエチルアミン(30. mL, 217 mmol)のジクロロメタン(205 mL)溶液に0℃でエチルマロニルクロリド(9.09 mL, 72.2 mmol)を加えた。反応溶液を室温で2.5時間攪拌後、1 M 塩酸を加えてジクロロメタンで2回抽出後、有機層を5%炭酸水素ナトリウム水溶液で洗浄した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮し、粗製の標記化合物(15.9 g, 85%)を得た。
(22b) エチル　(6S)-6-tert-ブチル-2,4-ジオキソピペリジン-3-カルボキシレート
　窒素雰囲気下、実施例22aで製造した粗製のメチル　(3S)-3-[(3-エトキシ-3-オキソプロパノイル)アミノ]-4,4-ジメチルペンタノエート(15.9 g, 58.1 mmol)のトルエン(111 mL)溶液に室温で20％ナトリウムエトキシド(エタノール溶液; 23.7 g, 70.0 mmol)を加え、反応溶液を80℃で1.5時間攪拌後した。室温まで冷却後、反応溶液に水を加えて酢酸エチルで2回抽出した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮し、粗製の標記化合物(12.7 g, 91%)を得た。
(22c) (6S)-6-tert-ブチルピペリジン-2,4-ジオン
　実施例22bで製造した粗製のエチル　(6S)-6-tert-ブチル-2,4-ジオキソピペリジン-3-カルボキシレート(12.7 g, 52.6 mmol)のアセトニトリル(254 mL)及び水(5 mL)溶液を加熱還流下7.5時間攪拌後した。室温まで冷却後、反応溶液を減圧濃縮し、残渣をエーテルで結晶化することにより標記化合物(4.06 g, 46%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.99 (9H, s), 2.48 (1H, dd, J = 9.0, 16.0 Hz), 2.65 (1H, dd, J = 4.7, 16.0 Hz), 3.29 (2H, d, J = 0.8 Hz), 3.39-3.44 (1H, m), 6.72 (1H, br).
(22d) tert-ブチル　6-{3-[(3S,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例1aで製造したtert-ブチル　6-{3-[(4,4-ジメチル-2,6-ジオキソシクロヘキシリデン)メチル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(9.50 g, 20.0 mmol)、実施例22cで製造した(6S)-6-tert-ブチルピペリジン-2,4-ジオン(3.50 g, 23.0 mmol)、DMF (42 mL)、炭酸セシウム(7.33 g, 22.5 mmol)、トリフェニルホスフィン(2.83 g, 10.8 mmol)、THF (42 mL)及びジ-tert-ブチルアゾジカルボキシレート(2.49 g, 10.8 mmol)を用い、実施例15aに準じて反応及び後処理を行うことにより、標記化合物(1.25 g, 23%)を得た。 
1H-NMR(400MHz, CDCl3):δ ppm: 0.89 (9H, s), 0.94 (3H, s), 1.09 (3H, s), 1.63 (9H, s), 2.12 (1H, dd, J = 1.2, 16.4 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.33 (1H, dd, J = 1.2, 17.6 Hz), 2.45 (1H, d, J = 17.6 Hz), 2.49 (3H, s), 2.53 (2H, d, J = 8.2 Hz),  2.84 (3H, s), 3.30 (1H, td, J = 2.4, 7.8 Hz), 3.69 (3H, s), 5.08 (1H, s), 5.16 (1H, d, J = 1.6 Hz), 6.67 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.6 Hz).
　また、副生したtert-ブチル　6-{3-[(3S,10S,10aR)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,6,7,8,9,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(1.47 g, 27%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.91 (9H, s), 0.97 (3H, s), 1.07 (3H, s), 1.64 (9H, s), 2.05 (1H, dd, J = 1.2, 16.4 Hz), 2.14 (1H, d, J = 16.4 Hz), 2.33 (1H, d, J = 17.6 Hz), 2.42 (1H, dd, J = 2.4, 18.0 Hz), 2.49 (3H, s), 2.70 (3H, s), 3.59-3.62 (1H, m), 3.75 (3H, s), 3.93-3.96 (1H, m), 4.50 (1H, d, J = 7.0 Hz), 5.55-5.58 (1H, m), 6.06 (1H, s), 6.72 (1H, d, J = 8.6 Hz), 7.30 (1H, d, J = 8.2 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.2 Hz).
(22e) tert-ブチル6-{3-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例22dで製造したtert-ブチル　6-{3-[(3S,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(250 mg, 0.407 mmol)、ヨウ化メチル(253 μL, 4.07 mmol)、DMF (5.0 mL)及び水素化ナトリウム(63%, 18.6 mg, 0.488 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物( 187 mg, 73%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.86 (9H, s), 0.96 (3H, s), 1.09 (3H, s), 1.64 (9H, s), 2.12 (1H, dd, J = 0.8, 16.0 Hz), 2.21 (1H, d, J = 16.0 Hz), 2.33 (1H, dd, J = 0.8, 17.6 Hz), 2.45 (1H, dd, J = 1.2, 16.8 Hz), 2.49 (3H, s), 2.53 (1H, d, J = 18.4 Hz), 2.86-2.93 (1H, m), 2.89 (3H, s), 3.00 (3H, s), 3.14 (1H, d, J = 8.6 Hz), 3.63 (3H, s), 5.26 (1H, s), 6.61 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.2 Hz), 7.41 (1H, d, J = 8.2 Hz), 7.52 (1H, d, J = 8.6 Hz).
(22f) 6-{3-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例22eで製造したtert-ブチル6-{3-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(185 mg, 0.294 mmol)、ジクロロメタン(6.0 mL)及びトリフルオロ酢酸(3.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(132 mg, 78%)を得た。 (Example 22)
6- {3-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid
(22a) Methyl (3S) -3-[(3-ethoxy-3-oxopropanoyl) amino] -4,4-dimethylpentanoate Methyl (3S) -3-amino-4,4-dimethylpentanoate Ethylmalonyl chloride (9.09 mL, 72.2 mmol) was added to a solution of hydrochloride (13.5 g, 68.7 mmol) and triethylamine (30. mL, 217 mmol) in dichloromethane (205 mL) at 0 ° C. The reaction solution was stirred at room temperature for 2.5 hours, 1 M hydrochloric acid was added, and the mixture was extracted twice with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude title compound (15.9 g, 85%).
(22b) Ethyl (6S) -6-tert-butyl-2,4-dioxopiperidine-3-carboxylate Crude methyl (3S) -3-[(3-ethoxylate prepared in Example 22a under nitrogen atmosphere -3-oxopropanoyl) amino] -4,4-dimethylpentanoate (15.9 g, 58.1 mmol) in toluene (111 mL) at room temperature with 20% sodium ethoxide (ethanol solution; 23.7 g, 70.0 mmol) And the reaction solution was stirred at 80 ° C. for 1.5 hours. After cooling to room temperature, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude title compound (12.7 g, 91%).
(22c) (6S) -6-tert-butylpiperidine-2,4-dione Crude ethyl (6S) -6-tert-butyl-2,4-dioxopiperidine-3-carboxylate prepared in Example 22b A solution of (12.7 g, 52.6 mmol) in acetonitrile (254 mL) and water (5 mL) was stirred with heating under reflux for 7.5 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was crystallized from ether to obtain the title compound (4.06 g, 46%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.99 (9H, s), 2.48 (1H, dd, J = 9.0, 16.0 Hz), 2.65 (1H, dd, J = 4.7, 16.0 Hz), 3.29 (2H, d, J = 0.8 Hz), 3.39-3.44 (1H, m), 6.72 (1H, br).
(22d) tert-butyl 6- {3-[(3S, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9, 10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate tert-butyl prepared in Example 1a 6 -{3-[(4,4-Dimethyl-2,6-dioxocyclohexylidene) methyl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (9.50 g, 20.0 mmol ), (6S) -6-tert-butylpiperidine-2,4-dione (3.50 g, 23.0 mmol), DMF (42 mL), cesium carbonate (7.33 g, 22.5 mmol), prepared in Example 22c, triphenyl The reaction was carried out according to Example 15a using phosphine (2.83 g, 10.8 mmol), THF (42 mL) and di-tert-butylazodicarboxylate (2.49 g, 10.8 mmol) to give the title. Compound (1.25 g, 23%) was obtained.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.89 (9H, s), 0.94 (3H, s), 1.09 (3H, s), 1.63 (9H, s), 2.12 (1H, dd, J = 1.2, 16.4 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.33 (1H, dd, J = 1.2, 17.6 Hz), 2.45 (1H, d, J = 17.6 Hz), 2.49 (3H, s) , 2.53 (2H, d, J = 8.2 Hz), 2.84 (3H, s), 3.30 (1H, td, J = 2.4, 7.8 Hz), 3.69 (3H, s), 5.08 (1H, s), 5.16 ( 1H, d, J = 1.6 Hz), 6.67 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.6 Hz).
Further, by-product tert-butyl 6- {3-[(3S, 10S, 10aR) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,6,7,8, 9,10,10a-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (1.47 g, 27% )
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.91 (9H, s), 0.97 (3H, s), 1.07 (3H, s), 1.64 (9H, s), 2.05 (1H, dd, J = 1.2, 16.4 Hz), 2.14 (1H, d, J = 16.4 Hz), 2.33 (1H, d, J = 17.6 Hz), 2.42 (1H, dd, J = 2.4, 18.0 Hz), 2.49 (3H, s) , 2.70 (3H, s), 3.59-3.62 (1H, m), 3.75 (3H, s), 3.93-3.96 (1H, m), 4.50 (1H, d, J = 7.0 Hz), 5.55-5.58 (1H , m), 6.06 (1H, s), 6.72 (1H, d, J = 8.6 Hz), 7.30 (1H, d, J = 8.2 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.52 (1H , d, J = 8.2 Hz).
(22e) tert-butyl 6- {3-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8, 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate tert-prepared in Example 22d Butyl 6- {3-[(3S, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (250 mg, 0.407 mmol), methyl iodide (253 μL, 4.07 mmol), DMF (5.0 mL) and sodium hydride (63%, 18.6 mg, 0.488 mmol) were used for the reaction and post-treatment according to Example 2a to give the title compound (187 mg, 73%) Got.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.86 (9H, s), 0.96 (3H, s), 1.09 (3H, s), 1.64 (9H, s), 2.12 (1H, dd, J = 0.8, 16.0 Hz), 2.21 (1H, d, J = 16.0 Hz), 2.33 (1H, dd, J = 0.8, 17.6 Hz), 2.45 (1H, dd, J = 1.2, 16.8 Hz), 2.49 (3H, s), 2.53 (1H, d, J = 18.4 Hz), 2.86-2.93 (1H, m), 2.89 (3H, s), 3.00 (3H, s), 3.14 (1H, d, J = 8.6 Hz), 3.63 (3H, s), 5.26 (1H, s), 6.61 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.2 Hz), 7.41 (1H, d, J = 8.2 Hz), 7.52 (1H, d, J = 8.6 Hz).
(22f) 6- {3-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10 -Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butyl 6- prepared in Example 22e {3-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H- Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (185 mg, 0.294 mmol), dichloromethane (6.0 mL) and trifluoro The title compound (132 mg, 78%) was obtained by conducting reaction and post-treatment according to Example 1d using acetic acid (3.0 mL).
(実施例23)
　6-{3-[(3S,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,6,7,8,9,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
(23a) tert-ブチル6-{3-[(3S,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,6,7,8,9,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例22dで副生したtert-ブチル　6-{3-[(3S,10S,10aR)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,6,7,8,9,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(1.47 g, 2.39 mmol)、ヨウ化メチル(1.49 mL, 23.9 mmol)、DMF (29 mL)及び水素化ナトリウム(63%, 109 mg, 2.87 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(1.50 g, 86%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.93 (3H, s), 0.96 (9H, s), 1.06 (3H, s), 1.64 (9H, s), 2.05 (1H, dd, J = 1.2, 16.4 Hz), 2.14 (1H, d, J = 16.4 Hz), 2.31 (1H, d, J = 17.6 Hz), 2.42 (1H, dd, J = 2.4, 17.6 Hz), 2.49 (3H, s), 2.87 (3H, s), 3.04 (3H, s), 3.51-3.54 (1H, m), 3.74 (3H, s), 3.79-3.82 (1H, m), 4.82 (1H, dd, J = 1.6, 5.8 Hz), 5.61 (1H, dd, J = 3.5, 6.3 Hz), 6.69 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.42 (1H, d, J = 7.8 Hz), 7.52 (1H, dd, J = 0.8, 8.6 Hz).
(23b) 6-{3-[(3S,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,6,7,8,9,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例23aで製造したtert-ブチル6-{3-[(3S,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,6,7,8,9,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(450 mg, 0.716 mmol)、ジクロロメタン(9.0 mL)及びトリフルオロ酢酸(4.5 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(290 mg, 71%)を得た。 (Example 23)
6- {3-[(3S, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,6,7,8,9,10,10a- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid
(23a) tert-butyl 6- {3-[(3S, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,6,7,8, 9,10,10a-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate by-product in Example 22d Tert-butyl 6- {3-[(3S, 10S, 10aR) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,6,7,8,9,10, 10a-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (1.47 g, 2.39 mmol), iodinated The title compound (1.50) was prepared by carrying out the reaction and workup according to Example 2a using methyl (1.49 mL, 23.9 mmol), DMF (29 mL) and sodium hydride (63%, 109 mg, 2.87 mmol). g, 86%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.93 (3H, s), 0.96 (9H, s), 1.06 (3H, s), 1.64 (9H, s), 2.05 (1H, dd, J = 1.2, 16.4 Hz), 2.14 (1H, d, J = 16.4 Hz), 2.31 (1H, d, J = 17.6 Hz), 2.42 (1H, dd, J = 2.4, 17.6 Hz), 2.49 (3H, s) , 2.87 (3H, s), 3.04 (3H, s), 3.51-3.54 (1H, m), 3.74 (3H, s), 3.79-3.82 (1H, m), 4.82 (1H, dd, J = 1.6, 5.8 Hz), 5.61 (1H, dd, J = 3.5, 6.3 Hz), 6.69 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.42 (1H, d, J = 7.8 Hz), 7.52 (1H, dd, J = 0.8, 8.6 Hz).
(23b) 6- {3-[(3S, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,6,7,8,9,10 , 10a-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butyl prepared in Example 23a 6- {3-[(3S, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,6,7,8,9,10,10a- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (450 mg, 0.716 mmol), dichloromethane (9.0 mL ) And trifluoroacetic acid (4.5 mL), and the reaction and post-treatment were performed according to Example 1d to obtain the title compound (290 mg, 71%).
(実施例24)
　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
(24a) tert-ブチル　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例23aで製造したtert-ブチル6-{3-[(3S,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,6,7,8,9,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(835 mg, 1.33 mmol)、パラジウム炭素(10%, 835 mg)、THF (17 mL)及びメタノール(17 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(689 mg, 50%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.92 (3H, s), 0.94 (9H, s), 1.04 (3H, s), 1.63 (9H, s), 1.96-2.04 (1H, m), 2.02 (1H, dd, J = 1.6, 16.4 Hz), 2.14 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 17.6 Hz), 2.34 (1H, dd, J = 2.4, 17.6 Hz), 2.48 (3H, s), 2.56-2.64 (1H, m), 2.87 (3H, s), 2.95 (3H, s), 3.23-3.32 (2H, m), 3.06-3.74 (1H, m), 3.71 (3, s), 4.66 (1H, dd, J = 2.0, 8.6 Hz), 6.66 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 8.6 Hz), 7.43 (1H, d, J = 8.3 Hz), 7.51 (1H, d, J = 8.2 Hz).
(24b) 6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例24aで製造したtert-ブチル　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(687 mg, 1.09 mmol)、ジクロロメタン(14 mL)及びトリフルオロ酢酸(7.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(509 mg, 81%)を得た。 (Example 24)
6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7,8, 9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid
(24a) tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate Tert-butyl 6- {3-[(3S, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,6,7 prepared in Example 23a , 8,9,10,10a-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (835 mg , 1.33 mmol), palladium on carbon (10%, 835 mg), THF (17 mL) and methanol (17 mL), the reaction and workup were carried out according to Example 18 to obtain the title compound (689 mg, 50%) was obtained.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.92 (3H, s), 0.94 (9H, s), 1.04 (3H, s), 1.63 (9H, s), 1.96-2.04 (1H, m) , 2.02 (1H, dd, J = 1.6, 16.4 Hz), 2.14 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 17.6 Hz), 2.34 (1H, dd, J = 2.4, 17.6 Hz), 2.48 (3H, s), 2.56-2.64 (1H, m), 2.87 (3H, s), 2.95 (3H, s), 3.23-3.32 (2H, m), 3.06-3.74 (1H, m) , 3.71 (3, s), 4.66 (1H, dd, J = 2.0, 8.6 Hz), 6.66 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 8.6 Hz), 7.43 (1H, d, J = 8.3 Hz), 7.51 (1H, d, J = 8.2 Hz).
(24b) 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-Butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7 , 8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid Example 24a Tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (687 mg, 1.09 mmol), dichloromethane (14 mL) and trifluoroacetic acid (7.0 mL) were used for the reaction and workup according to Example 1d to obtain the title compound (509 mg, 81%). It was.
(実施例25)
　6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1-オキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
(25a) 10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3,7,7-テトラメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例9bで製造した2-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン(2.00 g, 5.02 mmol)、6,6-ジメチルピペリジン-2,4-ジオン(780 mg, 5.52 mmol)、DMF (20 mL)、炭酸セシウム(4.42 g, 13.6 mmol)及びN-フェニルビス(トリフルオロメタンスルホンイミド)(2.33 g, 6.53 mmol)を用い、実施例9cに準じて反応及び後処理を行うことにより、標記化合物(1.30 g, 50%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.92 (3H, s), 1.08 (3H, s), 1.15 (3H, s), 1.24 (3H, s), 1.30 (12H, s), 2.11 (1H, d, J = 16.0 Hz), 2.21 (1H, d, J = 17.2 Hz), 2.31 (2H, d, J = 16.8 Hz), 2.44 (1H, d, J = 16.4 Hz), 2.63 (1H, dd, J = 2.4, 16.4 Hz), 3.12 (3H, s), 3.70 (3H, s), 4.94 (1H, s), 5.18 (1H, s), 6.59 (1H, d, J = 8.2 Hz), 7.59 (1H, d, J = 8.6 Hz).
(25b) 10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
実施例25aで製造した10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3,7,7-テトラメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(1.65 g, 3.16 mmol)、ヨウ化メチル(1.97 mL, 31.6 mmol)、DMF (33 mL)及び水素化ナトリウム(63%, 241 mg, 6.33 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(1.33 g, 79%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.91 (3H, s), 1.07 (3H, s), 1.08 (3H, s), 1.30 (12H, s), 1.33 (3H, s), 2.10 (1H, dd, J = 1.2, 16.4 Hz), 2.20 (1H, d, J = 16.4 Hz), 2.30 (2H, d, J = 16.8 Hz), 2.43 (1H, d, J = 16.8 Hz), 2.62 (1H, dd, J = 1.6, 16.8 Hz), 2.78 (3H, s), 3.15 (3H, s), 3.69 (3H, s), 5.20 (1H, s), 6.57 (1H, d, J = 8.2 Hz), 7.58 (1H, d, J = 8.2 Hz).
(25c) 10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,3,3,7,7-ペンタメチル-9-チオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1-オン
　実施例25bで製造した10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(1.33 g, 2.48 mmol)及びローソン試薬(1.21 g, 2.98 mmol)の1,4-ジオキサン(66 mL)溶液を70℃で4時間攪拌した。室温まで冷却後、反応溶液を濃縮し、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 1:1)で精製し、標記化合物(582 mg, 43%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.89 (3H, s), 1.03 (3H, s), 1.05 (3H, s), 1.32 (12H, s), 1.33 (3H, s), 2.32 (1H, d, J = 17.2 Hz), 2.37 (1H, dd, J = 0.8, 18.0 Hz), 2.44 (1H, d, J = 18.0 Hz), 2.64 (1H, dd, J = 1.6, 16.8 Hz), 2.70 (1H, d, J = 17.2 Hz), 2.78 (3H, s), 2.85 (1H, dd, J = 1.2, 16.8 Hz), 3.15 (3H, s), 3.68 (3H, s), 5.56 (1H, s), 6.56 (1H, d, J = 8.2 Hz), 7.54 (1H, d, J = 8.6 Hz).
(25d) 10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,3,3,7,7-ペンタメチル-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1-オン
　窒素雰囲気下、実施例25cで製造した10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,3,3,7,7-ペンタメチル-9-チオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1-オン(582 mg, 1.06 mmol)、2-クロロ-1,4-ベンゾキノン(902 mg, 6.33 mmol)及びラネーニッケル(エタノール懸濁液, 11 mL)のエタノール(58 mL)懸濁液を1時間攪拌した。反応溶液をろ過(セライト)し、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 7:3)で精製し、標記化合物(335 mg, 61%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.75 (3H, s), 0.94 (3H, s), 1.12 (3H, s), 1.14-1.28 (2H, m), 1.31 (3H, s), 1.32 (12H, s), 1.71-1.97 (4H, m), 2.21 (1H, d, J = 16.4 Hz), 2.55 (1H, dd, J = 1.6, 16.8 Hz), 2.77 (3H, s), 2.87 (3H, s), 3.68 (3H, s), 4.70 (1H, s), 6.63 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 8.2 Hz).
(25e) メチル　6-[4-メトキシ-2-メチル-3-(2,3,3,7,7-ペンタメチル-1-オキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)フェニル]-3-メチルピリジン-2-カルボキシレート
　実施例25dで製造した10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,3,3,7,7-ペンタメチル-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1-オン(400 mg, 0.767 mmol)、メチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(199 mg, 1.07 mmol)、2nd Generation X-Phos Precatalyst (121 mg, 0.153 mmol)、リン酸カリウム(293 mg, 1.38 mmol)、THF (2.0 mL)及び水(4.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(340 mg, 81%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.79 (3H, s), 0.96 (3H, s), 1.15 (3H, s), 1.19-1.26 (2H, m), 1.33 (3H, s), 1.81-1.97 (4H, m), 2.24 (1H, d, J = 16.8 Hz), 2.53 (1H, d, J = 16.4 Hz), 2.58 (3H, s), 2.59 (3H, s), 2.79 (3H, s), 3.71 (3H, s), 3.96 (3H, s), 4.70 (1H, s), 6.73 (1H, d, J = 8.6 Hz), 7.23 (1H, d, J = 8.6 Hz), 7.43 (1H, d, J = 7.8 Hz), 7.59 (1H, d, J = 7.8 Hz).
(25f) メチル6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1-オキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例25eで製造したメチル　6-[4-メトキシ-2-メチル-3-(2,3,3,7,7-ペンタメチル-1-オキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)フェニル]-3-メチルピリジン-2-カルボキシレート(290 mg)をChiral flash IA(ダイセル化学工業; エタノール)により光学分割し、高極性化合物(143 mg)及び低極性化合物(165 mg)を得た。
(25g) 6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1-オキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例25fで製造したメチル6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1-オキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(高極性化合物;145 mg, 0.266 mmol)、1 M水酸化ナトリウム水溶液(0.32 mL, 0.32 mmol)のTHF (0.60 mL)及びメタノール(0.60 mL)溶液を室温で2時間攪拌した。反応溶液をエーテルで2回抽出した後に、水層に10%クエン酸を加えた(pH = 4)。水層を酢酸エチルで3回抽出し、有機層を無水硫酸ナトリウムで乾燥、減圧濃縮し、標記化合物(132 mg, 93%)を得た。 (Example 25)
6- {4-Methoxy-2-methyl-3-[(10R) -2,3,3,7,7-pentamethyl-1-oxo-2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid
(25a) 10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3,7,7 -Tetramethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 2- [6-methoxy prepared in Example 9b -2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] -5,5-dimethylcyclohexane-1,3-dione (2.00 g, 5.02 mmol), 6,6-dimethylpiperidine-2,4-dione (780 mg, 5.52 mmol), DMF (20 mL), cesium carbonate (4.42 g, 13.6 mmol) and N-phenylbis (trifluoromethanesulfonimide) (2.33 g, 6.53 mmol) was used for the reaction and post-treatment according to Example 9c to obtain the title compound (1.30 g, 50%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.92 (3H, s), 1.08 (3H, s), 1.15 (3H, s), 1.24 (3H, s), 1.30 (12H, s), 2.11 (1H, d, J = 16.0 Hz), 2.21 (1H, d, J = 17.2 Hz), 2.31 (2H, d, J = 16.8 Hz), 2.44 (1H, d, J = 16.4 Hz), 2.63 (1H , dd, J = 2.4, 16.4 Hz), 3.12 (3H, s), 3.70 (3H, s), 4.94 (1H, s), 5.18 (1H, s), 6.59 (1H, d, J = 8.2 Hz) , 7.59 (1H, d, J = 8.6 Hz).
(25b) 10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2,3,3,7 , 7-Pentamethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 10- [6- Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3,7,7-tetramethyl-3,4, 6,7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (1.65 g, 3.16 mmol), methyl iodide (1.97 mL, 31.6 mmol), DMF (33 mL) and sodium hydride (63%, 241 mg, 6.33 mmol) were used for the reaction and workup according to Example 2a to obtain the title compound (1.33 g, 79%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.91 (3H, s), 1.07 (3H, s), 1.08 (3H, s), 1.30 (12H, s), 1.33 (3H, s), 2.10 (1H, dd, J = 1.2, 16.4 Hz), 2.20 (1H, d, J = 16.4 Hz), 2.30 (2H, d, J = 16.8 Hz), 2.43 (1H, d, J = 16.8 Hz), 2.62 (1H, dd, J = 1.6, 16.8 Hz), 2.78 (3H, s), 3.15 (3H, s), 3.69 (3H, s), 5.20 (1H, s), 6.57 (1H, d, J = 8.2 Hz), 7.58 (1H, d, J = 8.2 Hz).
(25c) 10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2,3,3,7 , 7-Pentamethyl-9-thioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-1-one 10- prepared in Example 25b [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2,3,3,7,7-pentamethyl- 3,4,6,7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (1.33 g, 2.48 mmol) and Lawson's reagent (1.21 g, 2.98 mmol) ) In 1,4-dioxane (66 mL) was stirred at 70 ° C. for 4 hours. After cooling to room temperature, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 1: 1) to obtain the title compound (582 mg, 43%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.89 (3H, s), 1.03 (3H, s), 1.05 (3H, s), 1.32 (12H, s), 1.33 (3H, s), 2.32 (1H, d, J = 17.2 Hz), 2.37 (1H, dd, J = 0.8, 18.0 Hz), 2.44 (1H, d, J = 18.0 Hz), 2.64 (1H, dd, J = 1.6, 16.8 Hz) , 2.70 (1H, d, J = 17.2 Hz), 2.78 (3H, s), 2.85 (1H, dd, J = 1.2, 16.8 Hz), 3.15 (3H, s), 3.68 (3H, s), 5.56 ( 1H, s), 6.56 (1H, d, J = 8.2 Hz), 7.54 (1H, d, J = 8.6 Hz).
(25d) 10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2,3,3,7 , 7-Pentamethyl-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-1-one 10-prepared in Example 25c under nitrogen atmosphere [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2,3,3,7,7-pentamethyl- 9-Thioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-1-one (582 mg, 1.06 mmol), 2-chloro-1 , 4-Benzoquinone (902 mg, 6.33 mmol) and Raney nickel (ethanol suspension, 11 mL) in ethanol (58 mL) were stirred for 1 hour. The reaction solution was filtered (celite) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate; 7: 3) to give the title compound (335 mg, 61%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.75 (3H, s), 0.94 (3H, s), 1.12 (3H, s), 1.14-1.28 (2H, m), 1.31 (3H, s) , 1.32 (12H, s), 1.71-1.97 (4H, m), 2.21 (1H, d, J = 16.4 Hz), 2.55 (1H, dd, J = 1.6, 16.8 Hz), 2.77 (3H, s), 2.87 (3H, s), 3.68 (3H, s), 4.70 (1H, s), 6.63 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 8.2 Hz).
(25e) Methyl 6- [4-methoxy-2-methyl-3- (2,3,3,7,7-pentamethyl-1-oxo-2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl) phenyl] -3-methylpyridine-2-carboxylate 10- [6-Methoxy-2-methyl-3- (prepared in Example 25d) 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2,3,3,7,7-pentamethyl-2,3,4,6,7,8, 9,10-octahydro-1H-chromeno [3,2-c] pyridin-1-one (400 mg, 0.767 mmol), methyl 6-chloro-3-methylpyridine-2-carboxylate (199 mg, 1.07 mmol) , 2nd Generation X-Phos Precatalyst (121 mg, 0.153 mmol), potassium phosphate (293 mg, 1.38 mmol), THF (2.0 mL) and water (4.0 mL), reaction and workup according to Example 9d To give the title compound (340 mg, 81%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.79 (3H, s), 0.96 (3H, s), 1.15 (3H, s), 1.19-1.26 (2H, m), 1.33 (3H, s) , 1.81-1.97 (4H, m), 2.24 (1H, d, J = 16.8 Hz), 2.53 (1H, d, J = 16.4 Hz), 2.58 (3H, s), 2.59 (3H, s), 2.79 ( 3H, s), 3.71 (3H, s), 3.96 (3H, s), 4.70 (1H, s), 6.73 (1H, d, J = 8.6 Hz), 7.23 (1H, d, J = 8.6 Hz), 7.43 (1H, d, J = 7.8 Hz), 7.59 (1H, d, J = 7.8 Hz).
(25f) methyl 6- {4-methoxy-2-methyl-3-[(10R) -2,3,3,7,7-pentamethyl-1-oxo-2,3,4,6,7,8, 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylate Methyl 6- [4-methoxy-2-prepared in Example 25e Methyl-3- (2,3,3,7,7-pentamethyl-1-oxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridine -10-yl) phenyl] -3-methylpyridine-2-carboxylate (290 mg) was optically resolved with Chiral flash IA (Daicel Chemical Industries; ethanol) to obtain a high polar compound (143 mg) and a low polar compound (165 mg).
(25g) 6- {4-Methoxy-2-methyl-3-[(10R) -2,3,3,7,7-pentamethyl-1-oxo-2,3,4,6,7,8,9 , 10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid Methyl 6- {4-methoxy-2-methyl prepared in Example 25f -3-[(10R) -2,3,3,7,7-pentamethyl-1-oxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2- c] Pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylate (high polarity compound; 145 mg, 0.266 mmol), 1 M aqueous sodium hydroxide (0.32 mL, 0.32 mmol) in THF (0.60 mL) ) And methanol (0.60 mL) were stirred at room temperature for 2 hours. The reaction solution was extracted twice with ether, and 10% citric acid was added to the aqueous layer (pH = 4). The aqueous layer was extracted 3 times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (132 mg, 93%).
(実施例26)
　6-{3-[(3S,10R)-3-tert-ブチル-2,7,7-トリメチル-1-オキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
(26a) (3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例9bで製造した2-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン(2.20 g, 5.52 mmol)、実施例22cで製造した(6S)-6-tert-ブチルピペリジン-2,4-ジオン(1.03 g, 6.08 mmol)、DMF (22 mL)、炭酸セシウム(4.50 g, 13.8 mmol)及びN-フェニルビス(トリフルオロメタンスルホンイミド) (2.37 g, 6.63 mmol)を用い、実施例9cに準じて反応及び後処理を行うことにより、標記化合物(887 mg, 29%)を得た。 
1H-NMR(400MHz, CDCl3):δ ppm: 0.83 (9H, s), 0.90 (3H, s), 1.06 (3H, s), 1.27 (12H, s), 2.08 (1H, dd, J = 1.6, 16.4 Hz), 2.18 (1H, d, J = 16.4 Hz), 2.28 (1H, dd, J = 1.6, 17.6 Hz), 2.42 (1H, d, J = 17.6 Hz), 2.49 (2H, d, J = 8.2 Hz), 3.08 (3H, s), 3.25 (1H, td, J = 2.1, 7.7 Hz), 3.64 (3H, s), 5.08 (1H, s), 5.24 (1H, s), 6.53 (1H, d, J = 8.2 Hz), 7.56 (1H, d, J = 8.2 Hz).
(26b) (3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例26aで製造した(3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(690 mg, 1.26 mmol)、ヨウ化メチル(782 μL, 12.6 mmol)、DMF (14 mL)及び水素化ナトリウム(63%, 57.4 mg, 1.51 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(610 mg, 86%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.85 (9H, s), 0.96 (3H, s), 1.10 (3H, s), 1.34 (12H, s), 2.12 (1H, d, J = 16.8 Hz), 2.22 (1H, d, J = 17.2 Hz), 2.33 (1H, d, J = 17.6 Hz), 2.46 (1H, d, J = 17.2 Hz), 2.54 (1H, d, J = 18.4 Hz), 2.87-2.94 (1H, m), 3.03 (3H, s), 3.14-3.16 (1H, m), 3.19 (3H, s), 3.63 (4H, s), 5.31 (1H, s), 6.53 (1H, d, J = 8.2 Hz), 7.59 (1H, d, J = 8.2 Hz).
(26c) (3S,10R)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-9-チオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1-オン
　実施例26bで製造した(3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(610 mg, 1.08 mmol)、ローソン試薬(876 mg, 2.17 mmol)及び1,4-ジオキサン(30 mL)を用い、実施例25cに準じて反応及び後処理を行うことにより、標記化合物(452 mg, 72%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.74 (9H, s), 0.88 (3H, s), 1.02 (3H, s), 1.29 (12H, s), 2.33 (1H, d, J = 18.4 Hz), 2.39 (1H, d, J = 16.8 Hz), 2.49 (1H, d, J = 18.0 Hz), 2.64 (1H, d, J = 16.8 Hz), 2.80-2.92 (2H, m), 2.97 (3H, s), 3.06-3.09 (1H, m), 3.13 (3H, s), 3.55 (3H, s), 5.59 (1H, s), 6.44 (1H, d, J = 8.6 Hz), 7.48 (1H, d, J = 8.2 Hz).
(26d) (3S,10R)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1-オン
　実施例26cで製造した(3S,10R)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-9-チオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1-オン(452 mg, 0.780 mmol)、2-クロロ-1,4-ベンゾキノン(667 mg, 4.68 mmol)、ラネーニッケル(エタノール懸濁液, 5 mL)及びエタノール(45 mL)を用い、実施例25dに準じて反応及び後処理を行うことにより、標記化合物(244 mg, 57%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.73 (3H, s), 0.79 (9H, s), 0.89 (3H, s), 1.10-1.23 (2H, m), 1.25 (12H, s), 1.66-1.71 (2H, m), 1.79 (1H, d, J = 16.4 Hz), 1.91 (1H, d, J = 16.4 Hz), 2.35-2.41 (1H, m), 2.75-2.83 (1H, m), 2.87 (3H, s), 2.95 (3H, s), 3.03-3.07 (1H, m), 3.56 (3H, s), 4.74 (1H, s), 6.53 (1H, d, J = 8.2 Hz), 7.55 (1H, d, J = 7.8 Hz).
(26e) ベンジル　6-{3-[(3S,10R)-3-tert-ブチル-2,7,7-トリメチル-1-オキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例26dで製造した(3S,10R)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1-オン(244 mg, 0.444 mmol)、実施例20eで製造したベンジル　6-クロロ-3-メチルピリジン-2-カルボキシレート(163 mg, 0.622 mmol)、2nd Generation X-Phos Precatalyst (69.9 mg, 0.0888 mmol)、リン酸カリウム(170 mg, 0.799 mmol)、THF (1.2 mL)及び水(2.4 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(235 mg, 82%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.80 (3H, s), 0.87 (9H, s), 0.96 (3H, s), 1.19-1.35 (2H, m), 1.76-2.00 (4H, m), 2.45 (1H, d, J = 18.0 Hz), 2.53 (3H, s), 2.66 (3H, s), 2.82-2.92 (1H, m), 3.00 (3H, s), 3.12 (1H, d, J = 9.0 Hz), 3.50 (3H, s), 4.79 (1H, s), 5.42 (1H, d, J = 12.5 Hz), 5.46 (1H, d, J = 12.9 Hz), 6.66 (1H, d, J = 8.6 Hz), 7.24 (1H, d, J = 8.6 Hz), 7.32-7.58 (7H, m).
(26f) 6-{3-[(3S,10R)-3-tert-ブチル-2,7,7-トリメチル-1-オキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例26eで製造したベンジル　6-{3-[(3S,10R)-3-tert-ブチル-2,7,7-トリメチル-1-オキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(235 mg, 0.362 mmol)、水酸化パラジウム炭素(20%, 94.0 mg)及びエタノール(24 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(195 mg, 96%)を得た。 (Example 26)
6- {3-[(3S, 10R) -3-tert-butyl-2,7,7-trimethyl-1-oxo-2,3,4,6,7,8,9,10-octahydro-1H- Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid
(26a) (3S, 10S) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) phenyl] -7,7-dimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione prepared in Example 9b 2- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] -5,5-dimethylcyclohexane-1, 3-dione (2.20 g, 5.52 mmol), (6S) -6-tert-butylpiperidine-2,4-dione (1.03 g, 6.08 mmol) prepared in Example 22c, DMF (22 mL), cesium carbonate ( 4.50 g, 13.8 mmol) and N-phenylbis (trifluoromethanesulfonimide) (2.37 g, 6.63 mmol) were used for the reaction and workup according to Example 9c to give the title compound (887 mg, 29% )
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.83 (9H, s), 0.90 (3H, s), 1.06 (3H, s), 1.27 (12H, s), 2.08 (1H, dd, J = 1.6, 16.4 Hz), 2.18 (1H, d, J = 16.4 Hz), 2.28 (1H, dd, J = 1.6, 17.6 Hz), 2.42 (1H, d, J = 17.6 Hz), 2.49 (2H, d, J = 8.2 Hz), 3.08 (3H, s), 3.25 (1H, td, J = 2.1, 7.7 Hz), 3.64 (3H, s), 5.08 (1H, s), 5.24 (1H, s), 6.53 ( 1H, d, J = 8.2 Hz), 7.56 (1H, d, J = 8.2 Hz).
(26b) (3S, 10S) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) phenyl] -2,7,7-trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione Example 26a (3S, 10S) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) phenyl] -7,7-dimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (690 mg, 1.26 mmol), methyl iodide (782 μL, 12.6 mmol), DMF (14 mL) and sodium hydride (63%, 57.4 mg, 1.51 mmol) using the reaction and workup according to Example 2a. The title compound (610 mg, 86%) was obtained.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.85 (9H, s), 0.96 (3H, s), 1.10 (3H, s), 1.34 (12H, s), 2.12 (1H, d, J = 16.8 Hz), 2.22 (1H, d, J = 17.2 Hz), 2.33 (1H, d, J = 17.6 Hz), 2.46 (1H, d, J = 17.2 Hz), 2.54 (1H, d, J = 18.4 Hz) ), 2.87-2.94 (1H, m), 3.03 (3H, s), 3.14-3.16 (1H, m), 3.19 (3H, s), 3.63 (4H, s), 5.31 (1H, s), 6.53 ( 1H, d, J = 8.2 Hz), 7.59 (1H, d, J = 8.2 Hz).
(26c) (3S, 10R) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) phenyl] -2,7,7-trimethyl-9-thioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-1-one (3S, 10S) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane) prepared in Example 26b -2-yl) phenyl] -2,7,7-trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (610 mg, 1.08 mmol), Lawesson's reagent (876 mg, 2.17 mmol) and 1,4-dioxane (30 mL) were used for the reaction and workup according to Example 25c to give the title compound (452 mg , 72%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.74 (9H, s), 0.88 (3H, s), 1.02 (3H, s), 1.29 (12H, s), 2.33 (1H, d, J = 18.4 Hz), 2.39 (1H, d, J = 16.8 Hz), 2.49 (1H, d, J = 18.0 Hz), 2.64 (1H, d, J = 16.8 Hz), 2.80-2.92 (2H, m), 2.97 (3H, s), 3.06-3.09 (1H, m), 3.13 (3H, s), 3.55 (3H, s), 5.59 (1H, s), 6.44 (1H, d, J = 8.6 Hz), 7.48 ( (1H, d, J = 8.2 Hz).
(26d) (3S, 10R) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) phenyl] -2,7,7-trimethyl-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-1-one in Example 26c Prepared (3S, 10R) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ) Phenyl] -2,7,7-trimethyl-9-thioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-1-one 452 mg, 0.780 mmol), 2-chloro-1,4-benzoquinone (667 mg, 4.68 mmol), Raney nickel (ethanol suspension, 5 mL) and ethanol (45 mL) according to Example 25d And the post-treatment was performed to obtain the title compound (244 mg, 57%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.73 (3H, s), 0.79 (9H, s), 0.89 (3H, s), 1.10-1.23 (2H, m), 1.25 (12H, s) , 1.66-1.71 (2H, m), 1.79 (1H, d, J = 16.4 Hz), 1.91 (1H, d, J = 16.4 Hz), 2.35-2.41 (1H, m), 2.75-2.83 (1H, m ), 2.87 (3H, s), 2.95 (3H, s), 3.03-3.07 (1H, m), 3.56 (3H, s), 4.74 (1H, s), 6.53 (1H, d, J = 8.2 Hz) , 7.55 (1H, d, J = 7.8 Hz).
(26e) Benzyl 6- {3-[(3S, 10R) -3-tert-butyl-2,7,7-trimethyl-1-oxo-2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (3S, 10R)-prepared in Example 26d 3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2,7, 7-Trimethyl-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-1-one (244 mg, 0.444 mmol), prepared in Example 20e Benzyl 6-chloro-3-methylpyridine-2-carboxylate (163 mg, 0.622 mmol), 2nd Generation X-Phos Precatalyst (69.9 mg, 0.0888 mmol), potassium phosphate (170 mg, 0.799 mmol), THF ( The title compound (235 mg, 82%) was obtained by performing the reaction and post-treatment according to Example 9d using 1.2 mL) and water (2.4 mL).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.80 (3H, s), 0.87 (9H, s), 0.96 (3H, s), 1.19-1.35 (2H, m), 1.76-2.00 (4H, m), 2.45 (1H, d, J = 18.0 Hz), 2.53 (3H, s), 2.66 (3H, s), 2.82-2.92 (1H, m), 3.00 (3H, s), 3.12 (1H, d , J = 9.0 Hz), 3.50 (3H, s), 4.79 (1H, s), 5.42 (1H, d, J = 12.5 Hz), 5.46 (1H, d, J = 12.9 Hz), 6.66 (1H, d , J = 8.6 Hz), 7.24 (1H, d, J = 8.6 Hz), 7.32-7.58 (7H, m).
(26f) 6- {3-[(3S, 10R) -3-tert-butyl-2,7,7-trimethyl-1-oxo-2,3,4,6,7,8,9,10-octahydro -1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid benzyl 6- {3- [prepared in Example 26e (3S, 10R) -3-tert-Butyl-2,7,7-trimethyl-1-oxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2- c) pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (235 mg, 0.362 mmol), palladium hydroxide on carbon (20%, 94.0 mg) and ethanol ( The title compound (195 mg, 96%) was obtained by performing the reaction and post-treatment according to Example 18 using 24 mL).
(実施例27)
　6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(27a) (3R,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,6,7,8,10,10a-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例9bで製造した2-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン(4.67 g, 11.7 mmol)及び公知化合物である(6S)-6-(プロパン-2-イル)ピペリジン-2,4-ジオン(Marin, J. et al, J. Org. Chem. (2004), 69(1), 130-141;2.00 g, 12.9 mmol)、DMF (92 mL)、炭酸セシウム(9.54 g, 29.3 mmol)、トリフェニルホスフィン(3.69 g, 14.1 mmol)、THF (92 mL)及びジ-tert-ブチルアゾジカルボキシレート(3.24 g, 14.1 mmol)を用い、実施例15aに準じて反応及び後処理を行うことにより、標記化合物(1.26 g, 20%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.89 (3H, d, J = 6.7 Hz), 0.90 (3H, d, J = 7.0 Hz), 0.97 (3H, s), 1.06 (3H, s), 1.31 (12H, s), 1.76-1.83 (1H, m), 2.04 (1H, dd, J = 1.6, 16.0 Hz), 2.12 (1H, d, J = 15.3 Hz), 2.32 (1H, d, J = 17.2 Hz), 2.41 (1H, dd, J = 2.7, 17.6 Hz), 2.90 (3H, s), 3.72 (3H, s), 3.84-3.88 (1H, m), 3.93-3.97 (1H, m), 4.45 (1H, dd, J = 1.2, 8.2 Hz), 5.44-5.46 (1H, m), 6.10 (1H, s), 6.61 (1H, d, J = 8.6 Hz), 7.64 (1H, d, J = 8.2 Hz).
(27b) (3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例27aで製造した(3R,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,6,7,8,10,10a-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(2.07 g, 3.87 mmol)、パラジウム炭素(10%, 2.07 g)及びTHF/メタノール(1:1, 42 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(1.29 g, 62%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.90-0.94 (9H, m), 1.04 (3H, s), 1.30 (12H, s), 1.64-1.72 (1H, m), 1.77 (1H, q, J = 11.9 Hz), 2.00 (1H, dd, J = 1.8, 16.2 Hz), 2.13 (1H, d, J = 16.4 Hz), 2.23 (1H, d, J = 17.6 Hz), 2.31-2.40 (2H, m), 2.98 (3H, s), 3.23-3.33 (2H, m), 3.68 (3H, s), 3.89 (1H, td, J = 3.4, 11.5 Hz), 4.43 (1H, dd, J = 1.8, 9.6 Hz), 5.43 (1H, s), 6.57 (1H, d, J = 8.2 Hz), 7.61 (1H, d, J = 8.2 Hz).
(27c) (3S,4aS,10S,10aR)-2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例27bで製造した(3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(410 mg, 0.763 mmol)、ヨウ化エチル(488 μL, 6.10 mmol)、1,3-ジメチル-3,4,5,6-テトラヒドロ-2(1H)-ピリミジノン(4.1 mL)及び水素化ナトリウム(55%, 83.3 mg, 1.91 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(431 mg, 99%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.77 (3H, d, J = 7.4 Hz), 0.89 (3H, s), 0.95 (3H, d, J = 6.6 Hz), 1.03 (3H, s), 1.05 (3H, t, J = 7.4 Hz), 1.30 (12H, s), 1.78-1.86 (1H, m), 1.94-2.40 (6H, m), 2.93 (3H, s), 3.02 (1H, dd, J = 7.4, 14.1 Hz), 3.15-3.20 (1H, m), 3.38-3.43 (1H, m), 3.63-3.79 (2H, m), 3.68 (3H, s), 4.56 (1H, d, J = 10.6 Hz), 6.57 (1H, d, J = 8.2 Hz), 7.61 (1H, d, J = 7.4 Hz).
(27d) tert-ブチル6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例27cで製造した(3S,4aS,10S,10aR)-2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(432 mg, 0.763 mmol)、公知化合物であるtert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(208 mg, 0.916 mmol)、2nd Generation X-Phos Precatalyst (120 mg, 0.153 mmol)、リン酸カリウム(259 mg, 1.22 mmol)、THF (4.3 mL)及び水(8.6 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(407 mg, 85%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.80 (3H, d, J = 7.0 Hz), 0.92 (3H, s), 0.95 (3H, d, J = 7.4 Hz), 1.04 (3H, s), 1.05 (3H, t, J = 7.4 Hz), 1.63 (9H, s), 1.79-2.42 (7H, m), 2.48 (3H, s), 2.93 (3H, s), 3.07 (1H, dd, J = 6.8, 13.9 Hz), 3.17-3.22 (1H, m), 3.37-3.43 (1H, m), 3.57-3.66 (1H, m), 3.72 (3H, s), 3.76 (1H, dd, J = 5.1, 11.3 Hz), 4.56 (1H, dd, J = 1.4, 8.8 Hz), 6.68 (1H, d, J = 8.2 Hz), 7.28 (1H, d, J = 7.8 Hz), 7.43 (1H, d, J = 7.8 Hz), 7.51 (1H, d, J = 8.6 Hz).
(27e) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例27dで製造したtert-ブチル6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(407 mg, 0.645 mmol)、ジクロロメタン(4.1 mL)及びトリフルオロ酢酸(2.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(368 mg, 99%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.81 (3H, d, J = 6.6 Hz), 0.96 (3H, s), 0.98 (3H, d, J = 7.0 Hz), 1.06 (3H, t, J = 6.3 Hz), 1.07 (3H, s), 1.81-1.90 (1H, m), 1.97-2.45 (6H, m), 2.79 (3H, s), 2.83 (3H, s), 3.03-3.13 (1H, m), 3.26-3.31 (1H, m), 3.42-3.47 (1H, m), 3.61-3.70 (1H, m), 3.76 (3H, s), 3.83 (1H, td, J = 4.7, 11.3 Hz), 4.47 (1H, d, J = 9.4 Hz), 6.74 (1H, d, J = 8.6 Hz), 7.18 (1H, d, J = 8.6 Hz), 7.66 (1H, d, J = 7.4 Hz), 7.80 (1H, d, J = 7.8 Hz).
MS(ESI/APCI)m/z: 575[M+H]+.
(27f) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例27eで製造した6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(368 mg, 0.640 mmol)、エタノール(7.4 mL)及びtert-ブチルアミン(87 μL, 0.832 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(375 mg, 90%)を得た。 (Example 27)
6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-Butylamine salt
(27a) (3R, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3- (propan-2-yl) -3,6,7,8,10,10a-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H)- Dione 2- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] -5,5 prepared in Example 9b -Dimethylcyclohexane-1,3-dione (4.67 g, 11.7 mmol) and the known compound (6S) -6- (propan-2-yl) piperidine-2,4-dione (Marin, J. et al, J Org. Chem. (2004), 69 (1), 130-141; 2.00 g, 12.9 mmol), DMF (92 mL), cesium carbonate (9.54 g, 29.3 mmol), triphenylphosphine (3.69 g, 14.1 mmol) ), THF (92 mL), and di-tert-butylazodicarboxylate (3.24 g, 14.1 mmol), and the reaction and workup according to Example 15a gave the title compound (1.26 g, 20% )
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.89 (3H, d, J = 6.7 Hz), 0.90 (3H, d, J = 7.0 Hz), 0.97 (3H, s), 1.06 (3H, s ), 1.31 (12H, s), 1.76-1.83 (1H, m), 2.04 (1H, dd, J = 1.6, 16.0 Hz), 2.12 (1H, d, J = 15.3 Hz), 2.32 (1H, d, J = 17.2 Hz), 2.41 (1H, dd, J = 2.7, 17.6 Hz), 2.90 (3H, s), 3.72 (3H, s), 3.84-3.88 (1H, m), 3.93-3.97 (1H, m ), 4.45 (1H, dd, J = 1.2, 8.2 Hz), 5.44-5.46 (1H, m), 6.10 (1H, s), 6.61 (1H, d, J = 8.6 Hz), 7.64 (1H, d, J = 8.2 Hz).
(27b) (3S, 4aS, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenyl] -7,7-dimethyl-3- (propan-2-yl) -3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c] pyridine-1 , 9 (2H) -dione (3R, 10S, 10aR) -10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,) prepared in Example 27a 2-Dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3- (propan-2-yl) -3,6,7,8,10,10a-hexahydro-1H-chromeno [3,2-c ] Reaction according to Example 18 using pyridine-1,9 (2H) -dione (2.07 g, 3.87 mmol), palladium on carbon (10%, 2.07 g) and THF / methanol (1: 1, 42 mL) And the workup gave the title compound (1.29 g, 62%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.90-0.94 (9H, m), 1.04 (3H, s), 1.30 (12H, s), 1.64-1.72 (1H, m), 1.77 (1H, q, J = 11.9 Hz), 2.00 (1H, dd, J = 1.8, 16.2 Hz), 2.13 (1H, d, J = 16.4 Hz), 2.23 (1H, d, J = 17.6 Hz), 2.31-2.40 ( 2H, m), 2.98 (3H, s), 3.23-3.33 (2H, m), 3.68 (3H, s), 3.89 (1H, td, J = 3.4, 11.5 Hz), 4.43 (1H, dd, J = 1.8, 9.6 Hz), 5.43 (1H, s), 6.57 (1H, d, J = 8.2 Hz), 7.61 (1H, d, J = 8.2 Hz).
(27c) (3S, 4aS, 10S, 10aR) -2-ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) phenyl] -7,7-dimethyl-3- (propan-2-yl) -3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c ] Pyridine-1,9 (2H) -dione (3S, 4aS, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetra) prepared in Example 27b Methyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3- (propan-2-yl) -3,4,4a, 6,7,8,10,10a-octahydro -1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (410 mg, 0.763 mmol), ethyl iodide (488 μL, 6.10 mmol), 1,3-dimethyl-3,4, The title compound was reacted and worked up according to Example 2a using 5,6-tetrahydro-2 (1H) -pyrimidinone (4.1 mL) and sodium hydride (55%, 83.3 mg, 1.91 mmol). (431 mg, 99%) was obtained.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.77 (3H, d, J = 7.4 Hz), 0.89 (3H, s), 0.95 (3H, d, J = 6.6 Hz), 1.03 (3H, s ), 1.05 (3H, t, J = 7.4 Hz), 1.30 (12H, s), 1.78-1.86 (1H, m), 1.94-2.40 (6H, m), 2.93 (3H, s), 3.02 (1H, dd, J = 7.4, 14.1 Hz), 3.15-3.20 (1H, m), 3.38-3.43 (1H, m), 3.63-3.79 (2H, m), 3.68 (3H, s), 4.56 (1H, d, J = 10.6 Hz), 6.57 (1H, d, J = 8.2 Hz), 7.61 (1H, d, J = 7.4 Hz).
(27d) tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2, 3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl Pyridine-2-carboxylate (3S, 4aS, 10S, 10aR) -2-ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl) prepared in Example 27c -1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3- (propan-2-yl) -3,4,4a, 6,7,8,10,10a-octahydro- 1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (432 mg, 0.763 mmol), known compound tert-butyl 6-chloro-3-methylpyridine-2-carboxylate (208 mg, 0.916 mmol), 2nd Generation X-Phos Precatalyst (120 mg, 0.153 mmol), potassium phosphate (259 mg, 1.22 mmol), THF (4.3 mL) and water (8.6 mL), according to Example 9d The title compound (407 mg, 85%) was obtained by reaction and post-treatment.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.80 (3H, d, J = 7.0 Hz), 0.92 (3H, s), 0.95 (3H, d, J = 7.4 Hz), 1.04 (3H, s ), 1.05 (3H, t, J = 7.4 Hz), 1.63 (9H, s), 1.79-2.42 (7H, m), 2.48 (3H, s), 2.93 (3H, s), 3.07 (1H, dd, J = 6.8, 13.9 Hz), 3.17-3.22 (1H, m), 3.37-3.43 (1H, m), 3.57-3.66 (1H, m), 3.72 (3H, s), 3.76 (1H, dd, J = 5.1, 11.3 Hz), 4.56 (1H, dd, J = 1.4, 8.8 Hz), 6.68 (1H, d, J = 8.2 Hz), 7.28 (1H, d, J = 7.8 Hz), 7.43 (1H, d, J = 7.8 Hz), 7.51 (1H, d, J = 8.6 Hz).
(27e) 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4 , 4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2 -Carboxylic acid tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propane-2) prepared in Example 27d -Yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methyl By reacting and working up according to Example 1d using phenyl} -3-methylpyridine-2-carboxylate (407 mg, 0.645 mmol), dichloromethane (4.1 mL) and trifluoroacetic acid (2.0 mL) The title compound (368 mg, 99%) was obtained.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.81 (3H, d, J = 6.6 Hz), 0.96 (3H, s), 0.98 (3H, d, J = 7.0 Hz), 1.06 (3H, t , J = 6.3 Hz), 1.07 (3H, s), 1.81-1.90 (1H, m), 1.97-2.45 (6H, m), 2.79 (3H, s), 2.83 (3H, s), 3.03-3.13 ( 1H, m), 3.26-3.31 (1H, m), 3.42-3.47 (1H, m), 3.61-3.70 (1H, m), 3.76 (3H, s), 3.83 (1H, td, J = 4.7, 11.3 Hz), 4.47 (1H, d, J = 9.4 Hz), 6.74 (1H, d, J = 8.6 Hz), 7.18 (1H, d, J = 8.6 Hz), 7.66 (1H, d, J = 7.4 Hz) , 7.80 (1H, d, J = 7.8 Hz).
MS (ESI / APCI) m / z: 575 [M + H] +.
(27f) 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4 , 4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2 -Carboxylic acid tert-butylamine salt 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propane- 2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2- Methylphenyl} -3-methylpyridine-2-carboxylic acid (368 mg, 0.640 mmol), ethanol (7.4 mL) and tert-butylamine (87 μL, 0.832 mmol), reaction and workup according to Example 3c To give the title compound (375 mg, 90%).
(実施例28)
　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
(28a) 6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例18で製造した6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(530 mg, 0.945 mmol)、カルボニルジイミダゾール(245 mg, 1.51 mmol)、DMF (5.3 mL)、メタンスルホンアミド(144 mg, 1.51 mmol)及びDBU (226 μL, 1.51 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(347 mg, 58%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.76 (3H, d, J = 6.7 Hz), 0.92-0.97 (6H, m), 1.04 (3H, s), 1.78-1.87 (1H, m), 2.05 (1H, d, J = 16.0 Hz), 2.15 (1H, d, J = 16.4 Hz), 2.21-2.42 (4H, m), 2.76 (3H, s), 2.79 (3H, s), 2.82 (3H, s), 3.25 (1H, t, J = 11.0 Hz), 3.34-3.39 (1H, m), 3.35 (3H, s), 3.73 (3H, s), 3.84 (1H, dt, J = 4.3, 11.0 Hz), 4.44 (1H, d, J = 9.8 Hz), 6.72 (1H, d, J = 8.2 Hz), 7.19 (1H, d, J = 9.4 Hz), 7.60-7.65 (2H, m).
MS(ESI/APCI)m/z: 638[M+H]+.
(28b) 6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
　実施例28aで製造した6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド(347 mg, 0.544 mmol)、エタノール(6.9 mL)及びtert-ブチルアミン(86 μL, 0.816 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(335 mg, 90%)を得た。 (Example 28)
6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2, 3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methyl-N- (methylsulfonyl) pyridine -2-carboxamide tert-butylamine salt
(28a) 6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methyl-N- (methyl (Sulfonyl) pyridine-2-carboxamide 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo prepared in Example 18 -3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl } -3-Methylpyridine-2-carboxylic acid (530 mg, 0.945 mmol), carbonyldiimidazole (245 mg, 1.51 mmol), DMF (5.3 mL), methanesulfonamide (144 mg, 1.51 mmol) and DBU (226 The title compound (347 mg, 58%) was obtained by performing reaction and a post-treatment according to Example 6a using μL, 1.51 mmol).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.76 (3H, d, J = 6.7 Hz), 0.92-0.97 (6H, m), 1.04 (3H, s), 1.78-1.87 (1H, m) , 2.05 (1H, d, J = 16.0 Hz), 2.15 (1H, d, J = 16.4 Hz), 2.21-2.42 (4H, m), 2.76 (3H, s), 2.79 (3H, s), 2.82 ( 3H, s), 3.25 (1H, t, J = 11.0 Hz), 3.34-3.39 (1H, m), 3.35 (3H, s), 3.73 (3H, s), 3.84 (1H, dt, J = 4.3, 11.0 Hz), 4.44 (1H, d, J = 9.8 Hz), 6.72 (1H, d, J = 8.2 Hz), 7.19 (1H, d, J = 9.4 Hz), 7.60-7.65 (2H, m).
MS (ESI / APCI) m / z: 638 [M + H] +.
(28b) 6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methyl-N- (methyl (Sulfonyl) pyridine-2-carboxamide tert-butylamine salt 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1 prepared in Example 28a , 9-Dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridine-10 -Yl] phenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide (347 mg, 0.544 mmol), ethanol (6.9 mL) and tert-butylamine (86 μL, 0.816 mmol) The title compound (335 mg, 90%) was obtained by reaction and post-treatment according to 3c.
(実施例29)
　6-[4-メトキシ-2-メチル-3-(2,2,8,8-テトラメチル-4,6-ジオキソ-3,4,6,7,8,9-ヘキサヒドロ-2H,5H-ピラノ[2,3-b]クロメン-5-イル)フェニル]-3-メチルピリジン-2-カルボン酸
(29a) 5-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,2,8,8-テトラメチル-2,3,5,7,8,9-ヘキサヒドロ-4H,6H-ピラノ[2,3-b]クロメン-4,6-ジオン
　実施例9bで製造した2-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン(2.00 g, 5.02 mmol)及び6,6-ジメチルジヒドロ-2H-ピラン-2,4(3H)-ジオン(857 mg, 6.03 mmol)のDMF (20 mL)溶液に室温でtert-ブトキシカリウム(676 mg, 6.03 mmol)を加えた。反応溶液を室温で30分攪拌後、酢酸(431 μL, 7.53 mmol)及び水(20 mL)を加えて反応溶液を更に1時間攪拌した。析出した固体をろ取し、付加物を得た。塩化亜鉛(130 mg, 0.951 mmol)の無水酢酸(32 mL)溶液に室温でこの付加物を加え、反応溶液を室温で2時間攪拌した。反応溶液を濃縮後、残渣を酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 3:1)で精製し、標記化合物(306 mg, 12%)を得た。
1H-NMR(500MHz, CDCl3):δ ppm: 0.93 (3H, s), 1.08 (3H, s), 1.30 (3H, s), 1.31 (12H, s), 1.52 (3H, s), 2.12 (1H, dd, J = 1.1, 16.4 Hz), 2.20 (1H, d, J = 16.4 Hz), 2.26 (1H, d, J = 16.7 Hz), 2.35 (1H, dd, J = 0.7, 17.7 Hz), 2.47 (1H, dd, J = 1.7, 17.6 Hz), 2.67 (1H, d, J = 16.7 Hz), 3.14 (3H, s), 3.70 (3H, s), 5.18 (1H, s), 6.59 (1H, d, J = 8.5 Hz), 7.60 (1H, d, J = 8.5 Hz).
　また、副生した10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3,7,7-テトラメチル-3,4,6,7,8,10-ヘキサヒドロ-1H,9H-ピラノ[4,3-b]クロメン-1,9-ジオン(571 mg, 23%)を得た。
1H-NMR(500MHz, CDCl3):δ ppm: 0.93 (3H, s), 1.09 (3H, s), 1.26 (3H, s), 1.31 (12H, s), 1.45 (3H, s), 2.12 (1H, dd, J = 1.7, 16.4 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.33 (1H, dd, J = 1.1, 17.6 Hz), 2.39 (1H, d, J = 17.3 Hz), 2.45 (1H, dd, J = 1.1, 17.6 Hz), 2.74 (1H, dd, J = 1.6, 17.4 Hz), 3.09 (3H, s), 3.70 (3H, s), 5.17 (1H, s), 6.59 (1H, d, J = 8.5 Hz), 7.60 (1H, d, J = 8.5 Hz).
(29b) ベンジル　6-[4-メトキシ-2-メチル-3-(2,2,8,8-テトラメチル-4,6-ジオキソ-3,4,6,7,8,9-ヘキサヒドロ-2H,5H-ピラノ[2,3-b]クロメン-5-イル)フェニル]-3-メチルピリジン-2-カルボキシレート
　実施例29aで製造した5-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,2,8,8-テトラメチル-2,3,5,7,8,9-ヘキサヒドロ-4H,6H-ピラノ[2,3-b]クロメン-4,6-ジオン(301 mg, 0.576 mmol)、実施例20eで製造したベンジル　6-クロロ-3-メチルピリジン-2-カルボキシレート(181 mg, 0.691 mmol)、2nd Generation X-Phos Precatalyst (22.7 mg, 0.0288 mmol)、リン酸カリウム(183 mg, 0.864 mmol)、THF (2.0 mL)及び水(4.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(232 mg, 65%)を得た。
1H-NMR(500MHz, CDCl3):δ ppm: 0.96 (3H, s), 1.10 (3H, s), 1.34 (3H, s), 1.54 (3H, s), 2.15 (1H, dd, J = 1.3, 16.3 Hz), 2.21 (1H, d, J = 16.2 Hz), 2.28 (1H, d, J = 16.7 Hz), 2.38 (1H, d, J = 17.0 Hz), 2.49 (1H, dd, J = 2.3, 17.6 Hz), 2.52 (3H, s), 2.68 (1H, d, J = 17.0 Hz), 2.88 (3H, s), 3.74 (3H, s), 5.16 (1H, s), 5.45 (2H, s), 6.72 (1H, d, J = 8.5 Hz), 7.30-7.34 (2H, m), 7.36-7.39 (2H, m), 7.51 (1H, d, J = 7.1 Hz), 7.47 (2H, d, J = 10.0 Hz), 7.60 (1H, d, J = 8.2 Hz).
(29c) 6-[4-メトキシ-2-メチル-3-(2,2,8,8-テトラメチル-4,6-ジオキソ-3,4,6,7,8,9-ヘキサヒドロ-2H,5H-ピラノ[2,3-b]クロメン-5-イル)フェニル]-3-メチルピリジン-2-カルボン酸
　実施例29bで製造したベンジル　6-[4-メトキシ-2-メチル-3-(2,2,8,8-テトラメチル-4,6-ジオキソ-3,4,6,7,8,9-ヘキサヒドロ-2H,5H-ピラノ[2,3-b]クロメン-5-イル)フェニル]-3-メチルピリジン-2-カルボキシレート(223 mg, 0.359 mmol)、パラジウム炭素(10%, 110 mg)、エタノール(4.0 mL)及びジクロロメタン(1.0 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(110 mg, 58%)を得た。 (Example 29)
6- [4-Methoxy-2-methyl-3- (2,2,8,8-tetramethyl-4,6-dioxo-3,4,6,7,8,9-hexahydro-2H, 5H-pyrano [2,3-b] chromen-5-yl) phenyl] -3-methylpyridine-2-carboxylic acid
(29a) 5- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2,2,8,8 -Tetramethyl-2,3,5,7,8,9-hexahydro-4H, 6H-pyrano [2,3-b] chromene-4,6-dione 2- [6-methoxy-, prepared in Example 9b 2-Methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] -5,5-dimethylcyclohexane-1,3-dione (2.00 g, 5.02 mmol) and 6,6-dimethyldihydro-2H-pyran-2,4 (3H) -dione (857 mg, 6.03 mmol) in DMF (20 mL) at room temperature at tert-butoxypotassium (676 mg, 6.03 mmol) Was added. After stirring the reaction solution at room temperature for 30 minutes, acetic acid (431 μL, 7.53 mmol) and water (20 mL) were added, and the reaction solution was further stirred for 1 hour. The precipitated solid was collected by filtration to obtain an adduct. The adduct was added to a solution of zinc chloride (130 mg, 0.951 mmol) in acetic anhydride (32 mL) at room temperature, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 3: 1) to obtain the title compound (306 mg, 12%).
1 H-NMR (500 MHz, CDCl 3 ): δ ppm: 0.93 (3H, s), 1.08 (3H, s), 1.30 (3H, s), 1.31 (12H, s), 1.52 (3H, s), 2.12 (1H, dd, J = 1.1, 16.4 Hz), 2.20 (1H, d, J = 16.4 Hz), 2.26 (1H, d, J = 16.7 Hz), 2.35 (1H, dd, J = 0.7, 17.7 Hz) , 2.47 (1H, dd, J = 1.7, 17.6 Hz), 2.67 (1H, d, J = 16.7 Hz), 3.14 (3H, s), 3.70 (3H, s), 5.18 (1H, s), 6.59 ( 1H, d, J = 8.5 Hz), 7.60 (1H, d, J = 8.5 Hz).
Further, by-product 10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3,7 , 7-Tetramethyl-3,4,6,7,8,10-hexahydro-1H, 9H-pyrano [4,3-b] chromene-1,9-dione (571 mg, 23%) was obtained.
1 H-NMR (500 MHz, CDCl 3 ): δ ppm: 0.93 (3H, s), 1.09 (3H, s), 1.26 (3H, s), 1.31 (12H, s), 1.45 (3H, s), 2.12 (1H, dd, J = 1.7, 16.4 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.33 (1H, dd, J = 1.1, 17.6 Hz), 2.39 (1H, d, J = 17.3 Hz) , 2.45 (1H, dd, J = 1.1, 17.6 Hz), 2.74 (1H, dd, J = 1.6, 17.4 Hz), 3.09 (3H, s), 3.70 (3H, s), 5.17 (1H, s), 6.59 (1H, d, J = 8.5 Hz), 7.60 (1H, d, J = 8.5 Hz).
(29b) Benzyl 6- [4-methoxy-2-methyl-3- (2,2,8,8-tetramethyl-4,6-dioxo-3,4,6,7,8,9-hexahydro-2H , 5H-pyrano [2,3-b] chromen-5-yl) phenyl] -3-methylpyridine-2-carboxylate 5- [6-methoxy-2-methyl-3- (4) prepared in Example 29a , 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2,2,8,8-tetramethyl-2,3,5,7,8,9-hexahydro- 4H, 6H-pyrano [2,3-b] chromene-4,6-dione (301 mg, 0.576 mmol), benzyl 6-chloro-3-methylpyridine-2-carboxylate prepared in Example 20e (181 mg , 0.691 mmol), 2nd Generation X-Phos Precatalyst (22.7 mg, 0.0288 mmol), potassium phosphate (183 mg, 0.864 mmol), THF (2.0 mL) and water (4.0 mL), according to Example 9d The title compound (232 mg, 65%) was obtained by reaction and workup.
1 H-NMR (500 MHz, CDCl 3 ): δ ppm: 0.96 (3H, s), 1.10 (3H, s), 1.34 (3H, s), 1.54 (3H, s), 2.15 (1H, dd, J = 1.3, 16.3 Hz), 2.21 (1H, d, J = 16.2 Hz), 2.28 (1H, d, J = 16.7 Hz), 2.38 (1H, d, J = 17.0 Hz), 2.49 (1H, dd, J = 2.3, 17.6 Hz), 2.52 (3H, s), 2.68 (1H, d, J = 17.0 Hz), 2.88 (3H, s), 3.74 (3H, s), 5.16 (1H, s), 5.45 (2H, s), 6.72 (1H, d, J = 8.5 Hz), 7.30-7.34 (2H, m), 7.36-7.39 (2H, m), 7.51 (1H, d, J = 7.1 Hz), 7.47 (2H, d , J = 10.0 Hz), 7.60 (1H, d, J = 8.2 Hz).
(29c) 6- [4-Methoxy-2-methyl-3- (2,2,8,8-tetramethyl-4,6-dioxo-3,4,6,7,8,9-hexahydro-2H, 5H-pyrano [2,3-b] chromen-5-yl) phenyl] -3-methylpyridine-2-carboxylic acid benzyl 6- [4-methoxy-2-methyl-3- (2) prepared in Example 29b , 2,8,8-Tetramethyl-4,6-dioxo-3,4,6,7,8,9-hexahydro-2H, 5H-pyrano [2,3-b] chromen-5-yl) phenyl] -3-Methylpyridine-2-carboxylate (223 mg, 0.359 mmol), palladium on carbon (10%, 110 mg), ethanol (4.0 mL) and dichloromethane (1.0 mL) were used and reacted according to Example 18. The title compound (110 mg, 58%) was obtained by post-treatment.
(実施例30)
　6-[4-メトキシ-2-メチル-3-(3,3,7,7-テトラメチル-1,9-ジオキソ-4,6,7,8,9,10-ヘキサヒドロ-1H,3H-ピラノ[4,3-b]クロメン-10-イル)フェニル]ピリジン-2-カルボン酸 (30a) tert-ブチル　6-[4-メトキシ-2-メチル-3-(3,3,7,7-テトラメチル-1,9-ジオキソ-4,6,7,8,9,10-ヘキサヒドロ-1H,3H-ピラノ[4,3-b]クロメン-10-イル)フェニル]ピリジン-2-カルボキシレート
　実施例29aで副生した10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3,7,7-テトラメチル-3,4,6,7,8,10-ヘキサヒドロ-1H,9H-ピラノ[4,3-b]クロメン-1,9-ジオン(250 mg, 0.479 mmol)、tert-ブチル　6-ブロモピリジン-2-カルボキシレート(136 mg, 0.526 mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0) (55.3 mg, 0.0479 mmol)、炭酸ナトリウム(152 mg, 1.44 mmol)、DME (2.0 mL)及び水(1.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(166 mg, 61%)を得た。
1H-NMR(500MHz, CDCl3):δ ppm: 0.97 (3H, s), 1.11 (3H, s), 1.30 (3H, s), 1.47 (3H, s), 1.64 (9H, s), 2.15 (1H, dd, J = 0.5, 16.6 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.36 (1H, d, J = 18.3 Hz), 2.43 (1H, d, J = 17.3 Hz), 2.47 (1H, dd, J = 0.7, 17.6 Hz), 2.77 (1H, dd, J = 1.5, 17.3 Hz), 2.83 (3H, s), 3.74 (3H, s), 5.15 (1H, s), 6.72 (1H, d, J = 8.5 Hz), 7.37 (1H, d, J = 8.5 Hz), 7.55 (1H, d, J = 8.1 Hz), 7.77 (1H, t, J = 7.8 Hz), 7.91 (1H, d, J = 7.6 Hz).
(30b) 6-[4-メトキシ-2-メチル-3-(3,3,7,7-テトラメチル-1,9-ジオキソ-4,6,7,8,9,10-ヘキサヒドロ-1H,3H-ピラノ[4,3-b]クロメン-10-イル)フェニル]ピリジン-2-カルボン酸
　実施例30aで製造したtert-ブチル　6-[4-メトキシ-2-メチル-3-(3,3,7,7-テトラメチル-1,9-ジオキソ-4,6,7,8,9,10-ヘキサヒドロ-1H,3H-ピラノ[4,3-b]クロメン-10-イル)フェニル]ピリジン-2-カルボキシレート(152 mg, 0.265 mmol) 、ジクロロメタン(2.0 mL)及びトリフルオロ酢酸(2.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(102 mg, 74%)を得た。 (Example 30)
6- [4-Methoxy-2-methyl-3- (3,3,7,7-tetramethyl-1,9-dioxo-4,6,7,8,9,10-hexahydro-1H, 3H-pyrano [4,3-b] chromen-10-yl) phenyl] pyridine-2-carboxylic acid (30a) tert-butyl 6- [4-methoxy-2-methyl-3- (3,3,7,7-tetra Methyl-1,9-dioxo-4,6,7,8,9,10-hexahydro-1H, 3H-pyrano [4,3-b] chromen-10-yl) phenyl] pyridine-2-carboxylate Examples 10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3,7 by-produced in 29a , 7-Tetramethyl-3,4,6,7,8,10-hexahydro-1H, 9H-pyrano [4,3-b] chromene-1,9-dione (250 mg, 0.479 mmol), tert-butyl 6-bromopyridine-2-carboxylate (136 mg, 0.526 mmol), tetrakis (triphenylphosphine) palladium (0) (55.3 mg, 0.0479 mmol), sodium carbonate (152 mg, 1.44 mmol), DME (2.0 mL) And water (1.0 mL) and the reaction according to Example 9d and By performing the process, to give the title compound (166 mg, 61%).
1 H-NMR (500 MHz, CDCl 3 ): δ ppm: 0.97 (3H, s), 1.11 (3H, s), 1.30 (3H, s), 1.47 (3H, s), 1.64 (9H, s), 2.15 (1H, dd, J = 0.5, 16.6 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.36 (1H, d, J = 18.3 Hz), 2.43 (1H, d, J = 17.3 Hz), 2.47 (1H, dd, J = 0.7, 17.6 Hz), 2.77 (1H, dd, J = 1.5, 17.3 Hz), 2.83 (3H, s), 3.74 (3H, s), 5.15 (1H, s), 6.72 ( 1H, d, J = 8.5 Hz), 7.37 (1H, d, J = 8.5 Hz), 7.55 (1H, d, J = 8.1 Hz), 7.77 (1H, t, J = 7.8 Hz), 7.91 (1H, d, J = 7.6 Hz).
(30b) 6- [4-Methoxy-2-methyl-3- (3,3,7,7-tetramethyl-1,9-dioxo-4,6,7,8,9,10-hexahydro-1H, 3H-pyrano [4,3-b] chromen-10-yl) phenyl] pyridine-2-carboxylic acid tert-butyl 6- [4-methoxy-2-methyl-3- (3,3) prepared in Example 30a , 7,7-Tetramethyl-1,9-dioxo-4,6,7,8,9,10-hexahydro-1H, 3H-pyrano [4,3-b] chromen-10-yl) phenyl] pyridine- The reaction was conducted according to Example 1d using 2-carboxylate (152 mg, 0.265 mmol), dichloromethane (2.0 mL) and trifluoroacetic acid (2.0 mL) to give the title compound (102 mg, 74 %).
(実施例31)
　6-[4-メトキシ-2-メチル-3-(3,3,7,7-テトラメチル-1,9-ジオキソ-4,6,7,8,9,10-ヘキサヒドロ-1H,3H-ピラノ[4,3-b]クロメン-10-イル)フェニル]-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例30で製造した6-[4-メトキシ-2-メチル-3-(3,3,7,7-テトラメチル-1,9-ジオキソ-4,6,7,8,9,10-ヘキサヒドロ-1H,3H-ピラノ[4,3-b]クロメン-10-イル)フェニル]ピリジン-2-カルボン酸(50.0 mg, 0.0966 mmol)、カルボニルジイミダゾール(18.8 mg, 0.116 mmol)、DMF (1.0 mL)、メタンスルホンアミド(11.9 mg, 0.126 mmol)及びDBU (19 μL, 0.126 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(47.0 mg, 82%)を得た。 (Example 31)
6- [4-Methoxy-2-methyl-3- (3,3,7,7-tetramethyl-1,9-dioxo-4,6,7,8,9,10-hexahydro-1H, 3H-pyrano [4,3-b] chromen-10-yl) phenyl] -N- (methylsulfonyl) pyridine-2-carboxamide 6- [4-methoxy-2-methyl-3- (3,3) prepared in Example 30 , 7,7-Tetramethyl-1,9-dioxo-4,6,7,8,9,10-hexahydro-1H, 3H-pyrano [4,3-b] chromen-10-yl) phenyl] pyridine- Using 2-carboxylic acid (50.0 mg, 0.0966 mmol), carbonyldiimidazole (18.8 mg, 0.116 mmol), DMF (1.0 mL), methanesulfonamide (11.9 mg, 0.126 mmol) and DBU (19 μL, 0.126 mmol) The title compound (47.0 mg, 82%) was obtained by carrying out the reaction and post-treatment according to Example 6a.
(実施例32)
　2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシ-6-(1H-ピラゾール-1-イル)安息香酸
(32a) エチル　3-ブロモ-2-(ブロモメチル)-6-メトキシベンゾエート
　エチル　3-ブロモ-6-メトキシ-2-メチルベンゾエート(110 g, 404 mmol)、2,2'-アゾビス(イソブチロニトリル) (6.64 g, 40.4 mmol)及びN-ブロモスクシイミド(79.2 g, 445 mmol)の四塩化炭素(500 mL)及びアセトニトリル(200 mL)溶液を80℃で24時間攪拌した。室温まで冷却後、析出物をろ過により除き、ろ液に5%チオ硫酸ナトリウム水溶液を加え、有機層を抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮後、標記化合物(142 g, 99%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 1.42 (3H, t, J = 7.0 Hz), 3.83 (3H, s), 4.46 (2H, q, J = 7.0 Hz), 4.57 (2H, s), 6.79 (1H, d, J = 8.6 Hz), 7.57 (1H, d, J = 9.0 Hz).
(32b) エチル3-ブロモ-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}ベンゾエート
　実施例32aで製造したエチル　3-ブロモ-2-(ブロモメチル)-6-メトキシベンゾエート(142 g, 404 mmol)及び4-メトキシベンジルアルコール(61.5 g, 445 mmol)のDMF (1.0 L)溶液に0℃で水素化ナトリウム(63%, 23.1 g, 606 mmol)を加え、反応溶液を0℃で2時間攪拌した。反応溶液に水を加え、酢酸エチルで2回抽出後、有機層を水で2回洗浄、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 1:1)で精製し、標記化合物(165 g, 99%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 1.27 (3H, t, J = 7.0 Hz), 3.80 (3H, s), 3.82 (3H, s), 4.25 (2H, q, J = 7.0 Hz), 4.44 (2H, s), 4.67 (2H, s), 6.78 (1H, d, J = 9.0 Hz), 6.87 (2H, d, J = 9.0 Hz), 7.28 (2H, d, J = 9.0 Hz), 7.53 (1H, d, J = 9.0 Hz).
(32c) エチル　6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾエート
　窒素雰囲気下、実施例32bで製造したエチル 3-ブロモ-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}ベンゾエート(20.0 g, 48.8 mmol)、ビス(ピナコラト)ジボロン(14.9 g, 58.6 mmol)及び酢酸カリウム(14.4 g, 147 mmol)の1,4-ジオキサン(200 mL)懸濁液にビス(トリフェニルホスフィン)パラジウム(II)ジクロリド(3.43 g, 4.88 mmol)を加え、加熱還流下で1時間攪拌した。室温まで冷却後、反応液に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 4:1)で精製し、標記化合物(18.8 g, 84％)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 1.27 (3H, t, J = 8.2 Hz), 1.28 (12H, s), 3.79 (3H, s), 3.84 (3H, s), 4.26 (2H, q, J = 7.2 Hz), 4.38 (2H, s), 4.83 (2H, s), 6.83-6.87 (3H, m), 7.24-7.26 (2H, m), 7.79 (1H, d, J = 8.2 Hz).
(32d) [3-(エトキシカルボニル)-4-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}フェニル]ボロン酸
　実施例32cで製造したエチル　6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾエート(18.8 g, 41.2 mmol)のTHF (180 mL)、水(45 mL)混合溶媒に室温で過ヨウ素酸ナトリウム(26.5 g, 124 mmol)を加えた。反応溶液を室温で1時間攪拌後、1 M塩酸(45 mL)を加え、反応溶液をさらに室温で5.5時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮後、残渣をヘキサン及びエーテルで結晶化し、標記化合物(11.6 g, 75％)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 1.29 (3H, t, J = 7.0 Hz), 3.69 (3H, s), 3.88 (3H, s), 4.29 (2H, q, J = 7.2 Hz), 4.42 (2H, s), 4.93 (2H, s), 6.69 (2H, dd, J = 2.0, 6.7 Hz), 6.87 (1H, d, J = 7.4 Hz), 7.10 (2H, dd, J = 2.0, 6.7 Hz), 7.79 (1H, d, J = 8.6 Hz).
(32e) エチル　6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)ベンゾエート
　窒素雰囲気下、実施例32dで製造した[3-(エトキシカルボニル)-4-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}フェニル]ボロン酸(10.8 g, 28.7 mmol)、モレキュラーシーブス(4A, 10.8 g)、ピラゾール(2.35 g, 34.5 mmol)、ピリジン(5.81 mL, 71.8 mmol)及び酢酸銅(II) (2.59 g, 6.53 mmol)のDMF (215 mL)溶液を室温で22時間攪拌した。反応液に酢酸エチルを加え、不溶物をろ過後(セライト)、ろ液を酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 2:1)で精製し、標記化合物(2.59 g, 23％)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 1.28 (3H, t, J = 7.0 Hz), 3.79 (3H, s), 3.88 (3H, s), 4.27 (2H, q, J = 7.2 Hz), 4.31 (2H, s), 4.33 (2H, s), 6.39 (1H, t, J = 2.2 Hz), 6.82 (2H, d, J = 8.6 Hz), 6.96 (1H, d, J = 9.0 Hz), 7.18 (2H, d, J = 9.0 Hz), 7.41 (1H, d, J = 9.0 Hz), 7.69 (1H, d, J = 2.7 Hz), 7.64 (1H, d, J = 2.7 Hz).
(32f) [6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)フェニル]メタノール
　窒素雰囲気下、実施例32eで製造したエチル　6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)ベンゾエート(2.58 g, 6.51 mmol)のトルエン(35 mL)溶液に-78℃でジイソブチルアルミニウムヒドリド(1.02 Mヘキサン; 16.0 mL, 16.3 mmol)を加え、反応溶液を0℃で16時間攪拌した。反応溶液に10％ロッシェル塩水溶液(70 mL)を加え、室温で3時間攪拌した。反応液を酢酸エチルで抽出後、有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮後、粗製の標記化合物を得た。
(32g) 6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)ベンズアルデヒド
　実施例32fで製造した粗製の[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)フェニル]メタノールのジクロロメタン(25 mL)溶液に室温でデスマーチンペルヨージナン(3.04 g, 7.17 mmol)を加え、反応溶液を室温で30分攪拌した。反応溶液に飽和炭酸水素ナトリウム水溶液及びチオ硫酸ナトリウム水溶液を加え、不溶物をろ別後(セライト)、酢酸エチルで2回抽出した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 2:1)で精製し、標記化合物(2.06 g, 90%, 2 steps)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 3.79 (3H, s), 3.95 (3H, s), 4.45 (2H, s), 4.49 (2H, s), 6.40 (1H, t, J = 2.0 Hz), 6.84 (2H, d, J = 9.0 Hz), 7.06 (1H, d, J = 9.0 Hz), 7.24 (2H, d, J = 9.0 Hz), 7.60 (1H, d, J = 9.0 Hz), 7.70 (1H, d, J = 2.0 Hz), 7.78 (1H, dd, J = 2.3, 0.8 Hz), 10.60 (1H, s).
(32h) 2-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン
実施例32gで製造した6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)ベンズアルデヒド(2.14 g, 6.07 mmol)及びジメドン(1.02 g, 7.29 mmol)のアセトニトリル(11 mL)溶液に室温でL-プロリン(35.0 mg, 0.304 mmol)を加え、反応溶液を室温で5時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、標記化合物(2.88 g, 99%)を得た。
(32i) (3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)フェニル]-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
実施例32hで製造した2-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン(961 mg, 2.03 mmol)、実施例22cで製造した(6S)-6-tert-ブチルピペリジン-2,4-ジオン(377 mg, 2.23 mmol)、DMF (5.0 mL)、炭酸セシウム(792 mg, 2.43 mmol)、トリブチルホスフィン(0.61 mL, 2.43 mmol)、DMF (13 mL)及びビス(2-メトキシエチル)アゾジカルボキシレート(569 mg, 2.43 mmol)を用い、実施例15aに準じて反応及び後処理を行うことにより、標記化合物(942 mg, 74%)を得た。 
1H-NMR(400MHz, CDCl3):δ ppm: 0.86 (9H, s), 0.95 (3H, s), 1.11 (3H, s), 2.17 (1H, d, J = 16.8 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.35 (1H, d, J = 17.2 Hz), 2.47 (1H, d, J = 16.8 Hz), 2.57 (2H, t, J = 7.0 Hz), 3.27 (1H, dt, J = 2.7, 8.6 Hz), 3.70 (3H, s), 3.79 (3H, s), 4.49 (1H, d, J = 11.3 Hz), 4.56 (1H, d, J = 11.3 Hz), 4.74 (1H, d, J = 10.6 Hz), 5.05 (1H, d, J = 11.0 Hz), 5.19 (1H, d, J = 2.0 Hz), 5.23 (1H, s), 6.29 (1H, t, J = 2.2 Hz), 6.75 (1H, d, J = 8.6 Hz), 6.83 (2H, dd, J = 6.7, 2.0 Hz), 7.22 (1H, d, J = 8.6 Hz), 7.35 (2H, d, J = 8.6 Hz), 7.62 (1H, d, J = 2.0 Hz), 8.00 (1H, d, J = 2.3 Hz).
(32j) (3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例32iで製造した(3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)フェニル]-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(923 mg, 1.48 mmol)、ヨウ化メチル(459 μL, 7.38 mmol)、DMF (9.0 mL)及び水素化ナトリウム(63%, 67.4 mg, 1.77 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(531 mg, 56%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.82 (9H, s), 0.98 (3H, s), 1.11 (3H, s), 2.22 (2H, s), 2.36 (1H, d, J = 17.6 Hz), 2.48 (1H, d, J = 17.6 Hz), 2.53 (1H, d, J = 18.4 Hz), 2.89 (1H, ddd, J = 2.0, 9.0, 18.0 Hz), 2.98 (3H, s), 3.12 (1H, d, J = 8.6 Hz), 3.65 (3H, s), 3.80 (3H, s), 4.42 (1H, d, J = 11.0 Hz), 4.46 (1H, d, J = 11.0 Hz), 4.70 (1H, d, J = 11.0 Hz), 5.45 (1H, s), 5.49 (1H, d, J = 10.6 Hz), 6.28 (1H, t, J = 2.2 Hz), 6.69 (1H, d, J = 9.0 Hz), 6.83-6.86 (2H, m), 7.22 (1H, d, J = 8.6 Hz), 7.40-7.43 (2H, m), 7.61 (1H, dd, J = 0.8, 2.0 Hz), 8.06 (1H, d, J = 2.3 Hz).
(32k) (3S,10S)-3-tert-ブチル-10-[2-(ヒドロキシメチル)-6-メトキシ-3-(1H-ピラゾール-1-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例32jで製造した(3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(526 mg, 0.822 mmol)及びリン酸バッファー(pH6.86, 0.55 mL)のジクロロメタン(5.5 mL)溶液に室温で2,3-ジクロロ-5,6-ジシアノ-1,4-ベンゾキノン(224 mg, 0.987 mmol)を加え、反応溶液を室温で1時間攪拌した。反応溶液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出後、有機層を飽和食塩水で2回洗浄、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 1:1)で精製し、標記化合物(368 mg, 86%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.86 (9H, s), 0.97 (3H, s), 1.11 (3H, s), 2.15 (1H, dd, J = 1.2, 16.4 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.37 (1H, dd, J = 1.2, 17.6 Hz), 2.50 (1H, d, J = 16.4 Hz), 2.57 (1H, d, J = 18.0 Hz), 2.94 (1H, ddd, J = 2.1, 9.1, 18.3 Hz), 3.00 (3H, s), 3.18 (1H, d, J = 9.0 Hz), 3.67 (3H, s), 5.00 (2H, d, J = 6.7 Hz), 5.32 (1H, s), 6.11 (1H, t, J = 6.5 Hz), 6.40 (1H, t, J = 2.2 Hz), 6.75 (1H, d, J = 9.0 Hz), 7.40 (1H, d, J = 9.0 Hz), 7.67 (1H, d, J = 2.0 Hz), 8.29 (1H, d, J = 2.3 Hz).
(32l) 2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシ-6-(1H-ピラゾール-1-イル)ベンズアルデヒド
　実施例32kで製造した(3S,10S)-3-tert-ブチル-10-[2-(ヒドロキシメチル)-6-メトキシ-3-(1H-ピラゾール-1-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(339 mg, 0.652 mmol)のジクロロメタン(4.0 mL)溶液に0℃でデスマーチンペルヨージナン(304 mg, 0.718 mmol)を加え、反応溶液を室温で4時間攪拌した。反応溶液に飽和炭酸水素ナトリウム水溶液及びチオ硫酸ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 2:3)で精製し、標記化合物(291 mg, 86%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.86 (9H, s), 0.99 (3H, s), 1.10 (3H, s), 2.14 (1H, dd, J = 1.2, 16.0 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.34 (1H, dd, J = 0.8, 17.6 Hz), 2.47 (1H, dd, J = 1.2, 16.8 Hz), 2.52 (1H, d, J = 17.6 Hz), 2.90 (2H, ddd, J = 2.3, 9.0, 18.0 Hz), 2.98 (3H, s), 3.14 (1H, d, J = 8.6 Hz), 3.69 (3H, s), 5.47 (1H, s), 6.37 (1H, t, J = 2.2 Hz), 6.86 (1H, d, J = 8.6 Hz), 7.30 (1H, d, J = 9.0 Hz), 7.64 (1H, dd, J = 0.8, 2.0 Hz), 7.70 (1H, dd, J = 0.8, 2.3 Hz), 10.67 (1H, s).
(32m) 2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシ-6-(1H-ピラゾール-1-イル)安息香酸
　実施例32lで製造した2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシ-6-(1H-ピラゾール-1-イル)ベンズアルデヒド(287 mg, 0.554 mmol)、2-メチル-2-ブテン(1.3 mL, 11.1 mmol)、りん酸二水素ナトリウム二水和物(433 mg, 2.77 mmol)の水(3.0 mL)、tert-ブタノール(12 mL)及びジクロロメタン(1.5 mL)混合溶媒に室温で亜塩素酸ナトリウム(313 mg, 2.77 mmol)を加え、反応溶液を室温で2時間攪拌した。反応溶液に水及びクエン酸を加え(pH = 4.0)、ジクロロメタンで抽出後、有機層を無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣を酢酸エチルで結晶化し、標記化合物(281 mg, 95%)を得た。 (Example 32)
2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxy-6- (1H-pyrazol-1-yl) benzoic acid
(32a) Ethyl 3-bromo-2- (bromomethyl) -6-methoxybenzoate Ethyl 3-bromo-6-methoxy-2-methylbenzoate (110 g, 404 mmol), 2,2'-azobis (isobutyronitrile ) (6.64 g, 40.4 mmol) and N-bromosuccinimide (79.2 g, 445 mmol) in carbon tetrachloride (500 mL) and acetonitrile (200 mL) were stirred at 80 ° C. for 24 hours. After cooling to room temperature, the precipitate was removed by filtration, and a 5% aqueous sodium thiosulfate solution was added to the filtrate to extract the organic layer. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (142 g, 99%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.42 (3H, t, J = 7.0 Hz), 3.83 (3H, s), 4.46 (2H, q, J = 7.0 Hz), 4.57 (2H, s ), 6.79 (1H, d, J = 8.6 Hz), 7.57 (1H, d, J = 9.0 Hz).
(32b) Ethyl 3-bromo-6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} benzoate Ethyl 3-bromo-2- (bromomethyl) -6-methoxybenzoate prepared in Example 32a (142 g, 404 mmol) and 4-methoxybenzyl alcohol (61.5 g, 445 mmol) in DMF (1.0 L) at 0 ° C, sodium hydride (63%, 23.1 g, 606 mmol) was added, and the reaction solution For 2 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with water and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 1: 1) to obtain the title compound (165 g, 99%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.27 (3H, t, J = 7.0 Hz), 3.80 (3H, s), 3.82 (3H, s), 4.25 (2H, q, J = 7.0 Hz ), 4.44 (2H, s), 4.67 (2H, s), 6.78 (1H, d, J = 9.0 Hz), 6.87 (2H, d, J = 9.0 Hz), 7.28 (2H, d, J = 9.0 Hz) ), 7.53 (1H, d, J = 9.0 Hz).
(32c) Ethyl 6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate Ethyl 3-bromo-6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} benzoate (20.0 g, 48.8 mmol), bis (pinacolato) diboron (14.9 g) prepared in Example 32b under nitrogen atmosphere Bis (triphenylphosphine) palladium (II) dichloride (3.43 g, 4.88 mmol) to a suspension of 1,4-dioxane (200 mL) in potassium acetate (14.4 g, 147 mmol) and heating. The mixture was stirred for 1 hour under reflux. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate; 4: 1) to obtain the title compound (18.8 g, 84%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.27 (3H, t, J = 8.2 Hz), 1.28 (12H, s), 3.79 (3H, s), 3.84 (3H, s), 4.26 (2H , q, J = 7.2 Hz), 4.38 (2H, s), 4.83 (2H, s), 6.83-6.87 (3H, m), 7.24-7.26 (2H, m), 7.79 (1H, d, J = 8.2 Hz).
(32d) [3- (Ethoxycarbonyl) -4-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} phenyl] boronic acid Ethyl 6-methoxy-2-{[(4 -Methoxybenzyl) oxy] methyl} -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (18.8 g, 41.2 mmol) in THF (180 mL), Sodium periodate (26.5 g, 124 mmol) was added to a mixed solvent of water (45 mL) at room temperature. The reaction solution was stirred at room temperature for 1 hour, 1 M hydrochloric acid (45 mL) was added, and the reaction solution was further stirred at room temperature for 5.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized from hexane and ether to obtain the title compound (11.6 g, 75%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.29 (3H, t, J = 7.0 Hz), 3.69 (3H, s), 3.88 (3H, s), 4.29 (2H, q, J = 7.2 Hz ), 4.42 (2H, s), 4.93 (2H, s), 6.69 (2H, dd, J = 2.0, 6.7 Hz), 6.87 (1H, d, J = 7.4 Hz), 7.10 (2H, dd, J = 2.0, 6.7 Hz), 7.79 (1H, d, J = 8.6 Hz).
(32e) Ethyl 6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) benzoate [3- (Ethoxy] prepared in Example 32d under nitrogen atmosphere Carbonyl) -4-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} phenyl] boronic acid (10.8 g, 28.7 mmol), molecular sieves (4A, 10.8 g), pyrazole (2.35 g, 34.5 mmol) , A solution of pyridine (5.81 mL, 71.8 mmol) and copper (II) acetate (2.59 g, 6.53 mmol) in DMF (215 mL) was stirred at room temperature for 22 hours. Ethyl acetate was added to the reaction mixture, the insoluble material was filtered off (Celite), and the filtrate was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 2: 1) to obtain the title compound (2.59 g, 23%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.28 (3H, t, J = 7.0 Hz), 3.79 (3H, s), 3.88 (3H, s), 4.27 (2H, q, J = 7.2 Hz ), 4.31 (2H, s), 4.33 (2H, s), 6.39 (1H, t, J = 2.2 Hz), 6.82 (2H, d, J = 8.6 Hz), 6.96 (1H, d, J = 9.0 Hz) ), 7.18 (2H, d, J = 9.0 Hz), 7.41 (1H, d, J = 9.0 Hz), 7.69 (1H, d, J = 2.7 Hz), 7.64 (1H, d, J = 2.7 Hz).
(32f) [6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) phenyl] methanol Ethyl 6- prepared in Example 32e under nitrogen atmosphere Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) benzoate (2.58 g, 6.51 mmol) in toluene (35 mL) at -78 ° C in diisobutylaluminum Hydride (1.02 M hexane; 16.0 mL, 16.3 mmol) was added, and the reaction solution was stirred at 0 ° C. for 16 hours. 10% Rochelle salt aqueous solution (70 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After the reaction solution was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude title compound.
(32 g) 6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) benzaldehyde Crude [6-methoxy-2- { To a solution of [(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) phenyl] methanol in dichloromethane (25 mL) was added desmartin periodinane (3.04 g, 7.17 mmol) at room temperature. The reaction solution was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution and aqueous sodium thiosulfate solution were added to the reaction solution, the insoluble material was filtered off (celite), and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate; 2: 1) to obtain the title compound (2.06 g, 90%, 2 steps).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 3.79 (3H, s), 3.95 (3H, s), 4.45 (2H, s), 4.49 (2H, s), 6.40 (1H, t, J = 2.0 Hz), 6.84 (2H, d, J = 9.0 Hz), 7.06 (1H, d, J = 9.0 Hz), 7.24 (2H, d, J = 9.0 Hz), 7.60 (1H, d, J = 9.0 Hz) ), 7.70 (1H, d, J = 2.0 Hz), 7.78 (1H, dd, J = 2.3, 0.8 Hz), 10.60 (1H, s).
(32h) 2- [6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) benzylidene] -5,5-dimethylcyclohexane-1,3- Dione 6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) benzaldehyde (2.14 g, 6.07 mmol) and dimedone (1.02 g) prepared in Example 32g , 7.29 mmol) in acetonitrile (11 mL) was added L-proline (35.0 mg, 0.304 mmol) at room temperature, and the reaction solution was stirred at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate to obtain the title compound (2.88 g, 99%).
(32i) (3S, 10S) -3-tert-butyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) phenyl] -7,7-dimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 2- [prepared in Example 32h 6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) benzylidene] -5,5-dimethylcyclohexane-1,3-dione (961 mg, 2.03 mmol), (6S) -6-tert-butylpiperidine-2,4-dione (377 mg, 2.23 mmol), DMF (5.0 mL), cesium carbonate (792 mg, 2.43 mmol), prepared in Example 22c, tributyl By using phosphine (0.61 mL, 2.43 mmol), DMF (13 mL) and bis (2-methoxyethyl) azodicarboxylate (569 mg, 2.43 mmol), the reaction and workup were carried out according to Example 15a. The title compound (942 mg, 74%) was obtained.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.86 (9H, s), 0.95 (3H, s), 1.11 (3H, s), 2.17 (1H, d, J = 16.8 Hz), 2.22 (1H , d, J = 16.4 Hz), 2.35 (1H, d, J = 17.2 Hz), 2.47 (1H, d, J = 16.8 Hz), 2.57 (2H, t, J = 7.0 Hz), 3.27 (1H, dt , J = 2.7, 8.6 Hz), 3.70 (3H, s), 3.79 (3H, s), 4.49 (1H, d, J = 11.3 Hz), 4.56 (1H, d, J = 11.3 Hz), 4.74 (1H , d, J = 10.6 Hz), 5.05 (1H, d, J = 11.0 Hz), 5.19 (1H, d, J = 2.0 Hz), 5.23 (1H, s), 6.29 (1H, t, J = 2.2 Hz ), 6.75 (1H, d, J = 8.6 Hz), 6.83 (2H, dd, J = 6.7, 2.0 Hz), 7.22 (1H, d, J = 8.6 Hz), 7.35 (2H, d, J = 8.6 Hz) ), 7.62 (1H, d, J = 2.0 Hz), 8.00 (1H, d, J = 2.3 Hz).
(32j) (3S, 10S) -3-tert-butyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) phenyl] -2,7,7-trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione prepared in Example 32i ( 3S, 10S) -3-tert-butyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) phenyl] -7,7 -Dimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (923 mg, 1.48 mmol), methyl iodide (459 μL, 7.38 mmol), DMF (9.0 mL) and sodium hydride (63%, 67.4 mg, 1.77 mmol) were used for the reaction and workup according to Example 2a to give the title compound (531 mg, 56 %).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.82 (9H, s), 0.98 (3H, s), 1.11 (3H, s), 2.22 (2H, s), 2.36 (1H, d, J = 17.6 Hz), 2.48 (1H, d, J = 17.6 Hz), 2.53 (1H, d, J = 18.4 Hz), 2.89 (1H, ddd, J = 2.0, 9.0, 18.0 Hz), 2.98 (3H, s) , 3.12 (1H, d, J = 8.6 Hz), 3.65 (3H, s), 3.80 (3H, s), 4.42 (1H, d, J = 11.0 Hz), 4.46 (1H, d, J = 11.0 Hz) , 4.70 (1H, d, J = 11.0 Hz), 5.45 (1H, s), 5.49 (1H, d, J = 10.6 Hz), 6.28 (1H, t, J = 2.2 Hz), 6.69 (1H, d, J = 9.0 Hz), 6.83-6.86 (2H, m), 7.22 (1H, d, J = 8.6 Hz), 7.40-7.43 (2H, m), 7.61 (1H, dd, J = 0.8, 2.0 Hz), 8.06 (1H, d, J = 2.3 Hz).
(32k) (3S, 10S) -3-tert-Butyl-10- [2- (hydroxymethyl) -6-methoxy-3- (1H-pyrazol-1-yl) phenyl] -2,7,7-trimethyl -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (3S, 10S) -3-tert prepared in Example 32j -Butyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) phenyl] -2,7,7-trimethyl-3,4 , 6,7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (526 mg, 0.822 mmol) and phosphate buffer (pH6.86, 0.55 mL) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (224 mg, 0.987 mmol) was added to a dichloromethane (5.5 mL) solution at room temperature, and the reaction solution was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 1: 1) to obtain the title compound (368 mg, 86%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.86 (9H, s), 0.97 (3H, s), 1.11 (3H, s), 2.15 (1H, dd, J = 1.2, 16.4 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.37 (1H, dd, J = 1.2, 17.6 Hz), 2.50 (1H, d, J = 16.4 Hz), 2.57 (1H, d, J = 18.0 Hz), 2.94 (1H, ddd, J = 2.1, 9.1, 18.3 Hz), 3.00 (3H, s), 3.18 (1H, d, J = 9.0 Hz), 3.67 (3H, s), 5.00 (2H, d, J = 6.7 Hz), 5.32 (1H, s), 6.11 (1H, t, J = 6.5 Hz), 6.40 (1H, t, J = 2.2 Hz), 6.75 (1H, d, J = 9.0 Hz), 7.40 (1H, d, J = 9.0 Hz), 7.67 (1H, d, J = 2.0 Hz), 8.29 (1H, d, J = 2.3 Hz).
(32l) 2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxy-6- (1H-pyrazol-1-yl) benzaldehyde (3S, 10S) -3-tert-butyl prepared in Example 32k -10- [2- (hydroxymethyl) -6-methoxy-3- (1H-pyrazol-1-yl) phenyl] -2,7,7-trimethyl-3,4,6,7,8,10-hexahydro -1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (339 mg, 0.652 mmol) in dichloromethane (4.0 mL) at 0 ° C with desmartin periodinane (304 mg, 0.718 mmol ) And the reaction solution was stirred at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution and an aqueous sodium thiosulfate solution were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate; 2: 3) to obtain the title compound (291 mg, 86%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.86 (9H, s), 0.99 (3H, s), 1.10 (3H, s), 2.14 (1H, dd, J = 1.2, 16.0 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.34 (1H, dd, J = 0.8, 17.6 Hz), 2.47 (1H, dd, J = 1.2, 16.8 Hz), 2.52 (1H, d, J = 17.6 Hz) , 2.90 (2H, ddd, J = 2.3, 9.0, 18.0 Hz), 2.98 (3H, s), 3.14 (1H, d, J = 8.6 Hz), 3.69 (3H, s), 5.47 (1H, s), 6.37 (1H, t, J = 2.2 Hz), 6.86 (1H, d, J = 8.6 Hz), 7.30 (1H, d, J = 9.0 Hz), 7.64 (1H, dd, J = 0.8, 2.0 Hz), 7.70 (1H, dd, J = 0.8, 2.3 Hz), 10.67 (1H, s).
(32m) 2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxy-6- (1H-pyrazol-1-yl) benzoic acid 2-[(3S, 10S) -3 prepared in Example 32l -tert-Butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridine-10 -Il] -3-methoxy-6- (1H-pyrazol-1-yl) benzaldehyde (287 mg, 0.554 mmol), 2-methyl-2-butene (1.3 mL, 11.1 mmol), sodium dihydrogen phosphate dihydrate Sodium chlorite (313 mg, 2.77 mmol) was added to a mixed solvent of water (3.0 mL), tert-butanol (12 mL) and dichloromethane (1.5 mL) in Japanese (433 mg, 2.77 mmol) at room temperature. Was stirred at room temperature for 2 hours. Water and citric acid were added to the reaction solution (pH = 4.0), extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was crystallized from ethyl acetate to obtain the title compound (281 mg, 95%).
(実施例33)
　3-メトキシ-6-(1H-ピラゾール-1-イル)-2-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]安息香酸
(33a) (3S,10S)-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例32hで製造した2-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン(961 mg, 2.03 mmol)、公知化合物である(6S)-6-(プロパン-2-イル)ピペリジン-2,4-ジオン(346 mg, 2.23 mmol)、アセトニトリル(10 mL)、炭酸セシウム(792 mg, 2.43 mmol)、トリブチルホスフィン(0.61 mL, 2.43 mmol)、DMF (13 mL)及びビス(2-メトキシエチル)アゾジカルボキシレート(569 mg, 2.43 mmol)を用い、実施例15aに準じて反応及び後処理を行うことにより、標記化合物(889 mg, 72%)を得た。 
1H-NMR(400MHz, CDCl3):δ ppm: 0.84 (3H, d, J = 7.4 Hz), 0.89 (3H, d, J = 6.3 Hz), 0.94 (3H, s), 1.10 (3H, s), 1.62-1.72 (1H, m), 2.14-2.24 (2H, m), 2.35 (1H, d, J = 16.4 Hz), 2.44-2.54 (2H, m), 2.69 (1H, ddd, J = 1.3, 6.9, 17.1 Hz), 3.17-3.23 (1H, m), 3.72 (3H, s), 3.79 (3H, s), 4.51 (1H, d, J = 11.0 Hz), 4.56 (1H, d, J = 11.3 Hz), 4.78 (1H, d, J = 11.0 Hz), 4.98 (1H, d, J = 11.0 Hz), 5.26 (1H, s), 5.31 (1H, d, J = 2.7 Hz), 6.29 (1H, t, J = 2.0 Hz), 6.77 (1H, d, J = 8.6 Hz), 6.83 (2H, d, J = 9.0 Hz), 7.23 (1H, d, J = 9.0 Hz), 7.37 (2H, d, J = 9.0 Hz), 7.62 (1H, d, J = 2.0 Hz), 8.02 (1H, d, J = 2.0 Hz).
(33b) (3S,10S)-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)フェニル]-2,7,7-トリメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例33aで製造した(3S,10S)-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(883 mg, 1.44 mmol)、ヨウ化メチル(449 μL, 7.22 mmol)、DMF (9.0 mL)及び水素化ナトリウム(63%, 66.0 mg, 1.73 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(544 mg, 60%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.78 (3H, d, J = 7.0 Hz), 0.83 (3H, d, J = 7.0 Hz), 0.97 (3H, s), 1.10 (3H, s), 1.85-1.93 (1H, m), 2.22 (2H, s), 2.35 (1H, d, J = 17.6 Hz), 2.45 (1H, d, J = 18.0 Hz), 2.47 (1H, d, J = 17.6 Hz), 2.85 (1H, ddd, J = 1.8, 7.8, 17.6 Hz), 2.92 (3H, s), 3.08 (1H, t, J = 6.7 Hz), 3.69 (3H, s), 3.79 (3H, s), 4.51 (1H, d, J = 11.0 Hz), 4.47 (1H, d, J = 11.3 Hz), 4.67 (1H, d, J = 11.3 Hz), 5.36 (1H, d, J = 11.0 Hz), 5.40 (1H, s), 6.29 (1H, t, J = 2.0 Hz), 6.73 (1H, d, J = 8.6 Hz), 6.82-6.85 (2H, m), 7.23 (1H, d, J = 8.6 Hz), 7.39-7.42 (2H, m), 7.62 (1H, d, J = 1.6 Hz), 8.06 (1H, d, J = 2.0 Hz).
(33c) (3S,10S)-10-[2-(ヒドロキシメチル)-6-メトキシ-3-(1H-ピラゾール-1-イル)フェニル]-2,7,7-トリメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例33bで製造した(3S,10S)-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)フェニル]-2,7,7-トリメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(536 mg, 0.857 mmol)、リン酸バッファー(pH6.86, 0.55 mL)、ジクロロメタン(5.5 mL)及び2,3-ジクロロ-5,6-ジシアノ-1,4-ベンゾキノン(233 mg, 1.03 mmol)を用い、実施例32kに準じて反応及び後処理を行うことにより、標記化合物(385 mg, 89%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.83 (3H, d, J = 7.0 Hz), 0.86 (3H, d, J = 6.7 Hz), 0.96 (3H, s), 1.10 (3H, s), 1.91-2.00 (1H, m), 2.15 (1H, dd, J = 1.2, 16.4 Hz), 2.24 (1H, d, J = 16.8 Hz), 2.36 (1H, dd, J = 1.2, 17.6 Hz), 2.49 (2H, d, J = 17.6 Hz), 2.86-2.93 (1H, m), 2.94 (3H, s), 3.14 (1H, t, J = 7.0 Hz), 3.72 (3H, s), 4.90 (1H, dd, J = 7.0, 12.5 Hz), 5.07 (1H, dd, J = 5.5, 12.5 Hz), 5.28 (1H, s), 6.13 (1H, dd, J = 5.5, 7.0 Hz), 6.40 (1H, t, J = 2.2 Hz), 6.79 (1H, d, J = 9.0 Hz), 7.41 (1H, d, J = 9.0 Hz), 7.67 (1H, d, J = 2.0 Hz), 8.30 (1H, dd, J = 0.8, 2.3 Hz).
(33d) 3-メトキシ-6-(1H-ピラゾール-1-イル)-2-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]ベンズアルデヒド
　実施例33cで製造した(3S,10S)-10-[2-(ヒドロキシメチル)-6-メトキシ-3-(1H-ピラゾール-1-イル)フェニル]-2,7,7-トリメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(358 mg, 0.708 mmol)、ジクロロメタン(4.0 mL)及びデスマーチンペルヨージナン(330 mg, 0.779 mmol)を用い、実施例32lに準じて反応及び後処理を行うことにより、標記化合物(316 mg, 89%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.81 (3H, d, J = 7.0 Hz), 0.87 (3H, d, J = 6.7 Hz), 0.97 (3H, s), 1.10 (3H, s), 1.93-2.02 (1H, m), 2.13 (1H, dd, J = 1.4, 16.2 Hz), 2.23 (1H, d, J = 16.4 Hz), 2.33 (1H, d, J = 17.6 Hz), 2.43 (1H, dd, J = 1.0, 11.2 Hz), 2.48 (1H, dd, J = 1.2, 11.0 Hz), 2.86 (1H, ddd, J = 2.3, 8.2, 17.6 Hz), 2.92 (3H, s), 3.14-3.17 (1H, m), 3.73 (3H, s), 5.47 (1H, s), 6.37 (1H, t, J = 2.2 Hz), 6.90 (1H, d, J = 9.0 Hz), 7.30 (1H, d, J = 8.6 Hz), 7.65 (1H, d, J = 1.6 Hz), 7.70 (1H, d, J = 2.3 Hz), 10.63 (1H, s).
(33e) 3-メトキシ-6-(1H-ピラゾール-1-イル)-2-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]安息香酸
　実施例33dで製造した3-メトキシ-6-(1H-ピラゾール-1-イル)-2-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]ベンズアルデヒド(313 mg, 0.622 mmol)、2-メチル-2-ブテン(1.5 mL, 12.4 mmol)、りん酸二水素ナトリウム二水和物(485 mg, 3.11 mmol)、水(3.0 mL)、tert-ブタノール(12 mL)、ジクロロメタン(1.5 mL)及び亜塩素酸ナトリウム(351 mg, 3.11 mmol) を用い、実施例32mに準じて反応及び後処理を行うことにより、標記化合物(323 mg, 99%)を得た。 (Example 33)
3-Methoxy-6- (1H-pyrazol-1-yl) -2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2 , 3,4,6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzoic acid
(33a) (3S, 10S) -10- [6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) phenyl] -7,7-dimethyl -3- (propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione prepared in Example 32h 2- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) benzylidene] -5,5-dimethylcyclohexane-1,3-dione 961 mg, 2.03 mmol), known compounds (6S) -6- (propan-2-yl) piperidine-2,4-dione (346 mg, 2.23 mmol), acetonitrile (10 mL), cesium carbonate (792 mg) , 2.43 mmol), tributylphosphine (0.61 mL, 2.43 mmol), DMF (13 mL) and bis (2-methoxyethyl) azodicarboxylate (569 mg, 2.43 mmol), and the reaction according to Example 15a The title compound (889 mg, 72%) was obtained by post-treatment.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.84 (3H, d, J = 7.4 Hz), 0.89 (3H, d, J = 6.3 Hz), 0.94 (3H, s), 1.10 (3H, s ), 1.62-1.72 (1H, m), 2.14-2.24 (2H, m), 2.35 (1H, d, J = 16.4 Hz), 2.44-2.54 (2H, m), 2.69 (1H, ddd, J = 1.3 , 6.9, 17.1 Hz), 3.17-3.23 (1H, m), 3.72 (3H, s), 3.79 (3H, s), 4.51 (1H, d, J = 11.0 Hz), 4.56 (1H, d, J = 11.3 Hz), 4.78 (1H, d, J = 11.0 Hz), 4.98 (1H, d, J = 11.0 Hz), 5.26 (1H, s), 5.31 (1H, d, J = 2.7 Hz), 6.29 (1H , t, J = 2.0 Hz), 6.77 (1H, d, J = 8.6 Hz), 6.83 (2H, d, J = 9.0 Hz), 7.23 (1H, d, J = 9.0 Hz), 7.37 (2H, d , J = 9.0 Hz), 7.62 (1H, d, J = 2.0 Hz), 8.02 (1H, d, J = 2.0 Hz).
(33b) (3S, 10S) -10- [6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) phenyl] -2,7,7 -Trimethyl-3- (propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione Example 33a (3S, 10S) -10- [6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) phenyl] -7,7-dimethyl -3- (propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (883 mg, 1.44 mmol), methyl iodide (449 μL, 7.22 mmol), DMF (9.0 mL) and sodium hydride (63%, 66.0 mg, 1.73 mmol), by carrying out the reaction and workup according to Example 2a. The title compound (544 mg, 60%) was obtained.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.78 (3H, d, J = 7.0 Hz), 0.83 (3H, d, J = 7.0 Hz), 0.97 (3H, s), 1.10 (3H, s ), 1.85-1.93 (1H, m), 2.22 (2H, s), 2.35 (1H, d, J = 17.6 Hz), 2.45 (1H, d, J = 18.0 Hz), 2.47 (1H, d, J = 17.6 Hz), 2.85 (1H, ddd, J = 1.8, 7.8, 17.6 Hz), 2.92 (3H, s), 3.08 (1H, t, J = 6.7 Hz), 3.69 (3H, s), 3.79 (3H, s), 4.51 (1H, d, J = 11.0 Hz), 4.47 (1H, d, J = 11.3 Hz), 4.67 (1H, d, J = 11.3 Hz), 5.36 (1H, d, J = 11.0 Hz) , 5.40 (1H, s), 6.29 (1H, t, J = 2.0 Hz), 6.73 (1H, d, J = 8.6 Hz), 6.82-6.85 (2H, m), 7.23 (1H, d, J = 8.6 Hz), 7.39-7.42 (2H, m), 7.62 (1H, d, J = 1.6 Hz), 8.06 (1H, d, J = 2.0 Hz).
(33c) (3S, 10S) -10- [2- (hydroxymethyl) -6-methoxy-3- (1H-pyrazol-1-yl) phenyl] -2,7,7-trimethyl-3- (propane- 2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione prepared in Example 33b (3S, 10S) -10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) phenyl] -2,7,7-trimethyl-3- (propane- 2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (536 mg, 0.857 mmol), phosphate buffer (pH 6.86, 0.55 mL), dichloromethane (5.5 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (233 mg, 1.03 mmol), and the reaction according to Example 32k and The title compound (385 mg, 89%) was obtained by post-treatment.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.83 (3H, d, J = 7.0 Hz), 0.86 (3H, d, J = 6.7 Hz), 0.96 (3H, s), 1.10 (3H, s ), 1.91-2.00 (1H, m), 2.15 (1H, dd, J = 1.2, 16.4 Hz), 2.24 (1H, d, J = 16.8 Hz), 2.36 (1H, dd, J = 1.2, 17.6 Hz) , 2.49 (2H, d, J = 17.6 Hz), 2.86-2.93 (1H, m), 2.94 (3H, s), 3.14 (1H, t, J = 7.0 Hz), 3.72 (3H, s), 4.90 ( 1H, dd, J = 7.0, 12.5 Hz), 5.07 (1H, dd, J = 5.5, 12.5 Hz), 5.28 (1H, s), 6.13 (1H, dd, J = 5.5, 7.0 Hz), 6.40 (1H , t, J = 2.2 Hz), 6.79 (1H, d, J = 9.0 Hz), 7.41 (1H, d, J = 9.0 Hz), 7.67 (1H, d, J = 2.0 Hz), 8.30 (1H, dd , J = 0.8, 2.3 Hz).
(33d) 3-Methoxy-6- (1H-pyrazol-1-yl) -2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) ) -2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzaldehyde (3S, 10S) -10 prepared in Example 33c -[2- (Hydroxymethyl) -6-methoxy-3- (1H-pyrazol-1-yl) phenyl] -2,7,7-trimethyl-3- (propan-2-yl) -3,4,6 , 7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (358 mg, 0.708 mmol), dichloromethane (4.0 mL) and desmartin periodinane (330 The title compound (316 mg, 89%) was obtained by carrying out the reaction and post-treatment according to Example 32l using mg, 0.779 mmol).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.81 (3H, d, J = 7.0 Hz), 0.87 (3H, d, J = 6.7 Hz), 0.97 (3H, s), 1.10 (3H, s ), 1.93-2.02 (1H, m), 2.13 (1H, dd, J = 1.4, 16.2 Hz), 2.23 (1H, d, J = 16.4 Hz), 2.33 (1H, d, J = 17.6 Hz), 2.43 (1H, dd, J = 1.0, 11.2 Hz), 2.48 (1H, dd, J = 1.2, 11.0 Hz), 2.86 (1H, ddd, J = 2.3, 8.2, 17.6 Hz), 2.92 (3H, s), 3.14-3.17 (1H, m), 3.73 (3H, s), 5.47 (1H, s), 6.37 (1H, t, J = 2.2 Hz), 6.90 (1H, d, J = 9.0 Hz), 7.30 (1H , d, J = 8.6 Hz), 7.65 (1H, d, J = 1.6 Hz), 7.70 (1H, d, J = 2.3 Hz), 10.63 (1H, s).
(33e) 3-Methoxy-6- (1H-pyrazol-1-yl) -2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) ) -2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzoic acid 3-Methoxy-6- prepared in Example 33d (1H-pyrazol-1-yl) -2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6 , 7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzaldehyde (313 mg, 0.622 mmol), 2-methyl-2-butene (1.5 mL, 12.4 mmol) , Sodium dihydrogen phosphate dihydrate (485 mg, 3.11 mmol), water (3.0 mL), tert-butanol (12 mL), dichloromethane (1.5 mL) and sodium chlorite (351 mg, 3.11 mmol). The title compound (323 mg, 99%) was obtained by reaction and post-treatment according to Example 32m.
(実施例34)
　2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシ-6-(ピリジン-2-イル)安息香酸
(34a) (3-ブロモ-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}フェニル)メタノール
　実施例32bで製造したエチル3-ブロモ-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}ベンゾエート(974 mg, 2.38 mmol)のジクロロメタン(10 mL)溶液に-78℃でジイソブチルアルミニウムヒドリド(1.04 Mトルエン溶液; 5.50 mL, 2.72 mmol)を加え、反応溶液を-78℃で2時間攪拌した。反応溶液に飽和塩化アンモニウム水溶液(1.5 mL)を加え、室温で18時間攪拌した。不要物をろ過により除き、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 1:2)で精製し、標記化合物(726 mg, 83%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 3.00 (1H, t, J = 6.7 Hz), 3.80 (3H, s), 3.85 (3H, s), 4.56 (2H, s), 4.76 (2H, d, J = 6.7 Hz), 4.84 (2H, s), 6.79 (1H, d, J = 9.0 Hz), 6.88 (2H, d, J = 8.6 Hz), 7.30 (2H, d, J = 8.6 Hz), 7.50 (1H, d, J = 8.6 Hz).
(34b) 3-ブロモ-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}ベンズアルデヒド
　実施例34aで製造した(3-ブロモ-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}フェニル)メタノール(723 mg, 1.97 mmol)のジクロロメタン(7.2 mL)溶液に室温でデスマーチンペルヨージナン(1.00 g, 2.36 mmol)を加え、反応溶液を室温で20分攪拌した。反応溶液に飽和炭酸水素ナトリウム水溶液及びチオ硫酸ナトリウム水溶液を加えエーテルで2回抽出した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 2:1)で精製し、標記化合物(587 mg, 82%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 3.80 (3H, s), 3.88 (3H, s), 4.54 (2H, s), 4.91 (2H, s), 6.86 (1H, d, J = 9.0 Hz), 6.87 (2H, d, J = 8.6 Hz), 7.31 (2H, d, J = 9.0 Hz), 7.67 (1H, d, J = 9.0 Hz), 10.48 (1H, s).
(34c) 6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンズアルデヒド
　実施例34bで製造した3-ブロモ-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}ベンズアルデヒド(3.70 g, 10.1 mmol)、ビス(ピナコラト)ジボロン(2.83 g, 11.1 mmol)、酢酸カリウム(2.98 g, 30.1 mmol)、ビス(トリフェニルホスフィン)パラジウム(II)ジクロリド(711 mg, 1.01 mmol)及び1,4-ジオキサン(37 mL)を用い、実施例9aに準じて反応及び後処理を行うことにより、標記化合物( 4.18 g, 79%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 1.30 (12H, s), 3.79 (3H, s), 3.90 (3H, s), 4.49 (2H, s), 5.01 (2H, s), 6.85 (2H, d, J = 8.6 Hz), 6.91 (1H, d, J = 8.2 Hz), 7.27 (2H, d, J = 8.6 Hz), 7.80 (1H, d, J = 8.2 Hz), 10.55 (1H, s).
