WO2016204134A1 - Dérivé hétérocyclique à six chaînons - Google Patents

Dérivé hétérocyclique à six chaînons Download PDF

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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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English (en)
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/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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

La présente invention concerne un composé, ou un sel pharmacologiquement acceptable de celui-ci, qui est représenté par la formule générale (I) et qui présente une excellente action hypoglycémique. [Dans la formule, les lignes doubles qui comprennent une ligne discontinue indiquent une liaison simple ou une liaison double, R1 représente un atome d'hydrogène, un groupe alkyle en C1 à C3, ou similaires, R2 représente un atome d'hydrogène, un groupe alkyle en C1 à C3, ou similaires, R3 représente un atome d'hydrogène, un groupe alkyle en C1 à C6, ou similaires, R4 représente un atome d'hydrogène, un groupe alkyle en C1 à C6, ou similaires, R5 représente un atome d'hydrogène ou similaire, R6 représente un groupe alkyle en C2 à C6 ou similaire, R7 représente un atome d'hydrogène ou similaire, V représente -CH2- ou -C(=O)-, W représente un groupe phényle ou similaire qui peut être substitué par 1 à 4 substituants identiques ou différents choisis dans le groupe α de substituants, le groupe α de substituants comprenant les groupes alkyle en C1 à C3 ou similaires, X représente -CH=, -CH2-, -O-, ou -N=, Y représente -CR3R4-, -NR5- ou -CR6=, et Z représente -CH2-, -O-, ou -NR7-, à condition que lorsque V représente -C(=O)- et que X et Z représentent -CH2-, Y ne représente pas -CR3R4-].
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001039984A (ja) * 1999-07-30 2001-02-13 Meiji Seika Kaisha Ltd チオフェン化合物
US20130324525A1 (en) * 2007-07-05 2013-12-05 Gilead Sciences, Inc. Substituted heterocyclic compounds
WO2014061764A1 (fr) * 2012-10-19 2014-04-24 第一三共株式会社 Dérivé de xanthène
WO2014142127A1 (fr) * 2013-03-12 2014-09-18 第一三共株式会社 Dérivé de phénylxanthène

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001039984A (ja) * 1999-07-30 2001-02-13 Meiji Seika Kaisha Ltd チオフェン化合物
US20130324525A1 (en) * 2007-07-05 2013-12-05 Gilead Sciences, Inc. Substituted heterocyclic compounds
WO2014061764A1 (fr) * 2012-10-19 2014-04-24 第一三共株式会社 Dérivé de xanthène
WO2014142127A1 (fr) * 2013-03-12 2014-09-18 第一三共株式会社 Dérivé de phénylxanthène

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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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