(34d) 2-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン
　実施例34cで製造した6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンズアルデヒド(5.24 g, 12.7 mmol)、ジメドン(1.96 g, 14.0 mmol)、アセトニトリル(25 mL)及びL-プロリン(73.2 mg, 0.635 mmol)を用い、実施例32hに準じて反応及び後処理を行うことにより、標記化合物(6.59 g, 97%)を得た。 Example 34
2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxy-6- (pyridin-2-yl) benzoic acid
(34a) (3-Bromo-6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} phenyl) methanol Ethyl 3-bromo-6-methoxy-2-{[(4 -Methoxybenzyl) oxy] methyl} benzoate (974 mg, 2.38 mmol) in dichloromethane (10 mL) at -78 ° C was added diisobutylaluminum hydride (1.04 M toluene solution; 5.50 mL, 2.72 mmol), and the reaction solution was- The mixture was stirred at 78 ° C. for 2 hours. A saturated aqueous ammonium chloride solution (1.5 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 18 hours. Unnecessary substances were removed by filtration, and after concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 1: 2) to obtain the title compound (726 mg, 83%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 3.00 (1H, t, J = 6.7 Hz), 3.80 (3H, s), 3.85 (3H, s), 4.56 (2H, s), 4.76 (2H , d, J = 6.7 Hz), 4.84 (2H, s), 6.79 (1H, d, J = 9.0 Hz), 6.88 (2H, d, J = 8.6 Hz), 7.30 (2H, d, J = 8.6 Hz) ), 7.50 (1H, d, J = 8.6 Hz).
(34b) 3-Bromo-6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} benzaldehyde (3-Bromo-6-methoxy-2-{[(4-methoxybenzyl) prepared in Example 34a Dess Martin periodinane (1.00 g, 2.36 mmol) was added to a solution of) oxy] methyl} phenyl) methanol (723 mg, 1.97 mmol) in dichloromethane (7.2 mL) at room temperature, and the reaction solution was stirred at room temperature for 20 minutes. A saturated aqueous sodium hydrogen carbonate solution and an aqueous sodium thiosulfate solution were added to the reaction solution, and the mixture was extracted twice with ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 2: 1) to obtain the title compound (587 mg, 82%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 3.80 (3H, s), 3.88 (3H, s), 4.54 (2H, s), 4.91 (2H, s), 6.86 (1H, d, J = 9.0 Hz), 6.87 (2H, d, J = 8.6 Hz), 7.31 (2H, d, J = 9.0 Hz), 7.67 (1H, d, J = 9.0 Hz), 10.48 (1H, s).
(34c) 6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde 3-Bromo-6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} benzaldehyde prepared in Example 34b (3.70 g, 10.1 mmol), bis (pinacolato) diboron (2.83 g, 11.1 mmol), acetic acid Reaction and workup according to Example 9a using potassium (2.98 g, 30.1 mmol), bis (triphenylphosphine) palladium (II) dichloride (711 mg, 1.01 mmol) and 1,4-dioxane (37 mL) To give the title compound (4.18 g, 79%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.30 (12H, s), 3.79 (3H, s), 3.90 (3H, s), 4.49 (2H, s), 5.01 (2H, s), 6.85 (2H, d, J = 8.6 Hz), 6.91 (1H, d, J = 8.2 Hz), 7.27 (2H, d, J = 8.6 Hz), 7.80 (1H, d, J = 8.2 Hz), 10.55 (1H , s).
(34d) 2- [6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) Benzylidene] -5,5-dimethylcyclohexane-1,3-dione 6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde (5.24 g, 12.7 mmol), dimedone (1.96 g, 14.0 mmol), acetonitrile (25 mL) and L-proline (73.2 mg, 0.635 mmol) The title compound (6.59 g, 97%) was obtained by reaction and workup according to Example 32h.
1H-NMR(400MHz, CDCl3):δ ppm: 1.06 (6H, s), 1.30 (12H, s), 2.42 (2H, s), 2.54 (2H, s), 3.74 (3H, s), 3.78 (3H, s), 4.40 (2H, s), 4.72 (2H, s), 6.80-6.84 (3H, m), 7.23 (2H, d, J = 8.6 Hz), 7.79 (1H, d, J = 8.6 Hz), 8.11 (1H, s).
(34e) (3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例34dで製造した2-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン(6.44 g, 12.0 mmol)、実施例22cで製造した(6S)-6-tert-ブチルピペリジン-2,4-ジオン(2.34 g, 13.9 mmol)、DMF (40 mL)、炭酸セシウム(4.91 g, 15.1 mmol)、トリブチルホスフィン(3.51 mL, 14.1 mmol)、DMF (40 mL)及びビス(2-メトキシエチル)アゾジカルボキシレート(3.29 g, 14.1 mmol)を用い、実施例15aに準じて反応及び後処理を行うことにより、標記化合物(3.39 g, 42%)を得た。  1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.06 (6H, s), 1.30 (12H, s), 2.42 (2H, s), 2.54 (2H, s), 3.74 (3H, s), 3.78 (3H, s), 4.40 (2H, s), 4.72 (2H, s), 6.80-6.84 (3H, m), 7.23 (2H, d, J = 8.6 Hz), 7.79 (1H, d, J = 8.6 Hz), 8.11 (1H, s).
(34e) (3S, 10S) -3-tert-butyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1, 9 (2H) -dione 2- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4,5,5-tetramethyl-1, prepared in Example 34d 3,2-dioxaborolan-2-yl) benzylidene] -5,5-dimethylcyclohexane-1,3-dione (6.44 g, 12.0 mmol), (6S) -6-tert-butylpiperidine- prepared in Example 22c 2,4-dione (2.34 g, 13.9 mmol), DMF (40 mL), cesium carbonate (4.91 g, 15.1 mmol), tributylphosphine (3.51 mL, 14.1 mmol), DMF (40 mL) and bis (2-methoxy Ethyl) azodicarboxylate (3.29 g, 14.1 mmol) was used for the reaction and workup according to Example 15a to give the title compound (3.39 g, 42%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.85 (9H, s), 0.91 (3H, s), 1.07 (3H, s), 1.22 (12H, s), 2.09 (1H, d, J = 16.0 Hz), 2.17 (1H, d, J = 16.0 Hz), 2.30 (1H, d, J = 16.8 Hz), 2.42 (1H, d, J = 18.0 Hz), 2.50 (2H, d, J = 7.8 Hz), 3.26 (1H, td, J = 2.0, 7.8 Hz), 3.65 (3H, s), 3.79 (3H, s), 4.59 (1H, d, J = 12.1 Hz), 4.63 (1H, d, J = 11.7 Hz), 4.92 (1H, s), 5.13 (1H, t, J = 0.8 Hz), 5.32 (1H, d, J = 12.1 Hz), 5.37 (1H, d, J = 12.5 Hz), 6.64 (1H, d, J = 8.2 Hz), 6.83 (2H, d, J = 9.3 Hz), 7.33 (1H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.6 Hz).
(34f) (3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例34eで製造した(3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(3.39 g, 4.94 mmol)、ヨウ化メチル(462 μL, 7.42 mmol)、DMF (34 mL)及び水素化ナトリウム(63%, 226 mg, 5.93 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(2.45 g, 71%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.85 (9H, s), 0.91 (3H, s), 1.07 (3H, s), 1.22 (12H, s), 2.09 (1H, d, J = 16.0 Hz), 2.17 (1H, d, J = 16.0 Hz), 2.30 (1H, d, J = 16.8 Hz), 2.42 (1H, d, J = 18.0 Hz), 2.50 (2H, d, J = 7.8 Hz ), 3.26 (1H, td, J = 2.0, 7.8 Hz), 3.65 (3H, s), 3.79 (3H, s), 4.59 (1H, d, J = 12.1 Hz), 4.63 (1H, d, J = 11.7 Hz), 4.92 (1H, s), 5.13 (1H, t, J = 0.8 Hz), 5.32 (1H, d, J = 12.1 Hz), 5.37 (1H, d, J = 12.5 Hz), 6.64 (1H , d, J = 8.2 Hz), 6.83 (2H, d, J = 9.3 Hz), 7.33 (1H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.6 Hz).
(34f) (3S, 10S) -3-tert-butyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl) phenyl] -2,7,7-trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine- 1,9 (2H) -dione (3S, 10S) -3-tert-butyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3-prepared in Example 34e (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (3.39 g, 4.94 mmol), methyl iodide (462 μL, 7.42 mmol), DMF (34 mL) and sodium hydride (63%, 226 The title compound (2.45 g, 71%) was obtained by carrying out the reaction and post-treatment according to Example 2a using mg, 5.93 mmol).
1H-NMR(400MHz, CDCl3):δ ppm: 0.80 (9H, s), 0.94 (3H, s), 1.07 (3H, s), 1.25 (12H, s), 2.09 (1H, d, J = 16.0 Hz), 2.16 (1H, d, J = 16.0 Hz), 2.30 (1H, d, J = 18.4 Hz), 2.41 (1H, d, J = 16.8 Hz), 2.49 (1H, d, J = 18.0 Hz), 2.85 (1H, ddd, J = 2.0, 9.0, 18.0 Hz), 2.96 (3H, s), 3.10 (1H, d, J = 8.6 Hz), 3.60 (3H, s), 3.79 (3H, s), 4.66 (2H, s), 5.08 (1H, s), 5.36 (1H, d, J = 13.3 Hz), 5.44 (1H, d, J = 13.3 Hz), 6.57 (1H, d, J = 8.2 Hz), 6.84 (2H, d, J = 9.0 Hz), 7.31 (1H, d, J = 7.8 Hz), 7.47 (2H, d, J = 9.0 Hz).
(34g) (3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(ピリジン-2-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例34fで製造した(3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(420 mg, 0.600 mmol)、2-クロロピリジン(81.8 mg, 0.720 mmol)、2nd Generation X-Phos Precatalyst (47.2 mg, 0.0600 mmol)、リン酸カリウム(191 mg, 0.900 mmol)、THF (3.0 mL)及び水(3.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(172 mg, 44%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.82 (9H, s), 0.99 (3H, s), 1.11 (3H, s), 2.22 (2H, s), 2.36 (1H, d, J = 17.6 Hz), 2.47 (1H, d, J = 17.2 Hz), 2.53 (1H, d, J = 18.0 Hz), 2.89 (1H, ddd, J = 1.9, 8.9, 17.9 Hz), 2.99 (3H, s), 3.12 (1H, d, J = 8.6 Hz), 3.65 (3H, s), 3.78 (3H, s), 4.38 (1H, d, J = 11.3 Hz), 4.60 (1H, d, J = 11.3 Hz), 4.99 (1H, d, J = 11.0 Hz), 5.46 (1H, s), 5.59 (1H, d, J = 11.0 Hz), 6.70 (1H, d, J = 8.2 Hz), 6.77 (2H, d, J = 9.1 Hz), 7.11-7.14 (1H, m), 7.16 (2H, d, J = 9.0 Hz), 7.24 (1H, d, J = 8.6 Hz), 7.54 (1H, td, J = 1.8, 7.7 Hz), 7.69-7.72 (1H, m), 8.55-8.57 (1H, m).
(34h) (3S,10S)-3-tert-ブチル-10-[2-(ヒドロキシメチル)-6-メトキシ-3-(ピリジン-2-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例34gで製造した(3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(ピリジン-2-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(172 mg, 0.264 mmol)及びアニソール(143 μL, 1.32 mmol)のジクロロメタン(2.0 mL)溶液に室温でトリフルオロ酢酸(200 μL, 2.61 mmol)を加え、反応溶液を室温で1時間攪拌した。反応溶液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出後、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル)で精製し、標記化合物(101 mg, 72%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.85 (9H, s), 0.97 (3H, s), 1.11 (3H, s), 2.15 (1H, dd, J = 1.6, 16.4 Hz), 2.25 (1H, d, J = 16.4 Hz), 2.37 (1H, dd, J = 1.2, 17.6 Hz), 2.50 (1H, d, J = 18.8 Hz), 2.57 (1H, d, J = 18.4 Hz), 2.93 (1H, ddd, J = 2.0, 9.2, 18.2 Hz), 2.99 (3H, s), 3.17 (1H, d, J = 8.6 Hz), 3.68 (3H, s), 5.08 (1H, dd, J = 6.3, 12.5 Hz), 5.25 (1H, dd, J = 6.1, 12.7 Hz), 5.36 (1H, s), 6.26 (1H, t, J = 6.3 Hz), 6.78 (1H, d, J = 9.0 Hz), 7.20 (1H, ddd, J = 1.1, 4.8, 7.5 Hz), 7.50 (1H, d, J = 8.6 Hz), 7.73 (1H, td, J = 2.0, 7.8 Hz), 8.08-8.11 (1H, m), 8.66-8.63 (1H, m).
(34i) 2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシ-6-(ピリジン-2-イル)安息香酸
　実施例34hで製造した(3S,10S)-3-tert-ブチル-10-[2-(ヒドロキシメチル)-6-メトキシ-3-(ピリジン-2-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(97.0 mg, 0.183 mmol)及びリン酸バッファー(pH7.2, 6.0 mL)のアセトニトリル(9.0 mL)溶液に室温で亜塩素酸ナトリウム(45.5 mg, 0.402 mmol)、nor-AZADO (25.3 mg, 0.0183 mmol)及び次亜塩素酸ナトリウム水溶液(312 μL, 0.400 mmol)を順次加え、反応溶液を室温で6時間攪拌した。反応溶液に10%チオ硫酸ナトリウム水溶液を加え、ジクロロメタンで抽出後、有機層を無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をヘキサン/酢酸エチルより結晶化し、標記化合物(77.1 mg, 77%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.80 (9H, s), 0.94 (3H, s), 1.07 (3H, s), 1.25 (12H, s), 2.09 (1H, d, J = 16.0 Hz), 2.16 (1H, d, J = 16.0 Hz), 2.30 (1H, d, J = 18.4 Hz), 2.41 (1H, d, J = 16.8 Hz), 2.49 (1H, d, J = 18.0 Hz) ), 2.85 (1H, ddd, J = 2.0, 9.0, 18.0 Hz), 2.96 (3H, s), 3.10 (1H, d, J = 8.6 Hz), 3.60 (3H, s), 3.79 (3H, s) , 4.66 (2H, s), 5.08 (1H, s), 5.36 (1H, d, J = 13.3 Hz), 5.44 (1H, d, J = 13.3 Hz), 6.57 (1H, d, J = 8.2 Hz) , 6.84 (2H, d, J = 9.0 Hz), 7.31 (1H, d, J = 7.8 Hz), 7.47 (2H, d, J = 9.0 Hz).
(34 g) (3S, 10S) -3-tert-butyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (pyridin-2-yl) phenyl] -2 , 7,7-Trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione prepared in Example 34f (3S 10S) -3-tert-butyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl) phenyl] -2,7,7-trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -Dione (420 mg, 0.600 mmol), 2-chloropyridine (81.8 mg, 0.720 mmol), 2nd Generation X-Phos Precatalyst (47.2 mg, 0.0600 mmol), potassium phosphate (191 mg, 0.900 mmol), THF (3.0 mL) and water (3.0 mL) were used, and the reaction and workup were performed according to Example 9d to obtain the title compound (172 mg, 44%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.82 (9H, s), 0.99 (3H, s), 1.11 (3H, s), 2.22 (2H, s), 2.36 (1H, d, J = 17.6 Hz), 2.47 (1H, d, J = 17.2 Hz), 2.53 (1H, d, J = 18.0 Hz), 2.89 (1H, ddd, J = 1.9, 8.9, 17.9 Hz), 2.99 (3H, s) , 3.12 (1H, d, J = 8.6 Hz), 3.65 (3H, s), 3.78 (3H, s), 4.38 (1H, d, J = 11.3 Hz), 4.60 (1H, d, J = 11.3 Hz) , 4.99 (1H, d, J = 11.0 Hz), 5.46 (1H, s), 5.59 (1H, d, J = 11.0 Hz), 6.70 (1H, d, J = 8.2 Hz), 6.77 (2H, d, J = 9.1 Hz), 7.11-7.14 (1H, m), 7.16 (2H, d, J = 9.0 Hz), 7.24 (1H, d, J = 8.6 Hz), 7.54 (1H, td, J = 1.8, 7.7 Hz), 7.69-7.72 (1H, m), 8.55-8.57 (1H, m).
(34h) (3S, 10S) -3-tert-butyl-10- [2- (hydroxymethyl) -6-methoxy-3- (pyridin-2-yl) phenyl] -2,7,7-trimethyl-3 , 4,6,7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (3S, 10S) -3-tert-butyl prepared in Example 34g -10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (pyridin-2-yl) phenyl] -2,7,7-trimethyl-3,4,6,7 , 8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (172 mg, 0.264 mmol) and anisole (143 μL, 1.32 mmol) in dichloromethane (2.0 mL) To the mixture was added trifluoroacetic acid (200 μL, 2.61 mmol) at room temperature, and the reaction solution was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (101 mg, 72%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.85 (9H, s), 0.97 (3H, s), 1.11 (3H, s), 2.15 (1H, dd, J = 1.6, 16.4 Hz), 2.25 (1H, d, J = 16.4 Hz), 2.37 (1H, dd, J = 1.2, 17.6 Hz), 2.50 (1H, d, J = 18.8 Hz), 2.57 (1H, d, J = 18.4 Hz), 2.93 (1H, ddd, J = 2.0, 9.2, 18.2 Hz), 2.99 (3H, s), 3.17 (1H, d, J = 8.6 Hz), 3.68 (3H, s), 5.08 (1H, dd, J = 6.3 , 12.5 Hz), 5.25 (1H, dd, J = 6.1, 12.7 Hz), 5.36 (1H, s), 6.26 (1H, t, J = 6.3 Hz), 6.78 (1H, d, J = 9.0 Hz), 7.20 (1H, ddd, J = 1.1, 4.8, 7.5 Hz), 7.50 (1H, d, J = 8.6 Hz), 7.73 (1H, td, J = 2.0, 7.8 Hz), 8.08-8.11 (1H, m) , 8.66-8.63 (1H, m).
(34i) 2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxy-6- (pyridin-2-yl) benzoic acid (3S, 10S) -3-tert-butyl-prepared in Example 34h 10- [2- (Hydroxymethyl) -6-methoxy-3- (pyridin-2-yl) phenyl] -2,7,7-trimethyl-3,4,6,7,8,10-hexahydro-1H- Chloreno [3,2-c] pyridine-1,9 (2H) -dione (97.0 mg, 0.183 mmol) and phosphate buffer (pH 7.2, 6.0 mL) in acetonitrile (9.0 mL) in chlorite at room temperature Sodium (45.5 mg, 0.402 mmol), nor-AZADO (25.3 mg, 0.0183 mmol) and sodium hypochlorite aqueous solution (312 μL, 0.400 mmol) were sequentially added, and the reaction solution was stirred at room temperature for 6 hours. A 10% aqueous sodium thiosulfate solution was added to the reaction solution, extracted with dichloromethane, and then the organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was crystallized from hexane / ethyl acetate to obtain the title compound (77.1 mg, 77%).
(実施例35)
　6-{3-[(3S,10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(35a) tert-ブチル　6-{3-[(3S,10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例9dで製造したtert-ブチル　6-{3-[(3S,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2メチルフェニル}-3-メチルピリジン-2-カルボキシレート(250 mg, 0.416 mmol)、ヨウ化エチル(333 μL, 4.16 mmol)、1,3-ジメチル-3,4,5,6-テトラヒドロ-2(1H)-ピリミジノン(7.1 mL)及び水素化ナトリウム(63%, 19.0 mg, 0.499 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(168 mg, 64%)を得た。 (Example 35)
6- {3-[(3S, 10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8, 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(35a) tert-butyl 6- {3-[(3S, 10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4, 6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate Examples Tert-butyl 6- {3-[(3S, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7 prepared in 9d , 8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2methylphenyl} -3-methylpyridine-2-carboxylate (250 mg, 0.416 mmol ), Ethyl iodide (333 μL, 4.16 mmol), 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (7.1 mL) and sodium hydride (63%, 19.0 mg, The title compound (168 mg, 64%) was obtained by performing the reaction and post-treatment according to Example 2a using 0.499 mmol).
1H-NMR(400MHz, CDCl3):δ ppm: 0.88 (6H, t, J = 7.0 Hz), 0.99 (3H, s), 1.12 (3H, t, J = 7.0 Hz), 1.12 (3H, s), 1.67 (9H, s), 1.91-2.00 (1H, m), 2.16 (1H, d, J = 16.0 Hz), 2.23 (1H, d, J = 16.4 Hz), 2.36 (1H, d, J = 17.2 Hz), 2.46 (1H, d, J = 18.4 Hz), 2.53 (3H, s), 2.54 (1H, dd, J = 2.5, 14.7 Hz), 2.61-2.69 (1H, m), 2.82 (1H, ddd, J = 2.3, 7.0, 18.4 Hz), 2.90 (3H, s), 3.10 (1H, t, J = 6.7 Hz), 3.71 (3H, s), 4.06-4.14 (1H, m), 5.27 (1H, s), 6.68 (1H, d, J = 8.6 Hz), 7.32 (1H, d, J = 8.2 Hz), 7.43 (1H, d, J = 7.8 Hz), 7.55 (1H, d, J = 8.2 Hz).
(35b) 6-{3-[(3S,10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例35aで製造したtert-ブチル　6-{3-[(3S,10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(102 mg, 0.162 mmol)、ジクロロメタン(1.0 mL)及びトリフルオロ酢酸(1.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(87.1 mg, 94%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.81 (3H, d, J = 6.6 Hz), 0.83 (3H, d, J = 6.6 Hz), 0.94 (3H, s), 1.07 (3H, t, J = 7.0 Hz), 1.07 (3H, s), 1.86-1.94 (1H, m), 2.11 (1H, dd, J = 1.2, 16.4 Hz), 2.19 (1H, d, J = 16.4 Hz), 2.31 (1H, dd, J = 1.2, 17.6 Hz), 2.42 (1H, dd, J = 1.0, 17.4 Hz), 2.48 (1H, dd, J = 1.0, 17.4 Hz), 2.54-2.63 (1H, m), 2.74-2.81 (1H, m), 2.76 (3H, s), 2.86 (3H, s), 3.08 (1H, t, J = 7.0 Hz), 3.68 (3H, s), 4.02-4.12 (1H, m), 5.20 (1H, s), 6.65 (1H, d, J = 8.6 Hz), 7.15 (1H, d, J = 8.6 Hz), 7.56 (1H, d, J = 8.2 Hz), 7.65 (1H, d, J = 7.8 Hz).
(35c) 6-{3-[(3S,10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例35bで製造した6-{3-[(3S,10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(85.6 mg, 0.149 mmol)、エタノール(0.9 mL)及びtert-ブチルアミン(31 μL, 0.299 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(94.5 mg, 98%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.88 (6H, t, J = 7.0 Hz), 0.99 (3H, s), 1.12 (3H, t, J = 7.0 Hz), 1.12 (3H, s ), 1.67 (9H, s), 1.91-2.00 (1H, m), 2.16 (1H, d, J = 16.0 Hz), 2.23 (1H, d, J = 16.4 Hz), 2.36 (1H, d, J = 17.2 Hz), 2.46 (1H, d, J = 18.4 Hz), 2.53 (3H, s), 2.54 (1H, dd, J = 2.5, 14.7 Hz), 2.61-2.69 (1H, m), 2.82 (1H, ddd, J = 2.3, 7.0, 18.4 Hz), 2.90 (3H, s), 3.10 (1H, t, J = 6.7 Hz), 3.71 (3H, s), 4.06-4.14 (1H, m), 5.27 (1H , s), 6.68 (1H, d, J = 8.6 Hz), 7.32 (1H, d, J = 8.2 Hz), 7.43 (1H, d, J = 7.8 Hz), 7.55 (1H, d, J = 8.2 Hz) ).
(35b) 6- {3-[(3S, 10S) -2-Ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7 , 8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid prepared in Example 35a Tert-butyl 6- {3-[(3S, 10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6, 7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (102 mg, 0.162 mmol), dichloromethane (1.0 mL) and trifluoroacetic acid (1.0 mL) were used to carry out the reaction and post-treatment according to Example 1d to obtain the title compound (87.1 mg, 94%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.81 (3H, d, J = 6.6 Hz), 0.83 (3H, d, J = 6.6 Hz), 0.94 (3H, s), 1.07 (3H, t , J = 7.0 Hz), 1.07 (3H, s), 1.86-1.94 (1H, m), 2.11 (1H, dd, J = 1.2, 16.4 Hz), 2.19 (1H, d, J = 16.4 Hz), 2.31 (1H, dd, J = 1.2, 17.6 Hz), 2.42 (1H, dd, J = 1.0, 17.4 Hz), 2.48 (1H, dd, J = 1.0, 17.4 Hz), 2.54-2.63 (1H, m), 2.74-2.81 (1H, m), 2.76 (3H, s), 2.86 (3H, s), 3.08 (1H, t, J = 7.0 Hz), 3.68 (3H, s), 4.02-4.12 (1H, m) , 5.20 (1H, s), 6.65 (1H, d, J = 8.6 Hz), 7.15 (1H, d, J = 8.6 Hz), 7.56 (1H, d, J = 8.2 Hz), 7.65 (1H, d, J = 7.8 Hz).
(35c) 6- {3-[(3S, 10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7 , 8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt 6- {3-[(3S, 10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6 prepared in Example 35b , 7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid (85.6 mg , 0.149 mmol), ethanol (0.9 mL) and tert-butylamine (31 μL, 0.299 mmol) were used for the reaction and post-treatment according to Example 3c to obtain the title compound (94.5 mg, 98%). It was.
(実施例36)
　6-{3-[(3S,10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
(36a) 6-{3-[(3S,10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例35bで製造した6-{3-[(3S,10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド(131 mg, 0.229 mmol)、カルボニルジイミダゾール(50.1 mg, 0.309 mmol)、DMF (1.5 mL)、メタンスルホンアミド(29.4 mg, 0.309 mmol)及びDBU (46 μL, 0.309 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(129 mg, 87%)をして得た。 Example 36
6- {3-[(3S, 10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8, 9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide tert- Butylamine salt
(36a) 6- {3-[(3S, 10S) -2-Ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7 , 8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2- Carboxamide 6- {3-[(3S, 10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4 prepared in Example 35b , 6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) Pyridine-2-carboxamide (131 mg, 0.229 mmol), carbonyldiimidazole (50.1 mg, 0.309 mmol), DMF (1.5 mL), methanesulfonamide (29.4 mg, 0.309 mmol) and DBU (46 μL, 0.309 mmol). The title compound (129 mg, 87%) was obtained by reaction and workup according to Example 6a.
1H-NMR(400MHz, CDCl3):δ ppm: 0.88 (3H, d, J = 6.3 Hz), 0.91 (3H, d, J = 6.7 Hz), 1.01 (3H, s), 1.14 (3H, t, J = 7.0 Hz), 1.14 (3H, s), 1.94-2.02 (1H, m), 2.17 (1H, d, J = 16.0 Hz), 2.25 (1H, d, J = 16.4 Hz), 2.39 (1H, d, J = 18.0 Hz), 2.50 (1H, d, J = 17.6 Hz), 2.56 (1H, d, J = 17.6 Hz), 2.62-2.71 (1H, m), 2.80 (3H, s), 2.81-2.89 (1H, m), 2.91 (3H, s), 3.16 (1H, t, J = 7.0 Hz), 3.42 (3H, s), 3.76 (3H, s), 4.08-4.17 (1H, m), 5.26 (1H, s), 6.74 (1H, d, J = 8.6 Hz), 7.22 (1H, d, J = 8.2 Hz), 7.62 (1H, d, J = 7.8 Hz), 7.69 (1H, d, J = 8.2 Hz).
(36b) 6-{3-[(3S,10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
　実施例35aで製造した6-{3-[(3S,10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド(129 mg, 0.199 mmol)、酢酸エチル(1.0 mL)及びtert-ブチルアミン(42 μL, 0.397 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(127 mg, 89%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.88 (3H, d, J = 6.3 Hz), 0.91 (3H, d, J = 6.7 Hz), 1.01 (3H, s), 1.14 (3H, t , J = 7.0 Hz), 1.14 (3H, s), 1.94-2.02 (1H, m), 2.17 (1H, d, J = 16.0 Hz), 2.25 (1H, d, J = 16.4 Hz), 2.39 (1H , d, J = 18.0 Hz), 2.50 (1H, d, J = 17.6 Hz), 2.56 (1H, d, J = 17.6 Hz), 2.62-2.71 (1H, m), 2.80 (3H, s), 2.81 -2.89 (1H, m), 2.91 (3H, s), 3.16 (1H, t, J = 7.0 Hz), 3.42 (3H, s), 3.76 (3H, s), 4.08-4.17 (1H, m), 5.26 (1H, s), 6.74 (1H, d, J = 8.6 Hz), 7.22 (1H, d, J = 8.2 Hz), 7.62 (1H, d, J = 7.8 Hz), 7.69 (1H, d, J = 8.2 Hz).
(36b) 6- {3-[(3S, 10S) -2-Ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7 , 8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2- Carboxamide tert-butylamine salt 6- {3-[(3S, 10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2 prepared in Example 35a , 3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (Methylsulfonyl) pyridine-2-carboxamide (129 mg, 0.199 mmol), ethyl acetate (1.0 mL) and tert-butylamine (42 μL, 0.397 mmol) should be used for the reaction and workup according to Example 3c. Gave the title compound (127 mg, 89%).
(実施例37)
　6-{3-[(10R)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(37a) 2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3,7,7-テトラメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例25aで製造した10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3,7,7-テトラメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(1.30 g, 2.49 mmol)、ヨウ化エチル(1.60 mL, 19.9 mmol)、DMF (20 mL)及び水素化ナトリウム(55%, 163 mg, 3.74 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(930 mg, 68%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.88 (3H, s), 1.03-1.08 (9H, m), 1.26 (12H, s), 1.35 (3H, s), 2.06 (1H, dd, J = 1.0, 16.2 Hz), 2.13-2.28 (3H, m), 2.38 (1H, d, J = 17.6 Hz), 2.62 (1H, dd, J = 1.6, 17.2 Hz), 2.90-2.98 (1H, m), 3.11 (3H, s), 3.47-3.55 (1H, m), 3.65 (3H, s), 5.18 (1H, s), 6.54 (1H, d, J = 8.6 Hz), 7.54 (1H, d, J = 8.2 Hz).
(37b) ベンジル　6-[3-(2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート
　実施例37aで製造した2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3,7,7-テトラメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(930 mg, 1.69 mmol)、実施例20eで製造したベンジル　6-クロロ-3-メチルピリジン-2-カルボキシレート(531 mg, 2.03 mmol)、2nd Generation X-Phos Precatalyst (266 mg, 0.338 mmol)、リン酸カリウム(575 mg, 2.71 mmol)、THF (9.0 mL)及び水(15 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(921 mg, 84%)を得た。 (Example 37)
6- {3-[(10R) -2-ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(37a) 2-Ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3 , 7,7-Tetramethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 10- prepared in Example 25a [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3,7,7-tetramethyl-3 , 4,6,7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (1.30 g, 2.49 mmol), ethyl iodide (1.60 mL, 19.9 mmol) ), DMF (20 mL) and sodium hydride (55%, 163 mg, 3.74 mmol), the title compound (930 mg, 68%) was obtained by carrying out the reaction and post-treatment according to Example 2a. It was.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.88 (3H, s), 1.03-1.08 (9H, m), 1.26 (12H, s), 1.35 (3H, s), 2.06 (1H, dd, J = 1.0, 16.2 Hz), 2.13-2.28 (3H, m), 2.38 (1H, d, J = 17.6 Hz), 2.62 (1H, dd, J = 1.6, 17.2 Hz), 2.90-2.98 (1H, m ), 3.11 (3H, s), 3.47-3.55 (1H, m), 3.65 (3H, s), 5.18 (1H, s), 6.54 (1H, d, J = 8.6 Hz), 7.54 (1H, d, J = 8.2 Hz).
(37b) Benzyl 6- [3- (2-ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl) -4-methoxy-2-methylphenyl] -3-methylpyridine-2-carboxylate 2-ethyl-10- [6- Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3,7,7-tetramethyl-3,4, 6,7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (930 mg, 1.69 mmol), benzyl 6-chloro-3 prepared in Example 20e -Methylpyridine-2-carboxylate (531 mg, 2.03 mmol), 2nd Generation X-Phos Precatalyst (266 mg, 0.338 mmol), potassium phosphate (575 mg, 2.71 mmol), THF (9.0 mL) and water (15 The title compound (921 mg, 84%) was obtained by performing the reaction and post-treatment according to Example 9d.
1H-NMR(400MHz, CDCl3):δ ppm: 0.84 (3H, t, J = 6.3 Hz), 0.87 (3H, s), 0.92 (3H, s), 1.06 (3H, s), 1.09 (3H, s), 2.10 (1H, dd, J = 1.0, 16.1 Hz), 2.18 (1H, d, J = 16.1 Hz), 2.22-2.33 (2H, m), 2.41 (1H, d, J = 17.6 Hz), 2.49 (3H, s), 2.65 (1H, dd, J = 1.5, 17.1 Hz), 2.86 (3H, s), 2.94-3.01 (1H, m), 3.50-3.57 (1H, m), 3.69 (3H, s), 5.19 (1H, s), 5.39 (1H, d, J = 12.7 Hz), 5.43 (1H, d, J = 12.2 Hz), 6.66 (1H, d, J = 8.3 Hz), 7.27-7.36 (4H, m), 7.42-7.54 (4H, m).
(37c) ベンジル　6-{3-[(10R)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例37bで製造したベンジル　6-[3-(2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート(921 mg)をChiral flash IA(ヘキサン/イソプロパノール; 4:6)により光学分割し、高極性化合物(406 mg)及び低極性化合物(410 mg)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.84 (3H, t, J = 6.3 Hz), 0.87 (3H, s), 0.92 (3H, s), 1.06 (3H, s), 1.09 (3H , s), 2.10 (1H, dd, J = 1.0, 16.1 Hz), 2.18 (1H, d, J = 16.1 Hz), 2.22-2.33 (2H, m), 2.41 (1H, d, J = 17.6 Hz) , 2.49 (3H, s), 2.65 (1H, dd, J = 1.5, 17.1 Hz), 2.86 (3H, s), 2.94-3.01 (1H, m), 3.50-3.57 (1H, m), 3.69 (3H , s), 5.19 (1H, s), 5.39 (1H, d, J = 12.7 Hz), 5.43 (1H, d, J = 12.2 Hz), 6.66 (1H, d, J = 8.3 Hz), 7.27-7.36 (4H, m), 7.42-7.54 (4H, m).
(37c) Benzyl 6- {3-[(10R) -2-ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10 -Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate benzyl 6- [3 prepared in Example 37b -(2-Ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c ] Pyridin-10-yl) -4-methoxy-2-methylphenyl] -3-methylpyridine-2-carboxylate (921 mg) was optically resolved with Chiral flash IA (hexane / isopropanol; 4: 6) A polar compound (406 mg) and a low polarity compound (410 mg) were obtained.
(37d) 6-{3-[(10R)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例37cで製造したベンジル　6-{3-[(10R)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(低極性化合物; 410 mg, 0.632 mmol)、パラジウム炭素(10%, 80 mg)、酢酸エチル(10 mL)及びメタノール(10 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(353 mg, 99%)を得た。 (37d) 6- {3-[(10R) -2-Ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid benzyl 6- {3- [(10R) -2-ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3, 2-c] Pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (low polarity compound; 410 mg, 0.632 mmol), palladium on carbon (10%, 80 mg ), Ethyl acetate (10 mL) and methanol (10 mL) were used for the reaction and post-treatment according to Example 18 to obtain the title compound (353 mg, 99%).
1H-NMR(400MHz, DMSO-d6):δ ppm: 0.89 (3H, s), 0.99 (3H, t, J = 6.8 Hz), 1.05 (3H, s), 1.09 (3H, s), 1.38 (3H, s), 2.03 (1H, d, J = 16.4 Hz), 2.26 (1H, d, J = 16.4 Hz), 2.37 (1H, d, J = 18.0 Hz), 2.44 (1H, d, J = 17.2 Hz), 2.49 (3H, s), 2.57 (1H, d, J = 17.2 Hz), 2.72 (1H, d, J = 18.0 Hz), 2.72 (3H, s), 2.98-3.07 (1H, m), 3.34-3.44 (1H, m), 3.71 (3H, s), 4.95 (1H, s), 6.83 (1H, d, J = 8.6 Hz), 7.12 (1H, d, J = 8.6 Hz), 7.40 (1H, d, J = 7.8 Hz), 7.80 (1H, d, J = 8.2 Hz).
(37e) 6-{3-[(10R)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例37dで製造した6-{3-[(10R)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(353 mg, 0.632 mmol)、エタノール(7.0 mL)及びtert-ブチルアミン(139 μL, 1.32 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(389 mg, 97%)を得た。 1 H-NMR (400 MHz, DMSO-d 6 ): δ ppm: 0.89 (3H, s), 0.99 (3H, t, J = 6.8 Hz), 1.05 (3H, s), 1.09 (3H, s), 1.38 (3H, s), 2.03 (1H, d, J = 16.4 Hz), 2.26 (1H, d, J = 16.4 Hz), 2.37 (1H, d, J = 18.0 Hz), 2.44 (1H, d, J = 17.2 Hz), 2.49 (3H, s), 2.57 (1H, d, J = 17.2 Hz), 2.72 (1H, d, J = 18.0 Hz), 2.72 (3H, s), 2.98-3.07 (1H, m) , 3.34-3.44 (1H, m), 3.71 (3H, s), 4.95 (1H, s), 6.83 (1H, d, J = 8.6 Hz), 7.12 (1H, d, J = 8.6 Hz), 7.40 ( 1H, d, J = 7.8 Hz), 7.80 (1H, d, J = 8.2 Hz).
(37e) 6- {3-[(10R) -2-Ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt 6-prepared in Example 37d {3-[(10R) -2-Ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid (353 mg, 0.632 mmol), ethanol (7.0 mL) and tert-butylamine (139 μL, 1.32 mmol) was used for the reaction and post-treatment according to Example 3c to obtain the title compound (389 mg, 97%).
(実施例38)
　6-{3-[(10S)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(38a) 6-{3-[(10S)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例37cで製造したベンジル　6-{3-[(10S)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(高極性化合物; 406 mg, 0.626 mmol)、パラジウム炭素(10%, 80 mg)、酢酸エチル(10 mL)及びメタノール(10 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(343 mg, 98%)を得た。 (Example 38)
6- {3-[(10S) -2-Ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(38a) 6- {3-[(10S) -2-Ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid benzyl 6- {3- [(10S) -2-ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3, 2-c] Pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (high polarity compound; 406 mg, 0.626 mmol), palladium on carbon (10%, 80 mg ), Ethyl acetate (10 mL) and methanol (10 mL) were used for the reaction and post-treatment according to Example 18 to obtain the title compound (343 mg, 98%).
(38b) 6-{3-[(10S)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例38aで製造した6-{3-[(10S)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(343 mg, 0.614 mmol)、エタノール(7.0 mL)及びtert-ブチルアミン(129 μL, 1.23 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(370 mg, 95%)を得た。 (38b) 6- {3-[(10S) -2-Ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt 6-prepared in Example 38a {3-[(10S) -2-Ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid (343 mg, 0.614 mmol), ethanol (7.0 mL) and tert-butylamine (129 μL, 1.23 mmol) was used for the reaction and post-treatment according to Example 3c to obtain the title compound (370 mg, 95%).
(実施例39)
　6-{3-[(5S)-8,8-ジメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3-プロピル-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
(39a) メチル　6-(3-ホルミル-4-メトキシ-2-メチルフェニル)-3-メチルピリジン-2-カルボキシレート
　実施例9aで製造した6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンズアルデヒド(10.0 g, 36.2 mmol)、メチル6-クロロ-3-メチル-ピリジン-2-カルボキシレート(7.39 g, 39.8 mmol)、2nd Generation X-Phos Precatalyst (285 mg, 0.362 mmol)、リン酸カリウム(11.5 g, 54.3 mmol)、THF (100 mL)及び水(100 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(8.86 g, 82%)を得た。 (Example 39)
6- {3-[(5S) -8,8-Dimethyl-4,6-dioxo-2- (propan-2-yl) -3-propyl-3,5,6,7,8,9-hexahydro- 4H-chromeno [2,3-d] pyrimidin-5-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid
(39a) Methyl 6- (3-formyl-4-methoxy-2-methylphenyl) -3-methylpyridine-2-carboxylate 6-methoxy-2-methyl-3- (4,4 prepared in Example 9a) , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde (10.0 g, 36.2 mmol), methyl 6-chloro-3-methyl-pyridine-2-carboxylate (7.39 g, 39.8 mmol) ), 2nd Generation X-Phos Precatalyst (285 mg, 0.362 mmol), potassium phosphate (11.5 g, 54.3 mmol), THF (100 mL) and water (100 mL), and the reaction according to Example 9d. The title compound (8.86 g, 82%) was obtained by the treatment.
1H-NMR(400MHz, CDCl3):δ ppm: 2.51 (3H, s), 2.62 (3H, s), 3.95 (3H, s), 3.97 (3H, s), 6.94 (1H, d, J = 8.6 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.58 (1H, d, J = 8.6 Hz), 7.67 (1H, d, J = 7.4 Hz), 10.69 (1H, s).
(39b) メチル　6-{3-[(4,4-ジメチル-2,6-ジオキソシクロヘキシリデン)メチル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例39aで製造したメチル　6-(3-ホルミル-4-メトキシ-2-メチルフェニル)-3-メチルピリジン-2-カルボキシレート(4.00 g, 13.4 mmol)、ジメドン(2.06 g, 14.7 mmol)、アセトニトリル(20 mL)及びL-プロリン(76.9 mg, 0.668 mmol)を用い、実施例32hに準じて反応及び後処理を行うことにより、標記化合物(4.71 g, 84%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 1.10 (6H, s), 2.20 (3H, s), 2.52 (2H, s), 2.57 (3H, s), 2.58 (2H, s), 3.73 (3H, s), 3.93 (3H, s), 6.76 (1H, d, J = 8.6 Hz), 7.34 (1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.61 (1H, d, J = 8.2 Hz), 7.88 (1H, s).
(39c) メチル　6-{3-[8,8-ジメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例39bで製造したメチル　6-{3-[(4,4-ジメチル-2,6-ジオキソシクロヘキシリデン)メチル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(2.00 g, 4.75 mmol)及び6-ヒドロキシ-2-(プロパン-2-イル)ピリミジン-4(3H)-オン(805 mg, 5.22 mmol)のDMF (6.7 mL)溶液に0℃で炭酸セシウム(3.87 g, 11.9 mmol)を加えた。反応溶液を0℃で1時間30分攪拌後、0℃でメタンスルホニルクロリド(444 μL, 5.69 mmol)を加え、反応溶液を室温で5時間攪拌した。反応溶液に10%クエン酸水溶液を加えて析出した結晶をろ取し、標記化合物(2.62 g, 99%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 2.51 (3H, s), 2.62 (3H, s), 3.95 (3H, s), 3.97 (3H, s), 6.94 (1H, d, J = 8.6 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.58 (1H, d, J = 8.6 Hz), 7.67 (1H, d, J = 7.4 Hz), 10.69 (1H, s).
(39b) Methyl 6- {3-[(4,4-dimethyl-2,6-dioxocyclohexylidene) methyl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate Methyl 6- (3-formyl-4-methoxy-2-methylphenyl) -3-methylpyridine-2-carboxylate (4.00 g, 13.4 mmol), dimedone (2.06 g, 14.7 mmol), acetonitrile prepared in Example 39a (20 mL) and L-proline (76.9 mg, 0.668 mmol) were used for the reaction and post-treatment according to Example 32h to obtain the title compound (4.71 g, 84%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.10 (6H, s), 2.20 (3H, s), 2.52 (2H, s), 2.57 (3H, s), 2.58 (2H, s), 3.73 (3H, s), 3.93 (3H, s), 6.76 (1H, d, J = 8.6 Hz), 7.34 (1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.61 (1H, d, J = 8.2 Hz), 7.88 (1H, s).
(39c) Methyl 6- {3- [8,8-dimethyl-4,6-dioxo-2- (propan-2-yl) -3,5,6,7,8,9-hexahydro-4H-chromeno [ 2,3-d] pyrimidin-5-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate Methyl 6- {3-[(4,4- Dimethyl-2,6-dioxocyclohexylidene) methyl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (2.00 g, 4.75 mmol) and 6-hydroxy-2- (propane Cesium carbonate (3.87 g, 11.9 mmol) was added to a solution of 2-yl) pyrimidin-4 (3H) -one (805 mg, 5.22 mmol) in DMF (6.7 mL) at 0 ° C. The reaction solution was stirred at 0 ° C. for 1 hour 30 minutes, methanesulfonyl chloride (444 μL, 5.69 mmol) was added at 0 ° C., and the reaction solution was stirred at room temperature for 5 hours. A 10% aqueous citric acid solution was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain the title compound (2.62 g, 99%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.98 (3H, s), 1.11 (3H, s), 1.19 (6H, d, J = 6.7 Hz), 2.16 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.49 (1H, d, J = 17.2 Hz), 2.58 (1H, d, J = 17.2 Hz), 2.60 (3H, s), 2.72-2.79 (1H, m), 2.89 (3H, s), 3.66 (3H, s), 3.94 (3H, s), 5.27 (1H, s), 6.69 (1H, d, J = 8.6 Hz), 7.22 (1H, d, J = 8.6 Hz), 7.37 (1H, d, J = 7.8 Hz), 7.59 (1H, t, J = 4.3 Hz), 8.03 (1H, s).
(39d) メチル　6-{3-[8,8-ジメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3-(プロパ-2-イン-1-イル)-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例39cで製造したメチル　6-{3-[8,8-ジメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(500 mg, 0.897 mmol)、プロパルギルブロミド(203 μL, 2.69 mmol)、炭酸セシウム(351 mg, 1.08 mmol)及びDMF (5.0 mL)を用い、実施例14bに準じて反応及び後処理を行うことにより、標記化合物(1.92 g, 60%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.98 (3H, s), 1.11 (3H, s), 1.19 (6H, d, J = 6.7 Hz), 2.16 (1H, d, J = 16.4 Hz ), 2.24 (1H, d, J = 16.4 Hz), 2.49 (1H, d, J = 17.2 Hz), 2.58 (1H, d, J = 17.2 Hz), 2.60 (3H, s), 2.72-2.79 (1H , m), 2.89 (3H, s), 3.66 (3H, s), 3.94 (3H, s), 5.27 (1H, s), 6.69 (1H, d, J = 8.6 Hz), 7.22 (1H, d, J = 8.6 Hz), 7.37 (1H, d, J = 7.8 Hz), 7.59 (1H, t, J = 4.3 Hz), 8.03 (1H, s).
(39d) Methyl 6- {3- [8,8-dimethyl-4,6-dioxo-2- (propan-2-yl) -3- (prop-2-yn-1-yl) -3,5, 6,7,8,9-Hexahydro-4H-chromeno [2,3-d] pyrimidin-5-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate in Example 39c Methyl 6- {3- [8,8-dimethyl-4,6-dioxo-2- (propan-2-yl) -3,5,6,7,8,9-hexahydro-4H-chromeno [2 , 3-d] pyrimidin-5-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (500 mg, 0.897 mmol), propargyl bromide (203 μL, 2.69 mmol), carbonic acid The title compound (1.92 g, 60%) was obtained by performing reaction and post-treatment according to Example 14b using cesium (351 mg, 1.08 mmol) and DMF (5.0 mL).
1H-NMR(400MHz, CDCl3):δ ppm: 0.98 (3H, s), 1.11 (3H, s), 1.32 (3H, d, J = 7.4 Hz), 1.41 (3H, d, J = 6.7 Hz), 2.16 (1H, d, J = 16.4 Hz), 2.23 (1H, d, J = 16.4 Hz), 2.51 (1H, d, J = 17.2 Hz), 2.61 (1H, d, J = 16.4 Hz), 2.61 (3H, s), 2.88 (3H, s), 3.24-3.33 (1H, m), 3.68 (3H, s), 3.96 (3H, s), 4.50 (1H, dd, J = 2.5, 17.4 Hz), 5.09 (1H, dd, J = 2.5, 17.4 Hz), 5.31 (1H, s), 5.33 (1H, s), 6.70 (1H, d, J = 8.6 Hz), 7.24-7.27 (1H, m), 7.46 (1H, d, J = 7.8 Hz), 7.61 (1H, d, J = 8.2 Hz).
(39e) メチル　6-{3-[8,8-ジメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3-プロピル-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例39dで製造したメチル　6-{3-[8,8-ジメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3-(プロパ-2-イン-1-イル)-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(235 mg, 0.395 mmol)、パラジウム炭素(10%, 47.0 mg)、酢酸エチル(2.4 mL)及びTHF (2.4 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(225 mg, 95%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.98 (3H, s), 1.11 (3H, s), 1.32 (3H, d, J = 7.4 Hz), 1.41 (3H, d, J = 6.7 Hz ), 2.16 (1H, d, J = 16.4 Hz), 2.23 (1H, d, J = 16.4 Hz), 2.51 (1H, d, J = 17.2 Hz), 2.61 (1H, d, J = 16.4 Hz), 2.61 (3H, s), 2.88 (3H, s), 3.24-3.33 (1H, m), 3.68 (3H, s), 3.96 (3H, s), 4.50 (1H, dd, J = 2.5, 17.4 Hz) , 5.09 (1H, dd, J = 2.5, 17.4 Hz), 5.31 (1H, s), 5.33 (1H, s), 6.70 (1H, d, J = 8.6 Hz), 7.24-7.27 (1H, m), 7.46 (1H, d, J = 7.8 Hz), 7.61 (1H, d, J = 8.2 Hz).
(39e) Methyl 6- {3- [8,8-dimethyl-4,6-dioxo-2- (propan-2-yl) -3-propyl-3,5,6,7,8,9-hexahydro- 4H-chromeno [2,3-d] pyrimidin-5-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate methyl 6- {3- [8 prepared in Example 39d , 8-Dimethyl-4,6-dioxo-2- (propan-2-yl) -3- (prop-2-yn-1-yl) -3,5,6,7,8,9-hexahydro-4H -Chromeno [2,3-d] pyrimidin-5-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (235 mg, 0.395 mmol), palladium on carbon (10%, 47.0 mg), ethyl acetate (2.4 mL), and THF (2.4 mL) were used, and the reaction and post-treatment were performed according to Example 18 to obtain the title compound (225 mg, 95%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.96 (3H, t, J = 7.3 Hz), 0.98 (3H, s), 1.11 (3H, s), 1.30 (3H, d, J = 7.0 Hz), 1.37 (3H, d, J = 7.8 Hz), 1.59-1.73 (2H, m), 2.16 (1H, d, J = 16.8 Hz), 2.23 (1H, d, J = 16.8 Hz), 2.52 (1H, d, J = 17.2 Hz), 2.58 (4H, d, J = 16.0 Hz), 2.61 (3H, s), 2.89 (3H, s), 3.03-3.10 (1H, m), 3.67 (3H, s), 3.70-3.76 (1H, m), 3.97 (3H, s), 4.02-4.11 (1H, m), 5.31 (1H, s), 6.70 (1H, d, J = 8.6 Hz), 7.26 (1H, d, J = 8.6 Hz), 7.47 (1H, d, J = 7.8 Hz), 7.60 (1H, d, J = 7.8 Hz).
(39f) メチル 6-{3-[(5S)-8,8-ジメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3-プロピル-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例39eで製造したメチル　6-{3-[8,8-ジメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3-プロピル-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(2225 mg)をChiral flash IA(2-プロパノール)により光学分割し、高極性化合物(98.6 mg)を得た。
(39g) 6-{3-[(5S)-8,8-ジメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3-プロピル-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例39fで製造したメチル6-{3-[(5S)-8,8-ジメチル-4,6-ジオキソ-2-(プロパン-2-イル)-3-プロピル-3,5,6,7,8,9-ヘキサヒドロ-4H-クロメノ[2,3-d]ピリミジン-5-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(高極性化合物; 86.5 mg, 0.144 mmol)、1 M水酸化ナトリウム水溶液(173 μL, 0.173 mmol)、THF (2.0 mL)及びメタノール(2.0 mL)を用い、実施例25gに準じて反応及び後処理を行うことにより、標記化合物(74.7 mg, 88%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.96 (3H, t, J = 7.3 Hz), 0.98 (3H, s), 1.11 (3H, s), 1.30 (3H, d, J = 7.0 Hz ), 1.37 (3H, d, J = 7.8 Hz), 1.59-1.73 (2H, m), 2.16 (1H, d, J = 16.8 Hz), 2.23 (1H, d, J = 16.8 Hz), 2.52 (1H , d, J = 17.2 Hz), 2.58 (4H, d, J = 16.0 Hz), 2.61 (3H, s), 2.89 (3H, s), 3.03-3.10 (1H, m), 3.67 (3H, s) , 3.70-3.76 (1H, m), 3.97 (3H, s), 4.02-4.11 (1H, m), 5.31 (1H, s), 6.70 (1H, d, J = 8.6 Hz), 7.26 (1H, d , J = 8.6 Hz), 7.47 (1H, d, J = 7.8 Hz), 7.60 (1H, d, J = 7.8 Hz).
(39f) Methyl 6- {3-[(5S) -8,8-dimethyl-4,6-dioxo-2- (propan-2-yl) -3-propyl-3,5,6,7,8, 9-Hexahydro-4H-chromeno [2,3-d] pyrimidin-5-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate Methyl 6- {prepared in Example 39e 3- [8,8-Dimethyl-4,6-dioxo-2- (propan-2-yl) -3-propyl-3,5,6,7,8,9-hexahydro-4H-chromeno [2,3 -d] pyrimidin-5-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (2225 mg) optically resolved with Chiral flash IA (2-propanol) (98.6 mg) was obtained.
(39g) 6- {3-[(5S) -8,8-Dimethyl-4,6-dioxo-2- (propan-2-yl) -3-propyl-3,5,6,7,8,9 -Hexahydro-4H-chromeno [2,3-d] pyrimidin-5-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid Methyl 6- {3 prepared in Example 39f -[(5S) -8,8-Dimethyl-4,6-dioxo-2- (propan-2-yl) -3-propyl-3,5,6,7,8,9-hexahydro-4H-chromeno [ 2,3-d] pyrimidin-5-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (high polarity compound; 86.5 mg, 0.144 mmol), 1 M aqueous sodium hydroxide solution (173 μL, 0.173 mmol), THF (2.0 mL) and methanol (2.0 mL) were used, and the reaction and post-treatment were performed according to Example 25g to obtain the title compound (74.7 mg, 88%).
(実施例40)
　6-{3-[(10S)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
(40a) 6-{3-[(10S)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例38aで製造した6-{3-[(10S)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(116 mg, 0.208 mmol)、カルボニルジイミダゾール(43.8 mg, 0.270 mmol)、DMF (2.0 mL)、メタンスルホンアミド(25.7 mg, 0.270 mmol)及びDBU (40 μL, 0.270 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(111 mg, 84%)を得た。 (Example 40)
6- {3-[(10S) -2-Ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt
(40a) 6- {3-[(10S) -2-Ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide prepared in Example 38a 6- {3-[(10S) -2-Ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid (116 mg, 0.208 mmol), carbonyldiimidazole (43.8 mg, 0.270 mmol), DMF (2.0 mL), methanesulfonamide (25.7 mg, 0.270 mmol) and DBU (40 μL, 0.270 mmol) were used for the reaction and workup according to Example 6a to give the title compound ( 111 mg, 84%).
1H-NMR(400MHz, CDCl3):δ ppm: 1.01 (3H, s), 1.13 (3H, t, J = 5.9 Hz), 1.13 (3H, s), 1.20 (3H, s), 1.45 (3H, s), 2.18 (1H, dd, J = 0.8, 16.4 Hz), 2.26 (1H, d, J = 16.0 Hz), 2.33 (1H, d, J = 18.2 Hz), 2.38 (1H, d, J = 19.6 Hz), 2.49 (1H, d, J = 17.6 Hz), 2.73 (1H, dd, J = 1.4, 17.0 Hz), 2.80 (3H, s), 2.90 (3H, s), 3.01-3.10 (1H, m), 3.42 (3H, s), 3.57-3.66 (1H, m), 3.79 (3H, s), 5.22 (1H, s), 6.77 (1H, d, J = 8.6 Hz), 7.23 (1H, d, J = 8.6 Hz), 7.61 (1H, d, J = 8.2 Hz), 7.68 (1H, d, J = 7.8 Hz).
(40b) 6-{3-[(10S)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド tert-ブチルアミン塩
　実施例40aで製造した6-{3-[(10S)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド(111 mg, 0.175 mmol)、エタノール(2.0 mL)及びtert-ブチルアミン(37 μL, 0.349 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(94.8 mg, 77%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.01 (3H, s), 1.13 (3H, t, J = 5.9 Hz), 1.13 (3H, s), 1.20 (3H, s), 1.45 (3H , s), 2.18 (1H, dd, J = 0.8, 16.4 Hz), 2.26 (1H, d, J = 16.0 Hz), 2.33 (1H, d, J = 18.2 Hz), 2.38 (1H, d, J = 19.6 Hz), 2.49 (1H, d, J = 17.6 Hz), 2.73 (1H, dd, J = 1.4, 17.0 Hz), 2.80 (3H, s), 2.90 (3H, s), 3.01-3.10 (1H, m), 3.42 (3H, s), 3.57-3.66 (1H, m), 3.79 (3H, s), 5.22 (1H, s), 6.77 (1H, d, J = 8.6 Hz), 7.23 (1H, d , J = 8.6 Hz), 7.61 (1H, d, J = 8.2 Hz), 7.68 (1H, d, J = 7.8 Hz).
(40b) 6- {3-[(10S) -2-Ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt Examples 6- {3-[(10S) -2-ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10 prepared in 40a -Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide (111 mg, 0.175 mmol), ethanol (2.0 mL) and tert-butylamine (37 μL, 0.349 mmol) were used for the reaction and post-treatment according to Example 3c to obtain the title compound (94.8 mg, 77%).
(実施例41)
　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(41a) 6-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]スピロ[2.5]オクタン-5,7-ジオン
　実施例9aで製造した6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンズアルデヒド(5.00 g, 18.1 mmol)のアセトニトリル(25 mL)溶液に60℃でスピロ[2.5]オクタン-5,7-ジオン(2.77 g, 20.1 mmol)及びL-プロリン(113 mg, 0.542 mmol)を加え、反応溶液を60℃で9時間攪拌した。放冷後、反応溶液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 7:3)で精製し、標記化合物(1.28 g, 18%)を得た。 (Example 41)
6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3, 4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2 -Carboxylic acid tert-butylamine salt
(41a) 6- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] spiro [2.5] octane-5, 7-dione 6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde prepared in Example 9a (5.00 g, 18.1 mmol Spiro [2.5] octane-5,7-dione (2.77 g, 20.1 mmol) and L-proline (113 mg, 0.542 mmol) at 60 ° C. in a solution of acetonitrile (25 mL) at 60 ° C. Stir for 9 hours. After allowing to cool, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 7: 3) to obtain the title compound (1.28 g, 18%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.55 (4H, d, J = 6.1 Hz), 1.29 (12H, s), 2.46 (3H, s), 2.51 (2H, s), 2.57 (2H, s), 3.75 (3H, s), 6.70 (1H, d, J = 8.5 Hz), 7.78 (1H, d, J = 7.9 Hz), 7.98 (1H, s).
(41b) (3R,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,6,10,10a-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン
　実施例41aで製造した6-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]スピロ[2.5]オクタン-5,7-ジオン(365 mg, 0.921 mmol)及びtert-ブチル　(6S)-2,4-ジオキソ-6-(プロパン-2-イル)ピペリジン-1-カルボキシレート(247 mg, 0.967 mmol)のアセトニトリル(3.7 mL)溶液に0℃で炭酸セシウム(360 mg, 1.11 mmol)を加えた。反応溶液を0℃で3時間攪拌後、水を加えて酢酸エチルで2回抽出、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮し、粗製の付加物を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.55 (4H, d, J = 6.1 Hz), 1.29 (12H, s), 2.46 (3H, s), 2.51 (2H, s), 2.57 (2H , s), 3.75 (3H, s), 6.70 (1H, d, J = 8.5 Hz), 7.78 (1H, d, J = 7.9 Hz), 7.98 (1H, s).
(41b) (3R, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3- (propan-2-yl) -3,6,10,10a-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -1,9 (2H, 8H)- Dione 6- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] spiro [2.5] prepared in Example 41a Octane-5,7-dione (365 mg, 0.921 mmol) and tert-butyl (6S) -2,4-dioxo-6- (propan-2-yl) piperidine-1-carboxylate (247 mg, 0.967 mmol) Cesium carbonate (360 mg, 1.11 mmol) was added to an acetonitrile (3.7 mL) solution at 0 ° C. The reaction solution was stirred at 0 ° C. for 3 hours, water was added and the mixture was extracted twice with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude adduct.
　粗製の付加物のジクロロメタン(6.0 mL)溶液に0℃でトリフルオロ酢酸(0.600 mL, 7.84 mmol)を加え、反応溶液を0℃で3時間攪拌した。反応溶液に0℃で飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで2回抽出後、有機層を無水硫酸ナトリウムで乾燥、減圧濃縮し、粗製の脱Boc体を得た。 To a solution of the crude adduct in dichloromethane (6.0 mL) was added trifluoroacetic acid (0.600 mL, 7.84 mL) at 0 ° C., and the reaction solution was stirred at 0 ° C. for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution at 0 ° C., and the mixture was extracted twice with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude de-Boc form.
　ジ-tert-ブチル　アゾジカルボキシレート(180 mg, 0.782 mmol)及びトリフェニルホスフィン(206 mg, 0.782 mmol)のトルエン溶液(6.6 mL)溶液を0℃で10分攪拌後、粗製の脱Boc体のトルエン(2.0 mL)溶液0℃で加え、反応溶液を0℃で1時間攪拌した。反応溶液を濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 1:1)で精製し、標記化合物(182 mg, 57%, 3 steps)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.26-0.46 (4H, m), 0.85 (3H, d, J = 7.0 Hz), 0.86 (3H, d, J = 7.0 Hz), 1.27 (12H, s), 1.70-1.80 (1H, m), 1.73 (1H, dd, J = 2.0, 17.2 Hz), 2.02 (1H, d, J = 18.4 Hz), 2.39 (1H, d, J = 17.2 Hz), 2.67 (1H, dd, J = 2.3, 16.4 Hz), 2.83 (3H, s), 3.71 (3H, s), 3.82-3.86 (1H, m), 3.90-3.94 (1H, m), 4.41 (1H, dd, J = 1.4, 8.8 Hz), 5.40-5.42 (1H, m), 5.73 (1H, s), 6.60 (1H, d, J = 8.6 Hz), 7.61 (1H, d, J = 8.2 Hz).
(41c) (3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,4a,6,10,10a-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン
　実施例41bで製造した(3R,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,6,10,10a-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン(182 mg, 0.341 mmol)、パラジウム炭素(10%, 91.0 mg)及びTHF (7.3 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(183 mg, 99%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.22-0.41 (4H, m), 0.87-0.91 (6H, m), 1.27 (12H, s), 1.60-1.78 (4H, m), 1.88 (1H, d, J = 18.0 Hz), 2.44 (1H, d, J = 16.8 Hz), 2.67 (1H, dd, J = 1.8, 17.8 Hz), 2.93 (3H, s), 3.20-3.31 (2H, m), 3.67 (3H, s), 3.86-3.93 (1H, m), 4.40 (1H, dd, J = 9.8, 2.0 Hz), 5.37 (1H, s), 6.56 (1H, d, J = 8.2 Hz), 7.57 (1H, d, J = 8.2 Hz).
(41d) (3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2-メチル-3-(プロパン-2-イル)-3,4,4a,6,10,10a-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン
　実施例41cで製造した(3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,4a,6,10,10a-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン(183 mg, 0.341 mmol)、ヨウ化メチル(170 μL, 2.73 mmol)、DMF (1.8 mL)及び水素化ナトリウム(55%, 22.3 mg, 0.512 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(153 mg, 82%)を得た。 After stirring a solution of di-tert-butyl azodicarboxylate (180 mg, 0.782 mmol) and triphenylphosphine (206 mg, 0.782 mmol) in toluene (6.6 mL) at 0 ° C. for 10 minutes, the crude de-Boc form was removed. A toluene (2.0 mL) solution was added at 0 ° C, and the reaction solution was stirred at 0 ° C for 1 hour. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 1: 1) to obtain the title compound (182 mg, 57%, 3 steps).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.26-0.46 (4H, m), 0.85 (3H, d, J = 7.0 Hz), 0.86 (3H, d, J = 7.0 Hz), 1.27 (12H , s), 1.70-1.80 (1H, m), 1.73 (1H, dd, J = 2.0, 17.2 Hz), 2.02 (1H, d, J = 18.4 Hz), 2.39 (1H, d, J = 17.2 Hz) , 2.67 (1H, dd, J = 2.3, 16.4 Hz), 2.83 (3H, s), 3.71 (3H, s), 3.82-3.86 (1H, m), 3.90-3.94 (1H, m), 4.41 (1H , dd, J = 1.4, 8.8 Hz), 5.40-5.42 (1H, m), 5.73 (1H, s), 6.60 (1H, d, J = 8.6 Hz), 7.61 (1H, d, J = 8.2 Hz) .
(41c) (3S, 4aS, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenyl] -3- (propan-2-yl) -3,4,4a, 6,10,10a-hexahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -1, 9 (2H, 8H) -dione (3R, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3) prepared in Example 41b , 2-Dioxaborolan-2-yl) phenyl] -3- (propan-2-yl) -3,6,10,10a-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane ] -1,9 (2H, 8H) -dione (182 mg, 0.341 mmol), palladium on carbon (10%, 91.0 mg) and THF (7.3 mL) are used for reaction and workup according to Example 18. This gave the title compound (183 mg, 99%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.22-0.41 (4H, m), 0.87-0.91 (6H, m), 1.27 (12H, s), 1.60-1.78 (4H, m), 1.88 ( 1H, d, J = 18.0 Hz), 2.44 (1H, d, J = 16.8 Hz), 2.67 (1H, dd, J = 1.8, 17.8 Hz), 2.93 (3H, s), 3.20-3.31 (2H, m ), 3.67 (3H, s), 3.86-3.93 (1H, m), 4.40 (1H, dd, J = 9.8, 2.0 Hz), 5.37 (1H, s), 6.56 (1H, d, J = 8.2 Hz) , 7.57 (1H, d, J = 8.2 Hz).
(41d) (3S, 4aS, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenyl] -2-methyl-3- (propan-2-yl) -3,4,4a, 6,10,10a-hexahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane ] -1,9 (2H, 8H) -dione (3S, 4aS, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-) prepared in Example 41c Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3- (propan-2-yl) -3,4,4a, 6,10,10a-hexahydrospiro [chromeno [3,2- c] Pyridine-7,1'-cyclopropane] -1,9 (2H, 8H) -dione (183 mg, 0.341 mmol), methyl iodide (170 μL, 2.73 mmol), DMF (1.8 mL) and hydrogenation The title compound (153 mg, 82%) was obtained by performing the reaction and post-treatment according to Example 2a using sodium (55%, 22.3 mg, 0.512 mmol).
1H-NMR(400MHz, CDCl3):δ ppm: 0.20-0.41 (4H, m), 0.70 (3H, d, J = 6.6 Hz), 0.91 (3H, d, J = 6.6 Hz), 1.26 (12H, s), 1.63 (1H, dd, J = 1.4, 17.0 Hz), 1.71-1.80 (1H, m), 1.87 (1H, d, J = 17.6 Hz), 2.17-2.35 (2H, m), 2.44 (1H, d, J = 16.8 Hz), 2.67 (1H, d, J = 17.2 Hz), 2.78 (3H, s), 3.04 (3H, s), 3.15 (1H, dd, J = 9.8, 10.9 Hz), 3.29-3.34 (1H, m), 3.66 (3H, s), 3.81 (1H, td, J = 4.2, 11.6 Hz), 4.47 (1H, dd, J = 2.0, 9.4 Hz), 6.56 (1H, d, J = 8.2 Hz), 7.57 (1H, d, J = 8.2 Hz).
(41e) tert-ブチル　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例41dで製造した(3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2-メチル-3-(プロパン-2-イル)-3,4,4a,6,10,10a-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン(151 mg, 0.275 mmol)、tert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(75.1 mg, 0.330 mmol)、2nd Generation X-Phos Precatalyst (43.2 mg, 0.0550 mmol)、リン酸カリウム(93.3 mg, 0.440 mmol)、THF (1.5 mL)及び水(3.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(148 mg, 88%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.20-0.41 (4H, m), 0.70 (3H, d, J = 6.6 Hz), 0.91 (3H, d, J = 6.6 Hz), 1.26 (12H , s), 1.63 (1H, dd, J = 1.4, 17.0 Hz), 1.71-1.80 (1H, m), 1.87 (1H, d, J = 17.6 Hz), 2.17-2.35 (2H, m), 2.44 ( 1H, d, J = 16.8 Hz), 2.67 (1H, d, J = 17.2 Hz), 2.78 (3H, s), 3.04 (3H, s), 3.15 (1H, dd, J = 9.8, 10.9 Hz), 3.29-3.34 (1H, m), 3.66 (3H, s), 3.81 (1H, td, J = 4.2, 11.6 Hz), 4.47 (1H, dd, J = 2.0, 9.4 Hz), 6.56 (1H, d, J = 8.2 Hz), 7.57 (1H, d, J = 8.2 Hz).
(41e) tert-butyl 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl)- 1,2,3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] phenyl}- 3-Methylpyridine-2-carboxylate (3S, 4aS, 10S, 10aR) -10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-) prepared in Example 41d 1,3,2-dioxaborolan-2-yl) phenyl] -2-methyl-3- (propan-2-yl) -3,4,4a, 6,10,10a-hexahydrospiro [chromeno [3,2 -c] pyridine-7,1'-cyclopropane] -1,9 (2H, 8H) -dione (151 mg, 0.275 mmol), tert-butyl 6-chloro-3-methylpyridine-2-carboxylate (75.1 mg, 0.330 mmol), 2nd Generation X-Phos Precatalyst (43.2 mg, 0.0550 mmol), potassium phosphate (93.3 mg, 0.440 mmol), THF (1.5 mL) and water (3.0 mL), according to Example 9d Reaction and post-treatment to give the title compound (148 mg, 88% )
1H-NMR(400MHz, CDCl3):δ ppm: 0.29-0.46 (4H, m), 0.76 (3H, d, J = 6.7 Hz), 0.95 (3H, d, J = 7.3 Hz), 1.63 (9H, s), 1.68 (1H, d, J = 16.5 Hz), 1.77-1.86 (1H, m), 1.93 (1H, d, J = 17.7 Hz), 2.20-2.40 (2H, m), 2.49 (1H, d, J = 17.7 Hz), 2.49 (3H, s), 2.71 (1H, d, J = 17.7 Hz), 2.80 (3H, s), 2.83 (3H, s), 3.24 (1H, t, J = 10.4 Hz), 3.33-3.38 (1H, m), 3.74 (3H, s), 3.84 (1H, td, J = 11.6, 4.3 Hz), 4.49 (1H, dd, J = 1.2, 9.2 Hz), 6.70 (1H, d, J = 8.5 Hz), 7.25 (1H, d, J = 7.3 Hz), 7.42 (1H, d, J = 7.9 Hz), 7.51 (1H, d, J = 7.9 Hz).
(41f) 6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸 tert-ブチルアミン塩
　実施例41eで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(148 mg, 0.241 mmol)のジクロロメタン(1.5 mL)溶液に室温でトリフルオロ酢酸(0.74 mL)を加え、反応溶液を室温で48時間攪拌した。反応溶液を濃縮し、粗製のカルボン酸を得た。粗製のカルボン酸の酢酸エチル(2.0 mL)溶液にtert-ブチルアミン(51 μL, 0.481 mmol)を加え、室温で30分攪拌した。反応溶液を濃縮後、残渣をジイソプロピルエーテルより結晶化し、標記化合物(138 mg, 91%, 2 steps)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.29-0.46 (4H, m), 0.76 (3H, d, J = 6.7 Hz), 0.95 (3H, d, J = 7.3 Hz), 1.63 (9H , s), 1.68 (1H, d, J = 16.5 Hz), 1.77-1.86 (1H, m), 1.93 (1H, d, J = 17.7 Hz), 2.20-2.40 (2H, m), 2.49 (1H, d, J = 17.7 Hz), 2.49 (3H, s), 2.71 (1H, d, J = 17.7 Hz), 2.80 (3H, s), 2.83 (3H, s), 3.24 (1H, t, J = 10.4 Hz), 3.33-3.38 (1H, m), 3.74 (3H, s), 3.84 (1H, td, J = 11.6, 4.3 Hz), 4.49 (1H, dd, J = 1.2, 9.2 Hz), 6.70 (1H , d, J = 8.5 Hz), 7.25 (1H, d, J = 7.3 Hz), 7.42 (1H, d, J = 7.9 Hz), 7.51 (1H, d, J = 7.9 Hz).
(41f) 6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2 , 3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] phenyl} -3-methyl Pyridine-2-carboxylic acid tert-butylamine salt tert-butyl 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9 prepared in Example 41e -Dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6,8,9,10,10a-decahydrospiro [chromeno [3,2-c] pyridine-7,1 '-Cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate (148 mg, 0.241 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.74 mL) at room temperature and reacted. The solution was stirred at room temperature for 48 hours. The reaction solution was concentrated to obtain a crude carboxylic acid. To a solution of crude carboxylic acid in ethyl acetate (2.0 mL) was added tert-butylamine (51 μL, 0.481 mmol), and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated, the residue was crystallized from diisopropyl ether to obtain the title compound (138 mg, 91%, 2 steps).
(実施例42)
　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(42a) 7-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]スピロ[3.5]ノナン-6,8-ジオン
　実施例9aで製造した6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンズアルデヒド(2.00 g, 7.24 mmol)、アセトニトリル(30 mL)、スピロ[3.5]ノナン-6,8-ジオン(1.21 g, 7.97 mmol)及びL-プロリン(83.4 mg, 0.724 mmol)を用い、実施例41aに準じて反応及び後処理を行うことにより、標記化合物(1.78 g, 60%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 1.28 (12H, s), 1.88-1.98 (6H, m), 2.39 (3H, s), 2.73 (2H, s), 2.79 (2H, s), 3.71 (3H, s), 6.66 (1H, d, J = 8.6 Hz), 7.74 (1H, d, J = 8.2 Hz), 7.87 (1H, s).
(42b) (6S)-3-{(S)-(6,8-ジオキソスピロ[3.5]ノナ-7-イル)[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]メチル}-6-(プロパン-2-イル)ピペリジン-2,4-ジオン
　実施例42aで製造した7-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]スピロ[3.5]ノナン-6,8-ジオン(750 mg, 1.83 mmol)及びtert-ブチル　(6S)-2,4-ジオキソ-6-(プロパン-2-イル)ピペリジン-1-カルボキシレート(513 mg, 2.01 mmol)のアセトニトリル(7.5 mL)溶液に0℃で炭酸セシウム(715 mg, 2.19 mmol)を加えた。反応溶液を0℃で3時間攪拌後、水を加えて酢酸エチルで2回抽出、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮し、粗製の付加物を得た。 (Example 42)
6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3, 4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2- Carboxylic acid tert-butylamine salt
(42a) 7- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] spiro [3.5] nonane-6, 8-Dione 6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde (2.00 g, 7.24 mmol) prepared in Example 9a ), Acetonitrile (30 mL), spiro [3.5] nonane-6,8-dione (1.21 g, 7.97 mmol) and L-proline (83.4 mg, 0.724 mmol) according to Example 41a and post-treatment To give the title compound (1.78 g, 60%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.28 (12H, s), 1.88-1.98 (6H, m), 2.39 (3H, s), 2.73 (2H, s), 2.79 (2H, s) , 3.71 (3H, s), 6.66 (1H, d, J = 8.6 Hz), 7.74 (1H, d, J = 8.2 Hz), 7.87 (1H, s).
(42b) (6S) -3-{(S)-(6,8-Dioxospiro [3.5] non-7-yl) [6-methoxy-2-methyl-3- (4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl) phenyl] methyl} -6- (propan-2-yl) piperidine-2,4-dione 7- [6-methoxy-2-prepared in Example 42a Methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] spiro [3.5] nonane-6,8-dione (750 mg, 1.83 mmol) and tert -Butyl (6S) -2,4-dioxo-6- (propan-2-yl) piperidine-1-carboxylate (513 mg, 2.01 mmol) in acetonitrile (7.5 mL) at 0 ° C with cesium carbonate (715 mg , 2.19 mmol). The reaction solution was stirred at 0 ° C. for 3 hours, water was added and the mixture was extracted twice with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude adduct.
　粗製の付加物のジクロロメタン(12 mL)溶液に0℃でトリフルオロ酢酸(1.2 mL, 15.9 mmol)を加え、反応溶液を0℃で3時間攪拌した。反応溶液に0℃で飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで2回抽出後、有機層を減圧濃縮した、濃縮残渣をヘキサン/酢酸エチル(1:1)より結晶化し、標記化合物(807 mg, 78%, 2 steps)をコンホマーの混合物として得た。
(42c) (3R,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,6,10,10a-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン
　ジ-tert-ブチル　アゾジカルボキシレート(457 mg, 1.99 mmol)及びトリフェニルホスフィン(521 mg, 1.99 mmol)のトルエン溶液(8.0 mL)溶液を0℃で10分攪拌後、実施例42bで製造した(6S)-3-{(S)-(6,8-ジオキソスピロ[3.5]ノナ-7-イル)[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]メチル}-6-(プロパン-2-イル)ピペリジン-2,4-ジオン(802 mg, 1.42 mmol)のトルエン(2.0 mL)溶液0℃で加え、反応溶液を0℃で15分間攪拌した。反応溶液を濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 1:1)で精製し、標記化合物(704 mg, 91%)を得た。 To a dichloromethane (12 mL) solution of the crude adduct was added trifluoroacetic acid (1.2 mL, 15.9 mmol) at 0 ° C., and the reaction solution was stirred at 0 ° C. for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution at 0 ° C., and the mixture was extracted twice with dichloromethane.The organic layer was concentrated under reduced pressure, and the concentrated residue was crystallized from hexane / ethyl acetate (1: 1) to give the title compound (807 mg, 78%, 2 steps) was obtained as a mixture of conformers.
(42c) (3R, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3- (propan-2-yl) -3,6,10,10a-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H) -dione Prepared in Example 42b after stirring a solution of di-tert-butyl azodicarboxylate (457 mg, 1.99 mmol) and triphenylphosphine (521 mg, 1.99 mmol) in toluene (8.0 mL) at 0 ° C. for 10 min. (6S) -3-{(S)-(6,8-Dioxospiro [3.5] non-7-yl) [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1 , 3,2-Dioxaborolan-2-yl) phenyl] methyl} -6- (propan-2-yl) piperidine-2,4-dione (802 mg, 1.42 mmol) in toluene (2.0 mL) at 0 ° C The reaction solution was stirred at 0 ° C. for 15 minutes. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 1: 1) to obtain the title compound (704 mg, 91%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.86 (3H, d, J = 6.6 Hz), 0.86 (3H, d, J = 6.6 Hz), 1.27 (12H, s), 1.73-1.85 (7H, m), 2.18 (1H, d, J = 16.4 Hz), 2.38 (1H, dd, J = 1.6, 16.4 Hz), 2.48 (1H, dd, J = 2.5, 17.4 Hz), 2.55-2.66 (1H, m), 2.83 (3H, s), 3.67 (3H, s), 3.81-3.84 (1H, m), 3.89-3.93 (1H, m), 4.37 (1H, d, J = 8.6 Hz), 5.41-5.43 (1H, m), 5.86 (1H, brs), 6.55 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 8.6 Hz).
(42d) (3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,4a,6,10,10a-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン
　実施例42cで製造した(3R,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,6,10,10a-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン(704 mg, 1.29 mmol)、パラジウム炭素(10%, 404 mg)及びTHF (33 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(694 mg, 98%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.89 (6H, t, J = 6.3 Hz), 1.27 (12H, s), 1.62-1.84 (9H, m), 2.17 (1H, d, J = 15.6 Hz), 2.30-2.59 (3H, m), 2.93 (3H, s), 3.20-3.33 (2H, m), 3.62 (3H, s), 3.86 (1H, dt, J = 3.5, 10.6 Hz), 4.36 (1H, d, J = 10.2 Hz), 5.33 (1H, s), 6.51 (1H, d, J = 8.2 Hz), 7.56 (1H, d, J = 8.2 Hz).
(42e) (3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2-メチル-3-(プロパン-2-イル)-3,4,4a,6,10,10a-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン
　実施例42dで製造した(3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,4a,6,10,10a-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン(694 mg, 1.26 mmol)、ヨウ化メチル(632 μL, 10.1 mmol)、DMF (7.0 mL)及び水素化ナトリウム(55%, 83.0 mg, 1.90 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(553 mg, 78%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.86 (3H, d, J = 6.6 Hz), 0.86 (3H, d, J = 6.6 Hz), 1.27 (12H, s), 1.73-1.85 (7H , m), 2.18 (1H, d, J = 16.4 Hz), 2.38 (1H, dd, J = 1.6, 16.4 Hz), 2.48 (1H, dd, J = 2.5, 17.4 Hz), 2.55-2.66 (1H, m), 2.83 (3H, s), 3.67 (3H, s), 3.81-3.84 (1H, m), 3.89-3.93 (1H, m), 4.37 (1H, d, J = 8.6 Hz), 5.41-5.43 (1H, m), 5.86 (1H, brs), 6.55 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 8.6 Hz).
(42d) (3S, 4aS, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenyl] -3- (propan-2-yl) -3,4,4a, 6,10,10a-hexahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H) -dione (3R, 10S, 10aR) -10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3, prepared in Example 42c 2-Dioxaborolan-2-yl) phenyl] -3- (propan-2-yl) -3,6,10,10a-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane]- By reacting and working up according to Example 18 using 1,9 (2H, 8H) -dione (704 mg, 1.29 mmol), palladium on carbon (10%, 404 mg) and THF (33 mL) The title compound (694 mg, 98%) was obtained.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.89 (6H, t, J = 6.3 Hz), 1.27 (12H, s), 1.62-1.84 (9H, m), 2.17 (1H, d, J = 15.6 Hz), 2.30-2.59 (3H, m), 2.93 (3H, s), 3.20-3.33 (2H, m), 3.62 (3H, s), 3.86 (1H, dt, J = 3.5, 10.6 Hz), 4.36 (1H, d, J = 10.2 Hz), 5.33 (1H, s), 6.51 (1H, d, J = 8.2 Hz), 7.56 (1H, d, J = 8.2 Hz).
(42e) (3S, 4aS, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenyl] -2-methyl-3- (propan-2-yl) -3,4,4a, 6,10,10a-hexahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H) -dione (3S, 4aS, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetra) prepared in Example 42d Methyl-1,3,2-dioxaborolan-2-yl) phenyl] -3- (propan-2-yl) -3,4,4a, 6,10,10a-hexahydrospiro [chromeno [3,2-c ] Pyridine-7,1'-cyclobutane] -1,9 (2H, 8H) -dione (694 mg, 1.26 mmol), methyl iodide (632 μL, 10.1 mmol), DMF (7.0 mL) and sodium hydride ( The title compound (553 mg, 78%) was obtained by performing the reaction and post-treatment according to Example 2a using 55%, 83.0 mg, 1.90 mmol).
1H-NMR(400MHz, CDCl3):δ ppm: 0.70 (3H, d, J = 6.1 Hz), 0.91 (3H, d, J = 7.0 Hz), 1.26 (12H, s), 1.71-1.83 (7H, m), 2.16-2.22 (2H, m), 2.30-2.43 (3H, m), 2.50 (1H, d, J = 17.6 Hz), 2.77 (3H, s), 3.03 (3H, s), 3.13 (1H, dd, J = 8.6, 10.9 Hz), 3.28-3.34 (1H, m), 3.63 (3H, s), 3.77 (1H, td, J = 4.3, 11.5 Hz), 4.43 (1H, dd, J = 2.3, 9.0 Hz), 6.50 (1H, d, J = 8.2 Hz), 7.55 (1H, d, J = 8.2 Hz).
(42f) tert-ブチル　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例42eで製造した(3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2-メチル-3-(プロパン-2-イル)-3,4,4a,6,10,10a-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン(553 mg, 0.981 mmol)、tert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(268 mg, 1.18 mmol)、2nd Generation X-Phos Precatalyst (154 mg, 0.196 mmol)、リン酸カリウム(333 mg, 1.57 mmol)、THF (5.5 mL)及び水(11 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(591 mg, 96%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.70 (3H, d, J = 6.1 Hz), 0.91 (3H, d, J = 7.0 Hz), 1.26 (12H, s), 1.71-1.83 (7H , m), 2.16-2.22 (2H, m), 2.30-2.43 (3H, m), 2.50 (1H, d, J = 17.6 Hz), 2.77 (3H, s), 3.03 (3H, s), 3.13 ( 1H, dd, J = 8.6, 10.9 Hz), 3.28-3.34 (1H, m), 3.63 (3H, s), 3.77 (1H, td, J = 4.3, 11.5 Hz), 4.43 (1H, dd, J = 2.3, 9.0 Hz), 6.50 (1H, d, J = 8.2 Hz), 7.55 (1H, d, J = 8.2 Hz).
(42f) tert-butyl 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl)- 1,2,3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} -3 -Methylpyridine-2-carboxylate (3S, 4aS, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1) prepared in Example 42e , 3,2-Dioxaborolan-2-yl) phenyl] -2-methyl-3- (propan-2-yl) -3,4,4a, 6,10,10a-hexahydrospiro [chromeno [3,2- c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H) -dione (553 mg, 0.981 mmol), tert-butyl 6-chloro-3-methylpyridine-2-carboxylate (268 mg, 1.18 mmol), 2nd Generation X-Phos Precatalyst (154 mg, 0.196 mmol), potassium phosphate (333 mg, 1.57 mmol), THF (5.5 mL) and water (11 mL) were used according to Example 9d. And the post-treatment was performed to obtain the title compound (591 mg, 96%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.72 (3H, d, J = 7.0 Hz), 0.92 (3H, d, J = 6.6 Hz), 1.21 (9H, s), 1.73-1.85 (7H, m), 2.19 (1H, d, J = 16.8 Hz), 2.32-2.44 (4H, m), 2.45 (3H, s), 2.53 (1H, d, J = 16.8 Hz), 2.76 (3H, s), 2.78 (3H, s), 3.18 (1H, dd, J = 9.0, 10.6 Hz), 3.29-3.35 (1H, m), 3.67 (3H, s), 3.77 (1H, dt, J = 3.9, 10.9 Hz), 4.42 (1H, d, J = 9.0 Hz), 6.61 (1H, d, J = 8.6 Hz), 7.21 (1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.47 (1H, d, J = 7.8 Hz).
(42g) 6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例42fで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(591 mg, 0.939 mmol)、ジクロロメタン(5.9 mL)及びトリフルオロ酢酸(3.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(309 mg, 58%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.72 (3H, d, J = 7.0 Hz), 0.92 (3H, d, J = 6.6 Hz), 1.21 (9H, s), 1.73-1.85 (7H , m), 2.19 (1H, d, J = 16.8 Hz), 2.32-2.44 (4H, m), 2.45 (3H, s), 2.53 (1H, d, J = 16.8 Hz), 2.76 (3H, s) , 2.78 (3H, s), 3.18 (1H, dd, J = 9.0, 10.6 Hz), 3.29-3.35 (1H, m), 3.67 (3H, s), 3.77 (1H, dt, J = 3.9, 10.9 Hz ), 4.42 (1H, d, J = 9.0 Hz), 6.61 (1H, d, J = 8.6 Hz), 7.21 (1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.47 (1H, d, J = 7.8 Hz).
(42g) 6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2 , 3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine -2-carboxylic acid tert-butyl 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- prepared in Example 42f (Propan-2-yl) -1,2,3,4,4a, 6,8,9,10,10a-decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane]- 10-yl] phenyl} -3-methylpyridine-2-carboxylate (591 mg, 0.939 mmol), dichloromethane (5.9 mL) and trifluoroacetic acid (3.0 mL), reaction and workup according to Example 1d To give the title compound (309 mg, 58%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.80 (3H, d, J = 6.7 Hz), 1.00 (3H, d, J = 7.0 Hz), 1.66-1.94 (7H, m), 2.26-2.64 (6H, m), 2.82 (3H, s), 2.84 (3H, s), 2.86 (3H, s), 3.29 (1H, t, J = 10.2 Hz), 3.38-3.43 (1H, m), 3.76 (3H, s), 3.89 (1H, td, J = 4.2, 11.5 Hz), 4.45 (1H, dd, J = 2.3, 9.8 Hz), 6.72 (1H, d, J = 8.6 Hz), 7.20 (1H, d, J = 8.6 Hz), 7.66 (1H, d, J = 7.8 Hz), 7.72 (1H, d, J = 7.4 Hz).
MS(ESI/APCI)m/z: 572[M+H]+.
(42h) 6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例42gで製造した6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(300 mg, 0.524 mmol)、エタノール(6.0 mL)及びtert-ブチルアミン(110 μL, 1.05 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(298 mg, 88%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.80 (3H, d, J = 6.7 Hz), 1.00 (3H, d, J = 7.0 Hz), 1.66-1.94 (7H, m), 2.26-2.64 (6H, m), 2.82 (3H, s), 2.84 (3H, s), 2.86 (3H, s), 3.29 (1H, t, J = 10.2 Hz), 3.38-3.43 (1H, m), 3.76 ( 3H, s), 3.89 (1H, td, J = 4.2, 11.5 Hz), 4.45 (1H, dd, J = 2.3, 9.8 Hz), 6.72 (1H, d, J = 8.6 Hz), 7.20 (1H, d , J = 8.6 Hz), 7.66 (1H, d, J = 7.8 Hz), 7.72 (1H, d, J = 7.4 Hz).
MS (ESI / APCI) m / z: 572 [M + H] +.
(42h) 6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2 , 3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine -2-carboxylic acid tert-butylamine salt 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3 prepared in Example 42g -(Propan-2-yl) -1,2,3,4,4a, 6,8,9,10,10a-decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid (300 mg, 0.524 mmol), ethanol (6.0 mL) and tert-butylamine (110 μL, 1.05 mmol) according to Example 3c The title compound (298 mg, 88%) was obtained by reaction and workup.
(実施例43)
　6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
(43a) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例27eで製造した6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(100 mg, 0.174 mmol)、カルボニルジイミダゾール(56.4 mg, 0.348 mmol)、DMF (1.0 mL)、メタンスルホンアミド(33.1 mg, 0.348 mmol)及びDBU (52 μL, 0.348 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(43.2 mg, 38%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.80 (3H, d, J = 6.6 Hz), 0.91-0.94 (6H, m), 0.97 (3H, s), 1.02 (3H, t, J = 6.6 Hz), 1.77-1.86 (1H, m), 2.01 (1H, d, J = 16.4 Hz), 2.09-2.40 (5H, m), 2.73 (3H, s), 2.79 (3H, s), 2.99-3.06 (1H, m), 3.22 (1H, dd, J = 9.4, 11.3 Hz), 3.34 (3H, s), 3.37-3.42 (1H, m), 3.59-3.79 (2H, m), 3.59 (3H, s), 4.47 (1H, dd, J = 1.2, 9.0 Hz), 6.69 (1H, d, J = 8.6 Hz), 7.17 (1H, d, J = 8.6 Hz), 7.60 (1H, d, J = 7.8 Hz), 7.60 (1H, d, J = 8.2 Hz).
(43b) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド tert-ブチルアミン塩
　実施例43aで製造した6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド(41.5 mg, 0.0637 mmol)、エタノール(0.83 mL)及びtert-ブチルアミン(13 μL, 0.127 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(46.2 mg, 77%)を得た。 (Example 43)
6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl Pyridine-2-carboxamide tert-butylamine salt
(43a) 6- {3-[(3S, 4aS, 10S, 10aR) -2-Ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4 , 4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (Methylsulfonyl) pyridine-2-carboxamide 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (prepared in Example 27e Propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy- 2-Methylphenyl} -3-methylpyridine-2-carboxylic acid (100 mg, 0.174 mmol), carbonyldiimidazole (56.4 mg, 0.348 mmol), DMF (1.0 mL), methanesulfonamide (33.1 mg, 0.348 mmol) And DBU (52 μL, 0.348 mmol) were used for the reaction and post-treatment according to Example 6a to obtain the title compound (43.2 mg, 38%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.80 (3H, d, J = 6.6 Hz), 0.91-0.94 (6H, m), 0.97 (3H, s), 1.02 (3H, t, J = 6.6 Hz), 1.77-1.86 (1H, m), 2.01 (1H, d, J = 16.4 Hz), 2.09-2.40 (5H, m), 2.73 (3H, s), 2.79 (3H, s), 2.99- 3.06 (1H, m), 3.22 (1H, dd, J = 9.4, 11.3 Hz), 3.34 (3H, s), 3.37-3.42 (1H, m), 3.59-3.79 (2H, m), 3.59 (3H, s), 4.47 (1H, dd, J = 1.2, 9.0 Hz), 6.69 (1H, d, J = 8.6 Hz), 7.17 (1H, d, J = 8.6 Hz), 7.60 (1H, d, J = 7.8 Hz), 7.60 (1H, d, J = 8.2 Hz).
(43b) 6- {3-[(3S, 4aS, 10S, 10aR) -2-Ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4 , 4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (Methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo prepared in Example 43a -3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl]- 4-Methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide (41.5 mg, 0.0637 mmol), ethanol (0.83 mL) and tert-butylamine (13 μL, 0.127 mmol) The title compound (46.2 mg, 77%) was obtained by reaction and post-treatment according to Example 3c.
(実施例44)
　6-{3-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2-(ヒドロキシメチル)-4-メトキシフェニル}-3-メチルピリジン-2-カルボン酸
(44a) tert-ブチル　6-(3-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}フェニル)-3-メチルピリジン-2-カルボキシレート
　実施例34fで製造した(3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(315 mg, 0.450 mmol)、tert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(123 mg, 0.540 mmol)、2nd Generation X-Phos Precatalyst (17.7 mg, 0.0600 mmol)、リン酸カリウム(143 mg, 0.675 mmol)、THF (2.5 mL)及び水(2.5 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(239 mg, 69%)を得た。 (Example 44)
6- {3-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl] -2- (hydroxymethyl) -4-methoxyphenyl} -3-methylpyridine-2-carboxylic acid
(44a) tert-Butyl 6- (3-[(3S, 10S) -3-tert-Butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8, 9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} phenyl) -3-methylpyridine-2 -Carboxylate (3S, 10S) -3-tert-Butyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4, prepared in Example 34f 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2,7,7-trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3, 2-c] pyridine-1,9 (2H) -dione (315 mg, 0.450 mmol), tert-butyl 6-chloro-3-methylpyridine-2-carboxylate (123 mg, 0.540 mmol), 2nd Generation X- Phos Precatalyst (17.7 mg, 0.0600 mmol), potassium phosphate (143 mg, 0.675 mmol), THF (2.5 mL) and water (2.5 mL) were used, followed by reaction and workup according to Example 9d. The title compound (239 mg, 69%) was obtained.
1H-NMR(400MHz, CDCl3):δ ppm: 0.87 (9H, s), 1.01 (3H, s), 1.13 (3H, s), 1.67 (9H, s), 2.23 (2H, s), 2.38 (1H, d, J = 17.2 Hz), 2.44-2.52 (1H, m), 2.50 (3H, s), 2.56 (1H, d, J = 18.0 Hz), 2.92 (1H, ddd, J = 2.0, 8.6, 17.2 Hz), 3.02 (3H, s), 3.16 (1H, d, J = 9.0 Hz), 3.67 (3H, s), 3.81 (3H, s), 4.45 (1H, d, J = 11.3 Hz), 4.67 (1H, d, J = 11.3 Hz), 5.05 (1H, d, J = 11.3 Hz), 5.47 (1H, s), 5.65 (1H, d, J = 11.3 Hz), 6.72 (1H, d, J = 8.6 Hz), 6.81 (2H, d, J = 8.6 Hz), 7.22 (2H, d, J = 9.0 Hz), 7.35 (1H, d, J = 8.6 Hz), 7.37 (1H, d, J = 7.8 Hz), 7.75 (1H, d, J = 7.8 Hz).
(44b) tert-ブチル　6-{3-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2-(ヒドロキシメチル)-4-メトキシフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例44aで製造したtert-ブチル　6-(3-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}フェニル)-3-メチルピリジン-2-カルボキシレート(235 mg, 0.307 mmol)、アニソール(167 μL, 1.54 mmol)、ジクロロメタン(4.0 mL)及びトリフルオロ酢酸(235 μL, 3.07 mmol) を用い、実施例34hに準じて反応及び後処理を行うことにより、標記化合物(198 mg, 99%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.87 (9H, s), 1.01 (3H, s), 1.13 (3H, s), 1.67 (9H, s), 2.23 (2H, s), 2.38 (1H, d, J = 17.2 Hz), 2.44-2.52 (1H, m), 2.50 (3H, s), 2.56 (1H, d, J = 18.0 Hz), 2.92 (1H, ddd, J = 2.0, 8.6 , 17.2 Hz), 3.02 (3H, s), 3.16 (1H, d, J = 9.0 Hz), 3.67 (3H, s), 3.81 (3H, s), 4.45 (1H, d, J = 11.3 Hz), 4.67 (1H, d, J = 11.3 Hz), 5.05 (1H, d, J = 11.3 Hz), 5.47 (1H, s), 5.65 (1H, d, J = 11.3 Hz), 6.72 (1H, d, J = 8.6 Hz), 6.81 (2H, d, J = 8.6 Hz), 7.22 (2H, d, J = 9.0 Hz), 7.35 (1H, d, J = 8.6 Hz), 7.37 (1H, d, J = 7.8 Hz), 7.75 (1H, d, J = 7.8 Hz).
(44b) tert-butyl 6- {3-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8, 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -2- (hydroxymethyl) -4-methoxyphenyl} -3-methylpyridine-2-carboxylate prepared in Example 44a Tert-butyl 6- (3-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9, 10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} phenyl) -3-methylpyridine-2-carboxy Use the rate (235 mg, 0.307 mmol), anisole (167 μL, 1.54 mmol), dichloromethane (4.0 mL) and trifluoroacetic acid (235 μL, 3.07 mmol) to carry out the reaction and workup according to Example 34h. Gave the title compound (198 mg, 99%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.85 (9H, s), 0.99 (3H, s), 1.13 (3H, s), 1.67 (9H, s), 2.16 (1H, dd, J = 1.2, 16.4 Hz), 2.26 (1H, d, J = 16.4 Hz), 2.39 (1H, dd, J = 1.4, 17.8 Hz), 2.52 (1H, d, J = 16.8 Hz), 2.54 (3H, s), 2.59 (1H, d, J = 18.0 Hz), 2.96 (1H, ddd, J = 2.0, 9.0, 18.0 Hz), 3.02 (3H, s), 3.20 (1H, d, J = 9.0 Hz), 3.70 (3H, s), 5.12 (1H, dd, J = 6.3, 12.5 Hz), 5.26 (1H, dd, J = 5.9, 12.5 Hz), 5.37 (1H, s), 6.31 (1H, t, J = 6.3 Hz), 6.81 (1H, d, J = 9.0 Hz), 7.62 (2H, d, J = 8.6 Hz), 8.17 (1H, d, J = 8.2 Hz).
(44c) 6-{3-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2-(ヒドロキシメチル)-4-メトキシフェニル}-3-メチルピリジン-2-カルボン酸
　実施例44bで製造したtert-ブチル　6-{3-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2-(ヒドロキシメチル)-4-メトキシフェニル}-3-メチルピリジン-2-カルボキシレート(193 mg, 0.299 mmol)、ジクロロメタン(4.0 mL)及びトリフルオロ酢酸(2.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(155 mg, 88%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.85 (9H, s), 0.99 (3H, s), 1.13 (3H, s), 1.67 (9H, s), 2.16 (1H, dd, J = 1.2, 16.4 Hz), 2.26 (1H, d, J = 16.4 Hz), 2.39 (1H, dd, J = 1.4, 17.8 Hz), 2.52 (1H, d, J = 16.8 Hz), 2.54 (3H, s) , 2.59 (1H, d, J = 18.0 Hz), 2.96 (1H, ddd, J = 2.0, 9.0, 18.0 Hz), 3.02 (3H, s), 3.20 (1H, d, J = 9.0 Hz), 3.70 ( 3H, s), 5.12 (1H, dd, J = 6.3, 12.5 Hz), 5.26 (1H, dd, J = 5.9, 12.5 Hz), 5.37 (1H, s), 6.31 (1H, t, J = 6.3 Hz ), 6.81 (1H, d, J = 9.0 Hz), 7.62 (2H, d, J = 8.6 Hz), 8.17 (1H, d, J = 8.2 Hz).
(44c) 6- {3-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10 -Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -2- (hydroxymethyl) -4-methoxyphenyl} -3-methylpyridine-2-carboxylic acid tert- prepared in Example 44b Butyl 6- {3-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro -1H-chromeno [3,2-c] pyridin-10-yl] -2- (hydroxymethyl) -4-methoxyphenyl} -3-methylpyridine-2-carboxylate (193 mg, 0.299 mmol), dichloromethane ( 4.0 mL) and trifluoroacetic acid (2.0 mL) were used for the reaction and post-treatment according to Example 1d to obtain the title compound (155 mg, 88%).
(実施例45)
　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(45a) (3S,10S,10aR)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,6,7,8,10,10a-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例9bで製造した2-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン(1.50 g, 3.77 mmol)及び実施例22cで製造した(6S)-6-tert-ブチルピペリジン-2,4-ジオン(669 mg, 3.95 mmol)のアセトニトリル(15 mL)溶液に0℃で炭酸セシウム(1.47 g, 4.52 mmol)を加えた。反応溶液を0℃で3時間攪拌後、水を加えて酢酸エチルで2回抽出、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮し、粗製の付加物を得た。 (Example 45)
6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,4a, 6,7,8,9, 10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(45a) (3S, 10S, 10aR) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) phenyl] -7,7-dimethyl-3,6,7,8,10,10a-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione Example 9b 2- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] -5,5-dimethylcyclohexane- To a solution of 1,3-dione (1.50 g, 3.77 mmol) and (6S) -6-tert-butylpiperidine-2,4-dione (669 mg, 3.95 mmol) prepared in Example 22c in acetonitrile (15 mL) Cesium carbonate (1.47 g, 4.52 mmol) was added at 0 ° C. The reaction solution was stirred at 0 ° C. for 3 hours, water was added and the mixture was extracted twice with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude adduct.
　ジ-tert-ブチル　アゾジカルボキシレート(1.13 g, 4.90 mmol)及びトリフェニルホスフィン(1.29 g, 4.90 mmol)のトルエン溶液(21 mL)溶液を0℃で10分攪拌後、粗製の付加物のトルエン(2.0 mL)溶液0℃で加え、反応溶液を0℃で1時間攪拌した。反応溶液を濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 1:1)で精製し、標記化合物(685 mg, 33%, 2 steps)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.87 (9H, s), 0.92 (3H, s), 1.01 (3H, s), 1.28 (12H, s), 1.99 (1H, d, J = 14.9 Hz), 2.09 (1H, d, J = 16.4 Hz), 2.27 (1H, d, J = 17.6 Hz), 2.36 (1H, dd, J = 3.1, 17.2 Hz), 2.90 (3H, s), 3.56-3.59 (1H, m), 3.68 (3H, s), 3.84-3.88 (1H, m), 4.45 (1H, d, J = 6.3 Hz), 5.50-5.53 (1H, m), 5.93 (1H, s), 6.57 (1H, d, J = 8.2 Hz), 7.60 (1H, d, J = 8.2 Hz).
(45b) (3S,4aS,10S,10aR)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例45aで製造した(3S,10S,10aR)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,6,7,8,10,10a-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(1.00 g, 1.82 mmol)、パラジウム炭素(10%, 400 mg)及びTHF (50 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(763 mg, 76%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.87 (9H, s), 0.88 (3H, s), 1.00 (3H, s), 1.27 (12H, s), 1.75 (1H, q, J = 12.0 Hz), 1.97 (1H, d, J = 18.0 Hz), 2.09 (1H, d, J = 16.4 Hz), 2.20 (1H, d, J = 18.0 Hz), 2.27-2.38 (2H, m), 2.95 (3H, s), 3.12 (1H, dd, J = 4.9, 11.5 Hz), 3.23 (1H, t, J = 10.6 Hz), 3.65 (3H, s), 3.85 (1H, dt, J = 4.3, 11.5 Hz), 4.40 (1H, dd, J = 1.6, 10.2 Hz), 5.40 (1H, s), 6.54 (1H, d, J = 8.6 Hz), 7.58 (1H, d, J = 8.6 Hz).
(45c) tert-ブチル　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例45bで製造した(3S,4aS,10S,10aR)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(763 mg, 1.38 mmol)、tert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(, 378 mg, 1.66 mmol)、2nd Generation X-Phos Precatalyst (218 mg, 0.277 mmol)、リン酸カリウム(470 mg, 2.21 mmol)、THF (7.6 mL)及び水(15 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(853 mg, 99%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.88 (9H, s), 0.92 (3H, s), 1.01 (3H, s), 1.60 (9H, s), 1.77 (1H, q, J = 12.0 Hz), 1.99 (1H, d, J = 16.0 Hz), 2.10 (1H, d, J = 16.4 Hz), 2.22 (1H, d, J = 18.0 Hz), 2.29-2.39 (2H, m), 2.46 (3H, s), 2.67 (3H, s), 3.13 (1H, dd, J = 5.1, 11.7 Hz), 3.29 (1H, t, J = 10.4 Hz), 3.68 (3H, s), 3.86 (1H, td, J = 3.3, 11.4 Hz), 4.37 (1H, d, J = 9.8 Hz), 5.43 (1H, s), 6.65 (1H, d, J = 8.6 Hz), 7.23 (1H, d, J = 6.6 Hz), 7.35 (1H, d, J = 7.8 Hz), 7.48 (1H, d, J = 7.8 Hz).
(45d) 6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例45cで製造したtert-ブチル　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(851 mg, 1.38 mmol)、ジクロロメタン(8.5 mL)、トリフルオロ酢酸(4.3 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(774 mg, 99%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.93 (9H, s), 0.98 (3H, s), 1.07 (3H, s), 1.77-1.86 (1H, m), 2.06 (1H, dd, J = 2.7, 16.0 Hz), 2.17 (1H, d, J = 16.4 Hz), 2.28 (1H, d, J = 18.0 Hz), 2.35-2.45 (2H, m), 2.70 (3H, s), 2.80 (3H, s), 3.19 (1H, dd, J = 5.1, 11.7 Hz), 3.34 (1H, t, J = 10.6 Hz), 3.75 (3H, s), 3.93 (1H, dt, J = 2.7, 11.3 Hz), 4.38 (1H, d, J = 9.8 Hz), 5.52 (1H, s), 6.73 (1H, d, J = 8.6 Hz), 7.19 (1H, d, J = 8.6 Hz), 7.60 (1H, d, J = 7.8 Hz), 7.70 (1H, d, J = 7.4 Hz).
MS(ESI/APCI)m/z: 561[M+H]+.
(45e) 6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例45dで製造した6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(774 mg, 1.38 mmol)、酢酸エチル(5.0 mL)及びtert-ブチルアミン(290 μL, 2.76 mmol) を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(520 mg, 60%)を得た。 After stirring a solution of di-tert-butyl azodicarboxylate (1.13 g, 4.90 mmol) and triphenylphosphine (1.29 g, 4.90 mmol) in toluene (21 mL) at 0 ° C. for 10 minutes, the crude adduct toluene (2.0 mL) solution was added at 0 ° C. and the reaction solution was stirred at 0 ° C. for 1 hour. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 1: 1) to obtain the title compound (685 mg, 33%, 2 steps).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.87 (9H, s), 0.92 (3H, s), 1.01 (3H, s), 1.28 (12H, s), 1.99 (1H, d, J = 14.9 Hz), 2.09 (1H, d, J = 16.4 Hz), 2.27 (1H, d, J = 17.6 Hz), 2.36 (1H, dd, J = 3.1, 17.2 Hz), 2.90 (3H, s), 3.56 -3.59 (1H, m), 3.68 (3H, s), 3.84-3.88 (1H, m), 4.45 (1H, d, J = 6.3 Hz), 5.50-5.53 (1H, m), 5.93 (1H, s ), 6.57 (1H, d, J = 8.2 Hz), 7.60 (1H, d, J = 8.2 Hz).
(45b) (3S, 4aS, 10S, 10aR) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H ) -Dione (3S, 10S, 10aR) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1, prepared in Example 45a) 3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3,6,7,8,10,10a-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H ) -Dione (1.00 g, 1.82 mmol), palladium on carbon (10%, 400 mg) and THF (50 mL) were used for the reaction and workup according to Example 18 to obtain the title compound (763 mg, 76%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.87 (9H, s), 0.88 (3H, s), 1.00 (3H, s), 1.27 (12H, s), 1.75 (1H, q, J = 12.0 Hz), 1.97 (1H, d, J = 18.0 Hz), 2.09 (1H, d, J = 16.4 Hz), 2.20 (1H, d, J = 18.0 Hz), 2.27-2.38 (2H, m), 2.95 (3H, s), 3.12 (1H, dd, J = 4.9, 11.5 Hz), 3.23 (1H, t, J = 10.6 Hz), 3.65 (3H, s), 3.85 (1H, dt, J = 4.3, 11.5 Hz), 4.40 (1H, dd, J = 1.6, 10.2 Hz), 5.40 (1H, s), 6.54 (1H, d, J = 8.6 Hz), 7.58 (1H, d, J = 8.6 Hz).
(45c) tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,4a, 6, 7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate Examples (3S, 4aS, 10S, 10aR) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2) prepared in 45b -Dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c] pyridine-1,9 ( 2H) -dione (763 mg, 1.38 mmol), tert-butyl 6-chloro-3-methylpyridine-2-carboxylate (, 378 mg, 1.66 mmol), 2nd Generation X-Phos Precatalyst (218 mg, 0.277 mmol) , Potassium phosphate (470 mg, 2.21 mmol), THF (7.6 mL) and water (15 mL) were used for the reaction and post-treatment according to Example 9d to give the title compound (853 mg, 99%) Got.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.88 (9H, s), 0.92 (3H, s), 1.01 (3H, s), 1.60 (9H, s), 1.77 (1H, q, J = 12.0 Hz), 1.99 (1H, d, J = 16.0 Hz), 2.10 (1H, d, J = 16.4 Hz), 2.22 (1H, d, J = 18.0 Hz), 2.29-2.39 (2H, m), 2.46 (3H, s), 2.67 (3H, s), 3.13 (1H, dd, J = 5.1, 11.7 Hz), 3.29 (1H, t, J = 10.4 Hz), 3.68 (3H, s), 3.86 (1H, td, J = 3.3, 11.4 Hz), 4.37 (1H, d, J = 9.8 Hz), 5.43 (1H, s), 6.65 (1H, d, J = 8.6 Hz), 7.23 (1H, d, J = 6.6 Hz), 7.35 (1H, d, J = 7.8 Hz), 7.48 (1H, d, J = 7.8 Hz).
(45d) 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,4a, 6,7,8 , 9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid prepared in Example 45c Tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,4a, 6,7, 8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (851 mg, 1.38 mmol), dichloromethane (8.5 mL), and trifluoroacetic acid (4.3 mL) were used for the reaction and post-treatment according to Example 1d to obtain the title compound (774 mg, 99%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.93 (9H, s), 0.98 (3H, s), 1.07 (3H, s), 1.77-1.86 (1H, m), 2.06 (1H, dd, J = 2.7, 16.0 Hz), 2.17 (1H, d, J = 16.4 Hz), 2.28 (1H, d, J = 18.0 Hz), 2.35-2.45 (2H, m), 2.70 (3H, s), 2.80 ( 3H, s), 3.19 (1H, dd, J = 5.1, 11.7 Hz), 3.34 (1H, t, J = 10.6 Hz), 3.75 (3H, s), 3.93 (1H, dt, J = 2.7, 11.3 Hz ), 4.38 (1H, d, J = 9.8 Hz), 5.52 (1H, s), 6.73 (1H, d, J = 8.6 Hz), 7.19 (1H, d, J = 8.6 Hz), 7.60 (1H, d , J = 7.8 Hz), 7.70 (1H, d, J = 7.4 Hz).
MS (ESI / APCI) m / z: 561 [M + H] +.
(45e) 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,4a, 6,7,8 , 9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,4a, 6,7 prepared in Example 45d , 8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid (774 mg , 1.38 mmol), ethyl acetate (5.0 mL) and tert-butylamine (290 μL, 2.76 mmol) were used for the reaction and post-treatment according to Example 3c to give the title compound (520 mg, 60%). Obtained.
(実施例46)
　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
(46a) 6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例45dで製造した6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(100 mg, 0.178 mmol)、カルボニルジイミダゾール(86.8 mg, 0.535 mmol)、DMF (1.0 mL)、メタンスルホンアミド(50.9 mg, 0.535 mmol)及びDBU (80 μL, 0.535 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(86.5 mg, 76%)を得た。 Example 46
6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,4a, 6,7,8,9, 10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide tert- Butylamine salt
(46a) 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,4a, 6,7,8 , 9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2- Carboxamide 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,4a, 6 prepared in Example 45d , 7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid ( Example 6a with 100 mg, 0.178 mmol), carbonyldiimidazole (86.8 mg, 0.535 mmol), DMF (1.0 mL), methanesulfonamide (50.9 mg, 0.535 mmol) and DBU (80 μL, 0.535 mmol). The title compound (86.5 mg, 76%) was obtained by carrying out the reaction and post-treatment in the same manner.
　1H-NMR(400MHz, CDCl3):δ ppm: 0.93 (9H, s), 0.99 (3H, s), 1.07 (3H, s), 1.82 (1H, q, J = 11.9 Hz), 2.07 (1H, d, J = 14.1 Hz), 2.17 (1H, d, J = 16.4 Hz), 2.28 (1H, d, J = 17.2 Hz), 2.35-2.44 (2H, m), 2.69 (3H, s), 2.77 (3H, s), 3.19 (1H, dd, J = 5.1, 11.7 Hz), 3.33 (1H, t, J = 10.8 Hz), 3.38 (3H, s), 3.75 (3H, s), 3.93 (1H, dt, J = 3.9, 11.7 Hz), 4.38 (1H, d, J = 8.6 Hz), 5.55 (1H, s), 6.73 (1H, d, J = 8.6 Hz), 7.21 (1H, d, J = 8.2 Hz), 7.59 (1H, d, J = 8.2 Hz), 7.65 (1H, d, J = 8.2 Hz).
(46b) 6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
　実施例46aで製造した6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド(86.3 mg, 0.135 mmol)、エタノール(1.7 mL)及びtert-ブチルアミン(28 μL, 0.271 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(71.0 mg, 74%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.93 (9H, s), 0.99 (3H, s), 1.07 (3H, s), 1.82 (1H, q, J = 11.9 Hz), 2.07 (1H , d, J = 14.1 Hz), 2.17 (1H, d, J = 16.4 Hz), 2.28 (1H, d, J = 17.2 Hz), 2.35-2.44 (2H, m), 2.69 (3H, s), 2.77 (3H, s), 3.19 (1H, dd, J = 5.1, 11.7 Hz), 3.33 (1H, t, J = 10.8 Hz), 3.38 (3H, s), 3.75 (3H, s), 3.93 (1H, dt, J = 3.9, 11.7 Hz), 4.38 (1H, d, J = 8.6 Hz), 5.55 (1H, s), 6.73 (1H, d, J = 8.6 Hz), 7.21 (1H, d, J = 8.2 Hz), 7.59 (1H, d, J = 8.2 Hz), 7.65 (1H, d, J = 8.2 Hz).
(46b) 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,4a, 6,7,8 , 9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2- Carboxamide tert-butylamine salt 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4 prepared in Example 46a , 4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (Methylsulfonyl) pyridine-2-carboxamide (86.3 mg, 0.135 mmol), ethanol (1.7 mL) and tert-butylamine (28 μL, 0.271 mmol) were used for the reaction and workup according to Example 3c. The title compound (71.0 mg, 74%) was obtained.
(実施例47)
　3-メトキシ-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボン酸 tert-ブチルアミン塩
(47a) (3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3-(プロパン-2-イル)-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例27bで製造した(3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(690 mg, 1.28 mmol)、ヨウ化メチル(640 μL, 10.0 mmol)、DMF (10 mL)及び水素化ナトリウム(63%, 125 mg, 3.28 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(519 mg, 73%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.73 (3H, d, J = 6.7 Hz), 0.90 (3H, s), 0.94 (3H, d, J = 6.7 Hz), 1.03 (3H, s), 1.30 (12H, s), 1.80 (1H, q, J = 11.5 Hz), 2.00 (1H, dd, J = 1.8, 16.4 Hz), 2.13 (1H, d, J = 16.4 Hz), 2.18-2.40 (4H, m), 2.81 (3H, s), 3.08 (3H, s), 3.17 (1H, dd, J = 9.7, 11.5 Hz), 3.32-3.38 (1H, m), 3.68 (3H, s), 3.81 (1H, td, J = 11.5, 4.3 Hz), 4.51 (1H, d, J = 9.1 Hz), 6.56 (1H, d, J = 8.5 Hz), 7.60 (1H, d, J = 8.5 Hz).
(47b) tert-ブチル　3-(ベンジルオキシ)-6-ブロモピリジン-2-カルボキシレート
　3-(ベンジルオキシ)-6-ブロモピリジン-2-カルボン酸(9.33 g, 30.3 mmol)及びピリジン(31 mL) のtert-ブタノール(93 mL)溶液に0℃でp-トルエンスルホニルクロリド(11.5 g, 60.6 mmol)を加え、反応溶液を0℃で96時間攪拌した。反応溶液に0℃で炭酸水素ナトリウム水溶液(5%, 232 mL)を加えて、tert-ブタノールを減圧濃縮した。濃縮残渣を酢酸エチルで抽出、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 8:2)で精製し、標記化合物(11.0 g, 99%)を得た。 (Example 47)
3-Methoxy-6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl ) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} pyridine-2-carboxylic acid tert- Butylamine salt
(47a) (3S, 4aS, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenyl] -2,7,7-trimethyl-3- (propan-2-yl) -3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c] pyridine -1,9 (2H) -dione (3S, 4aS, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-) prepared in Example 27b 1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3- (propan-2-yl) -3,4,4a, 6,7,8,10,10a-octahydro-1H -Chromeno [3,2-c] pyridine-1,9 (2H) -dione (690 mg, 1.28 mmol), methyl iodide (640 μL, 10.0 mmol), DMF (10 mL) and sodium hydride (63% , 125 mg, 3.28 mmol), and the reaction and post-treatment were performed according to Example 2a to obtain the title compound (519 mg, 73%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.73 (3H, d, J = 6.7 Hz), 0.90 (3H, s), 0.94 (3H, d, J = 6.7 Hz), 1.03 (3H, s ), 1.30 (12H, s), 1.80 (1H, q, J = 11.5 Hz), 2.00 (1H, dd, J = 1.8, 16.4 Hz), 2.13 (1H, d, J = 16.4 Hz), 2.18-2.40 (4H, m), 2.81 (3H, s), 3.08 (3H, s), 3.17 (1H, dd, J = 9.7, 11.5 Hz), 3.32-3.38 (1H, m), 3.68 (3H, s), 3.81 (1H, td, J = 11.5, 4.3 Hz), 4.51 (1H, d, J = 9.1 Hz), 6.56 (1H, d, J = 8.5 Hz), 7.60 (1H, d, J = 8.5 Hz).
(47b) tert-butyl 3- (benzyloxy) -6-bromopyridine-2-carboxylate 3- (benzyloxy) -6-bromopyridine-2-carboxylic acid (9.33 g, 30.3 mmol) and pyridine (31 mL P-toluenesulfonyl chloride (11.5 g, 60.6 mmol) was added to a tert-butanol (93 mL) solution at 0 ° C., and the reaction solution was stirred at 0 ° C. for 96 hours. To the reaction solution was added aqueous sodium hydrogen carbonate solution (5%, 232 mL) at 0 ° C., and tert-butanol was concentrated under reduced pressure. The concentrated residue was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 8: 2) to obtain the title compound (11.0 g, 99%).
1H-NMR(400MHz, CDCl3):δ ppm: 1.55 (9H, s), 5.12 (2H, s), 7.19 (1H, d, J = 8.6 Hz), 7.34-7.44 (6H, m).
(47c) tert-ブチル　3-(ベンジルオキシ)-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボキシレート
　実施例47aで製造した(3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3-(プロパン-2-イル)-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(268 mg, 0.486 mmol)、実施例47bで製造したtert-ブチル　3-(ベンジルオキシ)-6-ブロモピリジン-2-カルボキシレート(220 mg, 0.604 mmol)、2nd Generation X-Phos Precatalyst (79.0 mg, 0.100 mmol)、リン酸カリウム(168 mg, 0.791 mmol)、THF (4.0 mL)及び水(6.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(49.4 mg, 14%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.76 (3H, d, J = 6.7 Hz), 0.92 (3H, s), 0.95 (3H, d, J = 7.3 Hz), 1.04 (3H, s), 1.65 (9H, s), 1.82 (1H, q, J = 10.9 Hz), 2.01 (1H, d, J = 15.8 Hz), 2.14 (1H, d, J = 16.4 Hz), 2.22-2.41 (4H, m), 2.79 (3H, s), 2.82 (3H, s), 3.22 (1H, t, J = 10.3 Hz), 3.33-3.38 (1H, m), 3.71 (3H, s), 3.81 (1H, td, J = 4.0, 11.4 Hz), 4.48 (1H, d, J = 8.5 Hz), 5.16 (2H, s), 6.66 (1H, d, J = 8.5 Hz), 7.22-7.48 (8H, m).
(47d) tert-ブチル　3-ヒドロキシ-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボキシレート
　実施例47cで製造したtert-ブチル　3-(ベンジルオキシ)-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボキシレート(49.4 mg, 0.0697 mmol)、パラジウム炭素(10%, 19.0 mg)及びエタノール(4.0 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(35.6 mg, 83%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.55 (9H, s), 5.12 (2H, s), 7.19 (1H, d, J = 8.6 Hz), 7.34-7.44 (6H, m).
(47c) tert-butyl 3- (benzyloxy) -6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo -3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl } Pyridine-2-carboxylate (3S, 4aS, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1, prepared in Example 47a) 3,2-dioxaborolan-2-yl) phenyl] -2,7,7-trimethyl-3- (propan-2-yl) -3,4,4a, 6,7,8,10,10a-octahydro-1H -Chromeno [3,2-c] pyridine-1,9 (2H) -dione (268 mg, 0.486 mmol), tert-butyl 3- (benzyloxy) -6-bromopyridine-2-prepared in Example 47b Carboxylate (220 mg, 0.604 mmol), 2nd Generation X-Phos Precatalyst (79.0 mg, 0.100 mmol), potassium phosphate (168 mg, 0.791 mmol), THF (4.0 mL) and water (6.0 mL) Reaction and work-up according to Example 9d gave the title compound (49.4 m g, 14%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.76 (3H, d, J = 6.7 Hz), 0.92 (3H, s), 0.95 (3H, d, J = 7.3 Hz), 1.04 (3H, s ), 1.65 (9H, s), 1.82 (1H, q, J = 10.9 Hz), 2.01 (1H, d, J = 15.8 Hz), 2.14 (1H, d, J = 16.4 Hz), 2.22-2.41 (4H , m), 2.79 (3H, s), 2.82 (3H, s), 3.22 (1H, t, J = 10.3 Hz), 3.33-3.38 (1H, m), 3.71 (3H, s), 3.81 (1H, td, J = 4.0, 11.4 Hz), 4.48 (1H, d, J = 8.5 Hz), 5.16 (2H, s), 6.66 (1H, d, J = 8.5 Hz), 7.22-7.48 (8H, m).
(47d) tert-butyl 3-hydroxy-6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (Propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} pyridine- 2-carboxylate tert-Butyl 3- (benzyloxy) -6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7- prepared in Example 47c Trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] Pyridin-10-yl] phenyl} pyridine-2-carboxylate (49.4 mg, 0.0697 mmol), palladium on carbon (10%, 19.0 mg) and ethanol (4.0 mL) according to Example 18 for reaction and workup To give the title compound (35.6 mg, 83%).
　1H-NMR(400MHz, CDCl3):δ ppm: 0.76 (3H, d, J = 6.7 Hz), 0.95 (3H, s), 0.96 (3H, d, J = 7.9 Hz), 1.05 (3H, s), 1.66 (9H, s), 1.82 (1H, q, J = 10.9 Hz), 2.03 (1H, dd, J = 1.2, 15.8 Hz), 2.15 (1H, d, J = 16.4 Hz), 2.23-2.41 (4H, m), 2.78 (3H, s), 2.82 (3H, s), 3.24 (1H, dd, J = 9.7, 11.5 Hz), 3.33-3.39 (1H, m), 3.72 (3H, s), 3.82 (1H, dt, J = 4.3, 11.5 Hz), 4.46 (1H, d, J = 9.7 Hz), 6.67 (1H, d, J = 8.5 Hz), 7.24 (1H, d, J = 8.5 Hz), 7.30 (1H, d, J = 8.5 Hz), 7.54 (1H, d, J = 8.5 Hz), 10.99 (1H, s).
(47e) tert-ブチル　3-メトキシ-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボキシレート
　実施例47dで製造したtert-ブチル　3-ヒドロキシ-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボキシレート(14.6 mg, 0.0236 mmol)、ヨウ化メチル(10 μL, 0.200 mmol)、DMF (2.0 mL)及び水素化ナトリウム(63%, 4.2 mg, 0.110 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(14.9 mg, 99%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.76 (3H, d, J = 6.7 Hz), 0.93 (3H, s), 0.96 (3H, d, J = 6.7 Hz), 1.04 (3H, s), 1.62 (9H, s), 1.82 (1H, q, J = 10.9 Hz), 2.03 (1H, d, J = 18.8 Hz), 2.14 (1H, d, J = 15.8 Hz), 2.23-2.38 (4H, m), 2.79 (3H, s), 2.82 (3H, s), 3.22 (1H, t, J = 10.3 Hz), 3.33-3.39 (1H, m), 3.71 (3H, s), 3.81 (1H, dt, J = 4.3, 11.5 Hz), 3.91 (3H, s), 4.49 (1H, d, J = 9.1 Hz), 6.66 (1H, d, J = 8.5 Hz), 7.22-7.29 (2H, m), 7.47 (1H, d, J = 8.5 Hz).
(47f) 3-メトキシ-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボン酸
　実施例47eで製造したtert-ブチル　3-メトキシ-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボキシレート(15.2 mg, 0.0240 mmol)、ジクロロメタン(1.0 mL)及びトリフルオロ酢酸(0.5 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(13.9 mg, 99%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.76 (3H, d, J = 6.7 Hz), 0.95 (3H, s), 0.96 (3H, d, J = 7.9 Hz), 1.05 (3H, s ), 1.66 (9H, s), 1.82 (1H, q, J = 10.9 Hz), 2.03 (1H, dd, J = 1.2, 15.8 Hz), 2.15 (1H, d, J = 16.4 Hz), 2.23-2.41 (4H, m), 2.78 (3H, s), 2.82 (3H, s), 3.24 (1H, dd, J = 9.7, 11.5 Hz), 3.33-3.39 (1H, m), 3.72 (3H, s), 3.82 (1H, dt, J = 4.3, 11.5 Hz), 4.46 (1H, d, J = 9.7 Hz), 6.67 (1H, d, J = 8.5 Hz), 7.24 (1H, d, J = 8.5 Hz), 7.30 (1H, d, J = 8.5 Hz), 7.54 (1H, d, J = 8.5 Hz), 10.99 (1H, s).
(47e) tert-butyl 3-methoxy-6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (Propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} pyridine- 2-carboxylate tert-Butyl 3-hydroxy-6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1 prepared in Example 47d , 9-Dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridine-10 -Yl] phenyl} pyridine-2-carboxylate (14.6 mg, 0.0236 mmol), methyl iodide (10 μL, 0.200 mmol), DMF (2.0 mL) and sodium hydride (63%, 4.2 mg, 0.110 mmol). The title compound (14.9 mg, 99%) was obtained by performing reaction and post-treatment according to Example 2a.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.76 (3H, d, J = 6.7 Hz), 0.93 (3H, s), 0.96 (3H, d, J = 6.7 Hz), 1.04 (3H, s ), 1.62 (9H, s), 1.82 (1H, q, J = 10.9 Hz), 2.03 (1H, d, J = 18.8 Hz), 2.14 (1H, d, J = 15.8 Hz), 2.23-2.38 (4H , m), 2.79 (3H, s), 2.82 (3H, s), 3.22 (1H, t, J = 10.3 Hz), 3.33-3.39 (1H, m), 3.71 (3H, s), 3.81 (1H, dt, J = 4.3, 11.5 Hz), 3.91 (3H, s), 4.49 (1H, d, J = 9.1 Hz), 6.66 (1H, d, J = 8.5 Hz), 7.22-7.29 (2H, m), 7.47 (1H, d, J = 8.5 Hz).
(47f) 3-Methoxy-6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propane- 2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} pyridine-2-carboxylic Acid tert-Butyl 3-methoxy-6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9- prepared in Example 47e Dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] Phenyl} pyridine-2-carboxylate (15.2 mg, 0.0240 mmol), dichloromethane (1.0 mL) and trifluoroacetic acid (0.5 mL) were used for the reaction and workup according to Example 1d to give the title compound ( 13.9 mg, 99%) was obtained.
1H-NMR(400MHz, CDCl3):δ ppm: 0.77 (3H, d, J = 6.7 Hz), 0.98-0.99 (6H, m), 1.08 (3H, s), 1.85 (1H, q, J = 11.5 Hz), 2.10 (1H, d, J = 14.6 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.27-2.46 (4H, m), 2.59 (3H, s), 2.84 (3H, s), 3.34 (1H, t, J = 10.3 Hz), 3.40-3.46 (1H, m), 3.75 (3H, s), 3.93 (1H, dt, J = 3.6, 11.5 Hz), 4.09 (3H, s), 4.32 (1H, d, J = 9.7 Hz), 6.74 (1H, d, J = 8.5 Hz), 7.12 (1H, d, J = 8.5 Hz), 7.81 (2H, s).
(47g) 3-メトキシ-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボン酸 tert-ブチルアミン塩
　実施例47fで製造した3-メトキシ-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボン酸(13.8 mg, 0.0240 mmol)、エタノール(0.8 mL)及びtert-ブチルアミン(21 μL, 0.200 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(15.6 mg, 99%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.77 (3H, d, J = 6.7 Hz), 0.98-0.99 (6H, m), 1.08 (3H, s), 1.85 (1H, q, J = 11.5 Hz), 2.10 (1H, d, J = 14.6 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.27-2.46 (4H, m), 2.59 (3H, s), 2.84 (3H, s) , 3.34 (1H, t, J = 10.3 Hz), 3.40-3.46 (1H, m), 3.75 (3H, s), 3.93 (1H, dt, J = 3.6, 11.5 Hz), 4.09 (3H, s), 4.32 (1H, d, J = 9.7 Hz), 6.74 (1H, d, J = 8.5 Hz), 7.12 (1H, d, J = 8.5 Hz), 7.81 (2H, s).
(47 g) 3-Methoxy-6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propane- 2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} pyridine-2-carboxylic Acid tert-butylamine salt 3-methoxy-6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9 prepared in Example 47f -Dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl By reacting and working up according to Example 3c using phenyl} pyridine-2-carboxylic acid (13.8 mg, 0.0240 mmol), ethanol (0.8 mL) and tert-butylamine (21 μL, 0.200 mmol) The title compound (15.6 mg, 99%) was obtained.
(実施例48)
　6-{4-メトキシ-2-メチル-3-[(10S)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(48a) ベンジル　6-[4-メトキシ-2-メチル-3-(3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)フェニル]-3-メチルピリジン-2-カルボキシレート
　実施例25aで製造した10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3,7,7-テトラメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(300 mg, 0.575 mmol)、実施例20eで製造したベンジル　6-クロロ-3-メチルピリジン-2-カルボキシレート(181 mg, 0.690 mmol)、2nd Generation X-Phos Precatalyst (90.5 mg, 0.115 mmol)、リン酸カリウム(195 mg, 0.921 mmol)、THF (3.0 mL)及び水(5.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(306 mg, 86%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.96 (3H, s), 1.10 (3H, s), 1.18 (3H, s), 1.29 (3H, s), 2.13 (1H, dd, J = 1.0, 16.2 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.30-2.36 (2H, m), 2.46 (1H, d, J = 17.6 Hz), 2.52 (3H, s), 2.65 (1H, dd, J = 1.6, 16.8 Hz), 2.85 (3H, s), 3.73 (3H, s), 5.03 (1H, s), 5.17 (1H, s), 5.43 (2H, s), 6.70 (1H, d, J = 8.6 Hz), 7.26-7.33 (2H, m), 7.36-7.40 (2H, m), 7.44 (1H, d, J = 7.8 Hz), 7.49-7.57 (3H, m).
(48b) ベンジル　6-{4-メトキシ-2-メチル-3-[(10S)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例48aで製造したベンジル　6-[4-メトキシ-2-メチル-3-(3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)フェニル]-3-メチルピリジン-2-カルボキシレート(306 mg)をChiral flash IA(エタノール/ジクロロメタン; 9:1)により光学分割し、高極性化合物(149 mg)及び低極性化合物(142 mg)を得た。
(48c) 6-{4-メトキシ-2-メチル-3-[(10S)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例48bで製造したベンジル　6-{4-メトキシ-2-メチル-3-[(10S)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(高極性化合物; 149 mg, 0.240 mmol)、パラジウム炭素(10%, 30.0 mg)、酢酸エチル(3.0 mL)及びメタノール(3.0 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(117 mg, 92%)を得た。
1H-NMR(400MHz, DMSO-d6):δ ppm: 0.92 (3H, s), 1.08 (3H, s), 1.11 (3H, s), 1.25 (3H, s), 2.05 (1H, d, J = 16.6 Hz), 2.30 (1H, d, J = 16.1 Hz), 2.39 (1H, d, J = 16.6 Hz), 2.40 (1H, d, J = 16.6 Hz), 2.50 (3H, s), 2.60 (1H, d, J = 17.6 Hz), 2.65 (1H, dd, J = 1.5, 17.1 Hz), 2.72 (3H, s), 3.74 (3H, s), 4.95 (1H, s), 5.80 (1H, s), 6.87 (1H, d, J = 8.8 Hz), 7.14 (1H, d, J = 8.3 Hz), 7.18 (1H, s), 7.40 (1H, d, J = 7.8 Hz), 7.80 (1H, d, J = 8.3 Hz).
MS(ESI/APCI)m/z: 531[M+H]+.
(48d) 6-{4-メトキシ-2-メチル-3-[(10S)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例48cで製造した6-{4-メトキシ-2-メチル-3-[(10S)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(117 mg, 0.221 mmol)、エタノール(3.0 mL)及びtert-ブチルアミン(46 μL, 0.441 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(91.5 mg, 69%)を得た。 Example 48
6- {4-Methoxy-2-methyl-3-[(10S) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10 -Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(48a) Benzyl 6- [4-methoxy-2-methyl-3- (3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10 -Octahydro-1H-chromeno [3,2-c] pyridin-10-yl) phenyl] -3-methylpyridine-2-carboxylate 10- [6-methoxy-2-methyl-3- prepared in Example 25a (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3,7,7-tetramethyl-3,4,6,7,8,10- Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (300 mg, 0.575 mmol), benzyl 6-chloro-3-methylpyridine-2-carboxylate prepared in Example 20e (181 mg, 0.690 mmol), 2nd Generation X-Phos Precatalyst (90.5 mg, 0.115 mmol), potassium phosphate (195 mg, 0.921 mmol), THF (3.0 mL) and water (5.0 mL), Example 9d The title compound (306 mg, 86%) was obtained by reacting and working up according to.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.96 (3H, s), 1.10 (3H, s), 1.18 (3H, s), 1.29 (3H, s), 2.13 (1H, dd, J = 1.0, 16.2 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.30-2.36 (2H, m), 2.46 (1H, d, J = 17.6 Hz), 2.52 (3H, s), 2.65 (1H, dd, J = 1.6, 16.8 Hz), 2.85 (3H, s), 3.73 (3H, s), 5.03 (1H, s), 5.17 (1H, s), 5.43 (2H, s), 6.70 (1H, d , J = 8.6 Hz), 7.26-7.33 (2H, m), 7.36-7.40 (2H, m), 7.44 (1H, d, J = 7.8 Hz), 7.49-7.57 (3H, m).
(48b) Benzyl 6- {4-methoxy-2-methyl-3-[(10S) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8 , 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylate benzyl 6- [4-methoxy-2 prepared in Example 48a -Methyl-3- (3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c ] Pyridin-10-yl) phenyl] -3-methylpyridine-2-carboxylate (306 mg) was optically resolved with Chiral flash IA (ethanol / dichloromethane; 9: 1) to obtain high polar compounds (149 mg) and low Polar compound (142 mg) was obtained.
(48c) 6- {4-Methoxy-2-methyl-3-[(10S) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8, 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid benzyl 6- {4-methoxy-2-prepared in Example 48b Methyl-3-[(10S) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3, 2-c] Pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylate (high polarity compound; 149 mg, 0.240 mmol), palladium on carbon (10%, 30.0 mg), ethyl acetate (3.0 mL) The title compound (117 mg, 92%) was obtained by performing reaction and post-treatment according to Example 18 using methanol and methanol (3.0 mL).
1 H-NMR (400 MHz, DMSO-d 6 ): δ ppm: 0.92 (3H, s), 1.08 (3H, s), 1.11 (3H, s), 1.25 (3H, s), 2.05 (1H, d, J = 16.6 Hz), 2.30 (1H, d, J = 16.1 Hz), 2.39 (1H, d, J = 16.6 Hz), 2.40 (1H, d, J = 16.6 Hz), 2.50 (3H, s), 2.60 (1H, d, J = 17.6 Hz), 2.65 (1H, dd, J = 1.5, 17.1 Hz), 2.72 (3H, s), 3.74 (3H, s), 4.95 (1H, s), 5.80 (1H, s), 6.87 (1H, d, J = 8.8 Hz), 7.14 (1H, d, J = 8.3 Hz), 7.18 (1H, s), 7.40 (1H, d, J = 7.8 Hz), 7.80 (1H, d, J = 8.3 Hz).
MS (ESI / APCI) m / z: 531 [M + H] +.
(48d) 6- {4-Methoxy-2-methyl-3-[(10S) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8, 9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt 6- {4-methoxy prepared in Example 48c -2-Methyl-3-[(10S) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid (117 mg, 0.221 mmol), ethanol (3.0 mL) and tert-butylamine (46 μL, 0.441 mmol) The title compound (91.5 mg, 69%) was obtained by reaction and post-treatment according to Example 3c.
(実施例49)
　2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシ-6-(6-メチルピリダジン-3-イル)安息香酸
(49a) (3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(6-メチルピリダジン-3-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例34fで製造した(3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(209 mg, 0.314 mmol)、3-クロロ-6-メチルピリダジン(116 mg, 0.900 mmol)、2nd Generation X-Phos Precatalyst (70.8 mg, 0.0900 mmol)、リン酸カリウム(220 mg, 1.04 mmol)、THF (4.5 mL)及び水(4.5 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(266 mg, 89%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.84 (9H, s), 0.99 (3H, s), 1.11 (3H, s), 2.18 (1H, d, J = 15.7 Hz), 2.24 (1H, d, J = 16.0 Hz), 2.36 (1H, d, J = 17.6 Hz), 2.48 (1H, d, J = 17.6 Hz), 2.54 (1H, d, J = 18.0 Hz), 2.66 (3H, s), 2.90 (1H, ddd, J = 1.6, 9.0, 18.0 Hz), 2.99 (3H, s), 3.14 (1H, d, J = 8.6 Hz), 3.67 (3H, s), 3.78 (3H, s), 4.38 (1H, d, J = 11.0 Hz), 4.59 (1H, d, J = 11.3 Hz), 5.02 (1H, d, J = 11.7 Hz), 5.39 (1H, s), 5.64 (1H, d, J = 12.1 Hz), 6.74 (1H, d, J = 8.6 Hz), 6.78 (2H, dd, J = 2.0, 6.7 Hz), 7.04 (1H, d, J = 8.6 Hz), 7.17 (2H, d, J = 8.6 Hz), 7.35 (1H, d, J = 8.2 Hz), 7.78 (1H, d, J = 8.6 Hz).
(49b) (3S,10S)-3-tert-ブチル-10-[2-(ヒドロキシメチル)-6-メトキシ-3-(6-メチルピリダジン-3-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例49aで製造した(3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(6-メチルピリダジン-3-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(209 mg, 0.314 mmol)、アニソール(170 μL, 1.57 mmol)、ジクロロメタン(2.5 mL)及びトリフルオロ酢酸(240 μL, 3.14 mmol)を用い、実施例34hに準じて反応及び後処理を行うことにより、標記化合物(167 mg, 98%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.87 (9H, s), 0.97 (3H, s), 1.11 (3H, s), 2.15 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.38 (1H, d, J = 17.6 Hz), 2.50 (1H, d, J = 17.6 Hz), 2.57 (1H, d, J = 18.4 Hz), 2.75 (3H, s), 2.90-2.98 (1H, m), 3.00 (3H, s), 3.18 (1H, d, J = 9.0 Hz), 3.69 (3H, s), 5.04-5.15 (2H, m), 5.34 (1H, s), 6.34-6.39 (1H, m), 6.83 (1H, d, J = 8.6 Hz), 7.35 (1H, d, J = 9.0 Hz), 7.66 (1H, d, J = 8.6 Hz), 8.31 (1H, d, J = 8.6 Hz).
(49c) 2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシ-6-(6-メチルピリダジン-3-イル)安息香酸
　実施例49bで製造した(3S,10S)-3-tert-ブチル-10-[2-(ヒドロキシメチル)-6-メトキシ-3-(6-メチルピリダジン-3-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(167 mg, 0.306 mmol)、リン酸バッファー(pH7.2, 6.0 mL)、アセトニトリル(9.0 mL)、亜塩素酸ナトリウム(86.5 mg, 0.765 mmol)、nor-AZADO (4.2 mg, 0.0306 mmol)及び次亜塩素酸ナトリウム水溶液(522 μL, 0.673 mmol) を用い、実施例34iに準じて反応及び後処理を行うことにより、標記化合物(13.7 mg, 8%)を得た。 (Example 49)
2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxy-6- (6-methylpyridazin-3-yl) benzoic acid
(49a) (3S, 10S) -3-tert-butyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (6-methylpyridazin-3-yl) phenyl ] -2,7,7-Trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione Prepared in Example 34f (3S, 10S) -3-tert-butyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) phenyl] -2,7,7-trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (209 mg, 0.314 mmol), 3-chloro-6-methylpyridazine (116 mg, 0.900 mmol), 2nd Generation X-Phos Precatalyst (70.8 mg, 0.0900 mmol), potassium phosphate (220 mg, 1.04 mmol), THF (4.5 mL) and water (4.5 mL) were used, and the reaction and workup were carried out according to Example 9d to obtain the title compound (266 mg, 89%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.84 (9H, s), 0.99 (3H, s), 1.11 (3H, s), 2.18 (1H, d, J = 15.7 Hz), 2.24 (1H , d, J = 16.0 Hz), 2.36 (1H, d, J = 17.6 Hz), 2.48 (1H, d, J = 17.6 Hz), 2.54 (1H, d, J = 18.0 Hz), 2.66 (3H, s ), 2.90 (1H, ddd, J = 1.6, 9.0, 18.0 Hz), 2.99 (3H, s), 3.14 (1H, d, J = 8.6 Hz), 3.67 (3H, s), 3.78 (3H, s) , 4.38 (1H, d, J = 11.0 Hz), 4.59 (1H, d, J = 11.3 Hz), 5.02 (1H, d, J = 11.7 Hz), 5.39 (1H, s), 5.64 (1H, d, J = 12.1 Hz), 6.74 (1H, d, J = 8.6 Hz), 6.78 (2H, dd, J = 2.0, 6.7 Hz), 7.04 (1H, d, J = 8.6 Hz), 7.17 (2H, d, J = 8.6 Hz), 7.35 (1H, d, J = 8.2 Hz), 7.78 (1H, d, J = 8.6 Hz).
(49b) (3S, 10S) -3-tert-butyl-10- [2- (hydroxymethyl) -6-methoxy-3- (6-methylpyridazin-3-yl) phenyl] -2,7,7- Trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione prepared in Example 49a (3S, 10S) -3- tert-butyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (6-methylpyridazin-3-yl) phenyl] -2,7,7-trimethyl-3 , 4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (209 mg, 0.314 mmol), anisole (170 μL, 1.57 mmol), The title compound (167 mg, 98%) was obtained by performing reaction and post-treatment according to Example 34h using dichloromethane (2.5 mL) and trifluoroacetic acid (240 μL, 3.14 mmol).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.87 (9H, s), 0.97 (3H, s), 1.11 (3H, s), 2.15 (1H, d, J = 16.4 Hz), 2.24 (1H , d, J = 16.4 Hz), 2.38 (1H, d, J = 17.6 Hz), 2.50 (1H, d, J = 17.6 Hz), 2.57 (1H, d, J = 18.4 Hz), 2.75 (3H, s ), 2.90-2.98 (1H, m), 3.00 (3H, s), 3.18 (1H, d, J = 9.0 Hz), 3.69 (3H, s), 5.04-5.15 (2H, m), 5.34 (1H, s), 6.34-6.39 (1H, m), 6.83 (1H, d, J = 8.6 Hz), 7.35 (1H, d, J = 9.0 Hz), 7.66 (1H, d, J = 8.6 Hz), 8.31 ( (1H, d, J = 8.6 Hz).
(49c) 2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxy-6- (6-methylpyridazin-3-yl) benzoic acid (3S, 10S) -3-tert prepared in Example 49b -Butyl-10- [2- (hydroxymethyl) -6-methoxy-3- (6-methylpyridazin-3-yl) phenyl] -2,7,7-trimethyl-3,4,6,7,8, 10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (167 mg, 0.306 mmol), phosphate buffer (pH 7.2, 6.0 mL), acetonitrile (9.0 mL), Using sodium chlorite (86.5 mg, 0.765 mmol), nor-AZADO (4.2 mg, 0.0306 mmol) and aqueous sodium hypochlorite solution (522 μL, 0.673 mmol), the reaction and workup were carried out according to Example 34i. This gave the title compound (13.7 mg, 8%).
(実施例50)
　6-シクロプロピル-3-メトキシ-2-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]安息香酸
(50a) 3-シクロプロピル-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}ベンズアルデヒド
　実施例34bで製造した3-ブロモ-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}ベンズアルデヒド(10.0 g, 27.4 mmol)、シクロプロパンボロン酸(4.70 g, 54.8 mmol)、炭酸カリウム(7.57 g, 54.8 mmol)、ビス(ジ-tert-ブチル(4-ジメチルアミノフェニル)フォスフィン)ジクロロパラジウム(II) (96.9 mg, 1.37 mmol)及び1,4-ジオキサン(100 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(8.13 g, 91%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.55-0.59 (2H, m), 0.82-0.87 (2H, m), 1.95-2.02 (1H, m), 3.80 (3H, s), 3.86 (3H, s), 4.55 (2H, s), 5.01 (2H, s), 6.84-6.88 (3H, m), 7.22 (1H, d, J = 8.6 Hz), 7.30 (2H, d, J = 8.9 Hz), 10.57 (1H, s).
(50b) 2-(3-シクロプロピル-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}ベンジリデン)-5,5-ジメチルシクロヘキサン-1,3-ジオン
　実施例50aで製造した3-シクロプロピル-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}ベンズアルデヒド(8.13 g, 24.9 mmol)、ジメドン(3.74 g, 26.7 mmol)、アセトニトリル(81 mL)及びL-プロリン(287 mg, 2.49 mmol)を用い、実施例32hに準じて反応及び後処理を行うことにより、標記化合物(11.2 g, 99%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.59-0.63 (2H, m), 0.81-0.86 (2H, m), 1.08 (6H, s), 1.93-2.00 (1H, m), 2.46 (2H, s), 2.56 (2H, s), 3.69 (3H, s), 3.79 (3H, s), 4.45 (2H, s), 4.65 (2H, s), 6.72 (1H, d, J = 8.6 Hz), 6.85 (2H, d, J = 8.6 Hz), 7.04 (1H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6 Hz), 8.07 (1H, s).
(50c) (3S,10S)-10-(3-シクロプロピル-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}フェニル)-7,7-ジメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例50bで製造した2-(3-シクロプロピル-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}ベンジリデン)-5,5-ジメチルシクロヘキサン-1,3-ジオン(700 mg, 1.56 mmol)、(6S)-6-(プロパン-2-イル)ピペリジン-2,4-ジオン(266 mg, 1.72 mmol)、アセトニトリル(20 mL)、炭酸セシウム(610 mg, 1.87 mmol)、トリブチルホスフィン(468 μL, 1.87 mmol)、DMF (9.4 mL)及びビス(2-メトキシエチル)アゾジカルボキシレート(438 mg, 1.87 mmol)を用い、実施例15aに準じて反応及び後処理を行うことにより、標記化合物(650 mg, 71%)を得た。 
1H-NMR(400MHz, CDCl3):δ ppm: 0.38-0.46 (1H, m), 0.50-0.57 (1H, m), 0.66-0.71 (2H, m), 0.84 (3H, d, J = 6.6 Hz), 0.88 (3H, d, J = 5.9 Hz), 0.92 (3H, s), 1.09 (3H, s), 1.63-1.70 (1H, m), 2.11-2.25 (3H, m), 2.30-2.51 (3H, m), 2.60 (1H, dd, J = 6.3, 15.6 Hz), 3.20-3.24 (1H, m), 3.63 (3H, s), 3.79 (3H, s), 4.73 (1H, d, J = 11.7 Hz), 4.80 (1H, d, J = 11.7 Hz), 5.11 (1H, d, J = 10.6 Hz), 5.17 (1H, s), 5.26 (1H, d, J = 10.9 Hz), 5.29 (1H, s), 6.58 (1H, d, J = 8.6 Hz), 6.79 (1H, d, J = 8.6 Hz), 6.86 (2H, d, J = 9.0 Hz), 7.45 (2H, d, J = 8.6 Hz).
(50d) (3S,10S)-10-(3-シクロプロピル-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}フェニル)-2,7,7-トリメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例50cで製造した(3S,10S)-10-(3-シクロプロピル-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}フェニル)-7,7-ジメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(650 mg, 1.11 mmol)、ヨウ化メチル(345 μL, 5.55 mmol)、DMF (6.5 mL)及び水素化ナトリウム(55%, 96.8 mg, 2.22 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(420 mg, 63%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.41-0.45 (1H, m), 0.52-0.57 (1H, m), 0.66-0.71 (2H, m), 0.77 (3H, d, J = 7.4 Hz), 0.78 (3H, d, J = 7.0 Hz), 0.93 (3H, s), 1.07 (3H, s), 1.85-1.92 (1H, m), 2.10-2.25 (3H, m), 2.30 (1H, d, J = 18.0 Hz), 2.42 (2H, d, J = 17.6 Hz), 2.79-2.87 (1H, m), 2.92 (3H, s), 3.06 (1H, t, J = 6.6 Hz), 3.60 (3H, s), 3.80 (3H, s), 4.74 (1H, d, J = 11.3 Hz), 4.84 (1H, d, J = 11.7 Hz), 5.13 (1H, d, J = 10.6 Hz), 5.35 (1H, d, J = 10.9 Hz), 5.42 (1H, s), 6.54 (1H, d, J = 8.6 Hz), 6.76 (1H, d, J = 8.6 Hz), 6.85 (2H, d, J = 8.6 Hz), 7.47 (2H, d, J = 9.4 Hz).
(50e) (3S,10S)-10-[3-シクロプロピル-2-(ヒドロキシメチル)-6-メトキシフェニル]-2,7,7-トリメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例50dで製造した(3S,10S)-10-(3-シクロプロピル-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}フェニル)-2,7,7-トリメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(420 mg, 0.700 mmol)、リン酸バッファー(pH6.86, 0.84 mL)、ジクロロメタン(8.4 mL)及び2,3-ジクロロ-5,6-ジシアノ-1,4-ベンゾキノン(191 mg, 0.840 mmol)を用い、実施例32kに準じて反応及び後処理を行うことにより、標記化合物(278 mg, 83%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.50-0.72 (2H, m), 0.76 (3H, d, J = 7.0 Hz), 0.79 (3H, d, J = 6.6 Hz), 0.83-0.89 (2H, m), 0.90 (3H, s), 1.05 (3H, s), 1.85-1.93 (1H, m), 2.08 (1H, d, J = 16.8 Hz), 2.17-2.23 (1H, m), 2.18 (1H, d, J = 15.2 Hz), 2.29 (1H, d, J = 17.6 Hz), 2.41 (2H, d, J = 17.6 Hz), 2.83 (1H, ddd, J = 2.0, 7.8, 15.6 Hz), 2.89 (3H, s), 3.07 (1H, t, J = 7.0 Hz), 3.59 (3H, s), 5.25 (1H, s), 5.32 (1H, dd, J = 8.2, 12.5 Hz), 5.46 (1H, dd, J = 5.1, 12.9 Hz), 5.69 (1H, dd, J = 4.1, 7.8 Hz), 6.54 (1H, d, J = 8.6 Hz), 6.84 (1H, d, J = 8.2 Hz).
(50f) 6-シクロプロピル-3-メトキシ-2-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン10-イル]ベンズアルデヒド
　実施例50eで製造した(3S,10S)-10-[3-シクロプロピル-2-(ヒドロキシメチル)-6-メトキシフェニル]-2,7,7-トリメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(275 mg, 0.573 mmol)のジクロロメタン(5.5 mL)溶液に室温でヨードベンゼンジアセテート(415 mg, 1.26 mmol)及びnor-AZADO (15.8 mg, 0.115 mmol)を加え、反応溶液を室温で48時間攪拌した。反応溶液をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 3:2)で精製し、標記化合物(150 mg, 55%)を得た。 (Example 50)
6-cyclopropyl-3-methoxy-2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6, 7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzoic acid
(50a) 3-Cyclopropyl-6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} benzaldehyde 3-bromo-6-methoxy-2-{[(4-methoxybenzyl) prepared in Example 34b ) Oxy] methyl} benzaldehyde (10.0 g, 27.4 mmol), cyclopropaneboronic acid (4.70 g, 54.8 mmol), potassium carbonate (7.57 g, 54.8 mmol), bis (di-tert-butyl (4-dimethylaminophenyl) Phosphine) dichloropalladium (II) (96.9 mg, 1.37 mmol) and 1,4-dioxane (100 mL) were used for the reaction and workup according to Example 9d to give the title compound (8.13 g, 91% )
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.55-0.59 (2H, m), 0.82-0.87 (2H, m), 1.95-2.02 (1H, m), 3.80 (3H, s), 3.86 ( 3H, s), 4.55 (2H, s), 5.01 (2H, s), 6.84-6.88 (3H, m), 7.22 (1H, d, J = 8.6 Hz), 7.30 (2H, d, J = 8.9 Hz ), 10.57 (1H, s).
(50b) 2- (3-Cyclopropyl-6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} benzylidene) -5,5-dimethylcyclohexane-1,3-dione prepared in Example 50a 3-Cyclopropyl-6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} benzaldehyde (8.13 g, 24.9 mmol), dimedone (3.74 g, 26.7 mmol), acetonitrile (81 mL) and L-proline (287 mg, 2.49 mmol) was used for the reaction and post-treatment according to Example 32h to obtain the title compound (11.2 g, 99%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.59-0.63 (2H, m), 0.81-0.86 (2H, m), 1.08 (6H, s), 1.93-2.00 (1H, m), 2.46 ( 2H, s), 2.56 (2H, s), 3.69 (3H, s), 3.79 (3H, s), 4.45 (2H, s), 4.65 (2H, s), 6.72 (1H, d, J = 8.6 Hz ), 6.85 (2H, d, J = 8.6 Hz), 7.04 (1H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6 Hz), 8.07 (1H, s).
(50c) (3S, 10S) -10- (3-Cyclopropyl-6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} phenyl) -7,7-dimethyl-3- (propane-2 -Yl) -3,4,6,7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 2- (3-Cyclohexane prepared in Example 50b Propyl-6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} benzylidene) -5,5-dimethylcyclohexane-1,3-dione (700 mg, 1.56 mmol), (6S) -6- ( Propan-2-yl) piperidine-2,4-dione (266 mg, 1.72 mmol), acetonitrile (20 mL), cesium carbonate (610 mg, 1.87 mmol), tributylphosphine (468 μL, 1.87 mmol), DMF (9.4 mL) and bis (2-methoxyethyl) azodicarboxylate (438 mg, 1.87 mmol), and the reaction and workup according to Example 15a gave the title compound (650 mg, 71%). It was.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.38-0.46 (1H, m), 0.50-0.57 (1H, m), 0.66-0.71 (2H, m), 0.84 (3H, d, J = 6.6 Hz), 0.88 (3H, d, J = 5.9 Hz), 0.92 (3H, s), 1.09 (3H, s), 1.63-1.70 (1H, m), 2.11-2.25 (3H, m), 2.30-2.51 (3H, m), 2.60 (1H, dd, J = 6.3, 15.6 Hz), 3.20-3.24 (1H, m), 3.63 (3H, s), 3.79 (3H, s), 4.73 (1H, d, J = 11.7 Hz), 4.80 (1H, d, J = 11.7 Hz), 5.11 (1H, d, J = 10.6 Hz), 5.17 (1H, s), 5.26 (1H, d, J = 10.9 Hz), 5.29 ( 1H, s), 6.58 (1H, d, J = 8.6 Hz), 6.79 (1H, d, J = 8.6 Hz), 6.86 (2H, d, J = 9.0 Hz), 7.45 (2H, d, J = 8.6 Hz).
(50d) (3S, 10S) -10- (3-Cyclopropyl-6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} phenyl) -2,7,7-trimethyl-3- (propane -2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione prepared in Example 50c (3S, 10S ) -10- (3-Cyclopropyl-6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} phenyl) -7,7-dimethyl-3- (propan-2-yl) -3,4 , 6,7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (650 mg, 1.11 mmol), methyl iodide (345 μL, 5.55 mmol), The title compound (420 mg, 63%) was obtained by performing reaction and post-treatment according to Example 2a using DMF (6.5 mL) and sodium hydride (55%, 96.8 mg, 2.22 mmol).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.41-0.45 (1H, m), 0.52-0.57 (1H, m), 0.66-0.71 (2H, m), 0.77 (3H, d, J = 7.4 Hz), 0.78 (3H, d, J = 7.0 Hz), 0.93 (3H, s), 1.07 (3H, s), 1.85-1.92 (1H, m), 2.10-2.25 (3H, m), 2.30 (1H , d, J = 18.0 Hz), 2.42 (2H, d, J = 17.6 Hz), 2.79-2.87 (1H, m), 2.92 (3H, s), 3.06 (1H, t, J = 6.6 Hz), 3.60 (3H, s), 3.80 (3H, s), 4.74 (1H, d, J = 11.3 Hz), 4.84 (1H, d, J = 11.7 Hz), 5.13 (1H, d, J = 10.6 Hz), 5.35 (1H, d, J = 10.9 Hz), 5.42 (1H, s), 6.54 (1H, d, J = 8.6 Hz), 6.76 (1H, d, J = 8.6 Hz), 6.85 (2H, d, J = 8.6 Hz), 7.47 (2H, d, J = 9.4 Hz).
(50e) (3S, 10S) -10- [3-Cyclopropyl-2- (hydroxymethyl) -6-methoxyphenyl] -2,7,7-trimethyl-3- (propan-2-yl) -3, 4,6,7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (3S, 10S) -10- (3-cyclo) prepared in Example 50d Propyl-6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} phenyl) -2,7,7-trimethyl-3- (propan-2-yl) -3,4,6,7,8 , 10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (420 mg, 0.700 mmol), phosphate buffer (pH6.86, 0.84 mL), dichloromethane (8.4 mL) And 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (191 mg, 0.840 mmol), and the reaction and workup according to Example 32k gave the title compound (278 mg, 83 %).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.50-0.72 (2H, m), 0.76 (3H, d, J = 7.0 Hz), 0.79 (3H, d, J = 6.6 Hz), 0.83-0.89 (2H, m), 0.90 (3H, s), 1.05 (3H, s), 1.85-1.93 (1H, m), 2.08 (1H, d, J = 16.8 Hz), 2.17-2.23 (1H, m), 2.18 (1H, d, J = 15.2 Hz), 2.29 (1H, d, J = 17.6 Hz), 2.41 (2H, d, J = 17.6 Hz), 2.83 (1H, ddd, J = 2.0, 7.8, 15.6 Hz) ), 2.89 (3H, s), 3.07 (1H, t, J = 7.0 Hz), 3.59 (3H, s), 5.25 (1H, s), 5.32 (1H, dd, J = 8.2, 12.5 Hz), 5.46 (1H, dd, J = 5.1, 12.9 Hz), 5.69 (1H, dd, J = 4.1, 7.8 Hz), 6.54 (1H, d, J = 8.6 Hz), 6.84 (1H, d, J = 8.2 Hz) .
(50f) 6-cyclopropyl-3-methoxy-2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4 , 6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin10-yl] benzaldehyde (3S, 10S) -10- [3-Cyclopropyl-2 prepared in Example 50e -(Hydroxymethyl) -6-methoxyphenyl] -2,7,7-trimethyl-3- (propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3, 2-C] pyridine-1,9 (2H) -dione (275 mg, 0.573 mmol) in dichloromethane (5.5 mL) at room temperature with iodobenzene diacetate (415 mg, 1.26 mmol) and nor-AZADO (15.8 mg, 0.115 mmol) was added and the reaction solution was stirred at room temperature for 48 hours. The reaction solution was purified by silica gel column chromatography (hexane / ethyl acetate; 3: 2) to obtain the title compound (150 mg, 55%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.49-0.60 (2H, m), 0.80 (3H, d, J = 6.6 Hz), 0.85-0.90 (2H, m), 0.85 (3H, d, J = 5.9 Hz), 0.95 (3H, s), 1.09 (3H, s), 1.92-2.00 (1H, m), 2.13 (1H, d, J = 16.4 Hz), 2.21 (1H, d, J = 16.8 Hz), 2.32 (1H, d, J = 17.6 Hz), 2.38-2.47 (3H, m), 2.86 (2H, ddd, J = 2.2, 8.0, 17.6 Hz), 2.94 (3H, s), 3.14 (1H, t, J = 6.8 Hz), 3.66 (3H, s), 5.35 (1H, s), 6.74 (1H, d, J = 8.6 Hz), 6.87 (1H, d, J = 8.6 Hz), 11.31 (1H, s).
(50g) 6-シクロプロピル-3-メトキシ-2-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]安息香酸
　実施例50fで製造した6-シクロプロピル-3-メトキシ-2-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン10-イル]ベンズアルデヒド(148 mg, 0.310 mmol)、2-メチル-2-ブテン(732 μL, 6.20 mmol)、りん酸二水素ナトリウム二水和物(242 mg, 1.55 mmol)、水(1.5 mL)、tert-ブタノール(5.9 mL)、ジクロロメタン(0.7 mL)及び亜塩素酸ナトリウム(175 mg, 1.55 mmol)を用い、実施例32mに準じて反応及び後処理を行うことにより、標記化合物(125 mg, 82%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.49-0.60 (2H, m), 0.80 (3H, d, J = 6.6 Hz), 0.85-0.90 (2H, m), 0.85 (3H, d, J = 5.9 Hz), 0.95 (3H, s), 1.09 (3H, s), 1.92-2.00 (1H, m), 2.13 (1H, d, J = 16.4 Hz), 2.21 (1H, d, J = 16.8 Hz), 2.32 (1H, d, J = 17.6 Hz), 2.38-2.47 (3H, m), 2.86 (2H, ddd, J = 2.2, 8.0, 17.6 Hz), 2.94 (3H, s), 3.14 (1H , t, J = 6.8 Hz), 3.66 (3H, s), 5.35 (1H, s), 6.74 (1H, d, J = 8.6 Hz), 6.87 (1H, d, J = 8.6 Hz), 11.31 (1H , s).
(50 g) 6-Cyclopropyl-3-methoxy-2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4 , 6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzoic acid 6-cyclopropyl-3-methoxy-2-[( 3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin10-yl] benzaldehyde (148 mg, 0.310 mmol), 2-methyl-2-butene (732 μL, 6.20 mmol), sodium dihydrogen phosphate dihydrate (242 mg, 1.55 mmol), water (1.5 mL), tert-butanol (5.9 mL), dichloromethane (0.7 mL) and sodium chlorite (175 mg, 1.55 mmol), followed by reaction and workup according to Example 32m. Gave the title compound (125 mg, 82%).
(実施例51)
　2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-6-シクロプロピル-3-メトキシ安息香酸
(51a) (3S,10S)-3-tert-ブチル-10-(3-シクロプロピル-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}フェニル)-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例50bで製造した2-(3-シクロプロピル-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}ベンジリデン)-5,5-ジメチルシクロヘキサン-1,3-ジオン(940 mg, 2.10 mmol)、実施例22cで製造した(6S)-6-tert-ブチルピペリジン-2,4-ジオン(390 mg, 2.31 mmol)、アセトニトリル(20 mL)、炭酸セシウム(819 mg, 2.51 mmol)、トリブチルホスフィン(734 μL, 2.94 mmol)、DMF (13 mL)及びビス(2-メトキシエチル)アゾジカルボキシレート(689 mg, 2.94 mmol)を用い、実施例15aに準じて反応及び後処理を行うことにより、標記化合物(377 mg, 30%)を得た。 
1H-NMR(400MHz, CDCl3):δ ppm: 0.36-0.70 (4H, m), 0.86 (9H, s), 0.93 (3H, s), 1.09 (3H, s), 2.12-2.25 (3H, m), 2.32 (1H, d, J = 17.6 Hz), 2.44 (1H, d, J = 17.2 Hz), 2.50 (2H, d, J = 8.2 Hz), 3.29 (1H, dt, J = 2.3, 7.8 Hz), 3.61 (3H, s), 3.80 (3H, s), 4.72 (1H, d, J = 11.7 Hz), 4.81 (1H, d, J = 11.7 Hz), 5.07 (1H, s), 5.09 (1H, d, J = 10.6 Hz), 5.27 (1H, s), 5.29 (1H, d, J = 10.9 Hz), 6.57 (1H, d, J = 8.2 Hz), 6.80 (1H, d, J = 8.6 Hz), 6.86 (2H, d, J = 8.6 Hz), 7.45 (2H, d, J = 8.6 Hz).
(51b) (3S,10S)-3-tert-ブチル-10-(3-シクロプロピル-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}フェニル))-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例51aで製造した(3S,10S)-3-tert-ブチル-10-(3-シクロプロピル-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}フェニル)-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(377 mg, 0.629 mmol)、ヨウ化メチル(313 μL, 5.03 mmol)、DMF (3.8 mL)及び水素化ナトリウム(55%, 41.1 mg, 0.493 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(314 mg, 81%)を得た。 (Example 51)
2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -6-cyclopropyl-3-methoxybenzoic acid
(51a) (3S, 10S) -3-tert-butyl-10- (3-cyclopropyl-6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} phenyl) -7,7-dimethyl- 3,4,6,7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 2- (3-cyclopropyl-6- prepared in Example 50b Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} benzylidene) -5,5-dimethylcyclohexane-1,3-dione (940 mg, 2.10 mmol), prepared in Example 22c (6S) -6 -tert-Butylpiperidine-2,4-dione (390 mg, 2.31 mmol), acetonitrile (20 mL), cesium carbonate (819 mg, 2.51 mmol), tributylphosphine (734 μL, 2.94 mmol), DMF (13 mL) And bis (2-methoxyethyl) azodicarboxylate (689 mg, 2.94 mmol), the reaction and workup were carried out according to Example 15a to obtain the title compound (377 mg, 30%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.36-0.70 (4H, m), 0.86 (9H, s), 0.93 (3H, s), 1.09 (3H, s), 2.12-2.25 (3H, m), 2.32 (1H, d, J = 17.6 Hz), 2.44 (1H, d, J = 17.2 Hz), 2.50 (2H, d, J = 8.2 Hz), 3.29 (1H, dt, J = 2.3, 7.8 Hz), 3.61 (3H, s), 3.80 (3H, s), 4.72 (1H, d, J = 11.7 Hz), 4.81 (1H, d, J = 11.7 Hz), 5.07 (1H, s), 5.09 ( 1H, d, J = 10.6 Hz), 5.27 (1H, s), 5.29 (1H, d, J = 10.9 Hz), 6.57 (1H, d, J = 8.2 Hz), 6.80 (1H, d, J = 8.6 Hz), 6.86 (2H, d, J = 8.6 Hz), 7.45 (2H, d, J = 8.6 Hz).
(51b) (3S, 10S) -3-tert-butyl-10- (3-cyclopropyl-6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} phenyl))-2,7,7 -Trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (3S, 10S) -3 prepared in Example 51a -tert-butyl-10- (3-cyclopropyl-6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} phenyl) -7,7-dimethyl-3,4,6,7,8, 10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (377 mg, 0.629 mmol), methyl iodide (313 μL, 5.03 mmol), DMF (3.8 mL) and hydrogen The title compound (314 mg, 81%) was obtained by performing reaction and post-treatment according to Example 2a using sodium chloride (55%, 41.1 mg, 0.493 mmol).
1H-NMR(400MHz, CDCl3):δ ppm: 0.41-0.72 (4H, m), 0.80 (9H, s), 0.94 (3H, s), 1.08 (3H, s), 2.12-2.24 (3H, m), 2.31 (1H, d, J = 17.2 Hz), 2.43 (1H, d, J = 17.6 Hz), 2.51 (1H, d, J = 18.0 Hz), 2.88 (1H, dd, J = 9.0, 16.0 Hz), 3.00 (3H, s), 3.11 (1H, d, J = 9.0 Hz), 3.56 (3H, s), 3.80 (3H, s), 4.73 (1H, d, J = 11.7 Hz), 4.85 (1H, d, J = 11.7 Hz), 5.12 (1H, d, J = 10.6 Hz), 5.43 (1H, d, J = 10.6 Hz), 5.47 (1H, s), 6.49 (1H, d, J = 8.6 Hz), 6.76 (1H, d, J = 8.6 Hz), 6.85 (2H, d, J = 8.6 Hz), 7.48 (2H, d, J = 8.6 Hz).
(51c) (3S,10S)-3-tert-ブチル-10-[3-シクロプロピル-2-(ヒドロキシメチル)-6-メトキシフェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例51bで製造した(3S,10S)-3-tert-ブチル-10-(3-シクロプロピル-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}フェニル))-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(314 mg, 0.512 mmol)、リン酸バッファー(pH6.86, 0.63 mL)、ジクロロメタン(6.3 mL)及び2,3-ジクロロ-5,6-ジシアノ-1,4-ベンゾキノン(139 mg, 0.614 mmol)を用い、実施例32kに準じて反応及び後処理を行うことにより、標記化合物(229 mg, 91%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.41-0.72 (4H, m), 0.80 (9H, s), 0.94 (3H, s), 1.08 (3H, s), 2.12-2.24 (3H, m), 2.31 (1H, d, J = 17.2 Hz), 2.43 (1H, d, J = 17.6 Hz), 2.51 (1H, d, J = 18.0 Hz), 2.88 (1H, dd, J = 9.0, 16.0 Hz), 3.00 (3H, s), 3.11 (1H, d, J = 9.0 Hz), 3.56 (3H, s), 3.80 (3H, s), 4.73 (1H, d, J = 11.7 Hz), 4.85 ( 1H, d, J = 11.7 Hz), 5.12 (1H, d, J = 10.6 Hz), 5.43 (1H, d, J = 10.6 Hz), 5.47 (1H, s), 6.49 (1H, d, J = 8.6 Hz), 6.76 (1H, d, J = 8.6 Hz), 6.85 (2H, d, J = 8.6 Hz), 7.48 (2H, d, J = 8.6 Hz).
(51c) (3S, 10S) -3-tert-butyl-10- [3-cyclopropyl-2- (hydroxymethyl) -6-methoxyphenyl] -2,7,7-trimethyl-3,4,6, 7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (3S, 10S) -3-tert-butyl-10- (3 prepared in Example 51b -Cyclopropyl-6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} phenyl))-2,7,7-trimethyl-3,4,6,7,8,10-hexahydro-1H- Chromeno [3,2-c] pyridine-1,9 (2H) -dione (314 mg, 0.512 mmol), phosphate buffer (pH 6.86, 0.63 mL), dichloromethane (6.3 mL) and 2,3-dichloro- Using 5,6-dicyano-1,4-benzoquinone (139 mg, 0.614 mmol), the reaction and post-treatment were performed according to Example 32k to obtain the title compound (229 mg, 91%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.53-0.77 (2H, m), 0.83 (9H, s), 0.87-0.94 (2H, m), 0.94 (3H, s), 1.09 (3H, s), 2.11 (1H, d, J = 16.8 Hz), 2.19-2.27 (2H, m), 2.33 (1H, d, J = 17.6 Hz), 2.46 (1H, d, J = 16.8 Hz), 2.54 (1H, d, J = 18.0 Hz), 2.92 (1H, ddd, J = 2.3, 8.6, 17.6 Hz), 2.99 (3H, s), 3.15 (1H, d, J = 9.0 Hz), 3.58 (3H, s), 5.33 (1H, s), 5.48 (1H, dd, J = 5.1, 12.5 Hz), 5.41 (1H, dd, J = 6.6, 12.5 Hz), 5.74 (1H, dd, J = 7.4, 5.5 Hz), 6.54 (1H, d, J = 8.6 Hz), 6.87 (1H, d, J = 8.6 Hz).
(51d) 2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-6-シクロプロピル-3-メトキシベンズアルデヒド
　実施例51cで製造した(3S,10S)-3-tert-ブチル-10-[3-シクロプロピル-2-(ヒドロキシメチル)-6-メトキシフェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(227 mg, 0.460 mmol)、ジクロロメタン(4.5 mL)、ヨードベンゼンジアセテート(333 mg, 1.01 mmol)及びnor-AZADO (6.4 mg, 0.0460 mmol) を用い、実施例50fに準じて反応及び後処理を行うことにより、標記化合物(171 mg, 76%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.53-0.77 (2H, m), 0.83 (9H, s), 0.87-0.94 (2H, m), 0.94 (3H, s), 1.09 (3H, s), 2.11 (1H, d, J = 16.8 Hz), 2.19-2.27 (2H, m), 2.33 (1H, d, J = 17.6 Hz), 2.46 (1H, d, J = 16.8 Hz), 2.54 ( 1H, d, J = 18.0 Hz), 2.92 (1H, ddd, J = 2.3, 8.6, 17.6 Hz), 2.99 (3H, s), 3.15 (1H, d, J = 9.0 Hz), 3.58 (3H, s ), 5.33 (1H, s), 5.48 (1H, dd, J = 5.1, 12.5 Hz), 5.41 (1H, dd, J = 6.6, 12.5 Hz), 5.74 (1H, dd, J = 7.4, 5.5 Hz) , 6.54 (1H, d, J = 8.6 Hz), 6.87 (1H, d, J = 8.6 Hz).
(51d) 2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl] -6-cyclopropyl-3-methoxybenzaldehyde (3S, 10S) -3-tert-butyl-10- [3-cyclopropyl prepared in Example 51c Propyl-2- (hydroxymethyl) -6-methoxyphenyl] -2,7,7-trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1 , 9 (2H) -dione (227 mg, 0.460 mmol), dichloromethane (4.5 mL), iodobenzene diacetate (333 mg, 1.01 mmol) and nor-AZADO (6.4 mg, 0.0460 mmol). The title compound (171 mg, 76%) was obtained by performing the reaction and post-treatment in the same manner.
1H-NMR(400MHz, CDCl3):δ ppm: 0.47-0.61 (2H, m), 0.83 (9H, s), 0.85-0.89 (2H, m), 0.96 (3H, s), 1.09 (3H, s), 2.12 (1H, d, J = 16.4 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.32 (1H, d, J = 18.0 Hz), 2.37-2.43 (1H, m), 2.45 (1H, d, J = 17.6 Hz), 2.52 (1H, d, J = 18.4 Hz), 2.90 (1H, ddd, J = 2.2, 9.0, 18.2 Hz), 3.01 (3H, s), 3.14 (1H, d, J = 9.0 Hz), 3.61 (3H, s), 5.37 (1H, s), 6.69 (1H, d, J = 8.6 Hz), 6.86 (1H, d, J = 8.6 Hz), 11.32 (1H, s).
(51e) 2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-6-シクロプロピル-3-メトキシ安息香酸
　実施例51dで製造した2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-6-シクロプロピル-3-メトキシベンズアルデヒド(171 mg, 0.348 mmol)、2-メチル-2-ブテン(821 μL, 6.96 mmol)、りん酸二水素ナトリウム二水和物(271 mg, 1.74 mmol)、水(1.7 mL)、tert-ブタノール(6.8 mL)、ジクロロメタン(0.8 mL)及び亜塩素酸ナトリウム(197 mg, 1.74 mmol)を用い、実施例32mに準じて反応及び後処理を行うことにより、標記化合物(109 mg, 62%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.47-0.61 (2H, m), 0.83 (9H, s), 0.85-0.89 (2H, m), 0.96 (3H, s), 1.09 (3H, s), 2.12 (1H, d, J = 16.4 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.32 (1H, d, J = 18.0 Hz), 2.37-2.43 (1H, m), 2.45 ( 1H, d, J = 17.6 Hz), 2.52 (1H, d, J = 18.4 Hz), 2.90 (1H, ddd, J = 2.2, 9.0, 18.2 Hz), 3.01 (3H, s), 3.14 (1H, d , J = 9.0 Hz), 3.61 (3H, s), 5.37 (1H, s), 6.69 (1H, d, J = 8.6 Hz), 6.86 (1H, d, J = 8.6 Hz), 11.32 (1H, s ).
(51e) 2-[(3S, 10S) -3-tert-Butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl] -6-cyclopropyl-3-methoxybenzoic acid 2-[(3S, 10S) -3-tert-butyl-2, prepared in Example 51d 7,7-Trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -6-cyclo Propyl-3-methoxybenzaldehyde (171 mg, 0.348 mmol), 2-methyl-2-butene (821 μL, 6.96 mmol), sodium dihydrogen phosphate dihydrate (271 mg, 1.74 mmol), water (1.7 mL ), Tert-butanol (6.8 mL), dichloromethane (0.8 mL) and sodium chlorite (197 mg, 1.74 mmol) were used for the reaction and workup according to Example 32m to give the title compound (109 mg 62%).
(実施例52)
　6-シクロプロピル-3-メトキシ-N-(メチルスルホニル)-2-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]ベンズアミド
　実施例50gで製造した6-シクロプロピル-3-メトキシ-2-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]安息香酸(100 mg, 0.203 mmol)のジクロロメタン(2.0 mL)溶液に室温でピリジン(26 μL, 0.324 mmol)及びシアヌル酸フルオリド(26 μL, 0.304 mmol)を加え、反応溶液を室温で2時間攪拌した。反応溶液に水を加え、ジクロロメタンで2回抽出した。有機層を飽和炭酸水素ナトリウム水溶液、次いで飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮し、粗製の酸フルオリドを得た。粗製の酸フルオリド及びメタンスルホンアミド(23.1 mg, 0.243 mmol)のDMF (2.0 mL)溶液に室温で水素化ナトリウム(55%, 21.2 mg, 0.486 mmol)を加え、反応溶液を室温で12時間攪拌した。反応溶液に10%クエン酸水溶液を加え(pH = 4)、酢酸エチルで2回抽出した。有機層を水、次いで飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。反応溶液を濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 2:3)で精製し、標記化合物(50.6 mg, 44%)を得た。 (Example 52)
6-Cyclopropyl-3-methoxy-N- (methylsulfonyl) -2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2 , 3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzamide 6-cyclopropyl-3-methoxy-2 prepared in Example 50 g -[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl] benzoic acid (100 mg, 0.203 mmol) in dichloromethane (2.0 mL) at room temperature with pyridine (26 μL, 0.324 mmol) and cyanuric fluoride (26 μL , 0.304 mmol) and the reaction solution was stirred at room temperature for 2 hours. Water was added to the reaction solution, and extracted twice with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and then with a saturated saline solution and then dried over anhydrous sodium sulfate. Concentration under reduced pressure gave crude acid fluoride. To a solution of crude acid fluoride and methanesulfonamide (23.1 mg, 0.243 mmol) in DMF (2.0 mL) at room temperature was added sodium hydride (55%, 21.2 mg, 0.486 mmol), and the reaction solution was stirred at room temperature for 12 hours. . A 10% aqueous citric acid solution was added to the reaction solution (pH = 4), and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and then with saturated brine, and then dried over anhydrous sodium sulfate. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 2: 3) to obtain the title compound (50.6 mg, 44%).
(実施例53)
　2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-6-シクロプロピル-3-メトキシ-N-(メチルスルホニル)ベンズアミド
　実施例51eで製造した2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-6-シクロプロピル-3-メトキシ安息香酸(30.0 mg, 0.0591 mmol)、ジクロロメタン(0.9 mL)、ピリジン(11 μL, 0.130 mmol)、シアヌル酸フルオリド(10 μL, 0.118 mmol)、メタンスルホンアミド(22.5 mg, 0.236 mmol)、DMF (0.6 mL)及び水素化ナトリウム(55%, 14.2 mg, 0.325 mmol)を用い、実施例52に準じて反応及び後処理を行うことにより、標記化合物(6.0 mg, 17%)を2種類のコンフォマーの混合物として得た。 (Example 53)
2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -6-cyclopropyl-3-methoxy-N- (methylsulfonyl) benzamide 2-[(3S, 10S) -3-tert-butyl prepared in Example 51e -2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl]- 6-cyclopropyl-3-methoxybenzoic acid (30.0 mg, 0.0591 mmol), dichloromethane (0.9 mL), pyridine (11 μL, 0.130 mmol), cyanuric fluoride (10 μL, 0.118 mmol), methanesulfonamide (22.5 mg , 0.236 mmol), DMF (0.6 mL) and sodium hydride (55%, 14.2 mg, 0.325 mmol) were used for the reaction and workup according to Example 52 to give the title compound (6.0 mg, 17% ) Was obtained as a mixture of two conformers.
(実施例54)
　3-メトキシ-6-(ピリジン-2-イル)-2-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]安息香酸
　(54a) (3S,10S)-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例34dで製造した2-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン(5.17 g, 9.67 mmol)、(6S)-6-(プロパン-2-イル)ピペリジン-2,4-ジオン(1.65 g, 10.6 mmol)、アセトニトリル(40 mL)、炭酸セシウム(3.78 g, 11.6 mmol)、トリブチルホスフィン(2.90 mL, 11.6 mmol)、DMF (30 mL)及びビス(2-メトキシエチル)アゾジカルボキシレート(2.72 g, 11.6 mmol)を用い、実施例15aに準じて反応及び後処理を行うことにより、標記化合物(1.47 g, 23%)を得た。  Example 54
3-Methoxy-6- (pyridin-2-yl) -2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3 , 4,6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzoic acid (54a) (3S, 10S) -10- [6-Methoxy-2 -{[(4-Methoxybenzyl) oxy] methyl} -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3 -(Propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione prepared in Example 34d 2 -[6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene]- 5,5-dimethylcyclohexane-1,3-dione (5.17 g, 9.67 mmol), (6S) -6- (propan-2-yl) piperidine-2,4-dione (1.65 g, 10.6 mmol), acetonitrile ( 40 mL), cesium carbonate (3.78 g, 11.6 mmol), tributylphosphine (2.90 mL, 11.6 mmol), DMF (30 mL) and bis The title compound (1.47 g, 23%) was obtained by performing the reaction and post-treatment according to Example 15a using (2-methoxyethyl) azodicarboxylate (2.72 g, 11.6 mmol).
1H-NMR(400MHz, CDCl3):δ ppm: 0.82 (3H, d, J = 7.4 Hz), 0.87 (3H, d, J = 6.7 Hz), 0.90 (3H, s), 1.07 (3H, s), 1.22 (12H, s), 1.61-1.66 (1H, m), 2.08 (1H, d, J = 17.2 Hz), 2.16 (1H, d, J = 16.4 Hz), 2.30 (1H, d, J = 17.6 Hz), 2.39-2.50 (2H, m), 2.60 (1H, dd, J = 16.8, 6.7 Hz), 3.17-3.23 (1H, m), 3.67 (3H, s), 3.79 (3H, s), 4.59 (1H, d, J = 12.1 Hz), 4.64 (1H, d, J = 12.1 Hz), 4.94 (1H, s), 5.26 (1H, s), 5.32 (1H, d, J = 11.7 Hz), 5.37 (1H, d, J = 13.3 Hz), 6.65 (1H, d, J = 8.2 Hz), 6.84 (2H, d, J = 8.6 Hz), 7.33 (1H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.6 Hz).
(54b) (3S,10S)-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例54aで製造した(3S,10S)-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(1.47 g, 2.19 mmol)、ヨウ化メチル(273 μL, 4.38 mmol)、DMF (15 mL)及び水素化ナトリウム(63%, 83.8 mg, 2.20 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(1.16 g, 77%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.82 (3H, d, J = 7.4 Hz), 0.87 (3H, d, J = 6.7 Hz), 0.90 (3H, s), 1.07 (3H, s ), 1.22 (12H, s), 1.61-1.66 (1H, m), 2.08 (1H, d, J = 17.2 Hz), 2.16 (1H, d, J = 16.4 Hz), 2.30 (1H, d, J = 17.6 Hz), 2.39-2.50 (2H, m), 2.60 (1H, dd, J = 16.8, 6.7 Hz), 3.17-3.23 (1H, m), 3.67 (3H, s), 3.79 (3H, s), 4.59 (1H, d, J = 12.1 Hz), 4.64 (1H, d, J = 12.1 Hz), 4.94 (1H, s), 5.26 (1H, s), 5.32 (1H, d, J = 11.7 Hz), 5.37 (1H, d, J = 13.3 Hz), 6.65 (1H, d, J = 8.2 Hz), 6.84 (2H, d, J = 8.6 Hz), 7.33 (1H, d, J = 8.2 Hz), 7.44 ( (2H, d, J = 8.6 Hz).
(54b) (3S, 10S) -10- [6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl) phenyl] -2,7,7-trimethyl-3- (propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2- c] pyridine-1,9 (2H) -dione (3S, 10S) -10- [6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4) prepared in Example 54a , 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3- (propan-2-yl) -3,4,6,7,8 , 10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (1.47 g, 2.19 mmol), methyl iodide (273 μL, 4.38 mmol), DMF (15 mL) and The title compound (1.16 g, 77%) was obtained by performing reaction and post-treatment according to Example 2a using sodium hydride (63%, 83.8 mg, 2.20 mmol).
1H-NMR(400MHz, CDCl3):δ ppm: 0.76 (3H, d, J = 6.7 Hz), 0.80 (3H, d, J = 6.7 Hz), 0.92 (3H, s), 1.06 (3H, s), 1.24 (12H, d, J = 7.2 Hz), 1.84-1.93 (1H, m), 2.08 (1H, d, J = 16.4 Hz), 2.16 (1H, d, J = 16.4 Hz), 2.29 (1H, d, J = 17.2 Hz), 2.40 (2H, d, J = 16.8 Hz), 2.81 (1H, ddd, J = 3.1, 9.4, 18.0 Hz), 2.89 (3H, s), 3.05 (1H, t, J = 6.7 Hz), 3.64 (3H, s), 3.79 (3H, s), 4.66 (2H, s), 5.02 (1H, s), 5.34 (1H, d, J = 12.9 Hz), 5.42 (1H, d, J = 13.3 Hz), 6.61 (1H, d, J = 8.2 Hz), 6.84 (2H, d, J = 9.0 Hz), 7.31 (1H, d, J = 8.2 Hz), 7.46 (2H, d, J = 8.6 Hz).
(54c) (3S,10S)-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(ピリジン-2-イル)フェニル]-2,7,7-トリメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例54bで製造した(3S,10S)-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(412 mg, 0.601 mmol)、2-クロロピリジン(102 mg, 0.901 mmol)、2nd Generation X-Phos Precatalyst (47.3 mg, 0.0601 mmol)、リン酸カリウム(230 mg, 1.08 mmol)、THF (6.0 mL)及び水(6.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(285 mg, 75%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.76 (3H, d, J = 6.7 Hz), 0.80 (3H, d, J = 6.7 Hz), 0.92 (3H, s), 1.06 (3H, s ), 1.24 (12H, d, J = 7.2 Hz), 1.84-1.93 (1H, m), 2.08 (1H, d, J = 16.4 Hz), 2.16 (1H, d, J = 16.4 Hz), 2.29 (1H , d, J = 17.2 Hz), 2.40 (2H, d, J = 16.8 Hz), 2.81 (1H, ddd, J = 3.1, 9.4, 18.0 Hz), 2.89 (3H, s), 3.05 (1H, t, J = 6.7 Hz), 3.64 (3H, s), 3.79 (3H, s), 4.66 (2H, s), 5.02 (1H, s), 5.34 (1H, d, J = 12.9 Hz), 5.42 (1H, d, J = 13.3 Hz), 6.61 (1H, d, J = 8.2 Hz), 6.84 (2H, d, J = 9.0 Hz), 7.31 (1H, d, J = 8.2 Hz), 7.46 (2H, d, J = 8.6 Hz).
(54c) (3S, 10S) -10- [6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (pyridin-2-yl) phenyl] -2,7,7-trimethyl -3- (propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chrome [3,2-c] pyridine-1,9 (2H) -dione prepared in Example 54b (3S, 10S) -10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl) phenyl] -2,7,7-trimethyl-3- (propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] Pyridine-1,9 (2H) -dione (412 mg, 0.601 mmol), 2-chloropyridine (102 mg, 0.901 mmol), 2nd Generation X-Phos Precatalyst (47.3 mg, 0.0601 mmol), potassium phosphate (230 mg , 1.08 mmol), THF (6.0 mL) and water (6.0 mL) were used in the reaction and post-treatment according to Example 9d to obtain the title compound (285 mg, 75%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.79 (3H, d, J = 7.0 Hz), 0.82 (3H, d, J = 6.7 Hz), 0.97 (3H, s), 1.10 (3H, s), 1.24 (9H, s), 1.89-1.93 (1H, m), 2.21 (2H, s), 2.34 (1H, d, J = 17.6 Hz), 2.45 (2H, dd, J = 3.9, 17.2 Hz), 2.85 (1H, ddd, J = 0.4, 9.0, 16.4 Hz), 2.93 (3H, s), 3.08 (1H, t, J = 7.2 Hz), 3.69 (3H, s), 3.77 (3H, s), 4.37 (1H, d, J = 11.3 Hz), 4.54 (1H, d, J = 11.3 Hz), 5.06 (1H, d, J = 11.0 Hz), 5.40 (1H, s), 5.50 (1H, d, J = 11.3 Hz), 6.74 (3H, t, J = 8.0 Hz), 7.10-7.14 (3H, m), 7.23 (1H, d, J = 8.6 Hz), 7.55 (1H, td, J = 1.7, 7.7 Hz), 7.67 (1H, d, J = 7.8 Hz), 8.55 (1H, d, J = 3.9 Hz).
(54d) (3S,10S)-10-[2-(ヒドロキシメチル)-6-メトキシ-3-(ピリジン-2-イル)フェニル]-2,7,7-トリメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例54cで製造した(3S,10S)-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(ピリジン-2-イル)フェニル]-2,7,7-トリメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメ[3,2-c]ピリジン-1,9(2H)-ジオン(281 mg, 0.441 mmol)、アニソール(240 μL, 2.21 mmol)、ジクロロメタン(3.5 mL)及びトリフルオロ酢酸(350 μL, 4.57 mmol)を用い、実施例34hに準じて反応及び後処理を行うことにより、標記化合物(189 mg, 83%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.79 (3H, d, J = 7.0 Hz), 0.82 (3H, d, J = 6.7 Hz), 0.97 (3H, s), 1.10 (3H, s ), 1.24 (9H, s), 1.89-1.93 (1H, m), 2.21 (2H, s), 2.34 (1H, d, J = 17.6 Hz), 2.45 (2H, dd, J = 3.9, 17.2 Hz) , 2.85 (1H, ddd, J = 0.4, 9.0, 16.4 Hz), 2.93 (3H, s), 3.08 (1H, t, J = 7.2 Hz), 3.69 (3H, s), 3.77 (3H, s), 4.37 (1H, d, J = 11.3 Hz), 4.54 (1H, d, J = 11.3 Hz), 5.06 (1H, d, J = 11.0 Hz), 5.40 (1H, s), 5.50 (1H, d, J = 11.3 Hz), 6.74 (3H, t, J = 8.0 Hz), 7.10-7.14 (3H, m), 7.23 (1H, d, J = 8.6 Hz), 7.55 (1H, td, J = 1.7, 7.7 Hz ), 7.67 (1H, d, J = 7.8 Hz), 8.55 (1H, d, J = 3.9 Hz).
(54d) (3S, 10S) -10- [2- (Hydroxymethyl) -6-methoxy-3- (pyridin-2-yl) phenyl] -2,7,7-trimethyl-3- (propane-2- Yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (3S, 10S) -10 prepared in Example 54c -[6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (pyridin-2-yl) phenyl] -2,7,7-trimethyl-3- (propan-2-yl) -3,4,6,7,8,10-Hexahydro-1H-chrome [3,2-c] pyridine-1,9 (2H) -dione (281 mg, 0.441 mmol), anisole (240 μL, 2.21 mmol) ), Dichloromethane (3.5 mL) and trifluoroacetic acid (350 μL, 4.57 mmol), and the reaction and post-treatment were performed according to Example 34h to obtain the title compound (189 mg, 83%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.84 (6H, t, J = 6.5 Hz), 0.96 (3H, s), 1.10 (3H, s), 1.91-2.00 (1H, m), 2.14 (1H, dd, J = 1.6, 16.4 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.36 (1H, dd, J = 1.6, 17.2 Hz), 2.49 (2H, d, J = 16.8 Hz), 2.86-2.94 (1H, m), 2.94 (3H, s), 3.11 (1H, t, J = 6.7 Hz), 3.72 (3H, s), 5.11 (1H, dd, J = 5.9, 11.3 Hz), 5.17 (1H, dd, J = 5.1, 12.9 Hz), 5.32 (1H, s), 6.29 (1H, t, J = 6.1 Hz), 6.82 (1H, d, J = 8.6 Hz), 7.20 (1H, ddd, J = 1.2, 4.7, 7.4 Hz), 7.50 (1H, d, J = 8.6 Hz), 7.73 (1H, td, J = 7.6, 2.0 Hz), 8.09-8.11 (1H, m), 8.64 (1H, dq, J = 4.8, 0.9 Hz).
(54e) 3-メトキシ-6-(ピリジン-2-イル)-2-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]安息香酸
　実施例54dで製造した(3S,10S)-10-[2-(ヒドロキシメチル)-6-メトキシ-3-(ピリジン-2-イル)フェニル]-2,7,7-トリメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(185 mg, 0.358 mmol)、リン酸バッファー(pH7.2, 10 mL)、アセトニトリル(15 mL)、亜塩素酸ナトリウム(101 mg, 1.12 mmol)、nor-AZADO (7.5 mg, 0.0543 mmol)及び次亜塩素酸ナトリウム水溶液(644 μL, 0.831 mmol) を用い、実施例34iに準じて反応及び後処理を行うことにより、標記化合物(135 mg, 71%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.84 (6H, t, J = 6.5 Hz), 0.96 (3H, s), 1.10 (3H, s), 1.91-2.00 (1H, m), 2.14 (1H, dd, J = 1.6, 16.4 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.36 (1H, dd, J = 1.6, 17.2 Hz), 2.49 (2H, d, J = 16.8 Hz) , 2.86-2.94 (1H, m), 2.94 (3H, s), 3.11 (1H, t, J = 6.7 Hz), 3.72 (3H, s), 5.11 (1H, dd, J = 5.9, 11.3 Hz), 5.17 (1H, dd, J = 5.1, 12.9 Hz), 5.32 (1H, s), 6.29 (1H, t, J = 6.1 Hz), 6.82 (1H, d, J = 8.6 Hz), 7.20 (1H, ddd , J = 1.2, 4.7, 7.4 Hz), 7.50 (1H, d, J = 8.6 Hz), 7.73 (1H, td, J = 7.6, 2.0 Hz), 8.09-8.11 (1H, m), 8.64 (1H, dq, J = 4.8, 0.9 Hz).
(54e) 3-Methoxy-6- (pyridin-2-yl) -2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl)- 2,3,4,6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzoic acid Prepared in Example 54d (3S, 10S) -10- [2- (hydroxymethyl) -6-methoxy-3- (pyridin-2-yl) phenyl] -2,7,7-trimethyl-3- (propan-2-yl) -3,4,6,7, 8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (185 mg, 0.358 mmol), phosphate buffer (pH 7.2, 10 mL), acetonitrile (15 mL ), Sodium chlorite (101 mg, 1.12 mmol), nor-AZADO (7.5 mg, 0.0543 mmol) and aqueous sodium hypochlorite solution (644 μL, 0.831 mmol), and the reaction was carried out according to Example 34i. The title compound (135 mg, 71%) was obtained by treatment.
(実施例55)
　3-メトキシ-2-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-6-(ピリジン-2-イル)安息香酸
(55a) 10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3,7,7-テトラメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例34dで製造した2-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン(5.58 g, 10.4 mmol)、6,6-ジメチルピペリジン-2,4-ジオン(1.62 g, 11.5 mmol)、アセトニトリル(40 mL)、炭酸セシウム(4.08 g, 12.5 mmol)、トリブチルホスフィン(3.13 mL, 12.5 mmol)、DMF (40 mL)及びビス(2-メトキシエチル)アゾジカルボキシレート(2.93 g, 12.5 mmol)を用い、実施例15aに準じて反応及び後処理を行うことにより、標記化合物(1.98 g, 29%)を得た。 
1H-NMR(400MHz, CDCl3):δ ppm: 0.92 (3H, s), 1.07 (3H, s), 1.13 (3H, s), 1.23 (12H, s), 1.27 (3H, s), 2.09 (1H, d, J = 16.4 Hz), 2.17 (1H, d, J = 16.4 Hz), 2.30 (2H, dd, J = 2.7, 17.2 Hz), 2.42 (1H, d, J = 18.0 Hz), 2.61 (1H, d, J = 18.4 Hz), 3.69 (3H, s), 3.79 (3H, s), 4.60 (1H, d, J = 11.7 Hz), 4.63 (1H, d, J = 11.7 Hz), 4.99 (1H, s), 5.01 (1H, s), 5.32 (1H, d, J = 12.5 Hz), 5.37 (1H, d, J = 13.7 Hz), 6.66 (1H, d, J = 7.8 Hz), 6.84 (2H, dd, J = 2.0, 6.7 Hz), 7.34 (1H, d, J = 7.8 Hz), 7.45 (2H, d, J = 8.6 Hz).
(55b) 10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例55aで製造した10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3,7,7-テトラメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(1.98 g, 3.01 mmol)、ヨウ化メチル(469 μL, 7.53 mmol)、DMF (20 mL)及び水素化ナトリウム(63%, 229 mg, 6.02 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(1.49 g, 74%)を得た。 Example 55
3-Methoxy-2-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -6- (pyridin-2-yl) benzoic acid
(55a) 10- [6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) Phenyl] -3,3,7,7-tetramethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 2- [6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 prepared in Example 34d -Yl) benzylidene] -5,5-dimethylcyclohexane-1,3-dione (5.58 g, 10.4 mmol), 6,6-dimethylpiperidine-2,4-dione (1.62 g, 11.5 mmol), acetonitrile (40 mL) ), Cesium carbonate (4.08 g, 12.5 mmol), tributylphosphine (3.13 mL, 12.5 mmol), DMF (40 mL) and bis (2-methoxyethyl) azodicarboxylate (2.93 g, 12.5 mmol) The title compound (1.98 g, 29%) was obtained by reaction and workup according to Example 15a.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.92 (3H, s), 1.07 (3H, s), 1.13 (3H, s), 1.23 (12H, s), 1.27 (3H, s), 2.09 (1H, d, J = 16.4 Hz), 2.17 (1H, d, J = 16.4 Hz), 2.30 (2H, dd, J = 2.7, 17.2 Hz), 2.42 (1H, d, J = 18.0 Hz), 2.61 (1H, d, J = 18.4 Hz), 3.69 (3H, s), 3.79 (3H, s), 4.60 (1H, d, J = 11.7 Hz), 4.63 (1H, d, J = 11.7 Hz), 4.99 (1H, s), 5.01 (1H, s), 5.32 (1H, d, J = 12.5 Hz), 5.37 (1H, d, J = 13.7 Hz), 6.66 (1H, d, J = 7.8 Hz), 6.84 (2H, dd, J = 2.0, 6.7 Hz), 7.34 (1H, d, J = 7.8 Hz), 7.45 (2H, d, J = 8.6 Hz).
(55b) 10- [6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) Phenyl] -2,3,3,7,7-pentamethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 10- [6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-- prepared in Example 55a 2-yl) phenyl] -3,3,7,7-tetramethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) Reaction according to Example 2a with dione (1.98 g, 3.01 mmol), methyl iodide (469 μL, 7.53 mmol), DMF (20 mL) and sodium hydride (63%, 229 mg, 6.02 mmol) And the post-treatment was performed to obtain the title compound (1.49 g, 74%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.92 (3H, s), 1.04 (3H, s), 1.06 (3H, s), 1.23 (12H, d, J = 5.9 Hz), 1.31 (3H, s), 2.09 (1H, d, J = 16.0 Hz), 2.17 (1H, d, J = 16.4 Hz), 2.25 (1H, d, J = 16.8 Hz), 2.30 (1H, d, J = 18.0 Hz), 2.41 (1H, d, J = 17.6 Hz), 2.60 (1H, d, J = 17.2 Hz), 2.75 (3H, s), 3.68 (3H, s), 3.79 (3H, s), 4.65 (2H, s), 5.00 (1H, s), 5.35 (1H, d, J = 12.9 Hz), 5.42 (1H, d, J = 13.3 Hz), 6.65 (1H, d, J = 8.2 Hz), 6.84 (2H, dd, J = 6.7, 2.3 Hz), 7.32 (1H, d, J = 8.2 Hz), 7.47 (2H, d, J = 8.6 Hz).
(55c) 10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(ピリジン-2-イル)フェニル]-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例55bで製造した10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(1.49 g, 2.22 mmol)、2-クロロピリジン(378 mg, 3.33 mmol)、2nd Generation X-Phos Precatalyst (175 mg, 0.222 mmol)、リン酸カリウム(848 mg, 3.99 mmol)、THF (11 mL)及び水(11 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(504 mg, 37%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.92 (3H, s), 1.04 (3H, s), 1.06 (3H, s), 1.23 (12H, d, J = 5.9 Hz), 1.31 (3H , s), 2.09 (1H, d, J = 16.0 Hz), 2.17 (1H, d, J = 16.4 Hz), 2.25 (1H, d, J = 16.8 Hz), 2.30 (1H, d, J = 18.0 Hz) ), 2.41 (1H, d, J = 17.6 Hz), 2.60 (1H, d, J = 17.2 Hz), 2.75 (3H, s), 3.68 (3H, s), 3.79 (3H, s), 4.65 (2H , s), 5.00 (1H, s), 5.35 (1H, d, J = 12.9 Hz), 5.42 (1H, d, J = 13.3 Hz), 6.65 (1H, d, J = 8.2 Hz), 6.84 (2H , dd, J = 6.7, 2.3 Hz), 7.32 (1H, d, J = 8.2 Hz), 7.47 (2H, d, J = 8.6 Hz).
(55c) 10- [6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (pyridin-2-yl) phenyl] -2,3,3,7,7-pentamethyl-3 , 4,6,7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 10- [6-Methoxy-2-{[ (4-Methoxybenzyl) oxy] methyl} -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2,3,3,7,7- Pentamethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (1.49 g, 2.22 mmol), 2-chloropyridine (378 mg, 3.33 mmol), 2nd Generation X-Phos Precatalyst (175 mg, 0.222 mmol), potassium phosphate (848 mg, 3.99 mmol), THF (11 mL) and water (11 mL), according to Example 9d The title compound (504 mg, 37%) was obtained by reaction and workup.
1H-NMR(400MHz, CDCl3):δ ppm: 0.96 (3H, s), 1.07 (3H, s), 1.10 (3H, s), 1.34 (3H, s), 2.18 (1H, d, J = 16.0 Hz), 2.23 (1H, d, J = 16.4 Hz), 2.30 (1H, d, J = 16.4 Hz), 2.34 (1H, d, J = 18.0 Hz), 2.46 (1H, d, J = 17.6 Hz), 2.64 (1H, d, J = 17.2 Hz), 2.78 (3H, s), 3.73 (3H, s), 3.77 (3H, s), 4.37 (1H, d, J = 11.3 Hz), 4.52 (1H, d, J = 11.3 Hz), 5.12 (1H, d, J = 11.3 Hz), 5.36 (1H, s), 5.48 (1H, d, J = 11.3 Hz), 6.74-6.78 (3H, m), 7.09-7.14 (3H, m), 7.22 (1H, d, J = 8.6 Hz), 7.55 (1H, td, J = 1.8, 7.7 Hz), 7.67 (1H, d, J = 9.0 Hz), 8.54-8.56 (1H, m).
(55d) (10S)-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(ピリジン-2-イル)フェニル]-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例55cで製造した10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(ピリジン-2-イル)フェニル]-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(504 mg)をChiral flash IA(ヘキサン/エタノール; 1:4)により光学分割し、高極性化合物(201 mg)及び低極性化合物(222 mg)を得た。
(55e) (10S)-10-[2-(ヒドロキシメチル)-6-メトキシ-3-(ピリジン-2-イル)フェニル]-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例55dで製造した(10S)-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(ピリジン-2-イル)フェニル]-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(198 mg, 0.318 mmol)、アニソール(173 μL, 1.59 mmol)、ジクロロメタン(2.5 mL)及びトリフルオロ酢酸(244 μL, 3.19 mmol)を用い、実施例34hに準じて反応及び後処理を行うことにより、標記化合物(172 mg, 92%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.96 (3H, s), 1.07 (3H, s), 1.10 (3H, s), 1.34 (3H, s), 2.18 (1H, d, J = 16.0 Hz), 2.23 (1H, d, J = 16.4 Hz), 2.30 (1H, d, J = 16.4 Hz), 2.34 (1H, d, J = 18.0 Hz), 2.46 (1H, d, J = 17.6 Hz) ), 2.64 (1H, d, J = 17.2 Hz), 2.78 (3H, s), 3.73 (3H, s), 3.77 (3H, s), 4.37 (1H, d, J = 11.3 Hz), 4.52 (1H , d, J = 11.3 Hz), 5.12 (1H, d, J = 11.3 Hz), 5.36 (1H, s), 5.48 (1H, d, J = 11.3 Hz), 6.74-6.78 (3H, m), 7.09 -7.14 (3H, m), 7.22 (1H, d, J = 8.6 Hz), 7.55 (1H, td, J = 1.8, 7.7 Hz), 7.67 (1H, d, J = 9.0 Hz), 8.54-8.56 ( 1H, m).
(55d) (10S) -10- [6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (pyridin-2-yl) phenyl] -2,3,3,7,7 -Pentamethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 10- [6-Methoxy-produced in Example 55c 2-{[(4-Methoxybenzyl) oxy] methyl} -3- (pyridin-2-yl) phenyl] -2,3,3,7,7-pentamethyl-3,4,6,7,8,10 -Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (504 mg) was optically resolved with Chiral flash IA (hexane / ethanol; 1: 4) to obtain a highly polar compound (201 mg) and a low polarity compound (222 mg).
(55e) (10S) -10- [2- (Hydroxymethyl) -6-methoxy-3- (pyridin-2-yl) phenyl] -2,3,3,7,7-pentamethyl-3,4,6 , 7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (10S) -10- [6-methoxy-2-{[ (4-Methoxybenzyl) oxy] methyl} -3- (pyridin-2-yl) phenyl] -2,3,3,7,7-pentamethyl-3,4,6,7,8,10-hexahydro-1H -Chromeno [3,2-c] pyridine-1,9 (2H) -dione (198 mg, 0.318 mmol), anisole (173 μL, 1.59 mmol), dichloromethane (2.5 mL) and trifluoroacetic acid (244 μL, 3.19 The title compound (172 mg, 92%) was obtained by reaction and workup according to Example 34h.
1H-NMR(400MHz, CDCl3):δ ppm: 0.94 (3H, s), 1.10 (3H, s), 1.13 (3H, s), 1.36 (3H, s), 2.13 (1H, dd, J = 1.2, 16.4 Hz), 2.24 (1H, d, J = 16.8 Hz), 2.33-2.39 (2H, m), 2.49 (1H, d, J = 18.0 Hz), 2.67 (1H, d, J = 16.4 Hz), 2.81 (3H, s), 3.76 (3H, s), 4.98 (1H, dd, J = 6.6, 12.5 Hz), 5.28-5.32 (1H, m), 5.28 (1H, s), 6.35 (1H, t, J = 4.3 Hz), 6.86 (1H, d, J = 8.6 Hz), 7.20 (1H, ddd, J = 1.2, 4.7, 7.4 Hz), 7.50 (1H, d, J = 8.6 Hz), 7.74 (1H, td, J = 2.0, 7.8 Hz), 8.09 (1H, d, J = 7.8 Hz), 8.63-8.65 (1H, m).
(55f) 3-メトキシ-2-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-6-(ピリジン-2-イル)安息香酸
　実施例55eで製造した(10S)-10-[2-(ヒドロキシメチル)-6-メトキシ-3-(ピリジン-2-イル)フェニル]-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(169 mg, 0.288 mmol)、リン酸バッファー(pH7.2, 10 mL)、アセトニトリル(15 mL)、亜塩素酸ナトリウム(81.3 mg, 0.719 mmol)、nor-AZADO (59.6 mg, 0.431 mmol)及び次亜塩素酸ナトリウム水溶液(357 μL, 0.401 mmol) を用い、実施例34iに準じて反応及び後処理を行うことにより、標記化合物(125 mg, 84%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.94 (3H, s), 1.10 (3H, s), 1.13 (3H, s), 1.36 (3H, s), 2.13 (1H, dd, J = 1.2, 16.4 Hz), 2.24 (1H, d, J = 16.8 Hz), 2.33-2.39 (2H, m), 2.49 (1H, d, J = 18.0 Hz), 2.67 (1H, d, J = 16.4 Hz) , 2.81 (3H, s), 3.76 (3H, s), 4.98 (1H, dd, J = 6.6, 12.5 Hz), 5.28-5.32 (1H, m), 5.28 (1H, s), 6.35 (1H, t , J = 4.3 Hz), 6.86 (1H, d, J = 8.6 Hz), 7.20 (1H, ddd, J = 1.2, 4.7, 7.4 Hz), 7.50 (1H, d, J = 8.6 Hz), 7.74 (1H , td, J = 2.0, 7.8 Hz), 8.09 (1H, d, J = 7.8 Hz), 8.63-8.65 (1H, m).
(55f) 3-Methoxy-2-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl] -6- (pyridin-2-yl) benzoic acid (10S) -10- [2- (hydroxymethyl) -6-prepared in Example 55e Methoxy-3- (pyridin-2-yl) phenyl] -2,3,3,7,7-pentamethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] Pyridine-1,9 (2H) -dione (169 mg, 0.288 mmol), phosphate buffer (pH 7.2, 10 mL), acetonitrile (15 mL), sodium chlorite (81.3 mg, 0.719 mmol), nor- Using AZADO (59.6 mg, 0.431 mmol) and sodium hypochlorite aqueous solution (357 μL, 0.401 mmol), the title compound (125 mg, 84%) was obtained by reacting and working up according to Example 34i. Obtained.
(実施例56)
　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
(56a) 6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例42gで製造した6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(40.0 mg, 0.0698 mmol)、カルボニルジイミダゾール(18.1 mg, 0.112 mmol)、DMF (0.4 mL)、メタンスルホンアミド(10.6 mg, 0.112 mmol)及びDBU (17 μL, 0.112 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(35.0 mg, 77%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.77 (3H, d, J = 6.6 Hz), 0.97 (3H, d, J = 7.0 Hz), 1.79-1.92 (7H, m), 2.22-2.50 (5H, m), 2.59 (1H, d, J = 18.0 Hz), 2.77 (6H, s), 2.83 (3H, s), 3.26 (1H, t, J = 10.4 Hz), 3.34-3.39 (1H, m), 3.38 (3H, s), 3.73 (3H, s), 3.85 (1H, td, J = 3.9, 12.1 Hz), 4.41 (1H, d, J = 8.2 Hz), 6.70 (1H, d, J = 9.0 Hz), 7.18 (1H, d, J = 8.6 Hz), 7.62 (1H, d, J = 8.2 Hz), 7.65 (1H, d, J = 7.8 Hz).
(56b) 6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
　実施例56aで製造した6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド(35.0 mg, 0.0539 mmol)、エタノール(0.7 mL)及びtert-ブチルアミン(11 μL, 0.108 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(31.0 mg, 80%)を得た。 Example 56
6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3, 4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl] phenyl} -3-methyl-N- ( Methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt
(56a) 6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2 , 3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl] phenyl} -3-methyl- N- (Methylsulfonyl) pyridine-2-carboxamide 6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo prepared in Example 42g -3- (propan-2-yl) -1,2,3,4,4a, 6,8,9,10,10a-decahydrospiro [chromeno [3,2-c] pyridine-7,1'- Cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid (40.0 mg, 0.0698 mmol), carbonyldiimidazole (18.1 mg, 0.112 mmol), DMF (0.4 mL), methanesulfonamide (10.6 mg , 0.112 mmol) and DBU (17 μL, 0.112 mmol) were used for the reaction and post-treatment according to Example 6a to obtain the title compound (35.0 mg, 77%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.77 (3H, d, J = 6.6 Hz), 0.97 (3H, d, J = 7.0 Hz), 1.79-1.92 (7H, m), 2.22-2.50 (5H, m), 2.59 (1H, d, J = 18.0 Hz), 2.77 (6H, s), 2.83 (3H, s), 3.26 (1H, t, J = 10.4 Hz), 3.34-3.39 (1H, m), 3.38 (3H, s), 3.73 (3H, s), 3.85 (1H, td, J = 3.9, 12.1 Hz), 4.41 (1H, d, J = 8.2 Hz), 6.70 (1H, d, J = 9.0 Hz), 7.18 (1H, d, J = 8.6 Hz), 7.62 (1H, d, J = 8.2 Hz), 7.65 (1H, d, J = 7.8 Hz).
(56b) 6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2 , 3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl] phenyl} -3-methyl- N- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1 prepared in Example 56a , 9-Dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6,8,9,10,10a-decahydrospiro [chromeno [3,2-c] pyridine-7 , 1'-cyclobutane] -10-yl] phenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide (35.0 mg, 0.0539 mmol), ethanol (0.7 mL) and tert-butylamine (11 μL, The title compound (31.0 mg, 80%) was obtained by performing the reaction and post-treatment according to Example 3c using 0.108 mmol).
(実施例57)
　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3,4-ジメチルピリジン-2-カルボン酸 tert-ブチルアミン塩
(57a) 3,4-ジメチルピリジン-2-カルボニトリル　1-オキシド
　3,4-ジメチルピリジン-2-カルボニトリル(30.0 g, 227 mmol)、オキソン(101 g, 363 mmol)のメタノール(150 mL)及び水(150 mL)溶液を48時間室温で攪拌した。反応溶液をろ過後、チオ硫酸ナトリウム(3.0 g)及び塩化ナトリウム(33 g)を加え、反応溶液を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減圧濃縮し、標記化合物(33.3 g, 99%)を得た。
1H-NMR(400MHz, DMSO-d6):δ ppm: 2.26 (3H, s), 2.38 (3H, s), 7.49 (1H, d, J = 6.7 Hz), 8.25 (1H, d, J = 6.7 Hz).
(57b) 6-クロロ-3,4-ジメチルピリジン-2-カルボニトリル
　実施例57aで製造した3,4-ジメチルピリジン-2-カルボニトリル　1-オキシド(33.3 g, 225 mmol)の塩化ホスホリル(165 mL, 1.80 mol)溶液を120℃で12時間攪拌した。冷却した反応溶液を氷冷水(2.0 L)に流し込み、析出した結晶をろ取し、標記化合物(32.7 g, 87%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 2.36 (3H, s), 2.47 (3H, s), 7.33 (1H, s).
(57c) 6-クロロ-3,4-ジメチルピリジン-2-カルボン酸
　実施例57bで製造した6-クロロ-3,4-ジメチルピリジン-2-カルボニトリル(28.3 g, 170 mmol)及び水酸化カリウム(33.6 g, 510 mmol)の水(556 mL)溶液を120℃で2時間攪拌した。冷却した反応溶液に2 M塩酸(265 mL)を加え、反応溶液を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減圧濃縮し、標記化合物(28.3 g, 90%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 2.26 (3H, brs), 2.49 (3H, brs), 7.07 (1H, brs).
(57d) tert-ブチル　6-クロロ-3,4-ジメチルピリジン-2-カルボキシレート
　実施例57cで製造した6-クロロ-3,4-ジメチルピリジン-2-カルボン酸(15.0 g, 80.8 mmol)及びピリジン(45.0 mL)のtert-ブタノール(135 mL)溶液に0℃でp-トルエンスルホニルクロリド(38.5 g, 202 mmol)を加えた。反応溶液を室温で16時間攪拌後、飽和炭酸水素ナトリウム水溶液を加え、反応溶液を酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した後、減圧濃縮し、標記化合物(19.3 g, 99%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 1.62 (9H, s), 2.29 (3H, s), 2.39 (3H, s), 7.18 (1H, s).
(57e) tert-ブチル　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3,4-ジメチルピリジン-2-カルボキシレート
　実施例47aで製造した(3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3-(プロパン-2-イル)-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(336 mg, 0.609 mmol)、実施例57dで製造したtert-ブチル　6-クロロ-3,4-ジメチルピリジン-2-カルボキシレート(177 mg, 0.731 mmol)、2nd Generation X-Phos Precatalyst (95.9 mg, 0.122 mmol)、リン酸カリウム(197 mg, 0.975 mmol)、THF (3.4 mL)及び水(6.7 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(313 mg, 81%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.76 (3H, d, J = 7.0 Hz), 0.92 (3H, s), 0.96 (3H, d, J = 7.0 Hz), 1.04 (3H, s), 1.63 (9H, s), 1.78-1.86 (1H, m), 2.02 (1H, dd, J = 2.0, 15.7 Hz), 2.14 (1H, d, J = 16.4 Hz), 2.21-2.42 (4H, m), 2.31 (3H, s), 2.33 (3H, s), 2.81 (3H, s), 2.83 (3H, s), 3.21 (1H, dd, J = 10.2, 11.7 Hz), 3.33-3.38 (1H, m), 3.71 (3H, s), 3.80 (1H, dt, J = 3.9, 11.0 Hz), 4.51 (1H, d, J = 9.0 Hz), 6.66 (1H, d, J = 8.6 Hz), 7.21 (1H, d, J = 8.6 Hz), 7.27 (1H, s).
(57f) 6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3,4-ジメチルピリジン-2-カルボン酸 tert-ブチルアミン塩
　実施例57eで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3,4-ジメチルピリジン-2-カルボキシレート(313 mg, 0.496 mmol)、ジクロロメタン(3.1 mL)及びトリフルオロ酢酸(1.6 mL)、エタノール(1.0 mL)及びtert-ブチルアミン(104 μL, 0.992 mmol)を用い、実施例41fに準じて反応及び後処理を行うことにより、標記化合物(310 mg, 96%)を得た。 (Example 57)
6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2, 3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3,4-dimethylpyridine-2-carboxylic acid tert-Butylamine salt
(57a) 3,4-Dimethylpyridine-2-carbonitrile 1-oxide 3,4-Dimethylpyridine-2-carbonitrile (30.0 g, 227 mmol), Oxone (101 g, 363 mmol) in methanol (150 mL) And the water (150 mL) solution was stirred at room temperature for 48 hours. The reaction solution was filtered, sodium thiosulfate (3.0 g) and sodium chloride (33 g) were added, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (33.3 g, 99%).
1 H-NMR (400 MHz, DMSO-d 6 ): δ ppm: 2.26 (3H, s), 2.38 (3H, s), 7.49 (1H, d, J = 6.7 Hz), 8.25 (1H, d, J = (6.7 Hz).
(57b) 6-chloro-3,4-dimethylpyridine-2-carbonitrile 3,4-dimethylpyridine-2-carbonitrile 1-oxide prepared in Example 57a (33.3 g, 225 mmol) phosphoryl chloride (165 (mL, 1.80 mol) solution was stirred at 120 ° C. for 12 hours. The cooled reaction solution was poured into ice-cold water (2.0 L), and the precipitated crystals were collected by filtration to obtain the title compound (32.7 g, 87%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 2.36 (3H, s), 2.47 (3H, s), 7.33 (1H, s).
(57c) 6-chloro-3,4-dimethylpyridine-2-carboxylic acid 6-chloro-3,4-dimethylpyridine-2-carbonitrile prepared in Example 57b (28.3 g, 170 mmol) and potassium hydroxide A solution of (33.6 g, 510 mmol) in water (556 mL) was stirred at 120 ° C. for 2 hours. 2 M hydrochloric acid (265 mL) was added to the cooled reaction solution, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (28.3 g, 90%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 2.26 (3H, brs), 2.49 (3H, brs), 7.07 (1H, brs).
(57d) tert-butyl 6-chloro-3,4-dimethylpyridine-2-carboxylate 6-chloro-3,4-dimethylpyridine-2-carboxylic acid prepared in Example 57c (15.0 g, 80.8 mmol) and P-Toluenesulfonyl chloride (38.5 g, 202 mmol) was added to a solution of pyridine (45.0 mL) in tert-butanol (135 mL) at 0 ° C. The reaction solution was stirred at room temperature for 16 hours, saturated aqueous sodium hydrogen carbonate solution was added, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (19.3 g, 99%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.62 (9H, s), 2.29 (3H, s), 2.39 (3H, s), 7.18 (1H, s).
(57e) tert-butyl 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propane-2 -Yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3,4-dimethyl Pyridine-2-carboxylate (3S, 4aS, 10S, 10aR) -10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3) prepared in Example 47a , 2-Dioxaborolan-2-yl) phenyl] -2,7,7-trimethyl-3- (propan-2-yl) -3,4,4a, 6,7,8,10,10a-octahydro-1H- Chromeno [3,2-c] pyridine-1,9 (2H) -dione (336 mg, 0.609 mmol), tert-butyl 6-chloro-3,4-dimethylpyridine-2-carboxylate prepared in Example 57d (177 mg, 0.731 mmol), 2nd Generation X-Phos Precatalyst (95.9 mg, 0.122 mmol), potassium phosphate (197 mg, 0.975 mmol), THF (3.4 mL) and water (6.7 mL), Example 9d The title compound (313 mg, 81%) was obtained by reacting and working up according to.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.76 (3H, d, J = 7.0 Hz), 0.92 (3H, s), 0.96 (3H, d, J = 7.0 Hz), 1.04 (3H, s ), 1.63 (9H, s), 1.78-1.86 (1H, m), 2.02 (1H, dd, J = 2.0, 15.7 Hz), 2.14 (1H, d, J = 16.4 Hz), 2.21-2.42 (4H, m), 2.31 (3H, s), 2.33 (3H, s), 2.81 (3H, s), 2.83 (3H, s), 3.21 (1H, dd, J = 10.2, 11.7 Hz), 3.33-3.38 (1H , m), 3.71 (3H, s), 3.80 (1H, dt, J = 3.9, 11.0 Hz), 4.51 (1H, d, J = 9.0 Hz), 6.66 (1H, d, J = 8.6 Hz), 7.21 (1H, d, J = 8.6 Hz), 7.27 (1H, s).
(57f) 6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3,4-dimethylpyridine-2 -Carboxylic acid tert-butylamine salt tert-butyl 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1, prepared in Example 57e 9-Dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridine-10- Yl] phenyl} -3,4-dimethylpyridine-2-carboxylate (313 mg, 0.496 mmol), dichloromethane (3.1 mL) and trifluoroacetic acid (1.6 mL), ethanol (1.0 mL) and tert-butylamine (104 μL , 0.992 mmol), and the reaction and post-treatment were performed according to Example 41f to obtain the title compound (310 mg, 96%).
(実施例58)
　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボン酸 tert-ブチルアミン塩
(58a) tert-ブチル　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボキシレート
　実施例47aで製造した(3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3-(プロパン-2-イル)-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(100 mg, 0.181 mmol)、tert-ブチル　6-クロロピリジン-2-カルボキシレート(56.2 mg, 0.218 mmol)、2nd Generation X-Phos Precatalyst (14.3 mg, 0.0181 mmol)、リン酸カリウム(57.7 mg, 0.272 mmol)、THF (1.5 mL)及び水(1.5 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(96.1 mg, 88%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.76 (3H, d, J = 6.7 Hz), 0.93 (3H, s), 0.96 (3H, d, J = 7.0 Hz), 1.05 (3H, s), 1.64 (9H, s), 1.78-1.88 (1H, m), 2.02 (1H, dd, J = 2.3, 16.8 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.23-2.42 (4H, m), 2.82 (6H, s), 3.23 (1H, t, J = 10.4 Hz), 3.33-3.39 (1H, m), 3.73 (3H, s), 3.81 (1H, td, J = 4.3, 11.5 Hz), 4.50 (1H, d, J = 9.0 Hz), 6.69 (1H, d, J = 8.6 Hz), 7.33 (1H, d, J = 8.6 Hz), 7.60 (1H, dd, J = 0.8, 7.8 Hz), 7.75 (1H, t, J = 7.8 Hz), 7.90 (1H, dd, J = 1.0, 7.6 Hz).
(58b) 6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボン酸
　実施例58aで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボキシレート(92.1 mg, 0.153 mmol)、ジクロロメタン(1.0 mL)及びトリフルオロ酢酸(1.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(72.2 mg, 86%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.77 (3H, d, J = 6.7 Hz), 0.96 (3H, s), 0.97 (3H, d, J = 6.3 Hz), 1.06 (3H, s), 1.78-1.89 (1H, m), 2.05 (1H, dd, J = 2.0, 16.0 Hz), 2.17 (1H, d, J = 16.4 Hz), 2.22-2.43 (4H, m), 2.79 (3H, s), 2.83 (3H, s), 3.35-3.41 (1H, m), 3.27 (1H, t, J = 11.0 Hz), 3.75 (3H, s), 3.86 (1H, td, J = 4.3, 11.5 Hz), 4.45 (1H, d, J = 9.4 Hz), 6.73 (1H, d, J = 8.6 Hz), 7.19 (1H, d, J = 8.6 Hz), 7.73 (1H, dd, J = 0.8, 7.8 Hz), 7.93 (1H, t, J = 7.6 Hz), 8.14 (1H, dd, J = 1.0, 7.6 Hz).
(58c) 6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボン酸 tert-ブチルアミン塩
　実施例58bで製造した6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボン酸(66.6 mg, 0.122 mmol)、酢酸エチル(0.7 mL)及びtert-ブチルアミン(26 μL, 0.244 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(60.3 mg, 80%)を得た。 (Example 58)
6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2, 3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} pyridine-2-carboxylic acid tert-butylamine salt
(58a) tert-butyl 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propane-2 -Yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} pyridine-2-carboxylate (3S, 4aS, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) prepared in Example 47a -Yl) phenyl] -2,7,7-trimethyl-3- (propan-2-yl) -3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2- c] pyridine-1,9 (2H) -dione (100 mg, 0.181 mmol), tert-butyl 6-chloropyridine-2-carboxylate (56.2 mg, 0.218 mmol), 2nd Generation X-Phos Precatalyst (14.3 mg, 0.0181 mmol), potassium phosphate (57.7 mg, 0.272 mmol), THF (1.5 mL) and water (1.5 mL) were used for the reaction and workup according to Example 9d to give the title compound (96.1 mg, 88%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.76 (3H, d, J = 6.7 Hz), 0.93 (3H, s), 0.96 (3H, d, J = 7.0 Hz), 1.05 (3H, s ), 1.64 (9H, s), 1.78-1.88 (1H, m), 2.02 (1H, dd, J = 2.3, 16.8 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.23-2.42 (4H, m), 2.82 (6H, s), 3.23 (1H, t, J = 10.4 Hz), 3.33-3.39 (1H, m), 3.73 (3H, s), 3.81 (1H, td, J = 4.3, 11.5 Hz ), 4.50 (1H, d, J = 9.0 Hz), 6.69 (1H, d, J = 8.6 Hz), 7.33 (1H, d, J = 8.6 Hz), 7.60 (1H, dd, J = 0.8, 7.8 Hz) ), 7.75 (1H, t, J = 7.8 Hz), 7.90 (1H, dd, J = 1.0, 7.6 Hz).
(58b) 6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} pyridine-2-carboxylic acid Example 58a Tert-butyl 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propane-2 -Yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} pyridine-2-carboxylate (92.1 mg, 0.153 mmol), dichloromethane (1.0 mL) and trifluoroacetic acid (1.0 mL) were used for the reaction and workup according to Example 1d to obtain the title compound (72.2 mg, 86%). It was.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.77 (3H, d, J = 6.7 Hz), 0.96 (3H, s), 0.97 (3H, d, J = 6.3 Hz), 1.06 (3H, s ), 1.78-1.89 (1H, m), 2.05 (1H, dd, J = 2.0, 16.0 Hz), 2.17 (1H, d, J = 16.4 Hz), 2.22-2.43 (4H, m), 2.79 (3H, s), 2.83 (3H, s), 3.35-3.41 (1H, m), 3.27 (1H, t, J = 11.0 Hz), 3.75 (3H, s), 3.86 (1H, td, J = 4.3, 11.5 Hz ), 4.45 (1H, d, J = 9.4 Hz), 6.73 (1H, d, J = 8.6 Hz), 7.19 (1H, d, J = 8.6 Hz), 7.73 (1H, dd, J = 0.8, 7.8 Hz) ), 7.93 (1H, t, J = 7.6 Hz), 8.14 (1H, dd, J = 1.0, 7.6 Hz).
(58c) 6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} pyridine-2-carboxylic acid tert-butylamine Salt 6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propane-) prepared in Example 58b 2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} pyridine-2-carboxylic The title compound (60.3 mg, 0.122 mmol), ethyl acetate (0.7 mL) and tert-butylamine (26 μL, 0.244 mmol) were subjected to reaction and workup according to Example 3c. 80%).
(実施例59)
　6-{3-[(3S,4aS,10S,10aR)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸 tert-ブチルアミン塩
(59a) tert-ブチル　6-{3-[(3S,4aS,10S,10aR)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例27bで製造した(3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(140 mg, 0.261 mmol)、tert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(, 70.9 mg, 0.311 mmol)、2nd Generation X-Phos Precatalyst (38.5 mg, 0.0489 mmol)、リン酸カリウム(89.0 mg, 0.419 mmol)、THF (1.5 mL)及び水(3.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(118 mg, 75%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.92-0.95 (9H, m), 1.05 (3H, s), 1.64 (9H, s), 1.66-1.84 (2H, m), 2.03 (1H, d, J = 17.6 Hz), 2.14 (1H, d, J = 16.4 Hz), 2.24-2.42 (3H, m), 2.49 (3H, s), 2.71 (3H, s), 3.24-3.30 (1H, m), 3.37 (1H, t, J = 10.6 Hz), 3.72 (3H, s), 3.90 (1H, td, J = 3.0, 11.5 Hz), 4.40 (1H, d, J = 9.7 Hz), 5.39 (1H, s), 6.68 (1H, d, J = 8.5 Hz), 7.27 (1H, d, J = 8.5 Hz), 7.39 (1H, d, J = 7.9 Hz), 7.51 (1H, d, J = 8.5 Hz).
(59b) 6-{3-[(3S,4aS,10S,10aR)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例59aで製造したtert-ブチル　6-{3-[(3S,4aS,10S,10aR)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート (118 mg, 0.196 mmol)、クロロホルム(2.0 mL)及びトリフルオロ酢酸(1.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(87.0 mg, 81%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.94 (3H, d, J = 6.7 Hz), 0.96 (3H, d, J = 6.7 Hz), 0.98 (3H, s), 1.07 (3H, s), 1.68-1.86 (2H, m), 2.06 (1H, d, J = 16.4 Hz), 2.18 (1H, d, J = 16.4 Hz), 2.27-2.45 (3H, m), 2.69 (3H, s), 2.81 (3H, s), 3.28-3.33 (1H, m), 3.39 (1H, t, J = 10.3 Hz), 3.75 (3H, s), 3.95 (1H, td, J = 3.6, 11.5 Hz), 4.39 (1H, d, J = 9.7 Hz), 5.64 (1H, s), 6.73 (1H, d, J = 8.5 Hz), 7.19 (1H, d, J = 8.5 Hz), 7.60 (1H, d, J = 7.9 Hz), 7.71 (1H, d, J = 7.9 Hz).
MS(ESI/APCI)m/z: 547[M+H]+.
(59c) 6-{3-[(3S,4aS,10S,10aR)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸 tert-ブチルアミン塩
　実施例59bで製造した6-{3-[(3S,4aS,10S,10aR)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(87.0 mg, 0.159 mmol)、エタノール(2.0 mL)及びtert-ブチルアミン(22 μL, 0.210 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(87.1 mg, 88%)を得た。 (Example 59)
6- {3-[(3S, 4aS, 10S, 10aR) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7, 8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(59a) tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4, 4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2- Carboxylate (3S, 4aS, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane) prepared in Example 27b -2-yl) phenyl] -7,7-dimethyl-3- (propan-2-yl) -3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2- c] Pyridine-1,9 (2H) -dione (140 mg, 0.261 mmol), tert-butyl 6-chloro-3-methylpyridine-2-carboxylate (, 70.9 mg, 0.311 mmol), 2nd Generation X-Phos Precatalyst (38.5 mg, 0.0489 mmol), potassium phosphate (89.0 mg, 0.419 mmol), THF (1.5 mL) and water (3.0 mL) were used to carry out the reaction and workup according to Example 9d to give the title. The compound (118 mg, 75%) was obtained.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.92-0.95 (9H, m), 1.05 (3H, s), 1.64 (9H, s), 1.66-1.84 (2H, m), 2.03 (1H, d, J = 17.6 Hz), 2.14 (1H, d, J = 16.4 Hz), 2.24-2.42 (3H, m), 2.49 (3H, s), 2.71 (3H, s), 3.24-3.30 (1H, m ), 3.37 (1H, t, J = 10.6 Hz), 3.72 (3H, s), 3.90 (1H, td, J = 3.0, 11.5 Hz), 4.40 (1H, d, J = 9.7 Hz), 5.39 (1H , s), 6.68 (1H, d, J = 8.5 Hz), 7.27 (1H, d, J = 8.5 Hz), 7.39 (1H, d, J = 7.9 Hz), 7.51 (1H, d, J = 8.5 Hz) ).
(59b) 6- {3-[(3S, 4aS, 10S, 10aR) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6 , 7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid Tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3, prepared in Example 59a 4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine- By subjecting 2-carboxylate (118 mg, 0.196 mmol), chloroform (2.0 mL) and trifluoroacetic acid (1.0 mL) to the reaction and post-treatment according to Example 1d, the title compound (87.0 mg, 81 %).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.94 (3H, d, J = 6.7 Hz), 0.96 (3H, d, J = 6.7 Hz), 0.98 (3H, s), 1.07 (3H, s ), 1.68-1.86 (2H, m), 2.06 (1H, d, J = 16.4 Hz), 2.18 (1H, d, J = 16.4 Hz), 2.27-2.45 (3H, m), 2.69 (3H, s) , 2.81 (3H, s), 3.28-3.33 (1H, m), 3.39 (1H, t, J = 10.3 Hz), 3.75 (3H, s), 3.95 (1H, td, J = 3.6, 11.5 Hz), 4.39 (1H, d, J = 9.7 Hz), 5.64 (1H, s), 6.73 (1H, d, J = 8.5 Hz), 7.19 (1H, d, J = 8.5 Hz), 7.60 (1H, d, J = 7.9 Hz), 7.71 (1H, d, J = 7.9 Hz).
MS (ESI / APCI) m / z: 547 [M + H] +.
(59c) 6- {3-[(3S, 4aS, 10S, 10aR) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6 , 7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert -Butylamine salt 6- {3-[(3S, 4aS, 10S, 10aR) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3 prepared in Example 59b , 4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine The title compound (2- 87.1 mg, 88%) was obtained.
(実施例60)
　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-4-メチルピリジン-2-カルボン酸 tert-ブチルアミン塩
(60a) tert-ブチル　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-4-メチルピリジン-2-カルボキシレート
　実施例47aで製造した(3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3-(プロパン-2-イル)-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(100 mg, 0.181 mmol)、tert-ブチル　6-クロロ-4-メチルピリジン-2-カルボキシレート(49.5 mg, 0.218 mmol)、2nd Generation X-Phos Precatalyst (14.3 mg, 0.0181 mmol)、リン酸カリウム(57.7 mg, 0.272 mmol)、THF (1.5 mL)及び水(1.5 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(111 mg, 99%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.76 (3H, d, J = 6.6 Hz), 0.92 (3H, s), 0.96 (3H, d, J = 7.0 Hz), 1.04 (3H, s), 1.63 (9H, s), 1.79-1.87 (1H, m), 2.02 (1H, d, J = 16.0 Hz), 2.14 (1H, d, J = 16.0 Hz), 2.23-2.39 (4H, m), 2.42 (3H, s), 2.81 (3H, s), 2.83 (3H, s), 3.23 (1H, dd, J = 9.4, 11.3 Hz), 3.33-3.39 (1H, m), 3.72 (3H, s), 3.81 (1H, td, J = 4.3, 11.7 Hz), 4.50 (1H, dd, J = 1.6, 9.0 Hz), 6.67 (1H, d, J = 8.6 Hz), 7.30 (1H, d, J = 8.6 Hz), 7.42 (1H, s), 7.73 (1H, d, J = 0.8 Hz).
(60b) 6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-4-メチルピリジン-2-カルボン酸
　実施例60aで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-4-メチルピリジン-2-カルボキシレート(107 mg, 0.173 mmol)、ジクロロメタン(0.1 mL)及びトリフルオロ酢酸(1.9 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(91.5 mg, 94%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.76 (3H, d, J = 7.4 Hz), 0.96 (3H, s), 0.97 (3H, d, J = 7.8 Hz), 1.06 (3H, s), 1.79-1.87 (1H, m), 2.03-2.07 (1H, m), 2.17 (1H, d, J = 16.4 Hz), 2.22-2.44 (4H, m), 2.49 (3H, s), 2.77 (3H, s), 2.83 (3H, s), 3.27 (1H, t, J = 10.2 Hz), 3.36-3.41 (1H, m), 3.75 (3H, s), 3.86 (1H, td, J = 4.3, 11.5 Hz), 4.45 (1H, d, J = 7.8 Hz), 6.71 (1H, d, J = 8.6 Hz), 7.16 (1H, d, J = 8.6 Hz), 7.54 (1H, s), 7.98 (1H, s).
MS(ESI/APCI)m/z: 561[M+H]+.
(60c) 6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-4-メチルピリジン-2-カルボン酸 tert-ブチルアミン塩
　実施例60bで製造した6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-4-メチルピリジン-2-カルボン酸(91.5 mg, 0.163 mmol)、酢酸エチル(0.9 mL)及びtert-ブチルアミン(34 μL, 0.326 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(68.7 mg, 66%)を得た。 (Example 60)
6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2, 3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -4-methylpyridine-2-carboxylic acid tert- Butylamine salt
(60a) tert-butyl 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propane-2 -Yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -4-methylpyridine- 2-Carboxylate (3S, 4aS, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2) prepared in Example 47a -Dioxaborolan-2-yl) phenyl] -2,7,7-trimethyl-3- (propan-2-yl) -3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [ 3,2-c] pyridine-1,9 (2H) -dione (100 mg, 0.181 mmol), tert-butyl 6-chloro-4-methylpyridine-2-carboxylate (49.5 mg, 0.218 mmol), 2nd Generation X-Phos Precatalyst (14.3 mg, 0.0181 mmol), potassium phosphate (57.7 mg, 0.272 mmol), THF (1.5 mL) and water (1.5 mL) should be used for the reaction and workup according to Example 9d. Gave the title compound (111 mg, 99%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.76 (3H, d, J = 6.6 Hz), 0.92 (3H, s), 0.96 (3H, d, J = 7.0 Hz), 1.04 (3H, s ), 1.63 (9H, s), 1.79-1.87 (1H, m), 2.02 (1H, d, J = 16.0 Hz), 2.14 (1H, d, J = 16.0 Hz), 2.23-2.39 (4H, m) , 2.42 (3H, s), 2.81 (3H, s), 2.83 (3H, s), 3.23 (1H, dd, J = 9.4, 11.3 Hz), 3.33-3.39 (1H, m), 3.72 (3H, s ), 3.81 (1H, td, J = 4.3, 11.7 Hz), 4.50 (1H, dd, J = 1.6, 9.0 Hz), 6.67 (1H, d, J = 8.6 Hz), 7.30 (1H, d, J = 8.6 Hz), 7.42 (1H, s), 7.73 (1H, d, J = 0.8 Hz).
(60b) 6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -4-methylpyridine-2-carboxylic acid Acid tert-butyl 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- prepared in Example 60a (Propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -4 -The title compound (107 mg, 0.173 mmol), dichloromethane (0.1 mL) and trifluoroacetic acid (1.9 mL) were used for the reaction and after-treatment according to Example 1d. 91.5 mg, 94%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.76 (3H, d, J = 7.4 Hz), 0.96 (3H, s), 0.97 (3H, d, J = 7.8 Hz), 1.06 (3H, s ), 1.79-1.87 (1H, m), 2.03-2.07 (1H, m), 2.17 (1H, d, J = 16.4 Hz), 2.22-2.44 (4H, m), 2.49 (3H, s), 2.77 ( 3H, s), 2.83 (3H, s), 3.27 (1H, t, J = 10.2 Hz), 3.36-3.41 (1H, m), 3.75 (3H, s), 3.86 (1H, td, J = 4.3, 11.5 Hz), 4.45 (1H, d, J = 7.8 Hz), 6.71 (1H, d, J = 8.6 Hz), 7.16 (1H, d, J = 8.6 Hz), 7.54 (1H, s), 7.98 (1H , s).
MS (ESI / APCI) m / z: 561 [M + H] +.
(60c) 6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -4-methylpyridine-2-carboxylic acid Acid tert-butylamine salt 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3 prepared in Example 60b -(Propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl}- Perform the reaction and workup according to Example 3c using 4-methylpyridine-2-carboxylic acid (91.5 mg, 0.163 mmol), ethyl acetate (0.9 mL) and tert-butylamine (34 μL, 0.326 mmol). Gave the title compound (68.7 mg, 66%).
(実施例61)
　6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(61a) 2-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]シクロヘキサン-1,3-ジオン
　実施例9aで製造した6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンズアルデヒド(3.00 g, 10.9 mmol)、アセトニトリル(45 mL)、シクロヘキサン-1,3-ジオン(1.34 g, 12.0 mmol)及びL-プロリン(125 mg, 1.09 mmol)を用い、実施例41aに準じて反応及び後処理を行うことにより、標記化合物(1.83 g, 46%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 1.33 (12H, s), 2.05-2.11 (2H, m), 2.45 (3H, s), 2.64 (2H, t, J = 7.4 Hz), 2.70 (2H, t, J = 6.3 Hz), 3.76 (3H, s), 6.70 (1H, d, J = 8.6 Hz), 7.78 (1H, d, J = 8.6 Hz), 7.92 (1H, s).
(61b) (6S)-3-{(S)-(2,6-ジオキソシクロヘキシル)[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]メチル}-6-(プロパン-2-イル)ピペリジン-2,4-ジオン
　実施例61aで製造した2-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]シクロヘキサン-1,3-ジオン(750 mg, 2.03 mmol)、tert-ブチル　(6S)-2,4-ジオキソ-6-(プロパン-2-イル)ピペリジン-1-カルボキシレート(543 mg, 2.13 mmol)、アセトニトリル(7.5 mL)、炭酸セシウム(792 mg, 2.43 mmol)、ジクロロメタン(13 mL)及びトリフルオロ酢酸(1.27 mL, 16.6 mmol)を用い、実施例42bに準じて反応及び後処理を行うことにより、標記化合物(665 mg, 62%)をコンホマーの混合物として得た。
(61c) (3R,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,6,7,8,10,10a-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　ジ-tert-ブチル　アゾジカルボキシレート(408 mg, 1.77 mmol)、トリフェニルホスフィン(465 mg, 1.77 mmol)、トルエン溶液(6.7 mL)及び実施例61bで製造した(6S)-3-{(S)-(2,6-ジオキソシクロヘキシル)[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]メチル}-6-(プロパン-2-イル)ピペリジン-2,4-ジオン(665 mg, 1.27 mmol)を用い、実施例42cに準じて反応及び後処理を行うことにより、標記化合物(430 mg, 67%)を得た。 (Example 61)
6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8, 9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(61a) 2- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] cyclohexane-1,3-dione 6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde prepared in Example 9a (3.00 g, 10.9 mmol), acetonitrile ( 45 mL), cyclohexane-1,3-dione (1.34 g, 12.0 mmol) and L-proline (125 mg, 1.09 mmol) were used for the reaction and workup according to Example 41a to give the title compound ( 1.83 g, 46%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.33 (12H, s), 2.05-2.11 (2H, m), 2.45 (3H, s), 2.64 (2H, t, J = 7.4 Hz), 2.70 (2H, t, J = 6.3 Hz), 3.76 (3H, s), 6.70 (1H, d, J = 8.6 Hz), 7.78 (1H, d, J = 8.6 Hz), 7.92 (1H, s).
(61b) (6S) -3-{(S)-(2,6-dioxocyclohexyl) [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl) phenyl] methyl} -6- (propan-2-yl) piperidine-2,4-dione 2- [6-Methoxy-2-methyl-3- (4) prepared in Example 61a , 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] cyclohexane-1,3-dione (750 mg, 2.03 mmol), tert-butyl (6S) -2,4- Dioxo-6- (propan-2-yl) piperidine-1-carboxylate (543 mg, 2.13 mmol), acetonitrile (7.5 mL), cesium carbonate (792 mg, 2.43 mmol), dichloromethane (13 mL) and trifluoroacetic acid (1.27 mL, 16.6 mmol) was used for the reaction and post-treatment according to Example 42b to obtain the title compound (665 mg, 62%) as a mixture of conformers.
(61c) (3R, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3- (propan-2-yl) -3,6,7,8,10,10a-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione di-tert-butyl Azodicarboxylate (408 mg, 1.77 mmol), triphenylphosphine (465 mg, 1.77 mmol), toluene solution (6.7 mL) and (6S) -3-{(S)-(2, 6-dioxocyclohexyl) [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] methyl} -6- (propane The title compound (430 mg, 67%) was obtained by performing reaction and post-treatment according to Example 42c using -2-yl) piperidine-2,4-dione (665 mg, 1.27 mmol).
1H-NMR(400MHz, CDCl3):δ ppm: 0.89 (3H, d, J = 6.6 Hz), 0.90 (3H, d, J = 6.6 Hz), 1.31 (12H, s), 1.77-1.96 (3H, m), 2.12-2.26 (2H, m), 2.42-2.57 (2H, m), 2.88 (3H, s), 3.74 (3H, s), 3.86-3.95 (2H, m), 4.43 (1H, d, J = 8.6 Hz), 5.44-5.46 (1H, m), 5.82 (1H, s), 6.63 (1H, d, J = 8.2 Hz), 7.63 (1H, d, J = 8.2 Hz).
(61d) (3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例61cで製造した(3R,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,6,7,8,10,10a-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(430 mg, 0.847 mmol)、パラジウム炭素(10%, 215 mg)及びTHF (17 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、粗製の標記化合物を得た。
(61e) (3S,4aS,10S,10aR)-2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例61dで製造した粗製の(3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン、ヨウ化エチル(270 μL, 3.38 mmol)、1,3-ジメチル-3,4,5,6-テトラヒドロ-2(1H)-ピリミジノン(1.1 mL)及び水素化ナトリウム(55%, 27.6 mg, 0.633 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(97.1 mg, 21%, 2 steps)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.89 (3H, d, J = 6.6 Hz), 0.90 (3H, d, J = 6.6 Hz), 1.31 (12H, s), 1.77-1.96 (3H , m), 2.12-2.26 (2H, m), 2.42-2.57 (2H, m), 2.88 (3H, s), 3.74 (3H, s), 3.86-3.95 (2H, m), 4.43 (1H, d , J = 8.6 Hz), 5.44-5.46 (1H, m), 5.82 (1H, s), 6.63 (1H, d, J = 8.2 Hz), 7.63 (1H, d, J = 8.2 Hz).
(61d) (3S, 4aS, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenyl] -3- (propan-2-yl) -3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H)- Dione (3R, 10S, 10aR) -10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-prepared in Example 61c Yl) phenyl] -3- (propan-2-yl) -3,6,7,8,10,10a-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione ( 430 mg, 0.847 mmol), palladium on carbon (10%, 215 mg) and THF (17 mL) were used for the reaction and post-treatment according to Example 18 to obtain the crude title compound.
(61e) (3S, 4aS, 10S, 10aR) -2-Ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) phenyl] -3- (propan-2-yl) -3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione Crude (3S, 4aS, 10S, 10aR) -10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1, prepared in Example 61d 3,2-dioxaborolan-2-yl) phenyl] -3- (propan-2-yl) -3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c ] Pyridine-1,9 (2H) -dione, ethyl iodide (270 μL, 3.38 mmol), 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (1.1 mL) and The title compound (97.1 mg, 21%, 2 steps) was obtained by performing reaction and post-treatment according to Example 2a using sodium hydride (55%, 27.6 mg, 0.633 mmol).
1H-NMR(400MHz, CDCl3):δ ppm: 0.77 (3H, d, J = 6.6 Hz), 0.94 (3H, d, J = 7.0 Hz), 1.04 (3H, t, J = 7.2 Hz), 1.30 (12H, s), 1.65-2.45 (10H, m), 2.99-3.05 (1H, m), 3.11 (3H, s), 3.16 (1H, dd, J = 9.2, 11.5 Hz), 3.37-3.43 (1H, m), 3.65-3.77 (1H, m), 3.70 (3H, s), 4.54 (1H, d, J = 9.4 Hz), 6.59 (1H, d, J = 8.2 Hz), 7.60 (1H, d, J = 8.6 Hz).
(61f) tert-ブチル　6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例61eで製造した(3S,4aS,10S,10aR)-2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(97.1 mg, 0.217 mmol)、tert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(, 49.4 mg, 0.217 mmol)、2nd Generation X-Phos Precatalyst (28.4 mg, 0.0361 mmol)、リン酸カリウム(61.4 mg, 0.289 mmol)、THF (1.0 mL)及び水(1.9 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(97.5 mg, 90%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.81 (3H, d, J = 6.6 Hz), 0.95 (3H, d, J = 6.6 Hz), 1.05 (3H, t, J = 7.0 Hz), 1.63 (9H, s), 1.84-2.47 (9H, m), 2.49 (3H, s), 2.83 (3H, s), 3.03-3.11 (1H, m), 3.20 (1H, dd, J = 8.2, 10.2 Hz), 3.37-3.43 (1H, m), 3.62 (1H, dd, J = 7.0, 14.5 Hz), 3.73 (3H, s), 3.73-3.80 (1H, m), 4.53 (1H, d, J = 9.0 Hz), 6.71 (1H, d, J = 8.2 Hz), 7.24-7.28 (1H, m), 7.41 (1H, d, J = 7.8 Hz), 7.51 (1H, d, J = 7.0 Hz).
(61g) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例61fで製造したtert-ブチル　6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(97.5 mg, 0.162 mmol)、ジクロロメタン(1.0 mL)及びトリフルオロ酢酸(0.5 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(76.2 mg, 86%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.77 (3H, d, J = 6.6 Hz), 0.94 (3H, d, J = 7.0 Hz), 1.04 (3H, t, J = 7.2 Hz), 1.30 (12H, s), 1.65-2.45 (10H, m), 2.99-3.05 (1H, m), 3.11 (3H, s), 3.16 (1H, dd, J = 9.2, 11.5 Hz), 3.37-3.43 ( 1H, m), 3.65-3.77 (1H, m), 3.70 (3H, s), 4.54 (1H, d, J = 9.4 Hz), 6.59 (1H, d, J = 8.2 Hz), 7.60 (1H, d , J = 8.6 Hz).
(61f) tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (3S, 4aS, 10S, 10aR) -2-ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2) prepared in Example 61e -Dioxaborolan-2-yl) phenyl] -3- (propan-2-yl) -3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c] pyridine- 1,9 (2H) -dione (97.1 mg, 0.217 mmol), tert-butyl 6-chloro-3-methylpyridine-2-carboxylate (, 49.4 mg, 0.217 mmol), 2nd Generation X-Phos Precatalyst (28.4 mg , 0.0361 mmol), potassium phosphate (61.4 mg, 0.289 mmol), THF (1.0 mL) and water (1.9 mL) were used for the reaction and workup according to Example 9d to give the title compound (97.5 mg , 90%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.81 (3H, d, J = 6.6 Hz), 0.95 (3H, d, J = 6.6 Hz), 1.05 (3H, t, J = 7.0 Hz), 1.63 (9H, s), 1.84-2.47 (9H, m), 2.49 (3H, s), 2.83 (3H, s), 3.03-3.11 (1H, m), 3.20 (1H, dd, J = 8.2, 10.2 Hz), 3.37-3.43 (1H, m), 3.62 (1H, dd, J = 7.0, 14.5 Hz), 3.73 (3H, s), 3.73-3.80 (1H, m), 4.53 (1H, d, J = 9.0 Hz), 6.71 (1H, d, J = 8.2 Hz), 7.24-7.28 (1H, m), 7.41 (1H, d, J = 7.8 Hz), 7.51 (1H, d, J = 7.0 Hz).
(61g) 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7 , 8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid Example 61f Tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (97.5 mg, 0.162 mmol), dichloromethane (1.0 mL) and trifluoroacetic acid (0.5 mL) were used for the reaction and workup according to Example 1d to obtain the title compound (76.2 mg, 86%). It was.
1H-NMR(400MHz, CDCl3):δ ppm: 0.81 (3H, d, J = 7.3 Hz), 0.97 (3H, d, J = 7.3 Hz), 1.06 (3H, t, J = 7.0 Hz), 1.75-1.96 (3H, m), 2.13-2.47 (6H, m), 2.80 (3H, s), 2.81 (3H, s), 3.02-3.11 (1H, m), 3.25 (1H, dd, J = 9.2, 11.6 Hz), 3.41-3.46 (1H, m), 3.62-3.70 (1H, m), 3.77-3.85 (1H, m), 3.77 (3H, s), 4.46 (1H, d, J = 9.2 Hz), 6.76 (1H, d, J = 8.5 Hz), 7.17 (1H, d, J = 8.5 Hz), 7.64 (1H, d, J = 8.5 Hz), 7.77 (1H, d, J = 8.5 Hz).
MS(ESI/APCI)m/z: 547[M+H]+.
(61h) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例61gで製造した6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(76.2 mg, 0.139 mmol)、エタノール(1.5 mL)及びtert-ブチルアミン(29 μL, 0.279 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(84.2 mg, 98%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.81 (3H, d, J = 7.3 Hz), 0.97 (3H, d, J = 7.3 Hz), 1.06 (3H, t, J = 7.0 Hz), 1.75-1.96 (3H, m), 2.13-2.47 (6H, m), 2.80 (3H, s), 2.81 (3H, s), 3.02-3.11 (1H, m), 3.25 (1H, dd, J = 9.2 , 11.6 Hz), 3.41-3.46 (1H, m), 3.62-3.70 (1H, m), 3.77-3.85 (1H, m), 3.77 (3H, s), 4.46 (1H, d, J = 9.2 Hz) , 6.76 (1H, d, J = 8.5 Hz), 7.17 (1H, d, J = 8.5 Hz), 7.64 (1H, d, J = 8.5 Hz), 7.77 (1H, d, J = 8.5 Hz).
MS (ESI / APCI) m / z: 547 [M + H] +.
(61h) 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7 , 8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine Salt 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a prepared in Example 61g , 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid The title compound (84.2 mg, 98 mg) was prepared by carrying out the reaction and post-treatment according to Example 3c using acid (76.2 mg, 0.139 mmol), ethanol (1.5 mL) and tert-butylamine (29 μL, 0.279 mmol). %).
(実施例62)
　4-メトキシ-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボン酸
(62a) エチル　4-メトキシ-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボキシレート
　実施例47aで製造した(3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3-(プロパン-2-イル)-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(220 mg, 0.399 mmol)、エチル　6-クロロ-4-メトキシピリジン-2-カルボキシレート(103 mg, 0.479 mmol)、2nd Generation X-Phos Precatalyst (62.0 mg, 0.0788 mmol)、リン酸カリウム(133 mg, 0.627 mmol)、THF (2.0 mL)及び水(4.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(241 mg, 99%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.76 (3H, d, J = 6.7 Hz), 0.94 (3H, s), 0.96 (3H, d, J = 6.7 Hz), 1.05 (3H, s), 1.43 (3H, t, J = 6.7 Hz), 1.78-1.87 (1H, m), 2.03 (1H, d, J = 15.9 Hz), 2.15 (1H, d, J = 16.5 Hz), 2.21-2.41 (4H, m), 2.77 (3H, s), 2.83 (3H, s), 3.23 (1H, t, J = 10.1 Hz), 3.33-3.39 (1H, m), 3.72 (3H, s), 3.82 (1H, td, J = 11.6, 4.3 Hz), 3.92 (3H, s), 4.42-4.49 (3H, m), 6.67 (1H, d, J = 8.5 Hz), 7.11 (1H, d, J = 2.4 Hz), 7.20 (1H, d, J = 8.5 Hz), 7.59 (1H, d, J = 2.4 Hz).
(62b) 4-メトキシ-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボン酸
　実施例62aで製造したエチル　4-メトキシ-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボキシレート(241 mg, 0.399 mmol)、1 M水酸化ナトリウム水溶液(1.0　mL, 1.00 mmol)及びエタノール(3.0 mL)を用い、実施例25gに準じて反応及び後処理を行うことにより、標記化合物(168 mg, 73%)を得た。 (Example 62)
4-Methoxy-6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl ) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} pyridine-2-carboxylic acid
(62a) Ethyl 4-methoxy-6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propane -2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} pyridine-2- Carboxylate (3S, 4aS, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane) prepared in Example 47a -2-yl) phenyl] -2,7,7-trimethyl-3- (propan-2-yl) -3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3, 2-c] pyridine-1,9 (2H) -dione (220 mg, 0.399 mmol), ethyl 6-chloro-4-methoxypyridine-2-carboxylate (103 mg, 0.479 mmol), 2nd Generation X-Phos Precatalyst (62.0 mg, 0.0788 mmol), potassium phosphate (133 mg, 0.627 mmol), THF (2.0 mL) and water (4.0 mL) were used, and the reaction was conducted and worked up according to Example 9d to give the title compound. (241 mg, 99%) was obtained.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.76 (3H, d, J = 6.7 Hz), 0.94 (3H, s), 0.96 (3H, d, J = 6.7 Hz), 1.05 (3H, s ), 1.43 (3H, t, J = 6.7 Hz), 1.78-1.87 (1H, m), 2.03 (1H, d, J = 15.9 Hz), 2.15 (1H, d, J = 16.5 Hz), 2.21-2.41 (4H, m), 2.77 (3H, s), 2.83 (3H, s), 3.23 (1H, t, J = 10.1 Hz), 3.33-3.39 (1H, m), 3.72 (3H, s), 3.82 ( 1H, td, J = 11.6, 4.3 Hz), 3.92 (3H, s), 4.42-4.49 (3H, m), 6.67 (1H, d, J = 8.5 Hz), 7.11 (1H, d, J = 2.4 Hz ), 7.20 (1H, d, J = 8.5 Hz), 7.59 (1H, d, J = 2.4 Hz).
(62b) 4-Methoxy-6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propane- 2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} pyridine-2-carboxylic Acid Ethyl 4-methoxy-6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo- prepared in Example 62a 3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} By carrying out the reaction and post-treatment according to Example 25 g using pyridine-2-carboxylate (241 mg, 0.399 mmol), 1 M aqueous sodium hydroxide solution (1.0 mL, 1.00 mmol) and ethanol (3.0 mL). The title compound (168 mg, 73%) was obtained.
(実施例63)
　6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボン酸 tert-ブチルアミン塩
(63a) tert-ブチル　6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボキシレート
　実施例27cで製造した(3S,4aS,10S,10aR)-2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(450 mg, 0.796 mmol)、tert-ブチル　6-クロロピリジン-2-カルボキシレート(221 mg, 1.03 mmol)、2nd Generation X-Phos Precatalyst (125 mg, 0.159 mmol)、リン酸カリウム(270 mg, 1.27 mmol)、THF (2.3 mL)及び水(4.5 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(420 mg, 86%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.81 (3H, d, J = 6.7 Hz), 0.93 (3H, s), 0.96 (3H, d, J = 6.8 Hz), 1.04-1.07 (6H, m), 1.64 (9H, s), 1.81-1.92 (1H, m), 2.03 (1H, d, J = 15.7 Hz), 2.12-2.39 (5H, m), 2.82 (3H, s), 3.03-3.11 (1H, m), 3.22 (1H, dd, J = 10.2, 12.9 Hz), 3.38-3.43 (1H, m), 3.57-3.66 (1H, m), 3.73 (3H, s), 3.73-3.80 (1H, m), 4.53 (1H, d, J = 7.8 Hz), 6.69 (1H, d, J = 8.6 Hz), 7.30 (1H, d, J = 8.6 Hz), 7.60 (1H, d, J = 7.8 Hz), 7.76 (1H, t, J = 7.8 Hz), 7.91 (1H, d, J = 7.4 Hz).
(63b) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボン酸 tert-ブチルアミン塩
　実施例63aで製造したtert-ブチル　6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボキシレート(360 mg, 0.584 mmol)、ジクロロメタン(3.6 mL)及びトリフルオロ酢酸(1.8 mL)、エタノール(1.0 mL)及びtert-ブチルアミン(73 μL, 0.700 mmol)を用い、実施例41fに準じて反応及び後処理を行うことにより、標記化合物(257 mg, 69%)を得た。 (Example 63)
6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} pyridine-2-carboxylic acid tert-butylamine salt
(63a) tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2, 3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} pyridine-2- Carboxylate (3S, 4aS, 10S, 10aR) -2-ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3) prepared in Example 27c , 2-Dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3- (propan-2-yl) -3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [ 3,2-c] pyridine-1,9 (2H) -dione (450 mg, 0.796 mmol), tert-butyl 6-chloropyridine-2-carboxylate (221 mg, 1.03 mmol), 2nd Generation X-Phos Precatalyst (125 mg, 0.159 mmol), potassium phosphate (270 mg, 1.27 mmol), THF (2.3 mL) and water (4.5 mL) were used, and the reaction was conducted and worked up according to Example 9d to give the title compound. (420 mg, 86%) was obtained.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.81 (3H, d, J = 6.7 Hz), 0.93 (3H, s), 0.96 (3H, d, J = 6.8 Hz), 1.04-1.07 (6H , m), 1.64 (9H, s), 1.81-1.92 (1H, m), 2.03 (1H, d, J = 15.7 Hz), 2.12-2.39 (5H, m), 2.82 (3H, s), 3.03- 3.11 (1H, m), 3.22 (1H, dd, J = 10.2, 12.9 Hz), 3.38-3.43 (1H, m), 3.57-3.66 (1H, m), 3.73 (3H, s), 3.73-3.80 ( 1H, m), 4.53 (1H, d, J = 7.8 Hz), 6.69 (1H, d, J = 8.6 Hz), 7.30 (1H, d, J = 8.6 Hz), 7.60 (1H, d, J = 7.8 Hz), 7.76 (1H, t, J = 7.8 Hz), 7.91 (1H, d, J = 7.4 Hz).
(63b) 6- {3-[(3S, 4aS, 10S, 10aR) -2-Ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4 , 4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} pyridine-2-carboxylic acid tert -Butylamine salt tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propane-2) prepared in Example 63a -Yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methyl Phenyl} pyridine-2-carboxylate (360 mg, 0.584 mmol), dichloromethane (3.6 mL) and trifluoroacetic acid (1.8 mL), ethanol (1.0 mL) and tert-butylamine (73 μL, 0.700 mmol) The title compound (257 mg, 69%) was obtained by carrying out the reaction and post-treatment according to Example 41f.
(実施例64)
　6-{3-[(3S,4aS,10S,10aR)-3-シクロプロピル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(64a) (6S)-6-シクロプロピル-3-{(S)-(4,4-ジメチル-2,6-ジオキソシクロヘキシル)[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]メチル}ピペリジン-2,4-ジオン
　実施例9bで製造した2-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン(600 mg, 1.51 mmol)、tert-ブチル　(2S)-2-シクロプロピル-4,6-ジオキソピペリジン-1-カルボキシレート(420 mg, 1.66 mmol)、アセトニトリル(6.0 mL)及び炭酸セシウム(589 mg, 1.81 mmol)、次いでジクロロメタン(5 mL)及びトリフルオロ酢酸(0.5 mL, 7.00 mmol)を用いて実施例42bに準じて反応及び後処理を行うことにより、標記化合物(485 mg, 58%)をコンフォマーの混合物として得た。
(64b) (3R,10S,10aR)-3-シクロプロピル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,6,7,8,10,10a-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　ジ-tert-ブチル　アゾジカルボキシレート(220 mg, 0.957 mmol)、トリフェニルホスフィン(251 mg, 0.957 mmol)、トルエン溶液(5.0 mL)及び実施例64aで製造した(6S)-6-シクロプロピル-3-{(S)-(4,4-ジメチル-2,6-ジオキソシクロヘキシル)[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]メチル}ピペリジン-2,4-ジオン(480 mg, 0.870 mmol)を用いて実施例42cに準じて反応及び後処理を行うことにより、標記化合物(287 mg, 62%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.20-0.29 (2H, m), 0.47-0.57 (2H, m), 0.85-0.93 (1H, m), 0.98 (3H, s), 1.05 (3H, s), 1.31 (12H, s), 2.03 (1H, d, J = 16.0 Hz), 2.11 (1H, d, J = 16.4 Hz), 2.32 (1H, d, J = 18.0 Hz), 2.40 (1H, dd, J = 2.5, 17.8 Hz), 2.83 (3H, s), 3.19-3.24 (1H, m), 3.73 (3H, s), 4.02-4.07 (1H, m), 4.39 (1H, d, J = 9.0 Hz), 5.53-5.55 (1H, m), 6.32 (1H, s), 6.62 (1H, d, J = 8.6 Hz), 7.64 (1H, d, J = 8.6 Hz).
(64c) (3S,4aS,10S,10aR)-3-シクロプロピル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例64bで製造した(3R,10S,10aR)-3-シクロプロピル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,6,7,8,10,10a-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(283 mg, 0.530 mmol)、パラジウム炭素(10%, 56.0 mg)及びTHF (3.0 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(280 mg, 99%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.18-0.25 (2H, m), 0.50-0.59 (2H, m), 0.80-0.88 (1H, m), 0.92 (3H, s), 1.03 (3H, s), 1.31 (12H, s), 1.93-2.02 (1H, m), 2.12 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 17.6 Hz), 2.32 (1H, dd, J = 2.3, 16.4 Hz), 2.50-2.58 (2H, m), 2.96 (3H, s), 3.41 (1H, t, J = 10.4 Hz), 3.69 (3H, s), 3.73-3.77 (1H, m), 3.83 (1H, td, J = 2.9, 11.6 Hz), 4.40 (1H, d, J = 7.8 Hz), 5.63 (1H, s), 6.57 (1H, d, J = 8.6 Hz), 7.60 (1H, d, J = 8.2 Hz).
(64d) (3S,4aS,10S,10aR)-3-シクロプロピル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例64cで製造した(3S,4aS,10S,10aR)-3-シクロプロピル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(276 mg, 0.515 mmol)、ヨウ化メチル(257 μL, 4.12 mmol)、DMF (5.0 mL)及び水素化ナトリウム(63%, 29.5 mg, 0.773 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(223 mg, 79%)を得た。 (Example 64)
6- {3-[(3S, 4aS, 10S, 10aR) -3-cyclopropyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7,8,9 , 10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(64a) (6S) -6-cyclopropyl-3-{(S)-(4,4-dimethyl-2,6-dioxocyclohexyl) [6-methoxy-2-methyl-3- (4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] methyl} piperidine-2,4-dione 2- [6-Methoxy-2-methyl-3- (prepared in Example 9b) 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] -5,5-dimethylcyclohexane-1,3-dione (600 mg, 1.51 mmol), tert-butyl ( 2S) -2-cyclopropyl-4,6-dioxopiperidine-1-carboxylate (420 mg, 1.66 mmol), acetonitrile (6.0 mL) and cesium carbonate (589 mg, 1.81 mmol), then dichloromethane (5 mL) And trifluoroacetic acid (0.5 mL, 7.00 mmol) was used for the reaction and post-treatment according to Example 42b to obtain the title compound (485 mg, 58%) as a mixture of conformers.
(64b) (3R, 10S, 10aR) -3-Cyclopropyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Yl) phenyl] -7,7-dimethyl-3,6,7,8,10,10a-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione di-tert- Butyl azodicarboxylate (220 mg, 0.957 mmol), triphenylphosphine (251 mg, 0.957 mmol), toluene solution (5.0 mL) and (6S) -6-cyclopropyl-3-{( S)-(4,4-Dimethyl-2,6-dioxocyclohexyl) [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Il) phenyl] methyl} piperidine-2,4-dione (480 mg, 0.870 mmol) was used for the reaction and workup according to Example 42c to give the title compound (287 mg, 62%). It was.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.20-0.29 (2H, m), 0.47-0.57 (2H, m), 0.85-0.93 (1H, m), 0.98 (3H, s), 1.05 ( 3H, s), 1.31 (12H, s), 2.03 (1H, d, J = 16.0 Hz), 2.11 (1H, d, J = 16.4 Hz), 2.32 (1H, d, J = 18.0 Hz), 2.40 ( 1H, dd, J = 2.5, 17.8 Hz), 2.83 (3H, s), 3.19-3.24 (1H, m), 3.73 (3H, s), 4.02-4.07 (1H, m), 4.39 (1H, d, J = 9.0 Hz), 5.53-5.55 (1H, m), 6.32 (1H, s), 6.62 (1H, d, J = 8.6 Hz), 7.64 (1H, d, J = 8.6 Hz).
(64c) (3S, 4aS, 10S, 10aR) -3-cyclopropyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane) -2-yl) phenyl] -7,7-dimethyl-3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -Dione (3R, 10S, 10aR) -3-cyclopropyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3, prepared in Example 64b 2-Dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3,6,7,8,10,10a-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H)- The reaction was conducted according to Example 18 using dione (283 mg, 0.530 mmol), palladium on carbon (10%, 56.0 mg) and THF (3.0 mL), and the title compound (280 mg, 99% )
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.18-0.25 (2H, m), 0.50-0.59 (2H, m), 0.80-0.88 (1H, m), 0.92 (3H, s), 1.03 ( 3H, s), 1.31 (12H, s), 1.93-2.02 (1H, m), 2.12 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 17.6 Hz), 2.32 (1H, dd , J = 2.3, 16.4 Hz), 2.50-2.58 (2H, m), 2.96 (3H, s), 3.41 (1H, t, J = 10.4 Hz), 3.69 (3H, s), 3.73-3.77 (1H, m), 3.83 (1H, td, J = 2.9, 11.6 Hz), 4.40 (1H, d, J = 7.8 Hz), 5.63 (1H, s), 6.57 (1H, d, J = 8.6 Hz), 7.60 ( (1H, d, J = 8.2 Hz).
(64d) (3S, 4aS, 10S, 10aR) -3-cyclopropyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane) -2-yl) phenyl] -2,7,7-trimethyl-3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c] pyridine-1,9 ( (2H) -dione (3S, 4aS, 10S, 10aR) -3-cyclopropyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-) prepared in Example 64c 1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c] pyridine -1,9 (2H) -dione (276 mg, 0.515 mmol), methyl iodide (257 μL, 4.12 mmol), DMF (5.0 mL) and sodium hydride (63%, 29.5 mg, 0.773 mmol) The title compound (223 mg, 79%) was obtained by carrying out the reaction and post-treatment according to Example 2a.
1H-NMR(400MHz, CDCl3):δ ppm: 0.12-0.19 (1H, m), 0.40-0.45 (1H, m), 0.55-0.62 (1H, m), 0.74-0.80 (2H, m), 0.91 (3H, s), 1.04 (3H, s), 1.31 (12H, s), 1.96-2.05 (2H, m), 2.13 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 18.0 Hz), 2.34 (1H, dd, J = 2.7, 17.6 Hz), 2.48-2.55 (1H, m), 2.59-2.65 (1H, m), 2.97 (3H, s), 3.07 (3H, s), 3.36 (1H, t, J = 10.4 Hz), 3.69 (3H, s), 3.76 (1H, td, J = 3.8, 11.5 Hz), 4.48 (1H, d, J = 9.4 Hz), 6.57 (1H, d, J = 8.6 Hz), 7.61 (1H, d, J = 8.2 Hz).
(64e) tert-ブチル　6-{3-[(3S,4aS,10S,10aR)-3-シクロプロピル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例64dで製造した(3S,4aS,10S,10aR)-3-シクロプロピル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(210 mg, 0.382 mmol)、tert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(, 104 mg, 0.459 mmol)、2nd Generation X-Phos Precatalyst (30.1 mg, 0.0382 mmol)、リン酸カリウム(122 mg, 0.573 mmol)、THF (3.0 mL)及び水(2.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(200 mg, 85%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.12-0.19 (1H, m), 0.40-0.45 (1H, m), 0.55-0.62 (1H, m), 0.74-0.80 (2H, m), 0.91 (3H, s), 1.04 (3H, s), 1.31 (12H, s), 1.96-2.05 (2H, m), 2.13 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 18.0 Hz), 2.34 (1H, dd, J = 2.7, 17.6 Hz), 2.48-2.55 (1H, m), 2.59-2.65 (1H, m), 2.97 (3H, s), 3.07 (3H, s), 3.36 (1H, t, J = 10.4 Hz), 3.69 (3H, s), 3.76 (1H, td, J = 3.8, 11.5 Hz), 4.48 (1H, d, J = 9.4 Hz), 6.57 (1H, d , J = 8.6 Hz), 7.61 (1H, d, J = 8.2 Hz).
(64e) tert-Butyl 6- {3-[(3S, 4aS, 10S, 10aR) -3-Cyclopropyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6 , 7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (3S, 4aS, 10S, 10aR) -3-cyclopropyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2) prepared in Example 64d -Dioxaborolan-2-yl) phenyl] -2,7,7-trimethyl-3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c] pyridine-1, 9 (2H) -dione (210 mg, 0.382 mmol), tert-butyl 6-chloro-3-methylpyridine-2-carboxylate (, 104 mg, 0.459 mmol), 2nd Generation X-Phos Precatalyst (30.1 mg, 0.0382 mmol), potassium phosphate (122 mg, 0.573 mmol), THF (3.0 mL) and water (2.0 mL) were used for the reaction and workup according to Example 9d to give the title compound (200 mg, 85 %).
1H-NMR(400MHz, CDCl3):δ ppm: 0.12-0.19 (1H, m), 0.40-0.45 (1H, m), 0.56-0.63 (1H, m), 0.75-0.80 (2H, m), 0.93 (3H, s), 1.04 (3H, s), 1.64 (9H, s), 1.98-2.06 (2H, m), 2.14 (1H, d, J = 16.4 Hz), 2.25 (1H, d, J = 17.6 Hz), 2.34 (1H, d, J = 18.0 Hz), 2.49 (3H, s), 2.49-2.55 (1H, m), 2.60-2.66 (1H, m), 2.79 (3H, s), 2.97 (3H, s), 3.39 (1H, t, J = 10.4 Hz), 3.71-3.79 (1H, m), 3.72 (3H, s), 4.45 (1H, d, J = 9.0 Hz), 6.67 (1H, d, J = 8.6 Hz), 7.25 (1H, d, J = 9.0 Hz), 7.42 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.2 Hz).
(64f) 6-{3-[(3S,4aS,10S,10aR)-3-シクロプロピル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例64eで製造したtert-ブチル　6-{3-[(3S,4aS,10S,10aR)-3-シクロプロピル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(196 mg, 0.319 mmol)、ジクロロメタン(3.0 mL)、トリフルオロ酢酸(1.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(178 mg, 99%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.13-0.20 (1H, m), 0.41-0.46 (1H, m), 0.57-0.64 (1H, m), 0.74-0.80 (2H, m), 0.96 (3H, s), 1.06 (3H, s), 1.98-2.07 (2H, m), 2.16 (1H, d, J = 16.4 Hz), 2.28 (1H, d, J = 18.0 Hz), 2.37 (1H, d, J = 18.0 Hz), 2.51-2.57 (1H, m), 2.62-2.68 (1H, m), 2.77 (3H, s), 2.80 (3H, s), 2.98 (3H, s), 3.41 (1H, t, J = 10.4 Hz), 3.74 (3H, s), 3.80 (1H, td, J = 3.9, 11.5 Hz), 4.41 (1H, d, J = 7.8 Hz), 6.71 (1H, d, J = 8.6 Hz), 7.18 (1H, d, J = 8.2 Hz), 7.63 (1H, d, J = 7.8 Hz), 7.71 (1H, d, J = 7.4 Hz).
(64g) 6-{3-[(3S,4aS,10S,10aR)-3-シクロプロピル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例64fで製造した6-{3-[(3S,4aS,10S,10aR)-3-シクロプロピル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(175 mg, 0.313 mmol)、酢酸エチル(1.0 mL)及びtert-ブチルアミン(66 μL, 0.626 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(152 mg, 77%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.12-0.19 (1H, m), 0.40-0.45 (1H, m), 0.56-0.63 (1H, m), 0.75-0.80 (2H, m), 0.93 (3H, s), 1.04 (3H, s), 1.64 (9H, s), 1.98-2.06 (2H, m), 2.14 (1H, d, J = 16.4 Hz), 2.25 (1H, d, J = 17.6 Hz), 2.34 (1H, d, J = 18.0 Hz), 2.49 (3H, s), 2.49-2.55 (1H, m), 2.60-2.66 (1H, m), 2.79 (3H, s), 2.97 ( 3H, s), 3.39 (1H, t, J = 10.4 Hz), 3.71-3.79 (1H, m), 3.72 (3H, s), 4.45 (1H, d, J = 9.0 Hz), 6.67 (1H, d , J = 8.6 Hz), 7.25 (1H, d, J = 9.0 Hz), 7.42 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.2 Hz).
(64f) 6- {3-[(3S, 4aS, 10S, 10aR) -3-cyclopropyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7, 8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid In Example 64e Prepared tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -3-cyclopropyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6, 7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (196 mg, 0.319 mmol), dichloromethane (3.0 mL), trifluoroacetic acid (1.0 mL) were used for the reaction and post-treatment according to Example 1d to obtain the title compound (178 mg, 99%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.13-0.20 (1H, m), 0.41-0.46 (1H, m), 0.57-0.64 (1H, m), 0.74-0.80 (2H, m), 0.96 (3H, s), 1.06 (3H, s), 1.98-2.07 (2H, m), 2.16 (1H, d, J = 16.4 Hz), 2.28 (1H, d, J = 18.0 Hz), 2.37 (1H , d, J = 18.0 Hz), 2.51-2.57 (1H, m), 2.62-2.68 (1H, m), 2.77 (3H, s), 2.80 (3H, s), 2.98 (3H, s), 3.41 ( 1H, t, J = 10.4 Hz), 3.74 (3H, s), 3.80 (1H, td, J = 3.9, 11.5 Hz), 4.41 (1H, d, J = 7.8 Hz), 6.71 (1H, d, J = 8.6 Hz), 7.18 (1H, d, J = 8.2 Hz), 7.63 (1H, d, J = 7.8 Hz), 7.71 (1H, d, J = 7.4 Hz).
(64g) 6- {3-[(3S, 4aS, 10S, 10aR) -3-Cyclopropyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7, 8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt 6- {3-[(3S, 4aS, 10S, 10aR) -3-cyclopropyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6 prepared in Example 64f , 7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid ( 175 mg, 0.313 mmol), ethyl acetate (1.0 mL) and tert-butylamine (66 μL, 0.626 mmol) were used for the reaction and workup according to Example 3c to give the title compound (152 mg, 77% )
(実施例65)
　6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(65a) (3S,4aS,10S,10aR)-2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,4a,6,10,10a-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン
　実施例41cで製造した(3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,4a,6,10,10a-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン(2.14 g, 4.00 mmol)、ヨウ化エチル(2.56 mL, 32.0 mmol)、DMPU (21 mL)及び水素化ナトリウム(55%, 209 mg, 4.80 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(1.52, 68%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.24-0.45 (4H, m), 0.78 (3H, d, J = 7.0 Hz), 0.94 (3H, d, J = 6.7 Hz), 1.05 (3H, t, J = 7.0 Hz), 1.30 (12H, s), 1.67 (1H, d, J = 16.8 Hz), 1.77-1.85 (1H, m), 1.92 (1H, d, J = 18.0 Hz), 2.15-2.24 (1H, m), 2.33-2.39 (1H, m), 2.46 (1H, d, J = 16.8 Hz), 2.69 (1H, d, J = 15.7 Hz), 2.96-3.05 (1H, m), 3.10 (3H, s), 3.19 (1H, dd, J = 9.0, 11.3 Hz), 3.36-3.43 (1H, m), 3.66-3.73 (1H, m), 3.71 (3H, s), 3.79 (1H, dt, J = 4.7, 11.0 Hz), 4.55 (1H, d, J = 7.4 Hz), 6.60 (1H, d, J = 8.2 Hz), 7.60 (1H, d, J = 8.6 Hz).
(65b) tert-ブチル　6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例65aで製造した(3S,4aS,10S,10aR)-2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,4a,6,10,10a-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン(493 mg, 0.875 mmol)、tert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(, 232 mg, 1.02 mmol)、2nd Generation X-Phos Precatalyst (145 mg, 0.184 mmol)、リン酸カリウム(305 mg, 1.44 mmol)、THF (5.0 mL)及び水(7.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(318 mg, 58%)を得た。 Example 65
6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6,8, 9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2 -Carboxylic acid tert-butylamine salt
(65a) (3S, 4aS, 10S, 10aR) -2-ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) phenyl] -3- (propan-2-yl) -3,4,4a, 6,10,10a-hexahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane ] -1,9 (2H, 8H) -dione (3S, 4aS, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-) prepared in Example 41c Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3- (propan-2-yl) -3,4,4a, 6,10,10a-hexahydrospiro [chromeno [3,2- c] pyridine-7,1′-cyclopropane] -1,9 (2H, 8H) -dione (2.14 g, 4.00 mmol), ethyl iodide (2.56 mL, 32.0 mmol), DMPU (21 mL) and hydrogenation The title compound (1.52, 68%) was obtained by performing the reaction and post-treatment according to Example 2a using sodium (55%, 209 mg, 4.80 mmol).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.24-0.45 (4H, m), 0.78 (3H, d, J = 7.0 Hz), 0.94 (3H, d, J = 6.7 Hz), 1.05 (3H , t, J = 7.0 Hz), 1.30 (12H, s), 1.67 (1H, d, J = 16.8 Hz), 1.77-1.85 (1H, m), 1.92 (1H, d, J = 18.0 Hz), 2.15 -2.24 (1H, m), 2.33-2.39 (1H, m), 2.46 (1H, d, J = 16.8 Hz), 2.69 (1H, d, J = 15.7 Hz), 2.96-3.05 (1H, m), 3.10 (3H, s), 3.19 (1H, dd, J = 9.0, 11.3 Hz), 3.36-3.43 (1H, m), 3.66-3.73 (1H, m), 3.71 (3H, s), 3.79 (1H, dt, J = 4.7, 11.0 Hz), 4.55 (1H, d, J = 7.4 Hz), 6.60 (1H, d, J = 8.2 Hz), 7.60 (1H, d, J = 8.6 Hz).
(65b) tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4, 4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl}- 3-methylpyridine-2-carboxylate (3S, 4aS, 10S, 10aR) -2-ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5) prepared in Example 65a -Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3- (propan-2-yl) -3,4,4a, 6,10,10a-hexahydrospiro [chromeno [3,2 -c] pyridine-7,1'-cyclopropane] -1,9 (2H, 8H) -dione (493 mg, 0.875 mmol), tert-butyl 6-chloro-3-methylpyridine-2-carboxylate (, 232 mg, 1.02 mmol), 2nd Generation X-Phos Precatalyst (145 mg, 0.184 mmol), potassium phosphate (305 mg, 1.44 mmol), THF (5.0 mL) and water (7.0 mL) to Example 9d The title compound (318 mg, 58%) Obtained.
1H-NMR(400MHz, CDCl3):δ ppm: 0.29-0.46 (4H, m), 0.81 (3H, d, J = 6.7 Hz), 0.95 (3H, d, J = 6.7 Hz), 1.06 (3H, t, J = 7.0 Hz), 1.58 (9H, s), 1.70 (1H, d, J = 16.5 Hz), 1.77-1.89 (1H, m), 1.95 (1H, d, J = 17.7 Hz), 2.15-2.25 (1H, m), 2.35-2.41 (1H, m), 2.48 (1H, d, J = 17.7 Hz), 2.49 (3H, s), 2.70 (1H, d, J = 17.1 Hz), 2.84 (3H, s), 3.03-3.11 (1H, m), 3.23 (1H, dd, J = 9.2, 11.6 Hz), 3.37-3.43 (1H, m), 3.60-3.69 (1H, m), 3.75-3.83 (1H, m), 3.77 (3H, s), 4.56 (1H, d, J = 9.2 Hz), 6.71 (1H, d, J = 8.5 Hz), 7.27 (1H, d, J = 8.5 Hz), 7.43 (1H, d, J = 7.9 Hz), 7.51 (1H, d, J = 8.5 Hz).
(65c) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例65bで製造したtert-ブチル　6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(318 mg, 0.506 mmol)、クロロホルム(5.0 mL)及びトリフルオロ酢酸(2.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(282 mg, 97%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.29-0.46 (4H, m), 0.81 (3H, d, J = 6.7 Hz), 0.95 (3H, d, J = 6.7 Hz), 1.06 (3H , t, J = 7.0 Hz), 1.58 (9H, s), 1.70 (1H, d, J = 16.5 Hz), 1.77-1.89 (1H, m), 1.95 (1H, d, J = 17.7 Hz), 2.15 -2.25 (1H, m), 2.35-2.41 (1H, m), 2.48 (1H, d, J = 17.7 Hz), 2.49 (3H, s), 2.70 (1H, d, J = 17.1 Hz), 2.84 ( 3H, s), 3.03-3.11 (1H, m), 3.23 (1H, dd, J = 9.2, 11.6 Hz), 3.37-3.43 (1H, m), 3.60-3.69 (1H, m), 3.75-3.83 ( 1H, m), 3.77 (3H, s), 4.56 (1H, d, J = 9.2 Hz), 6.71 (1H, d, J = 8.5 Hz), 7.27 (1H, d, J = 8.5 Hz), 7.43 ( 1H, d, J = 7.9 Hz), 7.51 (1H, d, J = 8.5 Hz).
(65c) 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6 , 8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methyl Pyridine-2-carboxylic acid tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) prepared in Example 65b -1,2,3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] -4 -Methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (318 mg, 0.506 mmol), chloroform (5.0 mL) and trifluoroacetic acid (2.0 mL) and the reaction according to Example 1d and The title compound (282 mg, 97%) was obtained by post-treatment.
1H-NMR(400MHz, CDCl3):δ ppm: 0.31-0.49 (4H, m), 0.81 (3H, d, J = 6.7 Hz), 0.97 (3H, d, J = 6.7 Hz), 1.06 (3H, t, J = 7.0 Hz), 1.73 (1H, d, J = 16.4 Hz), 1.80-1.89 (1H, m), 1.96 (1H, d, J = 17.6 Hz), 2.19-2.28 (1H, m), 2.36-2.43 (1H, m), 2.51 (1H, d, J = 16.4 Hz), 2.73 (3H, s), 2.82 (3H, s), 3.03-3.11 (1H, m), 3.28 (1H, t, J = 10.6 Hz), 3.41-3.47 (1H, m), 3.62-3.69 (2H, m), 3.77 (3H, s), 3.86 (1H, td, J = 4.5, 11.4 Hz), 4.43 (1H, d, J = 9.7 Hz), 6.75 (1H, d, J = 9.1 Hz), 7.16 (1H, d, J = 8.5 Hz), 7.67 (1H, d, J = 7.9 Hz), 7.86 (1H, d, J = 7.3 Hz).
MS(ESI/APCI)m/z: 573[M+H]+.
(65d) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例65cで製造した6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(175 mg, 0.306 mmol)、酢酸エチル(2.0 mL)及びtert-ブチルアミン(40 μL, 0.380 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(90.6 mg, 46%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.31-0.49 (4H, m), 0.81 (3H, d, J = 6.7 Hz), 0.97 (3H, d, J = 6.7 Hz), 1.06 (3H , t, J = 7.0 Hz), 1.73 (1H, d, J = 16.4 Hz), 1.80-1.89 (1H, m), 1.96 (1H, d, J = 17.6 Hz), 2.19-2.28 (1H, m) , 2.36-2.43 (1H, m), 2.51 (1H, d, J = 16.4 Hz), 2.73 (3H, s), 2.82 (3H, s), 3.03-3.11 (1H, m), 3.28 (1H, t , J = 10.6 Hz), 3.41-3.47 (1H, m), 3.62-3.69 (2H, m), 3.77 (3H, s), 3.86 (1H, td, J = 4.5, 11.4 Hz), 4.43 (1H, d, J = 9.7 Hz), 6.75 (1H, d, J = 9.1 Hz), 7.16 (1H, d, J = 8.5 Hz), 7.67 (1H, d, J = 7.9 Hz), 7.86 (1H, d, J = 7.3 Hz).
MS (ESI / APCI) m / z: 573 [M + H] +.
(65d) 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6 , 8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methyl Pyridine-2-carboxylic acid tert-butylamine salt 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) prepared in Example 65c ) -1,2,3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl]- Example 4c using 4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid (175 mg, 0.306 mmol), ethyl acetate (2.0 mL) and tert-butylamine (40 μL, 0.380 mmol) The title compound (90.6 mg, 46%) was obtained by reacting and working up according to.
(実施例66)
　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
　実施例24bで製造した6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(100 mg, 0.174 mmol)及びカルボニルジイミダゾール(45.1 mg, 0.278 mmol)のDMF (1.0 mL)溶液を室温で2時間攪拌した。反応溶液にメタンスルホンアミド(26.4 mg, 0.278 mmol)及びDBU (42 μL, 0.278 mmol)を加え、反応溶液を室温で1日攪拌した。反応溶液に10%クエン酸水溶液和を加え(pH = 4)、析出した結晶をろ取した。析出した結晶のエタノール(2.0 mL)溶液にtert-ブチルアミン(24 μL, 0.226 mmol)を加え、反応溶液を室温で30分攪拌した。反応溶液を濃縮後、残渣をヘキサン及び酢酸エチルより結晶化し、標記化合物(76.5 mg, 61%, 2 steps)を得た。 Example 66
6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7,8, 9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide tert-Butylamine salt 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3, prepared in Example 24b 4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine- A solution of 2-carboxylic acid (100 mg, 0.174 mmol) and carbonyldiimidazole (45.1 mg, 0.278 mmol) in DMF (1.0 mL) was stirred at room temperature for 2 hours. Methanesulfonamide (26.4 mg, 0.278 mmol) and DBU (42 μL, 0.278 mmol) were added to the reaction solution, and the reaction solution was stirred at room temperature for 1 day. A 10% aqueous citric acid solution was added to the reaction solution (pH = 4), and the precipitated crystals were collected by filtration. To a solution of the precipitated crystals in ethanol (2.0 mL) was added tert-butylamine (24 μL, 0.226 mmol), and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and the residue was crystallized from hexane and ethyl acetate to obtain the title compound (76.5 mg, 61%, 2 steps).
(実施例67)
　6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(67a) (3S,4aS,10S,10aR)-2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,4a,6,10,10a-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン
　実施例42dで製造した(3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,4a,6,10,10a-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン(740 mg, 1.35 mmol)、ヨウ化エチル(860 μL, 11.0 mmol)、DMPU (8.0 mL)及び水素化ナトリウム(63%, 70.0 mg, 1.84 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(518 mg, 67%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.77 (3H, d, J = 6.7 Hz), 0.94 (3H, d, J = 6.7 Hz), 1.04 (3H, t, J = 7.0 Hz), 1.28 (12H, s), 1.72-1.87 (6H, m), 2.14-2.24 (2H, m), 2.34-2.46 (3H, m), 2.54 (1H, d, J = 17.0 Hz), 2.96-3.05 (1H, m), 3.10 (3H, s), 3.13-3.26 (2H, m), 3.36-3.42 (1H, m), 3.62-3.79 (2H, m), 3.62 (3H, s), 4.52 (1H, d, J = 9.1 Hz), 6.54 (1H, d, J = 7.9 Hz), 7.59 (1H, d, J = 8.5 Hz).
(67b) tert-ブチル　6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例67aで製造した(3S,4aS,10S,10aR)-2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,4a,6,10,10a-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン(518 mg, 0.897 mmol)、tert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(, 252 mg, 1.11 mmol)、2nd Generation X-Phos Precatalyst (139 mg, 0.177 mmol)、リン酸カリウム(321 mg, 0.306 mmol)、THF (5.0 mL)及び水(7.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(563 mg, 98%)を得た。 Example 67
6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6,8, 9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2- Carboxylic acid tert-butylamine salt
(67a) (3S, 4aS, 10S, 10aR) -2-Ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) phenyl] -3- (propan-2-yl) -3,4,4a, 6,10,10a-hexahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H) -dione (3S, 4aS, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetra) prepared in Example 42d Methyl-1,3,2-dioxaborolan-2-yl) phenyl] -3- (propan-2-yl) -3,4,4a, 6,10,10a-hexahydrospiro [chromeno [3,2-c ] Pyridine-7,1'-cyclobutane] -1,9 (2H, 8H) -dione (740 mg, 1.35 mmol), ethyl iodide (860 μL, 11.0 mmol), DMPU (8.0 mL) and sodium hydride ( The title compound (518 mg, 67%) was obtained by carrying out the reaction and post-treatment according to Example 2a using 63%, 70.0 mg, 1.84 mmol).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.77 (3H, d, J = 6.7 Hz), 0.94 (3H, d, J = 6.7 Hz), 1.04 (3H, t, J = 7.0 Hz), 1.28 (12H, s), 1.72-1.87 (6H, m), 2.14-2.24 (2H, m), 2.34-2.46 (3H, m), 2.54 (1H, d, J = 17.0 Hz), 2.96-3.05 ( 1H, m), 3.10 (3H, s), 3.13-3.26 (2H, m), 3.36-3.42 (1H, m), 3.62-3.79 (2H, m), 3.62 (3H, s), 4.52 (1H, d, J = 9.1 Hz), 6.54 (1H, d, J = 7.9 Hz), 7.59 (1H, d, J = 8.5 Hz).
(67b) tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4, 4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3 -Methylpyridine-2-carboxylate (3S, 4aS, 10S, 10aR) -2-ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-) prepared in Example 67a Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3- (propan-2-yl) -3,4,4a, 6,10,10a-hexahydrospiro [chromeno [3,2- c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H) -dione (518 mg, 0.897 mmol), tert-butyl 6-chloro-3-methylpyridine-2-carboxylate (, 252 mg , 1.11 mmol), 2nd Generation X-Phos Precatalyst (139 mg, 0.177 mmol), potassium phosphate (321 mg, 0.306 mmol), THF (5.0 mL) and water (7.0 mL), according to Example 9d The title compound (563 mg, 98%) was obtained by reaction and post-treatment. .
1H-NMR(400MHz, CDCl3):δ ppm: 0.81 (3H, d, J = 6.7 Hz), 0.96 (3H, d, J = 7.3 Hz), 1.05 (3H, t, J = 7.0 Hz), 1.63 (9H, s), 1.74-1.93 (6H, m), 2.16-2.26 (2H, m), 2.35-2.50 (3H, m), 2.40 (3H, s), 2.57 (1H, d, J = 17.1 Hz), 2.83 (3H, s), 3.02-3.11 (1H, m), 3.20 (1H, t, J = 10.1 Hz), 3.36-3.43 (1H, m), 3.58-3.66 (1H, m), 3.71-3.80 (1H, m), 3.71 (3H, s), 4.10-4.15 (1H, m), 4.52 (1H, d, J = 9.2 Hz), 6.65 (1H, d, J = 8.5 Hz), 7.25 (1H, d, J = 9.8 Hz), 7.43 (1H, d, J = 7.3 Hz), 7.51 (1H, d, J = 7.9 Hz).
(67c) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例67bで製造したtert-ブチル　6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(563 mg, 0.875 mmol)、クロロホルム(4.0 mL)及びトリフルオロ酢酸(2.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(375 mg, 73%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.81 (3H, d, J = 6.7 Hz), 0.96 (3H, d, J = 7.3 Hz), 1.05 (3H, t, J = 7.0 Hz), 1.63 (9H, s), 1.74-1.93 (6H, m), 2.16-2.26 (2H, m), 2.35-2.50 (3H, m), 2.40 (3H, s), 2.57 (1H, d, J = 17.1 Hz), 2.83 (3H, s), 3.02-3.11 (1H, m), 3.20 (1H, t, J = 10.1 Hz), 3.36-3.43 (1H, m), 3.58-3.66 (1H, m), 3.71 -3.80 (1H, m), 3.71 (3H, s), 4.10-4.15 (1H, m), 4.52 (1H, d, J = 9.2 Hz), 6.65 (1H, d, J = 8.5 Hz), 7.25 ( 1H, d, J = 9.8 Hz), 7.43 (1H, d, J = 7.3 Hz), 7.51 (1H, d, J = 7.9 Hz).
(67c) 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6 , 8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine -2-carboxylic acid tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl)-prepared in Example 67b 1,2,3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl] -4-methoxy -2-Methylphenyl} -3-methylpyridine-2-carboxylate (563 mg, 0.875 mmol), chloroform (4.0 mL) and trifluoroacetic acid (2.0 mL) were reacted and worked up according to Example 1d. To give the title compound (375 mg, 73%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.81 (3H, d, J = 6.7 Hz), 0.97 (3H, d, J = 6.7 Hz), 1.05 (3H, t, J = 7.0 Hz), 1.59-1.91 (6H, m), 2.19-2.28 (2H, m), 2.34-2.49 (3H, m), 2.59 (1H, d, J = 17.0 Hz), 2.80 (3H, s), 2.81 (3H, s), 2.98-3.07 (1H, m), 3.26 (1H, t, J = 10.3 Hz), 3.39-3.46 (1H, m), 3.62-3.84 (3H, m), 3.74 (3H, s), 4.46 (1H, d, J = 9.1 Hz), 6.69 (1H, d, J = 9.1 Hz), 7.17 (1H, d, J = 8.5 Hz), 7.62 (1H, d, J = 7.9 Hz), 7.69 (1H, d, J = 7.9 Hz).
MS(ESI/APCI)m/z: 587[M+H]+.
(67d) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例67cで製造した6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(200 mg, 0.341 mmol)、酢酸エチル(2.0 mL)及びtert-ブチルアミン(50 μL, 0.480 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(166 mg, 74%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.81 (3H, d, J = 6.7 Hz), 0.97 (3H, d, J = 6.7 Hz), 1.05 (3H, t, J = 7.0 Hz), 1.59-1.91 (6H, m), 2.19-2.28 (2H, m), 2.34-2.49 (3H, m), 2.59 (1H, d, J = 17.0 Hz), 2.80 (3H, s), 2.81 (3H, s), 2.98-3.07 (1H, m), 3.26 (1H, t, J = 10.3 Hz), 3.39-3.46 (1H, m), 3.62-3.84 (3H, m), 3.74 (3H, s), 4.46 (1H, d, J = 9.1 Hz), 6.69 (1H, d, J = 9.1 Hz), 7.17 (1H, d, J = 8.5 Hz), 7.62 (1H, d, J = 7.9 Hz), 7.69 (1H , d, J = 7.9 Hz).
MS (ESI / APCI) m / z: 587 [M + H] +.
(67d) 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6 , 8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine 2-Carboxylic acid tert-butylamine salt 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) prepared in Example 67c -1,2,3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] -4- Methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid (200 mg, 0.341 mmol), ethyl acetate (2.0 mL) and tert-butylamine (50 μL, 0.480 mmol) according to Example 3c The title compound (166 mg, 74%) was obtained by reaction and workup.
(実施例68)
　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}ピリジン-2-カルボン酸　tert-ブチルアミン塩
(68a) tert-ブチル　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}ピリジン-2-カルボキシレート
　実施例42eで製造した(3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2-メチル-3-(プロパン-2-イル)-3,4,4a,6,10,10a-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン(400 mg, 0.710 mmol)、tert-ブチル　6-ブロモピリジン-2-カルボキシレート(238 mg, 0.923 mmol)、2nd Generation X-Phos Precatalyst (168 mg, 0.213 mmol)、リン酸カリウム(241 mg, 1.14 mmol)、THF (6.0 mL)及び水(8.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(207 mg, 47%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.76 (3H, d, J = 6.7 Hz), 0.96 (3H, d, J = 6.7 Hz), 1.66 (9H, s), 1.72-1.89 (7H, m), 2.19-2.28 (2H, m), 2.36-2.48 (3H, m), 2.57 (1H, d, J = 16.4 Hz), 2.78 (3H, s), 2.82 (3H, s), 3.23 (1H, t, J = 9.8 Hz), 3.30-3.38 (1H, m), 3.72 (3H, s), 3.82 (1H, dt, J = 5.1, 11.7 Hz), 4.44 (1H, d, J = 9.4 Hz), 6.66 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.2 Hz), 7.59 (1H, dd, J = 0.8, 7.8 Hz), 7.75 (1H, t, J = 7.6 Hz), 7.90 (1H, dd, J = 0.8, 8.2 Hz).
(68b) 6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}ピリジン-2-カルボン酸
　実施例68aで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}ピリジン-2-カルボキシレート(207 mg, 0.337 mmol)、ジクロロメタン(2.1 mL)及びトリフルオロ酢酸(1.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(153 mg, 81%)を得た。 Example 68
6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3, 4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl] phenyl} pyridine-2-carboxylic acid tert- Butylamine salt
(68a) tert-butyl 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl)- 1,2,3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} pyridine- 2-carboxylate (3S, 4aS, 10S, 10aR) -10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2) prepared in Example 42e -Dioxaborolan-2-yl) phenyl] -2-methyl-3- (propan-2-yl) -3,4,4a, 6,10,10a-hexahydrospiro [chromeno [3,2-c] pyridine- 7,1'-cyclobutane] -1,9 (2H, 8H) -dione (400 mg, 0.710 mmol), tert-butyl 6-bromopyridine-2-carboxylate (238 mg, 0.923 mmol), 2nd Generation X- Phos Precatalyst (168 mg, 0.213 mmol), potassium phosphate (241 mg, 1.14 mmol), THF (6.0 mL) and water (8.0 mL) were used to carry out the reaction and post-treatment according to Example 9d. The title compound (207 mg, 47%) was obtained.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.76 (3H, d, J = 6.7 Hz), 0.96 (3H, d, J = 6.7 Hz), 1.66 (9H, s), 1.72-1.89 (7H , m), 2.19-2.28 (2H, m), 2.36-2.48 (3H, m), 2.57 (1H, d, J = 16.4 Hz), 2.78 (3H, s), 2.82 (3H, s), 3.23 ( 1H, t, J = 9.8 Hz), 3.30-3.38 (1H, m), 3.72 (3H, s), 3.82 (1H, dt, J = 5.1, 11.7 Hz), 4.44 (1H, d, J = 9.4 Hz ), 6.66 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.2 Hz), 7.59 (1H, dd, J = 0.8, 7.8 Hz), 7.75 (1H, t, J = 7.6 Hz) ), 7.90 (1H, dd, J = 0.8, 8.2 Hz).
(68b) 6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2 , 3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} pyridine-2-carvone Acid tert-butyl 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propane-2) prepared in Example 68a -Yl) -1,2,3,4,4a, 6,8,9,10,10a-decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl] Phenyl} pyridine-2-carboxylate (207 mg, 0.337 mmol), dichloromethane (2.1 mL) and trifluoroacetic acid (1.0 mL) were used for the reaction and workup according to Example 1d to give the title compound ( 153 mg, 81%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.77 (3H, d, J = 6.6 Hz), 0.97 (3H, d, J = 7.0 Hz), 1.60-1.92 (7H, m), 2.22-2.30 (2H, m), 2.37-2.51 (3H, m), 2.59 (1H, d, J = 17.6 Hz), 2.77 (3H, s), 2.83 (3H, s), 3.27 (1H, t, J = 10.4 Hz), 3.35-3.41 (1H, m), 3.74 (3H, s), 3.86 (1H, td, J = 11.5, 4.0 Hz), 4.41 (1H, d, J = 9.8 Hz), 6.70 (1H, d, J = 8.6 Hz), 7.18 (1H, d, J = 8.6 Hz), 7.73 (1H, dd, J = 0.8, 7.8 Hz), 7.94 (1H, t, J = 7.6 Hz), 8.14 (1H, dd, J = 1.0, 7.6 Hz).
MS(ESI/APCI)m/z: 559[M+H]+.
(68c) 6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}ピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例68bで製造した6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}ピリジン-2-カルボン酸(150 mg, 0.269 mmol)、エタノール(3.0 mL)及びtert-ブチルアミン(34 μL, 0.322 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(134 mg, 79%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.77 (3H, d, J = 6.6 Hz), 0.97 (3H, d, J = 7.0 Hz), 1.60-1.92 (7H, m), 2.22-2.30 (2H, m), 2.37-2.51 (3H, m), 2.59 (1H, d, J = 17.6 Hz), 2.77 (3H, s), 2.83 (3H, s), 3.27 (1H, t, J = 10.4 Hz), 3.35-3.41 (1H, m), 3.74 (3H, s), 3.86 (1H, td, J = 11.5, 4.0 Hz), 4.41 (1H, d, J = 9.8 Hz), 6.70 (1H, d , J = 8.6 Hz), 7.18 (1H, d, J = 8.6 Hz), 7.73 (1H, dd, J = 0.8, 7.8 Hz), 7.94 (1H, t, J = 7.6 Hz), 8.14 (1H, dd , J = 1.0, 7.6 Hz).
MS (ESI / APCI) m / z: 559 [M + H] +.
(68c) 6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2 , 3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} pyridine-2-carvone Acid tert-butylamine salt 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propane- 2-yl) -1,2,3,4,4a, 6,8,9,10,10a-decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl By reacting and working up according to Example 3c using phenyl} pyridine-2-carboxylic acid (150 mg, 0.269 mmol), ethanol (3.0 mL) and tert-butylamine (34 μL, 0.322 mmol) The title compound (134 mg, 79%) was obtained.
(実施例69)
　6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボン酸 tert-ブチルアミン塩
(69a) tert-ブチル　6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボキシレート
　実施例27cで製造した(3S,4aS,10S,10aR)-2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(400 mg, 0.707 mmol)、tert-ブチル　6-クロロ-4-メチルピリジン-2-カルボキシレート(209 mg, 0.919 mmol)、2nd Generation X-Phos Precatalyst (111 mg, 0.141 mmol)、リン酸カリウム(240 mg, 1.13 mmol)、THF (2.0 mL)及び水(4.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(360 mg, 81%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.81 (3H, d, J = 6.6 Hz), 0.93 (3H, s), 0.96 (3H, d, J = 6.6 Hz), 1.04-1.07 (6H, m), 1.63 (9H, s), 1.79-1.92 (1H, m), 2.03 (1H, d, J = 16.8 Hz), 2.14 (1H, d, J = 16.4 Hz), 2.16-2.22 (1H, m), 2.25 (1H, d, J = 16.8 Hz), 2.34 (1H, d, J = 18.4 Hz), 2.36-2.42 (1H, m), 2.42 (3H, s), 2.81 (3H, s), 3.04-3.13 (1H, m), 3.22 (1H, dd, J = 8.8, 11.5 Hz), 3.38-3.43 (1H, m), 3.61 (1H, dd, J = 7.0, 13.7 Hz), 3.72 (3H, s), 3.73-3.80 (1H, m), 4.54 (1H, d, J = 7.4 Hz), 6.67 (1H, d, J = 8.6 Hz), 7.26 (1H, d, J = 8.2 Hz), 7.41 (1H, s), 7.73 (1H, s).
(69b) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボン酸
　実施例69aで製造したtert-ブチル　6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボキシレート(360 mg, 0.571 mmol)、ジクロロメタン(3.6 mL)及びトリフルオロ酢酸(1.8 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(280 mg, 85%)を得た。 Example 69
6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -4-methylpyridine-2-carboxylic acid tert-Butylamine salt
(69a) tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2, 3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -4-methyl Pyridine-2-carboxylate (3S, 4aS, 10S, 10aR) -2-ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl) prepared in Example 27c -1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3- (propan-2-yl) -3,4,4a, 6,7,8,10,10a-octahydro- 1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (400 mg, 0.707 mmol), tert-butyl 6-chloro-4-methylpyridine-2-carboxylate (209 mg, 0.919 mmol) ), 2nd Generation X-Phos Precatalyst (111 mg, 0.141 mmol), potassium phosphate (240 mg, 1.13 mmol), THF (2.0 mL) and water (4.0 mL), and the reaction according to Example 9d. The title compound (360 mg, 81%) was obtained by the treatment.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.81 (3H, d, J = 6.6 Hz), 0.93 (3H, s), 0.96 (3H, d, J = 6.6 Hz), 1.04-1.07 (6H , m), 1.63 (9H, s), 1.79-1.92 (1H, m), 2.03 (1H, d, J = 16.8 Hz), 2.14 (1H, d, J = 16.4 Hz), 2.16-2.22 (1H, m), 2.25 (1H, d, J = 16.8 Hz), 2.34 (1H, d, J = 18.4 Hz), 2.36-2.42 (1H, m), 2.42 (3H, s), 2.81 (3H, s), 3.04-3.13 (1H, m), 3.22 (1H, dd, J = 8.8, 11.5 Hz), 3.38-3.43 (1H, m), 3.61 (1H, dd, J = 7.0, 13.7 Hz), 3.72 (3H, s), 3.73-3.80 (1H, m), 4.54 (1H, d, J = 7.4 Hz), 6.67 (1H, d, J = 8.6 Hz), 7.26 (1H, d, J = 8.2 Hz), 7.41 ( 1H, s), 7.73 (1H, s).
(69b) 6- {3-[(3S, 4aS, 10S, 10aR) -2-Ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4 , 4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -4-methylpyridine-2 -Carboxylic acid tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propane-2) prepared in Example 69a -Yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methyl Phenyl} -4-methylpyridine-2-carboxylate (360 mg, 0.571 mmol), dichloromethane (3.6 mL) and trifluoroacetic acid (1.8 mL) were used for the reaction and workup according to Example 1d. The title compound (280 mg, 85%) was obtained.
1H-NMR(400MHz, CDCl3):δ ppm: 0.81 (3H, d, J = 6.6 Hz), 0.95 (3H, s), 0.97 (3H, d, J = 6.6 Hz), 1.06 (3H, s), 1.06 (3H, t, J = 6.3 Hz), 1.81-1.90 (1H, m), 2.05 (1H, dd, J = 1.6, 16.4 Hz), 2.16 (1H, d, J = 16.4 Hz), 2.18-2.25 (1H, m), 2.27 (1H, d, J = 18.0 Hz), 2.34-2.44 (2H, m), 2.50 (3H, s), 2.80 (3H, s), 3.01-3.10 (1H, m), 3.27 (1H, dd, J = 9.4, 11.3 Hz), 3.41-3.46 (1H, m), 3.62-3.72 (1H, m), 3.75 (3H, s), 3.80 (1H, td, J = 4.7, 11.3 Hz), 4.50 (1H, d, J = 9.0 Hz), 6.72 (1H, d, J = 8.6 Hz), 7.16 (1H, d, J = 8.6 Hz), 7.53 (1H, s), 7.99 (1H, s).
MS(ESI/APCI)m/z: 575[M+H]+.
(69c) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボン酸 tert-ブチルアミン塩
　実施例69bで製造した6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボン酸(280 mg, 0.487 mmol)、エタノール(5.6 mL)及びtert-ブチルアミン(61 μL, 0.585 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(100 mg, 32%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.81 (3H, d, J = 6.6 Hz), 0.95 (3H, s), 0.97 (3H, d, J = 6.6 Hz), 1.06 (3H, s ), 1.06 (3H, t, J = 6.3 Hz), 1.81-1.90 (1H, m), 2.05 (1H, dd, J = 1.6, 16.4 Hz), 2.16 (1H, d, J = 16.4 Hz), 2.18 -2.25 (1H, m), 2.27 (1H, d, J = 18.0 Hz), 2.34-2.44 (2H, m), 2.50 (3H, s), 2.80 (3H, s), 3.01-3.10 (1H, m ), 3.27 (1H, dd, J = 9.4, 11.3 Hz), 3.41-3.46 (1H, m), 3.62-3.72 (1H, m), 3.75 (3H, s), 3.80 (1H, td, J = 4.7 , 11.3 Hz), 4.50 (1H, d, J = 9.0 Hz), 6.72 (1H, d, J = 8.6 Hz), 7.16 (1H, d, J = 8.6 Hz), 7.53 (1H, s), 7.99 ( 1H, s).
MS (ESI / APCI) m / z: 575 [M + H] +.
(69c) 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4 , 4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -4-methylpyridine-2 -Carboxylic acid tert-butylamine salt 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propane- 2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2- Methylphenyl} -4-methylpyridine-2-carboxylic acid (280 mg, 0.487 mmol), ethanol (5.6 mL) and tert-butylamine (61 μL, 0.585 mmol) were reacted and worked up according to Example 3c. To give the title compound (100 mg, 32%).
(実施例70)
　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-4-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(70a) tert-ブチル　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-4-メチルピリジン-2-カルボキシレート
　実施例42eで製造した(3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2-メチル-3-(プロパン-2-イル)-3,4,4a,6,10,10a-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン(400 mg, 0.710 mmol)、tert-ブチル　6-クロロ-4-メチルピリジン-2-カルボキシレート(210 mg, 0.923 mmol)、2nd Generation X-Phos Precatalyst (168 mg, 0.213 mmol)、リン酸カリウム(241 mg, 1.14 mmol)、THF (6.0 mL)及び水(8.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(434 mg, 97%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.77 (3H, d, J = 6.6 Hz), 0.96 (3H, d, J = 7.0 Hz), 1.63 (9H, s), 1.75-1.90 (7H, m), 2.20-2.28 (2H, m), 2.36-2.48 (3H, m), 2.42 (3H, s), 2.57 (1H, d, J = 18.0 Hz), 2.76 (3H, s), 2.82 (3H, s), 3.24 (1H, t, J = 9.8 Hz), 3.33-3.39 (1H, m), 3.71 (3H, s), 3.82 (1H, dt, J = 4.7, 11.3 Hz), 4.45 (1H, d, J = 8.2 Hz), 6.65 (1H, d, J = 8.6 Hz), 7.24 (1H, d, J = 8.6 Hz), 7.40 (1H, s), 7.74 (1H, s).
(70b) 6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-4-メチルピリジン-2-カルボン酸
　実施例70aで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-4-メチルピリジン-2-カルボキシレート(360 mg, 0.337 mmol)、ジクロロメタン(3.6 mL)及びトリフルオロ酢酸(1.8 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(289 mg, 88%)を得た。 Example 70
6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3, 4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl] phenyl} -4-methylpyridine-2- Carboxylic acid tert-butylamine salt
(70a) tert-butyl 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl)- 1,2,3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} -4 -Methylpyridine-2-carboxylate (3S, 4aS, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1) prepared in Example 42e , 3,2-Dioxaborolan-2-yl) phenyl] -2-methyl-3- (propan-2-yl) -3,4,4a, 6,10,10a-hexahydrospiro [chromeno [3,2- c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H) -dione (400 mg, 0.710 mmol), tert-butyl 6-chloro-4-methylpyridine-2-carboxylate (210 mg, 0.923 mmol), 2nd Generation X-Phos Precatalyst (168 mg, 0.213 mmol), potassium phosphate (241 mg, 1.14 mmol), THF (6.0 mL) and water (8.0 mL) were used according to Example 9d. And post-treatment to give the title compound (434 mg, 97%)
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.77 (3H, d, J = 6.6 Hz), 0.96 (3H, d, J = 7.0 Hz), 1.63 (9H, s), 1.75-1.90 (7H , m), 2.20-2.28 (2H, m), 2.36-2.48 (3H, m), 2.42 (3H, s), 2.57 (1H, d, J = 18.0 Hz), 2.76 (3H, s), 2.82 ( 3H, s), 3.24 (1H, t, J = 9.8 Hz), 3.33-3.39 (1H, m), 3.71 (3H, s), 3.82 (1H, dt, J = 4.7, 11.3 Hz), 4.45 (1H , d, J = 8.2 Hz), 6.65 (1H, d, J = 8.6 Hz), 7.24 (1H, d, J = 8.6 Hz), 7.40 (1H, s), 7.74 (1H, s).
(70b) 6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2 , 3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} -4-methylpyridine -2-carboxylic acid tert-butyl 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- prepared in Example 70a (Propan-2-yl) -1,2,3,4,4a, 6,8,9,10,10a-decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane]- 10-yl] phenyl} -4-methylpyridine-2-carboxylate (360 mg, 0.337 mmol), dichloromethane (3.6 mL) and trifluoroacetic acid (1.8 mL), reaction and workup according to Example 1d To give the title compound (289 mg, 88%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.77 (3H, d, J = 6.7 Hz), 0.97 (3H, d, J = 7.0 Hz), 1.61-1.90 (7H, m), 2.23-2.30 (2H, m), 2.37-2.51 (3H, m), 2.49 (3H, s), 2.59 (1H, d, J = 17.6 Hz), 2.75 (3H, s), 2.83 (3H, s), 3.26 (1H, t, J = 11.3 Hz), 3.35-3.40 (1H, m), 3.73 (3H, s), 4.41 (1H, d, J = 9.8 Hz), 3.85 (1H, dt, J = 4.7, 11.3 Hz), 6.68 (1H, d, J = 8.6 Hz), 7.14 (1H, d, J = 8.6 Hz), 7.53 (1H, s), 7.98 (1H, s).
MS(ESI/APCI)m/z: 573[M+H]+.
(70c) 6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-4-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例70bで製造した6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-4-メチルピリジン-2-カルボン酸(289 mg, 0.505 mmol)、エタノール(5.8 mL)及びtert-ブチルアミン(64 μL, 0.606 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(240 mg, 74%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.77 (3H, d, J = 6.7 Hz), 0.97 (3H, d, J = 7.0 Hz), 1.61-1.90 (7H, m), 2.23-2.30 (2H, m), 2.37-2.51 (3H, m), 2.49 (3H, s), 2.59 (1H, d, J = 17.6 Hz), 2.75 (3H, s), 2.83 (3H, s), 3.26 ( 1H, t, J = 11.3 Hz), 3.35-3.40 (1H, m), 3.73 (3H, s), 4.41 (1H, d, J = 9.8 Hz), 3.85 (1H, dt, J = 4.7, 11.3 Hz ), 6.68 (1H, d, J = 8.6 Hz), 7.14 (1H, d, J = 8.6 Hz), 7.53 (1H, s), 7.98 (1H, s).
MS (ESI / APCI) m / z: 573 [M + H] +.
(70c) 6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2 , 3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} -4-methylpyridine -2-carboxylic acid tert-butylamine salt 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3 prepared in Example 70b -(Propan-2-yl) -1,2,3,4,4a, 6,8,9,10,10a-decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} -4-methylpyridine-2-carboxylic acid (289 mg, 0.505 mmol), ethanol (5.8 mL) and tert-butylamine (64 μL, 0.606 mmol) according to Example 3c The title compound (240 mg, 74%) was obtained by reaction and workup.
(実施例71)
　6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
(71a) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例65cで製造した6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(107 mg, 0.186 mmol)、カルボニルジイミダゾール(94.0 mg, 0.580 mmol)、DMF (2.0 mL)、メタンスルホンアミド(54.0 mg, 0.568 mmol)及びDBU (84 μL, 0.560 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(68.1 mg, 56%)を得た。 Example 71
6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6,8, 9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (Methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt
(71a) 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6 , 8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methyl -N- (methylsulfonyl) pyridine-2-carboxamide 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propane-2) prepared in Example 65c -Yl) -1,2,3,4,4a, 6,8,9,10,10a-decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl ] -4-Methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid (107 mg, 0.186 mmol), carbonyldiimidazole (94.0 mg, 0.580 mmol), DMF (2.0 mL), methanesulfonamide ( 54.0 mg, 0.568 mmol) and DBU (84 μL, 0.560 mmol) were used, and the reaction and post-treatment were performed according to Example 6a to obtain the title compound (68.1 mg, 56%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.33-0.48 (4H, m), 0.81 (3H, d, J = 6.7 Hz), 0.96 (3H, d, J = 7.3 Hz), 1.06 (3H, t, J = 7.5 Hz), 1.73 (1H, d, J = 17.0 Hz), 1.80-1.89 (1H, m), 1.96 (1H, d, J = 17.6 Hz), 2.20-2.42 (2H, m), 2.50 (1H, d, J = 17.0 Hz), 2.72 (1H, dd, J = 2.4, 17.6 Hz), 2.77 (3H, s), 2.81 (3H, s), 3.04 (1H, dd, J = 7.0, 13.7 Hz), 3.25-3.31 (1H, m), 3.38 (3H, s), 3.40-3.45 (1H, m), 3.65-3.74 (1H, m), 3.77 (3H, s), 3.83 (1H, td, J = 4.7, 11.4 Hz), 4.50 (1H, d, J = 7.9 Hz), 6.75 (1H, d, J = 8.5 Hz), 7.20 (1H, d, J = 8.5 Hz), 7.61 (1H, d, J = 8.5 Hz), 7.65 (1H, d, J = 7.9 Hz).
MS(ESI/APCI)m/z: 650[M+H]+.
(71b) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
　実施例71aで製造した6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド(68.1 mg, 0.105 mmol)、酢酸エチル(2.0 mL)及びtert-ブチルアミン(20 μL, 0.190 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(50.2 mg, 66%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.33-0.48 (4H, m), 0.81 (3H, d, J = 6.7 Hz), 0.96 (3H, d, J = 7.3 Hz), 1.06 (3H , t, J = 7.5 Hz), 1.73 (1H, d, J = 17.0 Hz), 1.80-1.89 (1H, m), 1.96 (1H, d, J = 17.6 Hz), 2.20-2.42 (2H, m) , 2.50 (1H, d, J = 17.0 Hz), 2.72 (1H, dd, J = 2.4, 17.6 Hz), 2.77 (3H, s), 2.81 (3H, s), 3.04 (1H, dd, J = 7.0 , 13.7 Hz), 3.25-3.31 (1H, m), 3.38 (3H, s), 3.40-3.45 (1H, m), 3.65-3.74 (1H, m), 3.77 (3H, s), 3.83 (1H, td, J = 4.7, 11.4 Hz), 4.50 (1H, d, J = 7.9 Hz), 6.75 (1H, d, J = 8.5 Hz), 7.20 (1H, d, J = 8.5 Hz), 7.61 (1H, d, J = 8.5 Hz), 7.65 (1H, d, J = 7.9 Hz).
MS (ESI / APCI) m / z: 650 [M + H] +.
(71b) 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6 , 8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methyl -N- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- prepared in Example 71a (Propan-2-yl) -1,2,3,4,4a, 6,8,9,10,10a-decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide (68.1 mg, 0.105 mmol), ethyl acetate (2.0 mL) and tert-butylamine ( The title compound (50.2 mg, 66%) was obtained by performing the reaction and post-treatment according to Example 3c using 20 μL, 0.190 mmol).
(実施例72)
　6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
(72a) 6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例41fで製造した6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸tert-ブチルアミン塩(25.6 mg, 0.0405 mmol)の酢酸エチル溶液を10%クエン酸水溶液で洗浄した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮し、フリーのカルボン酸(22.0 mg, 97%)を得た。フリーのカルボン酸(22.0 mg, 0.0394 mmol)、カルボニルジイミダゾール(19.2 mg, 0.118 mmol)、DMF (0.5 mL)、メタンスルホンアミド(15.0 mg, 0.158 mmol)及びDBU (24 μL, 0.158 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(21.4 mg, 86%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.32-0.48 (4H, m), 0.77 (3H, d, J = 7.0 Hz), 0.96 (3H, d, J = 7.0 Hz), 1.72 (1H, d, J = 16.8 Hz), 1.82 (1H, q, J = 11.7 Hz), 1.95 (1H, d, J = 17.6 Hz), 2.23-2.41 (2H, m), 2.51 (1H, d, J = 16.8 Hz), 2.71-2.80 (1H, m), 2.77 (3H, s), 2.79 (3H, s), 2.84 (3H, s), 3.27 (1H, t, J = 10.4 Hz), 3.34-3.40 (1H, m), 3.38 (3H, s), 3.77 (3H, s), 3.88 (1H, dt, J = 3.1, 11.3 Hz), 4.45 (1H, d, J = 7.8 Hz), 6.75 (1H, d, J = 8.6 Hz), 7.20 (1H, d, J = 8.2 Hz), 7.62 (1H, d, J = 8.2 Hz), 7.65 (1H, d, J = 8.2 Hz).
(72b) 6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
　実施例72aで製造した6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド(21.4 mg, 0.0337 mmol)、酢酸エチル(0.5 mL)及びtert-ブチルアミン(5 μL, 0.0505 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(20.9 mg, 88%)を得た。 (Example 72)
6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3, 4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] phenyl} -3-methyl-N- (Methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt
(72a) 6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2 , 3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] phenyl} -3-methyl -N- (methylsulfonyl) pyridine-2-carboxamide 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9- prepared in Example 41f Dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6,8,9,10,10a-decahydrospiro [chromeno [3,2-c] pyridine-7,1 ' -Cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt (25.6 mg, 0.0405 mmol) in ethyl acetate was washed with 10% aqueous citric acid. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain free carboxylic acid (22.0 mg, 97%). Using free carboxylic acid (22.0 mg, 0.0394 mmol), carbonyldiimidazole (19.2 mg, 0.118 mmol), DMF (0.5 mL), methanesulfonamide (15.0 mg, 0.158 mmol) and DBU (24 μL, 0.158 mmol) The title compound (21.4 mg, 86%) was obtained by reaction and post-treatment according to Example 6a.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.32-0.48 (4H, m), 0.77 (3H, d, J = 7.0 Hz), 0.96 (3H, d, J = 7.0 Hz), 1.72 (1H , d, J = 16.8 Hz), 1.82 (1H, q, J = 11.7 Hz), 1.95 (1H, d, J = 17.6 Hz), 2.23-2.41 (2H, m), 2.51 (1H, d, J = 16.8 Hz), 2.71-2.80 (1H, m), 2.77 (3H, s), 2.79 (3H, s), 2.84 (3H, s), 3.27 (1H, t, J = 10.4 Hz), 3.34-3.40 ( 1H, m), 3.38 (3H, s), 3.77 (3H, s), 3.88 (1H, dt, J = 3.1, 11.3 Hz), 4.45 (1H, d, J = 7.8 Hz), 6.75 (1H, d , J = 8.6 Hz), 7.20 (1H, d, J = 8.2 Hz), 7.62 (1H, d, J = 8.2 Hz), 7.65 (1H, d, J = 8.2 Hz).
(72b) 6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2 , 3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] phenyl} -3-methyl -N- (Methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt 6- {4-Methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl- prepared in Example 72a 1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6,8,9,10,10a-decahydrospiro [chromeno [3,2-c] pyridine- 7,1′-cyclopropane] -10-yl] phenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide (21.4 mg, 0.0337 mmol), ethyl acetate (0.5 mL) and tert-butylamine ( The title compound (20.9 mg, 88%) was obtained by carrying out the reaction and post-treatment according to Example 3c using 5 μL, 0.0505 mmol).
(実施例73)
　5-フルオロ-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボン酸
(73a) エチル　5-フルオロ-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボキシレート
5-フルオロ-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボン酸実施例47aで製造した(3S,4aS,10S,10aR)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3-(プロパン-2-イル)-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(250 mg, 0.453 mmol)、エチル　6-クロロ-5-フルオロピリジン-2-カルボキシレート(113 mg, 0.554 mmol)、2nd Generation X-Phos Precatalyst (71.0 mg, 0.0902 mmol)、リン酸カリウム(159 mg, 0.749 mmol)、THF (3.0 mL)及び水(6.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(200 mg, 75%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.77 (3H, d, J = 7.3 Hz), 0.95 (3H, s), 0.96 (3H, d, J = 8.5 Hz), 1.05 (3H, s), 1.42 (3H, t, J = 7.0 Hz), 1.77-1.86 (1H, m), 2.04 (1H, d, J = 17.0 Hz), 2.14 (1H, d, J = 16.4 Hz), 2.23-2.41 (4H, m), 2.71 (3H, d, J = 2.4 Hz), 2.82 (3H, s), 3.24 (1H, t, J = 10.3 Hz), 3.33-3.38 (1H, m), 3.73 (3H, s), 3.82 (1H, td, J = 4.0, 11.4 Hz), 4.42-4.49 (3H, m), 6.72 (1H, d, J = 8.5 Hz), 7.21 (1H, d, J = 8.5 Hz), 7.52 (1H, t, J = 8.5 Hz), 8.12 (1H, dd, J = 8.5, 3.6 Hz).
(73b) 5-フルオロ-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボン酸
5-フルオロ-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボン酸実施例73aで製造したエチル　5-フルオロ-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}ピリジン-2-カルボキシレート(200 mg, 0.338 mmol)、1 M水酸化ナトリウム水溶液(2.0　mL, 2.00 mmol)及びエタノール(5.0 mL)を用い、実施例25gに準じて反応及び後処理を行うことにより、標記化合物(175 mg, 92%)を得た。 (Example 73)
5-Fluoro-6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl ) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} pyridine-2-carboxylic acid
(73a) Ethyl 5-fluoro-6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propane -2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} pyridine-2- Carboxylate
5-Fluoro-6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl ) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} pyridine-2-carboxylic acid Examples (3S, 4aS, 10S, 10aR) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) prepared in 47a ) Phenyl] -2,7,7-trimethyl-3- (propan-2-yl) -3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c] Pyridine-1,9 (2H) -dione (250 mg, 0.453 mmol), ethyl 6-chloro-5-fluoropyridine-2-carboxylate (113 mg, 0.554 mmol), 2nd Generation X-Phos Precatalyst (71.0 mg, 0.0902 mmol), potassium phosphate (159 mg, 0.749 mmol), THF (3.0 mL) and water (6.0 mL) were used for the reaction and workup according to Example 9d to give the title compound (200 mg, 75%) was obtained.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.77 (3H, d, J = 7.3 Hz), 0.95 (3H, s), 0.96 (3H, d, J = 8.5 Hz), 1.05 (3H, s ), 1.42 (3H, t, J = 7.0 Hz), 1.77-1.86 (1H, m), 2.04 (1H, d, J = 17.0 Hz), 2.14 (1H, d, J = 16.4 Hz), 2.23-2.41 (4H, m), 2.71 (3H, d, J = 2.4 Hz), 2.82 (3H, s), 3.24 (1H, t, J = 10.3 Hz), 3.33-3.38 (1H, m), 3.73 (3H, s), 3.82 (1H, td, J = 4.0, 11.4 Hz), 4.42-4.49 (3H, m), 6.72 (1H, d, J = 8.5 Hz), 7.21 (1H, d, J = 8.5 Hz), 7.52 (1H, t, J = 8.5 Hz), 8.12 (1H, dd, J = 8.5, 3.6 Hz).
(73b) 5-Fluoro-6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propane- 2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} pyridine-2-carboxylic acid
5-Fluoro-6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl ) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} pyridine-2-carboxylic acid Examples Ethyl 5-fluoro-6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- ( Propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} pyridine-2 -Carboxylate (200 mg, 0.338 mmol), 1 M aqueous sodium hydroxide solution (2.0 mL, 2.00 mmol) and ethanol (5.0 mL) were used to carry out the reaction and workup according to Example 25g to give the title compound. (175 mg, 92%) was obtained.
(実施例74)
　2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシ-6-(4-メチル-1H-ピラゾール-1-イル)安息香酸
(74a) (3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4-メチル-1H-ピラゾール-1-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例34fで製造した(3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(150 mg, 0.214 mmol)、4-メチルピラゾール(26 μL, 0.322 mmol)、ピリジン(43.1 μL, 0.536 mmol)、モレキュラーシーブス(4A, 150 mg)及び酢酸銅(II) (58.4 mg, 0.322 mmol)のDMF (1.5 mL)溶液を80℃で12時間攪拌した。空冷した反応溶液をろ過(セライト)後、ろ液に水及び酢酸エチルを加え、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル)で精製し、標記化合物(54.2 mg, 39%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.81 (9H, s), 0.98 (3H, s), 1.11 (3H, s), 2.10 (3H, s), 2.22 (2H, s), 2.36 (1H, d, J = 17.6 Hz), 2.47 (1H, d, J = 17.6 Hz), 2.53 (1H, d, J = 18.4 Hz), 2.88 (1H, ddd, J = 3.9, 8.2, 18.4 Hz), 2.98 (3H, s), 3.12 (1H, d, J = 8.6 Hz), 3.64 (3H, s), 3.80 (3H, s), 4.47 (1H, d, J = 11.0 Hz), 4.48 (1H, d, J = 11.3 Hz), 4.72 (1H, d, J = 11.0 Hz), 5.45 (1H, s), 5.46 (1H, d, J = 10.6 Hz), 6.67 (1H, d, J = 8.6 Hz), 6.85 (2H, d, J = 8.6 Hz), 7.18 (1H, d, J = 9.0 Hz), 7.39-7.42 (3H, m), 7.80 (1H, s).
(74b) (3S,10S)-3-tert-ブチル-10-[2-(ヒドロキシメチル)-6-メトキシ-3-(4-メチル-1H-ピラゾール-1-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例74aで製造した(3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4-メチル-1H-ピラゾール-1-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(53.2 mg, 0.0814 mmol)、リン酸バッファー(pH6.86, 0.20 mL)、ジクロロメタン(1.0 mL)及び2,3-ジクロロ-5,6-ジシアノ-1,4-ベンゾキノン(22.2 mg, 0.0976 mmol)を用い、実施例32kに準じて反応及び後処理を行うことにより、標記化合物(42.3 mg, 97%)を得た。 Example 74
2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxy-6- (4-methyl-1H-pyrazol-1-yl) benzoic acid
(74a) (3S, 10S) -3-tert-Butyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4-methyl-1H-pyrazole-1- Yl) phenyl] -2,7,7-trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione Example 34f (3S, 10S) -3-tert-butyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4,5,5-tetramethyl) -1,3,2-dioxaborolan-2-yl) phenyl] -2,7,7-trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine- 1,9 (2H) -dione (150 mg, 0.214 mmol), 4-methylpyrazole (26 μL, 0.322 mmol), pyridine (43.1 μL, 0.536 mmol), molecular sieves (4A, 150 mg) and copper acetate (II ) (58.4 mg, 0.322 mmol) in DMF (1.5 mL) was stirred at 80 ° C. for 12 hours. The air-cooled reaction solution was filtered (celite), water and ethyl acetate were added to the filtrate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (54.2 mg, 39%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.81 (9H, s), 0.98 (3H, s), 1.11 (3H, s), 2.10 (3H, s), 2.22 (2H, s), 2.36 (1H, d, J = 17.6 Hz), 2.47 (1H, d, J = 17.6 Hz), 2.53 (1H, d, J = 18.4 Hz), 2.88 (1H, ddd, J = 3.9, 8.2, 18.4 Hz) , 2.98 (3H, s), 3.12 (1H, d, J = 8.6 Hz), 3.64 (3H, s), 3.80 (3H, s), 4.47 (1H, d, J = 11.0 Hz), 4.48 (1H, d, J = 11.3 Hz), 4.72 (1H, d, J = 11.0 Hz), 5.45 (1H, s), 5.46 (1H, d, J = 10.6 Hz), 6.67 (1H, d, J = 8.6 Hz) , 6.85 (2H, d, J = 8.6 Hz), 7.18 (1H, d, J = 9.0 Hz), 7.39-7.42 (3H, m), 7.80 (1H, s).
(74b) (3S, 10S) -3-tert-Butyl-10- [2- (hydroxymethyl) -6-methoxy-3- (4-methyl-1H-pyrazol-1-yl) phenyl] -2,7 , 7-Trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione prepared in Example 74a (3S, 10S) -3-tert-butyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4-methyl-1H-pyrazol-1-yl) phenyl] -2,7 , 7-Trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (53.2 mg, 0.0814 mmol), phosphate buffer (pH 6.86, 0.20 mL), dichloromethane (1.0 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (22.2 mg, 0.0976 mmol), and the reaction according to Example 32k and The title compound (42.3 mg, 97%) was obtained by post-treatment.
1H-NMR(400MHz, CDCl3):δ ppm: 0.85 (9H, s), 0.97 (3H, s), 1.11 (3H, s), 2.15 (1H, d, J = 16.0 Hz), 2.15 (3H, s), 2.24 (1H, d, J = 17.6 Hz), 2.37 (1H, d, J = 18.8 Hz), 2.49 (1H, d, J = 17.2 Hz), 2.57 (1H, d, J = 18.0 Hz), 2.94 (1H, ddd, J = 1.6, 9.4, 18.4 Hz), 3.00 (3H, s), 3.17 (1H, d, J = 9.0 Hz), 3.66 (3H, s), 5.03 (2H, s), 5.30 (1H, s), 6.15 (1H, s), 6.73 (1H, d, J = 8.6 Hz), 7.36 (1H, d, J = 8.6 Hz), 7.47 (1H, s), 8.05 (1H, s).
(74c) 2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシ-6-(4-メチル-1H-ピラゾール-1-イル)ベンズアルデヒド
　実施例74bで製造した(3S,10S)-3-tert-ブチル-10-[2-(ヒドロキシメチル)-6-メトキシ-3-(4-メチル-1H-ピラゾール-1-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(39.3 mg, 0.0736 mmol)、ジクロロメタン(1.0 mL)及びデスマーチンペルヨージナン(138 mg, 0.325 mmol)を用い、実施例32lに準じて反応及び後処理を行うことにより、標記化合物(37.8 mg, 97%)をコンフォマーの混合物として得た。
(74d) 2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシ-6-(4-メチル-1H-ピラゾール-1-イル)安息香酸
　実施例74cで製造した2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシ-6-(4-メチル-1H-ピラゾール-1-イル)ベンズアルデヒド(37.8 mg, 0.0711 mmol)、2-メチル-2-ブテン(160 μL, 1.42 mmol)、りん酸二水素ナトリウム二水和物(55.5 mg, 0.356 mmol)、水(380 μL)、tert-ブタノール(1.5 mL)、ジクロロメタン(190 μL)及び亜塩素酸ナトリウム(40.2 mg, 0.356 mmol) を用い、実施例32mに準じて反応及び後処理を行うことにより、標記化合物(11.3 mg, 29%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.85 (9H, s), 0.97 (3H, s), 1.11 (3H, s), 2.15 (1H, d, J = 16.0 Hz), 2.15 (3H , s), 2.24 (1H, d, J = 17.6 Hz), 2.37 (1H, d, J = 18.8 Hz), 2.49 (1H, d, J = 17.2 Hz), 2.57 (1H, d, J = 18.0 Hz) ), 2.94 (1H, ddd, J = 1.6, 9.4, 18.4 Hz), 3.00 (3H, s), 3.17 (1H, d, J = 9.0 Hz), 3.66 (3H, s), 5.03 (2H, s) , 5.30 (1H, s), 6.15 (1H, s), 6.73 (1H, d, J = 8.6 Hz), 7.36 (1H, d, J = 8.6 Hz), 7.47 (1H, s), 8.05 (1H, s).
(74c) 2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxy-6- (4-methyl-1H-pyrazol-1-yl) benzaldehyde (3S, 10S) -3 prepared in Example 74b -tert-Butyl-10- [2- (hydroxymethyl) -6-methoxy-3- (4-methyl-1H-pyrazol-1-yl) phenyl] -2,7,7-trimethyl-3,4,6 , 7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (39.3 mg, 0.0736 mmol), dichloromethane (1.0 mL) and desmartin periodinane (138 The title compound (37.8 mg, 97%) was obtained as a mixture of conformers by performing the reaction and post-treatment according to Example 32l using mg, 0.325 mmol).
(74d) 2-[(3S, 10S) -3-tert-Butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxy-6- (4-methyl-1H-pyrazol-1-yl) benzoic acid 2-[(3S, prepared in Example 74c 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c ] Pyridin-10-yl] -3-methoxy-6- (4-methyl-1H-pyrazol-1-yl) benzaldehyde (37.8 mg, 0.0711 mmol), 2-methyl-2-butene (160 μL, 1.42 mmol) , Sodium dihydrogen phosphate dihydrate (55.5 mg, 0.356 mmol), water (380 μL), tert-butanol (1.5 mL), dichloromethane (190 μL) and sodium chlorite (40.2 mg, 0.356 mmol). The title compound (11.3 mg, 29%) was obtained by reaction and post-treatment according to Example 32m.
(実施例75)
　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(75a) (3S,4aS,10S,10aR)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例45bで製造した(3S,4aS,10S,10aR)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(506 mg, 0.917 mmol)、ヨウ化メチル(457 μL, 7.34 mmol)、DMF (5.1 mL)及び水素化ナトリウム(55%, 60.0 mg, 1.38 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(376 mg, 72%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.91 (3H, s), 0.92 (9H, s), 1.03 (3H, s), 1.29 (12H, s), 1.72-1.85 (1H, m), 2.00 (1H, d, J = 18.4 Hz), 2.10-2.26 (3H, m), 2.33 (1H, d, J = 16.8 Hz), 2.95 (3H, s), 3.14 (3H, s), 3.22-3.29 (2H, m), 3.68 (3H, s), 3.69-3.74 (1H, m), 4.65 (1H, d, J = 9.4 Hz), 6.55 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 8.2 Hz).
(75b) tert-ブチル　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボキシレート
　実施例75aで製造した(3S,4aS,10S,10aR)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(130 mg, 0.230 mmol)、tert-ブチル　6-クロロ-4-メチルピリジン-2-カルボキシレート(73.3 mg, 0.322 mmol)、2nd Generation X-Phos Precatalyst (54.3 mg, 0.0690 mmol)、リン酸カリウム(74.3 mg, 0.368 mmol)、THF (2.0 mL)及び水(2.6 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(92.5 mg, 64%)を得た。 (Example 75)
6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7,8, 9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -4-methylpyridine-2-carboxylic acid tert-butylamine salt
(75a) (3S, 4aS, 10S, 10aR) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl) phenyl] -2,7,7-trimethyl-3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (3S, 4aS, 10S, 10aR) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetra) prepared in Example 45b Methyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c ] Pyridine-1,9 (2H) -dione (506 mg, 0.917 mmol), methyl iodide (457 μL, 7.34 mmol), DMF (5.1 mL) and sodium hydride (55%, 60.0 mg, 1.38 mmol). The title compound (376 mg, 72%) was obtained by performing reaction and post-treatment according to Example 2a.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.91 (3H, s), 0.92 (9H, s), 1.03 (3H, s), 1.29 (12H, s), 1.72-1.85 (1H, m) , 2.00 (1H, d, J = 18.4 Hz), 2.10-2.26 (3H, m), 2.33 (1H, d, J = 16.8 Hz), 2.95 (3H, s), 3.14 (3H, s), 3.22- 3.29 (2H, m), 3.68 (3H, s), 3.69-3.74 (1H, m), 4.65 (1H, d, J = 9.4 Hz), 6.55 (1H, d, J = 8.6 Hz), 7.59 (1H , d, J = 8.2 Hz).
(75b) tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -4-methylpyridine-2-carboxylate (3S, 4aS, 10S, 10aR) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3) prepared in Example 75a , 2-Dioxaborolan-2-yl) phenyl] -2,7,7-trimethyl-3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c] pyridine- 1,9 (2H) -dione (130 mg, 0.230 mmol), tert-butyl 6-chloro-4-methylpyridine-2-carboxylate (73.3 mg, 0.322 mmol), 2nd Generation X-Phos Precatalyst (54.3 mg, 0.0690 mmol), potassium phosphate (74.3 mg, 0.368 mmol), THF (2.0 mL) and water (2.6 mL) were used for the reaction and workup according to Example 9d to give the title compound (92.5 mg, 64%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.93 (3H, s), 0.94 (9H, s), 1.04 (3H, s), 1.63 (9H, s), 1.96-2.06 (1H, m), 2.14 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 17.6 Hz), 2.28-2.37 (2H, m), 2.41 (3H, s), 2.56-2.64 (1H, m), 2.84 (3H, s), 2.96 (3H, s), 3.23-3.38 (2H, m), 3.67-3.75 (1H, m), 3.72 (3H, s), 4.65 (1H, d, J = 8.2 Hz), 6.66 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 6.6 Hz), 7.42 (1H, s), 7.72 (1H, s).
(75c) 6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例75bで製造したtert-ブチル　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボキシレート(121 mg, 0.192 mmol)、ジクロロメタン(1.2 mL)、トリフルオロ酢酸(0.6 mL)、エタノール(0.5 mL)及びtert-ブチルアミン(5 μL, 0.0480 mmol) を用い、実施例41fに準じて反応及び後処理を行うことにより、標記化合物(22.1 mg, 19%, 2 steps)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.93 (3H, s), 0.94 (9H, s), 1.04 (3H, s), 1.63 (9H, s), 1.96-2.06 (1H, m) , 2.14 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 17.6 Hz), 2.28-2.37 (2H, m), 2.41 (3H, s), 2.56-2.64 (1H, m), 2.84 (3H, s), 2.96 (3H, s), 3.23-3.38 (2H, m), 3.67-3.75 (1H, m), 3.72 (3H, s), 4.65 (1H, d, J = 8.2 Hz) , 6.66 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 6.6 Hz), 7.42 (1H, s), 7.72 (1H, s).
(75c) 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7 , 8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -4-methylpyridine-2-carboxylic acid tert-butylamine Salt tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3, prepared in Example 75b 4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -4-methylpyridine- According to Example 41f, using 2-carboxylate (121 mg, 0.192 mmol), dichloromethane (1.2 mL), trifluoroacetic acid (0.6 mL), ethanol (0.5 mL) and tert-butylamine (5 μL, 0.0480 mmol) The title compound (22.1 mg, 19%, 2 steps) was obtained by carrying out the reaction and post-treatment.
(実施例76)
　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボン酸　tert-ブチルアミン塩
(76a) tert-ブチル　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボキシレート
　実施例75aで製造した(3S,4aS,10S,10aR)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(147 mg, 0.260 mmol)、tert-ブチル　6-クロロピリジン-2-カルボキシレート(77.8 mg, 0.364 mmol)、2nd Generation X-Phos Precatalyst (61.4 mg, 0.0780 mmol)、リン酸カリウム(88.3 mg, 0.416 mmol)、THF (2.2 mL)及び水(2.9 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(56.0 mg, 35%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.93-0.95 (12H, m), 1.04 (3H, s), 1.61 (9H, s), 1.96-2.05 (1H, m), 2.14 (1H, d, J = 16.4 Hz), 2.21-2.37 (3H, m), 2.56-2.64 (1H, m), 2.87 (3H, s), 2.95 (3H, s), 3.23-3.37 (2H, m), 3.67-3.75 (1H, m), 3.68 (3H, s), 4.65 (1H, d, J = 6.6 Hz), 6.67 (1H, d, J = 8.6 Hz), 7.32 (1H, d, J = 8.6 Hz), 7.61 (1H, dd, J = 1.2, 7.4 Hz), 7.75 (1H, t, J = 7.6 Hz), 7.89 (1H, dd, J = 1.0, 7.6 Hz).
(76b) 6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボン酸
　実施例76aで製造したtert-ブチル　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボキシレート(56.0 mg, 0.0908 mmol)、ジクロロメタン(0.6 mL)及びトリフルオロ酢酸(0.3 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(43.0 mg, 85%)を得た。 (Example 76)
6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7,8, 9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} pyridine-2-carboxylic acid tert-butylamine salt
(76a) tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} pyridine-2-carboxylate in Example 75a Prepared (3S, 4aS, 10S, 10aR) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane) -2-yl) phenyl] -2,7,7-trimethyl-3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c] pyridine-1,9 ( 2H) -dione (147 mg, 0.260 mmol), tert-butyl 6-chloropyridine-2-carboxylate (77.8 mg, 0.364 mmol), 2nd Generation X-Phos Precatalyst (61.4 mg, 0.0780 mmol), potassium phosphate ( 88.3 mg, 0.416 mmol), THF (2.2 mL) and water (2.9 mL) were used, and the reaction and workup were carried out according to Example 9d to obtain the title compound (56.0 mg, 35%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.93-0.95 (12H, m), 1.04 (3H, s), 1.61 (9H, s), 1.96-2.05 (1H, m), 2.14 (1H, d, J = 16.4 Hz), 2.21-2.37 (3H, m), 2.56-2.64 (1H, m), 2.87 (3H, s), 2.95 (3H, s), 3.23-3.37 (2H, m), 3.67 -3.75 (1H, m), 3.68 (3H, s), 4.65 (1H, d, J = 6.6 Hz), 6.67 (1H, d, J = 8.6 Hz), 7.32 (1H, d, J = 8.6 Hz) , 7.61 (1H, dd, J = 1.2, 7.4 Hz), 7.75 (1H, t, J = 7.6 Hz), 7.89 (1H, dd, J = 1.0, 7.6 Hz).
(76b) 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-Butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7 , 8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} pyridine-2-carboxylic acid tert prepared in Example 76a -Butyl 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7, 8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} pyridine-2-carboxylate (56.0 mg, 0.0908 mmol), The title compound (43.0 mg, 85%) was obtained by performing the reaction and post-treatment according to Example 1d using dichloromethane (0.6 mL) and trifluoroacetic acid (0.3 mL).
1H-NMR(400MHz, CDCl3):δ ppm: 0.96 (12H, s), 1.06 (3H, s), 1.97-2.18 (3H, m), 2.26 (1H, d, J = 18.0 Hz), 2.37 (1H, d, J = 18.4 Hz), 2.58-2.66 (1H, m), 2.86 (3H, s), 2.97 (3H, s), 3.26-3.40 (2H, m), 3.74-3.81 (1H, m), 3.75 (3H, s), 4.59 (1H, d, J = 9.4 Hz), 6.71 (1H, d, J = 8.6 Hz), 7.19 (1H, d, J = 8.2 Hz), 7.74 (1H, d, J = 7.8 Hz), 7.93 (1H, t, J = 7.8 Hz), 8.14 (1H, d, J = 7.8 Hz).
MS(ESI/APCI)m/z: 561[M+H]+.
(76c) 6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例76bで製造した6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボン酸(43.0 mg, 0.0767 mmol)、エタノール(0.9 mL)及びtert-ブチルアミン(10 μL, 0.0920 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(41.2 mg, 85%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.96 (12H, s), 1.06 (3H, s), 1.97-2.18 (3H, m), 2.26 (1H, d, J = 18.0 Hz), 2.37 (1H, d, J = 18.4 Hz), 2.58-2.66 (1H, m), 2.86 (3H, s), 2.97 (3H, s), 3.26-3.40 (2H, m), 3.74-3.81 (1H, m ), 3.75 (3H, s), 4.59 (1H, d, J = 9.4 Hz), 6.71 (1H, d, J = 8.6 Hz), 7.19 (1H, d, J = 8.2 Hz), 7.74 (1H, d , J = 7.8 Hz), 7.93 (1H, t, J = 7.8 Hz), 8.14 (1H, d, J = 7.8 Hz).
MS (ESI / APCI) m / z: 561 [M + H] +.
(76c) 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7 , 8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} pyridine-2-carboxylic acid tert-butylamine salt Example 76b 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7 , 8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} pyridine-2-carboxylic acid (43.0 mg, 0.0767 mmol) , Ethanol (0.9 mL) and tert-butylamine (10 μL, 0.0920 mmol) were used for the reaction and post-treatment according to Example 3c to obtain the title compound (41.2 mg, 85%).
(実施例77)
　6-{4-メトキシ-2-メチル-3-[(3S,10S)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(77a) (6S)-3-{(S)-(5,7-ジオキソスピロ[2.5]オクタ-6-イル)[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]メチル}-6-(プロパン-2-イル)ピペリジン-2,4-ジオン
　実施例41aで製造した6-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]スピロ[2.5]オクタン-5,7-ジオン(4.59 g, 11.6 mmol)及びtert-ブチル　(6S)-2,4-ジオキソ-6-(プロパン-2-イル)ピペリジン-1-カルボキシレート(3.26 g, 12.8 mmol)のアセトニトリル(100 mL)溶液に0℃で炭酸セシウム(4.97 g, 15.3 mmol)を加えた。反応溶液を0℃で3時間攪拌後、水を加えて酢酸エチルで2回抽出、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮し、粗製の付加物を得た。 Example 77
6- {4-Methoxy-2-methyl-3-[(3S, 10S) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,6, 8,9,10-Octahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(77a) (6S) -3-{(S)-(5,7-Dioxospiro [2.5] oct-6-yl) [6-methoxy-2-methyl-3- (4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl) phenyl] methyl} -6- (propan-2-yl) piperidine-2,4-dione 6- [6-methoxy-2-prepared in Example 41a Methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] spiro [2.5] octane-5,7-dione (4.59 g, 11.6 mmol) and tert Cesium carbonate (4.97 g) at 0 ° C in a solution of 2-butyl (6S) -2,4-dioxo-6- (propan-2-yl) piperidine-1-carboxylate (3.26 g, 12.8 mmol) in acetonitrile (100 mL) , 15.3 mmol). The reaction solution was stirred at 0 ° C. for 3 hours, water was added and the mixture was extracted twice with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude adduct.
　粗製の付加物のジクロロメタン(80 mL)溶液に0℃でトリフルオロ酢酸(8.0 mL, 105 mmol)を加え、反応溶液を0℃で3時間攪拌した。反応溶液に0℃で飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで2回抽出後、有機層を無水硫酸ナトリウムで乾燥、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 1:1)で精製し、標記化合物(4.81 g, 75%, 2 steps)をコンフォマーの混合物として得た。
(77b) (3S,10S)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン
　実施例77aで製造した(6S)-3-{(S)-(5,7-ジオキソスピロ[2.5]オクタ-6-イル)[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]メチル}-6-(プロパン-2-イル)ピペリジン-2,4-ジオン(1.00 g, 1.81 mmol)の酢酸エチル(20 mL)溶液に室温で4 M塩酸(ジオキサン溶液; 5 mL, 20 mmol)を加え、反応溶液を室温で16時間攪拌した。反応溶液を濃縮後、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル)で精製し、標記化合物(963 mg, 99%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.32-0.50 (4H, m), 0.83 (3H, d, J = 6.7 Hz), 0.88 (3H, d, J = 6.1 Hz), 1.30 (12H, s), 1.64-1.73 (1H, m), 1.97 (1H, d, J = 17.0 Hz), 2.21 (1H, d, J = 17.6 Hz), 2.35 (1H, d, J = 16.4 Hz), 2.44-2.65 (3H, m), 3.11 (3H, s), 3.19-3.24 (1H, m), 3.69 (3H, s), 5.15 (1H, s), 5.29 (1H, s), 6.60 (1H, d, J = 7.9 Hz), 7.59 (1H, d, J = 8.5 Hz).
(77c) (3S,10S)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2-メチル-3-(プロパン-2-イル)-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン
　実施例77bで製造した(3S,10S)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン(280 mg, 0.525 mmol)、ヨウ化メチル(260 μL, 4.20 mmol)、DMF (4.0 mL)及び水素化ナトリウム(63%, 33.0 mg, 0.866 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(178 mg, 62%)を得た。 To a dichloromethane (80 mL) solution of the crude adduct was added trifluoroacetic acid (8.0 mL, 105 mmol) at 0 ° C., and the reaction solution was stirred at 0 ° C. for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution at 0 ° C., and the mixture was extracted twice with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The title compound (4.81 g, 75%, 2 steps) was obtained as a mixture of conformers.
(77b) (3S, 10S) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3 -(Propan-2-yl) -3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -1,9 (2H, 8H) -dione (6S) -3-{(S)-(5,7-Dioxospiro [2.5] oct-6-yl) [6-methoxy-2-methyl-3- (4,4,5,5) prepared in Example 77a -Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] methyl} -6- (propan-2-yl) piperidine-2,4-dione (1.00 g, 1.81 mmol) in ethyl acetate (20 mL ) 4 M hydrochloric acid (dioxane solution; 5 mL, 20 mmol) was added to the solution at room temperature, and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (963 mg, 99%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.32-0.50 (4H, m), 0.83 (3H, d, J = 6.7 Hz), 0.88 (3H, d, J = 6.1 Hz), 1.30 (12H , s), 1.64-1.73 (1H, m), 1.97 (1H, d, J = 17.0 Hz), 2.21 (1H, d, J = 17.6 Hz), 2.35 (1H, d, J = 16.4 Hz), 2.44 -2.65 (3H, m), 3.11 (3H, s), 3.19-3.24 (1H, m), 3.69 (3H, s), 5.15 (1H, s), 5.29 (1H, s), 6.60 (1H, d , J = 7.9 Hz), 7.59 (1H, d, J = 8.5 Hz).
(77c) (3S, 10S) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2 -Methyl-3- (propan-2-yl) -3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -1,9 (2H, 8H ) -Dione (3S, 10S) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-2) prepared in Example 77b Yl) phenyl] -3- (propan-2-yl) -3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -1,9 (2H , 8H) -dione (280 mg, 0.525 mmol), methyl iodide (260 μL, 4.20 mmol), DMF (4.0 mL) and sodium hydride (63%, 33.0 mg, 0.866 mmol) to Example 2a. The title compound (178 mg, 62%) was obtained by carrying out the reaction and post-treatment in the same manner.
1H-NMR(400MHz, CDCl3):δ ppm: 0.31-0.48 (4H, m), 0.79 (3H, d, J = 6.7 Hz), 0.80 (3H, d, J = 6.7 Hz), 1.30 (12H, s), 1.90-1.97 (2H, m), 2.18 (1H, d, J = 17.6 Hz), 2.36 (1H, d, J = 16.4 Hz), 2.41 (1H, d, J = 16.4 Hz), 2.57 (1H, d, J = 17.6 Hz), 2.80-2.91 (1H, m), 2.93 (3H, s), 3.06 (1H, t, J = 7.6 Hz), 3.14 (3H, s), 3.67 (3H, s), 5.26 (1H, s), 6.57 (1H, d, J = 8.5 Hz), 7.57 (1H, d, J = 8.5 Hz).
(77d) tert-ブチル　6-{4-メトキシ-2-メチル-3-[(3S,10S)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例77cで製造した(3S,10S)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2-メチル-3-(プロパン-2-イル)-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン(177 mg, 0.325 mmol)、tert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(90.0 mg, 0.395 mmol)、2nd Generation X-Phos Precatalyst (55.0 mg, 0.0699 mmol)、リン酸カリウム(115 mg, 0.542 mmol)、THF (3.0 mL)及び水(6.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(197 mg, 99%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.35-0.51 (4H, m), 0.83 (3H, d, J = 6.7 Hz), 0.86 (3H, d, J = 6.7 Hz), 1.64 (9H, s), 1.93-2.02 (2H, m), 2.21 (1H, d, J = 17.6 Hz), 2.37 (1H, d, J = 17.0 Hz), 2.44 (1H, d, J = 17.6 Hz), 2.49 (3H, s), 2.59 (1H, d, J = 17.0 Hz), 2.82-2.88 (1H, m), 2.87 (3H, s), 2.94 (3H, s), 3.07 (1H, t, J = 7.0 Hz), 3.70 (3H, s), 5.24 (1H, s), 6.68 (1H, d, J = 8.5 Hz), 7.29 (1H, d, J = 7.3 Hz), 7.40 (1H, d, J = 7.9 Hz), 7.53 (1H, d, J = 7.9 Hz).
(77e) 6-{4-メトキシ-2-メチル-3-[(3S,10S)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例77dで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[(3S,10S)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(197 mg, 0.321 mmol)、クロロホルム(5.0 mL)及びトリフルオロ酢酸(3.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(146 mg, 82%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.31-0.48 (4H, m), 0.79 (3H, d, J = 6.7 Hz), 0.80 (3H, d, J = 6.7 Hz), 1.30 (12H , s), 1.90-1.97 (2H, m), 2.18 (1H, d, J = 17.6 Hz), 2.36 (1H, d, J = 16.4 Hz), 2.41 (1H, d, J = 16.4 Hz), 2.57 (1H, d, J = 17.6 Hz), 2.80-2.91 (1H, m), 2.93 (3H, s), 3.06 (1H, t, J = 7.6 Hz), 3.14 (3H, s), 3.67 (3H, s), 5.26 (1H, s), 6.57 (1H, d, J = 8.5 Hz), 7.57 (1H, d, J = 8.5 Hz).
(77d) tert-butyl 6- {4-methoxy-2-methyl-3-[(3S, 10S) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2, 3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxy (3S, 10S) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) prepared in Example 77c Phenyl] -2-methyl-3- (propan-2-yl) -3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -1,9 (2H, 8H) -dione (177 mg, 0.325 mmol), tert-butyl 6-chloro-3-methylpyridine-2-carboxylate (90.0 mg, 0.395 mmol), 2nd Generation X-Phos Precatalyst (55.0 mg, 0.0699 mmol), potassium phosphate (115 mg, 0.542 mmol), THF (3.0 mL) and water (6.0 mL), and the reaction and workup according to Example 9d gave the title compound (197 mg, 99 %).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.35-0.51 (4H, m), 0.83 (3H, d, J = 6.7 Hz), 0.86 (3H, d, J = 6.7 Hz), 1.64 (9H , s), 1.93-2.02 (2H, m), 2.21 (1H, d, J = 17.6 Hz), 2.37 (1H, d, J = 17.0 Hz), 2.44 (1H, d, J = 17.6 Hz), 2.49 (3H, s), 2.59 (1H, d, J = 17.0 Hz), 2.82-2.88 (1H, m), 2.87 (3H, s), 2.94 (3H, s), 3.07 (1H, t, J = 7.0 Hz), 3.70 (3H, s), 5.24 (1H, s), 6.68 (1H, d, J = 8.5 Hz), 7.29 (1H, d, J = 7.3 Hz), 7.40 (1H, d, J = 7.9 Hz), 7.53 (1H, d, J = 7.9 Hz).
(77e) 6- {4-Methoxy-2-methyl-3-[(3S, 10S) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4 , 6,8,9,10-Octahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid Examples Tert-butyl 6- {4-methoxy-2-methyl-3-[(3S, 10S) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2 prepared in 77d , 3,4,6,8,9,10-Octahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2- By subjecting the carboxylate (197 mg, 0.321 mmol), chloroform (5.0 mL) and trifluoroacetic acid (3.0 mL) to the reaction and post-treatment according to Example 1d, the title compound (146 mg, 82%) Got.
1H-NMR(400MHz, CDCl3):δ ppm: 0.36-0.51 (4H, m), 0.84 (3H, d, J = 6.7 Hz), 0.86 (3H, d, J = 6.7 Hz), 1.96-2.02 (2H, m), 2.23 (1H, d, J = 17.6 Hz), 2.39 (1H, d, J = 17.0 Hz), 2.45 (1H, d, J = 17.6 Hz), 2.60 (1H, d, J = 17.6 Hz), 2.80 (3H, s), 2.85-2.91 (1H, m), 2.90 (3H, s), 2.96 (3H, s), 3.13 (1H, t, J = 7.3 Hz), 3.73 (3H, s), 5.24 (1H, s), 6.72 (1H, d, J = 8.5 Hz), 7.19 (1H, d, J = 8.5 Hz), 7.60 (1H, d, J = 7.9 Hz), 7.69 (1H, d, J = 7.9 Hz).
MS(ESI/APCI)m/z: 557[M+H]+.
(77f) 6-{4-メトキシ-2-メチル-3-[(3S,10S)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例77eで製造した6-{4-メトキシ-2-メチル-3-[(3S,10S)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(332 mg, 0.596 mmol) 、酢酸エチル(8.0 mL)及びtert-ブチルアミン(94 μL, 0.895 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(325 mg, 87%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.36-0.51 (4H, m), 0.84 (3H, d, J = 6.7 Hz), 0.86 (3H, d, J = 6.7 Hz), 1.96-2.02 (2H, m), 2.23 (1H, d, J = 17.6 Hz), 2.39 (1H, d, J = 17.0 Hz), 2.45 (1H, d, J = 17.6 Hz), 2.60 (1H, d, J = 17.6 Hz), 2.80 (3H, s), 2.85-2.91 (1H, m), 2.90 (3H, s), 2.96 (3H, s), 3.13 (1H, t, J = 7.3 Hz), 3.73 (3H, s), 5.24 (1H, s), 6.72 (1H, d, J = 8.5 Hz), 7.19 (1H, d, J = 8.5 Hz), 7.60 (1H, d, J = 7.9 Hz), 7.69 (1H, d, J = 7.9 Hz).
MS (ESI / APCI) m / z: 557 [M + H] +.
(77f) 6- {4-Methoxy-2-methyl-3-[(3S, 10S) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4 , 6,8,9,10-Octahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert- Butylamine salt 6- {4-Methoxy-2-methyl-3-[(3S, 10S) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1, prepared in Example 77e 2,3,4,6,8,9,10-Octahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2 -Carrying out the reaction and working up according to Example 3c using carboxylic acid (332 mg, 0.596 mmol), ethyl acetate (8.0 mL) and tert-butylamine (94 μL, 0.895 mmol), the title compound (325 mg, 87%).
(実施例78)
　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-5-フルオロピリジン-2-カルボン酸　tert-ブチルアミン塩
(78a) メチル　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-5-フルオロピリジン-2-カルボキシレート
　実施例75aで製造した(3S,4aS,10S,10aR)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(84.5 mg, 0.149 mmol)、メチル　6-クロロ-5-フルオロピリジン-2-カルボキシレート(39.7 mg, 0.209 mmol)、2nd Generation X-Phos Precatalyst (35.3 mg, 0.0448 mmol)、リン酸カリウム(50.7 mg, 0.239 mmol)、THF (1.3 mL)及び水(1.7 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(31.1 mg, 35%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.99 (12H, s), 1.09 (3H, s), 1.99-2.07 (1H, m), 2.10 (1H, d, J = 17.1 Hz), 2.20 (1H, d, J = 16.5 Hz), 2.30 (1H, d, J = 17.1 Hz), 2.40 (1H, dd, J = 2.4, 18.3 Hz), 2.61-2.69 (1H, m), 2.78 (3H, d, J = 1.8 Hz), 2.99 (3H, s), 3.31 (1H, dd, J = 5.8, 10.7 Hz), 3.42 (1H, dd, J = 9.2, 11.0 Hz), 3.77-3.85 (1H, m), 3.78 (3H, s), 4.59 (1H, d, J = 7.9 Hz), 6.76 (1H, d, J = 8.5 Hz), 7.18 (1H, d, J = 8.5 Hz), 7.70 (1H, t, J = 8.2 Hz), 8.26 (1H, dd, J = 4.0, 8.2 Hz).
(78b) 6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-5-フルオロピリジン-2-カルボン酸
　実施例78aで製造したメチル　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-5-フルオロピリジン-2-カルボキシレート(31.1 mg, 0.0525 mmol)、1 M水酸化ナトリウム水溶液(68 μL, 0.0680 mmol)、メタノール(0.16 mL)及びTHF (0.16 mL)を用い、実施例25gに準じて反応及び後処理を行うことにより、標記化合物(26.5 mg, 87%)を得た。 (Example 78)
6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7,8, 9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -5-fluoropyridine-2-carboxylic acid tert-butylamine salt
(78a) Methyl 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6, 7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -5-fluoropyridine-2-carboxylate Examples (3S, 4aS, 10S, 10aR) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2) prepared in 75a -Dioxaborolan-2-yl) phenyl] -2,7,7-trimethyl-3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c] pyridine-1, 9 (2H) -dione (84.5 mg, 0.149 mmol), methyl 6-chloro-5-fluoropyridine-2-carboxylate (39.7 mg, 0.209 mmol), 2nd Generation X-Phos Precatalyst (35.3 mg, 0.0448 mmol), The title compound (31.1 mg, 35%) was obtained by carrying out the reaction and post-treatment according to Example 9d using potassium phosphate (50.7 mg, 0.239 mmol), THF (1.3 mL) and water (1.7 mL). Obtained.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.99 (12H, s), 1.09 (3H, s), 1.99-2.07 (1H, m), 2.10 (1H, d, J = 17.1 Hz), 2.20 (1H, d, J = 16.5 Hz), 2.30 (1H, d, J = 17.1 Hz), 2.40 (1H, dd, J = 2.4, 18.3 Hz), 2.61-2.69 (1H, m), 2.78 (3H, d, J = 1.8 Hz), 2.99 (3H, s), 3.31 (1H, dd, J = 5.8, 10.7 Hz), 3.42 (1H, dd, J = 9.2, 11.0 Hz), 3.77-3.85 (1H, m ), 3.78 (3H, s), 4.59 (1H, d, J = 7.9 Hz), 6.76 (1H, d, J = 8.5 Hz), 7.18 (1H, d, J = 8.5 Hz), 7.70 (1H, t , J = 8.2 Hz), 8.26 (1H, dd, J = 4.0, 8.2 Hz).
(78b) 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-Butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7 , 8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -5-fluoropyridine-2-carboxylic acid Example 78a Methyl 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6, 7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -5-fluoropyridine-2-carboxylate (31.1 mg, 0.0525 mmol), 1 M aqueous sodium hydroxide solution (68 μL, 0.0680 mmol), methanol (0.16 mL) and THF (0.16 mL) were used, and the reaction and workup were carried out according to Example 25 g. The compound (26.5 mg, 87%) was obtained.
1H-NMR(400MHz, CDCl3):δ ppm: 0.97 (12H, s), 1.08 (3H, s), 1.99-2.39 (4H, m), 2.58-2.74 (2H, m), 2.74 (3H, s), 2.88-2.94 (1H, m), 2.97 (3H, s), 3.22-3.45 (2H, m), 3.74 (3H, s), 4.55-4.58 (1H, m), 6.73-6.76 (1H, m), 7.12-7.16 (1H, m), 7.66-7.69 (1H, m), 8.22-8.24 (1H, m).
(78c) 6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-5-フルオロピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例78bで製造した6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-5-フルオロピリジン-2-カルボン酸(30.4 mg, 0.0304 mmol)、エタノール(0.6 mL)及びtert-ブチルアミン(7 μL, 0.0630 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(25.3 mg, 74%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.97 (12H, s), 1.08 (3H, s), 1.99-2.39 (4H, m), 2.58-2.74 (2H, m), 2.74 (3H, s), 2.88-2.94 (1H, m), 2.97 (3H, s), 3.22-3.45 (2H, m), 3.74 (3H, s), 4.55-4.58 (1H, m), 6.73-6.76 (1H, m), 7.12-7.16 (1H, m), 7.66-7.69 (1H, m), 8.22-8.24 (1H, m).
(78c) 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7 , 8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -5-fluoropyridine-2-carboxylic acid tert-butylamine Salt 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a prepared in Example 78b , 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -5-fluoropyridine-2-carboxylic acid The title compound (25.3 mg, 74304) was prepared by reacting and working up with acid (30.4 mg, 0.0304 mmol), ethanol (0.6 mL) and tert-butylamine (7 μL, 0.0630 mmol) according to Example 3c. %).
(実施例79)
　6-{3-[(3S,10S)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
(79a) (3S,10S)-2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン
　実施例77bで製造した(3S,10S)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン(280 mg, 0.525 mmol)、ヨウ化エチル(340 μL, 4.30 mmol)、DMPU (4.0 mL)及び水素化ナトリウム(63%, 35.0 mg, 0.919 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(109 mg, 37%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.32-0.48 (4H, m), 0.77 (3H, d, J = 6.7 Hz), 0.82 (3H, d, J = 6.7 Hz), 1.08 (3H, t, J = 7.0 Hz), 1.31 (12H, s), 1.84-2.00 (2H, m), 2.17-2.25 (1H, m), 2.31-2.37 (1H, m), 2.46 (1H, d, J = 17.6 Hz), 2.51-2.64 (1H, m), 2.73-2.80 (1H, m), 3.05 (1H, t, J = 7.3 Hz), 3.14 (3H, s), 3.66 (3H, s), 3.84-3.90 (1H, m), 4.05-4.15 (1H, m), 5.28 (1H, s), 6.57 (1H, d, J = 8.5 Hz), 7.56 (1H, d, J = 8.5 Hz).
(79b) ベンジル　6-{3-[(3S,10S)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例79aで製造した(3S,10S)-2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン(109 mg, 0.195 mmol)、実施例20eで製造したベンジル　6-クロロ-3-メチルピリジン-2-カルボキシレート(66.0 mg, 0.252 mmol)、2nd Generation X-Phos Precatalyst (31.0 mg, 0.0394 mmol)、リン酸カリウム(65.0 mg, 0.306 mmol)、THF (1.5 mL)及び水(3.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(52.7 mg, 41%)を得た。 (Example 79)
6- {3-[(3S, 10S) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,6,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid
(79a) (3S, 10S) -2-Ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenyl] -3- (propan-2-yl) -3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -1,9 (2H, 8H ) -Dione (3S, 10S) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-2) prepared in Example 77b Yl) phenyl] -3- (propan-2-yl) -3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -1,9 (2H , 8H) -dione (280 mg, 0.525 mmol), ethyl iodide (340 μL, 4.30 mmol), DMPU (4.0 mL) and sodium hydride (63%, 35.0 mg, 0.919 mmol) to Example 2a. The title compound (109 mg, 37%) was obtained by carrying out the reaction and post-treatment in the same manner.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.32-0.48 (4H, m), 0.77 (3H, d, J = 6.7 Hz), 0.82 (3H, d, J = 6.7 Hz), 1.08 (3H , t, J = 7.0 Hz), 1.31 (12H, s), 1.84-2.00 (2H, m), 2.17-2.25 (1H, m), 2.31-2.37 (1H, m), 2.46 (1H, d, J = 17.6 Hz), 2.51-2.64 (1H, m), 2.73-2.80 (1H, m), 3.05 (1H, t, J = 7.3 Hz), 3.14 (3H, s), 3.66 (3H, s), 3.84 -3.90 (1H, m), 4.05-4.15 (1H, m), 5.28 (1H, s), 6.57 (1H, d, J = 8.5 Hz), 7.56 (1H, d, J = 8.5 Hz).
(79b) Benzyl 6- {3-[(3S, 10S) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,6,8,9, 10-octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (3S, 10S) -2-ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-prepared in Example 79a Yl) phenyl] -3- (propan-2-yl) -3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -1,9 (2H , 8H) -dione (109 mg, 0.195 mmol), benzyl 6-chloro-3-methylpyridine-2-carboxylate (66.0 mg, 0.252 mmol) prepared in Example 20e, 2nd Generation X-Phos Precatalyst (31.0 mg , 0.0394 mmol), potassium phosphate (65.0 mg, 0.306 mmol), THF (1.5 mL) and water (3.0 mL) were used in the reaction and post-treatment according to Example 9d to give the title compound (52.7 mg , 41%) It was.
1H-NMR(400MHz, CDCl3):δ ppm: 0.35-0.49 (4H, m), 0.84 (3H, d, J = 6.4 Hz), 0.86 (3H, d, J = 6.1 Hz), 1.09 (3H, t, J = 7.0 Hz), 1.91-2.01 (2H, m), 2.23 (1H, d, J = 17.7 Hz), 2.36 (1H, d, J = 16.5 Hz), 2.50 (1H, d, J = 18.3 Hz), 2.52 (3H, s), 2.56-2.65 (1H, m), 2.79 (1H, dd, J = 18.0, 8.2 Hz), 2.89 (3H, s), 3.07 (1H, t, J = 7.3 Hz), 3.71 (3H, s), 4.05-4.15 (2H, m), 5.28 (1H, s), 5.41 (1H, d, J = 12.2 Hz), 5.47 (1H, d, J = 12.2 Hz), 6.69 (1H, d, J = 9.2 Hz), 7.26-7.33 (2H, m), 7.38 (2H, t, J = 7.6 Hz), 7.45 (1H, d, J = 7.9 Hz), 7.51 (2H, d, J = 7.3 Hz), 7.56 (1H, d, J = 7.9 Hz).
(79c) 6-{3-[(3S,10S)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例79bで製造したベンジル　6-{3-[(3S,10S)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(52.7 mg, 0.0798 mmol)、パラジウム炭素(10%, 12.0 mg)、酢酸エチル(2.0 mL)及びメタノール(2.0 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(35.8 mg, 79%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.35-0.49 (4H, m), 0.84 (3H, d, J = 6.4 Hz), 0.86 (3H, d, J = 6.1 Hz), 1.09 (3H , t, J = 7.0 Hz), 1.91-2.01 (2H, m), 2.23 (1H, d, J = 17.7 Hz), 2.36 (1H, d, J = 16.5 Hz), 2.50 (1H, d, J = 18.3 Hz), 2.52 (3H, s), 2.56-2.65 (1H, m), 2.79 (1H, dd, J = 18.0, 8.2 Hz), 2.89 (3H, s), 3.07 (1H, t, J = 7.3 Hz), 3.71 (3H, s), 4.05-4.15 (2H, m), 5.28 (1H, s), 5.41 (1H, d, J = 12.2 Hz), 5.47 (1H, d, J = 12.2 Hz), 6.69 (1H, d, J = 9.2 Hz), 7.26-7.33 (2H, m), 7.38 (2H, t, J = 7.6 Hz), 7.45 (1H, d, J = 7.9 Hz), 7.51 (2H, d , J = 7.3 Hz), 7.56 (1H, d, J = 7.9 Hz).
(79c) 6- {3-[(3S, 10S) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,6,8,9,10 -Octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid Examples Benzyl 6- {3-[(3S, 10S) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,6,8,9 prepared in 79b , 10-Octahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (52.7 mg, 0.0798 mmol), palladium on carbon (10%, 12.0 mg), ethyl acetate (2.0 mL) and methanol (2.0 mL) were used for the reaction and post-treatment according to Example 18 to give the title compound. (35.8 mg, 79%) was obtained.
(実施例80)
　6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(80a) tert-ブチル　6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボキシレート
　実施例65aで製造した(3S,4aS,10S,10aR)-2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,4a,6,10,10a-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン(350 mg, 0.621 mmol)、tert-ブチル　6-クロロ-4-メチルピリジン-2-カルボキシレート(198 mg, 0.870 mmol)、2nd Generation X-Phos Precatalyst (147 mg, 0.186 mmol)、リン酸カリウム(211 mg, 0.994 mmol)、THF (5.3 mL)及び水(7.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(266 mg, 68%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.29-0.46 (4H, m), 0.81 (3H, d, J = 6.7 Hz), 0.95 (3H, d, J = 6.7 Hz), 1.06 (3H, t, J = 7.2 Hz), 1.64 (9H, s), 1.70 (1H, d, J = 16.8 Hz), 1.81-1.91 (1H, m), 1.94 (1H, d, J = 18.8 Hz), 2.16-2.24 (1H, m), 2.35-2.42 (1H, m), 2.42 (3H, s), 2.48 (1H, d, J = 16.8 Hz), 2.70 (1H, d, J = 19.6 Hz), 2.81 (3H, s), 3.03-3.12 (1H, m), 3.24 (1H, dd, J = 9.0, 11.7 Hz), 3.36-3.45 (1H, m), 3.59-3.68 (1H, m), 3.75 (3H, s), 3.79 (1H, dt, J = 4.7, 10.2 Hz), 4.55 (1H, d, J = 9.0 Hz), 6.70 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 9.0 Hz), 7.41 (1H, s), 7.73 (1H, s).
(80b) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボン酸
　実施例80aで製造したtert-ブチル　6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボキシレート(266 mg, 0.423 mmol)、ジクロロメタン(2.7 mL)及びトリフルオロ酢酸(1.3 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(213 mg, 88%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.31-0.51 (4H, m), 0.82 (3H, d, J = 7.0 Hz), 0.97 (3H, d, J = 7.0 Hz), 1.06 (3H, t, J = 7.0 Hz), 1.73 (1H, d, J = 16.8 Hz), 1.84 (1H, q, J = 11.3 Hz), 1.98 (1H, d, J = 18.0 Hz), 2.19-2.29 (1H, m), 2.37-2.43 (1H, m), 2.51 (1H, d, J = 16.8 Hz), 2.61 (3H, s), 2.67 (3H, s), 2.73 (1H, dd, J = 1.2, 16.8 Hz), 3.07-3.17 (1H, m), 3.25-3.30 (1H, m), 3.41-3.47 (1H, m), 3.56-3.65 (1H, m), 3.78 (3H, s), 3.88 (1H, td, J = 4.6, 11.4 Hz), 4.38 (1H, d, J = 9.4 Hz), 6.76 (1H, d, J = 8.6 Hz), 7.12 (1H, d, J = 8.6 Hz), 7.61 (1H, s), 8.18 (1H, s).
MS(ESI/APCI)m/z: 573[M+H]+.
(80c) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例80bで製造した6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボン酸(210 mg, 0.367 mmol)、エタノール(4.2 mL)及びtert-ブチルアミン(42 μL, 0.403 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(230 mg, 97%)を得た。 Example 80
6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6,8, 9,10,10a-decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -4-methylpyridine-2 -Carboxylic acid tert-butylamine salt
(80a) tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4, 4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl}- 4-Methylpyridine-2-carboxylate (3S, 4aS, 10S, 10aR) -2-ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5) prepared in Example 65a -Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3- (propan-2-yl) -3,4,4a, 6,10,10a-hexahydrospiro [chromeno [3,2 -c] pyridine-7,1'-cyclopropane] -1,9 (2H, 8H) -dione (350 mg, 0.621 mmol), tert-butyl 6-chloro-4-methylpyridine-2-carboxylate (198 mg, 0.870 mmol), 2nd Generation X-Phos Precatalyst (147 mg, 0.186 mmol), potassium phosphate (211 mg, 0.994 mmol), THF (5.3 mL) and water (7.0 mL), according to Example 9d Reaction and post-treatment to give the title compound (266 mg, 68%) Obtained.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.29-0.46 (4H, m), 0.81 (3H, d, J = 6.7 Hz), 0.95 (3H, d, J = 6.7 Hz), 1.06 (3H , t, J = 7.2 Hz), 1.64 (9H, s), 1.70 (1H, d, J = 16.8 Hz), 1.81-1.91 (1H, m), 1.94 (1H, d, J = 18.8 Hz), 2.16 -2.24 (1H, m), 2.35-2.42 (1H, m), 2.42 (3H, s), 2.48 (1H, d, J = 16.8 Hz), 2.70 (1H, d, J = 19.6 Hz), 2.81 ( 3H, s), 3.03-3.12 (1H, m), 3.24 (1H, dd, J = 9.0, 11.7 Hz), 3.36-3.45 (1H, m), 3.59-3.68 (1H, m), 3.75 (3H, s), 3.79 (1H, dt, J = 4.7, 10.2 Hz), 4.55 (1H, d, J = 9.0 Hz), 6.70 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 9.0 Hz), 7.41 (1H, s), 7.73 (1H, s).
(80b) 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6 , 8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -4-methyl Pyridine-2-carboxylic acid tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) prepared in Example 80a -1,2,3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] -4 -Methoxy-2-methylphenyl} -4-methylpyridine-2-carboxylate (266 mg, 0.423 mmol), dichloromethane (2.7 mL) and trifluoroacetic acid (1.3 mL) and the reaction according to Example 1d and The title compound (213 mg, 88%) was obtained by post-treatment.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.31-0.51 (4H, m), 0.82 (3H, d, J = 7.0 Hz), 0.97 (3H, d, J = 7.0 Hz), 1.06 (3H , t, J = 7.0 Hz), 1.73 (1H, d, J = 16.8 Hz), 1.84 (1H, q, J = 11.3 Hz), 1.98 (1H, d, J = 18.0 Hz), 2.19-2.29 (1H , m), 2.37-2.43 (1H, m), 2.51 (1H, d, J = 16.8 Hz), 2.61 (3H, s), 2.67 (3H, s), 2.73 (1H, dd, J = 1.2, 16.8 Hz), 3.07-3.17 (1H, m), 3.25-3.30 (1H, m), 3.41-3.47 (1H, m), 3.56-3.65 (1H, m), 3.78 (3H, s), 3.88 (1H, td, J = 4.6, 11.4 Hz), 4.38 (1H, d, J = 9.4 Hz), 6.76 (1H, d, J = 8.6 Hz), 7.12 (1H, d, J = 8.6 Hz), 7.61 (1H, s), 8.18 (1H, s).
MS (ESI / APCI) m / z: 573 [M + H] +.
(80c) 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6 , 8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -4-methyl Pyridine-2-carboxylic acid tert-butylamine salt 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) prepared in Example 80b ) -1,2,3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl]- 4-methoxy-2-methylphenyl} -4-methylpyridine-2-carboxylic acid (210 mg, 0.367 mmol), ethanol (4.2 mL) and tert-butylamine (42 μL, 0.403 mmol) were used in Example 3c. The title compound (230 mg, 97%) was obtained by carrying out the reaction and post-treatment in the same manner.
(実施例81)
　6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボン酸　tert-ブチルアミン塩
(81a) tert-ブチル　6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボキシレート
　実施例65aで製造した(3S,4aS,10S,10aR)-2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,4a,6,10,10a-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン(350 mg, 0.621 mmol)、tert-ブチル　6-ブロモピリジン-2-カルボキシレート(224 mg, 0.870 mmol)、2nd Generation X-Phos Precatalyst (147 mg, 0.186 mmol)、リン酸カリウム(211 mg, 0.994 mmol)、THF (5.3 mL)及び水(7.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(230 mg, 60%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.30-0.46 (4H, m), 0.81 (3H, d, J = 6.7 Hz), 0.95 (3H, d, J = 7.0 Hz), 1.05 (3H, t, J = 7.0 Hz), 1.62 (9H, s), 1.70 (1H, d, J = 16.8 Hz), 1.80-1.91 (1H, m), 1.95 (1H, d, J = 17.6 Hz), 2.18-2.25 (1H, m), 2.35-2.41 (1H, m), 2.48 (1H, d, J = 16.8 Hz), 2.70 (1H, d, J = 17.2 Hz), 2.83 (3H, s), 3.02-3.11 (1H, m), 3.23 (1H, dd, J = 9.2, 11.5 Hz), 3.37-3.43 (1H, m), 3.59-3.68 (1H, m), 3.75 (3H, s), 3.80 (1H, dt, J = 4.7, 11.3 Hz), 4.55 (1H, d, J = 8.6 Hz), 6.72 (1H, d, J = 10.0 Hz), 7.32 (1H, d, J = 8.2 Hz), 7.60 (1H, dd, J = 1.2, 7.8 Hz), 7.75 (1H, t, J = 7.6 Hz), 7.90 (1H, dd, J = 1.0, 7.6 Hz).
(81b) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボン酸
　実施例81aで製造したtert-ブチル　6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボキシレート(230 mg, 0.374 mmol)、ジクロロメタン(2.3 mL)及びトリフルオロ酢酸(1.2 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(187 mg, 89%)を得た。 Example 81
6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6,8, 9,10,10a-decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} pyridine-2-carboxylic acid tert -Butylamine salt
(81a) tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4, 4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} pyridine -2-Carboxylate (3S, 4aS, 10S, 10aR) -2-ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-) prepared in Example 65a 1,3,2-dioxaborolan-2-yl) phenyl] -3- (propan-2-yl) -3,4,4a, 6,10,10a-hexahydrospiro [chromeno [3,2-c] pyridine -7,1'-cyclopropane] -1,9 (2H, 8H) -dione (350 mg, 0.621 mmol), tert-butyl 6-bromopyridine-2-carboxylate (224 mg, 0.870 mmol), 2nd Generation Use X-Phos Precatalyst (147 mg, 0.186 mmol), potassium phosphate (211 mg, 0.994 mmol), THF (5.3 mL) and water (7.0 mL) to carry out the reaction and workup according to Example 9d. Gave the title compound (230 mg, 60%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.30-0.46 (4H, m), 0.81 (3H, d, J = 6.7 Hz), 0.95 (3H, d, J = 7.0 Hz), 1.05 (3H , t, J = 7.0 Hz), 1.62 (9H, s), 1.70 (1H, d, J = 16.8 Hz), 1.80-1.91 (1H, m), 1.95 (1H, d, J = 17.6 Hz), 2.18 -2.25 (1H, m), 2.35-2.41 (1H, m), 2.48 (1H, d, J = 16.8 Hz), 2.70 (1H, d, J = 17.2 Hz), 2.83 (3H, s), 3.02- 3.11 (1H, m), 3.23 (1H, dd, J = 9.2, 11.5 Hz), 3.37-3.43 (1H, m), 3.59-3.68 (1H, m), 3.75 (3H, s), 3.80 (1H, dt, J = 4.7, 11.3 Hz), 4.55 (1H, d, J = 8.6 Hz), 6.72 (1H, d, J = 10.0 Hz), 7.32 (1H, d, J = 8.2 Hz), 7.60 (1H, dd, J = 1.2, 7.8 Hz), 7.75 (1H, t, J = 7.6 Hz), 7.90 (1H, dd, J = 1.0, 7.6 Hz).
(81b) 6- {3-[(3S, 4aS, 10S, 10aR) -2-Ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6 , 8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} pyridine-2- Carboxylic acid tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2 prepared in Example 81a , 3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2 -Methylphenyl} pyridine-2-carboxylate (230 mg, 0.374 mmol), dichloromethane (2.3 mL) and trifluoroacetic acid (1.2 mL) were used to carry out the reaction and workup according to Example 1d. The compound (187 mg, 89%) was obtained.
1H-NMR(400MHz, CDCl3):δ ppm: 0.32-0.48 (4H, m), 0.82 (3H, d, J = 6.6 Hz), 0.97 (3H, d, J = 6.6 Hz), 1.06 (3H, t, J = 7.0 Hz), 1.74 (1H, d, J = 16.8 Hz), 1.85 (1H, q, J = 12.1 Hz), 1.98 (1H, d, J = 18.0 Hz), 2.19-2.28 (1H, m), 2.37-2.43 (1H, m), 2.51 (1H, d, J = 16.8 Hz), 2.74 (1H, d, J = 17.2 Hz), 2.76 (3H, s), 3.03-3.07 (1H, m), 3.29 (1H, dd, J = 9.4, 11.3 Hz), 3.40-3.47 (1H, m), 3.62-3.72 (1H, m), 3.78 (3H, s), 3.86 (1H, dt, J = 4.7, 10.9 Hz), 4.46 (1H, d, J = 9.0 Hz), 6.76 (1H, d, J = 8.6 Hz), 7.18 (1H, d, J = 8.6 Hz), 7.76 (1H, dd, J = 0.8, 7.8 Hz), 8.03 (1H, t, J = 7.8 Hz), 8.21 (1H, dd, J = 1.0, 7.6 Hz).
MS(ESI/APCI)m/z: 559[M+H]+.
(81c) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例81bで製造した6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボン酸(110 mg, 0.197 mmol)、酢酸エチル(2.2 mL)及びtert-ブチルアミン(16 μL, 0.217 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(51.3 mg, 41%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.32-0.48 (4H, m), 0.82 (3H, d, J = 6.6 Hz), 0.97 (3H, d, J = 6.6 Hz), 1.06 (3H , t, J = 7.0 Hz), 1.74 (1H, d, J = 16.8 Hz), 1.85 (1H, q, J = 12.1 Hz), 1.98 (1H, d, J = 18.0 Hz), 2.19-2.28 (1H , m), 2.37-2.43 (1H, m), 2.51 (1H, d, J = 16.8 Hz), 2.74 (1H, d, J = 17.2 Hz), 2.76 (3H, s), 3.03-3.07 (1H, m), 3.29 (1H, dd, J = 9.4, 11.3 Hz), 3.40-3.47 (1H, m), 3.62-3.72 (1H, m), 3.78 (3H, s), 3.86 (1H, dt, J = 4.7, 10.9 Hz), 4.46 (1H, d, J = 9.0 Hz), 6.76 (1H, d, J = 8.6 Hz), 7.18 (1H, d, J = 8.6 Hz), 7.76 (1H, dd, J = 0.8, 7.8 Hz), 8.03 (1H, t, J = 7.8 Hz), 8.21 (1H, dd, J = 1.0, 7.6 Hz).
MS (ESI / APCI) m / z: 559 [M + H] +.
(81c) 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6 , 8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} pyridine-2- Carboxylic acid tert-butylamine salt 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1, prepared in Example 81b 2,3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy- 2-Methylphenyl} pyridine-2-carboxylic acid (110 mg, 0.197 mmol), ethyl acetate (2.2 mL) and tert-butylamine (16 μL, 0.217 mmol) were used for the reaction and workup according to Example 3c. This gave the title compound (51.3 mg, 41%).
(実施例82)
　6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メトキシピリジン-2-カルボン酸　tert-ブチルアミン塩
(82a) エチル　6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メトキシピリジン-2-カルボキシレート
　実施例27cで製造した(3S,4aS,10S,10aR)-2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(170 mg, 0.301 mmol)、エチル　6-クロロ-4-メトキシピリジン-2-カルボキシレート(78.0 mg, 0.362 mmol)、2nd Generation X-Phos Precatalyst (39.0 mg, 0.0496 mmol)、リン酸カリウム(103 mg, 0.485 mmol)、THF (4.0 mL)及び水(6.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(111 mg, 60%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.81 (3H, d, J = 6.7 Hz), 0.93 (3H, s), 0.96 (3H, d, J = 6.7 Hz), 1.05 (3H, s), 1.06 (3H, t, J = 6.1 Hz), 1.42 (3H, t, J = 7.0 Hz), 1.81-1.89 (1H, m), 2.00-2.43 (6H, m), 2.81 (3H, s), 3.04-3.12 (1H, m), 3.20 (1H, dd, J = 11.5, 8.5 Hz), 3.37-3.43 (1H, m), 3.56-3.65 (1H, m), 3.72-3.80 (1H, m), 3.72 (3H, s), 3.92 (3H, s), 4.45 (2H, q, J = 7.1 Hz), 4.54 (1H, d, J = 9.1 Hz), 6.67 (1H, d, J = 8.5 Hz), 7.11 (1H, d, J = 2.4 Hz), 7.21 (1H, d, J = 8.5 Hz), 7.59 (1H, d, J = 2.4 Hz).
(82b) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メトキシピリジン-2-カルボン酸
　実施例82aで製造したエチル　6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メトキシピリジン-2-カルボキシレート(111 mg, 0.180 mmol)、1 M水酸化ナトリウム水溶液(1.0　mL, 1.00 mmol)及びエタノール(2.0 mL)を用い、実施例25gに準じて反応及び後処理を行うことにより、標記化合物(56.8 mg, 54%)を得た。 (Example 82)
6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -4-methoxypyridine-2-carboxylic acid tert-Butylamine salt
(82a) Ethyl 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3, 4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -4-methoxypyridine- 2-Carboxylate (3S, 4aS, 10S, 10aR) -2-ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1) prepared in Example 27c , 3,2-Dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3- (propan-2-yl) -3,4,4a, 6,7,8,10,10a-octahydro-1H- Chromeno [3,2-c] pyridine-1,9 (2H) -dione (170 mg, 0.301 mmol), ethyl 6-chloro-4-methoxypyridine-2-carboxylate (78.0 mg, 0.362 mmol), 2nd Generation Use X-Phos Precatalyst (39.0 mg, 0.0496 mmol), potassium phosphate (103 mg, 0.485 mmol), THF (4.0 mL) and water (6.0 mL) to carry out the reaction and workup according to Example 9d. Gave the title compound (111 mg, 60%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.81 (3H, d, J = 6.7 Hz), 0.93 (3H, s), 0.96 (3H, d, J = 6.7 Hz), 1.05 (3H, s ), 1.06 (3H, t, J = 6.1 Hz), 1.42 (3H, t, J = 7.0 Hz), 1.81-1.89 (1H, m), 2.00-2.43 (6H, m), 2.81 (3H, s) , 3.04-3.12 (1H, m), 3.20 (1H, dd, J = 11.5, 8.5 Hz), 3.37-3.43 (1H, m), 3.56-3.65 (1H, m), 3.72-3.80 (1H, m) , 3.72 (3H, s), 3.92 (3H, s), 4.45 (2H, q, J = 7.1 Hz), 4.54 (1H, d, J = 9.1 Hz), 6.67 (1H, d, J = 8.5 Hz) , 7.11 (1H, d, J = 2.4 Hz), 7.21 (1H, d, J = 8.5 Hz), 7.59 (1H, d, J = 2.4 Hz).
(82b) 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4 , 4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -4-methoxypyridine-2 -Carboxylic acid Ethyl 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) prepared in Example 82a ) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} 4-methoxypyridine-2-carboxylate (111 mg, 0.180 mmol), 1 M aqueous sodium hydroxide solution (1.0 mL, 1.00 mmol) and ethanol (2.0 mL) were reacted and worked up according to Example 25 g. To give the title compound (56.8 mg, 54%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.81 (3H, d, J = 6.7 Hz), 0.95 (3H, s), 0.97 (3H, d, J = 7.9 Hz), 1.06 (3H, t, J = 6.7 Hz), 1.06 (3H, s), 1.77-1.83 (1H, m), 2.04 (1H, d, J = 16.4 Hz), 2.16 (1H, d, J = 16.4 Hz), 2.20-2.44 (4H, m), 2.77 (3H, s), 3.02-3.11 (1H, m), 3.25 (1H, t, J = 10.3 Hz), 3.39-3.46 (1H, m), 3.60-3.69 (1H, m), 3.75 (3H, s), 3.81 (1H, dt, J = 3.6, 11.5 Hz), 3.99 (3H, s), 4.45 (1H, d, J = 8.5 Hz), 6.71 (1H, d, J = 7.9 Hz), 7.14 (1H, d, J = 8.5 Hz), 7.18 (1H, d, J = 2.4 Hz), 7.76 (1H, d, J = 2.4 Hz).
(82c) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メトキシピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例82bで製造した6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メトキシピリジン-2-カルボン酸(56.8 mg, 0.0962 mmol)、酢酸エチル(1.0 mL)及びtert-ブチルアミン(21 μL, 0.200 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(63.8 mg, 80%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.81 (3H, d, J = 6.7 Hz), 0.95 (3H, s), 0.97 (3H, d, J = 7.9 Hz), 1.06 (3H, t , J = 6.7 Hz), 1.06 (3H, s), 1.77-1.83 (1H, m), 2.04 (1H, d, J = 16.4 Hz), 2.16 (1H, d, J = 16.4 Hz), 2.20-2.44 (4H, m), 2.77 (3H, s), 3.02-3.11 (1H, m), 3.25 (1H, t, J = 10.3 Hz), 3.39-3.46 (1H, m), 3.60-3.69 (1H, m ), 3.75 (3H, s), 3.81 (1H, dt, J = 3.6, 11.5 Hz), 3.99 (3H, s), 4.45 (1H, d, J = 8.5 Hz), 6.71 (1H, d, J = 7.9 Hz), 7.14 (1H, d, J = 8.5 Hz), 7.18 (1H, d, J = 2.4 Hz), 7.76 (1H, d, J = 2.4 Hz).
(82c) 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4 , 4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -4-methoxypyridine-2 -Carboxylic acid tert-butylamine salt 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propane- 2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2- Methylphenyl} -4-methoxypyridine-2-carboxylic acid (56.8 mg, 0.0962 mmol), ethyl acetate (1.0 mL) and tert-butylamine (21 μL, 0.200 mmol) were used for the reaction according to Example 3c. The title compound (63.8 mg, 80%) was obtained by treatment.
(実施例83)
　6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-4-メトキシピリジン-2-カルボン酸　tert-ブチルアミン塩
(83a) エチル　6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-4-メトキシピリジン-2-カルボキシレート
　実施例65aで製造した(3S,4aS,10S,10aR)-2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,4a,6,10,10a-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン(172 mg, 0.305 mmol)、エチル　6-クロロ-4-メトキシピリジン-2-カルボキシレート(80.0 mg, 0.371 mmol)、2nd Generation X-Phos Precatalyst (48.0 mg, 0.0610 mmol)、リン酸カリウム(105 mg, 0.495 mmol)、THF (3.0 mL)及び水(6.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(158 mg, 84%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.29-0.47 (4H, m), 0.81 (3H, d, J = 6.7 Hz), 0.95 (3H, d, J = 6.7 Hz), 1.06 (3H, t, J = 7.0 Hz), 1.42 (3H, t, J = 7.0 Hz), 1.70 (1H, d, J = 16.4 Hz), 1.77-1.89 (1H, m), 1.95 (1H, d, J = 17.6 Hz), 2.18-2.23 (1H, m), 2.35-2.41 (1H, m), 2.48 (1H, d, J = 16.7 Hz), 2.71 (1H, dd, J = 2.4, 16.4 Hz), 2.79 (3H, s), 3.03-3.12 (1H, m), 3.23 (1H, dd, J = 8.5, 12.1 Hz), 3.37-3.43 (1H, m), 3.59-3.67 (1H, m), 3.75 (3H, s), 3.80 (1H, dt, J = 4.3, 12.1 Hz), 3.92 (3H, s), 4.44 (2H, q, J = 7.3 Hz), 4.53 (1H, d, J = 7.9 Hz), 6.70 (1H, d, J = 8.5 Hz), 7.10 (1H, d, J = 2.4 Hz), 7.20 (1H, d, J = 8.5 Hz), 7.59 (1H, d, J = 2.4 Hz).
(83b) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-4-メトキシピリジン-2-カルボン酸
　実施例83aで製造したエチル　6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-4-メトキシピリジン-2-カルボキシレート(158 mg, 0.257 mmol)、1 M水酸化ナトリウム水溶液(1.0　mL, 1.00 mmol)及びエタノール(3.0 mL)を用い、実施例25gに準じて反応及び後処理を行うことにより、標記化合物(55.6 mg, 37%)を得た。 Example 83
6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6,8, 9,10,10a-decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -4-methoxypyridine-2 -Carboxylic acid tert-butylamine salt
(83a) Ethyl 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -4- Methoxypyridine-2-carboxylate (3S, 4aS, 10S, 10aR) -2-ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetra) prepared in Example 65a Methyl-1,3,2-dioxaborolan-2-yl) phenyl] -3- (propan-2-yl) -3,4,4a, 6,10,10a-hexahydrospiro [chromeno [3,2-c ] Pyridine-7,1'-cyclopropane] -1,9 (2H, 8H) -dione (172 mg, 0.305 mmol), ethyl 6-chloro-4-methoxypyridine-2-carboxylate (80.0 mg, 0.371 mmol) ), 2nd Generation X-Phos Precatalyst (48.0 mg, 0.0610 mmol), potassium phosphate (105 mg, 0.495 mmol), THF (3.0 mL) and water (6.0 mL), and the reaction according to Example 9d. By treatment, the title compound (158 mg, 84%) It was.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.29-0.47 (4H, m), 0.81 (3H, d, J = 6.7 Hz), 0.95 (3H, d, J = 6.7 Hz), 1.06 (3H , t, J = 7.0 Hz), 1.42 (3H, t, J = 7.0 Hz), 1.70 (1H, d, J = 16.4 Hz), 1.77-1.89 (1H, m), 1.95 (1H, d, J = 17.6 Hz), 2.18-2.23 (1H, m), 2.35-2.41 (1H, m), 2.48 (1H, d, J = 16.7 Hz), 2.71 (1H, dd, J = 2.4, 16.4 Hz), 2.79 ( 3H, s), 3.03-3.12 (1H, m), 3.23 (1H, dd, J = 8.5, 12.1 Hz), 3.37-3.43 (1H, m), 3.59-3.67 (1H, m), 3.75 (3H, s), 3.80 (1H, dt, J = 4.3, 12.1 Hz), 3.92 (3H, s), 4.44 (2H, q, J = 7.3 Hz), 4.53 (1H, d, J = 7.9 Hz), 6.70 ( 1H, d, J = 8.5 Hz), 7.10 (1H, d, J = 2.4 Hz), 7.20 (1H, d, J = 8.5 Hz), 7.59 (1H, d, J = 2.4 Hz).
(83b) 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6 , 8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -4-methoxy Pyridine-2-carboxylic acid Ethyl 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1 prepared in Example 83a , 2,3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy Using 2-methylphenyl} -4-methoxypyridine-2-carboxylate (158 mg, 0.257 mmol), 1 M aqueous sodium hydroxide (1.0 mL, 1.00 mmol) and ethanol (3.0 mL), The title compound (55.6 mg, 37%) was obtained by carrying out the reaction and post-treatment in the same manner.
1H-NMR(400MHz, CDCl3):δ ppm: 0.31-0.49 (4H, m), 0.81 (3H, d, J = 6.7 Hz), 0.97 (3H, d, J = 7.3 Hz), 1.06 (3H, t, J = 7.3 Hz), 1.70-1.87 (2H, m), 1.96 (1H, d, J = 17.0 Hz), 2.20-2.27 (1H, m), 2.35-2.42 (1H, m), 2.50 (1H, d, J = 17.0 Hz), 2.73 (1H, d, J = 18.8 Hz), 2.76 (3H, s), 3.01-3.11 (1H, m), 3.26 (1H, t, J = 10.3 Hz), 3.39-3.46 (1H, m), 3.64-3.69 (1H, m), 3.77 (3H, s), 3.85 (1H, dt, J = 4.3, 11.5 Hz), 3.99 (3H, s), 4.46 (1H, d, J = 9.7 Hz), 6.74 (1H, d, J = 8.5 Hz), 7.14 (1H, d, J = 8.5 Hz), 7.17 (1H, d, J = 2.4 Hz), 7.76 (1H, d, J = 2.4 Hz).
(83c) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-4-メトキシピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例83bで製造した6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-4-メトキシピリジン-2-カルボン酸(55.6 mg, 0.0944 mmol)、酢酸エチル(1.0 mL)及びtert-ブチルアミン(20 μL, 0.190 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(50.1 mg, 80%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.31-0.49 (4H, m), 0.81 (3H, d, J = 6.7 Hz), 0.97 (3H, d, J = 7.3 Hz), 1.06 (3H , t, J = 7.3 Hz), 1.70-1.87 (2H, m), 1.96 (1H, d, J = 17.0 Hz), 2.20-2.27 (1H, m), 2.35-2.42 (1H, m), 2.50 ( 1H, d, J = 17.0 Hz), 2.73 (1H, d, J = 18.8 Hz), 2.76 (3H, s), 3.01-3.11 (1H, m), 3.26 (1H, t, J = 10.3 Hz), 3.39-3.46 (1H, m), 3.64-3.69 (1H, m), 3.77 (3H, s), 3.85 (1H, dt, J = 4.3, 11.5 Hz), 3.99 (3H, s), 4.46 (1H, d, J = 9.7 Hz), 6.74 (1H, d, J = 8.5 Hz), 7.14 (1H, d, J = 8.5 Hz), 7.17 (1H, d, J = 2.4 Hz), 7.76 (1H, d, J = 2.4 Hz).
(83c) 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6 , 8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -4-methoxy Pyridine-2-carboxylic acid tert-butylamine salt 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) prepared in Example 83b ) -1,2,3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl]- Example 3c using 4-methoxy-2-methylphenyl} -4-methoxypyridine-2-carboxylic acid (55.6 mg, 0.0944 mmol), ethyl acetate (1.0 mL) and tert-butylamine (20 μL, 0.190 mmol) The title compound (50.1 mg, 80%) was obtained by reacting and working up according to.
(実施例84)
　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2-エチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボン酸　tert-ブチルアミン塩
(84a) (3S,4aS,10S,10aR)-3-tert-ブチル-2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例45bで製造した(3S,4aS,10S,10aR)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(700 mg, 1.27 mmol)、ヨウ化エチル(812 μL, 10.2 mmol)、DMPU (7.0 mL)及び水素化ナトリウム(55%, 166 mg, 3.81 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(736 mg, 68%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.90 (12H, s), 1.01 (3H, t, J = 6.5 Hz), 1.03 (3H, s), 1.30 (12H, s), 1.96-2.05 (2H, m), 2.12 (1H, d, J = 16.4 Hz), 2.21 (1H, d, J = 17.6 Hz), 2.31 (1H, dd, J = 17.6, 2.3 Hz), 2.54-2.62 (1H, m), 2.71 (1H, dd, J = 13.7, 7.0 Hz), 3.15 (3H, s), 3.22-3.26 (1H, m), 3.32 (1H, dd, J = 11.7, 8.6 Hz), 3.60-3.67 (1H, m), 3.67 (3H, s), 4.04-4.13 (1H, m), 4.69 (1H, d, J = 8.2 Hz), 6.54 (1H, d, J = 8.6 Hz), 7.58 (1H, d, J = 8.2 Hz).
(84b) tert-ブチル　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2-エチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボキシレート
　実施例84aで製造した(3S,4aS,10S,10aR)-3-tert-ブチル-2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(181 mg, 0.312 mmol)、tert-ブチル　6-ブロモピリジン-2-カルボキシレート(113 mg, 0.437 mmol)、2nd Generation X-Phos Precatalyst (73.7 mg, 0.0937 mmol)、リン酸カリウム(106 mg, 0.500 mmol)、THF (2.7 mL)及び水(3.6 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(147 mg, 75%)を得た。 (Example 84)
6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2-ethyl-7,7-dimethyl-1,9-dioxo-2,3,4,4a, 6,7, 8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} pyridine-2-carboxylic acid tert-butylamine salt
(84a) (3S, 4aS, 10S, 10aR) -3-tert-butyl-2-ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c] pyridine-1 , 9 (2H) -dione (3S, 4aS, 10S, 10aR) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5) prepared in Example 45b -Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2 -c] pyridine-1,9 (2H) -dione (700 mg, 1.27 mmol), ethyl iodide (812 μL, 10.2 mmol), DMPU (7.0 mL) and sodium hydride (55%, 166 mg, 3.81 mmol The title compound (736 mg, 68%) was obtained by reaction and workup according to Example 2a.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.90 (12H, s), 1.01 (3H, t, J = 6.5 Hz), 1.03 (3H, s), 1.30 (12H, s), 1.96-2.05 (2H, m), 2.12 (1H, d, J = 16.4 Hz), 2.21 (1H, d, J = 17.6 Hz), 2.31 (1H, dd, J = 17.6, 2.3 Hz), 2.54-2.62 (1H, m), 2.71 (1H, dd, J = 13.7, 7.0 Hz), 3.15 (3H, s), 3.22-3.26 (1H, m), 3.32 (1H, dd, J = 11.7, 8.6 Hz), 3.60-3.67 (1H, m), 3.67 (3H, s), 4.04-4.13 (1H, m), 4.69 (1H, d, J = 8.2 Hz), 6.54 (1H, d, J = 8.6 Hz), 7.58 (1H, d, J = 8.2 Hz).
(84b) tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2-ethyl-7,7-dimethyl-1,9-dioxo-2,3,4, 4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} pyridine-2-carboxylate Examples (3S, 4aS, 10S, 10aR) -3-tert-butyl-2-ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1) prepared in 84a , 3,2-Dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2-c] pyridine- 1,9 (2H) -dione (181 mg, 0.312 mmol), tert-butyl 6-bromopyridine-2-carboxylate (113 mg, 0.437 mmol), 2nd Generation X-Phos Precatalyst (73.7 mg, 0.0937 mmol), The title compound (147 mg, 75%) was obtained by carrying out the reaction and post-treatment according to Example 9d using potassium phosphate (106 mg, 0.500 mmol), THF (2.7 mL) and water (3.6 mL). Obtained.
1H-NMR(400MHz, CDCl3):δ ppm: 0.93 (12H, s), 1.01 (3H, t, J = 7.0 Hz), 1.04 (3H, s), 1.63 (9H, s), 1.99-2.07 (2H, m), 2.15 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 17.6 Hz), 2.33 (1H, dd, J = 2.3, 16.8 Hz), 2.55-2.63 (1H, m), 2.70-2.80 (1H, m), 2.88 (3H, s), 3.25 (1H, dd, J = 4.3, 10.9 Hz), 3.34 (1H, dd, J = 8.4, 11.9 Hz), 3.59-3.67 (1H, m), 3.72 (3H, s), 4.00-4.09 (1H, m), 4.71 (1H, d, J = 6.6 Hz), 6.66 (1H, d, J = 8.6 Hz), 7.31 (1H, d, J = 8.6 Hz), 7.60 (1H, dd, J = 0.8, 7.8 Hz), 7.74 (1H, t, J = 7.8 Hz), 7.89 (1H, dd, J = 1.0, 7.6 Hz).
(84c) 6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2-エチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例84bで製造したtert-ブチル　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2-エチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボキシレート(147 mg, 0.233 mmol)、ジクロロメタン(1.5 mL)、トリフルオロ酢酸(0.7 mL)、酢酸エチル(5.0 mL)及びtert-ブチルアミン(26 μL, 0.245 mmol) を用い、実施例41fに準じて反応及び後処理を行うことにより、標記化合物(150 mg, 99%, 2 steps)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.93 (12H, s), 1.01 (3H, t, J = 7.0 Hz), 1.04 (3H, s), 1.63 (9H, s), 1.99-2.07 (2H, m), 2.15 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 17.6 Hz), 2.33 (1H, dd, J = 2.3, 16.8 Hz), 2.55-2.63 (1H, m), 2.70-2.80 (1H, m), 2.88 (3H, s), 3.25 (1H, dd, J = 4.3, 10.9 Hz), 3.34 (1H, dd, J = 8.4, 11.9 Hz), 3.59-3.67 (1H, m), 3.72 (3H, s), 4.00-4.09 (1H, m), 4.71 (1H, d, J = 6.6 Hz), 6.66 (1H, d, J = 8.6 Hz), 7.31 (1H, d, J = 8.6 Hz), 7.60 (1H, dd, J = 0.8, 7.8 Hz), 7.74 (1H, t, J = 7.8 Hz), 7.89 (1H, dd, J = 1.0, 7.6 Hz).
(84c) 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2-ethyl-7,7-dimethyl-1,9-dioxo-2,3,4,4a, 6 , 7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} pyridine-2-carboxylic acid tert-butylamine salt Tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2-ethyl-7,7-dimethyl-1,9-dioxo-2,3, prepared in Example 84b 4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} pyridine-2-carboxylate (147 mg, 0.233 mmol), dichloromethane (1.5 mL), trifluoroacetic acid (0.7 mL), ethyl acetate (5.0 mL) and tert-butylamine (26 μL, 0.245 mmol) were used according to Example 41f. The title compound (150 mg, 99%, 2 steps) was obtained by post-treatment.
(実施例85)
　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2-エチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボン酸
(85a) tert-ブチル　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2-エチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボキシレート
　実施例84aで製造した(3S,4aS,10S,10aR)-3-tert-ブチル-2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,4,4a,6,7,8,10,10a-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(200 mg, 0.345 mmol)、tert-ブチル　6-クロロ-4-メチルピリジン-2-カルボキシレート(110 mg, 0.483 mmol)、2nd Generation X-Phos Precatalyst (81.5 mg, 0.104 mmol)、リン酸カリウム(117 mg, 0.552 mmol)、THF (3.0 mL)及び水(4.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(193 mg, 87%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.93 (12H, s), 1.01 (3H, t, J = 6.8 Hz), 1.04 (3H, s), 1.63 (9H, s), 2.00-2.07 (2H, m), 2.15 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 18.0 Hz), 2.33 (1H, d, J = 19.9 Hz), 2.41 (3H, s), 2.55-2.64 (1H, m), 2.75 (1H, dd, J = 6.6, 13.7 Hz), 2.86 (3H, s), 3.25 (1H, dd, J = 4.3, 10.9 Hz), 3.34 (1H, dd, J = 8.4, 11.9 Hz), 3.59-3.66 (1H, m), 3.71 (3H, s), 4.02-4.13 (1H, m), 4.71 (1H, d, J = 7.0 Hz), 6.64 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 8.6 Hz), 7.42 (1H, s), 7.72 (1H, s).
(85b) 6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2-エチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボン酸
　実施例85aで製造したtert-ブチル　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2-エチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボキシレート(192 mg, 0.298 mmol)、ジクロロメタン(1.9 mL)及びトリフルオロ酢酸(1.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(153 mg, 87%)を得た。 Example 85
6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2-ethyl-7,7-dimethyl-1,9-dioxo-2,3,4,4a, 6,7, 8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -4-methylpyridine-2-carboxylic acid
(85a) tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2-ethyl-7,7-dimethyl-1,9-dioxo-2,3,4, 4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -4-methylpyridine-2- Carboxylate (3S, 4aS, 10S, 10aR) -3-tert-butyl-2-ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-) prepared in Example 84a Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3,4,4a, 6,7,8,10,10a-octahydro-1H-chromeno [3,2- c] Pyridine-1,9 (2H) -dione (200 mg, 0.345 mmol), tert-butyl 6-chloro-4-methylpyridine-2-carboxylate (110 mg, 0.483 mmol), 2nd Generation X-Phos Precatalyst (81.5 mg, 0.104 mmol), potassium phosphate (117 mg, 0.552 mmol), THF (3.0 mL) and water (4.0 mL) were used to carry out the reaction and workup according to Example 9d to give the title compound. (193 mg, 87%) was obtained.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.93 (12H, s), 1.01 (3H, t, J = 6.8 Hz), 1.04 (3H, s), 1.63 (9H, s), 2.00-2.07 (2H, m), 2.15 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 18.0 Hz), 2.33 (1H, d, J = 19.9 Hz), 2.41 (3H, s), 2.55 -2.64 (1H, m), 2.75 (1H, dd, J = 6.6, 13.7 Hz), 2.86 (3H, s), 3.25 (1H, dd, J = 4.3, 10.9 Hz), 3.34 (1H, dd, J = 8.4, 11.9 Hz), 3.59-3.66 (1H, m), 3.71 (3H, s), 4.02-4.13 (1H, m), 4.71 (1H, d, J = 7.0 Hz), 6.64 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 8.6 Hz), 7.42 (1H, s), 7.72 (1H, s).
(85b) 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-Butyl-2-ethyl-7,7-dimethyl-1,9-dioxo-2,3,4,4a, 6 , 7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -4-methylpyridine-2-carboxylic acid Tert-butyl 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2-ethyl-7,7-dimethyl-1,9-dioxo-2,3, prepared in Example 85a 4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -4-methylpyridine- The title compound (153 mg, 87 %).
(実施例86)
　6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メトキシ-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例82bで製造した6-{3-[(3S,4aS,10S,10aR)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メトキシピリジン-2-カルボン酸(30.7 mg, 0.0520 mmol)、カルボニルジイミダゾール(26.0 mg, 0.160 mmol)、DMF (1.0 mL)、メタンスルホンアミド(19.0 mg, 0.200 mmol)及びDBU (24 μL, 0.160 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(14.3 mg, 41%)を得た。 Example 86
6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -4-methoxy-N- (methylsulfonyl ) Pyridine-2-carboxamide 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propane-2) prepared in Example 82b -Yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methyl Phenyl} -4-methoxypyridine-2-carboxylic acid (30.7 mg, 0.0520 mmol), carbonyldiimidazole (26.0 mg, 0.160 mmol), DMF (1.0 mL), methanesulfonamide (19.0 mg, 0.200 mmol) and DBU ( The title compound (14.3 mg, 41%) was obtained by performing the reaction and post-treatment according to Example 6a using 24 μL, 0.160 mmol).
(実施例87)
　6-{3-[(3R,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(87a) tert-ブチル　[(3R)-1-(2,2-ジメチル-4,6-ジオキソ-1,3-ジオキサン-5-イル)-4,4-ジメチル-1-オキソペンタン-3-イル]カルバメート
　(3R)-3-[(tert-ブトキシカルボニル)アミノ]-4,4-ジメチルペンタノイックアシッド(15.0 g, 61.0 mmol)、ジメチルアミノピリジン(8.94 g, 73.2 mmol)、2,2-ジメチル-1,3-ジオキサン-4,6-ジオン(9.67 g, 67.1 mmol)及びWSC・HCl (14.0 g, 73.2 mmol)のジクロロメタン(200 mL)溶液を室温で16時間攪拌した。反応溶液を濃縮後、濃縮残渣を酢酸エチルで希釈した。有機層を5%クエン酸水溶液で2回、飽和食塩水で2回洗浄した。有機層を無水硫酸ナトリウムで乾燥後、濃縮し、粗製の標記化合物(21.5 g, 95%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.99 (9H, s), 1.36 (9H, s), 1.74 (3H, s), 1.78 (3H, s), 2.95 (1H, t, J = 11.7 Hz), 3.39 (1H, dd, J = 3.3, 11.9 Hz), 3.96 (1H, td, J = 3.1, 11.2 Hz), 4.66 (1H, d, J = 10.6 Hz).
(87b) tert-ブチル　(2R)-2-tert-ブチル-4,6-ジオキソピペリジン-1-カルボキシレート
　実施例87aで製造した粗製のtert-ブチル　[(3R)-1-(2,2-ジメチル-4,6-ジオキソ-1,3-ジオキサン-5-イル)-4,4-ジメチル-1-オキソペンタン-3-イル]カルバメート(21.7 g, 58.4 mmol)の酢酸エチル(200 mL)溶液を80℃で4時間攪拌した。室温まで冷却後、反応溶液を濃縮し、生成した結晶をヘキサンで洗浄し、標記化合物(9.10 g, 58%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.94 (9H, s), 1.56 (9H, s), 2.65 (1H, dd, J = 7.4, 16.8 Hz), 2.93 (1H, d, J = 16.8 Hz), 3.34 (1H, d, J = 21.5 Hz), 3.49 (1H, d, J = 21.5 Hz), 4.55 (1H, dd, J = 1.8, 7.2 Hz).
(87c) tert-ブチル　(6R)-6-tert-ブチル-3-{(S)-(4,4-ジメチル-2,6-ジオキソシクロヘキシル)[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]メチル}-2,4-ジオキソピペリジン-1-カルボキシレート
　実施例9bで製造した2-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン(4.00 g, 10.0 mmol)及び実施例87bで製造したtert-ブチル　(2R)-2-tert-ブチル-4,6-ジオキソピペリジン-1-カルボキシレート(2.98 g, 11.0 mmol)のアセトニトリル(40 mL)溶液に0℃で炭酸セシウム(3.93 g, 12.1 mmol)を加えた。反応溶液を0℃で3時間攪拌後、水を加えて酢酸エチルで2回抽出、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮し、粗製の標記化合物をジアステレオマーの混合物として得た。
(87d) (3R,10S)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例87cで製造した粗製のtert-ブチル　(6R)-6-tert-ブチル-3-{(S)-(4,4-ジメチル-2,6-ジオキソシクロヘキシル)[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]メチル}-2,4-ジオキソピペリジン-1-カルボキシレートの酢酸エチル(130 mL)に室温で4 M塩酸(1,4-ジオキサン溶液; 33 mL, 132 mmol)を加えた。反応溶液を室温で16時間攪拌後、1 M水酸化ナトリウム水溶液を加えて(pH = 12)、酢酸エチルで2回抽出、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮し、残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル; 4:6)で精製し、標記化合物(1.23 g, 22%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.92 (9H, s), 0.94 (3H, s), 1.08 (3H, s), 1.30 (12H, s), 2.11 (1H, d, J = 16.4 Hz), 2.19 (1H, d, J = 16.4 Hz), 2.30-2.54 (4H, m), 3.12 (3H, s), 3.18 (1H, dd, J = 5.1, 13.7 Hz), 3.71 (3H, s), 5.05 (1H, s), 5.19 (1H, s), 6.61 (1H, d, J = 8.2 Hz), 7.60 (1H, d, J = 8.6 Hz).
(87e) tert-ブチル　6-{3-[(3R,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例87dで製造した(3R,10S)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(450 mg, 0.819 mmol)、tert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(224 mg, 0.983 mmol)、2nd Generation X-Phos Precatalyst (193 mg, 0.246 mmol)、リン酸カリウム(278 mg, 1.31 mmol)、THF (6.8 mL)及び水(9.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(471 mg, 94%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.94 (9H, s), 0.97 (3H, s), 1.09 (3H, s), 1.63 (9H, s), 2.13 (1H, d, J = 16.4 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.32-2.55 (4H, m), 2.49 (3H, s), 2.85 (3H, s), 3.22 (1H, dd, J = 5.1, 13.7 Hz), 3.74 (3H, s), 5.09 (1H, s), 5.17 (1H, s), 6.72 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.2 Hz), 7.36 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 7.8 Hz).
(87f) 6-{3-[(3R,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例87eで製造したtert-ブチル　6-{3-[(3R,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(471 mg, 0.766 mmol)、ジクロロメタン(4.7 mL)及びトリフルオロ酢酸(2.4 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(371 mg, 87%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.96 (9H, s), 1.00 (3H, s), 1.12 (3H, s), 2.17 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.35-2.58 (4H, m), 2.81 (3H, s), 2.87 (3H, s), 3.25 (1H, dd, J = 5.3, 13.5 Hz), 3.79 (3H, s), 5.18 (1H, s), 5.27 (1H, s), 6.77 (1H, d, J = 8.6 Hz), 7.21 (1H, d, J = 8.6 Hz), 7.57 (1H, d, J = 7.8 Hz), 7.71 (1H, d, J = 8.2 Hz).
MS(ESI/APCI)m/z: 559[M+H]+.
(87g) 6-{3-[(3R,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例87fで製造した6-{3-[(3R,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(319 mg, 0.571 mmol)、酢酸エチル(6.4 mL)及びtert-ブチルアミン(46 μL, 0.628 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(307 mg, 85%)を得た。 Example 87
6- {3-[(3R, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H- Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(87a) tert-butyl [(3R) -1- (2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl) -4,4-dimethyl-1-oxopentane-3- Yl] carbamate (3R) -3-[(tert-butoxycarbonyl) amino] -4,4-dimethylpentanoic acid (15.0 g, 61.0 mmol), dimethylaminopyridine (8.94 g, 73.2 mmol), 2,2 A solution of -dimethyl-1,3-dioxane-4,6-dione (9.67 g, 67.1 mmol) and WSC · HCl (14.0 g, 73.2 mmol) in dichloromethane (200 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated, and the concentrated residue was diluted with ethyl acetate. The organic layer was washed twice with 5% aqueous citric acid solution and twice with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to give the crude title compound (21.5 g, 95%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.99 (9H, s), 1.36 (9H, s), 1.74 (3H, s), 1.78 (3H, s), 2.95 (1H, t, J = 11.7 Hz), 3.39 (1H, dd, J = 3.3, 11.9 Hz), 3.96 (1H, td, J = 3.1, 11.2 Hz), 4.66 (1H, d, J = 10.6 Hz).
(87b) tert-butyl (2R) -2-tert-butyl-4,6-dioxopiperidine-1-carboxylate Crude tert-butyl prepared in Example 87a [(3R) -1- (2,2 -Dimethyl-4,6-dioxo-1,3-dioxane-5-yl) -4,4-dimethyl-1-oxopentan-3-yl] carbamate (21.7 g, 58.4 mmol) in ethyl acetate (200 mL) The solution was stirred at 80 ° C. for 4 hours. After cooling to room temperature, the reaction solution was concentrated, and the resulting crystals were washed with hexane to obtain the title compound (9.10 g, 58%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.94 (9H, s), 1.56 (9H, s), 2.65 (1H, dd, J = 7.4, 16.8 Hz), 2.93 (1H, d, J = 16.8 Hz), 3.34 (1H, d, J = 21.5 Hz), 3.49 (1H, d, J = 21.5 Hz), 4.55 (1H, dd, J = 1.8, 7.2 Hz).
(87c) tert-butyl (6R) -6-tert-butyl-3-{(S)-(4,4-dimethyl-2,6-dioxocyclohexyl) [6-methoxy-2-methyl-3- ( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] methyl} -2,4-dioxopiperidine-1-carboxylate 2- [6 prepared in Example 9b -Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] -5,5-dimethylcyclohexane-1,3-dione (4.00 g, 10.0 mmol) and tert-butyl (2R) -2-tert-butyl-4,6-dioxopiperidine-1-carboxylate (2.98 g, 11.0 mmol) prepared in Example 87b in acetonitrile (40 mL) To the solution was added cesium carbonate (3.93 g, 12.1 mmol) at 0 ° C. The reaction solution was stirred at 0 ° C. for 3 hours, water was added and the mixture was extracted twice with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound as a mixture of diastereomers.
(87d) (3R, 10S) -3-tert-Butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) phenyl] -7,7-dimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione prepared in Example 87c Crude tert-butyl (6R) -6-tert-butyl-3-{(S)-(4,4-dimethyl-2,6-dioxocyclohexyl) [6-methoxy-2-methyl-3- ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] methyl} -2,4-dioxopiperidine-1-carboxylate in ethyl acetate (130 mL) at room temperature 4 M hydrochloric acid (1,4-dioxane solution; 33 mL, 132 mmol) was added. The reaction solution was stirred at room temperature for 16 hours, 1 M aqueous sodium hydroxide solution was added (pH = 12), extracted twice with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography (hexane / ethyl acetate; 4: 6) to obtain the title compound (1.23 g, 22%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.92 (9H, s), 0.94 (3H, s), 1.08 (3H, s), 1.30 (12H, s), 2.11 (1H, d, J = 16.4 Hz), 2.19 (1H, d, J = 16.4 Hz), 2.30-2.54 (4H, m), 3.12 (3H, s), 3.18 (1H, dd, J = 5.1, 13.7 Hz), 3.71 (3H, s), 5.05 (1H, s), 5.19 (1H, s), 6.61 (1H, d, J = 8.2 Hz), 7.60 (1H, d, J = 8.6 Hz).
(87e) tert-butyl 6- {3-[(3R, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9, 10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate prepared in Example 87d (3R, 10S ) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7, 7-dimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (450 mg, 0.819 mmol), tert-butyl 6 -Chloro-3-methylpyridine-2-carboxylate (224 mg, 0.983 mmol), 2nd Generation X-Phos Precatalyst (193 mg, 0.246 mmol), potassium phosphate (278 mg, 1.31 mmol), THF (6.8 mL) And water (9.0 mL) were used for the reaction and workup according to Example 9d to obtain the title compound (471 mg, 94%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.94 (9H, s), 0.97 (3H, s), 1.09 (3H, s), 1.63 (9H, s), 2.13 (1H, d, J = 16.4 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.32-2.55 (4H, m), 2.49 (3H, s), 2.85 (3H, s), 3.22 (1H, dd, J = 5.1, 13.7 Hz), 3.74 (3H, s), 5.09 (1H, s), 5.17 (1H, s), 6.72 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.2 Hz), 7.36 ( 1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 7.8 Hz).
(87f) 6- {3-[(3R, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro -1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butyl 6- {3 prepared in Example 87e -[(3R, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3, 2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (471 mg, 0.766 mmol), dichloromethane (4.7 mL) and trifluoroacetic acid (2.4 mL) The title compound (371 mg, 87%) was obtained by performing the reaction and post-treatment according to Example 1d.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.96 (9H, s), 1.00 (3H, s), 1.12 (3H, s), 2.17 (1H, d, J = 16.4 Hz), 2.24 (1H , d, J = 16.4 Hz), 2.35-2.58 (4H, m), 2.81 (3H, s), 2.87 (3H, s), 3.25 (1H, dd, J = 5.3, 13.5 Hz), 3.79 (3H, s), 5.18 (1H, s), 5.27 (1H, s), 6.77 (1H, d, J = 8.6 Hz), 7.21 (1H, d, J = 8.6 Hz), 7.57 (1H, d, J = 7.8 Hz), 7.71 (1H, d, J = 8.2 Hz).
MS (ESI / APCI) m / z: 559 [M + H] +.
(87g) 6- {3-[(3R, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro -1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt 6- {prepared in Example 87f 3-[(3R, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3 , 2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid (319 mg, 0.571 mmol), ethyl acetate (6.4 mL) and tert-butylamine ( The title compound (307 mg, 85%) was obtained by reaction and post-treatment according to Example 3c using 46 μL, 0.628 mmol).
(実施例88)
　2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシナフタレン-1-カルボン酸
(88a) エチル　1-ヒドロキシ-3-メトキシナフタレン-2-カルボキシレート
　エチル　1,3-ジヒドロキシナフタレン-2-カルボキシレート(3.00 g, 12.9 mmol)、トリフェニルホスフィン(5.25g, 20.0 mmol)及びメタノール(786 μL, 19.4 mmol)のTHF (90 mL)溶液に0℃でジイソプロピルアゾジカルボキシレート(4.01 mL, 20.0 mmol)を加え、反応溶液を室温で7時間攪拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで2回抽出後、有機層無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 9:1)で精製し、標記化合物(1.10 g, 35%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 1.45 (3H, t, J = 7.0 Hz), 3.94 (3H, s), 4.48 (2H, q, J = 7.2 Hz), 6.64 (1H, s), 7.32-7.36 (1H, m), 7.51-7.61 (2H, m), 8.30 (1H, d, J = 8.6 Hz), 12.89 (1H, s).
(88b) エチル　3-メトキシ-1-{[(トリフルオロメチル)スルホニル]オキシ}ナフタレン-2-カルボキシレート
　実施例88aで製造したエチル　1-ヒドロキシ-3-メトキシナフタレン-2-カルボキシレート(1.78 g, 7.23 mmol)、N-フェニルビス(トリフルオロメタンスルホンイミド) (3.36 g, 9.40 mmol)及び炭酸カリウム(3.00g, 21.7 mmol)のDMF (18 mL)溶液を70℃で4時間攪拌した。空冷後、反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで2回抽出後、有機層無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 9:1)で精製し、標記化合物(2.73 g, 99%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 1.45 (3H, t, J = 7.0 Hz), 4.10 (3H, s), 4.49 (2H, q, J = 7.2 Hz), 7.57 (1H, s), 7.60-7.67 (2H, m), 7.86-7.89 (1H, m), 8.18-8.21 (1H, m).
(88c) エチル　3-メトキシ-1-メチルナフタレン-2-カルボキシレート
　実施例88bで製造したエチル　3-メトキシ-1-{[(トリフルオロメチル)スルホニル]オキシ}ナフタレン-2-カルボキシレート(3.65 g, 9.65 mmol)、トリメチルボロキシン(50% in THF, 2.9 mL, 10.1 mmol)、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II) ジクロロメタン混合物(788 mg, 0.965 mmol)及びりん酸カリウム(6.35 g, 29.9 mmol)の1,4-ジオキサン(37 mL)溶液を窒素雰囲気下110℃で3時間攪拌した。放冷後、反応溶液に水を加えて酢酸エチルで2回抽出後、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 9:1)で精製し、標記化合物(2.28 g, 97%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 1.38 (3H, t, J = 7.2 Hz), 2.57 (3H, s), 3.89 (3H, s), 4.43 (2H, q, J = 7.2 Hz), 7.01 (1H, s), 7.42-7.47 (1H, m), 7.35-7.39 (1H, m), 7.69 (1H, d, J = 7.8 Hz), 7.91 (1H, d, J = 8.6 Hz).
(88d) エチル　1-(ブロモメチル)-3-メトキシナフタレン-2-カルボキシレート
　実施例88cで製造したエチル　3-メトキシ-1-メチルナフタレン-2-カルボキシレート(2.28 g, 9.33 mmol)、2,2'-アゾビス(イソブチロニトリル) (153 mg, 0.933 mmol)、N-ブロモスクシイミド(1.83 g, 10.3 mmol)及び四塩化炭素(46 mL)を用い、実施例32aに準じて反応及び後処理を行うことにより、標記化合物(2.94 g, 98%)を得た。 Example 88
2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxynaphthalene-1-carboxylic acid
(88a) Ethyl 1-hydroxy-3-methoxynaphthalene-2-carboxylate Ethyl 1,3-dihydroxynaphthalene-2-carboxylate (3.00 g, 12.9 mmol), triphenylphosphine (5.25 g, 20.0 mmol) and methanol ( To a solution of 786 μL, 19.4 mmol) in THF (90 mL) was added diisopropyl azodicarboxylate (4.01 mL, 20.0 mmol) at 0 ° C., and the reaction solution was stirred at room temperature for 7 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 9: 1) to obtain the title compound (1.10 g, 35%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.45 (3H, t, J = 7.0 Hz), 3.94 (3H, s), 4.48 (2H, q, J = 7.2 Hz), 6.64 (1H, s ), 7.32-7.36 (1H, m), 7.51-7.61 (2H, m), 8.30 (1H, d, J = 8.6 Hz), 12.89 (1H, s).
(88b) Ethyl 3-methoxy-1-{[(trifluoromethyl) sulfonyl] oxy} naphthalene-2-carboxylate Ethyl 1-hydroxy-3-methoxynaphthalene-2-carboxylate prepared in Example 88a (1.78 g , 7.23 mmol), N-phenylbis (trifluoromethanesulfonimide) (3.36 g, 9.40 mmol) and potassium carbonate (3.00 g, 21.7 mmol) in DMF (18 mL) were stirred at 70 ° C. for 4 hours. After air cooling, saturated aqueous ammonium chloride solution was added to the reaction solution, extracted twice with ethyl acetate, and dried over anhydrous sodium sulfate organic layer. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 9: 1) to obtain the title compound (2.73 g, 99%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.45 (3H, t, J = 7.0 Hz), 4.10 (3H, s), 4.49 (2H, q, J = 7.2 Hz), 7.57 (1H, s ), 7.60-7.67 (2H, m), 7.86-7.89 (1H, m), 8.18-8.21 (1H, m).
(88c) Ethyl 3-methoxy-1-methylnaphthalene-2-carboxylate Ethyl 3-methoxy-1-{[(trifluoromethyl) sulfonyl] oxy} naphthalene-2-carboxylate (3.65 g) prepared in Example 88b , 9.65 mmol), trimethylboroxine (50% in THF, 2.9 mL, 10.1 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane mixture (788 mg, 0.965 mmol) and phosphorus A solution of potassium acid (6.35 g, 29.9 mmol) in 1,4-dioxane (37 mL) was stirred at 110 ° C. for 3 hours under a nitrogen atmosphere. After allowing to cool, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 9: 1) to obtain the title compound (2.28 g, 97%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.38 (3H, t, J = 7.2 Hz), 2.57 (3H, s), 3.89 (3H, s), 4.43 (2H, q, J = 7.2 Hz ), 7.01 (1H, s), 7.42-7.47 (1H, m), 7.35-7.39 (1H, m), 7.69 (1H, d, J = 7.8 Hz), 7.91 (1H, d, J = 8.6 Hz) .
(88d) Ethyl 1- (bromomethyl) -3-methoxynaphthalene-2-carboxylate Ethyl 3-methoxy-1-methylnaphthalene-2-carboxylate prepared in Example 88c (2.28 g, 9.33 mmol), 2,2 '-Azobis (isobutyronitrile) (153 mg, 0.933 mmol), N-bromosuccinimide (1.83 g, 10.3 mmol) and carbon tetrachloride (46 mL) were used and reacted according to Example 32a. The title compound (2.94 g, 98%) was obtained by the treatment.
1H-NMR(400MHz, CDCl3):δ ppm: 1.46 (3H, t, J = 7.2 Hz), 3.94 (3H, s), 4.52 (2H, q, J = 7.0 Hz), 4.86 (2H, s), 7.19 (1H, s), 7.48-7.55 (2H, m), 7.76-7.79 (1H, m), 8.07-8.09 (1H, m).
(88e) エチル　3-メトキシ-1-{[(4-メトキシベンジル)オキシ]メチル}ナフタレン-2-カルボキシレート
　実施例88dで製造したエチル　1-(ブロモメチル)-3-メトキシナフタレン-2-カルボキシレート(2.42 g, 7.49 mmol)、4-メトキシベンジルアルコール(1.02 mL, 8.24 mmol)、DMF (19 mL)及び水素化ナトリウム(55%, 490 mg, 11.2 mmol)を用い、実施例32bに準じて反応及び後処理を行うことにより、標記化合物(2.75 g, 97%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 1.36 (3H, t, J = 7.2 Hz), 3.80 (3H, s), 3.94 (3H, s), 4.38 (2H, q, J = 7.2 Hz), 4.48 (2H, s), 4.92 (2H, s), 6.86 (2H, d, J = 8.6 Hz), 7.16-7.26 (3H, m), 7.38-7.42 (1H, m), 7.47-7.51 (1H, m), 7.75 (1H, d, J = 8.2 Hz), 8.12 (1H, d, J = 8.6 Hz).
(88f) (3-メトキシ-1-{[(4-メトキシベンジル)オキシ]メチル}ナフタレン-2-イル)メタノール
　実施例88eで製造したエチル　3-メトキシ-1-{[(4-メトキシベンジル)オキシ]メチル}ナフタレン-2-カルボキシレート(2.75 g, 7.23 mmol)、トルエン(41 mL)及びジイソブチルアルミニウムヒドリド(1.04 Mトルエン溶液; 16.0 mL, 16.6 mmol)を用い、実施例34aに準じて反応及び後処理を行うことにより、標記化合物(2.42 g, 99%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 3.81 (3H, s), 3.99 (3H, s), 4.61 (2H, s), 4.93 (2H, d, J = 6.6 Hz), 5.05 (2H, s), 6.90 (2H, d, J = 6.6 Hz), 7.18 (1H, s), 7.32 (2H, d, J = 8.6 Hz), 7.35-7.47 (2H, m), 7.74 (1H, d, J = 8.2 Hz), 8.00 (1H, d, J = 8.2 Hz).
(88g) 3-メトキシ-1-{[(4-メトキシベンジル)オキシ]メチル}ナフタレン-2-カルボアルデヒド
　実施例88fで製造した(3-メトキシ-1-{[(4-メトキシベンジル)オキシ]メチル}ナフタレン-2-イル)メタノール(2.42 g, 7.15 mmol)、ジクロロメタン(24 mL)及びデスマーチンペルヨージナン(3.34 g, 7.87 mmol)を用い、実施例34bに準じて反応及び後処理を行うことにより、標記化合物(2.18 g, 91%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 3.80 (3H, s), 3.99 (3H, s), 4.59 (2H, s), 5.22 (2H, s), 6.87 (2H, d, J = 8.6 Hz), 7.19 (1H, s), 7.29 (2H, d, J = 8.2 Hz), 7.39-7.43 (1H, m), 7.50-7.54 (1H, m), 7.73 (1H, d, J = 8.2 Hz), 8.18 (1H, d, J = 8.6 Hz), 10.70 (1H, d, J = 1.2 Hz).
(88h) (3Z,6S)-6-tert-ブチル-3-[(3-メトキシ-1-{[(4-メトキシベンジル)オキシ]メチル}ナフタレン-2-イル)メチリデン]ピペリジン-2,4-ジオン
　実施例88gで製造した3-メトキシ-1-{[(4-メトキシベンジル)オキシ]メチル}ナフタレン-2-カルボアルデヒド(1.08 g, 3.21 mmol)、実施例22cで製造した(6S)-6-tert-ブチルピペリジン-2,4-ジオン(570 mg, 3.37 mmol)及びL-プロリン(37.0 mg, 0.321 mmol)のアセトニトリル(16 mL)溶液を60℃で6時間攪拌した。放冷後、反応溶液に飽和炭酸水素ナトリウム水溶液を加えて、酢酸エチルで2回抽出後、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮し、粗製の標記化合物をジアステレオマーの混合物として得た。
(88i) (3S,10S)-3-tert-ブチル-10-(3-メトキシ-1-{[(4-メトキシベンジル)オキシ]メチル}ナフタレン-2-イル)-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例88hで製造した粗製の(3Z,6S)-6-tert-ブチル-3-[(3-メトキシ-1-{[(4-メトキシベンジル)オキシ]メチル}ナフタレン-2-イル)メチリデン]ピペリジン-2,4-ジオン、ジメドン(450 mg, 3.21 mmol)、DMF (15 mL)、炭酸セシウム(2.51 g, 7.70 mmol)及びN-フェニルビス(トリフルオロメタンスルホンイミド) (1.26 g, 3.53 mmol)を用い、実施例9cに準じて反応及び後処理を行うことにより、標記化合物(661 mg, 34%, 2 steps)をコンフォマーの混合物として得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.46 (3H, t, J = 7.2 Hz), 3.94 (3H, s), 4.52 (2H, q, J = 7.0 Hz), 4.86 (2H, s ), 7.19 (1H, s), 7.48-7.55 (2H, m), 7.76-7.79 (1H, m), 8.07-8.09 (1H, m).
(88e) Ethyl 3-methoxy-1-{[(4-methoxybenzyl) oxy] methyl} naphthalene-2-carboxylate Ethyl 1- (bromomethyl) -3-methoxynaphthalene-2-carboxylate prepared in Example 88d (2.42 g, 7.49 mmol), 4-methoxybenzyl alcohol (1.02 mL, 8.24 mmol), DMF (19 mL) and sodium hydride (55%, 490 mg, 11.2 mmol) were used according to Example 32b And the post-treatment was performed to obtain the title compound (2.75 g, 97%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.36 (3H, t, J = 7.2 Hz), 3.80 (3H, s), 3.94 (3H, s), 4.38 (2H, q, J = 7.2 Hz ), 4.48 (2H, s), 4.92 (2H, s), 6.86 (2H, d, J = 8.6 Hz), 7.16-7.26 (3H, m), 7.38-7.42 (1H, m), 7.47-7.51 ( 1H, m), 7.75 (1H, d, J = 8.2 Hz), 8.12 (1H, d, J = 8.6 Hz).
(88f) (3-Methoxy-1-{[(4-methoxybenzyl) oxy] methyl} naphthalen-2-yl) methanol Ethyl 3-methoxy-1-{[(4-methoxybenzyl) prepared in Example 88e Oxy] methyl} naphthalene-2-carboxylate (2.75 g, 7.23 mmol), toluene (41 mL) and diisobutylaluminum hydride (1.04 M toluene solution; 16.0 mL, 16.6 mmol) were used and reacted according to Example 34a Workup gave the title compound (2.42 g, 99%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 3.81 (3H, s), 3.99 (3H, s), 4.61 (2H, s), 4.93 (2H, d, J = 6.6 Hz), 5.05 (2H , s), 6.90 (2H, d, J = 6.6 Hz), 7.18 (1H, s), 7.32 (2H, d, J = 8.6 Hz), 7.35-7.47 (2H, m), 7.74 (1H, d, J = 8.2 Hz), 8.00 (1H, d, J = 8.2 Hz).
(88 g) 3-Methoxy-1-{[(4-methoxybenzyl) oxy] methyl} naphthalene-2-carbaldehyde (3-Methoxy-1-{[(4-methoxybenzyl) oxy] prepared in Example 88f Methyl} naphthalen-2-yl) methanol (2.42 g, 7.15 mmol), dichloromethane (24 mL) and desmartin periodinane (3.34 g, 7.87 mmol) are used for the reaction and workup according to Example 34b. This gave the title compound (2.18 g, 91%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 3.80 (3H, s), 3.99 (3H, s), 4.59 (2H, s), 5.22 (2H, s), 6.87 (2H, d, J = 8.6 Hz), 7.19 (1H, s), 7.29 (2H, d, J = 8.2 Hz), 7.39-7.43 (1H, m), 7.50-7.54 (1H, m), 7.73 (1H, d, J = 8.2 Hz), 8.18 (1H, d, J = 8.6 Hz), 10.70 (1H, d, J = 1.2 Hz).
(88h) (3Z, 6S) -6-tert-butyl-3-[(3-methoxy-1-{[(4-methoxybenzyl) oxy] methyl} naphthalen-2-yl) methylidene] piperidine-2,4 -Dione 3-methoxy-1-{[(4-methoxybenzyl) oxy] methyl} naphthalene-2-carbaldehyde prepared in Example 88g (1.08 g, 3.21 mmol), (6S)-prepared in Example 22c A solution of 6-tert-butylpiperidine-2,4-dione (570 mg, 3.37 mmol) and L-proline (37.0 mg, 0.321 mmol) in acetonitrile (16 mL) was stirred at 60 ° C. for 6 hours. After allowing to cool, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted twice with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound as a mixture of diastereomers.
(88i) (3S, 10S) -3-tert-butyl-10- (3-methoxy-1-{[(4-methoxybenzyl) oxy] methyl} naphthalen-2-yl) -7,7-dimethyl-3 , 4,6,7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione Crude (3Z, 6S) -6-tert prepared in Example 88h -Butyl-3-[(3-methoxy-1-{[(4-methoxybenzyl) oxy] methyl} naphthalen-2-yl) methylidene] piperidine-2,4-dione, dimedone (450 mg, 3.21 mmol), By reacting and working up according to Example 9c using DMF (15 mL), cesium carbonate (2.51 g, 7.70 mmol) and N-phenylbis (trifluoromethanesulfonimide) (1.26 g, 3.53 mmol) The title compound (661 mg, 34%, 2 steps) was obtained as a mixture of conformers.
　また、副生した(3S,10R)-3-tert-ブチル-10-(3-メトキシ-1-{[(4-メトキシベンジル)オキシ]メチル}ナフタレン-2-イル)-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(357 mg, 18%, 2 steps)をコンフォマーの混合物として得た。
(88j) (3S,10S)-3-tert-ブチル-10-(3-メトキシ-1-{[(4-メトキシベンジル)オキシ]メチル}ナフタレン-2-イル)-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例88iで製造した(3S,10S)-3-tert-ブチル-10-(3-メトキシ-1-{[(4-メトキシベンジル)オキシ]メチル}ナフタレン-2-イル)-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(661 mg, 1.08 mmol)、ヨウ化メチル(540 μL, 8.67 mmol)、DMF (6.6 mL)及び水素化ナトリウム(55%, 70.9 mg, 1.63 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(149 mg, 22%)をコンフォマーの混合物として得た。
(88k) (3S,10S)-3-tert-ブチル-10-[1-(ヒドロキシメチル)-3-メトキシナフタレン-2-イル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例88jで製造した(3S,10S)-3-tert-ブチル-10-(3-メトキシ-1-{[(4-メトキシベンジル)オキシ]メチル}ナフタレン-2-イル)-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(149 mg, 0.239 mmol)、リン酸バッファー(pH 6.86, 0.60 mL)、ジクロロメタン(6.0 mL)及び2,3-ジクロロ-5,6-ジシアノ-1,4-ベンゾキノン(70.5 mg, 0.311 mmol)を用い、実施例32kに準じて反応及び後処理を行うことにより、標記化合物(55.1 mg, 46%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.82 (9H, s), 0.96 (3H, s), 1.10 (3H, s), 2.10 (1H, d, J = 16.4 Hz), 2.22 (1H, d, J = 16.8 Hz), 2.36 (1H, d, J = 17.6 Hz), 2.49 (1H, d, J = 17.6 Hz), 2.56 (1H, d, J = 18.0 Hz), 2.90-2.97 (1H, m), 2.95 (3H, s), 3.15 (1H, d, J = 9.0 Hz), 3.73 (3H, s), 5.54-5.61 (2H, m), 5.63 (1H, s), 5.72 (1H, d, J = 10.9 Hz), 6.95 (1H, s), 7.36-7.41 (2H, m), 7.61-7.63 (1H, m), 8.33-8.36 (1H, m).
(88l) 2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシナフタレン-1-カルボアルデヒド
　実施例88kで製造した(3S,10S)-3-tert-ブチル-10-[1-(ヒドロキシメチル)-3-メトキシナフタレン-2-イル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(55.1 mg, 0.109 mmol)及びnor-AZADO (1.5 mg, 0.0109 mmol)のジクロロメタン(2.2 mL)溶液に室温で(ジアセトキシヨード)ベンゼン(79.1 mg, 0.241 mmol)を加え、室温で18時間攪拌した。反応溶液を減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 1:3)で精製し、標記化合物(42.8 mg, 78%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.83 (9H, s), 0.98 (3H, s), 1.10 (3H, s), 2.12 (1H, d, J = 16.0 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.37 (1H, d, J = 18.0 Hz), 2.49 (1H, d, J = 17.6 Hz), 2.56 (1H, d, J = 18.0 Hz), 2.92 (1H, dt, J = 2.7, 8.6 Hz), 2.97 (3H, s), 3.15 (1H, d, J = 9.0 Hz), 3.77 (3H, s), 5.69 (1H, s), 7.13 (1H, s), 7.42-7.34 (2H, m), 7.62 (1H, d, J = 7.4 Hz), 8.54 (1H, d, J = 7.8 Hz), 11.57 (1H, s).
(88m) 2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシナフタレン-1-カルボン酸
　実施例88lで製造した2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシナフタレン-1-カルボアルデヒド(42.8 mg, 0.0853 mmol)、2-メチル-2-ブテン(201 μL, 1.71 mmol)、リン酸二水素ナトリウム・二水和物(66.6 mg, 0.427 mmol)、ジクロロメタン(0.2 mL)、水(0.4 mL)、tert-ブタノール(1.7 mL)及び亜塩素酸ナトリウム(48.2 mg, 0.427 mmol) を用い、実施例32mに準じて反応及び後処理を行うことにより、標記化合物(36.1 mg, 82%)を得た。 In addition, by-product (3S, 10R) -3-tert-butyl-10- (3-methoxy-1-{[(4-methoxybenzyl) oxy] methyl} naphthalen-2-yl) -7,7-dimethyl -3,4,6,7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (357 mg, 18%, 2 steps) as a mixture of conformers Obtained.
(88j) (3S, 10S) -3-tert-Butyl-10- (3-methoxy-1-{[(4-methoxybenzyl) oxy] methyl} naphthalen-2-yl) -2,7,7-trimethyl -3,4,6,7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (3S, 10S) -3-tert prepared in Example 88i -Butyl-10- (3-methoxy-1-{[(4-methoxybenzyl) oxy] methyl} naphthalen-2-yl) -7,7-dimethyl-3,4,6,7,8,10-hexahydro -1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (661 mg, 1.08 mmol), methyl iodide (540 μL, 8.67 mmol), DMF (6.6 mL) and sodium hydride ( The title compound (149 mg, 22%) was obtained as a mixture of conformers by performing the reaction and post-treatment according to Example 2a using 55%, 70.9 mg, 1.63 mmol).
(88k) (3S, 10S) -3-tert-butyl-10- [1- (hydroxymethyl) -3-methoxynaphthalen-2-yl] -2,7,7-trimethyl-3,4,6,7 , 8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (3S, 10S) -3-tert-butyl-10- (3- Methoxy-1-{[(4-methoxybenzyl) oxy] methyl} naphthalen-2-yl) -2,7,7-trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3 , 2-c] pyridine-1,9 (2H) -dione (149 mg, 0.239 mmol), phosphate buffer (pH 6.86, 0.60 mL), dichloromethane (6.0 mL) and 2,3-dichloro-5,6- The title compound (55.1 mg, 46%) was obtained by carrying out the reaction and post-treatment according to Example 32k using dicyano-1,4-benzoquinone (70.5 mg, 0.311 mmol).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.82 (9H, s), 0.96 (3H, s), 1.10 (3H, s), 2.10 (1H, d, J = 16.4 Hz), 2.22 (1H , d, J = 16.8 Hz), 2.36 (1H, d, J = 17.6 Hz), 2.49 (1H, d, J = 17.6 Hz), 2.56 (1H, d, J = 18.0 Hz), 2.90-2.97 (1H , m), 2.95 (3H, s), 3.15 (1H, d, J = 9.0 Hz), 3.73 (3H, s), 5.54-5.61 (2H, m), 5.63 (1H, s), 5.72 (1H, d, J = 10.9 Hz), 6.95 (1H, s), 7.36-7.41 (2H, m), 7.61-7.63 (1H, m), 8.33-8.36 (1H, m).
(88l) 2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxynaphthalene-1-carbaldehyde Prepared in Example 88k (3S, 10S) -3-tert-butyl-10- [1- ( Hydroxymethyl) -3-methoxynaphthalen-2-yl] -2,7,7-trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1, To a solution of 9 (2H) -dione (55.1 mg, 0.109 mmol) and nor-AZADO (1.5 mg, 0.0109 mmol) in dichloromethane (2.2 mL) at room temperature was added (diacetoxyiodo) benzene (79.1 mg, 0.241 mmol). Stir at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 1: 3) to obtain the title compound (42.8 mg, 78%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.83 (9H, s), 0.98 (3H, s), 1.10 (3H, s), 2.12 (1H, d, J = 16.0 Hz), 2.22 (1H , d, J = 16.4 Hz), 2.37 (1H, d, J = 18.0 Hz), 2.49 (1H, d, J = 17.6 Hz), 2.56 (1H, d, J = 18.0 Hz), 2.92 (1H, dt , J = 2.7, 8.6 Hz), 2.97 (3H, s), 3.15 (1H, d, J = 9.0 Hz), 3.77 (3H, s), 5.69 (1H, s), 7.13 (1H, s), 7.42 -7.34 (2H, m), 7.62 (1H, d, J = 7.4 Hz), 8.54 (1H, d, J = 7.8 Hz), 11.57 (1H, s).
(88m) 2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxynaphthalene-1-carboxylic acid 2-[(3S, 10S) -3-tert-butyl-2,7 prepared in Example 88l , 7-Trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxynaphthalene -1-carbaldehyde (42.8 mg, 0.0853 mmol), 2-methyl-2-butene (201 μL, 1.71 mmol), sodium dihydrogen phosphate dihydrate (66.6 mg, 0.427 mmol), dichloromethane (0.2 mL) ), Water (0.4 mL), tert-butanol (1.7 mL) and sodium chlorite (48.2 mg, 0.427 mmol) were used for the reaction and workup according to Example 32m to give the title compound (36.1 mg 82%).
(実施例89)
　6-{3-[(3R,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボン酸
 (89a) tert-ブチル　6-{3-[(3R,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボキシレート
　実施例87dで製造した(3R,10S)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(100 mg, 0.182 mmol)、tert-ブチル　6-ブロモピリジン-2-カルボキシレート(61.1 mg, 0.237 mmol)、2nd Generation X-Phos Precatalyst (43.0 mg, 0.0546 mmol)、リン酸カリウム(61.8 mg, 0.291 mmol)、THF (1.5 mL)及び水(2.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(83.5 mg, 76%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.95 (9H, s), 0.98 (3H, s), 1.09 (3H, s), 1.64 (9H, s), 2.14 (1H, d, J = 16.4 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.33-2.56 (4H, m), 2.85 (3H, s), 3.23 (1H, dd, J = 5.5, 13.3 Hz), 3.75 (3H, s), 5.10 (1H, s), 5.17 (1H, s), 6.74 (1H, d, J = 8.6 Hz), 7.34 (1H, d, J = 8.6 Hz), 7.54 (1H, d, J = 6.6 Hz), 7.76 (1H, t, J = 7.8 Hz), 7.91 (1H, dd, J = 10.2, 7.8 Hz).
(89b) 6-{3-[(3R,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボン酸
　実施例89aで製造したtert-ブチル　6-{3-[(3R,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボキシレート(83.5 mg, 0.139 mmol)、ジクロロメタン(0.8 mL)及びトリフルオロ酢酸(0.4 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(70.2 mg, 93%)を得た。 Example 89
6- {3-[(3R, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H- Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} pyridine-2-carboxylic acid (89a) tert-butyl 6- {3-[(3R, 10S) -3- tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} pyridine-2-carboxylate (3R, 10S) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4) prepared in Example 87d 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3, 2-c] pyridine-1,9 (2H) -dione (100 mg, 0.182 mmol), tert-butyl 6-bromopyridine-2-carboxylate (61.1 mg, 0.237 mmol), 2nd Generation X-Phos Precatalyst (43.0 mg, 0.0546 mmol), potassium phosphate (61.8 mg, 0.291 mmol), THF (1.5 mL) and water (2.0 mL) By performing the reaction and treatment in accordance with 9d, the title compound was obtained (83.5 mg, 76%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.95 (9H, s), 0.98 (3H, s), 1.09 (3H, s), 1.64 (9H, s), 2.14 (1H, d, J = 16.4 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.33-2.56 (4H, m), 2.85 (3H, s), 3.23 (1H, dd, J = 5.5, 13.3 Hz), 3.75 (3H, s), 5.10 (1H, s), 5.17 (1H, s), 6.74 (1H, d, J = 8.6 Hz), 7.34 (1H, d, J = 8.6 Hz), 7.54 (1H, d, J = 6.6 Hz), 7.76 (1H, t, J = 7.8 Hz), 7.91 (1H, dd, J = 10.2, 7.8 Hz).
(89b) 6- {3-[(3R, 10S) -3-tert-Butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro -1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} pyridine-2-carboxylic acid tert-butyl 6- {3-[(3R prepared in Example 89a , 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] Example 1d using pyridin-10-yl] -4-methoxy-2-methylphenyl} pyridine-2-carboxylate (83.5 mg, 0.139 mmol), dichloromethane (0.8 mL) and trifluoroacetic acid (0.4 mL). The title compound (70.2 mg, 93%) was obtained by carrying out the reaction and post-treatment in the same manner.
(実施例90)
　6-{3-[(3R,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボン酸
(90a) tert-ブチル　6-{3-[(3R,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボキシレート
　実施例87dで製造した(3R,10S)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(100 mg, 0.182 mmol)、tert-ブチル　6-クロロ-4-メチルピリジン-2-カルボキシレート(53.9 mg, 0.237 mmol)、2nd Generation X-Phos Precatalyst (43.0 mg, 0.0546 mmol)、リン酸カリウム(61.8 mg, 0.291 mmol)、THF (1.5 mL)及び水(2.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(90.2 mg, 81%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.95 (9H, s), 0.98 (3H, s), 1.09 (3H, s), 1.63 (9H, s), 2.14 (1H, d, J = 15.6 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.33-2.56 (4H, m), 2.42 (3H, s), 2.84 (3H, s), 3.24 (1H, dd, J = 5.3, 13.5 Hz), 3.75 (3H, s), 5.10 (1H, s), 5.16 (1H, s), 6.72 (1H, d, J = 8.6 Hz), 7.31 (1H, d, J = 8.6 Hz), 7.35 (1H, s), 7.73 (1H, s).
(90b) 6-{3-[(3R,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボン酸
　実施例90aで製造したtert-ブチル　6-{3-[(3R,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-4-メチルピリジン-2-カルボキシレート(90.2 mg, 0.147 mmol)、ジクロロメタン(0.9 mL)及びトリフルオロ酢酸(0.5 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(60.9 mg, 74%)を得た。 Example 90
6- {3-[(3R, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H- Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -4-methylpyridine-2-carboxylic acid
(90a) tert-butyl 6- {3-[(3R, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9, 10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -4-methylpyridine-2-carboxylate prepared in Example 87d (3R, 10S ) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7, 7-dimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (100 mg, 0.182 mmol), tert-butyl 6 -Chloro-4-methylpyridine-2-carboxylate (53.9 mg, 0.237 mmol), 2nd Generation X-Phos Precatalyst (43.0 mg, 0.0546 mmol), potassium phosphate (61.8 mg, 0.291 mmol), THF (1.5 mL) And water (2.0 mL) were used for the reaction and post-treatment according to Example 9d to obtain the title compound (90.2 mg, 81%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.95 (9H, s), 0.98 (3H, s), 1.09 (3H, s), 1.63 (9H, s), 2.14 (1H, d, J = 15.6 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.33-2.56 (4H, m), 2.42 (3H, s), 2.84 (3H, s), 3.24 (1H, dd, J = 5.3, 13.5 Hz), 3.75 (3H, s), 5.10 (1H, s), 5.16 (1H, s), 6.72 (1H, d, J = 8.6 Hz), 7.31 (1H, d, J = 8.6 Hz), 7.35 ( 1H, s), 7.73 (1H, s).
(90b) 6- {3-[(3R, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro -1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -4-methylpyridine-2-carboxylic acid tert-butyl 6- {3 prepared in Example 90a -[(3R, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3, 2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -4-methylpyridine-2-carboxylate (90.2 mg, 0.147 mmol), dichloromethane (0.9 mL) and trifluoroacetic acid (0.5 mL) The title compound (60.9 mg, 74%) was obtained by carrying out the reaction and post-treatment according to Example 1d.
(実施例91)
　6-{4-メトキシ-2-メチル-3-[(3S,10S)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
(91a) (3S,10S)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン
　実施例42bで製造した(6S)-3-{(S)-(6,8-ジオキソスピロ[3.5]ノナ-7-イル)[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]メチル}-6-(プロパン-2-イル)ピペリジン-2,4-ジオン(1.00 g, 1.77 mmol)、酢酸エチル(20 mL)及び4 M塩酸(ジオキサン溶液; 5 mL, 20 mmol)を用い、実施例77bに準じて反応及び後処理を行うことにより、標記化合物(858 mg, 89%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.83 (3H, d, J = 6.7 Hz), 0.89 (3H, d, J = 6.4 Hz), 1.30 (12H, s), 1.64-1.89 (7H, m), 2.34 (1H, d, J = 16.4 Hz), 2.43-2.67 (5H, m), 3.09 (3H, s), 3.18-3.24 (1H, m), 3.67 (3H, s), 5.09 (1H, s), 5.22 (1H, s), 6.55 (1H, d, J = 8.5 Hz), 7.56 (1H, d, J = 8.5 Hz).
(91b) (3S,10S)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2-メチル-3-(プロパン-2-イル)-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン
　実施例91aで製造した(3S,10S)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン(355 mg, 0.648 mmol)、ヨウ化メチル(330 μL, 5.30 mmol)、DMF (6.0 mL)及び水素化ナトリウム(63%, 50.0 mg, 1.31 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(280 mg, 77%)を得た。 Example 91
6- {4-Methoxy-2-methyl-3-[(3S, 10S) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,6, 8,9,10-Octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid
(91a) (3S, 10S) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3 -(Propan-2-yl) -3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H) -dione Examples (6S) -3-{(S)-(6,8-Dioxospiro [3.5] non-7-yl) [6-methoxy-2-methyl-3- (4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] methyl} -6- (propan-2-yl) piperidine-2,4-dione (1.00 g, 1.77 mmol), ethyl acetate (20 mL) And 4M hydrochloric acid (dioxane solution; 5 mL, 20 mmol) was used for the reaction and post-treatment according to Example 77b to obtain the title compound (858 mg, 89%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.83 (3H, d, J = 6.7 Hz), 0.89 (3H, d, J = 6.4 Hz), 1.30 (12H, s), 1.64-1.89 (7H , m), 2.34 (1H, d, J = 16.4 Hz), 2.43-2.67 (5H, m), 3.09 (3H, s), 3.18-3.24 (1H, m), 3.67 (3H, s), 5.09 ( 1H, s), 5.22 (1H, s), 6.55 (1H, d, J = 8.5 Hz), 7.56 (1H, d, J = 8.5 Hz).
(91b) (3S, 10S) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2 -Methyl-3- (propan-2-yl) -3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H) -Dione (3S, 10S) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) prepared in Example 91a ) Phenyl] -3- (propan-2-yl) -3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H ) -Dione (355 mg, 0.648 mmol), methyl iodide (330 μL, 5.30 mmol), DMF (6.0 mL) and sodium hydride (63%, 50.0 mg, 1.31 mmol) according to Example 2a The title compound (280 mg, 77%) was obtained by reaction and workup.
1H-NMR(400MHz, CDCl3):δ ppm: 0.80 (6H, d, J = 6.1 Hz), 1.31 (12H, s), 1.64-1.96 (7H, m), 2.33 (1H, d, J = 16.4 Hz), 2.43 (1H, d, J = 16.4 Hz), 2.44 (1H, d, J = 16.4 Hz), 2.55 (1H, d, J = 17.6 Hz), 2.62 (1H, d, J = 17.0 Hz), 2.84 (1H, ddd, J = 1.8, 7.9, 17.0 Hz), 2.93 (3H, s), 3.06 (1H, dd, J = 7.0, 14.3 Hz), 3.13 (3H, s), 3.64 (3H, s), 5.20 (1H, s), 6.52 (1H, d, J = 8.5 Hz), 7.55 (1H, d, J = 8.5 Hz).
(91c) ベンジル　6-{4-メトキシ-2-メチル-3-[(3S,10S)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例91bで製造した(3S,10S)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2-メチル-3-(プロパン-2-イル)-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン(280 mg, 0.498 mmol)、ベンジル　6-クロロ-3-メチルピリジン-2-カルボキシレート(170 mg, 0.648 mmol)、2nd Generation X-Phos Precatalyst (78.0 mg, 0.0991 mmol)、リン酸カリウム(161 mg, 0.758 mmol)、THF (3.0 mL)及び水(6.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(241 mg, 73%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.85 (6H, t, J = 7.3 Hz), 1.67-2.00 (7H, m), 2.35 (1H, d, J = 16.5 Hz), 2.46 (1H, d, J = 17.1 Hz), 2.47 (1H, d, J = 16.5 Hz), 2.52 (3H, s), 2.57 (1H, d, J = 17.7 Hz), 2.65 (1H, d, J = 17.1 Hz), 2.83-2.90 (1H, m), 2.87 (3H, s), 2.94 (3H, s), 3.07 (1H, t, J = 7.0 Hz), 3.68 (3H, s), 5.20 (1H, s), 5.42 (1H, d, J = 12.2 Hz), 5.46 (1H, d, J = 12.2 Hz), 6.64 (1H, d, J = 8.5 Hz), 7.24 (1H, d, J = 8.5 Hz), 7.29-7.57 (7H, m).
(91d) 6-{4-メトキシ-2-メチル-3-[(3S,10S)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例91cで製造したベンジル　6-{4-メトキシ-2-メチル-3-[(3S,10S)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(241 mg, 0.364 mmol)、パラジウム炭素(10%, 25.0 mg)、酢酸エチル(3.0 mL)及びメタノール(3.0 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(196 mg, 94%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.80 (6H, d, J = 6.1 Hz), 1.31 (12H, s), 1.64-1.96 (7H, m), 2.33 (1H, d, J = 16.4 Hz), 2.43 (1H, d, J = 16.4 Hz), 2.44 (1H, d, J = 16.4 Hz), 2.55 (1H, d, J = 17.6 Hz), 2.62 (1H, d, J = 17.0 Hz) ), 2.84 (1H, ddd, J = 1.8, 7.9, 17.0 Hz), 2.93 (3H, s), 3.06 (1H, dd, J = 7.0, 14.3 Hz), 3.13 (3H, s), 3.64 (3H, s), 5.20 (1H, s), 6.52 (1H, d, J = 8.5 Hz), 7.55 (1H, d, J = 8.5 Hz).
(91c) Benzyl 6- {4-methoxy-2-methyl-3-[(3S, 10S) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3, 4,6,8,9,10-Octahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate Examples (3S, 10S) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]-prepared in 91b 2-Methyl-3- (propan-2-yl) -3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H ) -Dione (280 mg, 0.498 mmol), benzyl 6-chloro-3-methylpyridine-2-carboxylate (170 mg, 0.648 mmol), 2nd Generation X-Phos Precatalyst (78.0 mg, 0.0991 mmol), potassium phosphate (161 mg, 0.758 mmol), THF (3.0 mL) and water (6.0 mL) were used, and the reaction and post-treatment were performed according to Example 9d to obtain the title compound (241 mg, 73%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.85 (6H, t, J = 7.3 Hz), 1.67-2.00 (7H, m), 2.35 (1H, d, J = 16.5 Hz), 2.46 (1H , d, J = 17.1 Hz), 2.47 (1H, d, J = 16.5 Hz), 2.52 (3H, s), 2.57 (1H, d, J = 17.7 Hz), 2.65 (1H, d, J = 17.1 Hz ), 2.83-2.90 (1H, m), 2.87 (3H, s), 2.94 (3H, s), 3.07 (1H, t, J = 7.0 Hz), 3.68 (3H, s), 5.20 (1H, s) , 5.42 (1H, d, J = 12.2 Hz), 5.46 (1H, d, J = 12.2 Hz), 6.64 (1H, d, J = 8.5 Hz), 7.24 (1H, d, J = 8.5 Hz), 7.29 -7.57 (7H, m).
(91d) 6- {4-Methoxy-2-methyl-3-[(3S, 10S) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4 , 6,8,9,10-Octahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid Example 91c Benzyl 6- {4-methoxy-2-methyl-3-[(3S, 10S) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3, 4,6,8,9,10-Octahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate (241 mg, 0.364 mmol), palladium on carbon (10%, 25.0 mg), ethyl acetate (3.0 mL) and methanol (3.0 mL) were used for the reaction and workup according to Example 18 to obtain the title compound (196 mg, 94%).
(実施例92)
　6-{3-[(3S,10S)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
(92a) (3S,10S)-2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン
　実施例91aで製造した(3S,10S)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン(500 mg, 0.913 mmol)、ヨウ化エチル(580 μL, 7.30 mmol)、DMPU (6.0 mL)及び水素化ナトリウム(63%, 52.5 mg, 1.38 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(366 mg, 70%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.77 (3H, d, J = 6.7 Hz), 0.82 (3H, d, J = 6.1 Hz), 1.08 (3H, t, J = 7.0 Hz), 1.31 (12H, s), 1.62-1.89 (7H, m), 2.33 (1H, d, J = 16.4 Hz), 2.44 (1H, d, J = 15.2 Hz), 2.50-2.60 (4H, m), 2.74-2.81 (1H, m), 3.05 (1H, t, J = 7.0 Hz), 3.13 (3H, s), 3.64 (3H, s), 4.04-4.15 (1H, m), 5.23 (1H, s), 6.52 (1H, d, J = 7.9 Hz), 7.54 (1H, d, J = 7.9 Hz).
(92b) ベンジル　6-{3-[(3S,10S)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例92aで製造した(3S,10S)-2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン(366 mg, 0.636 mmol)、ベンジル　6-クロロ-3-メチルピリジン-2-カルボキシレート(307 mg, 0.454 mmol)、2nd Generation X-Phos Precatalyst (103 mg, 0.130 mmol)、リン酸カリウム(212 mg, 0.999 mmol)、THF (3.0 mL)及び水(6.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(307 mg, 71%)を得た。 (Example 92)
6- {3-[(3S, 10S) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,6,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid
(92a) (3S, 10S) -2-Ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenyl] -3- (propan-2-yl) -3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H) -Dione (3S, 10S) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) prepared in Example 91a ) Phenyl] -3- (propan-2-yl) -3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H ) -Dione (500 mg, 0.913 mmol), ethyl iodide (580 μL, 7.30 mmol), DMPU (6.0 mL) and sodium hydride (63%, 52.5 mg, 1.38 mmol) according to Example 2a The title compound (366 mg, 70%) was obtained by carrying out the reaction and post-treatment.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.77 (3H, d, J = 6.7 Hz), 0.82 (3H, d, J = 6.1 Hz), 1.08 (3H, t, J = 7.0 Hz), 1.31 (12H, s), 1.62-1.89 (7H, m), 2.33 (1H, d, J = 16.4 Hz), 2.44 (1H, d, J = 15.2 Hz), 2.50-2.60 (4H, m), 2.74 -2.81 (1H, m), 3.05 (1H, t, J = 7.0 Hz), 3.13 (3H, s), 3.64 (3H, s), 4.04-4.15 (1H, m), 5.23 (1H, s), 6.52 (1H, d, J = 7.9 Hz), 7.54 (1H, d, J = 7.9 Hz).
(92b) Benzyl 6- {3-[(3S, 10S) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,6,8,9, 10-Octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate Examples (3S, 10S) -2-Ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) prepared in 92a ) Phenyl] -3- (propan-2-yl) -3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H ) -Dione (366 mg, 0.636 mmol), benzyl 6-chloro-3-methylpyridine-2-carboxylate (307 mg, 0.454 mmol), 2nd Generation X-Phos Precatalyst (103 mg, 0.130 mmol), potassium phosphate (212 mg, 0.999 mmol), THF (3.0 mL) and water (6.0 mL) were used to carry out the reaction and post-treatment according to Example 9d to obtain the title compound (307 mg, 71%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.83 (3H, d, J = 6.7 Hz), 0.86 (3H, d, J = 6.7 Hz), 1.09 (3H, t, J = 7.0 Hz), 1.70-1.94 (7H, m), 2.35 (1H, d, J = 16.4 Hz), 2.47 (1H, d, J = 15.8 Hz), 2.52 (3H, s), 2.52-2.67 (4H, m), 2.75-2.82 (1H, m), 2.87 (3H, s), 3.07 (1H, t, J = 7.0 Hz), 3.68 (3H, s), 4.02-4.09 (1H, m), 5.22 (1H, s), 5.41 (1H, d, J = 12.1 Hz), 5.46 (1H, d, J = 12.8 Hz), 6.64 (1H, d, J = 9.1 Hz), 7.24 (1H, d, J = 8.5 Hz), 7.29-7.57 (7H, m).
(92c) 6-{3-[(3S,10S)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例92bで製造したベンジル　6-{3-[(3S,10S)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(307 mg, 0.454 mmol)、パラジウム炭素(10%, 35.0 mg)、酢酸エチル(4.0 mL)及びメタノール(4.0 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(166 mg, 63%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.83 (3H, d, J = 6.7 Hz), 0.86 (3H, d, J = 6.7 Hz), 1.09 (3H, t, J = 7.0 Hz), 1.70-1.94 (7H, m), 2.35 (1H, d, J = 16.4 Hz), 2.47 (1H, d, J = 15.8 Hz), 2.52 (3H, s), 2.52-2.67 (4H, m), 2.75 -2.82 (1H, m), 2.87 (3H, s), 3.07 (1H, t, J = 7.0 Hz), 3.68 (3H, s), 4.02-4.09 (1H, m), 5.22 (1H, s), 5.41 (1H, d, J = 12.1 Hz), 5.46 (1H, d, J = 12.8 Hz), 6.64 (1H, d, J = 9.1 Hz), 7.24 (1H, d, J = 8.5 Hz), 7.29- 7.57 (7H, m).
(92c) 6- {3-[(3S, 10S) -2-Ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,6,8,9,10 -Octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid Example 92b Benzyl 6- {3-[(3S, 10S) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,6,8,9, 10-octahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (307 mg, 0.454 mmol), palladium on carbon (10%, 35.0 mg), ethyl acetate (4.0 mL) and methanol (4.0 mL), and the reaction and workup according to Example 18 gave the title compound (166 mg, 63%).
(実施例93)
　6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
(93a) 6-{3-[(3S,4aS,10S,10aR)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例76bで製造した6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}ピリジン-2-カルボン酸(43.5 mg, 0.0776 mmol)、カルボニルジイミダゾール(16.4 mg, 0.101 mmol)、DMF (0.4 mL)、メタンスルホンアミド(11.8 mg, 0.124 mmol)及びDBU (19 μL, 0.124 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(38.9 mg, 79%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.93 (12H, s), 1.04 (3H, s), 1.95-2.06 (2H, m), 2.14 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 16.8 Hz), 2.35 (1H, dd, J = 2.0, 17.2 Hz), 2.57-2.67 (1H, m), 2.82 (3H, s), 2.95 (3H, s), 3.26 (1H, dd, J = 6.7, 10.6 Hz), 3.33-3.38 (1H, m), 3.37 (3H, s), 3.71-3.78 (1H, m), 3.74 (3H, s), 4.57 (1H, d, J = 9.8 Hz), 6.71 (1H, d, J = 8.6 Hz), 7.18 (1H, d, J = 8.2 Hz), 7.72 (1H, dd, J = 7.8, 1.2 Hz), 7.88 (1H, t, J = 7.6 Hz), 8.11 (1H, dd, J = 1.6, 7.4 Hz).
MS(ESI/APCI)m/z: 638[M+H]+.
(93b) 6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
　実施例93aで製造した6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-N-(メチルスルホニル)ピリジン-2-カルボキサミド(38.9 mg, 0.0610 mmol)、酢酸エチル(0.8 mL)及びtert-ブチルアミン(8 μL, 0.0732 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(23.5 mg, 54%)を得た。 (Example 93)
6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7,8, 9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -N- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt
(93a) 6- {3-[(3S, 4aS, 10S, 10aR) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6 , 8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methyl -N- (methylsulfonyl) pyridine-2-carboxamide 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1, prepared in Example 76b 9-Dioxo-2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methyl Phenyl} pyridine-2-carboxylic acid (43.5 mg, 0.0776 mmol), carbonyldiimidazole (16.4 mg, 0.101 mmol), DMF (0.4 mL), methanesulfonamide (11.8 mg, 0.124 mmol) and DBU (19 μL, 0.124 The title compound (38.9 mg, 79%) was obtained by reaction and workup according to Example 6a.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.93 (12H, s), 1.04 (3H, s), 1.95-2.06 (2H, m), 2.14 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 16.8 Hz), 2.35 (1H, dd, J = 2.0, 17.2 Hz), 2.57-2.67 (1H, m), 2.82 (3H, s), 2.95 (3H, s), 3.26 ( 1H, dd, J = 6.7, 10.6 Hz), 3.33-3.38 (1H, m), 3.37 (3H, s), 3.71-3.78 (1H, m), 3.74 (3H, s), 4.57 (1H, d, J = 9.8 Hz), 6.71 (1H, d, J = 8.6 Hz), 7.18 (1H, d, J = 8.2 Hz), 7.72 (1H, dd, J = 7.8, 1.2 Hz), 7.88 (1H, t, J = 7.6 Hz), 8.11 (1H, dd, J = 1.6, 7.4 Hz).
MS (ESI / APCI) m / z: 638 [M + H] +.
(93b) 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-Butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7 , 8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -N- (methylsulfonyl) pyridine-2-carboxamide tert -Butylamine salt 6- {3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4 prepared in Example 93a , 4a, 6,7,8,9,10,10a-Decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -N- (methylsulfonyl) The title compound was prepared by carrying out the reaction and post-treatment according to Example 3c using pyridine-2-carboxamide (38.9 mg, 0.0610 mmol), ethyl acetate (0.8 mL) and tert-butylamine (8 μL, 0.0732 mmol). (23.5 mg, 54%) was obtained.
(実施例94)
　6-{3-[(3R,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
(94a) 6-{3-[(3R,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例87fで製造した6-{3-[(3R,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(40.0 mg, 0.0716 mmol)、カルボニルジイミダゾール(15.1 mg, 0.0931 mmol)、DMF (0.8 mL)、メタンスルホンアミド(10.9 mg, 0.115 mmol)及びDBU (17 μL, 0.112 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(32.1 mg, 71%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.95 (9H, s), 1.00 (3H, s), 1.11 (3H, s), 2.16 (1H, d, J = 17.2 Hz), 2.23 (1H, d, J = 16.4 Hz), 2.33-2.53 (4H, m), 2.77 (3H, s), 2.84 (3H, s), 3.25 (1H, dd, J = 5.3, 13.5 Hz), 3.38 (3H, s), 3.78 (3H, s), 5.15 (1H, s), 5.26 (1H, s), 6.77 (1H, d, J = 8.6 Hz), 7.21 (1H, d, J = 8.6 Hz), 7.54 (1H, t, J = 9.2 Hz), 7.66 (1H, d, J = 8.2 Hz).
MS(ESI/APCI)m/z: 636[M+H]+.
(94b) 6-{3-[(3R,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド　tert-ブチルアミン塩
　実施例94aで製造した6-{3-[(3R,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド(22.0 mg, 0.0346 mmol)、酢酸エチル(0.4 mL)及びtert-ブチルアミン(4 μL, 0.0381 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(23.5 mg, 96%)を得た。 Example 94
6- {3-[(3R, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H- Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt
(94a) 6- {3-[(3R, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro -1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide prepared in Example 87f 6 -{3-[(3R, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid (40.0 mg, 0.0716 mmol), carbonyldiimidazole (15.1 mg, 0.0931 mmol) ), DMF (0.8 mL), methanesulfonamide (10.9 mg, 0.115 mmol) and DBU (17 μL, 0.112 mmol) were used for the reaction and workup according to Example 6a to give the title compound (32.1 mg , 71%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.95 (9H, s), 1.00 (3H, s), 1.11 (3H, s), 2.16 (1H, d, J = 17.2 Hz), 2.23 (1H , d, J = 16.4 Hz), 2.33-2.53 (4H, m), 2.77 (3H, s), 2.84 (3H, s), 3.25 (1H, dd, J = 5.3, 13.5 Hz), 3.38 (3H, s), 3.78 (3H, s), 5.15 (1H, s), 5.26 (1H, s), 6.77 (1H, d, J = 8.6 Hz), 7.21 (1H, d, J = 8.6 Hz), 7.54 ( 1H, t, J = 9.2 Hz), 7.66 (1H, d, J = 8.2 Hz).
MS (ESI / APCI) m / z: 636 [M + H] +.
(94b) 6- {3-[(3R, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro -1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt Example 94a 6- {3-[(3R, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro -1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide (22.0 mg, 0.0346 mmol) , Ethyl acetate (0.4 mL) and tert-butylamine (4 μL, 0.0381 mmol) were used for the reaction and post-treatment according to Example 3c to obtain the title compound (23.5 mg, 96%).
(実施例95)
　2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシ-6-(1-メチル-1H-ピラゾール-3-イル)安息香酸
(95a) (3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1-メチル-1H-ピラゾール-3-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例34fで製造した(3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(165 mg, 0.236 mmol)、3-ブロモ-1-メチル-1H-ピラゾール(75.9 mg, 0.472 mmol)、2nd Generation X-Phos Precatalyst (37.1 mg, 0.0472 mmol)、リン酸カリウム(115 mg, 0.542 mmol)、THF (5.0 mL)及び水(2.5 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(90.0 mg, 58%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.79 (9H, s), 0.98 (3H, s), 1.09 (3H, s), 2.21 (2H, s), 2.35 (1H, d, J = 17.6 Hz), 2.46 (1H, d, J = 17.6 Hz), 2.52 (1H, d, J = 18.0 Hz), 2.85-2.91 (1H, m), 2.97 (3H, s), 3.10 (1H, d, J = 8.6 Hz), 3.62 (3H, s), 3.80 (3H, s), 3.88 (3H, s), 4.59 (1H, d, J = 11.3 Hz), 4.79 (2H, t, J = 10.6 Hz), 5.49 (1H, s), 5.56 (1H, d, J = 10.6 Hz), 6.66 (1H, d, J = 8.6 Hz), 6.69 (1H, d, J = 2.3 Hz), 6.84 (2H, d, J = 8.6 Hz), 7.25 (1H, d, J = 2.3 Hz), 7.34 (1H, d, J = 8.2 Hz), 7.44 (2H, d, J = 9.0 Hz).
(95b) (3S,10S)-3-tert-ブチル-10-[2-(ヒドロキシメチル)-6-メトキシ-3-(1-メチル-1H-ピラゾール-3-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例95aで製造した(3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1-メチル-1H-ピラゾール-3-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(90.0 mg, 0.138 mmol)、リン酸バッファー(pH6.86, 0.40 mL)、ジクロロメタン(2.0 mL)及び2,3-ジクロロ-5,6-ジシアノ-1,4-ベンゾキノン(37.5 mg, 0.165 mmol)を用い、実施例32kに準じて反応及び後処理を行うことにより、標記化合物(53.8 mg, 73%)を得た。 (Example 95)
2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxy-6- (1-methyl-1H-pyrazol-3-yl) benzoic acid
(95a) (3S, 10S) -3-tert-butyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1-methyl-1H-pyrazole-3- Yl) phenyl] -2,7,7-trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione Example 34f (3S, 10S) -3-tert-butyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4,5,5-tetramethyl) -1,3,2-dioxaborolan-2-yl) phenyl] -2,7,7-trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine- 1,9 (2H) -dione (165 mg, 0.236 mmol), 3-bromo-1-methyl-1H-pyrazole (75.9 mg, 0.472 mmol), 2nd Generation X-Phos Precatalyst (37.1 mg, 0.0472 mmol), phosphorus The title compound (90.0 mg, 58%) was obtained by performing reaction and post-treatment according to Example 9d using potassium acid (115 mg, 0.542 mmol), THF (5.0 mL) and water (2.5 mL). It was.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.79 (9H, s), 0.98 (3H, s), 1.09 (3H, s), 2.21 (2H, s), 2.35 (1H, d, J = 17.6 Hz), 2.46 (1H, d, J = 17.6 Hz), 2.52 (1H, d, J = 18.0 Hz), 2.85-2.91 (1H, m), 2.97 (3H, s), 3.10 (1H, d, J = 8.6 Hz), 3.62 (3H, s), 3.80 (3H, s), 3.88 (3H, s), 4.59 (1H, d, J = 11.3 Hz), 4.79 (2H, t, J = 10.6 Hz) , 5.49 (1H, s), 5.56 (1H, d, J = 10.6 Hz), 6.66 (1H, d, J = 8.6 Hz), 6.69 (1H, d, J = 2.3 Hz), 6.84 (2H, d, J = 8.6 Hz), 7.25 (1H, d, J = 2.3 Hz), 7.34 (1H, d, J = 8.2 Hz), 7.44 (2H, d, J = 9.0 Hz).
(95b) (3S, 10S) -3-tert-butyl-10- [2- (hydroxymethyl) -6-methoxy-3- (1-methyl-1H-pyrazol-3-yl) phenyl] -2,7 , 7-Trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione prepared in Example 95a (3S, 10S) -3-tert-butyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1-methyl-1H-pyrazol-3-yl) phenyl] -2,7 , 7-Trimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (90.0 mg, 0.138 mmol), phosphate buffer (pH 6.86, 0.40 mL), dichloromethane (2.0 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (37.5 mg, 0.165 mmol), and the reaction according to Example 32k and The title compound (53.8 mg, 73%) was obtained by post-treatment.
1H-NMR(400MHz, CDCl3):δ ppm: 0.84 (9H, s), 0.95 (3H, s), 1.09 (3H, s), 2.13 (1H, d, J = 16.4 Hz), 2.23 (1H, d, J = 16.4 Hz), 2.35 (1H, d, J = 17.6 Hz), 2.48 (1H, d, J = 17.2 Hz), 2.55 (1H, d, J = 18.0 Hz), 2.92 (1H, dd, J = 9.0, 16.0 Hz), 2.99 (3H, s), 3.15 (1H, d, J = 8.6 Hz), 3.64 (3H, s), 3.93 (3H, s), 5.19-5.30 (2H, m), 5.37 (1H, s), 5.97 (1H, s), 6.70 (1H, d, J = 8.6 Hz), 6.87 (1H, d, J = 2.0 Hz), 7.35 (1H, d, J = 2.3 Hz), 7.48 (1H, d, J = 8.6 Hz).
(95c) 2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシ-6-(1-メチル-1H-ピラゾール-3-イル)ベンズアルデヒド
　実施例95bで製造した(3S,10S)-3-tert-ブチル-10-[2-(ヒドロキシメチル)-6-メトキシ-3-(1-メチル-1H-ピラゾール-3-イル)フェニル]-2,7,7-トリメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(53.8 mg, 0.101 mmol)、ジクロロメタン(2.0 mL)及びデスマーチンペルヨージナン(128 mg, 0.302 mmol)を用い、実施例32lに準じて反応及び後処理を行うことにより、標記化合物(44.6 mg, 83%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.83 (9H, s), 0.99 (3H, s), 1.10 (3H, s), 2.13 (1H, d, J = 16.4 Hz), 2.23 (1H, d, J = 16.0 Hz), 2.32 (1H, d, J = 17.6 Hz), 2.45 (1H, d, J = 16.4 Hz), 2.50 (1H, d, J = 17.6 Hz), 2.88 (1H, ddd, J = 2.3, 9.0, 18.0 Hz), 2.96 (3H, s), 3.12 (1H, d, J = 8.6 Hz), 3.66 (3H, s), 3.91 (3H, s), 5.56 (1H, s), 6.33 (1H, d, J = 2.3 Hz), 6.82 (1H, d, J = 8.6 Hz), 7.31 (1H, d, J = 2.3 Hz), 7.43 (1H, d, J = 9.0 Hz), 10.69 (1H, s).
(95d) 2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシ-6-(1-メチル-1H-ピラゾール-3-イル)安息香酸
　実施例95cで製造した2-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシ-6-(1-メチル-1H-ピラゾール-3-イル)ベンズアルデヒド(44.6 mg, 0.0839 mmol)、2-メチル-2-ブテン(188 μL, 1.68 mmol)、りん酸二水素ナトリウム二水和物(65.4 mg, 0.419 mmol)、水(500 μL)、tert-ブタノール(2.0 mL)、ジクロロメタン(250 μL)及び亜塩素酸ナトリウム(47.4 mg, 0.419 mmol) を用い、実施例32mに準じて反応及び後処理を行うことにより、標記化合物(37.3 mg, 81%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.84 (9H, s), 0.95 (3H, s), 1.09 (3H, s), 2.13 (1H, d, J = 16.4 Hz), 2.23 (1H , d, J = 16.4 Hz), 2.35 (1H, d, J = 17.6 Hz), 2.48 (1H, d, J = 17.2 Hz), 2.55 (1H, d, J = 18.0 Hz), 2.92 (1H, dd , J = 9.0, 16.0 Hz), 2.99 (3H, s), 3.15 (1H, d, J = 8.6 Hz), 3.64 (3H, s), 3.93 (3H, s), 5.19-5.30 (2H, m) , 5.37 (1H, s), 5.97 (1H, s), 6.70 (1H, d, J = 8.6 Hz), 6.87 (1H, d, J = 2.0 Hz), 7.35 (1H, d, J = 2.3 Hz) , 7.48 (1H, d, J = 8.6 Hz).
(95c) 2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxy-6- (1-methyl-1H-pyrazol-3-yl) benzaldehyde (3S, 10S) -3 prepared in Example 95b -tert-butyl-10- [2- (hydroxymethyl) -6-methoxy-3- (1-methyl-1H-pyrazol-3-yl) phenyl] -2,7,7-trimethyl-3,4,6 , 7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (53.8 mg, 0.101 mmol), dichloromethane (2.0 mL) and desmartin periodinane (128 The title compound (44.6 mg, 83%) was obtained by carrying out the reaction and post-treatment according to Example 32l using mg, 0.302 mmol).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.83 (9H, s), 0.99 (3H, s), 1.10 (3H, s), 2.13 (1H, d, J = 16.4 Hz), 2.23 (1H , d, J = 16.0 Hz), 2.32 (1H, d, J = 17.6 Hz), 2.45 (1H, d, J = 16.4 Hz), 2.50 (1H, d, J = 17.6 Hz), 2.88 (1H, ddd , J = 2.3, 9.0, 18.0 Hz), 2.96 (3H, s), 3.12 (1H, d, J = 8.6 Hz), 3.66 (3H, s), 3.91 (3H, s), 5.56 (1H, s) , 6.33 (1H, d, J = 2.3 Hz), 6.82 (1H, d, J = 8.6 Hz), 7.31 (1H, d, J = 2.3 Hz), 7.43 (1H, d, J = 9.0 Hz), 10.69 (1H, s).
(95d) 2-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxy-6- (1-methyl-1H-pyrazol-3-yl) benzoic acid 2-[(3S, prepared in Example 95c 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c ] Pyridin-10-yl] -3-methoxy-6- (1-methyl-1H-pyrazol-3-yl) benzaldehyde (44.6 mg, 0.0839 mmol), 2-methyl-2-butene (188 μL, 1.68 mmol) , Sodium dihydrogen phosphate dihydrate (65.4 mg, 0.419 mmol), water (500 μL), tert-butanol (2.0 mL), dichloromethane (250 μL) and sodium chlorite (47.4 mg, 0.419 mmol). The title compound (37.3 mg, 81%) was obtained by using the reaction and post-treatment according to Example 32m.
(実施例96)
　2-[(3S,10S)-3-tert-ブチル-2-エチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシ-6-(1H-ピラゾール-1-イル)安息香酸
(96a) (3S,10S)-3-tert-ブチル-2-エチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例34eで製造した(3S,10S)-3-tert-ブチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(600 mg, 0.875 mmol)、ヨウ化エチル(560 μL, 7.00 mmol)、DMPU (8.0 mL)及び水素化ナトリウム(63%, 107 mg, 2.81 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(295 mg, 47%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.79 (9H, s), 0.95 (3H, s), 1.05 (3H, t, J = 6.1 Hz), 1.07 (3H, s), 1.24 (12H, s), 2.09 (1H, d, J = 16.4 Hz), 2.16 (1H, d, J = 15.2 Hz), 2.31 (1H, d, J = 17.6 Hz), 2.40 (1H, d, J = 17.0 Hz), 2.51-2.67 (2H, m), 2.76 (1H, dd, J = 7.9, 17.0 Hz), 3.06-3.17 (1H, m), 3.59 (3H, s), 3.79 (3H, s), 4.09-4.15 (1H, m), 4.61 (1H, d, J = 12.1 Hz), 4.65 (1H, d, J = 12.1 Hz), 5.07 (1H, s), 5.35 (1H, d, J = 14.0 Hz), 5.43 (1H, d, J = 13.4 Hz), 6.57 (1H, d, J = 7.9 Hz), 6.83 (2H, d, J = 7.9 Hz), 7.30 (1H, d, J = 8.5 Hz), 7.45 (2H, d, J = 8.5 Hz).
(96b) (3S,10S)-3-tert-ブチル-2-エチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)フェニル]-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例96aで製造した(3S,10S)-3-tert-ブチル-2-エチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(209 mg, 0.292 mmol)、モレキュラーシーブス(4A, 200 mg)、ピラゾール(32.0 mg, 0.470 mmol)、ピリジン(59 μL, 0.730 mmol)及び酢酸銅(II) (82.0 mg, 0.451 mmol)のDMF (4.0 mL)溶液を100℃で6時間攪拌した。空冷後、反応液に酢酸エチルを加え、不溶物をろ過後(セライト)、ろ液を酢酸エチルで抽出した。有機層を水、次いで飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 1:1)で精製し、標記化合物(68.0 mg, 36％)を得た。 Example 96
2-[(3S, 10S) -3-tert-butyl-2-ethyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -3-methoxy-6- (1H-pyrazol-1-yl) benzoic acid
(96a) (3S, 10S) -3-tert-butyl-2-ethyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] Pyridine-1,9 (2H) -dione (3S, 10S) -3-tert-butyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl}-prepared in Example 34e 3- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3,4,6,7,8,10-hexahydro-1H -Chromeno [3,2-c] pyridine-1,9 (2H) -dione (600 mg, 0.875 mmol), ethyl iodide (560 μL, 7.00 mmol), DMPU (8.0 mL) and sodium hydride (63% , 107 mg, 2.81 mmol), and the reaction and post-treatment were performed according to Example 2a to obtain the title compound (295 mg, 47%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.79 (9H, s), 0.95 (3H, s), 1.05 (3H, t, J = 6.1 Hz), 1.07 (3H, s), 1.24 (12H , s), 2.09 (1H, d, J = 16.4 Hz), 2.16 (1H, d, J = 15.2 Hz), 2.31 (1H, d, J = 17.6 Hz), 2.40 (1H, d, J = 17.0 Hz) ), 2.51-2.67 (2H, m), 2.76 (1H, dd, J = 7.9, 17.0 Hz), 3.06-3.17 (1H, m), 3.59 (3H, s), 3.79 (3H, s), 4.09- 4.15 (1H, m), 4.61 (1H, d, J = 12.1 Hz), 4.65 (1H, d, J = 12.1 Hz), 5.07 (1H, s), 5.35 (1H, d, J = 14.0 Hz), 5.43 (1H, d, J = 13.4 Hz), 6.57 (1H, d, J = 7.9 Hz), 6.83 (2H, d, J = 7.9 Hz), 7.30 (1H, d, J = 8.5 Hz), 7.45 ( (2H, d, J = 8.5 Hz).
(96b) (3S, 10S) -3-tert-butyl-2-ethyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazole-1- Yl) phenyl] -7,7-dimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione prepared in Example 96a (3S, 10S) -3-tert-butyl-2-ethyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine- 1,9 (2H) -dione (209 mg, 0.292 mmol), molecular sieves (4A, 200 mg), pyrazole (32.0 mg, 0.470 mmol), pyridine (59 μL, 0.730 mmol) and copper (II) acetate (82.0 mg, 0.451 mmol) in DMF (4.0 mL) was stirred at 100 ° C. for 6 hours. After air cooling, ethyl acetate was added to the reaction solution, the insoluble material was filtered off (Celite), and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 1: 1) to obtain the title compound (68.0 mg, 36%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.81 (9H, s), 0.99 (3H, s), 1.07 (3H, t, J = 7.3 Hz), 1.11 (3H, s), 2.02-2.10 (2H, m), 2.36 (1H, d, J = 16.4 Hz), 2.47 (1H, d, J = 17.6 Hz), 2.53-2.67 (2H, m), 2.80 (1H, dd, J = 18.2, 8.5 Hz), 3.15 (1H, d, J = 8.5 Hz), 3.65 (3H, s), 3.79 (3H, s), 4.11-4.18 (1H, m), 4.43 (2H, t, J = 10.6 Hz), 4.66 (1H, d, J = 10.9 Hz), 5.45 (1H, s), 5.49 (1H, d, J = 10.9 Hz), 6.29 (1H, t, J = 2.1 Hz), 6.68 (1H, d, J = 8.5 Hz), 6.84 (2H, d, J = 9.1 Hz), 7.20 (1H, d, J = 8.5 Hz), 7.40 (2H, d, J = 8.5 Hz), 7.62 (1H, d, J = 1.8 Hz), 8.00 (1H, d, J = 2.4 Hz).
(96c) (3S,10S)-3-tert-ブチル-2-エチル-10-[2-(ヒドロキシメチル)-6-メトキシ-3-(1H-ピラゾール-1-イル)フェニル]-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例96bで製造した(3S,10S)-3-tert-ブチル-2-エチル-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)フェニル]-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(238 mg, 0.364 mmol)、リン酸バッファー(pH6.86, 1.0 mL)、ジクロロメタン(5.0 mL)及び2,3-ジクロロ-5,6-ジシアノ-1,4-ベンゾキノン(107 mg, 0.471 mmol)を用い、実施例32kに準じて反応及び後処理を行うことにより、標記化合物(157 mg, 81%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.85 (9H, s), 0.97 (3H, s), 1.08 (3H, t, J = 7.3 Hz), 1.11 (3H, s), 2.15 (1H, d, J = 17.6 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.37 (1H, d, J = 18.8 Hz), 2.49 (1H, d, J = 17.6 Hz), 2.59-2.71 (2H, m), 2.85 (1H, ddd, J = 2.0, 9.0, 18.1 Hz), 3.20 (1H, d, J = 9.1 Hz), 3.67 (3H, s), 4.10-4.21 (1H, m), 4.99 (2H, d, J = 6.1 Hz), 5.33 (1H, s), 6.14 (1H, t, J = 6.4 Hz), 6.40 (1H, t, J = 2.1 Hz), 6.75 (1H, d, J = 8.5 Hz), 7.39 (1H, d, J = 9.1 Hz), 7.67 (1H, d, J = 1.8 Hz), 8.26 (1H, d, J = 2.4 Hz).
(96d) 2-[(3S,10S)-3-tert-ブチル-2-エチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシ-6-(1H-ピラゾール-1-イル)ベンズアルデヒド
　実施例96cで製造した(3S,10S)-3-tert-ブチル-2-エチル-10-[2-(ヒドロキシメチル)-6-メトキシ-3-(1H-ピラゾール-1-イル)フェニル]-7,7-ジメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(157 mg, 0.293 mmol)、ジクロロメタン(4.0 mL)及びデスマーチンペルヨージナン(192 mg, 0.453 mmol)を用い、実施例32lに準じて反応及び後処理を行うことにより、標記化合物(119 mg, 77%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.85 (9H, s), 1.00 (3H, s), 1.05 (4H, t, J = 7.3 Hz), 1.11 (3H, s), 2.15 (1H, d, J = 15.8 Hz), 2.23 (1H, d, J = 16.4 Hz), 2.34 (1H, d, J = 17.6 Hz), 2.47 (1H, d, J = 17.6 Hz), 2.57 (1H, d, J = 18.2 Hz), 2.61-2.68 (1H, m), 2.82 (1H, ddd, J = 2.3, 8.7, 18.1 Hz), 3.18 (1H, d, J = 8.5 Hz), 3.68 (3H, s), 4.12-4.20 (1H, m), 5.46 (1H, s), 6.37 (1H, t, J = 2.1 Hz), 6.85 (1H, d, J = 8.5 Hz), 7.28 (1H, d, J = 7.3 Hz), 7.64 (1H, d, J = 2.4 Hz), 7.70 (1H, d, J = 2.4 Hz), 10.72 (1H, s).
(96e) 2-[(3S,10S)-3-tert-ブチル-2-エチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシ-6-(1H-ピラゾール-1-イル)安息香酸
　実施例96dで製造した2-[(3S,10S)-3-tert-ブチル-2-エチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-3-メトキシ-6-(1H-ピラゾール-1-イル)ベンズアルデヒド(119 mg, 0.224 mmol)、2-メチル-2-ブテン(500 μL, 4.00 mmol)、りん酸二水素ナトリウム二水和物(180 mg, 1.15 mmol)、水(1.0 mL)、tert-ブタノール(6.0 mL)、ジクロロメタン(500 μL)及び亜塩素酸ナトリウム(127 mg, 1.12 mmol) を用い、実施例32mに準じて反応及び後処理を行うことにより、標記化合物(96.3 mg, 78%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.81 (9H, s), 0.99 (3H, s), 1.07 (3H, t, J = 7.3 Hz), 1.11 (3H, s), 2.02-2.10 (2H, m), 2.36 (1H, d, J = 16.4 Hz), 2.47 (1H, d, J = 17.6 Hz), 2.53-2.67 (2H, m), 2.80 (1H, dd, J = 18.2, 8.5 Hz), 3.15 (1H, d, J = 8.5 Hz), 3.65 (3H, s), 3.79 (3H, s), 4.11-4.18 (1H, m), 4.43 (2H, t, J = 10.6 Hz), 4.66 (1H, d, J = 10.9 Hz), 5.45 (1H, s), 5.49 (1H, d, J = 10.9 Hz), 6.29 (1H, t, J = 2.1 Hz), 6.68 (1H, d, J = 8.5 Hz), 6.84 (2H, d, J = 9.1 Hz), 7.20 (1H, d, J = 8.5 Hz), 7.40 (2H, d, J = 8.5 Hz), 7.62 (1H, d, J = 1.8 Hz), 8.00 (1H, d, J = 2.4 Hz).
(96c) (3S, 10S) -3-tert-butyl-2-ethyl-10- [2- (hydroxymethyl) -6-methoxy-3- (1H-pyrazol-1-yl) phenyl] -7,7 -Dimethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (3S, 10S) -3 prepared in Example 96b -tert-Butyl-2-ethyl-10- [6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) phenyl] -7,7-dimethyl -3,4,6,7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (238 mg, 0.364 mmol), phosphate buffer (pH 6.86) , 1.0 mL), dichloromethane (5.0 mL), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (107 mg, 0.471 mmol), the reaction and post-treatment are performed according to Example 32k. This gave the title compound (157 mg, 81%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.85 (9H, s), 0.97 (3H, s), 1.08 (3H, t, J = 7.3 Hz), 1.11 (3H, s), 2.15 (1H , d, J = 17.6 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.37 (1H, d, J = 18.8 Hz), 2.49 (1H, d, J = 17.6 Hz), 2.59-2.71 (2H , m), 2.85 (1H, ddd, J = 2.0, 9.0, 18.1 Hz), 3.20 (1H, d, J = 9.1 Hz), 3.67 (3H, s), 4.10-4.21 (1H, m), 4.99 ( 2H, d, J = 6.1 Hz), 5.33 (1H, s), 6.14 (1H, t, J = 6.4 Hz), 6.40 (1H, t, J = 2.1 Hz), 6.75 (1H, d, J = 8.5 Hz), 7.39 (1H, d, J = 9.1 Hz), 7.67 (1H, d, J = 1.8 Hz), 8.26 (1H, d, J = 2.4 Hz).
(96d) 2-[(3S, 10S) -3-tert-butyl-2-ethyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxy-6- (1H-pyrazol-1-yl) benzaldehyde (3S, 10S) -3-tert prepared in Example 96c -Butyl-2-ethyl-10- [2- (hydroxymethyl) -6-methoxy-3- (1H-pyrazol-1-yl) phenyl] -7,7-dimethyl-3,4,6,7,8 , 10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (157 mg, 0.293 mmol), dichloromethane (4.0 mL) and desmartin periodinane (192 mg, 0.453 mmol) The title compound (119 mg, 77%) was obtained by carrying out the reaction and post-treatment according to Example 32l.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.85 (9H, s), 1.00 (3H, s), 1.05 (4H, t, J = 7.3 Hz), 1.11 (3H, s), 2.15 (1H , d, J = 15.8 Hz), 2.23 (1H, d, J = 16.4 Hz), 2.34 (1H, d, J = 17.6 Hz), 2.47 (1H, d, J = 17.6 Hz), 2.57 (1H, d , J = 18.2 Hz), 2.61-2.68 (1H, m), 2.82 (1H, ddd, J = 2.3, 8.7, 18.1 Hz), 3.18 (1H, d, J = 8.5 Hz), 3.68 (3H, s) , 4.12-4.20 (1H, m), 5.46 (1H, s), 6.37 (1H, t, J = 2.1 Hz), 6.85 (1H, d, J = 8.5 Hz), 7.28 (1H, d, J = 7.3 Hz), 7.64 (1H, d, J = 2.4 Hz), 7.70 (1H, d, J = 2.4 Hz), 10.72 (1H, s).
(96e) 2-[(3S, 10S) -3-tert-butyl-2-ethyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -3-methoxy-6- (1H-pyrazol-1-yl) benzoic acid 2-[(3S, 10S) prepared in Example 96d -3-tert-butyl-2-ethyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c ] Pyridin-10-yl] -3-methoxy-6- (1H-pyrazol-1-yl) benzaldehyde (119 mg, 0.224 mmol), 2-methyl-2-butene (500 μL, 4.00 mmol), diphosphate Example using sodium hydrogen dihydrate (180 mg, 1.15 mmol), water (1.0 mL), tert-butanol (6.0 mL), dichloromethane (500 μL) and sodium chlorite (127 mg, 1.12 mmol) The title compound (96.3 mg, 78%) was obtained by carrying out the reaction and post-treatment according to 32 m.
(実施例97)
　6-{3-[(3R,10S)-3-tert-ブチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
(97a) (3R,10S)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン
　実施例42aで製造した7-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]スピロ[3.5]ノナン-6,8-ジオン(1.30 g, 3.17 mmol)及び実施例87bで製造したtert-ブチル　(2R)-2-tert-ブチル-4,6-ジオキソピペリジン-1-カルボキシレート(896 mg, 3.33 mmol)のDMF (10 mL)溶液に室温で炭酸セシウム(1.24 g, 3.80 mmol)を加えた。反応溶液を室温で2時間攪拌後、反応溶液に酢酸エチル(26 mL)、次いで4 M塩酸(1,4-ジオキサン溶液; 5.20 mL)を加え、反応溶液を室温で18時間攪拌した。反応溶液に1 M水酸化ナトリウム水溶液を加えて(pH = 12)、酢酸エチルで2回抽出、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮し、残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル; 4:6)で精製し、標記化合物(518 mg, 29%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.92 (9H, s), 1.30 (12H, s), 1.68-1.92 (6H, m), 2.31-2.38 (2H, m), 2.42-2.58 (3H, m), 2.63 (1H, d, J = 16.8 Hz), 3.12 (3H, s), 3.18 (1H, dd, J = 5.1, 13.3 Hz), 3.71 (3H, s), 5.06 (1H, s), 5.17 (1H, s), 6.59 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 8.6 Hz).
(97b) tert-ブチル　6-{3-[(3R,10S)-3-tert-ブチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例97aで製造した(3R,10S)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン(300 mg, 0.534 mmol)、tert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(, 158 mg, 0.695 mmol)、2nd Generation X-Phos Precatalyst (126 mg, 0.160 mmol)、リン酸カリウム(181 mg, 0.855 mmol)、THF (4.5 mL)及び水(6.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(310 mg, 93%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.94 (9H, s), 1.63 (9H, s), 1.78-1.94 (6H, m), 2.34-2.51 (4H, m), 2.49 (3H, s), 2.57 (1H, d, J = 16.0 Hz), 2.66 (1H, d, J = 16.8 Hz), 2.84 (3H, s), 3.22 (1H, dd, J = 5.3, 13.5 Hz), 3.74 (3H, s), 5.09 (1H, s), 5.14 (1H, s), 6.70 (1H, d, J = 8.6 Hz), 7.25 (1H, d, J = 7.8 Hz), 7.36 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.2 Hz).
(97c) 6-{3-[(3R,10S)-3-tert-ブチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例97bで製造したtert-ブチル　6-{3-[(3R,10S)-3-tert-ブチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(300 mg, 0.479 mmol)、ジクロロメタン(3.0 mL)及びトリフルオロ酢酸(1.5 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(146 mg, 82%)を得た。 Example 97
6- {3-[(3R, 10S) -3-tert-butyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2- c] Pyridine-7,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid
(97a) (3R, 10S) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) phenyl] -3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H) -dione prepared in Example 42a 7- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] spiro [3.5] nonane-6,8-dione (1.30 g, 3.17 mmol) and tert-butyl (2R) -2-tert-butyl-4,6-dioxopiperidine-1-carboxylate (896 mg, 3.33 mmol) prepared in Example 87b in DMF (10 To the solution was added cesium carbonate (1.24 g, 3.80 mmol) at room temperature. After the reaction solution was stirred at room temperature for 2 hours, ethyl acetate (26 mL) and then 4 M hydrochloric acid (1,4-dioxane solution; 5.20 mL) were added to the reaction solution, and the reaction solution was stirred at room temperature for 18 hours. A 1 M aqueous sodium hydroxide solution was added to the reaction solution (pH = 12), extraction was performed twice with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography (hexane / ethyl acetate; 4: 6) to obtain the title compound (518 mg, 29%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.92 (9H, s), 1.30 (12H, s), 1.68-1.92 (6H, m), 2.31-2.38 (2H, m), 2.42-2.58 ( 3H, m), 2.63 (1H, d, J = 16.8 Hz), 3.12 (3H, s), 3.18 (1H, dd, J = 5.1, 13.3 Hz), 3.71 (3H, s), 5.06 (1H, s ), 5.17 (1H, s), 6.59 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 8.6 Hz).
(97b) tert-butyl 6- {3-[(3R, 10S) -3-tert-butyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [ Chromeno [3,2-c] pyridine-7,1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate prepared in Example 97a (3R , 10S) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]- 3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H) -dione (300 mg, 0.534 mmol), tert-butyl 6-chloro-3-methylpyridine-2-carboxylate (, 158 mg, 0.695 mmol), 2nd Generation X-Phos Precatalyst (126 mg, 0.160 mmol), potassium phosphate (181 mg, 0.855 mmol), THF (4.5 mL) and water (6.0 mL) were used for the reaction and post-treatment according to Example 9d to obtain the title compound (310 mg, 93%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.94 (9H, s), 1.63 (9H, s), 1.78-1.94 (6H, m), 2.34-2.51 (4H, m), 2.49 (3H, s), 2.57 (1H, d, J = 16.0 Hz), 2.66 (1H, d, J = 16.8 Hz), 2.84 (3H, s), 3.22 (1H, dd, J = 5.3, 13.5 Hz), 3.74 ( 3H, s), 5.09 (1H, s), 5.14 (1H, s), 6.70 (1H, d, J = 8.6 Hz), 7.25 (1H, d, J = 7.8 Hz), 7.36 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.2 Hz).
(97c) 6- {3-[(3R, 10S) -3-tert-butyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3 , 2-c] Pyridin-7,1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butyl 6- prepared in Example 97b {3-[(3R, 10S) -3-tert-butyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] Pyridine-7,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (300 mg, 0.479 mmol), dichloromethane (3.0 mL) and trifluoro The title compound (146 mg, 82%) was obtained by conducting reaction and post-treatment according to Example 1d using acetic acid (1.5 mL).
(実施例98)
　(3R,10S)-10-{3-[6-(ヒドロキシメチル)-5-メチルピリジン-2-イル]-6-メトキシ-2-メチルフェニル}-7,7-ジメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例11aで製造した(3R,10S)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(200 mg, 0.374 mmol)、(6-クロロ-3-メチルピリジン-2-イル)メタノール(64.8 mg, 0.411 mmol)、2nd Generation X-Phos Precatalyst (14.7 mg, 0.0187 mmol)、リン酸カリウム(119 mg, 0.560 mmol)、THF (2.0 mL)及び水(4.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(118 mg, 60%)を得た。 Example 98
(3R, 10S) -10- {3- [6- (Hydroxymethyl) -5-methylpyridin-2-yl] -6-methoxy-2-methylphenyl} -7,7-dimethyl-3- (propane- 2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione prepared in Example 11a (3R, 10S) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3- ( Propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (200 mg, 0.374 mmol), ( 6-chloro-3-methylpyridin-2-yl) methanol (64.8 mg, 0.411 mmol), 2nd Generation X-Phos Precatalyst (14.7 mg, 0.0187 mmol), potassium phosphate (119 mg, 0.560 mmol), THF (2.0 The title compound (118 mg, 60%) was obtained by performing the reaction and post-treatment according to Example 9d using mL) and water (4.0 mL).
(実施例99)
　(10S)-10-{3-[6-(ヒドロキシメチル)-5-メチルピリジン-2-イル]-6-メトキシ-2-メチルフェニル}-2,7,7-トリメチル-3-(プロパン-2-イル)-6,7,8,10-テトラヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例14cで製造した6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,6,7,8,9,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(357 mg, 0.641 mmol)及びカルボニルジイミダゾール(135 mg, 0.834 mmol)のTHF (7.0 mL)溶液を室温で2時間攪拌した。反応溶液に0℃で水素化ホウ素ナトリウム(25.5 mg, 0.674 mmol)の水(0.7 mL)溶液を加え、反応溶液を室温で75分攪拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル)で精製し、標記化合物(204 mg, 59%)を得た。 Example 99
(10S) -10- {3- [6- (Hydroxymethyl) -5-methylpyridin-2-yl] -6-methoxy-2-methylphenyl} -2,7,7-trimethyl-3- (propane- 2-yl) -6,7,8,10-tetrahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 6- {4-methoxy-2-prepared in Example 14c Methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,6,7,8,9,10-hexahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid (357 mg, 0.641 mmol) and carbonyldiimidazole (135 mg, 0.834 mmol) in THF (7.0 mL) Was stirred at room temperature for 2 hours. To the reaction solution was added a solution of sodium borohydride (25.5 mg, 0.674 mmol) in water (0.7 mL) at 0 ° C., and the reaction solution was stirred at room temperature for 75 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (204 mg, 59%).
(実施例100)
　6-{3-[(3R,10S)-3-tert-ブチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
(100a) (3R,10S)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン
　実施例41aで製造した6-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]スピロ[2.5]オクタン-5,7-ジオン(1.30 g, 3.28 mmol)、実施例87bで製造したtert-ブチル　(2R)-2-tert-ブチル-4,6-ジオキソピペリジン-1-カルボキシレート(928 mg, 3.44 mmol)、DMF (10 mL)、炭酸セシウム(1.28 g, 3.94 mmol)、酢酸エチル(26 mL)及び4 M塩酸(1,4-ジオキサン溶液; 5.20 mL) を用い、実施例97aに準じて反応及び後処理を行うことにより、標記化合物(493 mg, 27%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.33-0.48 (4H, m), 0.92 (9H, s), 1.30 (12H, s), 2.00 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 18.0 Hz), 2.30-2.36 (2H, m), 2.45-2.57 (2H, m), 3.13 (3H, s), 3.20 (1H, dd, J = 4.9, 13.5 Hz), 3.72 (3H, s), 5.21 (1H, s), 5.22 (1H, s), 6.64 (1H, d, J = 8.2 Hz), 7.61 (1H, d, J = 8.6 Hz).
(100b) tert-ブチル　6-{3-[(3R,10S)-3-tert-ブチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例100aで製造した(3R,10S)-3-tert-ブチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン(300 mg, 0.534 mmol)、tert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(, 162 mg, 0.712 mmol)、2nd Generation X-Phos Precatalyst (129 mg, 0.164 mmol)、リン酸カリウム(186 mg, 0.877 mmol)、THF (4.5 mL)及び水(6.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(305 mg, 91%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.36-0.50 (4H, m), 0.94 (9H, s), 1.63 (9H, s), 2.02 (1H, d, J = 16.4 Hz), 2.26 (1H, d, J = 17.6 Hz), 2.32-2.39 (2H, m), 2.47-2.58 (2H, m), 2.49 (3H, s), 2.85 (3H, s), 3.23 (1H, dd, J = 5.3, 13.5 Hz), 3.76 (3H, s), 5.11 (1H, s), 5.20 (1H, s), 6.75 (1H, d, J = 9.0 Hz), 7.27 (1H, d, J = 7.4 Hz), 7.36 (1H, d, J = 8.2 Hz), 7.53 (1H, d, J = 7.4 Hz).
(100c) 6-{3-[(3R,10S)-3-tert-ブチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例100bで製造したtert-ブチル　6-{3-[(3R,10S)-3-tert-ブチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(300 mg, 0.490 mmol)、ジクロロメタン(3.0 mL)及びトリフルオロ酢酸(1.5 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(240 mg, 88%)を得た。 (Example 100)
6- {3-[(3R, 10S) -3-tert-butyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2- c] Pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid
(100a) (3R, 10S) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) phenyl] -3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -1,9 (2H, 8H) -dione prepared in Example 41a 6- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] spiro [2.5] octane-5,7- Dione (1.30 g, 3.28 mmol), tert-butyl (2R) -2-tert-butyl-4,6-dioxopiperidine-1-carboxylate (928 mg, 3.44 mmol) prepared in Example 87b, DMF ( 10 mL), cesium carbonate (1.28 g, 3.94 mmol), ethyl acetate (26 mL) and 4 M hydrochloric acid (1,4-dioxane solution; 5.20 mL) are reacted and worked up according to Example 97a. This gave the title compound (493 mg, 27%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.33-0.48 (4H, m), 0.92 (9H, s), 1.30 (12H, s), 2.00 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 18.0 Hz), 2.30-2.36 (2H, m), 2.45-2.57 (2H, m), 3.13 (3H, s), 3.20 (1H, dd, J = 4.9, 13.5 Hz), 3.72 (3H, s), 5.21 (1H, s), 5.22 (1H, s), 6.64 (1H, d, J = 8.2 Hz), 7.61 (1H, d, J = 8.6 Hz).
(100b) tert-butyl 6- {3-[(3R, 10S) -3-tert-butyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [ Chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate prepared in Example 100a ( 3R, 10S) -3-tert-butyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -1,9 (2H, 8H) -dione (300 mg, 0.534 mmol), tert -Butyl 6-chloro-3-methylpyridine-2-carboxylate (, 162 mg, 0.712 mmol), 2nd Generation X-Phos Precatalyst (129 mg, 0.164 mmol), potassium phosphate (186 mg, 0.877 mmol), THF (4.5 mL) and water (6.0 mL) were used, and the reaction and post-treatment were performed according to Example 9d to obtain the title compound (305 mg, 91%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.36-0.50 (4H, m), 0.94 (9H, s), 1.63 (9H, s), 2.02 (1H, d, J = 16.4 Hz), 2.26 (1H, d, J = 17.6 Hz), 2.32-2.39 (2H, m), 2.47-2.58 (2H, m), 2.49 (3H, s), 2.85 (3H, s), 3.23 (1H, dd, J = 5.3, 13.5 Hz), 3.76 (3H, s), 5.11 (1H, s), 5.20 (1H, s), 6.75 (1H, d, J = 9.0 Hz), 7.27 (1H, d, J = 7.4 Hz ), 7.36 (1H, d, J = 8.2 Hz), 7.53 (1H, d, J = 7.4 Hz).
(100c) 6- {3-[(3R, 10S) -3-tert-butyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3 , 2-c] pyridine-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butyl prepared in Example 100b 6 -{3-[(3R, 10S) -3-tert-butyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c ] Pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (300 mg, 0.490 mmol), dichloromethane (3.0 mL) and The title compound (240 mg, 88%) was obtained by performing reaction and post-treatment according to Example 1d using trifluoroacetic acid (1.5 mL).
(実施例101)
　6-メトキシ-1-メチル-5-(2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)ナフタレン-2-カルボン酸
(101a) ベンジル　5-ホルミル-6-メトキシ-1-メチルナフタレン-2-カルボキシレート
　メチル　5-ホルミル-6-メトキシ-1-メチルナフタレン-2-カルボキシレート(8.60 g, 33.3 mmol)、2 M水酸化ナトリウム水溶液(83 mL, 166 mmol)のTHF/メタノール溶液(1:1, v/v; 340 mL)溶液を80℃で4時間攪拌した。放冷後、反応溶液を濃縮し、1 M塩酸(170 mL)を加えた。析出した結晶をろ取、水及びエーテルで洗浄し、粗製の5-ホルミル-6-メトキシ-1-メチルナフタレン-2-カルボン酸を得た。 (Example 101)
6-Methoxy-1-methyl-5- (2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl) naphthalene-2-carboxylic acid
(101a) Benzyl 5-formyl-6-methoxy-1-methylnaphthalene-2-carboxylate Methyl 5-formyl-6-methoxy-1-methylnaphthalene-2-carboxylate (8.60 g, 33.3 mmol), 2 M water A solution of sodium oxide aqueous solution (83 mL, 166 mmol) in THF / methanol solution (1: 1, v / v; 340 mL) was stirred at 80 ° C. for 4 hours. After allowing to cool, the reaction solution was concentrated, and 1 M hydrochloric acid (170 mL) was added. The precipitated crystals were collected by filtration and washed with water and ether to obtain crude 5-formyl-6-methoxy-1-methylnaphthalene-2-carboxylic acid.
　粗製の5-ホルミル-6-メトキシ-1-メチルナフタレン-2-カルボン酸、ベンジルブロミド(5.94 mL, 49.9 mmol)及び炭酸カリウム(9.20 g, 66.6 mmol)のDMF (150 mL)溶液を室温で22時間攪拌した。反応溶液に水を加えてジクロロメタンで抽出後、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ジクロロメタン)で精製し、標記化合物(9.87 g, 89％, 2 steps)を得た。
1H-NMR (500MHz, CDCl3) δ　ppm: 2.93 (3H, s), 4.08 (3H, s), 5.40 (2H, s), 7.33-7.42 (4H, m), 7.48 (2H, d, J = 7.4 Hz), 7.98 (1H, d, J = 9.1 Hz), 8.46 (1H, dd, J = 9.6, 0.6 Hz), 9.16 (1H, d, J = 9.4 Hz), 10.88 (1H, s).
(101b) ベンジル　5-[(Z)-(6,6-ジメチル-2,4-ジオキソピペリジン-3-イリデン)メチル]-6-メトキシ-1-メチルナフタレン-2-カルボキシレート
　実施例101aで製造したベンジル　5-ホルミル-6-メトキシ-1-メチルナフタレン-2-カルボキシレート(200 mg, 0.598 mmol)、L-プロリン(3.4 mg, 0.0299 mmol)、1,2-ジクロロエタン(4.0 mL)及び6,6-ジメチルピペリジン-2,4-ジオン(144 mg, 1.02 mmol)を用い、実施例41aに準じて反応及び後処理を行うことにより、標記化合物(274 mg, 57%)をジアステレオマーの混合物として得た。
(101c) ベンジル　6-メトキシ-1-メチル-5-(3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)ナフタレン-2-カルボキシレート
　実施例101bで製造したベンジル　5-[(Z)-(6,6-ジメチル-2,4-ジオキソピペリジン-3-イリデン)メチル]-6-メトキシ-1-メチルナフタレン-2-カルボキシレート(95.0 mg, 0.210 mmol)、ジメドン(32.0 mg, 0.230 mmol)、DMF (1.2 mL)、炭酸セシウム(170 mg, 0.520 mmol)及びメタンスルホニルクロリド(19 μL, 0.250 mmol)を用い、実施例1bに準じて反応及び後処理を行うことにより、標記化合物(23.0 mg, 19%)を得た。
1H-NMR (400MHz, CDCl3) δ　ppm: 0.93 (3H, s), 1.00 (3H, s), 1.08 (3H, s), 1.13 (3H, s), 2.05 (1H, d, J = 16.0 Hz), 2.18 (1H, d, J = 16.4 Hz), 2.29-2.38 (2H, m), 2.48 (1H, d, J = 17.6 Hz), 2.62 (1H, d, J = 17.2 Hz), 2.88 (3H, s), 3.85 (3H, s), 5.38 (3H, s), 5.68 (1H, s), 7.18 (1H, d, J = 9.4 Hz), 7.30-7.48 (5H, m), 8.03 (1H, d, J = 9.4 Hz), 8.08 (1H, d, J = 9.4 Hz), 8.75 (1H, d, J = 9.4 Hz).
(101d) ベンジル　6-メトキシ-1-メチル-5-(2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)ナフタレン-2-カルボキシレート
　実施例101cで製造したベンジル　6-メトキシ-1-メチル-5-(3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)ナフタレン-2-カルボキシレート(23.0 mg, 0.0400 mmol)、ヨウ化メチル(25 μL, 0.400 mmol)、DMF (0.5 mL)及び水素化ナトリウム(63%, 2.3 mg, 0.060 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(21.0 mg, 89%)を得た。
1H-NMR (400MHz, CDCl3) δ　ppm: 0.91 (3H, s), 1.08 (3H, s), 1.11 (3H, s), 1.33 (3H, s), 2.04 (1H, d, J = 16.4 Hz), 2.17 (1H, d, J = 16.4 Hz), 2.36 (1H, d, J = 16.4 Hz), 2.38 (1H, d, J = 16.0 Hz), 2.48 (1H, d, J = 17.6 Hz), 2.66 (1H, d, J = 18.0 Hz), 2.71 (3H, s), 2.89 (3H, s), 3.86 (3H, s), 5.38 (2H, s), 5.72 (1H, s), 7.18 (1H, d, J = 9.8 Hz), 7.31-7.48 (5H, m), 8.08 (1H, d, J = 9.0 Hz), 8.09 (1H, d, J = 9.8 Hz), 8.80 (1H, d, J = 9.8 Hz).
(101e) 6-メトキシ-1-メチル-5-(2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)ナフタレン-2-カルボン酸
　実施例101dで製造したベンジル　6-メトキシ-1-メチル-5-(2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)ナフタレン-2-カルボキシレート(21.0 mg, 0.0350 mmol)、パラジウム炭素(10%, 21.0 mg)及びエタノール(1.0 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(11.0 mg, 62%)を得た。 A solution of crude 5-formyl-6-methoxy-1-methylnaphthalene-2-carboxylic acid, benzyl bromide (5.94 mL, 49.9 mmol) and potassium carbonate (9.20 g, 66.6 mmol) in DMF (150 mL) at room temperature Stir for hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane) to obtain the title compound (9.87 g, 89%, 2 steps).
1 H-NMR (500MHz, CDCl 3 ) δ ppm: 2.93 (3H, s), 4.08 (3H, s), 5.40 (2H, s), 7.33-7.42 (4H, m), 7.48 (2H, d, J = 7.4 Hz), 7.98 (1H, d, J = 9.1 Hz), 8.46 (1H, dd, J = 9.6, 0.6 Hz), 9.16 (1H, d, J = 9.4 Hz), 10.88 (1H, s).
(101b) Benzyl 5-[(Z)-(6,6-dimethyl-2,4-dioxopiperidin-3-ylidene) methyl] -6-methoxy-1-methylnaphthalene-2-carboxylate in Example 101a Prepared benzyl 5-formyl-6-methoxy-1-methylnaphthalene-2-carboxylate (200 mg, 0.598 mmol), L-proline (3.4 mg, 0.0299 mmol), 1,2-dichloroethane (4.0 mL) and 6 , 6-Dimethylpiperidine-2,4-dione (144 mg, 1.02 mmol) was used for the reaction and workup according to Example 41a to give the title compound (274 mg, 57%) as a diastereomer. Obtained as a mixture.
(101c) Benzyl 6-methoxy-1-methyl-5- (3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl) naphthalene-2-carboxylate benzyl 5-[(Z)-(6,6-dimethyl-2,4-dioxopiperidine prepared in Example 101b -3-ylidene) methyl] -6-methoxy-1-methylnaphthalene-2-carboxylate (95.0 mg, 0.210 mmol), dimedone (32.0 mg, 0.230 mmol), DMF (1.2 mL), cesium carbonate (170 mg, 0.520 mmol) and methanesulfonyl chloride (19 μL, 0.250 mmol) were used for the reaction and post-treatment according to Example 1b to obtain the title compound (23.0 mg, 19%).
1 H-NMR (400MHz, CDCl 3 ) δ ppm: 0.93 (3H, s), 1.00 (3H, s), 1.08 (3H, s), 1.13 (3H, s), 2.05 (1H, d, J = 16.0 Hz), 2.18 (1H, d, J = 16.4 Hz), 2.29-2.38 (2H, m), 2.48 (1H, d, J = 17.6 Hz), 2.62 (1H, d, J = 17.2 Hz), 2.88 ( 3H, s), 3.85 (3H, s), 5.38 (3H, s), 5.68 (1H, s), 7.18 (1H, d, J = 9.4 Hz), 7.30-7.48 (5H, m), 8.03 (1H , d, J = 9.4 Hz), 8.08 (1H, d, J = 9.4 Hz), 8.75 (1H, d, J = 9.4 Hz).
(101d) Benzyl 6-methoxy-1-methyl-5- (2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro -1H-chromeno [3,2-c] pyridin-10-yl) naphthalene-2-carboxylate benzyl 6-methoxy-1-methyl-5- (3,3,7,7-tetra prepared in Example 101c Methyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl) naphthalene-2-carboxylate (23.0 mg, 0.0400 mmol), methyl iodide (25 μL, 0.400 mmol), DMF (0.5 mL) and sodium hydride (63%, 2.3 mg, 0.060 mmol) were used for the reaction and workup according to Example 2a. This gave the title compound (21.0 mg, 89%).
1 H-NMR (400MHz, CDCl 3 ) δ ppm: 0.91 (3H, s), 1.08 (3H, s), 1.11 (3H, s), 1.33 (3H, s), 2.04 (1H, d, J = 16.4 Hz), 2.17 (1H, d, J = 16.4 Hz), 2.36 (1H, d, J = 16.4 Hz), 2.38 (1H, d, J = 16.0 Hz), 2.48 (1H, d, J = 17.6 Hz) , 2.66 (1H, d, J = 18.0 Hz), 2.71 (3H, s), 2.89 (3H, s), 3.86 (3H, s), 5.38 (2H, s), 5.72 (1H, s), 7.18 ( 1H, d, J = 9.8 Hz), 7.31-7.48 (5H, m), 8.08 (1H, d, J = 9.0 Hz), 8.09 (1H, d, J = 9.8 Hz), 8.80 (1H, d, J = 9.8 Hz).
(101e) 6-Methoxy-1-methyl-5- (2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl) naphthalene-2-carboxylic acid benzyl 6-methoxy-1-methyl-5- (2,3,3,7,7-- prepared in Example 101d Pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl) naphthalene-2-carboxylate (21.0 mg, 0.0350 mmol), palladium on carbon (10%, 21.0 mg) and ethanol (1.0 mL) were used in the reaction and post-treatment according to Example 18 to obtain the title compound (11.0 mg, 62%). It was.
(実施例102)
　2,4-ジメチル-7-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボン酸
　又は、2,4-ジメチル-7-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボン酸
(102a) 7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-カルボン酸
　tert-ブチル　7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート(223 mg, 0.813 mmol)、ジクロロメタン(2.0 mL)及びトリフルオロ酢酸(1.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(171 mg, 96%)を得た。
1H-NMR (400MHz, DMSO-d6) δ　ppm: 2.51 (3H, d, J = 1.2 Hz), 2.74 (3H, s), 6.92 (1H, d, J = 1.2 Hz), 8.26 (1H, s), 10.22 (1H, s).
(102b) ベンジル　7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート
　実施例102aで製造した7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-カルボン酸(1.29 g, 5.91 mmol)、ベンジルブロミド(843 μL, 7.09 mmol)及び炭酸セシウム(2.89 g, 8.87 mmol)のDMF (20 mL)溶液を室温で2時間攪拌した。反応溶液に水を加えて酢酸エチルで2回抽出後、有機層を水で2回洗浄、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 5: 1)で精製し、標記化合物(1.13 g, 62％)を得た。
1H-NMR (400MHz, CDCl3) δ　ppm: 2.54 (3H, s), 2.79 (3H, s), 5.37 (2H, s), 6.55 (1H, d, J = 0.8 Hz), 7.32-7.47 (5H, m), 8.35 (1H, s), 10.31 (1H, s).
(102c) ベンジル　7-[(Z)-(6,6-ジメチル-2,4-ジオキソピペリジン-3-イリデン)メチル]-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート
　実施例102bで製造したベンジル　7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート(200 mg, 0.649 mmol)、6,6-ジメチルピペリジン-2,4-ジオン(101 mg, 0.714 mmol)及びL-プロリン(3.7 mg, 0.0324 mmol)のアセトニトリル(1.0 mL)溶液を室温で4日間攪拌した。反応溶液に水を加えてジクロロメタンで抽出後、有機層を無水硫酸ナトリウムで乾燥した。減圧濃縮し、粗製の標記化合物を得た。
(102d) ベンジル　2,4-ジメチル-7-(3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)-1-ベンゾフラン-5-カルボキシレート
　実施例102cで製造した粗製のベンジル　7-[(Z)-(6,6-ジメチル-2,4-ジオキソピペリジン-3-イリデン)メチル]-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート、ジメドン(100 mg, 0.714 mmol)、DMF (14 mL)、炭酸セシウム(529 mg, 1.62 mmol)及びメタンスルホニルクロリド(61 μL, 0.779 mmol)を用い、実施例1bに準じて反応及び後処理を行うことにより、標記化合物(240 mg, 67%, 2 steps)を得た。
1H-NMR (400MHz, CDCl3) δ　ppm: 0.85 (3H, s), 1.04 (3H, s), 1.08 (3H, s), 1.27 (3H, s), 2.10 (1H, d, J = 15.7 Hz), 2.22 (1H, d, J = 16.0 Hz), 2.39 (2H, d, J = 17.6 Hz), 2.43-2.51 (1H, m), 2.45 (3H, s), 2.63-2.69 (1H, m), 2.63 (3H, s), 5.00 (1H, s), 5.14 (1H, s), 5.32 (2H, d, J = 2.0 Hz), 6.39 (1H, d, J = 1.2 Hz), 7.31-7.47 (5H, m), 7.92 (1H, s).
(102e) ベンジル　2,4-ジメチル-7-[(10S)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート
又は、ベンジル　2,4-ジメチル-7-[(10R)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート
　実施例102dで製造したベンジル　2,4-ジメチル-7-(3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)-1-ベンゾフラン-5-カルボキシレート(240 mg)をChiral flash IA(ヘキサン/エタノール; 8:2)により光学分割し、高極性化合物(45.6 mg)及び低極性化合物(52.0 mg)を得た。
(102f) ベンジル　2,4-ジメチル-7-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート又は、ベンジル　2,4-ジメチル-7-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート
　実施例102eで製造したベンジル　2,4-ジメチル-7-[(10S)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート又は、ベンジル　2,4-ジメチル-7-[(10R)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート(高極性化合物; 45.6 mg, 0.0824 mmol)、ヨウ化メチル(6 μL, 0.0988 mmol)、DMF (1.0 mL)及び水素化ナトリウム(63%, 3.8 mg, 0.0988 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(31.1 mg, 67%)を得た。
1H-NMR (400MHz, CDCl3) δ　ppm: 0.82 (3H, s), 1.03 (3H, s), 1.07 (3H, s), 1.32 (3H, s), 2.08 (1H, d, J = 16.4 Hz), 2.20 (1H, d, J = 16.0 Hz), 2.37 (1H, d, J = 16.8 Hz), 2.41 (1H, d, J = 16.8 Hz), 2.46-2.50 (1H, m), 2.46 (3H, s), 2.62-2.67 (1H, m), 2.63 (3H, s), 2.75 (3H, s), 5.15 (1H, s), 5.29 (1H, d, J = 12.5 Hz), 5.34 (1H, d, J = 12.5 Hz), 6.39 (1H, d, J = 1.2 Hz), 7.29-7.47 (5H, m), 7.90 (1H, s).
(102g) 2,4-ジメチル-7-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボン酸
又は、2,4-ジメチル-7-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボン酸
　実施例102fで製造したベンジル　2,4-ジメチル-7-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレートもしくはベンジル　2,4-ジメチル-7-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート(31.1 mg, 0.0548 mmol)、パラジウム炭素(10%, 15.0 mg)及びエタノール(5.0 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(15.7 mg, 60%)を得た。 (Example 102)
2,4-Dimethyl-7-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylic acid or 2,4-dimethyl-7-[(10R) -2,3,3,7,7-pentamethyl -1,9-Dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylic acid
(102a) 7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylic acid tert-butyl 7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylate (223 mg, 0.813 mmol), The title compound (171 mg, 96%) was obtained by performing reaction and post-treatment according to Example 1d using dichloromethane (2.0 mL) and trifluoroacetic acid (1.0 mL).
1 H-NMR (400MHz, DMSO-d 6 ) δ ppm: 2.51 (3H, d, J = 1.2 Hz), 2.74 (3H, s), 6.92 (1H, d, J = 1.2 Hz), 8.26 (1H, s), 10.22 (1H, s).
(102b) Benzyl 7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylate 7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylic acid prepared in Example 102a (1.29 g, 5. A solution of benzyl bromide (843 μL, 7.09 mmol) and cesium carbonate (2.89 g, 8.87 mmol) in DMF (20 mL) was stirred at room temperature for 2 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with water and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 5: 1) to obtain the title compound (1.13 g, 62%).
1 H-NMR (400MHz, CDCl 3 ) δ ppm: 2.54 (3H, s), 2.79 (3H, s), 5.37 (2H, s), 6.55 (1H, d, J = 0.8 Hz), 7.32-7.47 ( 5H, m), 8.35 (1H, s), 10.31 (1H, s).
(102c) Benzyl 7-[(Z)-(6,6-dimethyl-2,4-dioxopiperidin-3-ylidene) methyl] -2,4-dimethyl-1-benzofuran-5-carboxylate Example 102b Benzyl 7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylate (200 mg, 0.649 mmol), 6,6-dimethylpiperidine-2,4-dione (101 mg, 0.714 mmol) and A solution of L-proline (3.7 mg, 0.0324 mmol) in acetonitrile (1.0 mL) was stirred at room temperature for 4 days. Water was added to the reaction solution and extracted with dichloromethane, and then the organic layer was dried over anhydrous sodium sulfate. Concentration in vacuo gave the crude title compound.
(102d) Benzyl 2,4-dimethyl-7- (3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H- Chromeno [3,2-c] pyridin-10-yl) -1-benzofuran-5-carboxylate Crude benzyl 7-[(Z)-(6,6-dimethyl-2,4-, prepared in Example 102c Dioxopiperidine-3-ylidene) methyl] -2,4-dimethyl-1-benzofuran-5-carboxylate, dimedone (100 mg, 0.714 mmol), DMF (14 mL), cesium carbonate (529 mg, 1.62 mmol) And methanesulfonyl chloride (61 μL, 0.779 mmol) were used for the reaction and post-treatment according to Example 1b to obtain the title compound (240 mg, 67%, 2 steps).
1 H-NMR (400MHz, CDCl 3 ) δ ppm: 0.85 (3H, s), 1.04 (3H, s), 1.08 (3H, s), 1.27 (3H, s), 2.10 (1H, d, J = 15.7 Hz), 2.22 (1H, d, J = 16.0 Hz), 2.39 (2H, d, J = 17.6 Hz), 2.43-2.51 (1H, m), 2.45 (3H, s), 2.63-2.69 (1H, m ), 2.63 (3H, s), 5.00 (1H, s), 5.14 (1H, s), 5.32 (2H, d, J = 2.0 Hz), 6.39 (1H, d, J = 1.2 Hz), 7.31-7.47 (5H, m), 7.92 (1H, s).
(102e) Benzyl 2,4-dimethyl-7-[(10S) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylate or benzyl 2,4-dimethyl-7-[(10R) -3,3,7,7 -Tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5 -Carboxylate Benzyl 2,4-dimethyl-7- (3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9, prepared in Example 102d 10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl) -1-benzofuran-5-carboxylate (240 mg) was optically resolved with Chiral flash IA (hexane / ethanol; 8: 2). Thus, a high polarity compound (45.6 mg) and a low polarity compound (52.0 mg) were obtained.
(102f) Benzyl 2,4-dimethyl-7-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10 -Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylate or benzyl 2,4-dimethyl-7-[(10R) -2,3,3, 7,7-Pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran -5-carboxylate benzyl 2,4-dimethyl-7-[(10S) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6, prepared in Example 102e 7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylate or benzyl 2,4-dimethyl-7-[(10R) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridine-10- Yl] -1-benzofuran-5-carboxylate (high polarity compound; 45.6 mg, 0.0824 mmol), methyl iodide (6 μL, 0.0988 mmol), DMF (1.0 mL) and sodium hydride (63%, 3.8 mg, 0.0988 mmol) were used for the reaction and post-treatment according to Example 2a to obtain the title compound (31.1 mg, 67%).
1 H-NMR (400MHz, CDCl 3 ) δ ppm: 0.82 (3H, s), 1.03 (3H, s), 1.07 (3H, s), 1.32 (3H, s), 2.08 (1H, d, J = 16.4 Hz), 2.20 (1H, d, J = 16.0 Hz), 2.37 (1H, d, J = 16.8 Hz), 2.41 (1H, d, J = 16.8 Hz), 2.46-2.50 (1H, m), 2.46 ( 3H, s), 2.62-2.67 (1H, m), 2.63 (3H, s), 2.75 (3H, s), 5.15 (1H, s), 5.29 (1H, d, J = 12.5 Hz), 5.34 (1H , d, J = 12.5 Hz), 6.39 (1H, d, J = 1.2 Hz), 7.29-7.47 (5H, m), 7.90 (1H, s).
(102 g) 2,4-Dimethyl-7-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylic acid or 2,4-dimethyl-7-[(10R) -2,3,3,7, 7-Pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5 -Carboxylic acid Benzyl 2,4-dimethyl-7-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7 prepared in Example 102f , 8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylate or benzyl 2,4-dimethyl-7-[(10R) -2 , 3,3,7,7-Pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl ] -1-Benzofuran-5-carboxylate (31.1 mg, 0.0548 mmol), palladium on carbon (10%, 15.0 mg) and ethanol (5.0 mL) were reacted according to Example 18 By performing fine post-treatment to give the title compound (15.7 mg, 60%).
(実施例103)
　2,4-ジメチル-7-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボン酸
又は、2,4-ジメチル-7-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボン酸
(103a) ベンジル　2,4-ジメチル-7-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート
又は、ベンジル　2,4-ジメチル-7-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート
　実施例102eで製造したベンジル　2,4-ジメチル-7-[(10S)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート又は、ベンジル　2,4-ジメチル-7-[(10R)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート(低極性化合物; 51.0 mg, 0.0921 mmol)、ヨウ化メチル(29 μL, 0.461 mmol)、DMF (1.0 mL)及び水素化ナトリウム(63%, 4.2 mg, 0.111 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(31.5 mg, 60%)を得た。
(103b) 2,4-ジメチル-7-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボン酸又は、2,4-ジメチル-7-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボン酸
　実施例103aで製造したベンジル　2,4-ジメチル-7-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレートもしくはベンジル　2,4-ジメチル-7-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート(31.5 mg, 0.0555 mmol)、パラジウム炭素(10%, 15.0 mg)、エタノール(5.0 mL)及びジクロロメタン(1.0 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(21.3 mg, 81%)を得た。 (Example 103)
2,4-Dimethyl-7-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylic acid or 2,4-dimethyl-7-[(10R) -2,3,3,7,7-pentamethyl -1,9-Dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylic acid
(103a) Benzyl 2,4-dimethyl-7-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10 -Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylate or benzyl 2,4-dimethyl-7-[(10R) -2,3,3, 7,7-Pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran -5-carboxylate benzyl 2,4-dimethyl-7-[(10S) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6, prepared in Example 102e 7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylate or benzyl 2,4-dimethyl-7-[(10R) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridine-10- Yl] -1-benzofuran-5-carboxylate (low polarity compound; 51.0 mg, 0.0921 mmol), methyl iodide (29 μL, 0.461 mmol), DMF (1.0 mL) and sodium hydride (63%, 4.2 mg, 0.111 mmol) were used for the reaction and post-treatment according to Example 2a to obtain the title compound (31.5 mg, 60%).
(103b) 2,4-Dimethyl-7-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylic acid or 2,4-dimethyl-7-[(10R) -2,3,3,7, 7-Pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5 -Carboxylic acid Benzyl 2,4-dimethyl-7-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7 prepared in Example 103a , 8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylate or benzyl 2,4-dimethyl-7-[(10R) -2 , 3,3,7,7-Pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl ] -1-Benzofuran-5-carboxylate (31.5 mg, 0.0555 mmol), palladium on carbon (10%, 15.0 mg), ethanol (5.0 mL) and dichloromethane (1.0 mL) By performing the reaction and treatment analogous to Example 18 to give the title compound (21.3 mg, 81%).
(実施例104)
　N-(エチルスルホニル)-6-{4-メトキシ-2-メチル-3-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキサミド
　実施例10bで製造した6-{4-メトキシ-2-メチル-3-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(300 mg, 0.537 mmol)、カルボニルジイミダゾール(268 mg, 1.65 mmol)、DMF (5.0 mL)、エタンスルホンアミド(177 mg, 1.62 mmol)及びDBU (240 μL, 1.60 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(123 mg, 35%)を得た。 (Example 104)
N- (Ethylsulfonyl) -6- {4-methoxy-2-methyl-3-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxamide in Example 10b The prepared 6- {4-methoxy-2-methyl-3-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3, 4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid (300 mg, 0.537 mmol), Using carbonyldiimidazole (268 mg, 1.65 mmol), DMF (5.0 mL), ethanesulfonamide (177 mg, 1.62 mmol) and DBU (240 μL, 1.60 mmol), the reaction and workup were carried out according to Example 6a. This gave the title compound (123 mg, 35%).
(実施例105)
　6-{3-[(3S,10S)-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(105a) tert-ブチル　6-{3-[(3S,10S)-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例77bで製造した(3S,10S)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3-(プロパン-2-イル)-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン(4.10 g, 7.69 mmol)、tert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(2.10 g, 9.22 mmol)、2nd Generation X-Phos Precatalyst (1.21 g, 1.54 mmol)、リン酸カリウム(2.61 g, 12.3 mmol)、THF (60 mL)及び水(80 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(4.47 g, 97%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.35-0.51 (4H, m), 0.88 (3H, d, J = 6.7 Hz), 0.91 (3H, d, J = 6.7 Hz), 1.63 (9H, s), 1.68-1.76 (1H, m), 1.99 (1H, d, J = 17.2 Hz), 2.23 (1H, d, J = 18.0 Hz), 2.37 (1H, d, J = 16.8 Hz), 2.47-2.67 (3H, m), 2.49 (3H, s), 2.84 (3H, s), 3.21-3.27 (1H, m), 3.72 (3H, s), 5.13 (1H, s), 5.22 (1H, s), 6.71 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.38 (1H, d, J = 8.2 Hz), 7.52 (1H, d, J = 8.2 Hz).
(105b) 6-{3-[(3S,10S)-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例105aで製造したtert-ブチル　6-{3-[(3S,10S)-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(616 mg, 1.03 mmol)、ジクロロメタン(6.0 mL)及びトリフルオロ酢酸(3.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(409 mg, 73%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.37-0.53 (4H, m), 0.90 (3H, d, J = 6.7 Hz), 0.93 (3H, d, J = 6.7 Hz), 1.71-1.80 (1H, m), 2.03 (1H, d, J = 16.8 Hz), 2.27 (1H, d, J = 17.6 Hz), 2.39 (1H, d, J = 16.8 Hz), 2.50-2.67 (3H, m), 2.81 (3H, s), 2.82 (3H, s), 3.31-3.37 (1H, m), 3.76 (3H, s), 5.10 (1H, s), 6.19 (1H, s), 6.76 (1H, d, J = 8.6 Hz), 7.20 (1H, d, J = 8.2 Hz), 7.57 (1H, d, J = 7.8 Hz), 7.71 (1H, d, J = 8.6 Hz).
(105c) 6-{3-[(3S,10S)-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例105bで製造した6-{3-[(3S,10S)-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(401 mg, 0.739 mmol)、酢酸エチル(4.0 mL)及びtert-ブチルアミン(85 μL, 0.812 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(419 mg, 91%)を得た。 (Example 105)
6- {3-[(3S, 10S) -1,9-Dioxo-3- (propan-2-yl) -1,2,3,4,6,8,9,10-octahydrospiro [chromeno [ 3,2-c] pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(105a) tert-butyl 6- {3-[(3S, 10S) -1,9-dioxo-3- (propan-2-yl) -1,2,3,4,6,8,9,10- Octahydrospiro [chromeno [3,2-c] pyridine-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate Example 77b (3S, 10S) -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3 -(Propan-2-yl) -3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -1,9 (2H, 8H) -dione ( 4.10 g, 7.69 mmol), tert-butyl 6-chloro-3-methylpyridine-2-carboxylate (2.10 g, 9.22 mmol), 2nd Generation X-Phos Precatalyst (1.21 g, 1.54 mmol), potassium phosphate (2.61 g, 12.3 mmol), THF (60 mL) and water (80 mL) were used for the reaction and workup according to Example 9d to obtain the title compound (4.47 g, 97%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.35-0.51 (4H, m), 0.88 (3H, d, J = 6.7 Hz), 0.91 (3H, d, J = 6.7 Hz), 1.63 (9H , s), 1.68-1.76 (1H, m), 1.99 (1H, d, J = 17.2 Hz), 2.23 (1H, d, J = 18.0 Hz), 2.37 (1H, d, J = 16.8 Hz), 2.47 -2.67 (3H, m), 2.49 (3H, s), 2.84 (3H, s), 3.21-3.27 (1H, m), 3.72 (3H, s), 5.13 (1H, s), 5.22 (1H, s ), 6.71 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.38 (1H, d, J = 8.2 Hz), 7.52 (1H, d, J = 8.2 Hz).
(105b) 6- {3-[(3S, 10S) -1,9-Dioxo-3- (propan-2-yl) -1,2,3,4,6,8,9,10-octahydrospiro [Chromeno [3,2-c] pyridine-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid prepared in Example 105a tert-Butyl 6- {3-[(3S, 10S) -1,9-Dioxo-3- (propan-2-yl) -1,2,3,4,6,8,9,10-octahydrospiro [Chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (616 mg, 1.03 mmol ), Dichloromethane (6.0 mL) and trifluoroacetic acid (3.0 mL) were used for the reaction and post-treatment according to Example 1d to obtain the title compound (409 mg, 73%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.37-0.53 (4H, m), 0.90 (3H, d, J = 6.7 Hz), 0.93 (3H, d, J = 6.7 Hz), 1.71-1.80 (1H, m), 2.03 (1H, d, J = 16.8 Hz), 2.27 (1H, d, J = 17.6 Hz), 2.39 (1H, d, J = 16.8 Hz), 2.50-2.67 (3H, m) , 2.81 (3H, s), 2.82 (3H, s), 3.31-3.37 (1H, m), 3.76 (3H, s), 5.10 (1H, s), 6.19 (1H, s), 6.76 (1H, d , J = 8.6 Hz), 7.20 (1H, d, J = 8.2 Hz), 7.57 (1H, d, J = 7.8 Hz), 7.71 (1H, d, J = 8.6 Hz).
(105c) 6- {3-[(3S, 10S) -1,9-Dioxo-3- (propan-2-yl) -1,2,3,4,6,8,9,10-octahydrospiro [Chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt Examples 6- {3-[(3S, 10S) -1,9-dioxo-3- (propan-2-yl) -1,2,3,4,6,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid (401 mg, 0.739 mmol), ethyl acetate (4.0 mL) and tert-butylamine (85 μL, 0.812 mmol), and the reaction and post-treatment were performed according to Example 3c to obtain the title compound (419 mg, 91%). .
(実施例106)
　6-シクロプロピル-3-メトキシ-2-[(10S)-2,3,3,7,7-ペンタメチル-1,9-dジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]安息香酸
(106a) 10-(3-シクロプロピル-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}フェニル)-3,3,7,7-テトラメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例50bで製造した2-(3-シクロプロピル-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}ベンジリデン)-5,5-ジメチルシクロヘキサン-1,3-ジオン(1.00 g, 2.23 mmol)、6,6-ジメチルピペリジン-2,4-ジオン(330 mg, 2.34 mmol)、DMF (15 mL)、炭酸セシウム(1.60 g, 4.90 mmol)及びN-フェニルビス(トリフルオロメタンメタンスルホンイミド) (836 mg, 2.34 mmol)を用い、実施例9cに準じて反応及び後処理を行うことにより、標記化合物(651 mg, 51%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.44-0.53 (2H, m), 0.65-0.71 (2H, m), 0.93 (3H, s), 1.08 (3H, s), 1.15 (3H, s), 1.28 (3H, s), 1.51-1.53 (1H, m), 2.11-2.34 (4H, m), 2.43 (1H, d, J = 17.6 Hz), 2.63 (1H, d, J = 16.8 Hz), 3.65 (3H, s), 3.80 (3H, s), 4.74 (1H, d, J = 11.3 Hz), 4.78 (1H, d, J = 11.3 Hz), 4.91 (1H, s), 5.16 (1H, d, J = 10.6 Hz), 5.23 (1H, d, J = 11.0 Hz), 5.36 (1H, s), 6.58 (1H, d, J = 8.6 Hz), 6.79 (1H, d, J = 8.6 Hz), 6.86 (2H, d, J = 8.6 Hz), 7.45 (2H, d, J = 8.6 Hz).
(106b) 10-(3-シクロプロピル-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}フェニル)-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例106aで製造した10-(3-シクロプロピル-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}フェニル)-3,3,7,7-テトラメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(651 mg, 1.14 mmol)、ヨウ化メチル(354 μL, 5.69 mmol)、DMF (6.5 mL)及び水素化ナトリウム(55%, 99.4 mg, 2.28 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(558 mg, 84%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.42-0.57 (2H, m), 0.64-0.74 (2H, m), 0.92 (3H, s), 1.07 (6H, s), 1.33 (3H, s), 1.52-1.59 (1H, m), 2.12-2.35 (4H, m), 2.43 (1H, d, J = 17.6 Hz), 2.61 (1H, d, J = 17.6 Hz), 2.78 (3H, s), 3.64 (3H, s), 3.80 (3H, s), 4.75 (1H, d, J = 11.7 Hz), 4.83 (1H, d, J = 11.7 Hz), 5.18 (1H, d, J = 10.6 Hz), 5.33 (1H, d, J = 10.6 Hz), 5.39 (1H, s), 6.58 (1H, d, J = 8.6 Hz), 6.79 (1H, d, J = 8.6 Hz), 6.86 (2H, d, J = 8.6 Hz), 7.47 (2H, d, J = 8.6 Hz).
(106c) (10S)-10-(3-シクロプロピル-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}フェニル)-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例106bで製造した10-(3-シクロプロピル-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}フェニル)-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(540 mg)をChiral flash IC(ヘキサン/エタノール; 3:7)により光学分割し、高極性化合物(153 mg)及び低極性化合物(181 mg)を得た。
(106d) (10S)-10-[3-シクロプロピル-2-(ヒドロキシメチル)-6-メトキシフェニル]-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例106cで製造した(10S)-10-(3-シクロプロピル-6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}フェニル)-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(高極性化合物; 152 mg, 0.260 mmol)、リン酸バッファー(pH6.86, 0.30 mL)、ジクロロメタン(3.0 mL)及び2,3-ジクロロ-5,6-ジシアノ-1,4-ベンゾキノン(70.7 mg, 0.311 mmol)を用い、実施例32kに準じて反応及び後処理を行うことにより、標記化合物(107 mg, 89%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.52-0.59 (1H, m), 0.70-0.77 (1H, m), 0.84-0.95 (2H, m), 0.93 (3H, s), 1.09 (3H, s), 1.10 (3H, s), 1.24-1.28 (1H, m), 1.34 (3H, s), 2.11 (1H, d, J = 16.4 Hz), 2.18-2.36 (3H, m), 2.46 (1H, d, J = 17.2 Hz), 2.64 (1H, d, J = 17.2 Hz), 2.79 (3H, s), 3.67 (3H, s), 5.25 (1H, s), 5.34 (1H, dd, J = 8.0, 12.3 Hz), 5.53 (1H, dd, J = 4.7, 12.1 Hz), 5.75 (1H, dd, J = 4.3, 8.2 Hz), 6.62 (1H, d, J = 8.6 Hz), 6.90 (1H, d, J = 8.6 Hz).
(106e) 6-シクロプロピル-3-メトキシ-2-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]ベンズアルデヒド
　実施例106dで製造した(10S)-10-[3-シクロプロピル-2-(ヒドロキシメチル)-6-メトキシフェニル]-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(105 mg, 0.226 mmol)、ジクロロメタン(2.1 mL)、ヨードベンゼンジアセテート(163 mg, 0.496 mmol)及びnor-AZADO (6.2 mg, 0.0451 mmol)を用い、実施例50fに準じて反応及び後処理を行うことにより、標記化合物(64.0 mg, 61%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.51-0.57 (2H, m), 0.83-0.90 (2H, m), 0.93 (3H, s), 1.08 (3H, s), 1.14 (3H, s), 1.34 (3H, s), 1.51-1.61 (1H, m), 2.12 (1H, d, J = 16.4 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.29-2.47 (3H, m), 2.61 (1H, d, J = 17.2 Hz), 2.79 (3H, s), 3.69 (3H, s), 5.32 (1H, s), 6.77 (1H, d, J = 8.6 Hz), 6.87 (1H, d, J = 8.6 Hz), 11.29 (1H, s).
(106f) 6-シクロプロピル-3-メトキシ-2-[(10S)-2,3,3,7,7-ペンタメチル-1,9-dジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]安息香酸
　実施例106eで製造した6-シクロプロピル-3-メトキシ-2-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]ベンズアルデヒド(64.0 mg, 0.138 mmol)、2-メチル-2-ブテン(326 μL, 2.76 mmol)、りん酸二水素ナトリウム二水和物(108 mg, 0.690 mmol)、水(0.6 mL)、tert-ブタノール(2.6 mL)、ジクロロメタン(0.3 mL)及び亜塩素酸ナトリウム(78.0 mg, 0.690 mmol)を用い、実施例32mに準じて反応及び後処理を行うことにより、標記化合物(49.5 mg, 75%)を得た。 (Example 106)
6-Cyclopropyl-3-methoxy-2-[(10S) -2,3,3,7,7-pentamethyl-1,9-ddioxo-2,3,4,6,7,8,9,10 -Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzoic acid
(106a) 10- (3-Cyclopropyl-6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} phenyl) -3,3,7,7-tetramethyl-3,4,6,7 , 8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 2- (3-cyclopropyl-6-methoxy-2-{[( 4-methoxybenzyl) oxy] methyl} benzylidene) -5,5-dimethylcyclohexane-1,3-dione (1.00 g, 2.23 mmol), 6,6-dimethylpiperidine-2,4-dione (330 mg, 2.34 mmol) ), DMF (15 mL), cesium carbonate (1.60 g, 4.90 mmol) and N-phenylbis (trifluoromethanemethanesulfonimide) (836 mg, 2.34 mmol), and the reaction and workup according to Example 9c. This gave the title compound (651 mg, 51%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.44-0.53 (2H, m), 0.65-0.71 (2H, m), 0.93 (3H, s), 1.08 (3H, s), 1.15 (3H, s), 1.28 (3H, s), 1.51-1.53 (1H, m), 2.11-2.34 (4H, m), 2.43 (1H, d, J = 17.6 Hz), 2.63 (1H, d, J = 16.8 Hz) ), 3.65 (3H, s), 3.80 (3H, s), 4.74 (1H, d, J = 11.3 Hz), 4.78 (1H, d, J = 11.3 Hz), 4.91 (1H, s), 5.16 (1H , d, J = 10.6 Hz), 5.23 (1H, d, J = 11.0 Hz), 5.36 (1H, s), 6.58 (1H, d, J = 8.6 Hz), 6.79 (1H, d, J = 8.6 Hz) ), 6.86 (2H, d, J = 8.6 Hz), 7.45 (2H, d, J = 8.6 Hz).
(106b) 10- (3-Cyclopropyl-6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} phenyl) -2,3,3,7,7-pentamethyl-3,4,6, 7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 10- (3-cyclopropyl-6-methoxy-2-{[[prepared in Example 106a] (4-Methoxybenzyl) oxy] methyl} phenyl) -3,3,7,7-tetramethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine- Performed with 1,9 (2H) -dione (651 mg, 1.14 mmol), methyl iodide (354 μL, 5.69 mmol), DMF (6.5 mL) and sodium hydride (55%, 99.4 mg, 2.28 mmol) The reaction and workup were carried out according to Example 2a to give the title compound (558 mg, 84%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.42-0.57 (2H, m), 0.64-0.74 (2H, m), 0.92 (3H, s), 1.07 (6H, s), 1.33 (3H, s), 1.52-1.59 (1H, m), 2.12-2.35 (4H, m), 2.43 (1H, d, J = 17.6 Hz), 2.61 (1H, d, J = 17.6 Hz), 2.78 (3H, s ), 3.64 (3H, s), 3.80 (3H, s), 4.75 (1H, d, J = 11.7 Hz), 4.83 (1H, d, J = 11.7 Hz), 5.18 (1H, d, J = 10.6 Hz) ), 5.33 (1H, d, J = 10.6 Hz), 5.39 (1H, s), 6.58 (1H, d, J = 8.6 Hz), 6.79 (1H, d, J = 8.6 Hz), 6.86 (2H, d , J = 8.6 Hz), 7.47 (2H, d, J = 8.6 Hz).
(106c) (10S) -10- (3-cyclopropyl-6-methoxy-2-{[(4-methoxybenzyl) oxy] methyl} phenyl) -2,3,3,7,7-pentamethyl-3, 4,6,7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 10- (3-Cyclopropyl-6-methoxy-prepared in Example 106b 2-{[(4-Methoxybenzyl) oxy] methyl} phenyl) -2,3,3,7,7-pentamethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2 -c] Pyridine-1,9 (2H) -dione (540 mg) was optically resolved with Chiral flash IC (hexane / ethanol; 3: 7) to obtain a high polar compound (153 mg) and a low polar compound (181 mg) Got.
(106d) (10S) -10- [3-Cyclopropyl-2- (hydroxymethyl) -6-methoxyphenyl] -2,3,3,7,7-pentamethyl-3,4,6,7,8, 10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (10S) -10- (3-cyclopropyl-6-methoxy-2-{[[prepared in Example 106c] (4-Methoxybenzyl) oxy] methyl} phenyl) -2,3,3,7,7-pentamethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine -1,9 (2H) -dione (high polarity compound; 152 mg, 0.260 mmol), phosphate buffer (pH 6.86, 0.30 mL), dichloromethane (3.0 mL) and 2,3-dichloro-5,6-dicyano The title compound (107 mg, 89%) was obtained by performing reaction and post-treatment according to Example 32k using -1,4-benzoquinone (70.7 mg, 0.311 mmol).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.52-0.59 (1H, m), 0.70-0.77 (1H, m), 0.84-0.95 (2H, m), 0.93 (3H, s), 1.09 ( 3H, s), 1.10 (3H, s), 1.24-1.28 (1H, m), 1.34 (3H, s), 2.11 (1H, d, J = 16.4 Hz), 2.18-2.36 (3H, m), 2.46 (1H, d, J = 17.2 Hz), 2.64 (1H, d, J = 17.2 Hz), 2.79 (3H, s), 3.67 (3H, s), 5.25 (1H, s), 5.34 (1H, dd, J = 8.0, 12.3 Hz), 5.53 (1H, dd, J = 4.7, 12.1 Hz), 5.75 (1H, dd, J = 4.3, 8.2 Hz), 6.62 (1H, d, J = 8.6 Hz), 6.90 ( (1H, d, J = 8.6 Hz).
(106e) 6-cyclopropyl-3-methoxy-2-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9 , 10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzaldehyde (10S) -10- [3-Cyclopropyl-2- (hydroxymethyl) -6-methoxy prepared in Example 106d Phenyl] -2,3,3,7,7-pentamethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione ( 105 mg, 0.226 mmol), dichloromethane (2.1 mL), iodobenzene diacetate (163 mg, 0.496 mmol) and nor-AZADO (6.2 mg, 0.0451 mmol) are used for the reaction and workup according to Example 50f. This gave the title compound (64.0 mg, 61%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.51-0.57 (2H, m), 0.83-0.90 (2H, m), 0.93 (3H, s), 1.08 (3H, s), 1.14 (3H, s), 1.34 (3H, s), 1.51-1.61 (1H, m), 2.12 (1H, d, J = 16.4 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.29-2.47 (3H, m ), 2.61 (1H, d, J = 17.2 Hz), 2.79 (3H, s), 3.69 (3H, s), 5.32 (1H, s), 6.77 (1H, d, J = 8.6 Hz), 6.87 (1H , d, J = 8.6 Hz), 11.29 (1H, s).
(106f) 6-cyclopropyl-3-methoxy-2-[(10S) -2,3,3,7,7-pentamethyl-1,9-ddioxo-2,3,4,6,7,8, 9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzoic acid 6-cyclopropyl-3-methoxy-2-[(10S) -2,3, prepared in Example 106e 3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzaldehyde ( 64.0 mg, 0.138 mmol), 2-methyl-2-butene (326 μL, 2.76 mmol), sodium dihydrogen phosphate dihydrate (108 mg, 0.690 mmol), water (0.6 mL), tert-butanol (2.6 mL), dichloromethane (0.3 mL) and sodium chlorite (78.0 mg, 0.690 mmol) were used in the reaction and after-treatment according to Example 32m to obtain the title compound (49.5 mg, 75%). .
(実施例107)
　6-シクロプロピル-N-(シクロプロピルスルホニル)-3-メトキシ-2-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]ベンズアミド
　実施例50gで製造した6-シクロプロピル-3-メトキシ-2-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]安息香酸(30.0 mg, 0.0608 mmol)のジクロロメタン(0.6 mL)溶液に0℃でビス(2-メトキシエチル)アミノサルファートリフルオリド(16 μL, 0.0729 mmol)を加え、反応溶液を0℃で0.5時間攪拌した。反応溶液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで2回抽出した。有機層を飽和炭酸水素ナトリウム水溶液、次いで飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。有機層を減圧濃縮し、粗製の酸フルオリドを得た。粗製の酸フルオリド及びシクロプロパンスルホンアミド(18.4 mg, 0.152 mmol)のDMF (0.6 mL)溶液に0℃で水素化ナトリウム(55%, 5.3 mg, 0.122 mmol)を加え、反応溶液を室温で12時間攪拌した。反応溶液に10%クエン酸水溶液を加え(pH = 4)、生成した結晶をろ取し、標記化合物(28.6 mg, 79%)を得た。 (Example 107)
6-Cyclopropyl-N- (cyclopropylsulfonyl) -3-methoxy-2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl)- 2,3,4,6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzamide 6-cyclopropyl-3-methoxy-prepared in Example 50 g 2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10-octahydro -1H-chromeno [3,2-c] pyridin-10-yl] benzoic acid (30.0 mg, 0.0608 mmol) in dichloromethane (0.6 mL) at 0 ° C. with bis (2-methoxyethyl) aminosulfur trifluoride (16 μL, 0.0729 mmol) was added and the reaction solution was stirred at 0 ° C. for 0.5 h. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and then with a saturated saline solution and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain crude acid fluoride. To a solution of crude acid fluoride and cyclopropanesulfonamide (18.4 mg, 0.152 mmol) in DMF (0.6 mL) was added sodium hydride (55%, 5.3 mg, 0.122 mmol) at 0 ° C, and the reaction solution was stirred at room temperature for 12 hours. Stir. A 10% aqueous citric acid solution was added to the reaction solution (pH = 4), and the resulting crystals were collected by filtration to obtain the title compound (28.6 mg, 79%).
(実施例108)
　3-メトキシ-2-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-6-(1H-ピラゾール-1-イル)安息香酸
(108a) 10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)フェニル]-3,3,7,7-テトラメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例32hで製造した2-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン(961 mg, 2.03 mmol)、6,6-ジメチルピペリジン-2,4-ジオン(314 mg, 2.23 mmol)、DMF (5.0 mL)、炭酸セシウム(792 mg, 2.43 mmol)、トリブチルホスフィン(0.61 mL, 2.43 mmol)、DMF (13 mL)及びビス(2-メトキシエチル)アゾジカルボキシレート(569 mg, 2.43 mmol)を用い、実施例15aに準じて反応及び後処理を行うことにより、標記化合物(483 mg, 40%)を得た。 (Example 108)
3-Methoxy-2-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -6- (1H-pyrazol-1-yl) benzoic acid
(108a) 10- [6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) phenyl] -3,3,7,7-tetramethyl- 3,4,6,7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 2- [6-methoxy-2- {prepared in Example 32h [(4-Methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) benzylidene] -5,5-dimethylcyclohexane-1,3-dione (961 mg, 2.03 mmol), 6,6- Dimethylpiperidine-2,4-dione (314 mg, 2.23 mmol), DMF (5.0 mL), cesium carbonate (792 mg, 2.43 mmol), tributylphosphine (0.61 mL, 2.43 mmol), DMF (13 mL) and bis ( The title compound (483 mg, 40%) was obtained by carrying out the reaction and post-treatment according to Example 15a using 2-methoxyethyl) azodicarboxylate (569 mg, 2.43 mmol).
1H-NMR(400MHz, DMSO-d6):δ ppm: 0.88 (3H, s), 1.04 (3H, s), 1.07 (3H, s), 1.21 (3H, s), 2.01 (1H, d, J = 18.0 Hz), 2.25 (1H, d, J = 16.4 Hz), 2.38 (2H, d, J = 16.8 Hz), 2.59 (2H, t, J = 18.0 Hz), 3.72 (3H, s), 3.73 (3H, s), 4.25 (1H, d, J = 11.3 Hz), 4.29 (1H, d, J = 11.7 Hz), 4.75 (1H, d, J = 11.0 Hz), 5.02 (1H, d, J = 11.0 Hz), 5.07 (1H, s), 6.40 (1H, t, J = 2.0 Hz), 6.81 (2H, d, J = 8.6 Hz), 6.98 (1H, d, J = 8.6 Hz), 7.12-7.17 (4H, m), 7.63 (1H, d, J = 1.6 Hz), 7.89 (1H, d, J = 2.0 Hz).
(108b) 10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)フェニル]-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例108aで製造した10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)フェニル]-3,3,7,7-テトラメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(480 mg, 0.803 mmol)、ヨウ化メチル(250 μL, 4.02 mmol)、DMF (5.0 mL)及び水素化ナトリウム(63%, 36.7 mg, 0.964 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(410 mg, 84%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.96 (3H, s), 1.06 (3H, s), 1.10 (3H, s), 1.34 (3H, s), 2.22 (2H, s), 2.31 (1H, d, J = 16.8 Hz), 2.34 (1H, d, J = 17.2 Hz), 2.47 (1H, d, J = 17.2 Hz), 2.65 (1H, d, J = 15.3 Hz), 2.78 (3H, s), 3.73 (3H, s), 3.80 (3H, s), 4.48 (1H, d, J = 11.0 Hz), 4.58 (1H, d, J = 11.0 Hz), 4.65 (1H, d, J = 11.3 Hz), 5.29 (1H, d, J = 10.6 Hz), 5.37 (1H, s), 6.29 (1H, t, J = 2.2 Hz), 6.77 (1H, d, J = 9.0 Hz), 6.84 (2H, d, J = 8.6 Hz), 7.22 (1H, d, J = 8.6 Hz), 7.41 (2H, d, J = 8.6 Hz), 7.61 (1H, d, J = 2.0 Hz), 8.07 (1H, d, J = 2.3 Hz).
(108c) (10S)-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)フェニル]-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例108bで製造した10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)フェニル]-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(404 mg)をChiral flash IA(ヘキサン/イソプロパノール; 7:3)により光学分割し、高極性化合物(164 mg)及び低極性化合物(189 mg)を得た。 1 H-NMR (400 MHz, DMSO-d 6 ): δ ppm: 0.88 (3H, s), 1.04 (3H, s), 1.07 (3H, s), 1.21 (3H, s), 2.01 (1H, d, J = 18.0 Hz), 2.25 (1H, d, J = 16.4 Hz), 2.38 (2H, d, J = 16.8 Hz), 2.59 (2H, t, J = 18.0 Hz), 3.72 (3H, s), 3.73 (3H, s), 4.25 (1H, d, J = 11.3 Hz), 4.29 (1H, d, J = 11.7 Hz), 4.75 (1H, d, J = 11.0 Hz), 5.02 (1H, d, J = 11.0 Hz), 5.07 (1H, s), 6.40 (1H, t, J = 2.0 Hz), 6.81 (2H, d, J = 8.6 Hz), 6.98 (1H, d, J = 8.6 Hz), 7.12-7.17 (4H, m), 7.63 (1H, d, J = 1.6 Hz), 7.89 (1H, d, J = 2.0 Hz).
(108b) 10- [6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) phenyl] -2,3,3,7,7-pentamethyl -3,4,6,7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 10- [6-methoxy-2-prepared in Example 108a {[(4-Methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) phenyl] -3,3,7,7-tetramethyl-3,4,6,7,8,10- Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (480 mg, 0.803 mmol), methyl iodide (250 μL, 4.02 mmol), DMF (5.0 mL) and sodium hydride (63%, 36.7 mg, 0.964 mmol) was used for the reaction and post-treatment according to Example 2a to obtain the title compound (410 mg, 84%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.96 (3H, s), 1.06 (3H, s), 1.10 (3H, s), 1.34 (3H, s), 2.22 (2H, s), 2.31 (1H, d, J = 16.8 Hz), 2.34 (1H, d, J = 17.2 Hz), 2.47 (1H, d, J = 17.2 Hz), 2.65 (1H, d, J = 15.3 Hz), 2.78 (3H , s), 3.73 (3H, s), 3.80 (3H, s), 4.48 (1H, d, J = 11.0 Hz), 4.58 (1H, d, J = 11.0 Hz), 4.65 (1H, d, J = 11.3 Hz), 5.29 (1H, d, J = 10.6 Hz), 5.37 (1H, s), 6.29 (1H, t, J = 2.2 Hz), 6.77 (1H, d, J = 9.0 Hz), 6.84 (2H , d, J = 8.6 Hz), 7.22 (1H, d, J = 8.6 Hz), 7.41 (2H, d, J = 8.6 Hz), 7.61 (1H, d, J = 2.0 Hz), 8.07 (1H, d , J = 2.3 Hz).
(108c) (10S) -10- [6-Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) phenyl] -2,3,3,7 , 7-Pentamethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 10- [6- Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) phenyl] -2,3,3,7,7-pentamethyl-3,4,6,7 , 8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (404 mg) optically resolved with Chiral flash IA (hexane / isopropanol; 7: 3) A polar compound (164 mg) and a low polarity compound (189 mg) were obtained.
(108d) (10S)-10-[2-(ヒドロキシメチル)-6-メトキシ-3-(1H-ピラゾール-1-イル)フェニル]-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例108cで製造した(10S)-10-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(1H-ピラゾール-1-イル)フェニル]-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(高極性化合物; 159 mg, 0.260 mmol)及びリン酸バッファー(pH6.86, 0.20 mL)、ジクロロメタン(2.0 mL)及び2,3-ジクロロ-5,6-ジシアノ-1,4-ベンゾキノン(70.8 mg, 0.312 mmol)を用い、実施例32kに準じて反応及び後処理を行うことにより、標記化合物(115 mg, 90%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.95 (3H, s), 1.10 (3H, s), 1.14 (3H, s), 1.36 (3H, s), 2.14 (1H, dd, J = 1.2, 16.8 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.36 (1H, dd, J = 1.2, 18.0 Hz), 2.38 (1H, d, J = 16.8 Hz), 2.49 (1H, d, J = 17.6 Hz), 2.67 (1H, dd, J = 1.6, 17.2 Hz), 2.81 (3H, s), 3.76 (3H, s), 4.78 (1H, dd, J = 7.6, 12.7 Hz), 5.18 (1H, dd, J = 5.1, 12.5 Hz), 5.24 (1H, s), 6.15 (1H, dd, J = 4.7, 7.8 Hz), 6.40 (1H, t, J = 2.2 Hz), 6.83 (1H, d, J = 8.6 Hz), 7.41 (1H, d, J = 8.6 Hz), 7.67 (1H, d, J = 1.2 Hz), 8.28 (1H, d, J = 2.3 Hz).
(108e) 3-メトキシ-2-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-6-(1H-ピラゾール-1-イル)ベンズアルデヒド
　実施例108dで製造した(10S)-10-[2-(ヒドロキシメチル)-6-メトキシ-3-(1H-ピラゾール-1-イル)フェニル]-2,3,3,7,7-ペンタメチル-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(111 mg, 0.226 mmol)、ジクロロメタン(2.0 mL)、デスマーチンペルヨージナン(149 mg, 0.319 mmol)を用い、実施例32lに準じて反応及び後処理を行うことにより、標記化合物(101 mg, 91%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.95 (3H, s), 1.10 (3H, s), 1.16 (3H, s), 1.34 (3H, s), 2.12 (1H, d, J = 16.4 Hz), 2.23 (1H, d, J = 16.4 Hz), 2.32 (1H, d, J = 17.6 Hz), 2.38 (1H, d, J = 16.8 Hz), 2.47 (1H, d, J = 16.4 Hz), 2.60 (1H, d, J = 14.9 Hz), 2.79 (3H, s), 3.77 (3H, s), 5.46 (1H, s), 6.38 (1H, t, J = 2.2 Hz), 6.93 (1H, d, J = 9.0 Hz), 7.30 (1H, d, J = 8.6 Hz), 7.65 (1H, d, J = 1.2 Hz), 7.70 (1H, d, J = 2.3 Hz), 10.59 (1H, s).
(108f) 3-メトキシ-2-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-6-(1H-ピラゾール-1-イル)安息香酸
　実施例108eで製造した3-メトキシ-2-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-6-(1H-ピラゾール-1-イル)ベンズアルデヒド(96.0 mg, 0.196 mmol)、2-メチル-2-ブテン(460 μL, 3.92 mmol)、りん酸二水素ナトリウム二水和物(153 mg, 0.980 mmol)、水(1.5 mL)、t-ブタノール(6.0 mL)、ジクロロメタン(0.8 mL)及び亜塩素酸ナトリウム(111 mg, 0.980 mmol)を用い、実施例32mに準じて反応及び後処理を行うことにより、標記化合物(59.7 mg, 60%)を得た。 (108d) (10S) -10- [2- (Hydroxymethyl) -6-methoxy-3- (1H-pyrazol-1-yl) phenyl] -2,3,3,7,7-pentamethyl-3,4 , 6,7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (10S) -10- [6-Methoxy-2-] prepared in Example 108c {[(4-Methoxybenzyl) oxy] methyl} -3- (1H-pyrazol-1-yl) phenyl] -2,3,3,7,7-pentamethyl-3,4,6,7,8,10 -Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (high polarity compound; 159 mg, 0.260 mmol) and phosphate buffer (pH 6.86, 0.20 mL), dichloromethane (2.0 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (70.8 mg, 0.312 mmol), and the reaction and workup according to Example 32k gave the title compound (115 mg , 90%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.95 (3H, s), 1.10 (3H, s), 1.14 (3H, s), 1.36 (3H, s), 2.14 (1H, dd, J = 1.2, 16.8 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.36 (1H, dd, J = 1.2, 18.0 Hz), 2.38 (1H, d, J = 16.8 Hz), 2.49 (1H, d, J = 17.6 Hz), 2.67 (1H, dd, J = 1.6, 17.2 Hz), 2.81 (3H, s), 3.76 (3H, s), 4.78 (1H, dd, J = 7.6, 12.7 Hz), 5.18 ( 1H, dd, J = 5.1, 12.5 Hz), 5.24 (1H, s), 6.15 (1H, dd, J = 4.7, 7.8 Hz), 6.40 (1H, t, J = 2.2 Hz), 6.83 (1H, d , J = 8.6 Hz), 7.41 (1H, d, J = 8.6 Hz), 7.67 (1H, d, J = 1.2 Hz), 8.28 (1H, d, J = 2.3 Hz).
(108e) 3-Methoxy-2-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl] -6- (1H-pyrazol-1-yl) benzaldehyde (10S) -10- [2- (hydroxymethyl) -6 prepared in Example 108d -Methoxy-3- (1H-pyrazol-1-yl) phenyl] -2,3,3,7,7-pentamethyl-3,4,6,7,8,10-hexahydro-1H-chromeno [3,2 -c] pyridine-1,9 (2H) -dione (111 mg, 0.226 mmol), dichloromethane (2.0 mL), desmartin periodinane (149 mg, 0.319 mmol) and the reaction according to Example 32l The title compound (101 mg, 91%) was obtained by post-treatment.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.95 (3H, s), 1.10 (3H, s), 1.16 (3H, s), 1.34 (3H, s), 2.12 (1H, d, J = 16.4 Hz), 2.23 (1H, d, J = 16.4 Hz), 2.32 (1H, d, J = 17.6 Hz), 2.38 (1H, d, J = 16.8 Hz), 2.47 (1H, d, J = 16.4 Hz) ), 2.60 (1H, d, J = 14.9 Hz), 2.79 (3H, s), 3.77 (3H, s), 5.46 (1H, s), 6.38 (1H, t, J = 2.2 Hz), 6.93 (1H , d, J = 9.0 Hz), 7.30 (1H, d, J = 8.6 Hz), 7.65 (1H, d, J = 1.2 Hz), 7.70 (1H, d, J = 2.3 Hz), 10.59 (1H, s ).
(108f) 3-Methoxy-2-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl] -6- (1H-pyrazol-1-yl) benzoic acid 3-methoxy-2-[(10S) -2,3 prepared in Example 108e , 3,7,7-Pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl]- 6- (1H-pyrazol-1-yl) benzaldehyde (96.0 mg, 0.196 mmol), 2-methyl-2-butene (460 μL, 3.92 mmol), sodium dihydrogen phosphate dihydrate (153 mg, 0.980 mmol ), Water (1.5 mL), t-butanol (6.0 mL), dichloromethane (0.8 mL) and sodium chlorite (111 mg, 0.980 mmol), and by performing the reaction and post-treatment according to Example 32m. The title compound (59.7 mg, 60%) was obtained.
(実施例109)
　6-シクロプロピル-N-(2-ヒドロキシエチル)-3-メトキシ-2-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]ベンズアミド
　実施例50gで製造した6-シクロプロピル-3-メトキシ-2-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]安息香酸(40.0 mg, 0.0810 mmol)のジクロロメタン(0.4 mL)溶液に0℃でビス(2-メトキシエチル)アミノサルファートリフルオリド(19 μL, 0.0891 mmol)を加え、反応溶液を0℃で0.5時間攪拌した。反応溶液に0℃でDMF (0.8 mL)、2-アミノエタノール(9.9 mg, 0.162 mmol)及びジイソプロピルエチルアミン(55 μL, 0.324 mmol)を順次加え、反応溶液を50℃で4時間攪拌した。空冷後、反応溶液に10%クエン酸を加え、酢酸エチルで2回抽出した。有機層を水及び飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/メタノール; 4:1)で精製し、標記化合物(31.5 mg, 72%)をコンフォマーの混合物として得た。 (Example 109)
6-Cyclopropyl-N- (2-hydroxyethyl) -3-methoxy-2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzamide 6-cyclopropyl-3-methoxy prepared in Example 50g -2-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] benzoic acid (40.0 mg, 0.0810 mmol) in dichloromethane (0.4 mL) at 0 ° C. with bis (2-methoxyethyl) aminosulfur trifluoride ( 19 μL, 0.0891 mmol) was added, and the reaction solution was stirred at 0 ° C. for 0.5 hour. DMF (0.8 mL), 2-aminoethanol (9.9 mg, 0.162 mmol) and diisopropylethylamine (55 μL, 0.324 mmol) were sequentially added to the reaction solution at 0 ° C., and the reaction solution was stirred at 50 ° C. for 4 hours. After air cooling, 10% citric acid was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / methanol; 4: 1) to obtain the title compound (31.5 mg, 72%) as a mixture of conformers.
(実施例110)
　6-{4-メトキシ-2-メチル-3-[2,3,3-トリメチル-1,9-ジオキソ-7-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
(110a) 2-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]-5-(プロパン-2-イル)シクロヘキサン-1,3-ジオン
　実施例9aで製造した6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンズアルデヒド(2.00 g, 7.24 mmol)、アセトニトリル(10 mL)、5-(プロパン-2-イル)シクロヘキサン-1,3-ジオン(2.23 g, 14.5 mmol)及びDL-プロリン(41.7 mg, 0.362 mmol)を用い、実施例41aに準じて反応及び後処理を行うことにより、標記化合物(1.86 g, 62%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.97 (3H, d, J = 7.4 Hz), 0.97 (3H, d, J = 7.4 Hz), 1.32 (12H, s), 1.64-1.72 (1H, m), 1.94-2.01 (1H, m), 2.38-2.49 (2H, m), 2.45 (3H, s), 2.66-2.72 (1H, m), 2.77-2.83 (1H, m), 3.75 (3H, s), 6.70 (1H, d, J = 8.2 Hz), 7.78 (1H, d, J = 8.2 Hz), 7.92 (1H, s).
(110b) 10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3-ジメチル-7-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例110aで製造した2-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]-5-(プロパン-2-イル)シクロヘキサン-1,3-ジオン(500 mg, 1.21 mmol)、6,6-ジメチルピペリジン-2,4-ジオン(188 mg, 1.33 mmol)、DMF (5.0 mL)、炭酸セシウム(988 mg, 3.03 mmol)及びN-フェニルビス(トリフルオロメタンメタンスルホンイミド) (476 mg, 1.33 mmol)を用い、実施例9cに準じて反応及び後処理を行うことにより、標記化合物(290 mg, 45%)をジアステレオマー混合物として得た。
(110c) tert-ブチル　6-{3-[3,3-ジメチル-1,9-ジオキソ-7-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例110bで製造した10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3-ジメチル-7-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(326 mg, 0.609 mmol)、tert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(, 166 mg, 0.731 mmol)、2nd Generation X-Phos Precatalyst (9.6 mg, 0.0122 mmol)、リン酸カリウム(194 mg, 0.913 mmol)、THF (3.0 mL)及び水(6.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(293 mg, 80%)をジアステレオマー混合物として得た。
(110d) tert-ブチル　6-{4-メトキシ-2-メチル-3-[2,3,3-トリメチル-1,9-ジオキソ-7-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例110cで製造したtert-ブチル　6-{3-[3,3-ジメチル-1,9-ジオキソ-7-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(288 mg, 0.479 mmol)、ヨウ化メチル(298 μL, 4.79 mmol)、DMF (3.0 mL)及び水素化ナトリウム(63%, 36.5 mg, 0.959 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(65.5 mg, 22%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.91 (3H, d, J = 6.3 Hz), 0.93 (3H, d, J = 6.7 Hz), 1.12 (3H, s), 1.34 (3H, s), 1.54-1.61 (1H, m), 1.63 (9H, s), 1.69-1.79 (1H, m), 2.03 (1H, dd, J = 13.3, 16.4 Hz), 2.27-2.34 (2H, m), 2.41 (1H, d, J = 16.0 Hz), 2.49-2.55 (1H, m), 2.49 (3H, s), 2.63 (1H, d, J = 16.8 Hz), 2.79 (3H, s), 2.87 (3H, s), 3.73 (3H, s), 5.17 (1H, s), 6.71 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 7.0 Hz), 7.37 (1H, d, J = 7.8 Hz), 7.52 (2H, d, J = 7.8 Hz).
(110e) 6-{4-メトキシ-2-メチル-3-[2,3,3-トリメチル-1,9-ジオキソ-7-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例110dで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[2,3,3-トリメチル-1,9-ジオキソ-7-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(65.5 mg, 0.107 mmol)、ジクロロメタン(2.0 mL)及びトリフルオロ酢酸(2.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(54.2 mg, 91%)を得た。 (Example 110)
6- {4-Methoxy-2-methyl-3- [2,3,3-trimethyl-1,9-dioxo-7- (propan-2-yl) -2,3,4,6,7,8, 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid
(110a) 2- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] -5- (propane-2- Yl) cyclohexane-1,3-dione 6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde prepared in Example 9a (2.00 g, 7.24 mmol), acetonitrile (10 mL), 5- (propan-2-yl) cyclohexane-1,3-dione (2.23 g, 14.5 mmol) and DL-proline (41.7 mg, 0.362 mmol) The title compound (1.86 g, 62%) was obtained by carrying out the reaction and post-treatment according to Example 41a.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.97 (3H, d, J = 7.4 Hz), 0.97 (3H, d, J = 7.4 Hz), 1.32 (12H, s), 1.64-1.72 (1H , m), 1.94-2.01 (1H, m), 2.38-2.49 (2H, m), 2.45 (3H, s), 2.66-2.72 (1H, m), 2.77-2.83 (1H, m), 3.75 (3H , s), 6.70 (1H, d, J = 8.2 Hz), 7.78 (1H, d, J = 8.2 Hz), 7.92 (1H, s).
(110b) 10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3-dimethyl-7 -(Propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione prepared in Example 110a 2 -[6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] -5- (propan-2-yl) cyclohexane- 1,3-dione (500 mg, 1.21 mmol), 6,6-dimethylpiperidine-2,4-dione (188 mg, 1.33 mmol), DMF (5.0 mL), cesium carbonate (988 mg, 3.03 mmol) and N The title compound (290 mg, 45%) was obtained as a diastereomeric mixture by reacting and working up according to Example 9c using -phenylbis (trifluoromethanemethanesulfonimide) (476 mg, 1.33 mmol). Obtained.
(110c) tert-butyl 6- {3- [3,3-dimethyl-1,9-dioxo-7- (propan-2-yl) -2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate 10- [6-methoxy prepared in Example 110b -2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3-dimethyl-7- (propan-2-yl)- 3,4,6,7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (326 mg, 0.609 mmol), tert-butyl 6-chloro-3 -Methylpyridine-2-carboxylate (, 166 mg, 0.731 mmol), 2nd Generation X-Phos Precatalyst (9.6 mg, 0.0122 mmol), potassium phosphate (194 mg, 0.913 mmol), THF (3.0 mL) and water ( 6.0 mL) was used for the reaction and post-treatment according to Example 9d to obtain the title compound (293 mg, 80%) as a diastereomeric mixture.
(110d) tert-butyl 6- {4-methoxy-2-methyl-3- [2,3,3-trimethyl-1,9-dioxo-7- (propan-2-yl) -2,3,4, 6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylate tert-Butyl prepared in Example 110c 6 -{3- [3,3-Dimethyl-1,9-dioxo-7- (propan-2-yl) -2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3 , 2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (288 mg, 0.479 mmol), methyl iodide (298 μL, 4.79 mmol), The title compound (65.5 mg, 22%) was obtained by performing reaction and post-treatment according to Example 2a using DMF (3.0 mL) and sodium hydride (63%, 36.5 mg, 0.959 mmol).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.91 (3H, d, J = 6.3 Hz), 0.93 (3H, d, J = 6.7 Hz), 1.12 (3H, s), 1.34 (3H, s ), 1.54-1.61 (1H, m), 1.63 (9H, s), 1.69-1.79 (1H, m), 2.03 (1H, dd, J = 13.3, 16.4 Hz), 2.27-2.34 (2H, m), 2.41 (1H, d, J = 16.0 Hz), 2.49-2.55 (1H, m), 2.49 (3H, s), 2.63 (1H, d, J = 16.8 Hz), 2.79 (3H, s), 2.87 (3H , s), 3.73 (3H, s), 5.17 (1H, s), 6.71 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 7.0 Hz), 7.37 (1H, d, J = 7.8 Hz), 7.52 (2H, d, J = 7.8 Hz).
(110e) 6- {4-Methoxy-2-methyl-3- [2,3,3-trimethyl-1,9-dioxo-7- (propan-2-yl) -2,3,4,6,7 , 8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butyl 6- {4 prepared in Example 110d -Methoxy-2-methyl-3- [2,3,3-trimethyl-1,9-dioxo-7- (propan-2-yl) -2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylate (65.5 mg, 0.107 mmol), dichloromethane (2.0 mL) and trifluoroacetic acid (2.0 mL) The title compound (54.2 mg, 91%) was obtained by reaction and workup according to Example 1d.
(実施例111)
　7-[(10S)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2,4-ジメチル-1-ベンゾフラン-5-カルボン酸
又は、7-[(10R) -2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2,4-ジメチル-1-ベンゾフラン-5-カルボン酸
(111a) ベンジル　7-[(10S)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート
又は、ベンジル　7-[(10R) -2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート
　実施例102eで製造したベンジル　2,4-ジメチル-7-[(10S)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート又はベンジル　2,4-ジメチル-7-[(10R)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート(低極性化合物; 438 mg, 0.792 mmol)、ヨウ化エチル(510 μL, 6.40 mmol)、DMPU (1.0 mL)及び水素化ナトリウム(63%, 62.2 mg, 1.63 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(101 mg, 22%)を得た。
1H-NMR (400MHz, CDCl3) δ　ppm: 0.83 (3H, s), 1.03-1.07 (3H, m), 1.03 (3H, s), 1.07 (3H, s), 1.38 (3H, s), 2.08 (1H, d, J = 15.2 Hz), 2.20 (1H, d, J = 16.4 Hz), 2.35 (1H, d, J = 17.0 Hz), 2.38 (1H, d, J = 17.6 Hz), 2.46 (3H, s), 2.47 (1H, d, J = 17.6 Hz), 2.63 (3H, s), 2.69 (1H, d, J = 16.4 Hz), 2.94-3.03 (1H, m), 3.43-3.52 (1H, m), 5.17 (1H, s), 5.29 (1H, d, J = 12.1 Hz), 5.34 (1H, d, J = 12.1 Hz), 6.39 (1H, s), 7.30-7.47 (5H, m), 7.90 (1H, s).
(111b) 7-[(10S)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2,4-ジメチル-1-ベンゾフラン-5-カルボン酸
又は、7-[(10R) -2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2,4-ジメチル-1-ベンゾフラン-5-カルボン酸
　実施例111aで製造したベンジル　7-[(10S)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートもしくはベンジル　7-[(10R) -2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート(101 mg, 0.174 mmol)、パラジウム炭素(10%, 14.0 mg)、メタノール(3.0 mL)及びTHF (3.0 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(85.5 mg, 99%)を得た。 (Example 111)
7-[(10S) -2-Ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [ 3,2-c] pyridin-10-yl] -2,4-dimethyl-1-benzofuran-5-carboxylic acid or 7-[(10R) -2-ethyl-3,3,7,7-tetramethyl -1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -2,4-dimethyl-1- Benzofuran-5-carboxylic acid
(111a) Benzyl 7-[(10S) -2-ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl] -2,4-dimethyl-1-benzofuran-5-carboxylate or benzyl 7-[(10R) -2-ethyl-3,3,7 , 7-Tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -2,4 -Dimethyl-1-benzofuran-5-carboxylate benzyl 2,4-dimethyl-7-[(10S) -3,3,7,7-tetramethyl-1,9-dioxo-2, prepared in Example 102e 3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylate or benzyl 2,4-dimethyl-7 -[(10R) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c ] Pyridin-10-yl] -1-benzofuran-5-carboxylate (low polarity compound; 438 mg, 0.792 mmol), ethyl iodide (510 μL, 6.40 mmol), DMPU (1.0 mL) and sodium hydride (63%, 62.2 mg, 1.63 mmol), and the reaction and workup according to Example 2a gave the title compound (101 mg, 22%). Obtained.
1 H-NMR (400MHz, CDCl 3 ) δ ppm: 0.83 (3H, s), 1.03-1.07 (3H, m), 1.03 (3H, s), 1.07 (3H, s), 1.38 (3H, s), 2.08 (1H, d, J = 15.2 Hz), 2.20 (1H, d, J = 16.4 Hz), 2.35 (1H, d, J = 17.0 Hz), 2.38 (1H, d, J = 17.6 Hz), 2.46 ( 3H, s), 2.47 (1H, d, J = 17.6 Hz), 2.63 (3H, s), 2.69 (1H, d, J = 16.4 Hz), 2.94-3.03 (1H, m), 3.43-3.52 (1H , m), 5.17 (1H, s), 5.29 (1H, d, J = 12.1 Hz), 5.34 (1H, d, J = 12.1 Hz), 6.39 (1H, s), 7.30-7.47 (5H, m) , 7.90 (1H, s).
(111b) 7-[(10S) -2-Ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -2,4-dimethyl-1-benzofuran-5-carboxylic acid or 7-[(10R) -2-ethyl-3,3,7,7 -Tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -2,4-dimethyl -1-Benzofuran-5-carboxylic acid benzyl 7-[(10S) -2-ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4, prepared in Example 111a 6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -2,4-dimethyl-1-benzofuran-5-carboxylate or benzyl 7-[(10R ) -2-Ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c ] Pyridin-10-yl] -2,4-dimethyl-1-benzofuran-5-carboxylate (101 mg, 0.174 mmol), palladium on carbon (10%, 14.0 mg), methanol (3.0 mL) and Using THF (3.0 mL), by carrying out the reaction and treatment analogous to Example 18 to give the title compound (85.5 mg, 99%).
(実施例112)
　2,4-ジメチル-7-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボン酸
(112a) ベンジル　7-[(4,4-ジメチル-2,6-ジオキソシクロヘキシリデン)メチル]-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート
実施例102bで製造したベンジル　7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート(2.00 g, 6.49 mmol)及びピロリジン(590 μL, 7.20 mmol)のトルエン(20 mL)溶液に室温でジメドン(1.04 g, 7.42 mmol)を加え、反応溶液を室温で40分間攪拌した。反応溶液に酢酸エチル(50 mL)及び0.5 M塩酸(30 mL)を加えて、反応溶液を室温でさらに24時間攪拌した。反応溶液を酢酸エチルで抽出後、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し、粗製の標記化合物を得た。
(112b) ベンジル　7-[(3S,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート
　実施例112aで製造した粗製のベンジル　7-[(4,4-ジメチル-2,6-ジオキソシクロヘキシリデン)メチル]-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート及び公知化合物である(6S)-6-(プロパン-2-イル)ピペリジン-2,4-ジオン(398 mg, 2.56 mmol)、DMF (20 mL)、炭酸セシウム(2.01 g, 6.17 mmol)及びメタンスルホニルクロリド(220 μL, 2.80 mmol)を用い、実施例1bに準じて反応及び後処理を行うことにより、標記化合物(481 mg, 37%, 2 steps)を得た。
1H-NMR (400MHz, CDCl3) δ　ppm: 0.78 (3H, d, J = 6.7 Hz), 0.82 (3H, d, J = 7.3 Hz), 0.84 (3H, s), 1.08 (3H, s), 1.60-1.66 (1H, m), 2.09 (1H, d, J = 16.4 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.38 (1H, d, J = 17.6 Hz), 2.45-2.55 (2H, m), 2.45 (3H, s), 2.62-2.69 (1H, m), 2.63 (3H, s), 3.31-3.36 (1H, m), 5.08 (1H, s), 5.16 (1H, s), 5.32 (2H, s), 6.40 (1H, s), 7.30-7.48 (5H, m), 7.90 (1H, s).
(112c) ベンジル　2,4-ジメチル-7-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート
　実施例112bで製造したベンジル　7-[(3S,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート(481 mg, 0.848 mmol)、ヨウ化メチル(490 μL, 7.90 mmol)、DMF (10 mL)及び水素化ナトリウム(63%, 48.0 mg, 1.26 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(435 mg, 88%)を得た。
1H-NMR (400MHz, CDCl3) δ　ppm: 0.59 (3H, d, J = 6.7 Hz), 0.73 (3H, d, J = 7.3 Hz), 0.86 (3H, s), 1.07 (3H, s), 1.80-1.89 (1H, m), 2.09 (1H, d, J = 16.4 Hz), 2.20 (1H, d, J = 17.0 Hz), 2.38 (1H, d, J = 17.6 Hz), 2.43-2.51 (2H, m), 2.46 (3H, s), 2.63 (3H, s), 2.86-2.93 (1H, m), 2.88 (3H, s), 3.16 (1H, t, J = 6.4 Hz), 5.19 (1H, s), 5.29 (1H, d, J = 12.8 Hz), 5.33 (1H, d, J = 12.8 Hz), 6.38 (1H, s), 7.30-7.52 (5H, m), 7.88 (1H, s).
(112d) 2,4-ジメチル-7-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボン酸
　実施例112cで製造したベンジル　2,4-ジメチル-7-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート(435 mg, 0.748 mmol)、パラジウム炭素(10%, 65.0 mg)及びメタノール(15 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(251 mg, 68%)を得た。 (Example 112)
2,4-Dimethyl-7-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8 , 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylic acid
(112a) Benzyl 7-[(4,4-dimethyl-2,6-dioxocyclohexylidene) methyl] -2,4-dimethyl-1-benzofuran-5-carboxylate The benzyl 7- prepared in Example 102b Dimedone (1.04 g, 7.42 mmol) in a solution of formyl-2,4-dimethyl-1-benzofuran-5-carboxylate (2.00 g, 6.49 mmol) and pyrrolidine (590 μL, 7.20 mmol) in toluene (20 mL) at room temperature And the reaction solution was stirred at room temperature for 40 minutes. Ethyl acetate (50 mL) and 0.5 M hydrochloric acid (30 mL) were added to the reaction solution, and the reaction solution was further stirred at room temperature for 24 hours. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude title compound.
(112b) Benzyl 7-[(3S, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10 -Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -2,4-dimethyl-1-benzofuran-5-carboxylate Crude benzyl 7-[(4,4) prepared in Example 112a -Dimethyl-2,6-dioxocyclohexylidene) methyl] -2,4-dimethyl-1-benzofuran-5-carboxylate and the known compound (6S) -6- (propan-2-yl) piperidine- Using 2,4-dione (398 mg, 2.56 mmol), DMF (20 mL), cesium carbonate (2.01 g, 6.17 mmol) and methanesulfonyl chloride (220 μL, 2.80 mmol) and reacting according to Example 1b The title compound (481 mg, 37%, 2 steps) was obtained by post-treatment.
1 H-NMR (400MHz, CDCl 3 ) δ ppm: 0.78 (3H, d, J = 6.7 Hz), 0.82 (3H, d, J = 7.3 Hz), 0.84 (3H, s), 1.08 (3H, s) , 1.60-1.66 (1H, m), 2.09 (1H, d, J = 16.4 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.38 (1H, d, J = 17.6 Hz), 2.45-2.55 ( 2H, m), 2.45 (3H, s), 2.62-2.69 (1H, m), 2.63 (3H, s), 3.31-3.36 (1H, m), 5.08 (1H, s), 5.16 (1H, s) , 5.32 (2H, s), 6.40 (1H, s), 7.30-7.48 (5H, m), 7.90 (1H, s).
(112c) Benzyl 2,4-dimethyl-7-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6 , 7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylate benzyl 7-[(3S, 10S prepared in Example 112b ) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2- c] Pyridin-10-yl] -2,4-dimethyl-1-benzofuran-5-carboxylate (481 mg, 0.848 mmol), methyl iodide (490 μL, 7.90 mmol), DMF (10 mL) and hydrogenation The title compound (435 mg, 88%) was obtained by performing the reaction and post-treatment according to Example 2a using sodium (63%, 48.0 mg, 1.26 mmol).
1 H-NMR (400MHz, CDCl 3 ) δ ppm: 0.59 (3H, d, J = 6.7 Hz), 0.73 (3H, d, J = 7.3 Hz), 0.86 (3H, s), 1.07 (3H, s) , 1.80-1.89 (1H, m), 2.09 (1H, d, J = 16.4 Hz), 2.20 (1H, d, J = 17.0 Hz), 2.38 (1H, d, J = 17.6 Hz), 2.43-2.51 ( 2H, m), 2.46 (3H, s), 2.63 (3H, s), 2.86-2.93 (1H, m), 2.88 (3H, s), 3.16 (1H, t, J = 6.4 Hz), 5.19 (1H , s), 5.29 (1H, d, J = 12.8 Hz), 5.33 (1H, d, J = 12.8 Hz), 6.38 (1H, s), 7.30-7.52 (5H, m), 7.88 (1H, s) .
(112d) 2,4-Dimethyl-7-[(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6, 7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylic acid benzyl 2,4-dimethyl-7-prepared in Example 112c [(3S, 10S) -2,7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylate (435 mg, 0.748 mmol), palladium on carbon (10%, 65.0 mg) and methanol (15 mL) The title compound (251 mg, 68%) was obtained by carrying out the reaction and post-treatment according to Example 18.
(実施例113)
　7-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2,4-ジメチル-1-ベンゾフラン-5-カルボン酸
(113a) ベンジル　7-[(4,4-ジメチル-2,6-ジオキソシクロヘキシリデン)メチル]-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート
　実施例102bで製造したベンジル　7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート(2.00 g, 6.49 mmol)及びピロリジン(590 μL, 7.20 mmol)のトルエン(20 mL)溶液に室温でジメドン(1.04 g, 7.42 mmol)を加え、反応溶液を室温で40分間攪拌した。反応溶液に酢酸エチル(50 mL)及び0.5 M塩酸(30 mL)を加えて、反応溶液を室温でさらに24時間攪拌した。反応溶液を酢酸エチルで抽出後、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し、粗製の標記化合物を得た。
(113b) ベンジル　7-[(S)-[(6S)-6-tert-ブチル-2,4-ジオキソピペリジン-3-イル](4,4-ジメチル-2,6-ジオキソシクロヘキシル)メチル]-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート
　実施例113aで製造した粗製のベンジル　7-[(4,4-ジメチル-2,6-ジオキソシクロヘキシリデン)メチル]-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート及び実施例22cで製造した(6S)-6-tert-ブチルピペリジン-2,4-ジオン(434 mg, 2.56 mmol)、DMF (20 mL)及び炭酸セシウム(1.91 g, 5.86 mmol)を用い、実施例14bに準じて反応及び後処理を行うことにより、標記化合物(788 mg, 57%, 2 steps)をコンフォマーの混合物として得た。
(113c) ベンジル　7-[(3S,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート
　実施例113bで製造したベンジル　7-[(S)-[(6S)-6-tert-ブチル-2,4-ジオキソピペリジン-3-イル](4,4-ジメチル-2,6-ジオキソシクロヘキシル)メチル]-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート(788 mg, 1.31 mmol)及び炭酸セシウム(1.13 g, 3.47 mmol)のDMF (15 mL)溶液に室温でN-フェニルビス(トリフルオロメタンスルホンイミド) (943 mg, 2.64 mmol)を加え、反応溶液を室温で6時間攪拌した。反応溶液に水を加え、酢酸エチルで抽出した。有機層を水で洗浄、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル)で精製し、標記化合物(706 mg, 92%)を得た。
1H-NMR (400MHz, CDCl3) δ　ppm: 0.80 (9H, s), 0.85 (3H, s), 1.09 (3H, s), 2.09 (1H, d, J = 16.4 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.39 (1H, d, J = 17.6 Hz), 2.45 (3H, s), 2.50 (1H, d, J = 17.6 Hz), 2.56-2.63 (2H, m), 2.63 (3H, s), 3.29 (1H, t, J = 7.6 Hz), 5.08 (1H, s), 5.19 (1H, s), 5.32 (2H, s), 6.39 (1H, s), 7.29-7.47 (5H, m), 7.87 (1H, s).
(113d) ベンジル　7-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート
　実施例113cで製造したベンジル　7-[(3S,10S)-3-tert-ブチル-7,7-ジメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート(352 mg, 0.605 mmol)、ヨウ化メチル(300 μL, 5.00 mmol)、DMF (6.0 mL)及び水素化ナトリウム(63%, 34.8 mg, 0.914 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(285 mg, 79%)を得た。
1H-NMR (400MHz, CDCl3) δ　ppm: 0.69 (9H, s), 0.88 (3H, s), 1.08 (3H, s), 2.08 (1H, d, J = 16.4 Hz), 2.20 (1H, d, J = 16.4 Hz), 2.37-2.47 (2H, m), 2.45 (3H, s), 2.52 (1H, d, J = 18.2 Hz), 2.63 (3H, s), 2.90-2.99 (1H, m), 2.97 (3H, s), 3.10 (1H, d, J = 9.1 Hz), 5.23 (1H, s), 5.27 (1H, d, J = 12.8 Hz), 5.33 (1H, d, J = 12.8 Hz), 6.38 (1H, s), 7.31-7.49 (5H, m), 7.84 (1H, s).
(113e) 7-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2,4-ジメチル-1-ベンゾフラン-5-カルボン酸
　実施例113dで製造したベンジル　7-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート(285 mg, 0.478 mmol)、パラジウム炭素(10%, 28.0 mg)及びメタノール(15 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(161 mg, 67%)を得た。 (Example 113)
7-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -2,4-dimethyl-1-benzofuran-5-carboxylic acid
(113a) Benzyl 7-[(4,4-dimethyl-2,6-dioxocyclohexylidene) methyl] -2,4-dimethyl-1-benzofuran-5-carboxylate The benzyl 7- prepared in Example 102b Dimedone (1.04 g, 7.42 mmol) in a solution of formyl-2,4-dimethyl-1-benzofuran-5-carboxylate (2.00 g, 6.49 mmol) and pyrrolidine (590 μL, 7.20 mmol) in toluene (20 mL) at room temperature And the reaction solution was stirred at room temperature for 40 minutes. Ethyl acetate (50 mL) and 0.5 M hydrochloric acid (30 mL) were added to the reaction solution, and the reaction solution was further stirred at room temperature for 24 hours. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude title compound.
(113b) Benzyl 7-[(S)-[(6S) -6-tert-butyl-2,4-dioxopiperidin-3-yl] (4,4-dimethyl-2,6-dioxocyclohexyl) methyl ] -2,4-Dimethyl-1-benzofuran-5-carboxylate Crude benzyl 7-[(4,4-dimethyl-2,6-dioxocyclohexylidene) methyl] -2, prepared in Example 113a 4-Dimethyl-1-benzofuran-5-carboxylate and (6S) -6-tert-butylpiperidine-2,4-dione (434 mg, 2.56 mmol), DMF (20 mL) and carbonate prepared in Example 22c The title compound (788 mg, 57%, 2 steps) was obtained as a mixture of conformers by performing reaction and post-treatment according to Example 14b using cesium (1.91 g, 5.86 mmol).
(113c) Benzyl 7-[(3S, 10S) -3-tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -2,4-dimethyl-1-benzofuran-5-carboxylate benzyl 7-[(S)-[(6S) -6 prepared in Example 113b -tert-butyl-2,4-dioxopiperidin-3-yl] (4,4-dimethyl-2,6-dioxocyclohexyl) methyl] -2,4-dimethyl-1-benzofuran-5-carboxylate ( 788 mg, 1.31 mmol) and cesium carbonate (1.13 g, 3.47 mmol) in DMF (15 mL) at room temperature with N-phenylbis (trifluoromethanesulfonimide) (943 mg, 2.64 mmol), and the reaction solution For 6 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (706 mg, 92%).
1 H-NMR (400MHz, CDCl 3 ) δ ppm: 0.80 (9H, s), 0.85 (3H, s), 1.09 (3H, s), 2.09 (1H, d, J = 16.4 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.39 (1H, d, J = 17.6 Hz), 2.45 (3H, s), 2.50 (1H, d, J = 17.6 Hz), 2.56-2.63 (2H, m), 2.63 ( 3H, s), 3.29 (1H, t, J = 7.6 Hz), 5.08 (1H, s), 5.19 (1H, s), 5.32 (2H, s), 6.39 (1H, s), 7.29-7.47 (5H , m), 7.87 (1H, s).
(113d) Benzyl 7-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro -1H-chromeno [3,2-c] pyridin-10-yl] -2,4-dimethyl-1-benzofuran-5-carboxylate benzyl 7-[(3S, 10S) -3- prepared in Example 113c tert-butyl-7,7-dimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -2,4-dimethyl-1-benzofuran-5-carboxylate (352 mg, 0.605 mmol), methyl iodide (300 μL, 5.00 mmol), DMF (6.0 mL) and sodium hydride (63%, 34.8 mg, The title compound (285 mg, 79%) was obtained by performing the reaction and post-treatment according to Example 2a using 0.914 mmol).
1 H-NMR (400MHz, CDCl 3 ) δ ppm: 0.69 (9H, s), 0.88 (3H, s), 1.08 (3H, s), 2.08 (1H, d, J = 16.4 Hz), 2.20 (1H, d, J = 16.4 Hz), 2.37-2.47 (2H, m), 2.45 (3H, s), 2.52 (1H, d, J = 18.2 Hz), 2.63 (3H, s), 2.90-2.99 (1H, m ), 2.97 (3H, s), 3.10 (1H, d, J = 9.1 Hz), 5.23 (1H, s), 5.27 (1H, d, J = 12.8 Hz), 5.33 (1H, d, J = 12.8 Hz) ), 6.38 (1H, s), 7.31-7.49 (5H, m), 7.84 (1H, s).
(113e) 7-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro- 1H-chromeno [3,2-c] pyridin-10-yl] -2,4-dimethyl-1-benzofuran-5-carboxylic acid benzyl 7-[(3S, 10S) -3-tert prepared in Example 113d -Butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl ] -2,4-Dimethyl-1-benzofuran-5-carboxylate (285 mg, 0.478 mmol), palladium on carbon (10%, 28.0 mg) and methanol (15 mL) were reacted according to Example 18 and The title compound (161 mg, 67%) was obtained by post-treatment.
(実施例114)
　N-(エチルスルホニル)-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキサミド　tert-ブチルアミン塩
 (114a) N-(エチルスルホニル)-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキサミド
　実施例18で製造した6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(300 mg, 0.475 mmol)、カルボニルジイミダゾール(117 mg, 0.722 mmol)、DMF (5.0 mL)、エタンスルホンアミド(78.8 mg, 0.722 mmol)及びDBU (108 μL, 0.722 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(310 mg, 89%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.77 (3H, d, J = 6.7 Hz), 0.97 (3H, d, J = 7.0 Hz), 0.97 (3H, s), 1.06 (3H, s), 1.45 (3H, t, J = 7.4 Hz), 1.78-1.87 (1H, m), 2.06 (1H, d, J = 16.4 Hz), 2.16 (1H, d, J = 16.4 Hz), 2.24-2.29 (2H, m), 2.35-2.43 (2H, m), 2.76 (3H, s), 2.80 (3H, s), 2.83 (3H, s), 3.27 (1H, t, J = 11.3 Hz), 3.35-3.41 (1H, m), 3.55 (2H, q, J = 7.4 Hz), 3.75 (3H, s), 3.85 (1H, dt, J = 3.9, 11.3 Hz), 4.45 (1H, d, J = 9.4 Hz), 6.73 (1H, d, J = 8.6 Hz), 7.21 (1H, d, J = 8.6 Hz), 7.61-7.66 (2H, m).
MS(ESI/APCI)m/z: 652[M+H]+.
(114b) N-(エチルスルホニル)-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキサミド　tert-ブチルアミン塩
　実施例114aで製造したN-(エチルスルホニル)-6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキサミド(310 mg, 0.476 mmol)、エタノール(6.2 mL)及びtert-ブチルアミン(75 μL, 0.713 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(225 mg, 65%)を得た。 (Example 114)
N- (ethylsulfonyl) -6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (propane- 2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine -2-carboxamide tert-butylamine salt (114a) N- (ethylsulfonyl) -6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl- 1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridine- 10-yl] phenyl} -3-methylpyridine-2-carboxamide 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7 prepared in Example 18 -Trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c ] Pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid (300 mg, 0.475 mmol), carbonyldiimidazole (117 mg, 0.722 mmol), DMF (5.0 mL), The title compound (310 mg, 89%) was obtained by performing reaction and post-treatment according to Example 6a using tansulfonamide (78.8 mg, 0.722 mmol) and DBU (108 μL, 0.722 mmol).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.77 (3H, d, J = 6.7 Hz), 0.97 (3H, d, J = 7.0 Hz), 0.97 (3H, s), 1.06 (3H, s ), 1.45 (3H, t, J = 7.4 Hz), 1.78-1.87 (1H, m), 2.06 (1H, d, J = 16.4 Hz), 2.16 (1H, d, J = 16.4 Hz), 2.24-2.29 (2H, m), 2.35-2.43 (2H, m), 2.76 (3H, s), 2.80 (3H, s), 2.83 (3H, s), 3.27 (1H, t, J = 11.3 Hz), 3.35- 3.41 (1H, m), 3.55 (2H, q, J = 7.4 Hz), 3.75 (3H, s), 3.85 (1H, dt, J = 3.9, 11.3 Hz), 4.45 (1H, d, J = 9.4 Hz ), 6.73 (1H, d, J = 8.6 Hz), 7.21 (1H, d, J = 8.6 Hz), 7.61-7.66 (2H, m).
MS (ESI / APCI) m / z: 652 [M + H] +.
(114b) N- (Ethylsulfonyl) -6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2,7,7-trimethyl-1,9-dioxo-3- (Propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3 -Methylpyridine-2-carboxamide tert-butylamine salt N- (ethylsulfonyl) -6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2, prepared in Example 114a, 7,7-trimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,4a, 6,7,8,9,10,10a-decahydro-1H-chromeno [3, Example using 2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxamide (310 mg, 0.476 mmol), ethanol (6.2 mL) and tert-butylamine (75 μL, 0.713 mmol) The title compound (225 mg, 65%) was obtained by reacting and working up according to 3c.
(実施例115)
　6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
(115a) 10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3-ジメチル-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン
　実施例42aで製造した7-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]スピロ[3.5]ノナン-6,8-ジオン(6.66 g, 16.2 mmol)及び6,6-ジメチルピペリジン-2,4-ジオン(2.52 g, 17.9 mmol)のアセトニトリル(20 mL)溶液に0℃で炭酸カリウム(5.61 g, 40.6 mmol)を加えた。反応溶液を室温で3時間攪拌後、0℃で反応溶液に4 M塩酸(酢酸エチル溶液, 61 mL, 244 mmol)を加え、反応溶液を室温で6時間攪拌した。反応溶液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで2回抽出後、有機層を減圧濃縮した。濃縮残渣をヘキサン/酢酸エチル(2:1)より結晶化し、標記化合物(7.38 g, 85%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 1.12 (3H, s), 1.27 (3H, s), 1.30 (12H, s), 1.63-1.91 (6H, m), 2.28-2.38 (2H, m), 2.45 (1H, d, J = 16.4 Hz), 2.54-2.65 (3H, m), 3.10 (3H, s), 3.69 (3H, s), 5.08 (1H, s), 5.16 (1H, s), 6.56 (1H, d, J = 8.6 Hz), 7.57 (1H, d, J = 8.6 Hz).
(115b) 2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3-ジメチル-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン
　実施例115aで製造した10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3-ジメチル-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン(5.32 g, 9.97 mmol)、ヨウ化エチル(6.40 mL, 79.8 mmol)、DMF (80 mL)及び水素化ナトリウム(63%, 761 mg, 19.9 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(2.02 g, 36%)を得た。 (Example 115)
6- {3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-7,1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid or 6- {3-[(10R)- 2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1 ' -Cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid
(115a) 10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3-dimethyl-3 , 4,6,10-Tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H) -dione 7- [6-Methoxy prepared in Example 42a -2-Methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] spiro [3.5] nonane-6,8-dione (6.66 g, 16.2 mmol ) And 6,6-dimethylpiperidine-2,4-dione (2.52 g, 17.9 mmol) in acetonitrile (20 mL) were added potassium carbonate (5.61 g, 40.6 mmol) at 0 ° C. The reaction solution was stirred at room temperature for 3 hours, 4 M hydrochloric acid (ethyl acetate solution, 61 mL, 244 mmol) was added to the reaction solution at 0 ° C., and the reaction solution was stirred at room temperature for 6 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction twice with ethyl acetate, and then the organic layer was concentrated under reduced pressure. The concentrated residue was crystallized from hexane / ethyl acetate (2: 1) to obtain the title compound (7.38 g, 85%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.12 (3H, s), 1.27 (3H, s), 1.30 (12H, s), 1.63-1.91 (6H, m), 2.28-2.38 (2H, m), 2.45 (1H, d, J = 16.4 Hz), 2.54-2.65 (3H, m), 3.10 (3H, s), 3.69 (3H, s), 5.08 (1H, s), 5.16 (1H, s ), 6.56 (1H, d, J = 8.6 Hz), 7.57 (1H, d, J = 8.6 Hz).
(115b) 2-Ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3 -Dimethyl-3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H) -dione 10- prepared in Example 115a [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3-dimethyl-3,4,6, 10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H) -dione (5.32 g, 9.97 mmol), ethyl iodide (6.40 mL, 79.8 mmol) ), DMF (80 mL) and sodium hydride (63%, 761 mg, 19.9 mmol), the title compound (2.02 g, 36%) was obtained by carrying out the reaction and post-treatment according to Example 2a. It was.
1H-NMR(400MHz, CDCl3):δ ppm: 1.08 (3H, t, J = 7.0 Hz), 1.09 (3H, s), 1.30 (12H, s), 1.38 (3H, s), 1.61-1.91 (6H, m), 2.23-2.37 (2H, m), 2.44 (1H, d, J = 16.0 Hz), 2.57-2.68 (3H, m), 2.95-3.02 (1H, m), 3.14 (3H, s), 3.51-3.58 (1H, m), 3.68 (3H, s), 5.19 (1H, s), 6.56 (2H, d, J = 8.6 Hz), 7.56 (1H, d, J = 8.2 Hz).
(115c) tert-ブチル　6-[3-(2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート
　実施例115bで製造した2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3-ジメチル-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン(2.00 g, 3.56 mmol)、公知化合物であるtert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(1.05 g, 4.63 mmol)、2nd Generation X-Phos Precatalyst (560 mg, 0.712 mmol)、リン酸カリウム(1.25 g, 5.70 mmol)、THF (10 mL)及び水(20 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(1.50 g, 67%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 1.09 (3H, t, J = 7.0 Hz), 1.12 (3H, s), 1.24 (3H, s), 1.63 (9H, s), 1.68-1.91 (6H, m), 2.27 (1H, d, J = 17.2 Hz), 2.36 (1H, d, J = 16.0 Hz), 2.47 (1H, d, J = 16.0 Hz), 2.49 (3H, s), 2.57 (1H, d, J = 17.2 Hz), 2.65 (1H, d, J = 17.6 Hz), 2.68 (1H, dd, J = 1.6, 16.0 Hz), 2.86 (3H, s), 2.96-3.04 (1H, m), 3.51-3.58 (1H, m), 3.72 (3H, s), 5.18 (1H, s), 6.66 (1H, d, J = 8.2 Hz), 7.26 (1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 7.8 Hz).
(115d) tert-ブチル　6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
及び、tert-ブチル　6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例115cで製造したtert-ブチル　6-[3-(2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート(1.89 g)をChiral flash IA(ダイセル化学工業; ヘキサン/イソプロパノール；85:15)により光学分割し、高極性化合物(638 mg)及び低極性化合物(654 mg)を得た。
(115e) 6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例115dで製造したtert-ブチル　6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
もしくはtert-ブチル　6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート (低極性化合物; 654 mg, 1.04 mmol)、ジクロロメタン(6.5 mL)及びトリフルオロ酢酸(3.3 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(573 mg, 96%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.08 (3H, t, J = 7.0 Hz), 1.09 (3H, s), 1.30 (12H, s), 1.38 (3H, s), 1.61-1.91 (6H, m), 2.23-2.37 (2H, m), 2.44 (1H, d, J = 16.0 Hz), 2.57-2.68 (3H, m), 2.95-3.02 (1H, m), 3.14 (3H, s ), 3.51-3.58 (1H, m), 3.68 (3H, s), 5.19 (1H, s), 6.56 (2H, d, J = 8.6 Hz), 7.56 (1H, d, J = 8.2 Hz).
(115c) tert-butyl 6- [3- (2-ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [ 3,2-c] Pyridin-7,1′-cyclobutane] -10-yl) -4-methoxy-2-methylphenyl] -3-methylpyridine-2-carboxylate 2-ethyl-prepared in Example 115b 10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3-dimethyl-3,4, 6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H) -dione (2.00 g, 3.56 mmol), a known compound tert-butyl 6-chloro-3-methylpyridine-2-carboxylate (1.05 g, 4.63 mmol), 2nd Generation X-Phos Precatalyst (560 mg, 0.712 mmol), potassium phosphate (1.25 g, 5.70 mmol), THF (10 mL ) And water (20 mL), and the reaction and workup were performed according to Example 9d to give the title compound (1.50 g, 67%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.09 (3H, t, J = 7.0 Hz), 1.12 (3H, s), 1.24 (3H, s), 1.63 (9H, s), 1.68-1.91 (6H, m), 2.27 (1H, d, J = 17.2 Hz), 2.36 (1H, d, J = 16.0 Hz), 2.47 (1H, d, J = 16.0 Hz), 2.49 (3H, s), 2.57 (1H, d, J = 17.2 Hz), 2.65 (1H, d, J = 17.6 Hz), 2.68 (1H, dd, J = 1.6, 16.0 Hz), 2.86 (3H, s), 2.96-3.04 (1H, m), 3.51-3.58 (1H, m), 3.72 (3H, s), 5.18 (1H, s), 6.66 (1H, d, J = 8.2 Hz), 7.26 (1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 7.8 Hz).
(115d) tert-butyl 6- {3-[(10S) -2-ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-7,1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate and tert-butyl 6 -{3-[(10R) -2-ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2 -c] pyridine-7,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate tert-butyl 6- [3 prepared in Example 115c -(2-ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7, 1′-cyclobutane] -10-yl) -4-methoxy-2-methylphenyl] -3-methylpyridine-2-carboxylate (1.89 g) was added to Chiral flash IA (Daicel Chemical Industries; hexane / isopropanol; 85:15 ) Compound (638 mg) and low polarity compound (654 mg) was obtained.
(115e) 6- {3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid or 6- {3-[( 10R) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7 , 1'-Cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butyl 6- {3-[(10S)-prepared in Example 115d 2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1 ' -Cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate or tert-butyl 6- {3-[(10R) -2-ethyl-3,3- Dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cycl Butane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (low polarity compound; 654 mg, 1.04 mmol), dichloromethane (6.5 mL) and trifluoroacetic acid (3.3 The title compound (573 mg, 96%) was obtained by performing the reaction and post-treatment according to Example 1d using mL).
(実施例116)
　6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例115dで製造したtert-ブチル　6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
もしくはtert-ブチル　6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート (高極性化合物; 638 mg, 1.02 mmol)、ジクロロメタン(6.4 mL)及びトリフルオロ酢酸(3.2 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(560 mg, 96%)を得た。 (Example 116)
6- {3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-7,1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid or 6- {3-[(10R)- 2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1 ' -Cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butyl 6- {3-[(10S) -2-ethyl prepared in Example 115d -3,3-Dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate or tert-butyl 6- {3-[(10R) -2-ethyl-3,3-dimethyl-1 , 9-Dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobuta ] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (high polarity compound; 638 mg, 1.02 mmol), dichloromethane (6.4 mL) and trifluoroacetic acid (3.2 The title compound (560 mg, 96%) was obtained by carrying out the reaction and post-treatment according to Example 1d.
(実施例117)
　6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
(117a) 10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3-ジメチル-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン
　実施例41aで製造した6-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]スピロ[2.5]オクタン-5,7-ジオン(6.67 g, 16.8 mmol)、アセトニトリル(133 mL)、炭酸カリウム(5.82 g, 42.1 mmol)及び4 M塩酸(酢酸エチル溶液, 84 mL, 337 mmol) を用い、実施例115aに準じて反応及び後処理を行うことにより、標記化合物(4.82 g, 55%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.32-0.51 (4H, m), 1.12 (3H, s), 1.27 (3H, s), 1.30 (12H, s), 1.97 (1H, d, J = 17.2 Hz), 2.21 (1H, d, J = 17.6 Hz), 2.28 (1H, d, J = 18.0 Hz), 2.36 (1H, d, J = 16.4 Hz), 2.56 (1H, d, J = 18.4 Hz), 2.62 (1H, d, J = 16.4 Hz), 3.12 (3H, s), 3.71 (3H, s), 5.17 (1H, s), 5.21 (1H, s), 6.61 (1H, d, J = 8.2 Hz), 7.59 (1H, d, J = 8.2 Hz).
(117b) 2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3-ジメチル-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン
　実施例117aで製造した10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3-ジメチル-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン(3.10 g, 5.97 mmol)、ヨウ化エチル(4.77 mL, 59.7 mmol)、DMPU (62 mL)及び水素化ナトリウム(63%, 818 mg, 21.5 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(2.00 g, 61%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.31-0.46 (4H, m), 1.08 (3H, t, J = 7.8 Hz), 1.09 (3H, s), 1.30 (12H, s), 1.38 (3H, s), 1.96 (1H, d, J = 17.6 Hz), 2.17-2.28 (2H, m), 2.35 (1H, d, J = 16.8 Hz), 2.56 (1H, d, J = 18.0 Hz), 2.65 (1H, d, J = 16.8 Hz), 2.96-3.03 (1H, m), 3.16 (3H, s), 3.51-3.59 (1H, m), 3.70 (3H, s), 5.24 (1H, s), 6.60 (1H, d, J = 8.2 Hz), 7.58 (1H, d, J = 8.2 Hz).
(117c) tert-ブチル　6-[3-(2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート
　実施例117bで製造した2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3-ジメチル-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン(1.80 g, 3.29 mmol)、公知化合物であるtert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(973 mg, 4.27 mmol)、2nd Generation X-Phos Precatalyst (560 mg, 0.712 mmol)、リン酸カリウム(1.25 g, 5.70 mmol)、THF (10 mL)及び水(20 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(1.30 g, 65%)を得た。 (Example 117)
6- {3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid or 6- {3-[(10R) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1 '-Cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid
(117a) 10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3-dimethyl-3 , 4,6,10-Tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -1,9 (2H, 8H) -dione 6- [6- Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] spiro [2.5] octane-5,7-dione (6.67 g, 16.8 mmol), acetonitrile (133 mL), potassium carbonate (5.82 g, 42.1 mmol) and 4 M hydrochloric acid (ethyl acetate solution, 84 mL, 337 mmol) were used to carry out the reaction and workup according to Example 115a. The title compound (4.82 g, 55%) was obtained.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.32-0.51 (4H, m), 1.12 (3H, s), 1.27 (3H, s), 1.30 (12H, s), 1.97 (1H, d, J = 17.2 Hz), 2.21 (1H, d, J = 17.6 Hz), 2.28 (1H, d, J = 18.0 Hz), 2.36 (1H, d, J = 16.4 Hz), 2.56 (1H, d, J = 18.4 Hz), 2.62 (1H, d, J = 16.4 Hz), 3.12 (3H, s), 3.71 (3H, s), 5.17 (1H, s), 5.21 (1H, s), 6.61 (1H, d, J = 8.2 Hz), 7.59 (1H, d, J = 8.2 Hz).
(117b) 2-Ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3 -Dimethyl-3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -1,9 (2H, 8H) -dione 10 prepared in Example 117a -[6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3-dimethyl-3,4,6 , 10-Tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -1,9 (2H, 8H) -dione (3.10 g, 5.97 mmol), ethyl iodide (4.77 mL, 59.7 mmol), DMPU (62 mL) and sodium hydride (63%, 818 mg, 21.5 mmol) were used for the reaction and workup according to Example 2a to give the title compound (2.00 g, 61%) Got.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.31-0.46 (4H, m), 1.08 (3H, t, J = 7.8 Hz), 1.09 (3H, s), 1.30 (12H, s), 1.38 (3H, s), 1.96 (1H, d, J = 17.6 Hz), 2.17-2.28 (2H, m), 2.35 (1H, d, J = 16.8 Hz), 2.56 (1H, d, J = 18.0 Hz) , 2.65 (1H, d, J = 16.8 Hz), 2.96-3.03 (1H, m), 3.16 (3H, s), 3.51-3.59 (1H, m), 3.70 (3H, s), 5.24 (1H, s ), 6.60 (1H, d, J = 8.2 Hz), 7.58 (1H, d, J = 8.2 Hz).
(117c) tert-butyl 6- [3- (2-ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [ 3,2-c] pyridine-7,1′-cyclopropane] -10-yl) -4-methoxy-2-methylphenyl] -3-methylpyridine-2-carboxylate 2-ethyl prepared in Example 117b -10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3-dimethyl-3,4 , 6,10-Tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -1,9 (2H, 8H) -dione (1.80 g, 3.29 mmol), a known compound tert -Butyl 6-chloro-3-methylpyridine-2-carboxylate (973 mg, 4.27 mmol), 2nd Generation X-Phos Precatalyst (560 mg, 0.712 mmol), potassium phosphate (1.25 g, 5.70 mmol), THF ( The title compound (1.30 g, 65%) was obtained by performing the reaction and post-treatment according to Example 9d using 10 mL) and water (20 mL).
1H-NMR(400MHz, CDCl3):δ ppm: 0.35-0.49 (4H, m), 1.09 (3H, t, J = 7.0 Hz), 1.12 (3H, s), 1.40 (3H, s), 1.63 (9H, s), 1.99 (1H, d, J = 17.6 Hz), 2.22 (1H, d, J = 17.6 Hz), 2.25 (1H, d, J = 17.2 Hz), 2.36 (1H, d, J = 16.8 Hz), 2.49 (3H, s), 2.57 (1H, d, J = 17.6 Hz), 2.67 (1H, d, J = 16.8 Hz), 2.88 (3H, s), 2.96-3.05 (1H, m), 3.52-3.61 (1H, m), 3.73 (3H, s), 5.23 (1H, s), 6.71 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 9.0 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.2 Hz).
(117d) tert-ブチル　6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
及び、tert-ブチル　6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
実施例117cで製造したtert-ブチル　6-[3-(2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート(1.30 g)をChiral flash IA(ダイセル化学工業; ヘキサン/イソプロパノール；85:15)により光学分割し、高極性化合物(606 mg)及び低極性化合物(609 mg)を得た。
(117e) 6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例117dで製造したtert-ブチル　6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレートもしくはtert-ブチル　6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート (低極性化合物; 609 mg, 0.994 mmol)、ジクロロメタン(6.1 mL)及びトリフルオロ酢酸(3.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(503 mg, 91%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.35-0.49 (4H, m), 1.09 (3H, t, J = 7.0 Hz), 1.12 (3H, s), 1.40 (3H, s), 1.63 (9H, s), 1.99 (1H, d, J = 17.6 Hz), 2.22 (1H, d, J = 17.6 Hz), 2.25 (1H, d, J = 17.2 Hz), 2.36 (1H, d, J = 16.8 Hz), 2.49 (3H, s), 2.57 (1H, d, J = 17.6 Hz), 2.67 (1H, d, J = 16.8 Hz), 2.88 (3H, s), 2.96-3.05 (1H, m) , 3.52-3.61 (1H, m), 3.73 (3H, s), 5.23 (1H, s), 6.71 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 9.0 Hz), 7.38 ( 1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.2 Hz).
(117d) tert-butyl 6- {3-[(10S) -2-ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate and tert-butyl 6- {3-[(10R) -2-ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] Pyridin-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate tert-butyl 6-prepared in Example 117c [3- (2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine- 7,1′-cyclopropane] -10-yl) -4-methoxy-2-methylphenyl] -3-methylpyridine-2-carboxylate (1.30 g) in Chiral flash IA (Daicel Chemical Industries; hexane / isopropanol; 85:15) To give more polar compound (606 mg) and low polarity compound (609 mg).
(117e) 6- {3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid or 6- {3- [ (10R) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine- 7,1′-Cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butyl 6- {3-[(10S prepared in Example 117d ) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7, 1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate or tert-butyl 6- {3-[(10R) -2-ethyl-3 , 3-Dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1 ' -Cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (low polarity compound; 609 mg, 0.994 mmol), dichloromethane (6.1 mL) and trifluoroacetic acid (3.0 mL) was used for the reaction and post-treatment according to Example 1d to obtain the title compound (503 mg, 91%).
(実施例118)
　2,6-ジメチル-7-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボン酸
又は、2,6-ジメチル-7-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボン酸
(118a) 7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,6-ジメチル-1-ベンゾフラン-5-カルボン酸
　公知化合物である[(5-ブロモ-2,6-ジメチル-1-ベンゾフラン-7-イル)メトキシ](tert-ブチル)ジメチルシラン(1.48 g, 4.01 mmol)のTHF (15 mL)溶液に-78℃でn-ブチルリチウム(1.6 M inヘキサン; 3.01 mL, 4.81 mmol)を加え、-78℃で1時間攪拌した。反応溶液にドライアイスを加え、室温に昇温した。反応溶液を減圧下濃縮し、水(30 mL)を加え、水層をジエチルエーテルで洗浄した後、1 M塩酸を加えてpHを弱酸性に調整した。水層を酢酸エチルで2回抽出し、有機層を水、次いで飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮し、評価化合物(1.34 g, 99%)を得た。 (Example 118)
2,6-dimethyl-7-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylic acid or 2,6-dimethyl-7-[(10R) -2,3,3,7,7-pentamethyl -1,9-Dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylic acid
(118a) 7-({[tert-Butyl (dimethyl) silyl] oxy} methyl) -2,6-dimethyl-1-benzofuran-5-carboxylic acid [(5-bromo-2,6-dimethyl -1-benzofuran-7-yl) methoxy] (tert-butyl) dimethylsilane (1.48 g, 4.01 mmol) in THF (15 mL) at −78 ° C. at n-butyllithium (1.6 M in hexane; 3.01 mL, 4.81 mmol) was added, and the mixture was stirred at -78 ° C for 1 hour. Dry ice was added to the reaction solution, and the temperature was raised to room temperature. The reaction solution was concentrated under reduced pressure, water (30 mL) was added, the aqueous layer was washed with diethyl ether, and 1 M hydrochloric acid was added to adjust the pH to slightly acidic. The aqueous layer was extracted twice with ethyl acetate, and the organic layer was washed with water and then with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the evaluation compound (1.34 g, 99%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.07 (6H, s), 0.90 (9H, s), 2.47 (3H, d, J = 1.2 Hz), 2.75 (3H, s), 5.05 (2H, s), 6.38 (1H, d, J = 1.2 Hz), 8.11 (1H, s).
(118b) ベンジル　7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,6-ジメチル-1-ベンゾフラン-5-カルボキシレート
　実施例118aで製造した7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,6-ジメチル-1-ベンゾフラン-5-カルボン酸(1.34 g, 4.01 mmol)のDMF (14 mL)溶液に、室温で炭酸セシウム(1.96 g, 6.02 mmol)及びベンジルブロミド(572 μL, 4.81 mmol)を加え、室温で2時間攪拌した。反応液に水を加え、トルエンで2回抽出後、有機層を水で2回、飽和食塩水で1回洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 4:1)で精製し、標記化合物(1.61 g, 95%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.06 (6H, s), 0.89 (9H, s), 2.45 (3H, d, J = 1.2 Hz), 2.69 (3H, s), 5.03 (2H, s), 5.35 (2H, s), 6.34 (1H, d, J = 1.2 Hz), 7.34-7.48 (5H, m), 7.97 (1H, s).
(118c) ベンジル　7-(ヒドロキシメチル)-2,6-ジメチル-1-ベンゾフラン-5-カルボキシレート
　実施例118bで製造したベンジル　7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,6-ジメチル-1-ベンゾフラン-5-カルボキシレート(1.61 g, 3.79 mmol)、酢酸(521 μL, 9.10 mmol)及びテトラブチルアンモニウムフルオリド(1.0 M in THF; 7.58 mL, 7.58 mmol)のTHF (16 mL)溶液を50℃で7時間攪拌した。空冷後、反応溶液に水を加え、酢酸エチルで2回抽出し、有機層を水、次いで飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 3:2)で精製し、標記化合物(940 mg, 80%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.07 (6H, s), 0.90 (9H, s), 2.47 (3H, d, J = 1.2 Hz), 2.75 (3H, s), 5.05 (2H , s), 6.38 (1H, d, J = 1.2 Hz), 8.11 (1H, s).
(118b) Benzyl 7-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2,6-dimethyl-1-benzofuran-5-carboxylate 7-({[tert-butyl prepared in Example 118a (Dimethyl) silyl] oxy} methyl) -2,6-dimethyl-1-benzofuran-5-carboxylic acid (1.34 g, 4.01 mmol) in DMF (14 mL) at room temperature with cesium carbonate (1.96 g, 6.02 mmol) ) And benzyl bromide (572 μL, 4.81 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice with toluene. The organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 4: 1) to obtain the title compound (1.61 g, 95%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.06 (6H, s), 0.89 (9H, s), 2.45 (3H, d, J = 1.2 Hz), 2.69 (3H, s), 5.03 (2H , s), 5.35 (2H, s), 6.34 (1H, d, J = 1.2 Hz), 7.34-7.48 (5H, m), 7.97 (1H, s).
(118c) Benzyl 7- (hydroxymethyl) -2,6-dimethyl-1-benzofuran-5-carboxylate Benzyl 7-({[tert-butyl (dimethyl) silyl] oxy} methyl)-prepared in Example 118b 2,6-Dimethyl-1-benzofuran-5-carboxylate (1.61 g, 3.79 mmol), acetic acid (521 μL, 9.10 mmol) and tetrabutylammonium fluoride (1.0 M in THF; 7.58 mL, 7.58 mmol) in THF The solution (16 mL) was stirred at 50 ° C. for 7 hours. After cooling with air, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and then with saturated brine, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 3: 2) to obtain the title compound (940 mg, 80%).
1H-NMR(400MHz, CDCl3):δ ppm: 1.73 (1H, t, J = 5.8 Hz), 2.46 (3H, d, J = 1.2 Hz), 2.71 (3H, s), 5.06 (2H, d, J = 5.9 Hz), 6.36 (2H, s), 6.36 (1H, d, J = 1.2 Hz), 7.35-7.48 (5H, m), 7.99 (1H, s).
(118d) ベンジル　7-ホルミル-2,6-ジメチル-1-ベンゾフラン-5-カルボキシレート
　実施例118cで製造したベンジル　7-(ヒドロキシメチル)-2,6-ジメチル-1-ベンゾフラン-5-カルボキシレート(940 mg, 3.03 mmol)、ジクロロメタン(10 mL)及びデスマーチンペルヨージナン(1.54 g, 3.63 mmol)を用い、実施例32lに準じて反応及び後処理を行うことにより、標記化合物(894 mg, 96%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 2.52 (3H, d, J = 0.8 Hz), 2.92 (3H, s), 5.37 (2H, s), 6.42 (1H, d, J = 1.2 Hz), 7.36-7.48 (5H, m), 8.15 (1H, s), 10.82 (1H, s).
(118e) ベンジル　7-[(4,4-ジメチル-2,6-ジオキソシクロヘキシリデン)メチル]-2,6-ジメチル-1-ベンゾフラン-5-カルボキシレート
　実施例118dで製造したベンジル　7-ホルミル-2,6-ジメチル-1-ベンゾフラン-5-カルボキシレート(157 mg, 0.508 mmol)、ピロリジン(46 μL, 0.560 mmol)、トルエン(3.0 mL)、ジメドン(77.3 mg, 0.551 mmol)及び0.5 M塩酸(6.0 mL)を用い、実施例112aに準じて反応及び後処理を行うことにより、粗製の標記化合物を得た。
(118f) ベンジル　2,6-ジメチル-7-(3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)-1-ベンゾフラン-5-カルボキシレート
　実施例118eで製造した粗製のベンジル　7-[(4,4-ジメチル-2,6-ジオキソシクロヘキシリデン)メチル]-2,6-ジメチル-1-ベンゾフラン-5-カルボキシレート(219 mg, 0.508 mmol)、DMF (4.0 mL)、炭酸セシウム(429 mg, 1.32 mmol)及びメタンスルホニルクロリド(48 μL, 0.620 mmol)を用い、実施例1bに準じて反応及び後処理を行うことにより、標記化合物(155 mg, 55%, 2 steps)を得た。
1H-NMR (400MHz, CDCl3) δ ppm: 0.74 (3H, s), 0.94 (3H, s), 1.08 (3H, s), 1.28 (3H, s), 2.07 (1H, d, J = 17.0 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.34 (3H, s), 2.36 (2H, d, J = 15.2 Hz), 2.50 (1H, d, J = 17.6 Hz), 2.68 (1H, d, J = 16.4 Hz), 3.08 (3H, s), 4.99 (1H, s), 5.31 (1H, s), 5.32 (2H, s), 6.23 (1H, s), 7.32-7.47 (5H, m), 7.76 (1H, s).
(118g) ベンジル　2,6-ジメチル-7-[(10S)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート
又は、ベンジル　2,6-ジメチル-7-[(10R)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート
　実施例118fで製造したベンジル　2,6-ジメチル-7-(3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル)-1-ベンゾフラン-5-カルボキシレート(155 mg)をChiral flash IA(ヘキサン/エタノール; 2:8)により光学分割し、高極性化合物(67.9 mg)及び低極性化合物(68.8 mg)を得た。
(118h) ベンジル　2,6-ジメチル-7-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート
又は、ベンジル　2,6-ジメチル-7-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート
　実施例118gで製造したベンジル　2,6-ジメチル-7-[(10S)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレートもしくはベンジル　2,6-ジメチル-7-[(10R)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート(低極性化合物; 68.8 mg, 0.124 mmol)、ヨウ化メチル(40 μL, 0.640 mmol)、DMF (2.0 mL)及び水素化ナトリウム(63%, 12.0 mg, 0.315 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(53.6 mg, 76%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.73 (1H, t, J = 5.8 Hz), 2.46 (3H, d, J = 1.2 Hz), 2.71 (3H, s), 5.06 (2H, d , J = 5.9 Hz), 6.36 (2H, s), 6.36 (1H, d, J = 1.2 Hz), 7.35-7.48 (5H, m), 7.99 (1H, s).
(118d) Benzyl 7-formyl-2,6-dimethyl-1-benzofuran-5-carboxylate Benzyl 7- (hydroxymethyl) -2,6-dimethyl-1-benzofuran-5-carboxylate prepared in Example 118c (940 mg, 3.03 mmol), dichloromethane (10 mL) and desmartin periodinane (1.54 g, 3.63 mmol) were used for the reaction and workup according to Example 32l to give the title compound (894 mg, 96%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 2.52 (3H, d, J = 0.8 Hz), 2.92 (3H, s), 5.37 (2H, s), 6.42 (1H, d, J = 1.2 Hz ), 7.36-7.48 (5H, m), 8.15 (1H, s), 10.82 (1H, s).
(118e) Benzyl 7-[(4,4-dimethyl-2,6-dioxocyclohexylidene) methyl] -2,6-dimethyl-1-benzofuran-5-carboxylate The benzyl 7- prepared in Example 118d Formyl-2,6-dimethyl-1-benzofuran-5-carboxylate (157 mg, 0.508 mmol), pyrrolidine (46 μL, 0.560 mmol), toluene (3.0 mL), dimedone (77.3 mg, 0.551 mmol) and 0.5 M The crude title compound was obtained by performing reaction and post-treatment according to Example 112a using hydrochloric acid (6.0 mL).
(118f) Benzyl 2,6-dimethyl-7- (3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H- Chromeno [3,2-c] pyridin-10-yl) -1-benzofuran-5-carboxylate Crude benzyl 7-[(4,4-dimethyl-2,6-dioxocyclohexylene) prepared in Example 118e. Den) methyl] -2,6-dimethyl-1-benzofuran-5-carboxylate (219 mg, 0.508 mmol), DMF (4.0 mL), cesium carbonate (429 mg, 1.32 mmol) and methanesulfonyl chloride (48 μL, The title compound (155 mg, 55%, 2 steps) was obtained by carrying out the reaction and post-treatment according to Example 1b using 0.620 mmol).
1 H-NMR (400MHz, CDCl 3 ) δ ppm: 0.74 (3H, s), 0.94 (3H, s), 1.08 (3H, s), 1.28 (3H, s), 2.07 (1H, d, J = 17.0 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.34 (3H, s), 2.36 (2H, d, J = 15.2 Hz), 2.50 (1H, d, J = 17.6 Hz), 2.68 (1H, d, J = 16.4 Hz), 3.08 (3H, s), 4.99 (1H, s), 5.31 (1H, s), 5.32 (2H, s), 6.23 (1H, s), 7.32-7.47 (5H, m ), 7.76 (1H, s).
(118 g) Benzyl 2,6-dimethyl-7-[(10S) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylate or benzyl 2,6-dimethyl-7-[(10R) -3,3,7,7 -Tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5 -Carboxylate Benzyl 2,6-dimethyl-7- (3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9, prepared in Example 118f 10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl) -1-benzofuran-5-carboxylate (155 mg) was optically resolved with Chiral flash IA (hexane / ethanol; 2: 8). Thus, a high polarity compound (67.9 mg) and a low polarity compound (68.8 mg) were obtained.
(118h) Benzyl 2,6-dimethyl-7-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10 -Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylate or benzyl 2,6-dimethyl-7-[(10R) -2,3,3, 7,7-Pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran -5-Carboxylate Benzyl 2,6-dimethyl-7-[(10S) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6, prepared in Example 118g 7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylate or benzyl 2,6-dimethyl-7-[(10R)- 3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl ] -1-benzofuran-5-carboxylate (low polarity compound; 68.8 mg, 0.124 mmol), methyl iodide (40 μL, 0.640 mmol), DMF (2 .0 mL) and sodium hydride (63%, 12.0 mg, 0.315 mmol) were used in the reaction and after-treatment according to Example 2a to obtain the title compound (53.6 mg, 76%).
1H-NMR (400MHz, CDCl3) δ ppm: 0.72 (3H, s), 0.89 (3H, s), 1.07 (3H, s), 1.33 (3H, s), 2.07 (1H, d, J = 15.2 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.31-2.38 (2H, m), 2.34 (3H, s), 2.50 (1H, d, J = 17.6 Hz), 2.67 (1H, d, J = 15.2 Hz), 2.75 (3H, s), 3.11 (3H, s), 5.32 (2H, s), 5.32 (1H, s), 6.22 (1H, s), 7.32-7.47 (5H, m), 7.76 (1H, s).
(118i) 2,6-ジメチル-7-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボン酸
又は、2,6-ジメチル-7-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボン酸
　実施例118hで製造したベンジル　2,6-ジメチル-7-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレートもしくはベンジル　2,6-ジメチル-7-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート(53.6 mg, 0.0944 mmol)、パラジウム炭素(10%, 11.0 mg)及びメタノール(4.0 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(42.0 mg, 93%)を得た。 1 H-NMR (400MHz, CDCl 3 ) δ ppm: 0.72 (3H, s), 0.89 (3H, s), 1.07 (3H, s), 1.33 (3H, s), 2.07 (1H, d, J = 15.2 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.31-2.38 (2H, m), 2.34 (3H, s), 2.50 (1H, d, J = 17.6 Hz), 2.67 (1H, d, J = 15.2 Hz), 2.75 (3H, s), 3.11 (3H, s), 5.32 (2H, s), 5.32 (1H, s), 6.22 (1H, s), 7.32-7.47 (5H, m), 7.76 (1H, s).
(118i) 2,6-Dimethyl-7-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylic acid or 2,6-dimethyl-7-[(10R) -2,3,3,7, 7-Pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5 -Carboxylic acid Benzyl 2,6-dimethyl-7-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7 prepared in Example 118h , 8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylate or benzyl 2,6-dimethyl-7-[(10R) -2 , 3,3,7,7-Pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl ] -1-Benzofuran-5-carboxylate (53.6 mg, 0.0944 mmol), palladium on carbon (10%, 11.0 mg) and methanol (4.0 mL) were reacted according to Example 18 By performing fine post-treatment to give the title compound (42.0 mg, 93%).
(実施例119)
　2,6-ジメチル-7-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボン酸
又は、2,6-ジメチル-7-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボン酸
(119a) ベンジル　2,6-ジメチル-7-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート
又は、ベンジル　2,6-ジメチル-7-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート
　実施例118gで製造したベンジル　2,6-ジメチル-7-[(10S)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレートもしくはベンジル　2,6-ジメチル-7-[(10R)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート(高極性化合物; 67.9 mg, 0.123 mmol)、ヨウ化メチル(40 μL, 0.640 mmol)、DMF (2.0 mL)及び水素化ナトリウム(63%, 12.0 mg, 0.315 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(56.0 mg, 80%)を得た。
(119b) 2,6-ジメチル-7-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボン酸
又は、2,6-ジメチル-7-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボン酸
　実施例119aで製造したベンジル　2,6-ジメチル-7-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレートもしくはベンジル　2,6-ジメチル-7-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-1-ベンゾフラン-5-カルボキシレート(56.0 mg, 0.0986 mmol)、1 M 水酸化ナトリウム水溶液(1.0 mL, 1.0 mmol)及びメタノール(2.0 mL)を用い、実施例25gに準じて反応及び後処理を行うことにより、標記化合物(44.0 mg, 93%)を得た。 (Example 119)
2,6-dimethyl-7-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylic acid or 2,6-dimethyl-7-[(10R) -2,3,3,7,7-pentamethyl -1,9-Dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylic acid
(119a) Benzyl 2,6-dimethyl-7-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10 -Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylate or benzyl 2,6-dimethyl-7-[(10R) -2,3,3, 7,7-Pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran -5-Carboxylate Benzyl 2,6-dimethyl-7-[(10S) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6, prepared in Example 118g 7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylate or benzyl 2,6-dimethyl-7-[(10R)- 3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl ] -1-Benzofuran-5-carboxylate (high polarity compound; 67.9 mg, 0.123 mmol), methyl iodide (40 μL, 0.640 mmol), DMF (2 .0 mL) and sodium hydride (63%, 12.0 mg, 0.315 mmol) were used for the reaction and workup according to Example 2a to obtain the title compound (56.0 mg, 80%).
(119b) 2,6-Dimethyl-7-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylic acid or 2,6-dimethyl-7-[(10R) -2,3,3,7, 7-Pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5 -Carboxylic acid Benzyl 2,6-dimethyl-7-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7 prepared in Example 119a , 8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -1-benzofuran-5-carboxylate or benzyl 2,6-dimethyl-7-[(10R) -2 , 3,3,7,7-Pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl ] Example 1 using 1-benzofuran-5-carboxylate (56.0 mg, 0.0986 mmol), 1 M aqueous sodium hydroxide solution (1.0 mL, 1.0 mmol) and methanol (2.0 mL) The title compound (44.0 mg, 93%) was obtained by carrying out the reaction and post-treatment according to 5 g.
(実施例120)
　6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例117dで製造したtert-ブチル　6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレートもしくはtert-ブチル　6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート (高極性化合物; 606 mg, 0.989 mmol)、ジクロロメタン(6.1 mL)及びトリフルオロ酢酸(3.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(498 mg, 90%)を得た。 (Example 120)
6- {3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid or 6- {3-[(10R) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1 '-Cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butyl 6- {3-[(10S) -2 prepared in Example 117d -Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1'- Cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate or tert-butyl 6- {3-[(10R) -2-ethyl-3,3- Dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cycl Lopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (high polarity compound; 606 mg, 0.989 mmol), dichloromethane (6.1 mL) and trifluoroacetic acid (3.0 The title compound (498 mg, 90%) was obtained by carrying out the reaction and post-treatment according to Example 1d.
(実施例121)
　6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
又は、6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例115eで製造した6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸もしくは6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(40.0 mg, 0.0701 mmol) 、カルボニルジイミダゾール(14.8 mg, 0.0911 mmol)、DMF (0.8 mL)、メタンスルホンアミド(10.7 mg, 0.112 mmol)及びDBU (17 μL, 0.112 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(29.3 mg, 65%)を得た。 (Example 121)
6- {3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-7,1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide or 6- {3 -[(10R) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] Pyridine-7,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide 6- {3 prepared in Example 115e -[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] Pyridine-7,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid or 6- {3-[(10R) -2-ethyl-3 , 3-Dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] Lysine-7,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid (40.0 mg, 0.0701 mmol), carbonyldiimidazole (14.8 mg, 0.0911 The title compound (29.3 mg, 65%).
(実施例122)
　6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
又は、6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例116で製造した6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸もしくは6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(40.0 mg, 0.0701 mmol) 、カルボニルジイミダゾール(14.8 mg, 0.0911 mmol)、DMF (0.8 mL)、メタンスルホンアミド(10.7 mg, 0.112 mmol)及びDBU (17 μL, 0.112 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(26.3 mg, 58%)を得た。 (Example 122)
6- {3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-7,1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide or 6- {3 -[(10R) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] Pyridine-7,1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide 6- {3 prepared in Example 116 -[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] Pyridine-7,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid or 6- {3-[(10R) -2-ethyl-3 , 3-Dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pi Lysine-7,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid (40.0 mg, 0.0701 mmol), carbonyldiimidazole (14.8 mg, 0.0911 The title compound (26.3 mg, 58%).
(実施例123)
　6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
又は、6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例117eで製造した6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸もしくは6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(40.0 mg, 0.0719 mmol) 、カルボニルジイミダゾール(15.1 mg, 0.0934 mmol)、DMF (0.8 mL)、メタンスルホンアミド(10.9 mg, 0.115 mmol)及びDBU (17 μL, 0.115 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(19.8 mg, 44%)を得た。 (Example 123)
6- {3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide or 6- { 3-[(10R) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c ] Pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide 6-prepared in Example 117e {3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2- c] Pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid or 6- {3-[(10R) -2- Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid (40.0 mg, 0.0719 mmol), Using carbonyldiimidazole (15.1 mg, 0.0934 mmol), DMF (0.8 mL), methanesulfonamide (10.9 mg, 0.115 mmol) and DBU (17 μL, 0.115 mmol), the reaction and workup were carried out according to Example 6a. This gave the title compound (19.8 mg, 44%).
(実施例124)
　6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
又は、6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例120で製造した6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸もしくは6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(40.0 mg, 0.0719 mmol) 、カルボニルジイミダゾール(15.1 mg, 0.0934 mmol)、DMF (0.8 mL)、メタンスルホンアミド(10.9 mg, 0.115 mmol)及びDBU (17 μL, 0.115 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(17.6 mg, 39%)を得た。 (Example 124)
6- {3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide or 6- { 3-[(10R) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c ] Pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide 6- {3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2- c] Pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid or 6- {3-[(10R) -2- Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [ 3,2-c] pyridine-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid (40.0 mg, 0.0719 mmol), carbonyl Using diimidazole (15.1 mg, 0.0934 mmol), DMF (0.8 mL), methanesulfonamide (10.9 mg, 0.115 mmol) and DBU (17 μL, 0.115 mmol), the reaction and workup are performed according to Example 6a. This gave the title compound (17.6 mg, 39%).
(実施例125)
　6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
(125a) ベンジル　6-[4-メトキシ-2-メチル-3-(2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル)フェニル]-3-メチルピリジン-2-カルボン酸
　実施例13dで製造した6-[4-メトキシ-2-メチル-3-(2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル)フェニル]-3-メチルピリジン-2-カルボン酸(85.0 mg, 0.153 mmol)、ベンジルブロミド(20 μL, 0.168 mmol)、炭酸セシウム(59.7 mg, 0.183 mmol)及びDMF (0.9 mL)を用い、実施例20eに準じて反応及び後処理を行うことにより、標記化合物(95.3 mg, 97%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.96 (3H, s), 1.10 (3H, s), 1.73-1.95 (4H, m), 2.02-2.07 (1H, m), 2.13 (1H, d, J = 16.0 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.34 (1H, d, J = 17.6 Hz), 2.47 (1H, d, J = 17.2 Hz), 2.52 (3H, s), 2.63-2.76 (3H, m), 2.87 (3H, s), 2.94 (3H, s), 3.72 (3H, s), 5.17 (1H, s), 5.42 (1H, d, J = 11.7 Hz), 5.45 (1H, d, J = 12.9 Hz), 6.67 (1H, d, J = 8.6 Hz), 7.24 (1H, d, J = 8.2 Hz), 7.32 (1H, d, J = 7.4 Hz), 7.38 (2H, t, J = 7.4 Hz), 7.45 (1H, d, J = 8.2 Hz), 7.50 (2H, d, J = 7.0 Hz), 7.56 (1H, d, J = 8.2 Hz).
(125b) ベンジル　6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
又は、ベンジル　6-{4-メトキシ-2-メチル-3-[(10R)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例125aで製造したベンジル　6-[4-メトキシ-2-メチル-3-(2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル)フェニル]-3-メチルピリジン-2-カルボン酸(105 mg)をChiral flash IA(ヘキサン/イソプロパノール; 4:6)により光学分割し、高極性化合物(44.8 mg)及び低極性化合物(47.7 mg)を得た。
(125c) 6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例125bで製造したベンジル　6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレートもしくはベンジル　6-{4-メトキシ-2-メチル-3-[(10R)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(高極性化合物; 44.0 mg, 0.0680 mmol)、パラジウム炭素(10%, 13.2 mg)、酢酸エチル(1.3 mL)及びメタノール(1.3 mL)を用い、実施例18に準じて反応及び後処理を行うことにより、標記化合物(23.2 mg, 61%)を得た。 (Example 125)
6- {4-Methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-3,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2-methyl-3 -[(10R) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine- 3,1'-Cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid
(125a) Benzyl 6- [4-methoxy-2-methyl-3- (2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-3,1'-cyclobutane] -10-yl) phenyl] -3-methylpyridine-2-carboxylic acid 6- [4-methoxy-2 prepared in Example 13d -Methyl-3- (2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine- 3,1'-cyclobutane] -10-yl) phenyl] -3-methylpyridine-2-carboxylic acid (85.0 mg, 0.153 mmol), benzyl bromide (20 μL, 0.168 mmol), cesium carbonate (59.7 mg, 0.183 mmol) ) And DMF (0.9 mL), and the reaction and post-treatment were performed according to Example 20e to obtain the title compound (95.3 mg, 97%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.96 (3H, s), 1.10 (3H, s), 1.73-1.95 (4H, m), 2.02-2.07 (1H, m), 2.13 (1H, d, J = 16.0 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.34 (1H, d, J = 17.6 Hz), 2.47 (1H, d, J = 17.2 Hz), 2.52 (3H, s) , 2.63-2.76 (3H, m), 2.87 (3H, s), 2.94 (3H, s), 3.72 (3H, s), 5.17 (1H, s), 5.42 (1H, d, J = 11.7 Hz), 5.45 (1H, d, J = 12.9 Hz), 6.67 (1H, d, J = 8.6 Hz), 7.24 (1H, d, J = 8.2 Hz), 7.32 (1H, d, J = 7.4 Hz), 7.38 ( 2H, t, J = 7.4 Hz), 7.45 (1H, d, J = 8.2 Hz), 7.50 (2H, d, J = 7.0 Hz), 7.56 (1H, d, J = 8.2 Hz).
(125b) Benzyl 6- {4-methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9, 10-octahydrospiro [chromeno [3,2-c] pyridin-3,1′-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate or benzyl 6- {4-methoxy- 2-Methyl-3-[(10R) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2 -c] pyridin-3,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate benzyl 6- [4-methoxy-2-methyl-3- (prepared in Example 125a) 2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-3,1'-cyclobutane ] -10-yl) phenyl] -3-methylpyridine-2-carboxylic acid (105 mg) was optically resolved with Chiral flash IA (hexane / isopropanol; 4: 6) to obtain high polar compounds (44.8 mg) and low polarity Compound (47.7 mg) was obtained.
(125c) 6- {4-Methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10 -Octahydrospiro [chromeno [3,2-c] pyridine-3,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2- Methyl-3-[(10R) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c ] Pyridine-3,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid benzyl 6- {4-methoxy-2-methyl-3-[(10S ) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-3,1 ' -Cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate or benzyl 6- {4-methoxy-2-methyl-3-[(10R) -2,7,7-trimethyl-1, 9-Dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-3,1'-cyclobut N] -10-yl] phenyl} -3-methylpyridine-2-carboxylate (high polarity compound; 44.0 mg, 0.0680 mmol), palladium on carbon (10%, 13.2 mg), ethyl acetate (1.3 mL) and methanol ( 1.3 mL), and the reaction and post-treatment were performed according to Example 18 to obtain the title compound (23.2 mg, 61%).
(実施例126)
　6-{4-メトキシ-3-[2-(2-メトキシエチル)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(126a) tert-ブチル　6-{3-[2-(2,3-ジヒドロキシプロピル)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
実施例5aで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[3,3,7,7-テトラメチル-1,9-ジオキソ-2-(プロパ-2-エン-1-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(212 mg, 0.338 mmol)、四酸化オスミウム(4% THF溶液, 107 mg, 0.0168 mmol)及び水(0.2 mL)のTHF/tert-BuOH (3.0 mL, 2:1)溶液に室温でN-メチルモリホリンオキシド(39.6 mg, 0.676 mmol)を加えた。反応溶液を2時間室温で攪拌後、チオ硫酸ナトリウム水溶液水を加えて酢酸エチルで2回抽出した。有機層を水及び飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル)で精製し、標記化合物(190 mg, 85%)をジアステレオマー混合物として得た。
(126b) tert-ブチル　6-{4-メトキシ-2-メチル-3-[3,3,7,7-テトラメチル-1,9-ジオキソ-2-(2-オキソエチル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例126aで製造したtert-ブチル　6-{3-[2-(2,3-ジヒドロキシプロピル)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(128 mg, 0.193 mmol)のTHF/水(3.0 mL, 2:1)溶液に室温で過ヨウ素酸ナトリウム(103 mg, 0.483 mmol)を加えた。反応溶液を1時間室温で攪拌後、チオ硫酸ナトリウム水溶液水を加えて酢酸エチルで2回抽出した。有機層を水及び飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。有機層を減圧濃縮し、粗製の標記化合物を得た。
(126c) tert-ブチル　6-{3-[2-(2-ヒドロキシエチル)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例126bで製造した粗製のtert-ブチル　6-{4-メトキシ-2-メチル-3-[3,3,7,7-テトラメチル-1,9-ジオキソ-2-(2-オキソエチル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレートのメタノール(1.0 mL)溶液に0℃で水素化ホウ素ナトリウム(10.8 mg, 0.285 mmol)を加えた。反応溶液を1時間0℃で攪拌後、塩化アンモニウム水溶液水を加えてジクロロメタンで2回抽出した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル)で精製し、標記化合物(114 mg, 95%, 2 steps)を得た。 Example 126
6- {4-methoxy-3- [2- (2-methoxyethyl) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9, 10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(126a) tert-butyl 6- {3- [2- (2,3-dihydroxypropyl) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7, 8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate prepared in Example 5a tert-butyl 6- {4-methoxy-2-methyl-3- [3,3,7,7-tetramethyl-1,9-dioxo-2- (prop-2-en-1-yl) -2, 3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylate (212 mg, 0.338 mmol ), Osmium tetroxide (4% THF solution, 107 mg, 0.0168 mmol) and water (0.2 mL) in THF / tert-BuOH (3.0 mL, 2: 1) at room temperature with N-methylmorpholine oxide (39.6 mg). , 0.676 mmol). The reaction solution was stirred for 2 hours at room temperature, aqueous sodium thiosulfate solution was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (190 mg, 85%) as a diastereomer mixture.
(126b) tert-butyl 6- {4-methoxy-2-methyl-3- [3,3,7,7-tetramethyl-1,9-dioxo-2- (2-oxoethyl) -2,3,4 , 6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylate tert-butyl prepared in Example 126a 6- {3- [2- (2,3-dihydroxypropyl) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (128 mg, 0.193 mmol) in THF / water ( To a 3.0 mL, 2: 1) solution, sodium periodate (103 mg, 0.483 mmol) was added at room temperature. The reaction solution was stirred for 1 hour at room temperature, aqueous sodium thiosulfate solution was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to give the crude title compound.
(126c) tert-butyl 6- {3- [2- (2-hydroxyethyl) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8, 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate Crude prepared in Example 126b tert-butyl 6- {4-methoxy-2-methyl-3- [3,3,7,7-tetramethyl-1,9-dioxo-2- (2-oxoethyl) -2,3,4,6, Hydrogen at 0 ° C in a solution of 7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylate in methanol (1.0 mL) Sodium borohydride (10.8 mg, 0.285 mmol) was added. The reaction solution was stirred for 1 hour at 0 ° C., aqueous ammonium chloride solution was added, and the mixture was extracted twice with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (114 mg, 95%, 2 steps).
1H-NMR(400MHz, CDCl3):δ ppm: 0.96 (3H, s), 1.09 (3H, s), 1.13 (3H, s), 1.38 (3H, s), 1.64 (9H, s), 2.14 (1H, d, J = 16.0 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.31 (1H, d, J = 16.8 Hz), 2.34 (1H, d, J = 17.2 Hz), 2.45 (1H, d, J = 17.6 Hz), 2.50 (3H, s), 2.74 (1H, d, J = 16.8 Hz), 2.83 (3H, s), 3.13-3.20 (1H, m), 3.61-3.72 (3H, m), 3.72 (3H, s), 5.17 (1H, s), 6.69 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 7.8 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.53 (1H, d, J = 8.2 Hz).
(126d) tert-ブチル　6-{4-メトキシ-3-[2-(2-メトキシエチル)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例126cで製造したtert-ブチル　6-{3-[2-(2-ヒドロキシエチル)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(86.3 mg, 0.137 mmol)、ヨウ化メチル(42 μL, 0.685 mmol)、DMF (1.0 mL)及び水素化ナトリウム(60%, 8.2 mg, 0.203 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(60.4 mg, 68%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.95 (3H, s), 1.09 (3H, s), 1.12 (3H, s), 1.40 (3H, s), 1.63 (9H, s), 2.13 (1H, d, J = 16.0 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.28 (1H, d, J = 16.8 Hz), 2.33 (1H, d, J = 16.4 Hz), 2.44 (1H, d, J = 18.0 Hz), 2.49 (3H, s), 2.69 (1H, d, J = 16.8 Hz), 2.86 (3H, s), 3.17-3.24 (1H, m), 3.29 (3H, s), 3.39-3.45 (2H, m), 3.55-3.63 (1H, m), 3.72 (3H, s), 5.19 (1H, s), 6.69 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 7.8 Hz).
(126e) 6-{4-メトキシ-3-[2-(2-メトキシエチル)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例126dで製造したtert-ブチル　6-{4-メトキシ-3-[2-(2-メトキシエチル)-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(60.4 mg, 0.0937 mmol)、ジクロロメタン(3.0 mL)、トリフルオロ酢酸(1.0 mL)、エタノール(2.0 mL)及びtert-ブチルアミン(10 μL, 0.0937 mmol) を用い、実施例41fに準じて反応及び後処理を行うことにより、標記化合物(19.0 mg, 31%, 2 steps)を得た。 1 H-NMR (400MHz, CDCl 3 ): δ ppm: 0.96 (3H, s), 1.09 (3H, s), 1.13 (3H, s), 1.38 (3H, s), 1.64 (9H, s), 2.14 (1H, d, J = 16.0 Hz), 2.22 (1H, d, J = 16.4 Hz), 2.31 (1H, d, J = 16.8 Hz), 2.34 (1H, d, J = 17.2 Hz), 2.45 (1H , d, J = 17.6 Hz), 2.50 (3H, s), 2.74 (1H, d, J = 16.8 Hz), 2.83 (3H, s), 3.13-3.20 (1H, m), 3.61-3.72 (3H, m), 3.72 (3H, s), 5.17 (1H, s), 6.69 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 7.8 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.53 (1H, d, J = 8.2 Hz).
(126d) tert-butyl 6- {4-methoxy-3- [2- (2-methoxyethyl) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6, 7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -2-methylphenyl} -3-methylpyridine-2-carboxylate tert-prepared in Example 126c Butyl 6- {3- [2- (2-hydroxyethyl) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro -1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (86.3 mg, 0.137 mmol), methyl iodide (42 μL, 0.685 mmol), DMF (1.0 mL) and sodium hydride (60%, 8.2 mg, 0.203 mmol) were used for the reaction and workup according to Example 2a to give the title compound (60.4 mg, 68 %).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.95 (3H, s), 1.09 (3H, s), 1.12 (3H, s), 1.40 (3H, s), 1.63 (9H, s), 2.13 (1H, d, J = 16.0 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.28 (1H, d, J = 16.8 Hz), 2.33 (1H, d, J = 16.4 Hz), 2.44 (1H , d, J = 18.0 Hz), 2.49 (3H, s), 2.69 (1H, d, J = 16.8 Hz), 2.86 (3H, s), 3.17-3.24 (1H, m), 3.29 (3H, s) , 3.39-3.45 (2H, m), 3.55-3.63 (1H, m), 3.72 (3H, s), 5.19 (1H, s), 6.69 (1H, d, J = 8.6 Hz), 7.28 (1H, d , J = 8.6 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 7.8 Hz).
(126e) 6- {4-Methoxy-3- [2- (2-methoxyethyl) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8 , 9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt tert prepared in Example 126d -Butyl 6- {4-methoxy-3- [2- (2-methoxyethyl) -3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8, 9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -2-methylphenyl} -3-methylpyridine-2-carboxylate (60.4 mg, 0.0937 mmol), dichloromethane (3.0 mL ), Trifluoroacetic acid (1.0 mL), ethanol (2.0 mL) and tert-butylamine (10 μL, 0.0937 mmol). 31%, 2 steps).
(実施例127)
　3-[(3S,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシビフェニル-2-カルボン酸
(127a) (3S,10S)-10-(1-ヒドロキシ-5-メトキシ-1,3-ジヒドロ-2,1-ベンゾキサボロール-4-イル)-7,7-ジメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例34dで製造した2-[6-メトキシ-2-{[(4-メトキシベンジル)オキシ]メチル}-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン(170 mg, 0.318 mmol)及び公知化合物である(6S)-6-(プロパン-2-イル)ピペリジン-2,4-ジオン(54.3 mg, 0.350 mmol)のアセトニトリル(2.0 mL)溶液に0℃で炭酸セシウム(124 mg, 0.382 mmol)を加えた。反応溶液を0℃で3時間攪拌後、水を加えて酢酸エチルで2回抽出後、有機層を水で洗浄した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮し、粗製の付加物を得た。粗製の付加物の酢酸エチル(20 mL)溶液に室温で4 M塩酸(1,4-ジオキサン溶液; 2.0 mL)を加え、反応溶液を室温で48時間攪拌した。反応溶液を濃縮後、残渣をシリカゲルカラムクロマトグラフィー(ジクロロメタン/メタノール; 95:5)で精製し、標記化合物(137 mg, 95%)をジアステレオマー混合物として得た。
(127b) (3S,10S)-10-[2-(ヒドロキシメチル)-4-メトキシビフェニル-3-イル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例127aで製造した(3S,10S)-10-(1-ヒドロキシ-5-メトキシ-1,3-ジヒドロ-2,1-ベンゾキサボロール-4-イル)-7,7-ジメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(ジアステレオマー混合物; 136 mg, 0.301 mmol)、クロロベンゼン(37 μL, 0.362 mmol)、2nd Generation X-Phos Precatalyst (47.4 mg, 0.0603 mmol)、リン酸カリウム(102 mg, 0.482 mmol)、THF (0.7 mL)及び水(1.4 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(22.1 mg, 15%)を淡黄色アモルファスとして得た。 (Example 127)
3-[(3S, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -4-methoxybiphenyl-2-carboxylic acid
(127a) (3S, 10S) -10- (1-Hydroxy-5-methoxy-1,3-dihydro-2,1-benzoxabolol-4-yl) -7,7-dimethyl-3- (propane -2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione 2- [6 prepared in Example 34d -Methoxy-2-{[(4-methoxybenzyl) oxy] methyl} -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] -5,5 -Dimethylcyclohexane-1,3-dione (170 mg, 0.318 mmol) and acetonitrile of the known compound (6S) -6- (propan-2-yl) piperidine-2,4-dione (54.3 mg, 0.350 mmol) Cesium carbonate (124 mg, 0.382 mmol) was added to the (2.0 mL) solution at 0 ° C. The reaction solution was stirred at 0 ° C. for 3 hours, water was added and the mixture was extracted twice with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude adduct. To a solution of the crude adduct in ethyl acetate (20 mL) was added 4 M hydrochloric acid (1,4-dioxane solution; 2.0 mL) at room temperature, and the reaction solution was stirred at room temperature for 48 hours. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (dichloromethane / methanol; 95: 5) to obtain the title compound (137 mg, 95%) as a diastereomer mixture.
(127b) (3S, 10S) -10- [2- (Hydroxymethyl) -4-methoxybiphenyl-3-yl] -7,7-dimethyl-3- (propan-2-yl) -3,4,6 , 7,8,10-Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (3S, 10S) -10- (1-Hydroxy-5- prepared in Example 127a Methoxy-1,3-dihydro-2,1-benzoxabolol-4-yl) -7,7-dimethyl-3- (propan-2-yl) -3,4,6,7,8,10- Hexahydro-1H-chromeno [3,2-c] pyridine-1,9 (2H) -dione (diastereomeric mixture; 136 mg, 0.301 mmol), chlorobenzene (37 μL, 0.362 mmol), 2nd Generation X-Phos Precatalyst (47.4 mg, 0.0603 mmol), potassium phosphate (102 mg, 0.482 mmol), THF (0.7 mL) and water (1.4 mL) were used to carry out the reaction and workup according to Example 9d to give the title compound. (22.1 mg, 15%) was obtained as a pale yellow amorphous.
1H-NMR(400MHz, CDCl3):δ ppm: 0.84 (3H, d, J = 6.7 Hz), 0.88 (3H, d, J = 7.0 Hz), 0.96 (3H, s), 1.10 (3H, s), 1.67-1.76 (1H, m), 2.15 (1H, d, J = 17.6 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.37 (1H, d, J = 17.6 Hz), 2.47-2.55 (2H, m), 2.63 (1H, dd, J = 6.7, 16.8 Hz), 3.27-3.33 (1H, m), 3.72 (3H, s), 4.79 (1H, dd, J = 7.0, 12.1 Hz), 5.16 (1H, s), 5.24 (1H, dd, J = 3.9, 12.1 Hz), 5.86 (1H, s), 6.13 (1H, dd, J = 3.9, 7.4 Hz), 6.77 (1H, d, J = 8.6 Hz), 7.15 (1H, d, J = 8.2 Hz), 7.28-7.31 (1H, m), 7.38 (2H, t, J = 7.4 Hz), 7.59 (2H, d, J = 7.0 Hz).
(127c) 3-[(3S,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシビフェニル-2-カルボアルデヒド
　実施例127bで製造した(3S,10S)-10-[2-(ヒドロキシメチル)-4-メトキシビフェニル-3-イル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(22.1 mg, 0.0441 mmol)、ジクロロメタン(2.0 mL)、デスマーチンペルヨージナン(20.6 mg, 0.0485 mmol)を用い、実施例32lに準じて反応及び後処理を行うことにより、標記化合物(19.1 mg, 87%)を無色オイルとして得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.90 (6H, t, J = 7.0 Hz), 0.97 (3H, s), 1.10 (3H, s), 1.67-1.76 (1H, m), 2.12 (1H, d, J = 16.0 Hz), 2.23 (1H, d, J = 16.0 Hz), 2.33 (1H, d, J = 18.0 Hz), 2.44-2.55 (3H, m), 3.31-3.38 (1H, m), 3.75 (3H, s), 5.47 (1H, s), 5.76 (1H, s), 6.93 (1H, d, J = 8.6 Hz), 7.18 (1H, d, J = 8.6 Hz), 7.29-7.38 (5H, m), 10.36 (1H, s).
(127d) 3-[(3S,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシビフェニル-2-カルボン酸
　実施例127cで製造した3-[(3S,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシビフェニル-2-カルボアルデヒド(19.1 mg, 0.0382 mmol)、2-メチル-2-ブテン(90 μL, 0.765 mmol)、りん酸二水素ナトリウム二水和物(29.8 mg, 0.191 mmol)、水(1.0 mL)、t-ブタノール(2.0 mL)、ジクロロメタン(0.5 mL)及び亜塩素酸ナトリウム(21.6 mg, 0.191 mmol)を用い、実施例32mに準じて反応及び後処理を行うことにより、標記化合物(10.2 mg, 52%)を白色固体として得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.84 (3H, d, J = 6.7 Hz), 0.88 (3H, d, J = 7.0 Hz), 0.96 (3H, s), 1.10 (3H, s ), 1.67-1.76 (1H, m), 2.15 (1H, d, J = 17.6 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.37 (1H, d, J = 17.6 Hz), 2.47-2.55 (2H, m), 2.63 (1H, dd, J = 6.7, 16.8 Hz), 3.27-3.33 (1H, m), 3.72 (3H, s), 4.79 (1H, dd, J = 7.0, 12.1 Hz), 5.16 (1H, s), 5.24 (1H, dd, J = 3.9, 12.1 Hz), 5.86 (1H, s), 6.13 (1H, dd, J = 3.9, 7.4 Hz), 6.77 (1H, d, J = 8.6 Hz), 7.15 (1H, d, J = 8.2 Hz), 7.28-7.31 (1H, m), 7.38 (2H, t, J = 7.4 Hz), 7.59 (2H, d, J = 7.0 Hz).
(127c) 3-[(3S, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxybiphenyl-2-carbaldehyde (3S, 10S) -10- [2- (hydroxymethyl)-prepared in Example 127b 4-methoxybiphenyl-3-yl] -7,7-dimethyl-3- (propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] Using pyridine-1,9 (2H) -dione (22.1 mg, 0.0441 mmol), dichloromethane (2.0 mL), desmartin periodinane (20.6 mg, 0.0485 mmol), the reaction and workup were carried out according to Example 32l. By performing, the title compound (19.1 mg, 87%) was obtained as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.90 (6H, t, J = 7.0 Hz), 0.97 (3H, s), 1.10 (3H, s), 1.67-1.76 (1H, m), 2.12 (1H, d, J = 16.0 Hz), 2.23 (1H, d, J = 16.0 Hz), 2.33 (1H, d, J = 18.0 Hz), 2.44-2.55 (3H, m), 3.31-3.38 (1H, m), 3.75 (3H, s), 5.47 (1H, s), 5.76 (1H, s), 6.93 (1H, d, J = 8.6 Hz), 7.18 (1H, d, J = 8.6 Hz), 7.29- 7.38 (5H, m), 10.36 (1H, s).
(127d) 3-[(3S, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10- Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxybiphenyl-2-carboxylic acid 3-[(3S, 10S) -7,7-dimethyl-1 prepared in Example 127c , 9-Dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl]- 4-Methoxybiphenyl-2-carbaldehyde (19.1 mg, 0.0382 mmol), 2-methyl-2-butene (90 μL, 0.765 mmol), sodium dihydrogen phosphate dihydrate (29.8 mg, 0.191 mmol), water (1.0 mL), t-butanol (2.0 mL), dichloromethane (0.5 mL) and sodium chlorite (21.6 mg, 0.191 mmol) were used, and the reaction was carried out according to Example 32m and worked up by the post-treatment. (10.2 mg, 52%) was obtained as a white solid.
(実施例128)
　6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
(128a) 10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,3,3-トリメチル-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン
　実施例117aで製造した10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3-ジメチル-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン(2.40 g, 4.62 mmol)、ヨウ化メチル(1.44 mL, 23.1 mmol)、DMF (48 mL)及び水素化ナトリウム(55%, 302 mg, 6.93 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(1.97 g, 80%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.31-0.50 (4H, m), 1.09 (3H, s), 1.30 (12H, s), 1.33 (3H, s), 1.96 (1H, d, J = 17.2 Hz), 2.19 (1H, d, J = 17.6 Hz), 2.29 (1H, d, J = 16.8 Hz), 2.36 (1H, d, J = 16.8 Hz), 2.59 (2H, t, J = 16.0 Hz), 2.79 (3H, s), 3.15 (3H, s), 3.70 (3H, s), 5.22 (1H, s), 6.60 (1H, d, J = 8.6 Hz), 7.58 (1H, d, J = 8.2 Hz).
(128b) tert-ブチル　6-[4-メトキシ-2-メチル-3-(2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル)フェニル]-3-メチルピリジン-2-カルボキシレート
　実施例128aで製造した10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,3,3-トリメチル-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-1,9(2H,8H)-ジオン(1.97 g, 3.69 mmol)、公知化合物であるtert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(1.01 g, 4.43 mmol)、2nd Generation X-Phos Precatalyst (581 mg, 0.739 mmol)、リン酸カリウム(1.25 g, 5.91 mmol)、THF (10 mL)及び水(20 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(1.91 g, 86%)を得た。 (Example 128)
6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2-methyl- 3-[(10R) -2,3,3-Trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine -7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid
(128a) 10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2,3,3-trimethyl -3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -1,9 (2H, 8H) -dione 10- [prepared in Example 117a 6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3-dimethyl-3,4,6,10 -Tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -1,9 (2H, 8H) -dione (2.40 g, 4.62 mmol), methyl iodide (1.44 mL, 23.1 mmol ), DMF (48 mL) and sodium hydride (55%, 302 mg, 6.93 mmol), the title compound (1.97 g, 80%) was obtained by carrying out the reaction and post-treatment according to Example 2a. It was.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.31-0.50 (4H, m), 1.09 (3H, s), 1.30 (12H, s), 1.33 (3H, s), 1.96 (1H, d, J = 17.2 Hz), 2.19 (1H, d, J = 17.6 Hz), 2.29 (1H, d, J = 16.8 Hz), 2.36 (1H, d, J = 16.8 Hz), 2.59 (2H, t, J = 16.0 Hz), 2.79 (3H, s), 3.15 (3H, s), 3.70 (3H, s), 5.22 (1H, s), 6.60 (1H, d, J = 8.6 Hz), 7.58 (1H, d, J = 8.2 Hz).
(128b) tert-Butyl 6- [4-methoxy-2-methyl-3- (2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10- Octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl) phenyl] -3-methylpyridine-2-carboxylate 10- [6- Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2,3,3-trimethyl-3,4,6,10 -Tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -1,9 (2H, 8H) -dione (1.97 g, 3.69 mmol), a known compound tert-butyl 6- Chloro-3-methylpyridine-2-carboxylate (1.01 g, 4.43 mmol), 2nd Generation X-Phos Precatalyst (581 mg, 0.739 mmol), potassium phosphate (1.25 g, 5.91 mmol), THF (10 mL) and The title compound (1.91 g, 86%) was obtained by performing reaction and post-treatment according to Example 9d using water (20 mL).
1H-NMR(400MHz, CDCl3):δ ppm: 0.36-0.50 (4H, m), 1.11 (3H, s), 1.34 (3H, s), 1.64 (9H, s), 1.99 (1H, d, J = 16.8 Hz), 2.22 (1H, d, J = 17.6 Hz), 2.29 (1H, d, J = 16.8 Hz), 2.38 (1H, d, J = 16.8 Hz), 2.49 (3H, s), 2.61 (2H, t, J = 16.8 Hz), 2.79 (3H, s), 2.88 (3H, s), 3.73 (3H, s), 5.21 (1H, s), 6.72 (1H, d, J = 8.6 Hz), 7.29 (1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 7.8 Hz).
(128c) tert-ブチル　6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
及び、tert-ブチル　6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例128bで製造したtert-ブチル　6-[4-メトキシ-2-メチル-3-(2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル)フェニル]-3-メチルピリジン-2-カルボキシレート(1.91 g)をChiral flash IA(ダイセル化学工業; ヘキサン/イソプロパノール；60:40)により光学分割し、高極性化合物(1.00 g)及び低極性化合物(1.06 g)を得た。
(128d) 6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例128cで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレートもしくはtert-ブチル　6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(高極性化合物; 1.00 g, 1.67 mmol)、ジクロロメタン(10 mL)及びトリフルオロ酢酸(5.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(801 mg, 88%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.36-0.50 (4H, m), 1.11 (3H, s), 1.34 (3H, s), 1.64 (9H, s), 1.99 (1H, d, J = 16.8 Hz), 2.22 (1H, d, J = 17.6 Hz), 2.29 (1H, d, J = 16.8 Hz), 2.38 (1H, d, J = 16.8 Hz), 2.49 (3H, s), 2.61 (2H, t, J = 16.8 Hz), 2.79 (3H, s), 2.88 (3H, s), 3.73 (3H, s), 5.21 (1H, s), 6.72 (1H, d, J = 8.6 Hz) , 7.29 (1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 7.8 Hz).
(128c) tert-butyl 6- {4-methoxy-2-methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8, 9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate and tert-butyl 6- {4-Methoxy-2-methyl-3-[(10R) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [ Chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate tert-butyl 6- [4-methoxy prepared in Example 128b -2-Methyl-3- (2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] Pyridine-7,1'-cyclopropane] -10-yl) phenyl] -3-methylpyridine-2-carboxylate (1.91 g) optically by Chiral flash IA (Daicel Chemical Industries; hexane / isopropanol; 60:40) Split into highly polar compounds ( 1.00 g) and a low polarity compound (1.06 g) were obtained.
(128d) 6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10 -Octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2 -Methyl-3-[(10R) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2- c] Pyridine-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butyl 6- {4-methoxy-2-methyl-3 prepared in Example 128c -[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine- 7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate or tert-butyl 6- {4-methoxy-2-methyl-3-[(10R) -2,3 , 3-Trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1'- Example using cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate (high polarity compound; 1.00 g, 1.67 mmol), dichloromethane (10 mL) and trifluoroacetic acid (5.0 mL) The title compound (801 mg, 88%) was obtained by carrying out the reaction and post-treatment according to 1d.
(実施例129)
　6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例128cで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレートもしくはtert-ブチル　6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(低極性化合物; 1.06 g, 1.77 mmol)、ジクロロメタン(11 mL)及びトリフルオロ酢酸(5.3 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(738 mg, 77%)を得た。 (Example 129)
6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2-methyl- 3-[(10R) -2,3,3-Trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine -7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butyl 6- {4-methoxy-2-methyl-3-[( 10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1 '-Cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate or tert-butyl 6- {4-methoxy-2-methyl-3-[(10R) -2,3,3- Trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cycl Propane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate (low polarity compound; 1.06 g, 1.77 mmol), dichloromethane (11 mL) and trifluoroacetic acid (5.3 mL), Example 1d The title compound (738 mg, 77%) was obtained by reacting and working up according to.
(実施例130)
　6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(130a) 10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-6,7,8,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-1,9(2H,4H)-ジオン
　実施例9bで製造した2-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]-5,5-ジメチルシクロヘキサン-1,3-ジオン(1.41 g, 3.54 mmol)及び公知化合物である4-アザスピロ[2.5]オクタン-5,7-ジオン(640 mg, 4.60 mmol)のアセトニトリル(30 mL)溶液に室温で炭酸カリウム(1.22 g, 8.85 mmol)を加えた。反応溶液を室温で5時間攪拌後、0℃で反応溶液に水(120 mL)を加え、析出した固体をろ取し、付加物を得た。付加物及び炭酸セシウム(2.71 g, 8.33 mmol)のDMF (18 mL)溶液に室温でN-フェニルビス(トリフルオロメタンスルホンイミド) (1.43 g, 4.00 mmol)を加え、反応溶液を室温で24時間攪拌した。反応溶液に0℃で水(72 mL)を加え、析出した固体をろ取し、シリカゲルカラムクロマトグラフィー(酢酸エチル)で精製し、標記化合物(1.29 g, 70%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.52-0.74 (4H, m), 0.93 (3H, s), 1.08 (3H, s), 1.30 (12H, s), 2.08 (1H, d, J = 17.2 Hz), 2.11 (1H, d, J = 15.7 Hz), 2.20 (1H, d, J = 16.4 Hz), 2.31 (1H, d, J = 17.6 Hz), 2.42 (1H, d, J = 16.8 Hz), 2.93 (1H, d, J = 17.2 Hz), 3.10 (3H, s), 3.71 (3H, s), 5.17 (1H, s), 5.47 (1H, s), 6.61 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 8.2 Hz).
(130b) 10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-6,7,8,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-1,9(2H,4H)-ジオン
　実施例130aで製造した10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-6,7,8,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-1,9(2H,4H)-ジオン(1.29 g, 2.48 mmol)、ヨウ化メチル(1.55 mL, 24.8 mmol)、DMF (26 mL)及び水素化ナトリウム(63%, 114 mg, 2.98 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(1.31 g, 99%)を得た。 (Example 130)
6- {4-Methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-3,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt or 6- {4-methoxy- 2-Methyl-3-[(10R) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2 -c] pyridine-3,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(130a) 10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-6 , 7,8,10-Tetrahydrospiro [chromeno [3,2-c] pyridine-3,1'-cyclopropane] -1,9 (2H, 4H) -dione 2- [6- Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] -5,5-dimethylcyclohexane-1,3-dione (1.41 g , 3.54 mmol) and a known compound 4-azaspiro [2.5] octane-5,7-dione (640 mg, 4.60 mmol) in acetonitrile (30 mL) at room temperature with potassium carbonate (1.22 g, 8.85 mmol) It was. The reaction solution was stirred at room temperature for 5 hours, water (120 mL) was added to the reaction solution at 0 ° C., and the precipitated solid was collected by filtration to give an adduct. N-phenylbis (trifluoromethanesulfonimide) (1.43 g, 4.00 mmol) was added to a DMF (18 mL) solution of the adduct and cesium carbonate (2.71 g, 8.33 mmol) at room temperature, and the reaction solution was stirred at room temperature for 24 hours. did. Water (72 mL) was added to the reaction solution at 0 ° C., and the precipitated solid was collected by filtration and purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (1.29 g, 70%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.52-0.74 (4H, m), 0.93 (3H, s), 1.08 (3H, s), 1.30 (12H, s), 2.08 (1H, d, J = 17.2 Hz), 2.11 (1H, d, J = 15.7 Hz), 2.20 (1H, d, J = 16.4 Hz), 2.31 (1H, d, J = 17.6 Hz), 2.42 (1H, d, J = 16.8 Hz), 2.93 (1H, d, J = 17.2 Hz), 3.10 (3H, s), 3.71 (3H, s), 5.17 (1H, s), 5.47 (1H, s), 6.61 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 8.2 Hz).
(130b) 10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2,7,7-trimethyl -6,7,8,10-tetrahydrospiro [chromeno [3,2-c] pyridine-3,1'-cyclopropane] -1,9 (2H, 4H) -dione 10- [prepared in Example 130a 6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-6,7,8,10 -Tetrahydrospiro [chromeno [3,2-c] pyridine-3,1'-cyclopropane] -1,9 (2H, 4H) -dione (1.29 g, 2.48 mmol), methyl iodide (1.55 mL, 24.8 mmol) ), DMF (26 mL) and sodium hydride (63%, 114 mg, 2.98 mmol), the title compound (1.31 g, 99%) was obtained by carrying out the reaction and post-treatment according to Example 2a. It was.
1H-NMR(400MHz, CDCl3):δ ppm: 0.50-0.68 (3H, m), 0.92 (3H, s), 1.07 (3H, s), 1.18-1.25 (1H, m), 1.30 (12H, s), 1.91 (1H, d, J = 16.8 Hz), 2.11 (1H, d, J = 17.6 Hz), 2.19 (1H, d, J = 16.4 Hz), 2.29 (1H, d, J = 17.2 Hz), 2.41 (1H, d, J = 17.2 Hz), 2.67 (3H, s), 2.96 (1H, d, J = 16.8 Hz), 3.14 (3H, s), 3.70 (3H, s), 5.24 (1H, s), 6.60 (1H, d, J = 8.6 Hz), 7.58 (1H, d, J = 8.2 Hz).
(130c) tert-ブチル　6-[4-メトキシ-2-メチル-3-(2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル)フェニル]-3-メチルピリジン-2-カルボキシレート
　実施例130bで製造した10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,7,7-トリメチル-6,7,8,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-1,9(2H,4H)-ジオン(1.31 g, 2.46 mmol)、公知化合物であるtert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(671 mg, 2.95 mmol)、2nd Generation X-Phos Precatalyst (96.6 mg, 0.123 mmol)、リン酸カリウム(782 mg, 3.68 mmol)、THF (14 mL)及び水(21 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(1.02 g, 69%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.56-0.70 (3H, m), 0.97 (3H, s), 1.09 (3H, s), 1.19-1.26 (1H, m), 1.63 (9H, s), 1.90 (1H, d, J = 16.8 Hz), 2.14 (1H, d, J = 17.2 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.32 (1H, d, J = 17.6 Hz), 2.43 (1H, d, J = 18.4 Hz), 2.48 (3H, s), 2.68 (3H, s), 2.86 (3H, s), 3.01 (1H, d, J = 16.8 Hz), 3.74 (3H, s), 5.22 (1H, s), 6.71 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 8.2 Hz), 7.52 (1H, d, J = 8.2 Hz).
(130d) tert-ブチル　6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
及び、tert-ブチル　6-{4-メトキシ-2-メチル-3-[(10R)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例130cで製造したtert-ブチル　6-[4-メトキシ-2-メチル-3-(2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル)フェニル]-3-メチルピリジン-2-カルボキシレート(1.14 g)をChiral flash IA(ダイセル化学工業; ヘキサン/イソプロパノール；85:15)により光学分割し、高極性化合物(574 mg)及び低極性化合物(572 mg)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.50-0.68 (3H, m), 0.92 (3H, s), 1.07 (3H, s), 1.18-1.25 (1H, m), 1.30 (12H, s), 1.91 (1H, d, J = 16.8 Hz), 2.11 (1H, d, J = 17.6 Hz), 2.19 (1H, d, J = 16.4 Hz), 2.29 (1H, d, J = 17.2 Hz) , 2.41 (1H, d, J = 17.2 Hz), 2.67 (3H, s), 2.96 (1H, d, J = 16.8 Hz), 3.14 (3H, s), 3.70 (3H, s), 5.24 (1H, s), 6.60 (1H, d, J = 8.6 Hz), 7.58 (1H, d, J = 8.2 Hz).
(130c) tert-butyl 6- [4-methoxy-2-methyl-3- (2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10- Octahydrospiro [chromeno [3,2-c] pyridin-3,1'-cyclopropane] -10-yl) phenyl] -3-methylpyridine-2-carboxylate 10- [6- Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2,7,7-trimethyl-6,7,8,10 -Tetrahydrospiro [chromeno [3,2-c] pyridine-3,1'-cyclopropane] -1,9 (2H, 4H) -dione (1.31 g, 2.46 mmol), a known compound tert-butyl 6- Chloro-3-methylpyridine-2-carboxylate (671 mg, 2.95 mmol), 2nd Generation X-Phos Precatalyst (96.6 mg, 0.123 mmol), potassium phosphate (782 mg, 3.68 mmol), THF (14 mL) and The title compound (1.02 g, 69%) was obtained by performing reaction and post-treatment according to Example 9d using water (21 mL).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.56-0.70 (3H, m), 0.97 (3H, s), 1.09 (3H, s), 1.19-1.26 (1H, m), 1.63 (9H, s), 1.90 (1H, d, J = 16.8 Hz), 2.14 (1H, d, J = 17.2 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.32 (1H, d, J = 17.6 Hz) , 2.43 (1H, d, J = 18.4 Hz), 2.48 (3H, s), 2.68 (3H, s), 2.86 (3H, s), 3.01 (1H, d, J = 16.8 Hz), 3.74 (3H, s), 5.22 (1H, s), 6.71 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 8.2 Hz), 7.52 (1H, d, J = 8.2 Hz).
(130d) tert-butyl 6- {4-methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8, 9,10-octahydrospiro [chromeno [3,2-c] pyridine-3,1′-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate and tert-butyl 6- {4-Methoxy-2-methyl-3-[(10R) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [ Chromeno [3,2-c] pyridin-3,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate tert-butyl 6- [4-methoxy prepared in Example 130c -2-Methyl-3- (2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] Pyridine-3,1'-cyclopropane] -10-yl) phenyl] -3-methylpyridine-2-carboxylate (1.14 g) optically by Chiral flash IA (Daicel Chemical Industries; hexane / isopropanol; 85:15) Split into highly polar compounds ( 574 mg) and a low polarity compound (572 mg) were obtained.
(130e) 6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例130dで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレートもしくはtert-ブチル　6-{4-メトキシ-2-メチル-3-[(10R)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(低極性化合物; 570 mg, 0.952 mmol)、ジクロロメタン(2.9 mL)及びトリフルオロ酢酸(2.9 mL) を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(496 mg, 96%)を得た。 (130e) 6- {4-Methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10 -Octahydrospiro [chromeno [3,2-c] pyridine-3,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2 -Methyl-3-[(10R) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2- c] Pyridine-3,1′-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butyl 6- {4-methoxy-2-methyl-3 prepared in Example 130d -[(10S) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine- 3,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate or tert-butyl 6- {4-methoxy-2-methyl-3-[(10R) -2,7 , 7-Trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-3,1'- Example using cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate (low polarity compound; 570 mg, 0.952 mmol), dichloromethane (2.9 mL) and trifluoroacetic acid (2.9 mL) The title compound (496 mg, 96%) was obtained by carrying out the reaction and post-treatment according to 1d.
1H-NMR(400MHz, CDCl3):δ ppm: 0.57-0.77 (3H, m), 0.97 (3H, s), 1.10 (3H, s), 1.19-1.26 (1H, m), 2.01 (1H, d, J = 16.8 Hz), 2.15 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.34 (1H, d, J = 17.6 Hz), 2.46 (1H, d, J = 17.6 Hz), 2.70 (3H, s), 2.80 (3H, s), 2.88 (3H, s), 2.96 (1H, d, J = 16.8 Hz), 3.77 (3H, s), 5.21 (1H, s), 6.75 (1H, d, J = 8.6 Hz), 7.20 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 7.8 Hz), 7.69 (1H, d, J = 8.2 Hz).
MS(EI)m/z: 543[M+H]+.
(130f) 6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例130eで製造した6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸もしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(485 mg, 0.894 mmol)、ジクロロメタン(2.5 mL)及びtert-ブチルアミン(188 μL, 1.79 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(515 mg, 94%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.57-0.77 (3H, m), 0.97 (3H, s), 1.10 (3H, s), 1.19-1.26 (1H, m), 2.01 (1H, d, J = 16.8 Hz), 2.15 (1H, d, J = 16.4 Hz), 2.24 (1H, d, J = 16.4 Hz), 2.34 (1H, d, J = 17.6 Hz), 2.46 (1H, d, J = 17.6 Hz), 2.70 (3H, s), 2.80 (3H, s), 2.88 (3H, s), 2.96 (1H, d, J = 16.8 Hz), 3.77 (3H, s), 5.21 (1H, s), 6.75 (1H, d, J = 8.6 Hz), 7.20 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 7.8 Hz), 7.69 (1H, d, J = 8.2 Hz) .
MS (EI) m / z: 543 [M + H] +.
(130f) 6- {4-Methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10 -Octahydrospiro [chromeno [3,2-c] pyridine-3,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt or 6- {4 -Methoxy-2-methyl-3-[(10R) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [ 3,2-c] Pyridin-3,1′-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt 6- {4-methoxy-prepared in Example 130e 2-Methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2 -c] pyridin-3,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2-methyl-3-[(10R) -2 , 7,7-Trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pi Lysine-3,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid (485 mg, 0.894 mmol), dichloromethane (2.5 mL) and tert-butylamine (188 μL, 1.79 mmol) The title compound (515 mg, 94%) was obtained by reaction and workup according to Example 3c.
(実施例131)
　6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(131a) 6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例130dで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレートもしくはtert-ブチル　6-{4-メトキシ-2-メチル-3-[(10R)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(高極性化合物; 570 mg, 0.952 mmol)、ジクロロメタン(2.9 mL)及びトリフルオロ酢酸(2.9 mL) を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(493 mg, 95%)を得た。 (Example 131)
6- {4-Methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-3,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt or 6- {4-methoxy- 2-Methyl-3-[(10R) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2 -c] pyridine-3,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(131a) 6- {4-Methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10 -Octahydrospiro [chromeno [3,2-c] pyridine-3,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2 -Methyl-3-[(10R) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2- c] Pyridine-3,1′-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butyl 6- {4-methoxy-2-methyl-3 prepared in Example 130d -[(10S) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine- 3,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate or tert-butyl 6- {4-methoxy-2-methyl-3-[(10R) -2,7 , 7-Trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-3,1'- Example using cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate (high polarity compound; 570 mg, 0.952 mmol), dichloromethane (2.9 mL) and trifluoroacetic acid (2.9 mL) The title compound (493 mg, 95%) was obtained by reaction and post-treatment according to 1d.
MS(EI)m/z: 543[M+H]+.
(131b) 6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例131aで製造した6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸もしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(478 mg, 0.881 mmol)、ジクロロメタン(2.5 mL)及びtert-ブチルアミン(185 μL, 1.76 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(500 mg, 92%)を得た。 MS (EI) m / z: 543 [M + H] +.
(131b) 6- {4-Methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10 -Octahydrospiro [chromeno [3,2-c] pyridine-3,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt or 6- {4 -Methoxy-2-methyl-3-[(10R) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [ 3,2-c] Pyridin-3,1′-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt 6- {4-Methoxy-produced in Example 131a 2-Methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2 -c] pyridin-3,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2-methyl-3-[(10R) -2 , 7,7-Trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pi Lysine-3,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid (478 mg, 0.881 mmol), dichloromethane (2.5 mL) and tert-butylamine (185 μL, 1.76 mmol) The title compound (500 mg, 92%) was obtained by performing the reaction and post-treatment according to Example 3c.
(実施例132)
　6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
(132a) 10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,3,3-トリメチル-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン
　実施例115aで製造した10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-3,3-ジメチル-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン(2.05 g, 3.84 mmol)、ヨウ化メチル(359 μL, 5.76 mmol)、DMF (21 mL)及び水素化ナトリウム(55%, 218 mg, 5.00 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、粗製の標記化合物を得た。 (Example 132)
6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2-methyl-3 -[(10R) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine- 7,1'-Cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid
(132a) 10- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2,3,3-trimethyl -3,4,6,10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H) -dione 10- [6 prepared in Example 115a -Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3,3-dimethyl-3,4,6,10- Tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H) -dione (2.05 g, 3.84 mmol), methyl iodide (359 μL, 5.76 mmol), The crude title compound was obtained by reaction and workup according to Example 2a using DMF (21 mL) and sodium hydride (55%, 218 mg, 5.00 mmol).
(132b) tert-ブチル　6-[4-メトキシ-2-メチル-3-(2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル)フェニル]-3-メチルピリジン-2-カルボキシレート
　実施例132aで製造した粗製の10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2,3,3-トリメチル-3,4,6,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-1,9(2H,8H)-ジオン、公知化合物であるtert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(1.11 g, 4.87 mmol)、2nd Generation X-Phos Precatalyst (589 mg, 0.749 mmol)、リン酸カリウム(1.27 g, 5.99 mmol)、THF (10 mL)及び水(20 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(1.20 g, 51%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 1.10 (3H, s), 1.35 (3H, s), 1.63 (9H, s), 1.67-1.92 (6H, m), 2.31 (1H, d, J = 16.8 Hz), 2.36 (1H, d, J = 16.4 Hz), 2.47 (1H, d, J = 16.0 Hz), 2.49 (3H, s), 2.58 (1H, d, J = 17.2 Hz), 2.65 (2H, d, J = 16.8 Hz), 2.79 (3H, s), 2.86 (3H, s), 3.72 (3H, s), 5.16 (1H, s), 6.66 (1H, d, J = 8.2 Hz), 7.27 (1H, d, J = 8.2 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.2 Hz).
(132c) tert-ブチル　6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
及び、tert-ブチル　6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例132bで製造したtert-ブチル　6-[4-メトキシ-2-メチル-3-(2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル)フェニル]-3-メチルピリジン-2-カルボキシレート(1.20 g)をChiral flash IA(ダイセル化学工業; ヘキサン/エタノール；70:30)により光学分割し、高極性化合物(572 mg)及び低極性化合物(600 mg)を得た。 (132b) tert-butyl 6- [4-methoxy-2-methyl-3- (2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10- Octahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclobutane] -10-yl) phenyl] -3-methylpyridine-2-carboxylate Crude 10- [6 prepared in Example 132a -Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2,3,3-trimethyl-3,4,6, 10-tetrahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -1,9 (2H, 8H) -dione, known compound tert-butyl 6-chloro-3-methylpyridine- Using 2-carboxylate (1.11 g, 4.87 mmol), 2nd Generation X-Phos Precatalyst (589 mg, 0.749 mmol), potassium phosphate (1.27 g, 5.99 mmol), THF (10 mL) and water (20 mL) The title compound (1.20 g, 51%) was obtained by carrying out the reaction and post-treatment according to Example 9d.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.10 (3H, s), 1.35 (3H, s), 1.63 (9H, s), 1.67-1.92 (6H, m), 2.31 (1H, d, J = 16.8 Hz), 2.36 (1H, d, J = 16.4 Hz), 2.47 (1H, d, J = 16.0 Hz), 2.49 (3H, s), 2.58 (1H, d, J = 17.2 Hz), 2.65 (2H, d, J = 16.8 Hz), 2.79 (3H, s), 2.86 (3H, s), 3.72 (3H, s), 5.16 (1H, s), 6.66 (1H, d, J = 8.2 Hz) , 7.27 (1H, d, J = 8.2 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.2 Hz).
(132c) tert-butyl 6- {4-methoxy-2-methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8, 9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1′-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate and tert-butyl 6- { 4-Methoxy-2-methyl-3-[(10R) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridin-7,1′-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate tert-butyl 6- [4-methoxy-2 prepared in Example 132b -Methyl-3- (2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine- 7,1′-cyclobutane] -10-yl) phenyl] -3-methylpyridine-2-carboxylate (1.20 g) was optically resolved by Chiral flash IA (Daicel Chemical Industries; hexane / ethanol; 70:30) High polarity compound (572 mg) and low Give sex compound (600 mg).
(132d) 6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン
　実施例132cで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレートもしくはtert-ブチル　6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(低極性化合物; 600 mg, 0.979 mmol)、ジクロロメタン(6.0 mL)及びトリフルオロ酢酸(3.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(489 mg, 90%)を得た。 (132d) 6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10 -Octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2- Methyl-3-[(10R) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c ] Pyridine-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butyl 6- {4-methoxy-2-methyl-3-[( 10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1 '-Cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate or tert-butyl 6- {4-methoxy-2-methyl-3-[(10R) -2,3,3-trimethyl -1,9-Dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobut Tan] -10-yl] phenyl} -3-methylpyridine-2-carboxylate (low polarity compound; 600 mg, 0.979 mmol), dichloromethane (6.0 mL) and trifluoroacetic acid (3.0 mL), Example 1d The title compound (489 mg, 90%) was obtained by reacting and working up according to.
(実施例133)
　6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(133a) 6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例132cで製造したt tert-ブチル　6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレートもしくはtert-ブチル　6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(高極性化合物; 572 mg, 0.933 mmol)、ジクロロメタン(5.7 mL)及びトリフルオロ酢酸(2.9 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(480 mg, 92%)を得た。 (Example 133)
6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt or 6- {4-methoxy-2 -Methyl-3-[(10R) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2- c] Pyridine-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(133a) 6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10 -Octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2- Methyl-3-[(10R) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c ] Pyridine-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid t tert-butyl 6- {4-methoxy-2-methyl-3- prepared in Example 132c [(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7 , 1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate or tert-butyl 6- {4-methoxy-2-methyl-3-[(10R) -2,3,3 -Trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cycl Example 1d with butane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate (high polarity compound; 572 mg, 0.933 mmol), dichloromethane (5.7 mL) and trifluoroacetic acid (2.9 mL) The title compound (480 mg, 92%) was obtained by reacting and working up according to.
(133b) 6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例133aで製造した6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸もしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(392 mg, 0.704 mmol)、酢酸エチル(5.0 mL)、ジクロロメタン(3.0 mL)及びtert-ブチルアミン(111 μL, 1.06 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(444 mg, 99%)を得た。 (133b) 6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10 -Octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt or 6- {4- Methoxy-2-methyl-3-[(10R) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3 , 2-c] Pyridin-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt 6- {4-Methoxy-2-prepared in Example 133a Methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c ] Pyridine-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2-methyl-3-[(10R) -2,3, 3-Trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine -7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid (392 mg, 0.704 mmol), ethyl acetate (5.0 mL), dichloromethane (3.0 mL) and tert-butylamine ( The title compound (444 mg, 99%) was obtained by carrying out the reaction and post-treatment according to Example 3c using 111 μL, 1.06 mmol).
(実施例134)
　6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例実施例133aで製造した6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸もしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(50.0 mg, 0.0898 mmol)、カルボニルジイミダゾール(18.9 mg, 0.117 mmol)、DMF (1.0 mL)、メタンスルホンアミド(13.7 mg, 0.144 mmol)及びDBU (22 μL, 0.144 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(12.1 mg, 21%)を得た。 (Example 134)
6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide or 6- {4-methoxy -2-methyl-3-[(10R) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] Pyridin-7,1′-cyclobutane] -10-yl] phenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide Example 6- {4-Methoxy prepared in Example 133a -2-methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] Pyridin-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2-methyl-3-[(10R) -2 , 3,3-Trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [ 3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid (50.0 mg, 0.0898 mmol), carbonyldiimidazole (18.9 mg, 0.117 mmol) , DMF (1.0 mL), methanesulfonamide (13.7 mg, 0.144 mmol) and DBU (22 μL, 0.144 mmol) were used for the reaction and workup according to Example 6a to give the title compound (12.1 mg, 21%) was obtained.
(実施例135)
　6-{3-[(3S,10S)-2-(2-フルオロエチル)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
(135a) (3S,10S)-2-(2-フルオロエチル)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン
　実施例9cで製造した(3S,10S)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(200 mg, 0.374 mmol)、1-ブロモ-2-フルオロエタン(285 mg, 2.24 mmol)、DMF (4.0 mL)及び水素化ナトリウム(55%, 65.2 mg, 1.49 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(101 mg, 47%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.78 (3H, d, J = 7.0 Hz), 0.84 (3H, d, J = 6.7 Hz), 0.92 (3H, s), 1.08 (3H, s), 1.31 (12H, s), 1.84-1.94 (1H, m), 2.10 (1H, d, J = 18.0 Hz), 2.19 (1H, d, J = 16.4 Hz), 2.31 (1H, d, J = 18.0 Hz), 2.45 (2H, t, J = 17.8 Hz), 2.87-3.03 (2H, m), 3.12 (3H, s), 3.17 (1H, t, J = 7.8 Hz), 4.16-4.67 (3H, m), 3.66 (3H, s), 5.24 (1H, s), 6.55 (1H, d, J = 8.6 Hz), 7.57 (1H, d, J = 8.2 Hz).
(135b) メチル　6-{3-[(3S,10S)-2-(2-フルオロエチル)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例135aで製造した(3S,10S)-2-(2-フルオロエチル)-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-3-(プロパン-2-イル)-3,4,6,7,8,10-ヘキサヒドロ-1H-クロメノ[3,2-c]ピリジン-1,9(2H)-ジオン(100 mg, 0.172 mmol)、メチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(47.9 mg, 0.258 mmol)、2nd Generation X-Phos Precatalyst (27.1 mg, 0.0344 mmol)、リン酸カリウム(58.4 mg, 0.275 mmol)、THF (0.5 mL)及び水(1.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(78.0 mg, 75%)を得た。 (Example 135)
6- {3-[(3S, 10S) -2- (2-fluoroethyl) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6 , 7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid
(135a) (3S, 10S) -2- (2-Fluoroethyl) -10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane) -2-yl) phenyl] -7,7-dimethyl-3- (propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] pyridine- 1,9 (2H) -dione (3S, 10S) -10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2) prepared in Example 9c -Dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3- (propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2-c] Pyridine-1,9 (2H) -dione (200 mg, 0.374 mmol), 1-bromo-2-fluoroethane (285 mg, 2.24 mmol), DMF (4.0 mL) and sodium hydride (55%, 65.2 mg, The title compound (101 mg, 47%) was obtained by carrying out the reaction and post-treatment according to Example 2a using 1.49 mmol).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.78 (3H, d, J = 7.0 Hz), 0.84 (3H, d, J = 6.7 Hz), 0.92 (3H, s), 1.08 (3H, s ), 1.31 (12H, s), 1.84-1.94 (1H, m), 2.10 (1H, d, J = 18.0 Hz), 2.19 (1H, d, J = 16.4 Hz), 2.31 (1H, d, J = 18.0 Hz), 2.45 (2H, t, J = 17.8 Hz), 2.87-3.03 (2H, m), 3.12 (3H, s), 3.17 (1H, t, J = 7.8 Hz), 4.16-4.67 (3H, m), 3.66 (3H, s), 5.24 (1H, s), 6.55 (1H, d, J = 8.6 Hz), 7.57 (1H, d, J = 8.2 Hz).
(135b) Methyl 6- {3-[(3S, 10S) -2- (2-fluoroethyl) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3 , 4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxy (3S, 10S) -2- (2-fluoroethyl) -10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3) prepared in Example 135a , 2-Dioxaborolan-2-yl) phenyl] -7,7-dimethyl-3- (propan-2-yl) -3,4,6,7,8,10-hexahydro-1H-chromeno [3,2- c] pyridine-1,9 (2H) -dione (100 mg, 0.172 mmol), methyl 6-chloro-3-methylpyridine-2-carboxylate (47.9 mg, 0.258 mmol), 2nd Generation X-Phos Precatalyst (27.1 mg, 0.0344 mmol), potassium phosphate (58.4 mg, 0.275 mmol), THF (0.5 mL) and water (1.0 mL) were used for the reaction and workup according to Example 9d to give the title compound (78.0 mg, 75%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.86 (6H, t, J = 7.0 Hz), 0.96 (3H, s), 1.10 (3H, s), 1.88-1.97 (1H, m), 2.13 (1H, d, J = 16.0 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.34 (1H, d, J = 17.6 Hz), 2.45 (1H, d, J = 17.2 Hz), 2.51 (1H, d, J = 17.2 Hz), 2.60 (3H, s), 2.84 (3H, s), 2.90-3.06 (2H, m), 3.18 (1H, t, J = 7.4 Hz), 3.70 (3H, s), 3.95 (3H, s), 4.15-4.66 (3H, m), 5.22 (1H, s), 6.67 (1H, d, J = 8.6 Hz), 7.24 (1H, d, J = 8.2 Hz), 7.46 (1H, d, J = 7.8 Hz), 7.59 (1H, d, J = 8.2 Hz).
(135c) 6-{3-[(3S,10S)-2-(2-フルオロエチル)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例135bで製造したメチル　6-{3-[(3S,10S)-2-(2-フルオロエチル)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(78.0 mg, 0.129 mmol)、1 M 水酸化ナトリウム水溶液(0.15 mL, 0.150 mmol)、メタノール(0.4 mL)及びTHF (0.4 mL)を用い、実施例25gに準じて反応及び後処理を行うことにより、標記化合物(30.1 mg, 40%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.86 (6H, t, J = 7.0 Hz), 0.96 (3H, s), 1.10 (3H, s), 1.88-1.97 (1H, m), 2.13 (1H, d, J = 16.0 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.34 (1H, d, J = 17.6 Hz), 2.45 (1H, d, J = 17.2 Hz), 2.51 (1H , d, J = 17.2 Hz), 2.60 (3H, s), 2.84 (3H, s), 2.90-3.06 (2H, m), 3.18 (1H, t, J = 7.4 Hz), 3.70 (3H, s) , 3.95 (3H, s), 4.15-4.66 (3H, m), 5.22 (1H, s), 6.67 (1H, d, J = 8.6 Hz), 7.24 (1H, d, J = 8.2 Hz), 7.46 ( 1H, d, J = 7.8 Hz), 7.59 (1H, d, J = 8.2 Hz).
(135c) 6- {3-[(3S, 10S) -2- (2-fluoroethyl) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3, 4,6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid Methyl 6- {3-[(3S, 10S) -2- (2-fluoroethyl) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl)-prepared in Example 135b 2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine- 2-Carboxylate (78.0 mg, 0.129 mmol), 1 M aqueous sodium hydroxide solution (0.15 mL, 0.150 mmol), methanol (0.4 mL) and THF (0.4 mL) were used according to Example 25 g for reaction and workup. To give the title compound (30.1 mg, 40%).
(実施例136)
　6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド
　実施例128dで製造した6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸もしくは6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(51.0 mg, 0.0940 mmol)、カルボニルジイミダゾール(19.8 mg, 0.122 mmol)、DMF (1.0 mL)、メタンスルホンアミド(14.3 mg, 0.150 mmol)及びDBU (22 μL, 0.150 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(43.2 mg, 74%)を得た。 (Example 136)
6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] phenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide or 6- {4- Methoxy-2-methyl-3-[(10R) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3 , 2-c] Pyridin-7,1'-cyclopropane] -10-yl] phenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide 6- {4-methoxy prepared in Example 128d -2-methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-7,1′-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2-methyl-3-[(10R)- 2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [ 3,2-c] pyridine-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid (51.0 mg, 0.0940 mmol), carbonyldiimidazole (19.8 mg, 0.122 mmol) ), DMF (1.0 mL), methanesulfonamide (14.3 mg, 0.150 mmol) and DBU (22 μL, 0.150 mmol) were used for the reaction and workup according to Example 6a to give the title compound (43.2 mg , 74%).
(実施例137)
　7-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2,4-ジメチル-N-(メチルスルホニル)-1-ベンゾフラン-5-カルボキサミド
　実施例113eで製造した7-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2,4-ジメチル-1-ベンゾフラン-5-カルボン酸(205 mg, 0.405 mmol)、カルボニルジイミダゾール(209 mg, 1.29 mmol)、DMF (4.0 mL)、メタンスルホンアミド(121 mg, 1.27 mmol)及びDBU (200 μL, 1.30 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(196 mg, 83%)を得た。 (Example 137)
7-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -2,4-dimethyl-N- (methylsulfonyl) -1-benzofuran-5-carboxamide 7-[(3S, 10S) -3 prepared in Example 113e -tert-Butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridine-10 -Yl] -2,4-dimethyl-1-benzofuran-5-carboxylic acid (205 mg, 0.405 mmol), carbonyldiimidazole (209 mg, 1.29 mmol), DMF (4.0 mL), methanesulfonamide (121 mg, 1.27 mmol) and DBU (200 μL, 1.30 mmol) were used and reacted and worked up according to Example 6a to give the title compound (196 mg, 83%).
(実施例138)
　7-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-N-(エチルスルホニル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキサミド
　実施例113eで製造した7-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-2,4-ジメチル-1-ベンゾフラン-5-カルボン酸(205 mg, 0.405 mmol)、カルボニルジイミダゾール(205 mg, 1.26 mmol)、DMF (4.0 mL)、エタンスルホンアミド(128 mg, 1.17 mmol)及びDBU (200 μL, 1.30 mmol)を用い、実施例6aに準じて反応及び後処理を行うことにより、標記化合物(169 mg, 70%)を得た。 (Example 138)
7-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -N- (ethylsulfonyl) -2,4-dimethyl-1-benzofuran-5-carboxamide 7-[(3S, 10S) -3 prepared in Example 113e -tert-Butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridine-10 -Yl] -2,4-dimethyl-1-benzofuran-5-carboxylic acid (205 mg, 0.405 mmol), carbonyldiimidazole (205 mg, 1.26 mmol), DMF (4.0 mL), ethanesulfonamide (128 mg, 1.17 mmol) and DBU (200 μL, 1.30 mmol) were used for the reaction and post-treatment according to Example 6a to obtain the title compound (169 mg, 70%).
(実施例139)
　6-{3-[(3S,10S)-2-(2-ヒドロキシエチル)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
(139a) tert-ブチル　6-{3-[(3S,10S)-2-(2-フルオロエチル)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例9dで製造したtert-ブチル　6-{3-[(3S,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2メチルフェニル}-3-メチルピリジン-2-カルボキシレート(300 mg, 0.499 mmol)、1-ブロモ-2-フルオロエタン(634 mg, 4.99 mmol)、DMF (6.0 mL)及び水素化ナトリウム(55%, 109 mg, 2.50 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(145 mg, 45%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.85 (3H, d, J = 6.6 Hz), 0.87 (3H, d, J = 6.6 Hz), 0.96 (3H, s), 1.09 (3H, s), 1.63 (9H, s), 1.88-1.97 (1H, m), 2.13 (1H, d, J = 16.4 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.34 (1H, d, J = 17.6 Hz), 2.45 (1H, d, J = 18.4 Hz), 2.49 (3H, s), 2.50 (1H, d, J = 17.6 Hz), 2.84 (3H, s), 2.90-3.05 (2H, m), 3.18 (1H, t, J = 7.2 Hz), 3.69 (3H, s), 4.15-4.65 (3H, m), 5.22 (1H, s), 6.66 (1H, d, J = 8.6 Hz), 7.29 (1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 8.2 Hz), 7.52 (1H, d, J = 8.6 Hz).
(139b) 6-{3-[(3S,10S)-2-(2-ヒドロキシエチル)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例139aで製造したtert-ブチル　6-{3-[(3S,10S)-2-(2-フルオロエチル)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(154 mg, 0.238 mmol)、ジクロロメタン(1.5 mL)及びトリフルオロ酢酸(0.77 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(111 mg, 79%)を無色固体として得た。 (Example 139)
6- {3-[(3S, 10S) -2- (2-hydroxyethyl) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6 , 7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid
(139a) tert-Butyl 6- {3-[(3S, 10S) -2- (2-fluoroethyl) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2 , 3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2 -Carboxylate tert-butyl 6- {3-[(3S, 10S) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3, prepared in Example 9d 4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2methylphenyl} -3-methylpyridine-2-carboxylate ( 300 mg, 0.499 mmol), 1-bromo-2-fluoroethane (634 mg, 4.99 mmol), DMF (6.0 mL) and sodium hydride (55%, 109 mg, 2.50 mmol) according to Example 2a The title compound (145 mg, 45%) was obtained by reaction and workup.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.85 (3H, d, J = 6.6 Hz), 0.87 (3H, d, J = 6.6 Hz), 0.96 (3H, s), 1.09 (3H, s ), 1.63 (9H, s), 1.88-1.97 (1H, m), 2.13 (1H, d, J = 16.4 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.34 (1H, d, J = 17.6 Hz), 2.45 (1H, d, J = 18.4 Hz), 2.49 (3H, s), 2.50 (1H, d, J = 17.6 Hz), 2.84 (3H, s), 2.90-3.05 (2H, m) , 3.18 (1H, t, J = 7.2 Hz), 3.69 (3H, s), 4.15-4.65 (3H, m), 5.22 (1H, s), 6.66 (1H, d, J = 8.6 Hz), 7.29 ( 1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 8.2 Hz), 7.52 (1H, d, J = 8.6 Hz).
(139b) 6- {3-[(3S, 10S) -2- (2-hydroxyethyl) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3, 4,6,7,8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid Tert-butyl 6- {3-[(3S, 10S) -2- (2-fluoroethyl) -7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) prepared in Example 139a ) -2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl The title compound (111 mg) was prepared by carrying out the reaction and post-treatment according to Example 1d using pyridine-2-carboxylate (154 mg, 0.238 mmol), dichloromethane (1.5 mL) and trifluoroacetic acid (0.77 mL). 79%) as a colorless solid.
(実施例140)
　6-{3-[(10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
又は、6-{3-[(10R)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(140a) 2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-6,7,8,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-1,9(2H,4H)-ジオン
　実施例13aで製造した10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-6,7,8,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-1,9(2H,4H)-ジオン(900 mg, 1.69 mmol)、ヨウ化エチル(1.08 mL, 13.5 mmol)、DMPU (18 mL)及び水素化ナトリウム(55%, 221 mg, 5.06 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(768 mg, 81%)を得た。 (Example 140)
6- {3-[(10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-3,1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt or 6- {3- [ (10R) -2-ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine- 3,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(140a) 2-Ethyl-10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7 -Dimethyl-6,7,8,10-tetrahydrospiro [chromeno [3,2-c] pyridine-3,1'-cyclobutane] -1,9 (2H, 4H) -dione 10- prepared in Example 13a [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-6,7,8, 10-tetrahydrospiro [chromeno [3,2-c] pyridine-3,1'-cyclobutane] -1,9 (2H, 4H) -dione (900 mg, 1.69 mmol), ethyl iodide (1.08 mL, 13.5 mmol) ), DMPU (18 mL) and sodium hydride (55%, 221 mg, 5.06 mmol), and the reaction and post-treatment were performed according to Example 2a to obtain the title compound (768 mg, 81%). It was.
1H-NMR(400MHz, CDCl3):δ ppm: 0.92 (3H, s), 1.03 (3H, t, J = 7.0 Hz), 1.03 (3H, s), 1.30 (12H, s), 1.74-2.00 (6H, m), 2.10 (1H, d, J = 17.6 Hz), 2.19 (1H, d, J = 16.0 Hz), 2.31 (1H, d, J = 17.6 Hz), 2.43 (1H, d, J = 17.2 Hz), 2.57-2.73 (2H, m), 3.10-3.16 (1H, m), 3.13 (3H, s), 3.68 (3H, s), 3.80-3.90 (1H, m), 5.22 (1H, s), 6.56 (1H, d, J = 8.2 Hz), 7.56 (1H, d, J = 8.6 Hz).
(140b) tert-ブチル　6-[3-(2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート
　実施例140aで製造した2-エチル-10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-6,7,8,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-1,9(2H,4H)-ジオン(768 mg, 1.37 mmol)、公知化合物であるtert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(374 mg, 1.64 mmol)、2nd Generation X-Phos Precatalyst (215 mg, 0.274 mmol)、リン酸カリウム(465 mg, 2.19 mmol)、THF (7.7 mL)及び水(11.5 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(550 mg, 52%, 2 steps)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.96 (3H, s), 1.05 (3H, t, J = 7.2 Hz), 1.09 (3H, s), 1.63 (9H, s), 1.73-2.01 (6H, m), 2.13 (1H, d, J = 15.3 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.34 (1H, d, J = 17.6 Hz), 2.45 (1H, d, J = 18.4 Hz), 2.48 (3H, s), 2.68 (1H, d, J = 17.6 Hz), 2.76 (1H, d, J = 16.4 Hz), 2.85 (3H, s), 3.10-3.18 (1H, m), 3.72 (3H, s), 3.78-3.87 (1H, m), 5.20 (1H, s), 6.66 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 8.6 Hz), 7.38 (1H, d, J = 8.2 Hz), 7.51 (1H, d, J = 7.8 Hz).
(140c) tert-ブチル　6-{3-[(10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
及び、tert-ブチル　6-{3-[(10R)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例140bで製造したtert-ブチル　6-[3-(2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート(550 mg)をChiral flash IA(ダイセル化学工業; ジクロロメタン)により光学分割し、高極性化合物(227 mg)及び低極性化合物(216 mg)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.92 (3H, s), 1.03 (3H, t, J = 7.0 Hz), 1.03 (3H, s), 1.30 (12H, s), 1.74-2.00 (6H, m), 2.10 (1H, d, J = 17.6 Hz), 2.19 (1H, d, J = 16.0 Hz), 2.31 (1H, d, J = 17.6 Hz), 2.43 (1H, d, J = 17.2 Hz), 2.57-2.73 (2H, m), 3.10-3.16 (1H, m), 3.13 (3H, s), 3.68 (3H, s), 3.80-3.90 (1H, m), 5.22 (1H, s ), 6.56 (1H, d, J = 8.2 Hz), 7.56 (1H, d, J = 8.6 Hz).
(140b) tert-butyl 6- [3- (2-ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [ 3,2-c] pyridin-3,1′-cyclobutane] -10-yl) -4-methoxy-2-methylphenyl] -3-methylpyridine-2-carboxylate 2-ethyl-prepared in Example 140a 10- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-6,7, 8,10-tetrahydrospiro [chromeno [3,2-c] pyridine-3,1'-cyclobutane] -1,9 (2H, 4H) -dione (768 mg, 1.37 mmol), a known compound tert-butyl 6-chloro-3-methylpyridine-2-carboxylate (374 mg, 1.64 mmol), 2nd Generation X-Phos Precatalyst (215 mg, 0.274 mmol), potassium phosphate (465 mg, 2.19 mmol), THF (7.7 mL) ) And water (11.5 mL), and the reaction and workup were performed according to Example 9d to give the title compound (550 mg, 52%, 2 steps).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.96 (3H, s), 1.05 (3H, t, J = 7.2 Hz), 1.09 (3H, s), 1.63 (9H, s), 1.73-2.01 (6H, m), 2.13 (1H, d, J = 15.3 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.34 (1H, d, J = 17.6 Hz), 2.45 (1H, d, J = 18.4 Hz), 2.48 (3H, s), 2.68 (1H, d, J = 17.6 Hz), 2.76 (1H, d, J = 16.4 Hz), 2.85 (3H, s), 3.10-3.18 (1H, m) , 3.72 (3H, s), 3.78-3.87 (1H, m), 5.20 (1H, s), 6.66 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 8.6 Hz), 7.38 ( 1H, d, J = 8.2 Hz), 7.51 (1H, d, J = 7.8 Hz).
(140c) tert-butyl 6- {3-[(10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-3,1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate and tert-butyl 6 -{3-[(10R) -2-ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2 -c] pyridin-3,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate tert-butyl 6- [3 prepared in Example 140b -(2-ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-3, 1′-cyclobutane] -10-yl) -4-methoxy-2-methylphenyl] -3-methylpyridine-2-carboxylate (550 mg) was optically resolved with Chiral flash IA (Daicel Chemical Industries, dichloromethane) High polar compound (227 mg) and To give the less polar compound (216 mg).
(140d) 6-{3-[(10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{3-[(10R)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例140cで製造したtert-ブチル　6-{3-[(10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレートもしくはtert-ブチル　6-{3-[(10R)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(高極性化合物; 227 mg, 0.362 mmol)、ジクロロメタン(2.3 mL)及びトリフルオロ酢酸(1.1 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(132 mg, 64%)を得た。 (140d) 6- {3-[(10S) -2-Ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridin-3,1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid or 6- {3-[( 10R) -2-Ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-3 , 1'-Cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butyl 6- {3-[(10S)-prepared in Example 140c 2-Ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-3,1 ' -Cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate or tert-butyl 6- {3-[(10R) -2-ethyl-7,7- Dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-3,1'-cycl Butane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (high polarity compound; 227 mg, 0.362 mmol), dichloromethane (2.3 mL) and trifluoroacetic acid (1.1 The title compound (132 mg, 64%) was obtained by carrying out the reaction and post-treatment according to Example 1d.
1H-NMR(400MHz, CDCl3):δ ppm: 0.97 (3H, s), 1.06 (3H, t, J = 7.0 Hz), 1.10 (3H, s), 1.77-2.01 (6H, m), 2.14 (1H, d, J = 16.4 Hz), 2.23 (1H, d, J = 15.8 Hz), 2.36 (1H, d, J = 17.6 Hz), 2.48 (1H, d, J = 17.6 Hz), 2.60-2.77 (2H, m), 2.80 (3H, s), 2.88 (3H, s), 3.11-3.20 (1H, m), 3.75 (3H, s), 3.80-3.89 (1H, m), 5.19 (1H, s), 6.71 (1H, d, J = 9.1 Hz), 7.19 (1H, d, J = 8.5 Hz), 7.58 (1H, d, J = 7.9 Hz), 7.69 (1H, d, J = 7.9 Hz).
MS(EI)m/z: 571[M+H]+.
(140e) 6-{3-[(10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
又は、6-{3-[(10R)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例140dで製造した6-{3-[(10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸もしくは6-{3-[(10R)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(154 mg, 0.270 mmol)、酢酸エチル(1.5 mL)及びtert-ブチルアミン(34 μL, 0.324 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(165 mg, 95%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.97 (3H, s), 1.06 (3H, t, J = 7.0 Hz), 1.10 (3H, s), 1.77-2.01 (6H, m), 2.14 (1H, d, J = 16.4 Hz), 2.23 (1H, d, J = 15.8 Hz), 2.36 (1H, d, J = 17.6 Hz), 2.48 (1H, d, J = 17.6 Hz), 2.60-2.77 (2H, m), 2.80 (3H, s), 2.88 (3H, s), 3.11-3.20 (1H, m), 3.75 (3H, s), 3.80-3.89 (1H, m), 5.19 (1H, s ), 6.71 (1H, d, J = 9.1 Hz), 7.19 (1H, d, J = 8.5 Hz), 7.58 (1H, d, J = 7.9 Hz), 7.69 (1H, d, J = 7.9 Hz).
MS (EI) m / z: 571 [M + H] +.
(140e) 6- {3-[(10S) -2-Ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridin-3,1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt or 6- { 3-[(10R) -2-Ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c ] Pyridin-3,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt 6- {3- [(10S) -2-Ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine -3,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid or 6- {3-[(10R) -2-ethyl-7, 7-Dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridy -3,1'-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid (154 mg, 0.270 mmol), ethyl acetate (1.5 mL) and tert- The title compound (165 mg, 95%) was obtained by carrying out the reaction and post-treatment according to Example 3c using butylamine (34 μL, 0.324 mmol).
(実施例141)
　6-{3-[(10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
又は、6-{3-[(10R)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(141a) tert-ブチル　6-[3-(7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート
　実施例130aで製造した10-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-7,7-ジメチル-6,7,8,10-テトラヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-1,9(2H,4H)-ジオン(3.85 g, 7.41 mmol)、公知化合物であるtert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(1.69 g, 7.41 mmol)、2nd Generation X-Phos Precatalyst (292 mg, 0.371 mmol)、リン酸カリウム(2.36 g, 11.1 mmol)、THF (40 mL)及び水(60 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(1.24 g, 29%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.60-0.72 (4H, m), 0.97 (3H, s), 1.09 (3H, s), 1.63 (9H, s), 2.08 (1H, d, J = 17.2 Hz), 2.14 (1H, d, J = 17.2 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.33 (1H, d, J = 17.6 Hz), 2.43 (1H, d, J = 17.6 Hz), 2.48 (3H, s), 2.83 (3H, s), 2.98 (1H, d, J = 16.4 Hz), 3.74 (3H, s), 5.17 (1H, s), 5.36 (1H, s), 6.72 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.2 Hz), 7.37 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.6 Hz).
(141b) tert-ブチル　6-[3-(2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート
　実施例141aで製造したtert-ブチル　6-[3-(7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート(1.24 g, 2.12 mmol)、ヨウ化エチル(1.70 mL, 21.2 mmol)、DMF (25 mL)及び水素化ナトリウム(63%, 162 mg, 4.24 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(1.14 g, 88%)を得た。 (Example 141)
6- {3-[(10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-3,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt or 6- {3- [(10R) -2-Ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine -3,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(141a) tert-butyl 6- [3- (7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2- c] Pyridine-3,1′-cyclopropane] -10-yl) -4-methoxy-2-methylphenyl] -3-methylpyridine-2-carboxylate 10- [6-Methoxy-produced in Example 130a 2-Methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -7,7-dimethyl-6,7,8,10-tetrahydrospiro [ Chromeno [3,2-c] pyridine-3,1′-cyclopropane] -1,9 (2H, 4H) -dione (3.85 g, 7.41 mmol), a known compound tert-butyl 6-chloro-3- Methylpyridine-2-carboxylate (1.69 g, 7.41 mmol), 2nd Generation X-Phos Precatalyst (292 mg, 0.371 mmol), potassium phosphate (2.36 g, 11.1 mmol), THF (40 mL) and water (60 mL The title compound (1.24 g, 29%) was obtained by reaction and workup according to Example 9d.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.60-0.72 (4H, m), 0.97 (3H, s), 1.09 (3H, s), 1.63 (9H, s), 2.08 (1H, d, J = 17.2 Hz), 2.14 (1H, d, J = 17.2 Hz), 2.21 (1H, d, J = 16.4 Hz), 2.33 (1H, d, J = 17.6 Hz), 2.43 (1H, d, J = 17.6 Hz), 2.48 (3H, s), 2.83 (3H, s), 2.98 (1H, d, J = 16.4 Hz), 3.74 (3H, s), 5.17 (1H, s), 5.36 (1H, s) , 6.72 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.2 Hz), 7.37 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.6 Hz).
(141b) tert-butyl 6- [3- (2-ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [ 3,2-c] pyridine-3,1′-cyclopropane] -10-yl) -4-methoxy-2-methylphenyl] -3-methylpyridine-2-carboxylate tert-butyl prepared in Example 141a 6- [3- (7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-3, 1′-cyclopropane] -10-yl) -4-methoxy-2-methylphenyl] -3-methylpyridine-2-carboxylate (1.24 g, 2.12 mmol), ethyl iodide (1.70 mL, 21.2 mmol), The title compound (1.14 g, 88%) was obtained by performing reaction and post-treatment according to Example 2a using DMF (25 mL) and sodium hydride (63%, 162 mg, 4.24 mmol).
1H-NMR(400MHz, CDCl3):δ ppm: 0.55-0.79 (3H, m), 0.96 (3H, s), 1.00 (3H, t, J = 7.2 Hz), 1.08 (3H, s), 1.16-1.21 (1H, m), 1.63 (9H, s), 1.78 (1H, d, J = 16.8 Hz), 2.13 (1H, d, J = 16.4 Hz), 2.20 (1H, d, J = 16.4 Hz), 2.32 (1H, d, J = 17.6 Hz), 2.41 (1H, d, J = 18.0 Hz), 2.48 (3H, s), 2.61-2.69 (1H, m), 2.85 (3H, s), 3.03 (1H, d, J = 16.4 Hz), 3.67-3.74 (1H, m), 3.73 (3H, s), 5.25 (1H, s), 6.70 (1H, d, J = 8.2 Hz), 7.27 (1H, d, J = 8.6 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.51 (1H, d, J = 8.6 Hz).
(141c) tert-ブチル　6-{3-[(10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
及び、tert-ブチル　6-{3-[(10R)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例141bで製造したtert-ブチル　6-[3-(2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート(1.30 g)をChiral flash IA(ダイセル化学工業; ヘキサン/イソプロパノール；85:15)により光学分割し、高極性化合物(650 mg)及び低極性化合物(650 mg)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.55-0.79 (3H, m), 0.96 (3H, s), 1.00 (3H, t, J = 7.2 Hz), 1.08 (3H, s), 1.16 -1.21 (1H, m), 1.63 (9H, s), 1.78 (1H, d, J = 16.8 Hz), 2.13 (1H, d, J = 16.4 Hz), 2.20 (1H, d, J = 16.4 Hz) , 2.32 (1H, d, J = 17.6 Hz), 2.41 (1H, d, J = 18.0 Hz), 2.48 (3H, s), 2.61-2.69 (1H, m), 2.85 (3H, s), 3.03 ( 1H, d, J = 16.4 Hz), 3.67-3.74 (1H, m), 3.73 (3H, s), 5.25 (1H, s), 6.70 (1H, d, J = 8.2 Hz), 7.27 (1H, d , J = 8.6 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.51 (1H, d, J = 8.6 Hz).
(141c) tert-butyl 6- {3-[(10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-3,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate and tert-butyl 6- {3-[(10R) -2-ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3, 2-c] Pyridin-3,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate tert-Butyl prepared in Example 141b 6- [3- (2-Ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine- 3,1′-Cyclopropane] -10-yl) -4-methoxy-2-methylphenyl] -3-methylpyridine-2-carboxylate (1.30 g) in Chiral flash IA (Daicel Chemical Industries; hexane / isopropanol; 85:15) To give more polar compound (650 mg) and low polarity compound (650 mg).
(141d) 6-{3-[(10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{3-[(10R)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例141cで製造したtert-ブチル　6-{3-[(10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレートもしくはtert-ブチル　6-{3-[(10R)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(高極性化合物; 650 mg, 1.06 mmol)、ジクロロメタン(3.2 mL)及びトリフルオロ酢酸(3.2 mL) を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(561 mg, 95%)を得た。 (141d) 6- {3-[(10S) -2-Ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridin-3,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid or 6- {3- [ (10R) -2-ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine- 3,1′-Cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butyl 6- {3-[(10S prepared in Example 141c ) -2-Ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-3, 1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate or tert-butyl 6- {3-[(10R) -2-ethyl-7 , 7-Dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-3,1 ' -Cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (high polarity compound; 650 mg, 1.06 mmol), dichloromethane (3.2 mL) and trifluoroacetic acid (3.2 mL) was used for the reaction and post-treatment according to Example 1d to obtain the title compound (561 mg, 95%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.61-0.83 (3H, m), 0.98 (3H, s), 1.02 (3H, t, J = 7.0 Hz), 1.10 (3H, s), 1.17-1.26 (1H, m), 1.87 (1H, d, J = 16.8 Hz), 2.16 (1H, d, J = 16.0 Hz), 2.23 (1H, d, J = 16.4 Hz), 2.35 (1H, d, J = 17.2 Hz), 2.44 (1H, d, J = 18.0 Hz), 2.62-2.71 (1H, m), 2.80 (3H, s), 2.88 (3H, s), 3.02 (1H, d, J = 15.7 Hz), 3.66-3.79 (1H, m), 3.78 (3H, s), 5.25 (1H, s), 6.75 (1H, d, J = 8.6 Hz), 7.20 (1H, d, J = 8.6 Hz), 7.58 (1H, d, J = 7.8 Hz), 7.69 (1H, d, J = 8.2 Hz).
MS(EI)m/z: 557[M+H]+.
(141e) 6-{3-[(10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
又は、6-{3-[(10R)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例141dで製造した6-{3-[(10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸もしくは6-{3-[(10R)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(548 mg, 0.984 mmol)、ジクロロメタン(2.5 mL)及びtert-ブチルアミン(207 μL, 1.97 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(595 mg, 96%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.61-0.83 (3H, m), 0.98 (3H, s), 1.02 (3H, t, J = 7.0 Hz), 1.10 (3H, s), 1.17 -1.26 (1H, m), 1.87 (1H, d, J = 16.8 Hz), 2.16 (1H, d, J = 16.0 Hz), 2.23 (1H, d, J = 16.4 Hz), 2.35 (1H, d, J = 17.2 Hz), 2.44 (1H, d, J = 18.0 Hz), 2.62-2.71 (1H, m), 2.80 (3H, s), 2.88 (3H, s), 3.02 (1H, d, J = 15.7 Hz), 3.66-3.79 (1H, m), 3.78 (3H, s), 5.25 (1H, s), 6.75 (1H, d, J = 8.6 Hz), 7.20 (1H, d, J = 8.6 Hz), 7.58 (1H, d, J = 7.8 Hz), 7.69 (1H, d, J = 8.2 Hz).
MS (EI) m / z: 557 [M + H] +.
(141e) 6- {3-[(10S) -2-Ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridin-3,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt or 6- {3-[(10R) -2-Ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2- c] Pyridine-3,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt 6- {prepared in Example 141d 3-[(10S) -2-Ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c ] Pyridine-3,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid or 6- {3-[(10R) -2-ethyl -7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] Lysine-3,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid (548 mg, 0.984 mmol), dichloromethane (2.5 mL) and tert The title compound (595 mg, 96%) was obtained by performing reaction and post-treatment according to Example 3c using -butylamine (207 μL, 1.97 mmol).
(実施例142)
　6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
又は、6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(142a) 10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-1',9'(4'H,8'H)-ジオン
　実施例41aで製造した6-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]スピロ[2.5]オクタン-5,7-ジオン(700 mg, 1.76 mmol)、公知化合物である5-アザスピロ[3.5]ノナン-6,8-ジオン(298 mg, 1.94 mmol)、アセトニトリル(14 mL)、炭酸カリウム(586 mg, 4.24 mmol)及び4 M塩酸(酢酸エチル溶液; 4.4 mL) を用い、実施例97aに準じて反応及び後処理を行うことにより、標記化合物(770 mg, 82%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.32-0.50 (4H, m), 1.30 (12H, s), 1.67-2.14 (7H, m), 2.22 (1H, d, J = 17.6 Hz), 2.34 (1H, d, J = 16.8 Hz), 2.57 (1H, d, J = 17.6 Hz), 2.65 (1H, d, J = 16.8 Hz), 2.70 (1H, d, J = 17.2 Hz), 3.11 (3H, s), 3.70 (3H, s), 5.18 (1H, s), 5.61-5.78 (1H, m), 6.59 (1H, d, J = 8.2 Hz), 7.58 (1H, d, J = 8.2 Hz)..
(142b) 2'-エチル-10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-1',9'(4'H,8'H)-ジオン
　実施例142aで製造した10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-1',9'(4'H,8'H)-ジオン(745 mg, 1.40 mmol)、ヨウ化エチル(1.12 mL, 14.0 mmol)、DMF (15 mL)及び水素化ナトリウム(55%, 275 mg, 6.31 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(460 mg, 59%)を得た。 (Example 142)
6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H-dispiro [cyclobutane -1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2- Carboxylic acid tert-butylamine salt or 6- {3-[(10′R) -2′-ethyl-1 ′, 9′-dioxo-1 ′, 4 ′, 6 ′, 8 ′, 9 ′, 10 ′ -Hexahydro-2'H-dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methyl Phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(142a) 10 '-[6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -6', 10'- Dihydro-2'H-dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-1', 9 '(4'H, 8'H) -Dione 6- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] spiro [2.5 prepared in Example 41a ] Octane-5,7-dione (700 mg, 1.76 mmol), 5-azaspiro [3.5] nonane-6,8-dione (298 mg, 1.94 mmol), acetonitrile (14 mL), potassium carbonate ( 586 mg, 4.24 mmol) and 4 M hydrochloric acid (ethyl acetate solution; 4.4 mL) were used for the reaction and post-treatment according to Example 97a to obtain the title compound (770 mg, 82%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.32-0.50 (4H, m), 1.30 (12H, s), 1.67-2.14 (7H, m), 2.22 (1H, d, J = 17.6 Hz) , 2.34 (1H, d, J = 16.8 Hz), 2.57 (1H, d, J = 17.6 Hz), 2.65 (1H, d, J = 16.8 Hz), 2.70 (1H, d, J = 17.2 Hz), 3.11 (3H, s), 3.70 (3H, s), 5.18 (1H, s), 5.61-5.78 (1H, m), 6.59 (1H, d, J = 8.2 Hz), 7.58 (1H, d, J = 8.2 Hz) ..
(142b) 2'-ethyl-10 '-[6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -6 ', 10'-dihydro-2'H-dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclopropane] -1 ', 9'(4'H , 8'H) -dione 10 '-[6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) prepared in Example 142a ) Phenyl] -6 ', 10'-dihydro-2'H-dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclopropane] -1 ', 9 '(4'H, 8'H) -dione (745 mg, 1.40 mmol), ethyl iodide (1.12 mL, 14.0 mmol), DMF (15 mL) and sodium hydride (55%, 275 mg, 6.31 mmol) The title compound (460 mg, 59%) was obtained by carrying out the reaction and post-treatment according to Example 2a.
1H-NMR(400MHz, CDCl3):δ ppm: 0.32-0.49 (4H, m), 1.03 (3H, t, J = 7.0 Hz), 1.30 (12H, s), 1.72-2.00 (7H, m), 2.20 (1H, d, J = 17.6 Hz), 2.35 (1H, d, J = 16.8 Hz), 2.54-2.77 (3H, m), 3.08-3.14 (1H, m), 3.14 (3H, s), 3.70 (3H, s), 3.78-3.90 (1H, m), 5.24 (1H, s), 6.59 (1H, d, J = 8.2 Hz), 7.57 (1H, d, J = 8.2 Hz).
(142c) tert-ブチル　6-[3-(2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート
　実施例142bで製造した2'-エチル-10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-1',9'(4'H,8'H)-ジオン(460 mg, 0.822 mmol)、tert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(225 mg, 0.987 mmol)、2nd Generation X-Phos Precatalyst (129 mg, 0.164 mmol)、リン酸カリウム(279 mg, 1.32 mmol)、THF (4.6 mL)及び水(6.9 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(368 mg, 72%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.35-0.51 (4H, m), 1.05 (3H, t, J = 7.0 Hz), 1.63 (9H, s), 1.73-2.01 (7H, m), 2.23 (1H, d, J = 17.6 Hz), 2.37 (1H, d, J = 16.8 Hz), 2.48 (3H, s), 2.57-2.77 (3H, m), 2.86 (3H, s), 3.08-3.19 (1H, m), 3.74 (3H, s), 3.78-3.87 (1H, m), 5.23 (1H, s), 6.70 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.2 Hz).
(142d) tert-ブチル　6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
及び、tert-ブチル　6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例142cで製造したtert-ブチル　6-[3-(2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート(368 ｍg)をChiral flash IA(ダイセル化学工業; ヘキサン/イソプロパノール；70:30)により光学分割し、高極性化合物(139 mg)及び低極性化合物(150 mg)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.32-0.49 (4H, m), 1.03 (3H, t, J = 7.0 Hz), 1.30 (12H, s), 1.72-2.00 (7H, m) , 2.20 (1H, d, J = 17.6 Hz), 2.35 (1H, d, J = 16.8 Hz), 2.54-2.77 (3H, m), 3.08-3.14 (1H, m), 3.14 (3H, s), 3.70 (3H, s), 3.78-3.90 (1H, m), 5.24 (1H, s), 6.59 (1H, d, J = 8.2 Hz), 7.57 (1H, d, J = 8.2 Hz).
(142c) tert-butyl 6- [3- (2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H-dispiro [Cyclobutane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl) -4-methoxy-2-methylphenyl] -3-methylpyridine- 2-Carboxylate 2′-Ethyl-10 ′-[6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) prepared in Example 142b -Yl) phenyl] -6 ', 10'-dihydro-2'H-dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclopropane] -1 ' , 9 '(4'H, 8'H) -dione (460 mg, 0.822 mmol), tert-butyl 6-chloro-3-methylpyridine-2-carboxylate (225 mg, 0.987 mmol), 2nd Generation X- By performing the reaction and post-treatment according to Example 9d using Phos Precatalyst (129 mg, 0.164 mmol), potassium phosphate (279 mg, 1.32 mmol), THF (4.6 mL) and water (6.9 mL), The title compound (368 mg, 72%) was obtained.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.35-0.51 (4H, m), 1.05 (3H, t, J = 7.0 Hz), 1.63 (9H, s), 1.73-2.01 (7H, m) , 2.23 (1H, d, J = 17.6 Hz), 2.37 (1H, d, J = 16.8 Hz), 2.48 (3H, s), 2.57-2.77 (3H, m), 2.86 (3H, s), 3.08- 3.19 (1H, m), 3.74 (3H, s), 3.78-3.87 (1H, m), 5.23 (1H, s), 6.70 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.2 Hz).
(142d) tert-butyl 6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2 'H-Disspiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclopropane] -10'-yl] -4-methoxy-2-methylphenyl} -3 -Methylpyridine-2-carboxylate and tert-butyl 6- {3-[(10'R) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9 ', 10'-Hexahydro-2'H-dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclopropane] -10'-yl] -4- Methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate tert-butyl 6- [3- (2′-ethyl-1 ′, 9′-dioxo-1 ′, 4 ′ prepared in Example 142c , 6 ', 8', 9 ', 10'-Hexahydro-2'H-dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclopropane] -10 '-Yl) -4-methoxy-2-methylphenyl] -3-methylpyridine-2-carboxylate (368 mg) was converted to Chiral flash IA (Daicel Chemical Industries) Optical resolution with hexane / isopropanol; 70:30) to obtain a highly polar compound (139 mg) and a less polar compound (150 mg).
(142e) 6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例142dで製造したtert-ブチル　6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレートもしくはtert-ブチル　6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(高極性化合物; 138 mg, 0.221 mmol)、ジクロロメタン(1.4 mL)及びトリフルオロ酢酸(0.69 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(123 mg, 98%)を得た。 (142e) 6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H- Dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine -2-carboxylic acid or 6- {3-[(10'R) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'- Hexahydro-2'H-dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl } -3-Methylpyridine-2-carboxylic acid tert-butyl 6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6 prepared in Example 142d ', 8', 9 ', 10'-Hexahydro-2'H-dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclopropane] -10'- Yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate or tert-butyl 6- {3-[(10'R) -2'-ethyl-1 ', 9'-dioxo -1 ', 4', 6 ', 8', 9 ', 10'-f Xahydro-2'H-Disspiro [cyclobutane-1,3'-chromeno [3,2-c] pyridin-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl } -3-Methylpyridine-2-carboxylate (high polarity compound; 138 mg, 0.221 mmol), dichloromethane (1.4 mL) and trifluoroacetic acid (0.69 mL) were used for the reaction and workup according to Example 1d. This gave the title compound (123 mg, 98%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.37-0.52 (4H, m), 1.05 (3H, t, J = 7.0 Hz), 1.77-2.03 (7H, m), 2.26 (1H, d, J = 17.6 Hz), 2.38 (1H, d, J = 16.8 Hz), 2.59-2.76 (3H, m), 2.80 (3H, s), 2.89 (3H, s), 3.11-3.20 (1H, m), 3.77 (3H, s), 3.81-3.89 (1H, m), 5.22 (1H, s), 6.74 (1H, d, J = 8.6 Hz), 7.20 (1H, d, J = 8.6 Hz), 7.58 (1H, d, J = 7.8 Hz), 7.69 (1H, d, J = 8.2 Hz).
(142f) 6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
又は、6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例142eで製造した6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸もしくは6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(123 mg, 0.216 mmol)、酢酸エチル(1.2 mL)及びtert-ブチルアミン(34 μL, .0324 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(85.2 mg, 61%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.37-0.52 (4H, m), 1.05 (3H, t, J = 7.0 Hz), 1.77-2.03 (7H, m), 2.26 (1H, d, J = 17.6 Hz), 2.38 (1H, d, J = 16.8 Hz), 2.59-2.76 (3H, m), 2.80 (3H, s), 2.89 (3H, s), 3.11-3.20 (1H, m), 3.77 (3H, s), 3.81-3.89 (1H, m), 5.22 (1H, s), 6.74 (1H, d, J = 8.6 Hz), 7.20 (1H, d, J = 8.6 Hz), 7.58 (1H , d, J = 7.8 Hz), 7.69 (1H, d, J = 8.2 Hz).
(142f) 6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H- Dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine -2-carboxylic acid tert-butylamine salt or 6- {3-[(10′R) -2′-ethyl-1 ′, 9′-dioxo-1 ′, 4 ′, 6 ′, 8 ′, 9 ′ , 10'-Hexahydro-2'H-dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy- 2-Methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt 6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1' prepared in Example 142e , 4 ', 6', 8 ', 9', 10'-Hexahydro-2'H-dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane ] -10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid or 6- {3-[(10'R) -2'-ethyl-1 ', 9' -Dioxo-1 ', 4', 6 ', 8', 9 ', 10'-Hexahydro-2'H-dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclopropane] -10'- Yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid (123 mg, 0.216 mmol), ethyl acetate (1.2 mL) and tert-butylamine (34 μL, .0324 mmol) The title compound (85.2 mg, 61%) was obtained by reaction and post-treatment according to Example 3c.
(実施例143)
　6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロブタン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロブタン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
(143a) 10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロブタン]-1',9'(4'H,8'H)-ジオン
　実施例42aで製造した7-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]スピロ[3.5]ノナン-6,8-ジオン(2.24 g, 5.46 mmol) 、公知化合物である5-アザスピロ[3.5]ノナン-6,8-ジオン(920 mg, 6.01 mmol)、アセトニトリル(45 mL)、炭酸カリウム(1.81 g, 13.1 mmol)及び4 M塩酸(酢酸エチル溶液; 14 mL) を用い、実施例97aに準じて反応及び後処理を行うことにより、標記化合物(2.30 g, 77%)を得た。 (Example 143)
6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H-dispiro [cyclobutane -1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclobutane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid Acid or 6- {3-[(10'R) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2 ' H-Disspiro [cyclobutane-1,3'-chromeno [3,2-c] pyridin-7 ', 1''-cyclobutane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methyl Pyridine-2-carboxylic acid
(143a) 10 '-[6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -6', 10'- Dihydro-2'H-Disspiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclobutane]-1', 9 '(4'H, 8'H)- Dione 7- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] spiro [3.5] prepared in Example 42a Nonane-6,8-dione (2.24 g, 5.46 mmol), known compounds 5-azaspiro [3.5] nonane-6,8-dione (920 mg, 6.01 mmol), acetonitrile (45 mL), potassium carbonate (1.81 g, 13.1 mmol) and 4 M hydrochloric acid (ethyl acetate solution; 14 mL) were used for the reaction and workup according to Example 97a to obtain the title compound (2.30 g, 77%).
1H-NMR(400MHz, CDCl3):δ ppm: 1.30 (12H, s), 1.67-2.13 (12H, m), 2.34 (1H, d, J = 16.4 Hz), 2.45 (1H, d, J = 15.6 Hz), 2.57 (1H, d, J = 16.4 Hz), 2.62-2.74 (3H, m), 3.10 (3H, s), 3.69 (3H, s), 5.13 (1H, s), 5.40 (1H, s), 6.55 (1H, d, J = 8.2 Hz), 7.57 (1H, d, J = 8.2 Hz).
(143b) 2'-エチル-10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロブタン]-1',9'(4'H,8'H)-ジオン
　実施例143aで製造した10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロブタン]-1',9'(4'H,8'H)-ジオン(1.05 g, 1.92 mmol)、ヨウ化エチル(1.54 mL, 19.2 mmol)、DMF (21 mL)及び水素化ナトリウム(55%, 126 mg, 2.89 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(881 mg, 80%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 1.03 (3H, t, J = 7.0 Hz), 1.30 (12H, s), 1.66-1.95 (12H, m), 2.33 (1H, d, J = 16.2 Hz), 2.44 (1H, d, J = 16.4 Hz), 2.56 (1H, d, J = 16.4 Hz), 2.63 (1H, d, J = 18.0 Hz), 2.70-2.76 (2H, m), 3.06-3.13 (1H, m), 3.12 (3H, s), 3.68 (3H, s), 3.77-3.89 (1H, m), 5.19 (1H, s), 6.54 (1H, d, J = 8.6 Hz), 7.55 (1H, d, J = 8.2 Hz).
(143c) tert-ブチル　6-[3-(2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロブタン]-10'-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート
　実施例143bで製造した2'-エチル-10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロブタン]-1',9'(4'H,8'H)-ジオン(881 mg, 1.54 mmol)、tert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(420 mg, 1.84 mmol)、2nd Generation X-Phos Precatalyst (242 mg, 0.307 mmol)、リン酸カリウム(522 mg, 0.497 mmol)、THF (8.8 mL)及び水(13 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(759 mg, 77%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.30 (12H, s), 1.67-2.13 (12H, m), 2.34 (1H, d, J = 16.4 Hz), 2.45 (1H, d, J = 15.6 Hz), 2.57 (1H, d, J = 16.4 Hz), 2.62-2.74 (3H, m), 3.10 (3H, s), 3.69 (3H, s), 5.13 (1H, s), 5.40 (1H, s), 6.55 (1H, d, J = 8.2 Hz), 7.57 (1H, d, J = 8.2 Hz).
(143b) 2'-Ethyl-10 '-[6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -6 ', 10'-dihydro-2'H-dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclobutane] -1 ', 9'(4'H,8'H) -dione 10 '-[6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) prepared in Example 143a Phenyl] -6 ', 10'-dihydro-2'H-dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclobutane] -1 ', 9' ( Using 4'H, 8'H) -dione (1.05 g, 1.92 mmol), ethyl iodide (1.54 mL, 19.2 mmol), DMF (21 mL) and sodium hydride (55%, 126 mg, 2.89 mmol) The title compound (881 mg, 80%) was obtained by carrying out the reaction and post-treatment according to Example 2a.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.03 (3H, t, J = 7.0 Hz), 1.30 (12H, s), 1.66-1.95 (12H, m), 2.33 (1H, d, J = 16.2 Hz), 2.44 (1H, d, J = 16.4 Hz), 2.56 (1H, d, J = 16.4 Hz), 2.63 (1H, d, J = 18.0 Hz), 2.70-2.76 (2H, m), 3.06 -3.13 (1H, m), 3.12 (3H, s), 3.68 (3H, s), 3.77-3.89 (1H, m), 5.19 (1H, s), 6.54 (1H, d, J = 8.6 Hz), 7.55 (1H, d, J = 8.2 Hz).
(143c) tert-butyl 6- [3- (2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H-dispiro [Cyclobutane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclobutane]-10'-yl) -4-methoxy-2-methylphenyl] -3-methylpyridine-2 -Carboxylate 2'-Ethyl-10 '-[6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-2) prepared in Example 143b Yl) phenyl] -6 ', 10'-dihydro-2'H-dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclobutane] -1 ', 9 '(4'H, 8'H) -dione (881 mg, 1.54 mmol), tert-butyl 6-chloro-3-methylpyridine-2-carboxylate (420 mg, 1.84 mmol), 2nd Generation X-Phos Precatalyst (242 mg, 0.307 mmol), potassium phosphate (522 mg, 0.497 mmol), THF (8.8 mL) and water (13 mL) were used, and the title compound was obtained by carrying out the reaction and post-treatment according to Example 9d. (759 mg, 77%) was obtained.
1H-NMR(400MHz, CDCl3):δ ppm: 1.04 (3H, t, J = 7.0 Hz), 1.63 (9H, s), 1.72-1.98 (12H, m), 2.36 (1H, d, J = 16.4 Hz), 2.47 (1H, d, J = 15.2 Hz), 2.48 (3H, s), 2.58 (1H, d, J = 17.2 Hz), 2.63-2.71 (2H, m), 2.76 (1H, d, J = 16.8 Hz), 2.85 (3H, s), 3.09-3.18 (1H, m), 3.72 (3H, s), 3.77-3.86 (1H, m), 5.18 (1H, s), 6.65 (1H, d, J = 8.6 Hz), 7.25 (1H, d, J = 9.0 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 7.4 Hz).
(143d) tert-ブチル　6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロブタン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
及び、tert-ブチル　6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロブタン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例143cで製造したtert-ブチル　6-[3-(2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロブタン]-10'-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート(759 mg)をChiral flash IA(ダイセル化学工業; ヘキサン/イソプロパノール；70:30)により光学分割し、高極性化合物(352 mg)及び低極性化合物(340 mg)を得た。
(143e) 6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロブタン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロブタン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例143dで製造したtert-ブチル　6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロブタン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレートもしくはtert-ブチル　6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロブタン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(高極性化合物; 352 mg, 0.551 mmol)、ジクロロメタン(3.5 mL)及びトリフルオロ酢酸(1.8 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(253 mg, 79%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 1.04 (3H, t, J = 7.0 Hz), 1.63 (9H, s), 1.72-1.98 (12H, m), 2.36 (1H, d, J = 16.4 Hz), 2.47 (1H, d, J = 15.2 Hz), 2.48 (3H, s), 2.58 (1H, d, J = 17.2 Hz), 2.63-2.71 (2H, m), 2.76 (1H, d, J = 16.8 Hz), 2.85 (3H, s), 3.09-3.18 (1H, m), 3.72 (3H, s), 3.77-3.86 (1H, m), 5.18 (1H, s), 6.65 (1H, d , J = 8.6 Hz), 7.25 (1H, d, J = 9.0 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 7.4 Hz).
(143d) tert-butyl 6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2 'H-Disspiro [cyclobutane-1,3'-chromeno [3,2-c] pyridin-7', 1 ''-cyclobutane] -10'-yl] -4-methoxy-2-methylphenyl} -3- Methylpyridine-2-carboxylate and tert-butyl 6- {3-[(10′R) -2′-ethyl-1 ′, 9′-dioxo-1 ′, 4 ′, 6 ′, 8 ′, 9 ', 10'-Hexahydro-2'H-dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclobutane] -10'-yl] -4-methoxy- 2-Methylphenyl} -3-methylpyridine-2-carboxylate tert-butyl 6- [3- (2′-ethyl-1 ′, 9′-dioxo-1 ′, 4 ′, 6 prepared in Example 143c ', 8', 9 ', 10'-Hexahydro-2'H-dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclobutane] -10'-yl ) -4-Methoxy-2-methylphenyl] -3-methylpyridine-2-carboxylate (759 mg) with Chiral flash IA (Daicel Chemical Industries; Hexa And high resolution compound (352 mg) and low polarity compound (340 mg).
(143e) 6- {3-[(10'S) -2'-Ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-Hexahydro-2'H- Disspiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclobutane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine- 2-carboxylic acid or 6- {3-[(10'R) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro -2'H-Disspiro [cyclobutane-1,3'-chromeno [3,2-c] pyridin-7 ', 1''-cyclobutane]-10'-yl] -4-methoxy-2-methylphenyl}- 3-methylpyridine-2-carboxylic acid tert-butyl 6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', prepared in Example 143d, 8 ', 9', 10'-Hexahydro-2'H-dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclobutane]-10'-yl]- 4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate or tert-butyl 6- {3-[(10'R) -2'-ethyl-1 ', 9'-dioxo-1' , 4 ', 6', 8 ', 9', 10'-hexahi Dro-2'H-Disspiro [cyclobutane-1,3'-chromeno [3,2-c] pyridin-7 ', 1''-cyclobutane]-10'-yl] -4-methoxy-2-methylphenyl} -3-Methylpyridine-2-carboxylate (high polarity compound; 352 mg, 0.551 mmol), dichloromethane (3.5 mL) and trifluoroacetic acid (1.8 mL) are used for the reaction and workup according to Example 1d. This gave the title compound (253 mg, 79%).
(実施例144)
　6-{4-メトキシ-2-メチル-3-[(10'S)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
又は、6-{4-メトキシ-2-メチル-3-[(10'R)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(144a) 10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-1',9'(4'H,8'H)-ジオン
　実施例42aで製造した7-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン]スピロ[3.5]ノナン-6,8-ジオン(2.00 g, 4.87 mmol) 、公知化合物である4-アザスピロ[2.5]オクタン-5,7-ジオン(745 mg, 5.35 mmol)、DMF (40 mL)、炭酸セシウム(6.60 g, 20.0 mmol)及びN-フェニルビス(トリフルオロメタンスルホンイミド) (3.11 g, 8.71 mmol)を用い、実施例9cに準じて反応及び後処理を行うことにより、標記化合物(1.64 g, 63%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.52-0.77 (4H, m), 1.30 (12H, s), 1.63-1.92 (6H, m), 2.08 (1H, d, J = 17.0 Hz), 2.35 (1H, d, J = 15.8 Hz), 2.45 (1H, d, J = 16.4 Hz), 2.56 (1H, d, J = 17.0 Hz), 2.63 (1H, d, J = 17.0 Hz), 2.96 (1H, d, J = 17.0 Hz), 3.09 (3H, s), 3.71 (3H, s), 5.16 (1H, s), 5.20 (1H, s), 6.59 (1H, d, J = 8.5 Hz), 7.58 (1H, d, J = 8.5 Hz).
(144b) (10'S)-10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-1',9'(4'H,8'H)-ジオン
及び、(10'R)-10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-1',9'(4'H,8'H)-ジオン
　実施例144aで製造した10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-1',9'(4'H,8'H)-ジオン(1.64 g)をChiral flash IA(ダイセル化学工業; ヘキサン/エタノール；80:20)により光学分割し、高極性化合物(504 mg)及び低極性化合物(606 mg)を得た。 (Example 144)
6- {4-Methoxy-2-methyl-3-[(10'S) -2'-methyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro -2'H-Disspiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3 ', 1''-cyclopropane]-10'-yl] phenyl} -3-methylpyridine-2- Carboxylic acid tert-butylamine salt or 6- {4-methoxy-2-methyl-3-[(10′R) -2′-methyl-1 ′, 9′-dioxo-1 ′, 4 ′, 6 ′, 8 ', 9', 10'-Hexahydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3 ', 1''-cyclopropane]-10'-yl] Phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(144a) 10 '-[6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -6', 10'- Dihydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3 ', 1''-cyclopropane]-1', 9 '(4'H, 8'H) 7- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] spiro [3.5-dione prepared in Example 42a ] Nonane-6,8-dione (2.00 g, 4.87 mmol), known compounds 4-azaspiro [2.5] octane-5,7-dione (745 mg, 5.35 mmol), DMF (40 mL), cesium carbonate ( 6.60 g, 20.0 mmol) and N-phenylbis (trifluoromethanesulfonimide) (3.11 g, 8.71 mmol) were used for the reaction and workup according to Example 9c to give the title compound (1.64 g, 63% )
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.52-0.77 (4H, m), 1.30 (12H, s), 1.63-1.92 (6H, m), 2.08 (1H, d, J = 17.0 Hz) , 2.35 (1H, d, J = 15.8 Hz), 2.45 (1H, d, J = 16.4 Hz), 2.56 (1H, d, J = 17.0 Hz), 2.63 (1H, d, J = 17.0 Hz), 2.96 (1H, d, J = 17.0 Hz), 3.09 (3H, s), 3.71 (3H, s), 5.16 (1H, s), 5.20 (1H, s), 6.59 (1H, d, J = 8.5 Hz) , 7.58 (1H, d, J = 8.5 Hz).
(144b) (10'S) -10 '-[6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -6' , 10'-dihydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3 ', 1''-cyclopropane]-1', 9 '(4'H, 8'H) -dione and (10'R) -10 '-[6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) phenyl] -6 ', 10'-dihydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3', 1 ''-cyclopropane] -1 ', 9 ′ (4′H, 8′H) -dione 10 ′-[6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2) prepared in Example 144a -Dioxaborolan-2-yl) phenyl] -6 ', 10'-dihydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3', 1 ''-cyclopropane ] -1 ', 9'(4'H,8'H) -dione (1.64 g) was optically resolved with Chiral flash IA (Daicel Chemical Industries; hexane / ethanol; 80:20) to obtain a highly polar compound (504 mg ) And low Polar compound (606 mg) was obtained.
(144c) (10'S)-10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2'-メチル-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-1',9'(4'H,8'H)-ジオン
又は、(10'R)-10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2'-メチル-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-1',9'(4'H,8'H)-ジオン
　実施例144bで製造した(10'S)-10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-1',9'(4'H,8'H)-ジオンもしくは(10'R)-10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-1',9'(4'H,8'H)-ジオン(高極性化合物；250 mg, 0.470 mmol)、ヨウ化メチル(150 μL, 79.8 mmol)、DMF (8.0 mL)及び水素化ナトリウム(63%, 36.0 mg, 0.945 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(222 mg, 86%)を得た。 (144c) (10'S) -10 '-[6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2' -Methyl-6 ', 10'-dihydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3', 1 ''-cyclopropane] -1 ', 9'(4'H,8'H) -dione or (10'R) -10 '-[6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2) -Dioxaborolan-2-yl) phenyl] -2'-methyl-6 ', 10'-dihydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3', 1 '' -Cyclopropane] -1 ', 9'(4'H,8'H) -dione (10'S) -10 '-[6-methoxy-2-methyl-3- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -6 ', 10'-dihydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2 -c] pyridine-3 ', 1''-cyclopropane]-1', 9 '(4'H, 8'H) -dione or (10'R) -10'-[6-methoxy-2-methyl -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) Phenyl] -6 ', 10'-dihydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3', 1 ''-cyclopropane] -1 ', 9 '(4'H, 8'H) -dione (high polarity compound; 250 mg, 0.470 mmol), methyl iodide (150 μL, 79.8 mmol), DMF (8.0 mL) and sodium hydride (63%, 36.0 mg , 0.945 mmol), and the reaction and post-treatment were performed according to Example 2a to obtain the title compound (222 mg, 86%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.51-0.69 (3H, m), 1.14-1.23 (1H, m), 1.30 (12H, s), 1.62-1.89 (6H, m), 1.92 (1H, d, J = 16.4 Hz), 2.34 (1H, d, J = 16.4 Hz), 2.44 (1H, d, J = 16.4 Hz), 2.55 (1H, d, J = 16.4 Hz), 2.62 (1H, d, J = 17.0 Hz), 2.67 (3H, s), 2.97 (1H, d, J = 17.0 Hz), 3.13 (3H, s), 3.71 (3H, s), 5.21 (1H, s), 6.58 (1H, d, J = 8.5 Hz), 7.57 (1H, d, J = 8.5 Hz).
(144d) tert-ブチル　6-{4-メトキシ-2-メチル-3-[(10'S)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
又は、tert-ブチル　6-{4-メトキシ-2-メチル-3-[(10'R)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例144cで製造した(10'S)-10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2'-メチル-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-1',9'(4'H,8'H)-ジオンもしくは(10'R)-10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-2'-メチル-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-1',9'(4'H,8'H)-ジオン(222 mg, 0.406 mmol)、tert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(104 mg, 0.457 mmol)、2nd Generation X-Phos Precatalyst (65.0 mg, 0.0826 mmol)、リン酸カリウム(142 mg, 0.669 mmol)、THF (4.0 mL)及び水(6.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(217 mg, 88%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.51-0.69 (3H, m), 1.14-1.23 (1H, m), 1.30 (12H, s), 1.62-1.89 (6H, m), 1.92 ( 1H, d, J = 16.4 Hz), 2.34 (1H, d, J = 16.4 Hz), 2.44 (1H, d, J = 16.4 Hz), 2.55 (1H, d, J = 16.4 Hz), 2.62 (1H, d, J = 17.0 Hz), 2.67 (3H, s), 2.97 (1H, d, J = 17.0 Hz), 3.13 (3H, s), 3.71 (3H, s), 5.21 (1H, s), 6.58 ( 1H, d, J = 8.5 Hz), 7.57 (1H, d, J = 8.5 Hz).
(144d) tert-butyl 6- {4-methoxy-2-methyl-3-[(10'S) -2'-methyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9 ', 10'-Hexahydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3', 1 ''-cyclopropane] -10'-yl] phenyl} -3 -Methylpyridine-2-carboxylate or tert-butyl 6- {4-methoxy-2-methyl-3-[(10'R) -2'-methyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-Hexahydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3 ', 1''-cyclopropane]-10'-yl] phenyl} -3-methylpyridine-2-carboxylate (10'S) -10 '-[6-methoxy-2-methyl-3- (4,4,5,5-) prepared in Example 144c Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2'-methyl-6 ', 10'-dihydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2- c] pyridine-3 ′, 1 ″ -cyclopropane] -1 ′, 9 ′ (4′H, 8′H) -dione or (10′R) -10 ′-[6-methoxy-2-methyl- 3- (4,4,5,5-Te Lamethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2'-methyl-6 ', 10'-dihydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c ] Pyridine-3 ', 1''-cyclopropane]-1', 9 '(4'H, 8'H) -dione (222 mg, 0.406 mmol), tert-butyl 6-chloro-3-methylpyridine- Using 2-carboxylate (104 mg, 0.457 mmol), 2nd Generation X-Phos Precatalyst (65.0 mg, 0.0826 mmol), potassium phosphate (142 mg, 0.669 mmol), THF (4.0 mL) and water (6.0 mL) The title compound (217 mg, 88%) was obtained by reaction and post-treatment according to Example 9d.
1H-NMR(400MHz, CDCl3):δ ppm: 0.54-0.72 (3H, m), 1.21-1.25 (1H, m), 1.63 (9H, s), 1.67-1.92 (7H, m), 2.36 (1H, d, J = 16.4 Hz), 2.47 (1H, d, J = 13.4 Hz), 2.49 (3H, s), 2.57 (1H, d, J = 17.0 Hz), 2.65 (1H, d, J = 17.6 Hz), 2.68 (3H, s), 2.85 (3H, s), 3.02 (1H, d, J = 17.0 Hz), 3.74 (3H, s), 5.20 (1H, s), 6.69 (1H, d, J = 8.5 Hz), 7.27 (1H, d, J = 6.7 Hz), 7.38 (1H, d, J = 7.9 Hz), 7.52 (1H, d, J = 8.5 Hz).
(144e) 6-{4-メトキシ-2-メチル-3-[(10'S)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{4-メトキシ-2-メチル-3-[(10'R)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例144dで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[(10'S)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボキシレートもしくはtert-ブチル　6-{4-メトキシ-2-メチル-3-[(10'R)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(217 mg, 0.356 mmol)、クロロホルム(2.0 mL)及びトリフルオロ酢酸(2.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(179 mg, 91%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.54-0.72 (3H, m), 1.21-1.25 (1H, m), 1.63 (9H, s), 1.67-1.92 (7H, m), 2.36 ( 1H, d, J = 16.4 Hz), 2.47 (1H, d, J = 13.4 Hz), 2.49 (3H, s), 2.57 (1H, d, J = 17.0 Hz), 2.65 (1H, d, J = 17.6 Hz), 2.68 (3H, s), 2.85 (3H, s), 3.02 (1H, d, J = 17.0 Hz), 3.74 (3H, s), 5.20 (1H, s), 6.69 (1H, d, J = 8.5 Hz), 7.27 (1H, d, J = 6.7 Hz), 7.38 (1H, d, J = 7.9 Hz), 7.52 (1H, d, J = 8.5 Hz).
(144e) 6- {4-Methoxy-2-methyl-3-[(10'S) -2'-methyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10 '-Hexahydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3', 1 ''-cyclopropane] -10'-yl] phenyl} -3-methylpyridine -2-carboxylic acid or 6- {4-methoxy-2-methyl-3-[(10'R) -2'-methyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-Hexahydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3 ', 1''-cyclopropane]-10'-yl] phenyl } -3-Methylpyridine-2-carboxylic acid tert-butyl 6- {4-methoxy-2-methyl-3-[(10'S) -2'-methyl-1 ', 9'-dioxo prepared in Example 144d -1 ', 4', 6 ', 8', 9 ', 10'-hexahydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3', 1 '' -Cyclopropane] -10'-yl] phenyl} -3-methylpyridine-2-carboxylate or tert-butyl 6- {4-methoxy-2-methyl-3-[(10'R) -2'-methyl -1 ', 9'-Geo So-1 ', 4', 6 ', 8', 9 ', 10'-Hexahydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3', 1 ''-Cyclopropane]-10'-yl] phenyl} -3-methylpyridine-2-carboxylate (217 mg, 0.356 mmol), chloroform (2.0 mL) and trifluoroacetic acid (2.0 mL), Example 1d The title compound (179 mg, 91%) was obtained by reacting and working up according to.
1H-NMR(400MHz, CDCl3):δ ppm: 0.58-0.76 (3H, m), 1.20-1.30 (1H, m), 1.67-1.94 (6H, m), 2.01 (1H, d, J = 16.4 Hz), 2.38 (1H, d, J = 16.4 Hz), 2.49 (1H, d, J = 15.8 Hz), 2.59 (1H, d, J = 17.0 Hz), 2.66 (1H, d, J = 17.0 Hz), 2.70 (3H, s), 2.80 (3H, s), 2.87 (3H, s), 2.97 (1H, d, J = 17.0 Hz), 3.77 (3H, s), 5.18 (1H, s), 6.73 (1H, d, J = 9.1 Hz), 7.18 (1H, d, J = 8.5 Hz), 7.59 (1H, d, J = 7.9 Hz), 7.70 (1H, d, J = 7.9 Hz).
MS(ESI/APCI)m/z: 555[M+H]+.
(144f) 6-{4-メトキシ-2-メチル-3-[(10'S)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
又は、6-{4-メトキシ-2-メチル-3-[(10'R)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例144eで製造した6-{4-メトキシ-2-メチル-3-[(10'S)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸もしくは6-{4-メトキシ-2-メチル-3-[(10'R)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸(179 mg, 0.323 mmol)、酢酸エチル(3.0 mL)及びtert-ブチルアミン(51 μL, 0.490 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(184 mg, 91%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.58-0.76 (3H, m), 1.20-1.30 (1H, m), 1.67-1.94 (6H, m), 2.01 (1H, d, J = 16.4 Hz), 2.38 (1H, d, J = 16.4 Hz), 2.49 (1H, d, J = 15.8 Hz), 2.59 (1H, d, J = 17.0 Hz), 2.66 (1H, d, J = 17.0 Hz) , 2.70 (3H, s), 2.80 (3H, s), 2.87 (3H, s), 2.97 (1H, d, J = 17.0 Hz), 3.77 (3H, s), 5.18 (1H, s), 6.73 ( 1H, d, J = 9.1 Hz), 7.18 (1H, d, J = 8.5 Hz), 7.59 (1H, d, J = 7.9 Hz), 7.70 (1H, d, J = 7.9 Hz).
MS (ESI / APCI) m / z: 555 [M + H] +.
(144f) 6- {4-Methoxy-2-methyl-3-[(10'S) -2'-methyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10 '-Hexahydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3', 1 ''-cyclopropane] -10'-yl] phenyl} -3-methylpyridine -2-carboxylic acid tert-butylamine salt or 6- {4-methoxy-2-methyl-3-[(10′R) -2′-methyl-1 ′, 9′-dioxo-1 ′, 4 ′, 6 ', 8', 9 ', 10'-Hexahydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3', 1 ''-cyclopropane] -10 ' -Yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt 6- {4-methoxy-2-methyl-3-[(10'S) -2'-methyl-1 'prepared in Example 144e , 9'-Dioxo-1 ', 4', 6 ', 8', 9 ', 10'-hexahydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3 ', 1''-cyclopropane]-10'-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2-methyl-3-[(10'R) -2' -Methyl -1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] Pyridine-3 ', 1''-cyclopropane]-10'-yl] phenyl} -3-methylpyridine-2-carboxylic acid (179 mg, 0.323 mmol), ethyl acetate (3.0 mL) and tert-butylamine (51 The title compound (184 mg, 91%) was obtained by performing the reaction and post-treatment according to Example 3c using μL, 0.490 mmol).
(実施例145)
　6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
又は、6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(145a) (10'S)-2'-エチル-10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-1',9'(4'H,8'H)-ジオン
又は、(10'R)-2'-エチル-10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-1',9'(4'H,8'H)-ジオン
　実施例144bで製造した(10'S)-10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-1',9'(4'H,8'H)-ジオンもしくは(10'R)-10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-1',9'(4'H,8'H)-ジオン(高極性化合物；250 mg, 0.470 mmol)、ヨウ化エチル(300 μL, 4.00 mmol)、DMF (8.0 mL)及び水素化ナトリウム(63%, 27.0 mg, 0.709 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(263 mg, 99%)を得た。 (Example 145)
6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H-dispiro [cyclobutane -1,7'-chromeno [3,2-c] pyridine-3 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2- Carboxylic acid tert-butylamine salt or 6- {3-[(10′R) -2′-ethyl-1 ′, 9′-dioxo-1 ′, 4 ′, 6 ′, 8 ′, 9 ′, 10 ′ -Hexahydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridin-3 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methyl Phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(145a) (10'S) -2'-Ethyl-10 '-[6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenyl] -6 ', 10'-dihydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3', 1 ''-cyclopropane] -1 ', 9'(4'H,8'H) -dione or (10'R) -2'-ethyl-10 '-[6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) phenyl] -6 ', 10'-dihydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3', 1 '' -Cyclopropane] -1 ', 9'(4'H,8'H) -dione (10'S) -10 '-[6-methoxy-2-methyl-3- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -6 ', 10'-dihydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2 -c] pyridine-3 ', 1''-cyclopropane]-1', 9 '(4'H, 8'H) -dione or (10'R) -10'-[6-methoxy-2-methyl -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) Phenyl] -6 ', 10'-dihydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3', 1 ''-cyclopropane] -1 ', 9 '(4'H, 8'H) -dione (high polarity compound; 250 mg, 0.470 mmol), ethyl iodide (300 μL, 4.00 mmol), DMF (8.0 mL) and sodium hydride (63%, 27.0 mg , 0.709 mmol), and the reaction and post-treatment were performed according to Example 2a to obtain the title compound (263 mg, 99%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.52-0.78 (3H, m), 0.99 (3H, t, J = 7.0 Hz), 1.13-1.19 (1H, m), 1.30 (12H, s), 1.64-1.89 (7H, m), 2.34 (1H, d, J = 16.4 Hz), 2.44 (1H, d, J = 16.4 Hz), 2.52-2.65 (3H, m), 3.00 (1H, d, J = 16.4 Hz), 3.12 (3H, s), 3.64-3.76 (1H, m), 3.71 (3H, s), 5.25 (1H, s), 6.58 (1H, d, J = 8.5 Hz), 7.57 (1H, d, J = 8.5 Hz).
(145b) tert-ブチル　6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
又は、tert-ブチル　6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例145aで製造した(10'S)-2'-エチル-10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-1',9'(4'H,8'H)-ジオンもしくは(10'R)-2'-エチル-10'-[6-メトキシ-2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-6',10'-ジヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-1',9'(4'H,8'H)-ジオン(263 mg, 0.470 mmol)、tert-ブチル　6-クロロ-3-メチルピリジン-2-カルボキシレート(112 mg, 0.492 mmol)、2nd Generation X-Phos Precatalyst (73.0 mg, 0.0928 mmol)、リン酸カリウム(167 mg, 0.787 mmol)、THF (4.0 mL)及び水(6.0 mL)を用い、実施例9dに準じて反応及び後処理を行うことにより、標記化合物(194 mg, 66%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.52-0.78 (3H, m), 0.99 (3H, t, J = 7.0 Hz), 1.13-1.19 (1H, m), 1.30 (12H, s) , 1.64-1.89 (7H, m), 2.34 (1H, d, J = 16.4 Hz), 2.44 (1H, d, J = 16.4 Hz), 2.52-2.65 (3H, m), 3.00 (1H, d, J = 16.4 Hz), 3.12 (3H, s), 3.64-3.76 (1H, m), 3.71 (3H, s), 5.25 (1H, s), 6.58 (1H, d, J = 8.5 Hz), 7.57 (1H , d, J = 8.5 Hz).
(145b) tert-butyl 6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2 'H-Disspiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3', 1 ''-cyclopropane] -10'-yl] -4-methoxy-2-methylphenyl} -3 -Methylpyridine-2-carboxylate or tert-butyl 6- {3-[(10'R) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9 ', 10'-Hexahydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3', 1 ''-cyclopropane] -10'-yl] -4- Methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (10 ′S) -2′-ethyl-10 ′-[6-methoxy-2-methyl-3- (4,4) prepared in Example 145a , 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -6 ', 10'-dihydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2- c] pyridine-3 ′, 1 ″ -cyclopropane] -1 ′, 9 ′ (4′H, 8′H) -dione or (10′R) -2′-ethyl-10 ′-[6-methoxy -2-methyl-3- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -6 ', 10'-dihydro-2'H-dispiro [cyclobutane-1,7'-chromeno [ 3,2-c] pyridine-3 ', 1''-cyclopropane]-1', 9 '(4'H, 8'H) -dione (263 mg, 0.470 mmol), tert-butyl 6-chloro- 3-methylpyridine-2-carboxylate (112 mg, 0.492 mmol), 2nd Generation X-Phos Precatalyst (73.0 mg, 0.0928 mmol), potassium phosphate (167 mg, 0.787 mmol), THF (4.0 mL) and water ( The title compound (194 mg, 66%) was obtained by carrying out the reaction and post-treatment according to Example 9d using 6.0 mL).
1H-NMR(400MHz, CDCl3):δ ppm: 0.54-0.80 (3H, m), 1.00 (3H, t, J = 7.0 Hz), 1.16-1.22 (1H, m), 1.63 (9H, s), 1.70-1.93 (7H, m), 2.37 (1H, d, J = 15.8 Hz), 2.47 (1H, d, J = 18.2 Hz), 2.49 (3H, s), 2.56 (1H, d, J = 17.6 Hz), 2.61-2.70 (2H, m), 2.84 (3H, s), 3.05 (1H, d, J = 17.0 Hz), 3.64 (3H, s), 3.74-3.74 (1H, m), 5.23 (1H, s), 6.69 (1H, d, J = 8.5 Hz), 7.27 (1H, d, J = 7.9 Hz), 7.38 (1H, d, J = 7.9 Hz), 7.52 (1H, d, J = 7.9 Hz).
(145c) 6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例145bで製造したtert-ブチル　6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレートもしくはtert-ブチル　6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(194 mg, 0.311 mmol)、クロロホルム(2.0 mL)及びトリフルオロ酢酸(2.0 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(139 mg, 79%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.54-0.80 (3H, m), 1.00 (3H, t, J = 7.0 Hz), 1.16-1.22 (1H, m), 1.63 (9H, s) , 1.70-1.93 (7H, m), 2.37 (1H, d, J = 15.8 Hz), 2.47 (1H, d, J = 18.2 Hz), 2.49 (3H, s), 2.56 (1H, d, J = 17.6 Hz), 2.61-2.70 (2H, m), 2.84 (3H, s), 3.05 (1H, d, J = 17.0 Hz), 3.64 (3H, s), 3.74-3.74 (1H, m), 5.23 (1H , s), 6.69 (1H, d, J = 8.5 Hz), 7.27 (1H, d, J = 7.9 Hz), 7.38 (1H, d, J = 7.9 Hz), 7.52 (1H, d, J = 7.9 Hz) ).
(145c) 6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H- Dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine -2-carboxylic acid or 6- {3-[(10'R) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'- Hexahydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridin-3 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl } -3-Methylpyridine-2-carboxylic acid tert-butyl 6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6 prepared in Example 145b ', 8', 9 ', 10'-Hexahydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3', 1 ''-cyclopropane] -10'- Yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate or tert-butyl 6- {3-[(10'R) -2'-ethyl-1 ', 9'-dioxo -1 ', 4', 6 ', 8', 9 ', 10'-f Xahydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridin-3 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl } -3-Methylpyridine-2-carboxylate (194 mg, 0.311 mmol), chloroform (2.0 mL) and trifluoroacetic acid (2.0 mL) were used according to Example 1d for reaction and workup. The title compound (139 mg, 79%) was obtained.
1H-NMR(400MHz, CDCl3):δ ppm: 0.61-0.83 (3H, m), 1.02 (3H, t, J = 7.0 Hz), 1.17-1.23 (1H, m), 1.68-1.93 (7H, m), 2.38 (1H, d, J = 16.4 Hz), 2.49 (1H, d, J = 16.4 Hz), 2.56-2.70 (3H, m), 2.80 (3H, s), 2.87 (3H, s), 3.03 (1H, d, J = 15.2 Hz), 3.70-3.76 (1H, m), 3.77 (3H, s), 5.23 (1H, s), 6.73 (1H, d, J = 8.5 Hz), 7.19 (1H, d, J = 8.5 Hz), 7.58 (1H, d, J = 7.9 Hz), 7.69 (1H, d, J = 7.9 Hz).
MS(ESI/APCI)m/z: 569[M+H]+.
(145d) 6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
又は、6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例145cで製造した6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸もしくは6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸(139 mg, 0.244 mmol)、酢酸エチル(3.0 mL)及びtert-ブチルアミン(51 μL, 0.490 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(153 mg, 98%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.62-0.84 (3H, m), 1.02 (3H, t, J = 7.0 Hz), 1.09 (9H, s), 1.16-1.21 (1H, m), 1.69-1.96 (7H, m), 2.41 (1H, d, J = 15.9 Hz), 2.46 (1H, d, J = 17.1 Hz), 2.60 (1H, d, J = 17.1 Hz), 2.65-2.73 (2H, m), 2.70 (3H, s), 2.77 (3H, s), 2.96 (1H, d, J = 17.1 Hz), 3.62-3.72 (1H, m), 3.76 (3H, s), 5.16 (1H, s), 6.69 (1H, d, J = 8.5 Hz), 7.10 (1H, d, J = 7.9 Hz), 7.35 (1H, d, J = 7.3 Hz), 7.62 (1H, d, J = 7.9 Hz). 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.61-0.83 (3H, m), 1.02 (3H, t, J = 7.0 Hz), 1.17-1.23 (1H, m), 1.68-1.93 (7H, m), 2.38 (1H, d, J = 16.4 Hz), 2.49 (1H, d, J = 16.4 Hz), 2.56-2.70 (3H, m), 2.80 (3H, s), 2.87 (3H, s), 3.03 (1H, d, J = 15.2 Hz), 3.70-3.76 (1H, m), 3.77 (3H, s), 5.23 (1H, s), 6.73 (1H, d, J = 8.5 Hz), 7.19 (1H , d, J = 8.5 Hz), 7.58 (1H, d, J = 7.9 Hz), 7.69 (1H, d, J = 7.9 Hz).
MS (ESI / APCI) m / z: 569 [M + H] +.
(145d) 6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H- Dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine -2-carboxylic acid tert-butylamine salt or 6- {3-[(10′R) -2′-ethyl-1 ′, 9′-dioxo-1 ′, 4 ′, 6 ′, 8 ′, 9 ′ , 10'-Hexahydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3 ', 1''-cyclopropane]-10'-yl] -4-methoxy- 2-Methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt 6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1' prepared in Example 145c , 4 ', 6', 8 ', 9', 10'-Hexahydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3 ', 1''-cyclopropane ] -10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid or 6- {3-[(10'R) -2'-ethyl-1 ', 9' -Dioxo-1 ', 4', 6 ', 8', 9 ', 10'-Hexahydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3', 1 ''-cyclopropane] -10'- Yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid (139 mg, 0.244 mmol), ethyl acetate (3.0 mL) and tert-butylamine (51 μL, 0.490 mmol), The title compound (153 mg, 98%) was obtained by carrying out the reaction and post-treatment according to Example 3c.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.62-0.84 (3H, m), 1.02 (3H, t, J = 7.0 Hz), 1.09 (9H, s), 1.16-1.21 (1H, m) , 1.69-1.96 (7H, m), 2.41 (1H, d, J = 15.9 Hz), 2.46 (1H, d, J = 17.1 Hz), 2.60 (1H, d, J = 17.1 Hz), 2.65-2.73 ( 2H, m), 2.70 (3H, s), 2.77 (3H, s), 2.96 (1H, d, J = 17.1 Hz), 3.62-3.72 (1H, m), 3.76 (3H, s), 5.16 (1H , s), 6.69 (1H, d, J = 8.5 Hz), 7.10 (1H, d, J = 7.9 Hz), 7.35 (1H, d, J = 7.3 Hz), 7.62 (1H, d, J = 7.9 Hz) ).
(実施例146)
　6-{4-メトキシ-2-メチル-3-[(10S)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,6,8,9,10-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(146a) tert-ブチル　6-{3-[(10S)-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,6,8,9,10-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例105aで製造したtert-ブチル　6-{3-[(3S,10S)-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(1.04 g, 1.74 mmol)、2,3-ジクロロ-5,6-ジシアノ-1,4-ベンゾキノン(789 mg, 3.47 mmol)及びトルエン(21 mL)を用い、実施例14aに準じて反応及び後処理を行うことにより、標記化合物(530 mg, 51%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.37-0.51 (4H, m), 1.08 (6H, t, J = 7.4 Hz), 1.63 (9H, s), 2.02 (1H, d, J = 16.4 Hz), 2.29 (1H, d, J = 17.6 Hz), 2.36 (1H, d, J = 16.8 Hz), 2.45-2.53 (1H, m), 2.49 (3H, s), 2.61 (1H, d, J = 17.6 Hz), 2.91 (3H, s), 3.62 (3H, s), 5.24 (1H, s), 5.77 (1H, s), 6.67 (1H, d, J = 8.2 Hz), 7.25 (1H, d, J = 8.2 Hz), 7.33 (1H, d, J = 7.8 Hz), 7.51 (1H, d, J = 7.8 Hz).
(146b) tert-ブチル　6-{4-メトキシ-2-メチル-3-[(10S)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,6,8,9,10-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例146aで製造したtert-ブチル　6-{3-[(10S)-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,6,8,9,10-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(153 mg, 0.256 mmol)、ヨウ化メチル(160 μL, 2.56 mmol)、DMF (3.1 mL)及び水素化ナトリウム(55%, 13.4 mg, 0.308 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(47.6 mg, 30%)を得た。 Example 146
6- {4-Methoxy-2-methyl-3-[(10S) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,6,8,9,10- Hexahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(146a) tert-butyl 6- {3-[(10S) -1,9-dioxo-3- (propan-2-yl) -1,2,6,8,9,10-hexahydrospiro [chromeno [ 3,2-c] pyridine-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate tert-butyl prepared in Example 105a 6- {3-[(3S, 10S) -1,9-Dioxo-3- (propan-2-yl) -1,2,3,4,6,8,9,10-octahydrospiro [chromeno [ 3,2-c] pyridine-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (1.04 g, 1.74 mmol), 2 , 3-Dichloro-5,6-dicyano-1,4-benzoquinone (789 mg, 3.47 mmol) and toluene (21 mL) were reacted and worked up according to Example 14a to give the title compound ( 530 mg, 51%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.37-0.51 (4H, m), 1.08 (6H, t, J = 7.4 Hz), 1.63 (9H, s), 2.02 (1H, d, J = 16.4 Hz), 2.29 (1H, d, J = 17.6 Hz), 2.36 (1H, d, J = 16.8 Hz), 2.45-2.53 (1H, m), 2.49 (3H, s), 2.61 (1H, d, J = 17.6 Hz), 2.91 (3H, s), 3.62 (3H, s), 5.24 (1H, s), 5.77 (1H, s), 6.67 (1H, d, J = 8.2 Hz), 7.25 (1H, d, J = 8.2 Hz), 7.33 (1H, d, J = 7.8 Hz), 7.51 (1H, d, J = 7.8 Hz).
(146b) tert-butyl 6- {4-methoxy-2-methyl-3-[(10S) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,6, 8,9,10-Hexahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate prepared in Example 146a Tert-butyl 6- {3-[(10S) -1,9-dioxo-3- (propan-2-yl) -1,2,6,8,9,10-hexahydrospiro [chromeno [3, 2-c] Pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (153 mg, 0.256 mmol), methyl iodide (160 μL, 2.56 mmol), DMF (3.1 mL) and sodium hydride (55%, 13.4 mg, 0.308 mmol) were used for the reaction and workup according to Example 2a to give the title compound (47.6 mg , 30%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.37-0.52 (4H, m), 1.25 (3H, d, J = 6.7 Hz), 1.25 (3H, d, J = 7.0 Hz), 1.64 (9H, s), 2.01 (1H, d, J = 16.8 Hz), 2.30 (1H, d, J = 17.6 Hz), 2.38 (1H, d, J = 16.8 Hz), 2.50 (3H, s), 2.64 (1H, d, J = 18.4 Hz), 2.95-3.02 (1H, m), 2.95 (3H, s), 3.45 (3H, s), 3.65 (3H, s), 5.30 (1H, s), 5.91 (1H, s), 6.70 (1H, d, J = 8.2 Hz), 7.27 (1H, d, J = 7.4 Hz), 7.42 (1H, d, J = 8.2 Hz), 7.53 (1H, d, J = 7.8 Hz).
(146c) 6-{4-メトキシ-2-メチル-3-[(10S)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,6,8,9,10-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例146bで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[(10S)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,6,8,9,10-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(63.2 mg, 0.103 mmol)、ジクロロメタン(0.6 mL)及びトリフルオロ酢酸(0.3 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(47.5 mg, 83%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.37-0.52 (4H, m), 1.25 (3H, d, J = 6.7 Hz), 1.25 (3H, d, J = 7.0 Hz), 1.64 (9H , s), 2.01 (1H, d, J = 16.8 Hz), 2.30 (1H, d, J = 17.6 Hz), 2.38 (1H, d, J = 16.8 Hz), 2.50 (3H, s), 2.64 (1H , d, J = 18.4 Hz), 2.95-3.02 (1H, m), 2.95 (3H, s), 3.45 (3H, s), 3.65 (3H, s), 5.30 (1H, s), 5.91 (1H, s), 6.70 (1H, d, J = 8.2 Hz), 7.27 (1H, d, J = 7.4 Hz), 7.42 (1H, d, J = 8.2 Hz), 7.53 (1H, d, J = 7.8 Hz) .
(146c) 6- {4-Methoxy-2-methyl-3-[(10S) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,6,8,9 , 10-Hexahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-prepared in Example 146b Butyl 6- {4-methoxy-2-methyl-3-[(10S) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,6,8,9,10 -Hexahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylate (63.2 mg, 0.103 mmol), dichloromethane ( The title compound (47.5 mg, 83%) was obtained by performing the reaction and post-treatment according to Example 1d using 0.6 mL) and trifluoroacetic acid (0.3 mL).
1H-NMR(400MHz, CDCl3):δ ppm:0.39-0.54 (4H, m), 1.24-1.28 (6H, m), 2.05 (1H, d, J = 16.4 Hz), 2.33 (1H, d, J = 17.6 Hz), 2.40 (1H, d, J = 16.4 Hz), 2.66 (1H, d, J = 18.4 Hz), 2.81 (3H, s), 2.97 (3H, s), 2.96-3.04 (1H, m), 3.47 (3H, s), 3.69 (3H, s), 5.30 (1H, s), 5.94 (1H, s), 6.74 (1H, d, J = 8.6 Hz), 7.19 (1H, d, J = 8.6 Hz), 7.62 (1H, d, J = 7.8 Hz), 7.71 (1H, d, J = 7.8 Hz).
MS(ESI/APCI)m/z: 555[M+H]+.
(146d) 6-{4-メトキシ-2-メチル-3-[(10S)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,6,8,9,10-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例146cで製造した6-{4-メトキシ-2-メチル-3-[(10S)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,6,8,9,10-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸(47.5 mg, 0.0856 mmol)、酢酸エチル(0.5 mL)及びtert-ブチルアミン(18 μL, 0.171 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(37.5 mg, 70%)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.39-0.54 (4H, m), 1.24-1.28 (6H, m), 2.05 (1H, d, J = 16.4 Hz), 2.33 (1H, d, J = 17.6 Hz), 2.40 (1H, d, J = 16.4 Hz), 2.66 (1H, d, J = 18.4 Hz), 2.81 (3H, s), 2.97 (3H, s), 2.96-3.04 (1H, m), 3.47 (3H, s), 3.69 (3H, s), 5.30 (1H, s), 5.94 (1H, s), 6.74 (1H, d, J = 8.6 Hz), 7.19 (1H, d, J = 8.6 Hz), 7.62 (1H, d, J = 7.8 Hz), 7.71 (1H, d, J = 7.8 Hz).
MS (ESI / APCI) m / z: 555 [M + H] +.
(146d) 6- {4-Methoxy-2-methyl-3-[(10S) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,6,8,9 , 10-Hexahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt In Example 146c The prepared 6- {4-methoxy-2-methyl-3-[(10S) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,6,8,9, 10-hexahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid (47.5 mg, 0.0856 mmol), acetic acid The title compound (37.5 mg, 70%) was obtained by reacting and working up according to Example 3c using ethyl (0.5 mL) and tert-butylamine (18 μL, 0.171 mmol).
(実施例147)
　6-{4-メトキシ-2-メチル-3-[(10'S)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
又は、6-{4-メトキシ-2-メチル-3-[(10'R)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
(147a) tert-ブチル　6-{3-[(5,7-ジオキソスピロ[2.5]オクタ-6-イリデン)メチル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　公知化合物であるtert-ブチル　6-(3-ホルミル-4-メトキシ-2-メチルフェニル)-3-メチルピリジン-2-カルボキシレート(1.40 g, 4.10 mmol)及びピロリジン(682 μL, 8.25 mmol)のトルエン(25 mL)溶液を室温で2時間攪拌した。反応溶液にスピロ[2.5]オクタン-5,7-ジオン(2.07 g, 15.0 mmol)を加え、反応溶液を室温で90時間攪拌した。反応溶液に酢酸エチル(25 mL)及び0.5 M塩酸(65 mL)を加えて、反応溶液を室温でさらに2時間攪拌した。反応溶液を酢酸エチルで抽出後、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル; 4:6)で精製し、標記化合物(2.18 g, 68%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.55-0.58 (4H, m), 1.63 (9H, s), 2.29 (3H, s), 2.51 (3H, s), 2.54 (2H, s), 2.59 (2H, s), 3.78 (3H, s), 6.80 (1H, d, J = 8.6 Hz), 7.37 (1H, d, J = 8.2 Hz), 7.40 (1H, d, J = 9.0 Hz), 7.59 (1H, d, J = 7.4 Hz), 7.96 (1H, s).
(147b) tert-ブチル　6-{3-[(5,7-ジオキソ-4-アザスピロ[2.5]オクタ-6-イル)(5,7-ジオキソスピロ[2.5]オクタ-6-イル)メチル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例147aで製造したtert-ブチル　6-{3-[(5,7-ジオキソスピロ[2.5]オクタ-6-イリデン)メチル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(2.18 g, 4.72 mmol)及び公知化合物である4-アザスピロ[2.5]オクタン-5,7-ジオン(854 mg, 6.14 mmol)のアセトニトリル(45 mL)溶液に室温で炭酸カリウム(1.63 g, 11.8 mmol)を加えた。反応溶液を室温で6時間攪拌後、水(180 mL)を加えて、析出した固体をろ取し、標記化合物(2.54 g, 90%)をロータマーの混合物として得た。
(147c) tert-ブチル　6-[3-(1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート
実施例147bで製造したtert-ブチル　6-{3-[(5,7-ジオキソ-4-アザスピロ[2.5]オクタ-6-イル)(5,7-ジオキソスピロ[2.5]オクタ-6-イル)メチル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(2.51 g, 4.18 mmol)のDMF (25 mL)溶液に室温で炭酸セシウム(3.40 g, 10.4 mmol)及びN-フェニルビス(トリフルオロメタンスルホンイミド) (1.79 g, 5.01 mmol)を加え、反応溶液を室温で14時間攪拌した。反応溶液に水(100 mL)を加えて、析出した固体をろ取し、標記化合物(1.92 g, 79%)を得た。 (Example 147)
6- {4-Methoxy-2-methyl-3-[(10'S) -2'-methyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro -2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] phenyl} -3-methylpyridine-2 -Carboxylic acid tert-butylamine salt or 6- {4-methoxy-2-methyl-3-[(10'R) -2'-methyl-1 ', 9'-dioxo-1', 4 ', 6' , 8 ', 9', 10'-Hexahydro-2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'- Yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt
(147a) tert-butyl 6- {3-[(5,7-dioxospiro [2.5] oct-6-ylidene) methyl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate Compounds of tert-butyl 6- (3-formyl-4-methoxy-2-methylphenyl) -3-methylpyridine-2-carboxylate (1.40 g, 4.10 mmol) and pyrrolidine (682 μL, 8.25 mmol) in toluene (25 mL) The solution was stirred at room temperature for 2 hours. Spiro [2.5] octane-5,7-dione (2.07 g, 15.0 mmol) was added to the reaction solution, and the reaction solution was stirred at room temperature for 90 hours. Ethyl acetate (25 mL) and 0.5 M hydrochloric acid (65 mL) were added to the reaction solution, and the reaction solution was further stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 4: 6) to obtain the title compound (2.18 g, 68%).
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.55-0.58 (4H, m), 1.63 (9H, s), 2.29 (3H, s), 2.51 (3H, s), 2.54 (2H, s) , 2.59 (2H, s), 3.78 (3H, s), 6.80 (1H, d, J = 8.6 Hz), 7.37 (1H, d, J = 8.2 Hz), 7.40 (1H, d, J = 9.0 Hz) , 7.59 (1H, d, J = 7.4 Hz), 7.96 (1H, s).
(147b) tert-Butyl 6- {3-[(5,7-Dioxo-4-azaspiro [2.5] oct-6-yl) (5,7-dioxospiro [2.5] oct-6-yl) methyl] -4 -Methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate tert-butyl 6- {3-[(5,7-dioxospiro [2.5] oct-6-ylidene) methyl] prepared in Example 147a -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (2.18 g, 4.72 mmol) and the known compound 4-azaspiro [2.5] octane-5,7-dione (854 mg, 6.14) mmol) in acetonitrile (45 mL) was added potassium carbonate (1.63 g, 11.8 mmol) at room temperature. The reaction solution was stirred at room temperature for 6 hours, water (180 mL) was added, and the precipitated solid was collected by filtration to obtain the title compound (2.54 g, 90%) as a mixture of rotamers.
(147c) tert-butyl 6- [3- (1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H-dispiro [cyclopropane-1 , 3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl) -4-methoxy-2-methylphenyl] -3-methylpyridine-2-carboxylate Tert-Butyl 6- {3-[(5,7-dioxo-4-azaspiro [2.5] oct-6-yl) (5,7-dioxospiro [2.5] oct-6-yl) methyl prepared in Example 147b ] -4-Methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (2.51 g, 4.18 mmol) in DMF (25 mL) at room temperature with cesium carbonate (3.40 g, 10.4 mmol) and N- Phenylbis (trifluoromethanesulfonimide) (1.79 g, 5.01 mmol) was added, and the reaction solution was stirred at room temperature for 14 hours. Water (100 mL) was added to the reaction solution, and the precipitated solid was collected by filtration to obtain the title compound (1.92 g, 79%).
1H-NMR(400MHz, CDCl3):δ ppm: 0.37-0.77 (8H, m), 1.63 (9H, s), 2.06 (2H, t, J = 19.2 Hz), 2.27 (1H, d, J = 17.6 Hz), 2.34 (1H, d, J = 16.8 Hz), 2.48 (3H, s), 2.53 (1H, d, J = 17.6 Hz), 2.83 (3H, s), 2.97 (1H, d, J = 16.8 Hz), 3.76 (3H, s), 5.18 (1H, s), 5.20 (1H, s), 6.75 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.36 (1H, d, J = 8.2 Hz), 7.52 (1H, d, J = 7.4 Hz).
(147d) tert-ブチル　6-[4-メトキシ-2-メチル-3-(2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル)フェニル]-3-メチルピリジン-2-カルボキシレート
　実施例147cで製造したtert-ブチル　6-[3-(1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート(640 mg, 1.10 mmol)、ヨウ化メチル(684 μL, 11.0 mmol)、DMF (13 mL)及び水素化ナトリウム(63%, 50.2 mg, 1.32 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(634 mg, 97%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.36-0.69 (7H, m), 1.21-1.28 (1H, m), 1.63 (9H, s), 1.90 (1H, d, J = 16.8 Hz), 2.03 (1H, d, J = 16.8 Hz), 2.25 (1H, d, J = 17.2 Hz), 2.34 (1H, d, J = 16.8 Hz), 2.48 (3H, s), 2.53 (1H, d, J = 17.6 Hz), 2.68 (3H, s), 2.86 (3H, s), 2.99 (1H, d, J = 16.8 Hz), 3.75 (3H, s), 5.25 (1H, s), 6.74 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.2 Hz), 7.38 (1H, d, J = 8.2 Hz), 7.52 (1H, d, J = 7.8 Hz).
(147e) tert-ブチル　6-{4-メトキシ-2-メチル-3-[(10'S)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
及び、tert-ブチル　6-{4-メトキシ-2-メチル-3-[(10'R)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボキシレート
　実施例147dで製造したtert-ブチル　6-[4-メトキシ-2-メチル-3-(2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル)フェニル]-3-メチルピリジン-2-カルボキシレート(630 mg)をChiral flash IA(ダイセル化学工業; ヘキサン/イソプロパノール；85:15)により光学分割し、高極性化合物(313 mg)及び低極性化合物(314 mg)を得た。 1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.37-0.77 (8H, m), 1.63 (9H, s), 2.06 (2H, t, J = 19.2 Hz), 2.27 (1H, d, J = 17.6 Hz), 2.34 (1H, d, J = 16.8 Hz), 2.48 (3H, s), 2.53 (1H, d, J = 17.6 Hz), 2.83 (3H, s), 2.97 (1H, d, J = 16.8 Hz), 3.76 (3H, s), 5.18 (1H, s), 5.20 (1H, s), 6.75 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.36 (1H, d, J = 8.2 Hz), 7.52 (1H, d, J = 7.4 Hz).
(147d) tert-butyl 6- [4-methoxy-2-methyl-3- (2'-methyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10 '-Hexahydro-2'H-dispiro[cyclopropane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl) phenyl] -3-methylpyridine -2-carboxylate tert-butyl 6- [3- (1 ′, 9′-dioxo-1 ′, 4 ′, 6 ′, 8 ′, 9 ′, 10′-hexahydro-2 ′ prepared in Example 147c H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl) -4-methoxy-2-methylphenyl] -3 -Methylpyridine-2-carboxylate (640 mg, 1.10 mmol), methyl iodide (684 μL, 11.0 mmol), DMF (13 mL) and sodium hydride (63%, 50.2 mg, 1.32 mmol) The title compound (634 mg, 97%) was obtained by carrying out the reaction and post-treatment according to Example 2a.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.36-0.69 (7H, m), 1.21-1.28 (1H, m), 1.63 (9H, s), 1.90 (1H, d, J = 16.8 Hz) , 2.03 (1H, d, J = 16.8 Hz), 2.25 (1H, d, J = 17.2 Hz), 2.34 (1H, d, J = 16.8 Hz), 2.48 (3H, s), 2.53 (1H, d, J = 17.6 Hz), 2.68 (3H, s), 2.86 (3H, s), 2.99 (1H, d, J = 16.8 Hz), 3.75 (3H, s), 5.25 (1H, s), 6.74 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.2 Hz), 7.38 (1H, d, J = 8.2 Hz), 7.52 (1H, d, J = 7.8 Hz).
(147e) tert-butyl 6- {4-methoxy-2-methyl-3-[(10'S) -2'-methyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9 ', 10'-Hexahydro-2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclopropane] -10'-yl] phenyl}- 3-methylpyridine-2-carboxylate and tert-butyl 6- {4-methoxy-2-methyl-3-[(10′R) -2′-methyl-1 ′, 9′-dioxo-1 ′, 4 ', 6', 8 ', 9', 10'-Hexahydro-2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane ] -10'-yl] phenyl} -3-methylpyridine-2-carboxylate tert-butyl 6- [4-methoxy-2-methyl-3- (2'-methyl-1 ', prepared in Example 147d, 9'-dioxo-1 ', 4', 6 ', 8', 9 ', 10'-hexahydro-2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-Cyclopropane]-10'-yl) phenyl] -3-methylpyridine-2-carboxylate (630 mg) with Chiral flash IA Industrial; hexane / isopropanol; 85: 15) to optical resolution to obtain high-polar compound (313 mg) and low polarity compound (314 mg).
(147f) 6-{4-メトキシ-2-メチル-3-[(10'S)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{4-メトキシ-2-メチル-3-[(10'R)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸
　実施例147eで製造したtert-ブチル　6-{4-メトキシ-2-メチル-3-[(10'S)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボキシレートもしくはtert-ブチル　6-{4-メトキシ-2-メチル-3-[(10'R)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボキシレート(高極性化合物；310 mg, 0.520 mmol)、ジクロロメタン(1.6 mL)及びトリフルオロ酢酸(1.6 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(269 mg, 96%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.37-0.80 (7H, m), 1.19-1.25 (1H, m), 2.01 (1H, d, J = 17.2 Hz), 2.05 (1H, d, J = 17.2 Hz), 2.28 (1H, d, J = 17.6 Hz), 2.36 (1H, d, J = 16.8 Hz), 2.56 (1H, d, J = 17.6 Hz), 2.70 (3H, s), 2.80 (3H, s), 2.89 (3H, s), 2.95 (1H, d, J = 16.8 Hz), 3.79 (3H, s), 5.24 (1H, s), 6.78 (1H, d, J = 8.2 Hz), 7.21 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 7.8 Hz), 7.69 (1H, d, J = 8.2 Hz).
MS(ESI/APCI)m/z: 541[M+H]+.
(147g) 6-{4-メトキシ-2-メチル-3-[(10'S)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
又は、6-{4-メトキシ-2-メチル-3-[(10'R)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸　tert-ブチルアミン塩
　実施例147fで製造した6-{4-メトキシ-2-メチル-3-[(10'S)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸もしくは6-{4-メトキシ-2-メチル-3-[(10'R)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸(259 mg, 0.596 mmol)、ジクロロメタン(1.5 mL)及びtert-ブチルアミン(101 μL, 0.958 mmol)を用い、実施例3cに準じて反応及び後処理を行うことにより、標記化合物(269 mg, 92%)を得た。 (147f) 6- {4-Methoxy-2-methyl-3-[(10'S) -2'-methyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10 '-Hexahydro-2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclopropane] -10'-yl] phenyl} -3-methyl Pyridine-2-carboxylic acid or 6- {4-methoxy-2-methyl-3-[(10′R) -2′-methyl-1 ′, 9′-dioxo-1 ′, 4 ′, 6 ′, 8 ', 9', 10'-Hexahydro-2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl ] Phenyl} -3-methylpyridine-2-carboxylic acid tert-butyl 6- {4-methoxy-2-methyl-3-[(10'S) -2'-methyl-1 ', 9' prepared in Example 147e -Dioxo-1 ', 4', 6 ', 8', 9 ', 10'-hexahydro-2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclopropane] -10'-yl] phenyl} -3-methylpyridine-2-carboxylate or tert-butyl 6- {4-methoxy-2-methyl-3-[(10'R) -2 '-Methyl-1', 9 ' -Dioxo-1 ', 4', 6 ', 8', 9 ', 10'-hexahydro-2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7', 1 ″ -cyclopropane] -10′-yl] phenyl} -3-methylpyridine-2-carboxylate (high polarity compound; 310 mg, 0.520 mmol), dichloromethane (1.6 mL) and trifluoroacetic acid (1.6 mL) The title compound (269 mg, 96%) was obtained by carrying out the reaction and post-treatment according to Example 1d.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.37-0.80 (7H, m), 1.19-1.25 (1H, m), 2.01 (1H, d, J = 17.2 Hz), 2.05 (1H, d, J = 17.2 Hz), 2.28 (1H, d, J = 17.6 Hz), 2.36 (1H, d, J = 16.8 Hz), 2.56 (1H, d, J = 17.6 Hz), 2.70 (3H, s), 2.80 (3H, s), 2.89 (3H, s), 2.95 (1H, d, J = 16.8 Hz), 3.79 (3H, s), 5.24 (1H, s), 6.78 (1H, d, J = 8.2 Hz) , 7.21 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 7.8 Hz), 7.69 (1H, d, J = 8.2 Hz).
MS (ESI / APCI) m / z: 541 [M + H] +.
(147g) 6- {4-Methoxy-2-methyl-3-[(10'S) -2'-methyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10 '-Hexahydro-2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclopropane] -10'-yl] phenyl} -3-methyl Pyridine-2-carboxylic acid tert-butylamine salt or 6- {4-methoxy-2-methyl-3-[(10'R) -2'-methyl-1 ', 9'-dioxo-1', 4 ' , 6 ', 8', 9 ', 10'-Hexahydro-2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclopropane]- 10'-yl] phenyl} -3-methylpyridine-2-carboxylic acid tert-butylamine salt 6- {4-methoxy-2-methyl-3-[(10'S) -2'-methyl- prepared in Example 147f 1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] Pyridine-7 ', 1''-cyclopropane]-10'-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2-methyl-3-[(10'R) -2'- Methyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H-dispiro [cyclopropane-1,3'-chromeno [3,2- c] Pyridine-7 ', 1''-cyclopropane]-10'-yl] phenyl} -3-methylpyridine-2-carboxylic acid (259 mg, 0.596 mmol), dichloromethane (1.5 mL) and tert-butylamine ( The title compound (269 mg, 92%) was obtained by performing reaction and post-treatment according to Example 3c using 101 μL, 0.958 mmol).
(実施例148)
　6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
(148a) tert-ブチル　6-[3-(2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート
　実施例147cで製造したtert-ブチル　6-[3-(1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート(960 mg, 1.65 mmol)、ヨウ化エチル(1.32 mL, 16.5 mmol)、DMF (19 mL)及び水素化ナトリウム(63%, 126 mg, 3.30 mmol)を用い、実施例2aに準じて反応及び後処理を行うことにより、標記化合物(730 mg, 73%)を得た。
1H-NMR(400MHz, CDCl3):δ ppm: 0.36-0.80 (7H, m), 1.01 (3H, t, J = 7.0 Hz), 1.16-1.28 (1H, m), 1.63 (9H, s), 1.78 (1H, d, J = 16.8 Hz), 2.04 (1H, d, J = 16.8 Hz), 2.27 (1H, d, J = 17.6 Hz), 2.33 (1H, d, J = 16.8 Hz), 2.49 (3H, s), 2.51 (1H, d, J = 19.6 Hz), 2.61-2.70 (1H, m), 2.86 (3H, s), 3.03 (1H, d, J = 16.4 Hz), 3.65-3.74 (1H, m), 3.75 (3H, s), 5.29 (1H, s), 6.74 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.38 (1H, d, J = 8.2 Hz), 7.52 (1H, d, J = 7.8 Hz).
(148b) tert-ブチル　6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
及び、tert-ブチル　6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート
　実施例148aで製造したtert-ブチル　6-[3-(2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル)-4-メトキシ-2-メチルフェニル]-3-メチルピリジン-2-カルボキシレート(730 mg)をChiral flash IA(ダイセル化学工業; ヘキサン/エタノール；50:50)により光学分割し、高極性化合物(352 mg)及び低極性化合物(358 mg)を得た。 (Example 148)
6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H-dispiro [cyclo Propane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2 -Carboxylic acid or 6- {3-[(10'R) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro- 2'H-Disspiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid
(148a) tert-butyl 6- [3- (2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H-dispiro [Cyclopropane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl) -4-methoxy-2-methylphenyl] -3-methylpyridine -2-carboxylate tert-butyl 6- [3- (1 ′, 9′-dioxo-1 ′, 4 ′, 6 ′, 8 ′, 9 ′, 10′-hexahydro-2 ′ prepared in Example 147c H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl) -4-methoxy-2-methylphenyl] -3 -Methylpyridine-2-carboxylate (960 mg, 1.65 mmol), ethyl iodide (1.32 mL, 16.5 mmol), DMF (19 mL) and sodium hydride (63%, 126 mg, 3.30 mmol) The title compound (730 mg, 73%) was obtained by carrying out the reaction and post-treatment according to Example 2a.
1 H-NMR (400 MHz, CDCl 3 ): δ ppm: 0.36-0.80 (7H, m), 1.01 (3H, t, J = 7.0 Hz), 1.16-1.28 (1H, m), 1.63 (9H, s) , 1.78 (1H, d, J = 16.8 Hz), 2.04 (1H, d, J = 16.8 Hz), 2.27 (1H, d, J = 17.6 Hz), 2.33 (1H, d, J = 16.8 Hz), 2.49 (3H, s), 2.51 (1H, d, J = 19.6 Hz), 2.61-2.70 (1H, m), 2.86 (3H, s), 3.03 (1H, d, J = 16.4 Hz), 3.65-3.74 ( 1H, m), 3.75 (3H, s), 5.29 (1H, s), 6.74 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.38 (1H, d, J = 8.2 Hz), 7.52 (1H, d, J = 7.8 Hz).
(148b) tert-butyl 6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2 'H-Disspiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclopropane] -10'-yl] -4-methoxy-2-methylphenyl}- 3-methylpyridine-2-carboxylate and tert-butyl 6- {3-[(10′R) -2′-ethyl-1 ′, 9′-dioxo-1 ′, 4 ′, 6 ′, 8 ′ , 9 ', 10'-Hexahydro-2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclopropane] -10'-yl]- 4-Methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate tert-butyl 6- [3- (2′-ethyl-1 ′, 9′-dioxo-1 ′, prepared in Example 148a, 4 ', 6', 8 ', 9', 10'-Hexahydro-2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane ] -10'-yl) -4-methoxy-2-methylphenyl] -3-methylpyridine-2-carboxylate (730 mg) to Chiral flash IA Industrial; hexane / ethanol; 50: 50) to optical resolution to obtain high-polar compound (352 mg) and low polarity compound (358 mg).
(148c) 6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例148bで製造したtert-ブチル　6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレートもしくはtert-ブチル　6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(低極性化合物；353 mg, 0.578 mmol)、ジクロロメタン(1.8 mL)及びトリフルオロ酢酸(1.8 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(282 mg, 88%)を得た。 (148c) 6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H- Disspiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methyl Pyridine-2-carboxylic acid or 6- {3-[(10′R) -2′-ethyl-1 ′, 9′-dioxo-1 ′, 4 ′, 6 ′, 8 ′, 9 ′, 10 ′ -Hexahydro-2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2- Methylphenyl} -3-methylpyridine-2-carboxylic acid tert-butyl 6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 'prepared in Example 148b , 6 ', 8', 9 ', 10'-Hexahydro-2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclopropane]- 10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate or tert-butyl 6- {3-[(10'R) -2'-ethyl-1 ', 9 '-Dioxo-1', 4 ', 6', 8 ', 9 ', 10'-Hexahydro-2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclopropane] -10'-yl] -4- Methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate (low polarity compound; 353 mg, 0.578 mmol), dichloromethane (1.8 mL) and trifluoroacetic acid (1.8 mL) according to Example 1d The title compound (282 mg, 88%) was obtained by reaction and post-treatment.
(実施例149)
　6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
又は、6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸
　実施例148bで製造したtert-ブチル　6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレートもしくはtert-ブチル　6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボキシレート(高極性化合物；346 mg, 0.567 mmol)、ジクロロメタン(1.8 mL)及びトリフルオロ酢酸(1.8 mL)を用い、実施例1dに準じて反応及び後処理を行うことにより、標記化合物(288 mg, 92%)を得た。 (Example 149)
6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H-dispiro [cyclo Propane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2 -Carboxylic acid or 6- {3-[(10'R) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro- 2'H-Disspiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl} -3-Methylpyridine-2-carboxylic acid tert-butyl 6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6' prepared in Example 148b , 8 ', 9', 10'-Hexahydro-2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'- Yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylate or tert-butyl 6- {3-[(10'R) -2'-ethyl-1 ', 9'-dioxo -1 ', 4', 6 ', 8', 9 ', 10'- Xahydro-2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridin-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methyl Phenyl} -3-methylpyridine-2-carboxylate (high polarity compound; 346 mg, 0.567 mmol), dichloromethane (1.8 mL) and trifluoroacetic acid (1.8 mL), reaction and workup according to Example 1d To give the title compound (288 mg, 92%).
　以下、実施例記載の化合物の物性値（Data）及び対応するフリー体化合物の化学構造（Structure）を示す。 Hereinafter, the physical properties (Data) of the compounds described in the Examples and the chemical structures (Structure) of the corresponding free compounds are shown.
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000054
＜試験例１＞　経口糖負荷試験
（１）使用動物
　市販のマウス（C57BL/6Jマウス、雄、使用時8～12週齡、日本チャールス・リバー(株)販売）
（２）実験方法・結果
　マウスに飼料（FR-2、株式会社フナバシファーム）を1週間以上自由摂取させ予備飼育した後、一晩絶食し、試験に用いた。マウスへの投与液は、被験化合物の濃度を1 mg/mLとした0.5％メチルセルロース（和光純薬工業(株)）溶液(0.5％MC)、を調製した。調整した投与液を、各群4～5匹のマウスに対し、被検化合物の用量が10 mg/kgとなるように強制経口投与した。対照群は、0.5％メチルセルロース溶液（用量：10 mL/kg）を経口投与した。経口糖負荷は、被験化合物投与30分後にグルコース溶液（大塚糖液50％:(株)大塚製薬工業）を3g/kgの用量で経口投与して行った。 <Test Example 1> Oral glucose tolerance test (1) Animal used Commercially available mouse (C57BL / 6J mouse, male, 8-12 weeks old when used, sold by Charles River Japan Co., Ltd.)
(2) Experimental method / results Mice were allowed to freely ingest feed (FR-2, Funabashi Farm Co., Ltd.) for 1 week or longer and pre-bred, then fasted overnight and used for the test. As a liquid for administration to mice, a 0.5% methylcellulose (Wako Pure Chemical Industries, Ltd.) solution (0.5% MC) with a test compound concentration of 1 mg / mL was prepared. The prepared dosing solution was orally administered by gavage so that the dose of the test compound was 10 mg / kg to 4 to 5 mice in each group. In the control group, 0.5% methylcellulose solution (dose: 10 mL / kg) was orally administered. The oral glucose load was performed 30 minutes after administration of the test compound by oral administration of a glucose solution (Otsuka sugar solution 50%: Otsuka Pharmaceutical Co., Ltd.) at a dose of 3 g / kg.
　被験化合物投与直前（T0）、被験化合物投与25分後(T1)、経口糖負荷30分後(T2)および90分後(T3)に、マウスの尾静脈より採血を行い、血糖測定器（アキュチェックアビバ：ロシュ・ダイアグノスティックス（株））にて血糖値を測定した。また、T1血糖値は化合物投与30分後の糖負荷直前値として解析した。下記式より、血糖値曲線下面積を求め、対照群からの血糖低下率（％）を算出し、表２に示した。 Blood was collected from the tail vein of the mouse immediately before administration of the test compound (T0), 25 minutes after administration of the test compound (T1), 30 minutes after oral glucose load (T2) and 90 minutes (T3). Blood glucose level was measured with Check Aviva: Roche Diagnostics Co., Ltd. The T1 blood glucose level was analyzed as the value immediately before glucose load 30 minutes after compound administration. The area under the blood glucose level curve was determined from the following formula, and the blood glucose reduction rate (%) from the control group was calculated.
　血糖値曲線下面積＝[（T0血糖値＋T1血糖値）×30]÷2 ＋[（T1血糖値＋T2血糖値）×30]÷2 ＋[（T2血糖値＋T3血糖値）×60]÷2
　血糖低下率（％）＝[１－(被験化合物投与群血糖値曲線下面積／対照群血糖値曲線下面積)]×100  Area under the blood glucose level curve = [(T0 blood sugar level + T1 blood sugar level) x 30] + 2 + [(T1 blood sugar level + T2 blood sugar level) x 30] / 2 + [(T2 blood sugar level + T3 blood sugar level) x 60] / 2
Blood glucose reduction rate (%) = [1- (Area under test compound administration group blood glucose level curve / Area under control group blood glucose level curve)] × 100
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000055
＜試験例２＞　経口糖負荷試験
（１）使用動物
　市販のラット（Zucker fattyラット、雄、使用時9週齡、日本チャールス・リバー(株)販売）
（２）実験方法・結果
　ラットに飼料（F-2、株式会社フナバシファーム）を2週間自由摂取させ予備飼育した後、一晩絶食し、試験に用いた。ラットへの投与液は、被験化合物の濃度を2.5 mg/mLとした0.5％メチルセルロース（和光純薬工業(株)）溶液(0.5％MC)を調製した。調製した投与液を、各群5匹のラットに対し、被検化合物の用量が10 mg/kgとなるように強制経口投与した。対照群は、0.5％メチルセルロース溶液（用量：4 mL/kg）を経口投与した。経口糖負荷は、被験化合物投与30分後にグルコース溶液（大塚糖液50％:(株)大塚製薬工業）を2.5g/kgの用量で経口投与して行った。 <Test Example 2> Oral glucose tolerance test (1) Animal used Commercially available rat (Zucker fatty rat, male, 9 weeks old when used, sold by Nippon Charles River Co., Ltd.)
(2) Experimental methods and results Rats were allowed to freely take a feed (F-2, Funabashi Farm Co., Ltd.) for 2 weeks, preliminarily bred, then fasted overnight and used for the test. As a solution for administration to rats, a 0.5% methylcellulose (Wako Pure Chemical Industries, Ltd.) solution (0.5% MC) with a test compound concentration of 2.5 mg / mL was prepared. The prepared dosing solution was forcibly orally administered to 5 rats in each group so that the test compound dose was 10 mg / kg. In the control group, 0.5% methylcellulose solution (dose: 4 mL / kg) was orally administered. The oral glucose load was performed 30 minutes after administration of the test compound by orally administering a glucose solution (Otsuka sugar solution 50%: Otsuka Pharmaceutical Co., Ltd.) at a dose of 2.5 g / kg.
　被験化合物投与直前（T0）、被験化合物投与25分後(T1)、経口糖負荷30分後(T2)、60分後(T3)、120分後(T4)および180分後(T5)に、ラットの尾静脈より採血を行い、血糖測定器（アキュチェックアビバ：ロシュ・ダイアグノスティックス（株））にて血糖値を測定した。また、T1血糖値は化合物投与30分後の糖負荷直前値として解析した。下記式より、血糖値曲線下面積を求め、対照群からの血糖低下率（％）を算出し、表３に示した。 Immediately before test compound administration (T0), 25 minutes after test compound administration (T1), 30 minutes after oral glucose load (T2), 60 minutes (T3), 120 minutes (T4) and 180 minutes (T5), Blood was collected from the tail vein of the rat, and the blood glucose level was measured with a blood glucose meter (Accu Check Aviva: Roche Diagnostics Co., Ltd.). The T1 blood glucose level was analyzed as the value immediately before glucose load 30 minutes after compound administration. From the following formula, the area under the blood glucose level curve was determined, and the blood glucose reduction rate (%) from the control group was calculated.
　血糖値曲線下面積＝[（T0血糖値＋T1血糖値）×30]÷2 ＋[（T1血糖値＋T2血糖値）×30]÷2 ＋[（T2血糖値＋T3血糖値）×30]÷2 ＋[（T3血糖値＋T4血糖値）×60]÷2 ＋[（T4血糖値＋T5血糖値）×60]÷2
　血糖低下率（％）＝[１－(被験化合物投与群血糖値曲線下面積／対照群血糖値曲線下面積)]×100 Area under the blood glucose curve = [(T0 blood sugar level + T1 blood sugar level) x 30] ÷ 2 + [(T1 blood sugar level + T2 blood sugar level) x 30] ÷ 2 + [(T2 blood sugar level + T3 blood sugar level) x 30] ÷ 2 + [(T3 blood glucose level + T4 blood glucose level) × 60] ÷ 2 + [((T4 blood glucose level + T5 blood glucose level) × 60] ÷ 2
Blood glucose reduction rate (%) = [1- (Area under test compound administration group blood glucose level curve / Area under control group blood glucose level curve)] × 100
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000056
　上記の試験より、本発明化合物は、優れた血糖低下作用、食後血糖抑制作用、耐糖能不全改善作用等を有することがわかる。従って、本発明の化合物は、高血糖症、糖尿病及びそれら疾病に関連する病態または疾患の予防・治療薬として有用であると考えられる。 From the above test, it can be seen that the compound of the present invention has an excellent blood glucose lowering effect, postprandial blood glucose suppression effect, glucose tolerance deficiency improving effect and the like. Therefore, the compound of the present invention is considered to be useful as a prophylactic / therapeutic agent for hyperglycemia, diabetes, and pathological conditions or diseases associated with these diseases.
＜製剤例＞
　（製剤例１）カプセル剤
実施例４又は１３の化合物　　５０ｍｇ
乳糖　　　　　　　　　　　１２８ｍｇ
トウモロコシデンプン　　　　７０ｍｇ
ステアリン酸マグネシウム　　　２ｍｇ
－－－－－－－－－－－－－－－－－
　　　　　　　　　　　　　２５０ｍｇ
上記処方の粉末を混合し、60メッシュのふるいを通した後、この粉末を250mgのゼラチンカプセルに入れ、カプセル剤とする。 <Formulation example>
(Formulation Example 1) Capsules Example 4 or 13 Compound 50 mg
Lactose 128mg
Corn starch 70mg
Magnesium stearate 2mg
-----------------
250mg
After mixing the powder of the above formulation and passing through a 60 mesh sieve, this powder is put into a 250 mg gelatin capsule to form a capsule.
　（製剤例２）錠剤
実施例２１又は１０の化合物　　５０ｍｇ
乳糖　　　　　　　　　　　　１２６ｍｇ
トウモロコシデンプン　　　　　２３ｍｇ
ステアリン酸マグネシウム　　　　１ｍｇ
－－－－－－－－－－－－－－－－－
　　　　　　　　　　　　　　２００ｍｇ
上記処方の粉末を混合し、トウモロコシデンプン糊を用いて造粒、乾燥した後、打錠機により打錠して、１錠200mgの錠剤とする。この錠剤は必要に応じて糖衣を施すことができる。 (Formulation Example 2) Tablet Example 21 or 10 Compound 50 mg
Lactose 126mg
Corn starch 23mg
Magnesium stearate 1mg
-----------------
200mg
The powder of the above formulation is mixed, granulated and dried using corn starch paste, and then tableted by a tableting machine to make one tablet of 200 mg. This tablet can be sugar-coated if necessary.
　本発明の前記一般式（I）で表される新規な６員ヘテロ環誘導体又はその薬理上許容される塩は、優れた血糖降下作用を有し、医薬として有用である。 The novel 6-membered heterocyclic derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof of the present invention has an excellent hypoglycemic action and is useful as a medicine.

Claims (24)

  1. 　下記一般式（I）
    Figure JPOXMLDOC01-appb-C000001
    ［式中、破線を含む二重線は、単結合又は二重結合を示し、
    R1は、水素原子、C1-C3アルキル基又はC3-C6シクロアルキル基を示し、
    R2は、水素原子若しくはC1-C3アルキル基を示すか又は、R1のC1-C3アルキル基と結合して 3-6員飽和炭素環を形成していてもよく、
    Vは、-CH2-又は-C(=O)-を示し、
    Wは、フェニル基（該フェニル基は、置換基群αより選択される同一または異なった1-4個の置換基で置換されていても良い）、ビフェニル基（該ビフェニル基は、置換基群αより選択される同一または異なった1-8個の置換基で置換されていても良い）、窒素、酸素及び硫黄から選択される同一若しくは異なった1-4個のヘテロ原子を含む5-10員ヘテロアリールフェニル基（該ヘテロアリールフェニル基は、置換基群αより選択される同一または異なった1-8個の置換基で置換されていても良い）、7-ベンゾフラニル基（該7-ベンゾフラニル基は、置換基群αより選択される同一または異なった1-4個の置換基で置換されていても良い）又は、ナフチル基（該ナフチル基は、置換基群αより選択される同一または異なった1-4個の置換基で置換されていても良い）を示し、
    Xは、-CH=、-CH2-、-O- 又は -N=を示し、
    Yは、 
    Figure JPOXMLDOC01-appb-C000002
    、-N(-R5)-又は-C(-R6)=を示し、
    R3は、水素原子、C1-C6アルキル基又はC3-C6シクロアルキル基を示し、
    R4は、水素原子若しくはC1-C6アルキル基を示すか又は、R3のC1-C6アルキル基と結合して3-6員飽和炭素環を形成していてもよく、
    R5は、水素原子、C1-C6 アルキル基又はC3-C6シクロアルキル基を示し、
    R6は、C2-C6 アルキル基又はC3-C6シクロアルキル基を示し、
    Zは、-CH2-、-O-又は-N(-R7)-を示し、
    R7は、水素原子、C1-C6 アルキル基、ヒドロキシC1-C3アルキル基、C1-C3アルコキシC1-C3アルキル基、カルボキシC1-C3アルキル基、ハロC1-C3アルキル基、C2-C6アルケニル基、C2-C6 アルキニル基又はC3-C6シクロアルキル基を示す。
    ただし、 V が-C(=O)-を示し、かつX及びZが-CH2-を示す場合、Yは
    Figure JPOXMLDOC01-appb-C000003
    ではない。
    ＜置換基群α＞
    C1-C3アルキル基（該アルキル基は、水酸基で1個置換されていてもよい）、
    C3-C6シクロアルキル基（該シクロアルキル基は、C1-C3アルキル基又はカルボキシル基で1個置換されていてもよい）、C1-C3アルコキシ基、カルバモイル基（該カルバモイル基は、C1-C3アルコキシ基で1個置換されていてもよいC1-C3アルキルスルホニル基、C3-C6シクロアルキルスルホニル基又は、ヒドロキシC1-C3アルキル基で1個置換されていてもよい）、窒素、酸素及び硫黄から選択される同一若しくは異なった1-4個のヘテロ原子を含む3-10員ヘテロシクリル基、窒素、酸素及び硫黄から選択される同一若しくは異なった1-4個のヘテロ原子を含む3-10員ヘテロシクリルカルボニル基、アミノ基（該アミノ基は、C1-C3アルキルスルホニル基、C1-C3アルキルカルボニル基又はカルボキシC1-C3アルキル基で1個置換されていてもよい）、ハロゲン原子、カルボキシル基、水酸基及びシアノ基］で表される化合物又はその薬理上許容される塩。
          The following general formula (I)
    Figure JPOXMLDOC01-appb-C000001
    [In the formula, a double line including a broken line represents a single bond or a double bond,
    R 1 represents a hydrogen atom, a C1-C3 alkyl group or a C3-C6 cycloalkyl group,
    R 2 represents a hydrogen atom or a C1-C3 alkyl group, or may combine with the C1-C3 alkyl group of R 1 to form a 3-6 membered saturated carbocycle,
    V represents —CH 2 — or —C (═O) —,
    W is a phenyl group (the phenyl group may be substituted with the same or different 1-4 substituents selected from the substituent group α), a biphenyl group (the biphenyl group is a substituent group) 5-10 containing the same or different 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted with the same or different 1-8 substituents selected from α) A membered heteroarylphenyl group (the heteroarylphenyl group may be substituted with the same or different 1-8 substituents selected from the substituent group α), a 7-benzofuranyl group (the 7-benzofuranyl group) Group may be substituted with the same or different 1-4 substituents selected from substituent group α) or a naphthyl group (the naphthyl group is the same or selected from substituent group α) May be substituted with 1-4 different substituents )
    X represents -CH =, -CH 2- , -O- or -N =,
    Y is
    Figure JPOXMLDOC01-appb-C000002
    , -N (-R 5 )-or -C (-R 6 ) =
    R 3 represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group,
    R 4 represents a hydrogen atom or a C1-C6 alkyl group, or may combine with the C1-C6 alkyl group of R 3 to form a 3-6 membered saturated carbocycle,
    R 5 represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group,
    R 6 represents a C2-C6 alkyl group or a C3-C6 cycloalkyl group,
    Z represents -CH 2- , -O- or -N (-R 7 )-,
    R 7 is a hydrogen atom, a C1-C6 alkyl group, a hydroxy C1-C3 alkyl group, a C1-C3 alkoxy C1-C3 alkyl group, a carboxy C1-C3 alkyl group, a halo C1-C3 alkyl group, a C2-C6 alkenyl group, C2-C6 represents an alkynyl group or a C3-C6 cycloalkyl group.
    However, when V represents -C (= O)-and X and Z represent -CH 2- , Y is
    Figure JPOXMLDOC01-appb-C000003
    is not.
    <Substituent group α>
    A C1-C3 alkyl group (the alkyl group may be substituted with one hydroxyl group),
    C3-C6 cycloalkyl group (the cycloalkyl group may be substituted with one C1-C3 alkyl group or carboxyl group), C1-C3 alkoxy group, carbamoyl group (the carbamoyl group is C1-C3 alkoxy) Selected from a C1-C3 alkylsulfonyl group, a C3-C6 cycloalkylsulfonyl group, or a hydroxy C1-C3 alkyl group optionally substituted by one group), nitrogen, oxygen and sulfur A 3-10 membered heterocyclyl group containing the same or different 1-4 heteroatoms, selected from nitrogen, oxygen and sulfur, or a 3-10 membered heterocyclylcarbonyl containing the same or different 1-4 heteroatoms A group, an amino group (the amino group may be substituted by a C1-C3 alkylsulfonyl group, a C1-C3 alkylcarbonyl group or a carboxy C1-C3 alkyl group), a halogen atom, a carboxy Group, a hydroxyl group and a compound or a pharmacologically acceptable salt thereof represented by the cyano group.
  2. 　R1が、C1-C3アルキル基であり、R2が、C1-C3アルキル基であるか又はR1のC1-C3アルキル基と結合して 3-6員飽和炭素環を形成していてもよい、請求項１に記載の化合物若しくはその薬理上許容される塩。
          R 1 is a C1-C3 alkyl group, and R 2 is a C1-C3 alkyl group or bonded to the C1-C3 alkyl group of R 1 to form a 3-6 membered saturated carbocycle. The compound according to claim 1 or a pharmacologically acceptable salt thereof.
  3. 　R3が、C1-C6アルキル基であり、R4が、C1-C6アルキル基であるか又はR3のC1-C6アルキル基と結合して3-6員飽和炭素環を形成していてもよい、請求項１又は２に記載の化合物若しくはその薬理上許容される塩。
          R 3 is a C1-C6 alkyl group, and R 4 is a C1-C6 alkyl group or bonded to the C1-C6 alkyl group of R 3 to form a 3-6 membered saturated carbocycle. The compound according to claim 1 or 2, or a pharmacologically acceptable salt thereof.
  4. 　Zが、-N(-R7)-であり、Xが、-CH=又は-CH2-である、請求項１乃至３から選択されるいずれか１項に記載の化合物又はその薬理上許容される塩。
          The compound according to any one of claims 1 to 3, or a pharmacologically acceptable salt thereof, wherein Z is -N (-R 7 )-and X is -CH = or -CH 2-. Salt.
  5. 　Zが、-N(-R7)-であり、Yが、
    Figure JPOXMLDOC01-appb-C000004
    であり、Xが、-CH2-である、請求項１乃至４から選択されるいずれか１項に記載の化合物又はその薬理上許容される塩。
          Z is -N (-R 7 )-and Y is
    Figure JPOXMLDOC01-appb-C000004
    The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 4, wherein X is -CH 2- .
  6. 　R7が、C1-C6 アルキル基である、請求項１乃至５から選択されるいずれか１項に記載の化合物又はその薬理上許容される塩。
          6. The compound according to any one of claims 1 to 5 or a pharmacologically acceptable salt thereof, wherein R 7 is a C1-C6 alkyl group.
  7. 　R7が、メチル基又はエチル基である、請求項１乃至５から選択されるいずれか１項に記載の化合物又はその薬理上許容される塩。
          The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 5, wherein R 7 is a methyl group or an ethyl group.
  8. 　Wが、窒素、酸素及び硫黄から選択される同一若しくは異なった1-4個のヘテロ原子を含む5-10員ヘテロアリールフェニル基（該ヘテロアリールフェニル基は、置換基群αより選択される同一または異なった1-8個の置換基で置換されていても良い）である、請求項１乃至７から選択されるいずれか１項に記載の化合物又はその薬理上許容される塩。
    ＜置換基群α＞
    C1-C3アルキル基（該アルキル基は、水酸基で1個置換されていてもよい）、
    C3-C6シクロアルキル基（該シクロアルキル基は、C1-C3アルキル基又はカルボキシル基で1個置換されていてもよい）、C1-C3アルコキシ基、カルバモイル基（該カルバモイル基は、C1-C3アルコキシ基で1個置換されていてもよいC1-C3アルキルスルホニル基、C3-C6シクロアルキルスルホニル基又は、ヒドロキシC1-C3アルキル基で1個置換されていてもよい）、窒素、酸素及び硫黄から選択される同一若しくは異なった1-4個のヘテロ原子を含む3-10員ヘテロシクリル基、窒素、酸素及び硫黄から選択される同一若しくは異なった1-4個のヘテロ原子を含む3-10員ヘテロシクリルカルボニル基、アミノ基（該アミノ基は、C1-C3アルキルスルホニル基、C1-C3アルキルカルボニル基又はカルボキシC1-C3アルキル基で1個置換されていてもよい）、ハロゲン原子、カルボキシル基、水酸基及びシアノ基
          W is a 5- to 10-membered heteroarylphenyl group containing 1-4 heteroatoms which are the same or different selected from nitrogen, oxygen and sulfur (the heteroarylphenyl groups are the same selected from the substituent group α) Or a pharmacologically acceptable salt thereof according to any one of claims 1 to 7, which may be substituted with 1 to 8 different substituents.
    <Substituent group α>
    A C1-C3 alkyl group (the alkyl group may be substituted with one hydroxyl group),
    C3-C6 cycloalkyl group (the cycloalkyl group may be substituted with one C1-C3 alkyl group or carboxyl group), C1-C3 alkoxy group, carbamoyl group (the carbamoyl group is C1-C3 alkoxy) Selected from a C1-C3 alkylsulfonyl group, a C3-C6 cycloalkylsulfonyl group, or a hydroxy C1-C3 alkyl group optionally substituted by one group), nitrogen, oxygen and sulfur A 3-10 membered heterocyclyl group containing the same or different 1-4 heteroatoms, selected from nitrogen, oxygen and sulfur, or a 3-10 membered heterocyclylcarbonyl containing the same or different 1-4 heteroatoms A group, an amino group (the amino group may be substituted by a C1-C3 alkylsulfonyl group, a C1-C3 alkylcarbonyl group or a carboxy C1-C3 alkyl group), a halogen atom, a carboxy Group, hydroxyl group and cyano group
  9. 　Wが、ピリジルフェニル基（該ピリジルフェニル基は、C1-C3アルキル基、C1-C3アルコキシ基及びカルボキシル基から選ばれる3～4個の置換基で置換されていても良い）である、請求項１乃至７から選択されるいずれか１項に記載の化合物又はその薬理上許容される塩。
          The W is a pyridylphenyl group (the pyridylphenyl group may be substituted with 3 to 4 substituents selected from a C1-C3 alkyl group, a C1-C3 alkoxy group, and a carboxyl group). 8. The compound according to any one of 1 to 7 or a pharmacologically acceptable salt thereof selected from 1 to 7.
  10. 　6-{3-[(3S,10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、
    6-{3-[(10R)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、6-{3-[(10S)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、
    6-{4-メトキシ-2-メチル-3-[(3S,10S)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、6-{3-[(3S,10S)-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、又は、
    6-{4-メトキシ-2-メチル-3-[(10S)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,6,8,9,10-ヘキサヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸。
          6- {3-[(3S, 10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8, 9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid,
    6- {3-[(10R) -2-ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H -Chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid, 6- {3-[(10S) -2-ethyl- 3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl ] -4-Methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid,
    6- {4-Methoxy-2-methyl-3-[(3S, 10S) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,6, 8,9,10-Octahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid, 6- {3 -[(3S, 10S) -1,9-dioxo-3- (propan-2-yl) -1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2- c] pyridine-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid, 6- {4-methoxy-2-methyl-3 -[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine- 7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid, 6- {4-methoxy-2-methyl-3-[(10R) -2,3,3-trimethyl -1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl } -3-Methylpyridi -2-carboxylic acid, or
    6- {4-Methoxy-2-methyl-3-[(10S) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,6,8,9,10- Hexahydrospiro [chromeno [3,2-c] pyridine-7,1′-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid.
  11. 　6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、
    6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、
    6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、
    6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸。
          6- {3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-7,1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid, 6- {3-[(10R) -2 -Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1'- Cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid,
    6- {3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] Pyridin-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid, 6- {3-[(10R)- 2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1 ' -Cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid,
    6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid, 6- {4-methoxy-2-methyl-3 -[(10R) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine- 7,1'-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid,
    6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid or 6- {4-methoxy-2-methyl- 3-[(10R) -2,3,3-Trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine -7,1'-cyclobutane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid.
  12. 　6-{4-メトキシ-2-メチル-3-[(10S)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、
    6-{4-メトキシ-2-メチル-3-[(10R)-2,7,7-トリメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、
    6-{3-[(10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、6-{3-[(10R)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロブタン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、
    6-{3-[(10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、又は、6-{3-[(10R)-2-エチル-7,7-ジメチル-1,9-ジオキソ-1,2,4,6,7,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-3,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸。
          6- {4-Methoxy-2-methyl-3-[(10S) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-3,1′-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid,
    6- {4-Methoxy-2-methyl-3-[(10R) -2,7,7-trimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydro Spiro [chromeno [3,2-c] pyridine-3,1′-cyclopropane] -10-yl] phenyl} -3-methylpyridine-2-carboxylic acid,
    6- {3-[(10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-3,1′-cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid, 6- {3-[(10R) -2 -Ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-3,1'- Cyclobutane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid,
    6- {3-[(10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-3,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid or 6- {3-[(10R ) -2-Ethyl-7,7-dimethyl-1,9-dioxo-1,2,4,6,7,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-3, 1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid.
  13. 　6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、
    6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロブタン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロブタン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、
    6-{4-メトキシ-2-メチル-3-[(10'S)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸、6-{4-メトキシ-2-メチル-3-[(10'R)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸、
    6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,7'-クロメノ[3,2-c]ピリジン-3',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、
    6-{4-メトキシ-2-メチル-3-[(10'S)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸、6-{4-メトキシ-2-メチル-3-[(10'R)-2'-メチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]フェニル}-3-メチルピリジン-2-カルボン酸、
    6-{3-[(10'S)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、又は、6-{3-[(10'R)-2'-エチル-1',9'-ジオキソ-1',4',6',8',9',10'-ヘキサヒドロ-2'H-ジスピロ[シクロプロパン-1,3'-クロメノ[3,2-c]ピリジン-7',1''-シクロプロパン]-10'-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸。
          6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H-dispiro [cyclobutane -1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2- Carboxylic acid, 6- {3-[(10'R) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2 ' H-dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl} -3- Methylpyridine-2-carboxylic acid,
    6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H-dispiro [cyclobutane -1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclobutane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid Acid, 6- {3-[(10'R) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H -Dispiro [cyclobutane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclobutane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine -2-carboxylic acid,
    6- {4-Methoxy-2-methyl-3-[(10'S) -2'-methyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro -2'H-Disspiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3 ', 1''-cyclopropane]-10'-yl] phenyl} -3-methylpyridine-2- Carboxylic acid, 6- {4-methoxy-2-methyl-3-[(10'R) -2'-methyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9' , 10'-Hexahydro-2'H-dispiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3 ', 1''-cyclopropane]-10'-yl] phenyl} -3- Methylpyridine-2-carboxylic acid,
    6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H-dispiro [cyclobutane -1,7'-chromeno [3,2-c] pyridine-3 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2- Carboxylic acid, 6- {3-[(10'R) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2 ' H-Disspiro [cyclobutane-1,7'-chromeno [3,2-c] pyridine-3 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl} -3- Methylpyridine-2-carboxylic acid,
    6- {4-Methoxy-2-methyl-3-[(10'S) -2'-methyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro -2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] phenyl} -3-methylpyridine-2 -Carboxylic acid, 6- {4-methoxy-2-methyl-3-[(10'R) -2'-methyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9 ', 10'-Hexahydro-2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7', 1 ''-cyclopropane] -10'-yl] phenyl}- 3-methylpyridine-2-carboxylic acid,
    6- {3-[(10'S) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro-2'H-dispiro [cyclo Propane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2 -Carboxylic acid or 6- {3-[(10'R) -2'-ethyl-1 ', 9'-dioxo-1', 4 ', 6', 8 ', 9', 10'-hexahydro -2'H-dispiro [cyclopropane-1,3'-chromeno [3,2-c] pyridine-7 ', 1''-cyclopropane]-10'-yl] -4-methoxy-2-methylphenyl } -3-Methylpyridine-2-carboxylic acid.
  14. 　6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルl-N-(メチルスルホニル)ピリジン-2-カルボキサミド、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3,7,7-ペンタメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチルl-N-(メチルスルホニル)ピリジン-2-カルボキサミド、6-{3-[(3R,10S)-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、6-{4-メトキシ-2-メチル-3-[(3S,10S)-2,7,7-トリメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド、6-{3-[(3S,10S)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸、6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチルピリジン-2-カルボン酸、6-{3-[(10S)-2-エチル-3,3,7,7-テトラメチル-1,9-ジオキソ-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド、6-{4-メトキシ-2-メチル-3-[(3S,4aS,10S,10aR)-2-メチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,4a,6,8,9,10,10a-デカヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド、又は、6-{3-[(3S,10S)-2-エチル-1,9-ジオキソ-3-(プロパン-2-イル)-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチルピリジン-2-カルボン酸。
          6- {4-Methoxy-2-methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9, 10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methylpyridine-2-carboxylic acid, 6- {4-methoxy-2-methyl-3-[(10R) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridine-10 -Yl] phenyl} -3-methylpyridine-2-carboxylic acid, 6- {4-methoxy-2-methyl-3-[(10S) -2,3,3,7,7-pentamethyl-1,9- Dioxo-2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methyllN- (methylsulfonyl) pyridine- 2-carboxamide, 6- {4-methoxy-2-methyl-3-[(10R) -2,3,3,7,7-pentamethyl-1,9-dioxo-2,3,4,6,7, 8,9,10-Octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl} -3-methyllN- (methylsulfonyl) pyridine-2-carboxamide, 6- {3-[(3R , 10S) -7,7-dimethyl-1, 9-Dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4 -Methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid, 6- {4-methoxy-2-methyl-3-[(3S, 10S) -2,7,7-trimethyl-1,9 -Dioxo-3- (propan-2-yl) -2,3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] phenyl}- 3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide, 6- {3-[(3S, 10S) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2, 3,4,6,7,8,9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2- Carboxylic acid, 6- {4-methoxy-2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2 , 3,4,4a, 6,8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] phenyl} -3-methyl Pyridine-2-carbo Acid, 6- {3-[(10S) -2-ethyl-3,3,7,7-tetramethyl-1,9-dioxo-2,3,4,6,7,8,9,10-octahydro -1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide, 6- {4-methoxy -2-methyl-3-[(3S, 4aS, 10S, 10aR) -2-methyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,4a, 6, 8,9,10,10a-Decahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclobutane] -10-yl] phenyl} -3-methyl-N- (methylsulfonyl) pyridine-2 -Carboxamide or 6- {3-[(3S, 10S) -2-ethyl-1,9-dioxo-3- (propan-2-yl) -1,2,3,4,6,8,9 , 10-Octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methylpyridine-2-carboxylic acid .
  15. 　6-{3-[(3S,10S)-2-エチル-7,7-ジメチル-1,9-ジオキソ-3-(プロパン-2-イル)-2,3,4,6,7,8,9,10-オクタヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド、6-{3-[(3S,4aS,10S,10aR)-3-tert-ブチル-2,7,7-トリメチル-1,9-ジオキソ-2,3,4,4a,6,7,8,9,10,10a-デカヒドロ-1H-クロメノ[3,2-c]ピリジン-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド、6-{3-[(10S)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド、6-{3-[(10R)-2-エチル-3,3-ジメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]-4-メトキシ-2-メチルフェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド、6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロブタン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド、6-{4-メトキシ-2-メチル-3-[(10S)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド、又は、6-{4-メトキシ-2-メチル-3-[(10R)-2,3,3-トリメチル-1,9-ジオキソ-1,2,3,4,6,8,9,10-オクタヒドロスピロ[クロメノ[3,2-c]ピリジン-7,1'-シクロプロパン]-10-イル]フェニル}-3-メチル-N-(メチルスルホニル)ピリジン-2-カルボキサミド。
          6- {3-[(3S, 10S) -2-ethyl-7,7-dimethyl-1,9-dioxo-3- (propan-2-yl) -2,3,4,6,7,8, 9,10-octahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide, 6 -{3-[(3S, 4aS, 10S, 10aR) -3-tert-butyl-2,7,7-trimethyl-1,9-dioxo-2,3,4,4a, 6,7,8,9 , 10,10a-decahydro-1H-chromeno [3,2-c] pyridin-10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide, 6- {3-[(10S) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3, 2-c] pyridine-7,1′-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide, 6- {3 -[(10R) -2-Ethyl-3,3-dimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] Pyridine -7,1'-cyclopropane] -10-yl] -4-methoxy-2-methylphenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide, 6- {4-methoxy-2- Methyl-3-[(10S) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c ] Pyridine-7,1'-cyclobutane] -10-yl] phenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide, 6- {4-methoxy-2-methyl-3-[(10R ) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1 ' -Cyclobutane] -10-yl] phenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide, 6- {4-methoxy-2-methyl-3-[(10S) -2,3,3 -Trimethyl-1,9-dioxo-1,2,3,4,6,8,9,10-octahydrospiro [chromeno [3,2-c] pyridine-7,1'-cyclopropane] -10- Yl] phenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxyl Or 6- {4-methoxy-2-methyl-3-[(10R) -2,3,3-trimethyl-1,9-dioxo-1,2,3,4,6,8,9, 10-octahydrospiro [chromeno [3,2-c] pyridin-7,1'-cyclopropane] -10-yl] phenyl} -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide.
  16. 　請求項１０乃至１５のいずれか１項に記載の化合物又はその薬理上許容される塩。
          The compound or pharmacologically acceptable salt thereof according to any one of claims 10 to 15.
  17. 　請求項１乃至１５のいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する血糖降下剤。
          A hypoglycemic agent comprising the compound according to any one of claims 1 to 15 or a pharmacologically acceptable salt thereof as an active ingredient.
  18. 　請求項１乃至１５のいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する医薬。
          A medicament comprising the compound according to any one of claims 1 to 15 or a pharmacologically acceptable salt thereof as an active ingredient.
  19. 　糖尿病、食後過血糖症、耐糖能障害、糖尿病性神経障害、糖尿病性腎症、糖尿病性網膜症、高脂血症、動脈硬化症、血栓性疾患、肥満、高血圧、浮腫、インスリン抵抗性、不安定糖尿病、インスリノーマ又は高インスリン血症の治療若しくは予防のための、請求項１８に記載の医薬。
          Diabetes, postprandial hyperglycemia, glucose intolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, non The medicament according to claim 18, for the treatment or prevention of stable diabetes, insulinoma or hyperinsulinemia.
  20. 　2型糖尿病の治療のための、請求項１８に記載の医薬。
          19. A medicament according to claim 18 for the treatment of type 2 diabetes.
  21. 　医薬組成物を製造するための、請求項１乃至１５ら選択されるいずれか１項に記載された化合物又はその薬理上許容される塩の使用。
          Use of the compound according to any one of claims 1 to 15 or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition.
  22. 　請求項１乃至１５から選択されるいずれか１項に記載された化合物又はその薬理上許容される塩の薬理的な有効量を温血動物に投与することを含む、2型糖尿病の治療又は予防方法。
          Treatment or prevention of type 2 diabetes, comprising administering to a warm-blooded animal a pharmacologically effective amount of a compound according to any one of claims 1 to 15 or a pharmacologically acceptable salt thereof. Method.
  23. 　疾患の治療若しくは予防のための方法における使用のための、請求項１乃至１５から選択されるいずれか１項に記載された化合物又はその薬理上許容される塩。
          A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15 for use in a method for the treatment or prevention of a disease.
  24. 　疾患が2型糖尿病である、請求項２３に記載された化合物又はその薬理上許容される塩。 24. The compound or pharmacologically acceptable salt thereof according to claim 23, wherein the disease is type 2 diabetes.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001039984A (en) * 1999-07-30 2001-02-13 Meiji Seika Kaisha Ltd Thiophene compound
US20130324525A1 (en) * 2007-07-05 2013-12-05 Gilead Sciences, Inc. Substituted heterocyclic compounds
WO2014061764A1 (en) * 2012-10-19 2014-04-24 第一三共株式会社 Xanthene derivative
WO2014142127A1 (en) * 2013-03-12 2014-09-18 第一三共株式会社 Phenylxanthene derivative

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001039984A (en) * 1999-07-30 2001-02-13 Meiji Seika Kaisha Ltd Thiophene compound
US20130324525A1 (en) * 2007-07-05 2013-12-05 Gilead Sciences, Inc. Substituted heterocyclic compounds
WO2014061764A1 (en) * 2012-10-19 2014-04-24 第一三共株式会社 Xanthene derivative
WO2014142127A1 (en) * 2013-03-12 2014-09-18 第一三共株式会社 Phenylxanthene derivative

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KEUPER,R. ET AL.: "Synthesis and characterization of novel pyridines and 3,3'-bridged bipyridines using 1, x-cyclohexanediones", EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, vol. 11, 1998, pages 2609 - 2615, XP055337630 *
YOU,X. ET AL.: "Synthesis of 9-aryl-3-methyl-1, 8-dioxo-2,10-dioxanthens", CHIN. J. ORG. CHEM., vol. 32, no. 1, 2012, pages 156 - 159 *

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