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WO2019103060A1 - Composé tricyclique condensé - Google Patents

Composé tricyclique condensé Download PDF

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Publication number
WO2019103060A1
WO2019103060A1 PCT/JP2018/043065 JP2018043065W WO2019103060A1 WO 2019103060 A1 WO2019103060 A1 WO 2019103060A1 JP 2018043065 W JP2018043065 W JP 2018043065W WO 2019103060 A1 WO2019103060 A1 WO 2019103060A1
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group
methyl
compound
mmol
reaction
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PCT/JP2018/043065
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English (en)
Japanese (ja)
Inventor
中尾　彰
森　誠
理樹 宮崎
暁丈 山口
義浩 小倉
麻由子 秋生
明日香 河村
美穂 早川
正二郎 宮崎
壽紘 石濱
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第一三共株式会社
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Publication of WO2019103060A1 publication Critical patent/WO2019103060A1/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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound having a novel tricyclic skeleton which has an agonist activity at the GLP-1 receptor and can be used for the prevention or treatment of obesity or the prevention or treatment of type 2 diabetes.
  • Obesity and overweight are defined as abnormal or excessive accumulation of fat in the body at risk for health hazards. Generally, it is judged using BMI (Body Mass Index) whether it is obese or not, and according to WHO definition, BMI value is 25 or more and overweight, and 30 or more is obese. On the other hand, in Japan, it is considered to be obese with a BMI value of 25 or more. Obesity and overweight are recognized as risk factors for various diseases such as cardiovascular disease, hypertension, type 2 diabetes and cancer, and it is necessary to eliminate obesity and overweight before suffering from these diseases. , Has become an important issue (non-patent documents 1-2).
  • Type 2 diabetes is a disease in which hyperglycemia is chronically sustained due to decreased insulin secretion in pancreatic ⁇ cells and / or decreased insulin action in insulin-sensitive organs such as muscle, adipose tissue and liver.
  • type 2 diabetes it is known that persistent hyperglycemia not only causes retinopathy, nephropathy, neuropathy and the like but also increases the risk of myocardial infarction and cerebral infarction. It is considered important to control the patient's blood sugar level in order to prevent them.
  • Various types of drugs for controlling blood glucose levels are known, and include, for example, insulin preparations, biguanides, SGLT2 inhibitors, DPP-4 inhibitors, GLP-1 receptor agonists (non- Patent Document 3).
  • Glucagon-like peptide-1 (GLP-1: Glucagon-Like Peptide-1) is an endogenous peptide secreted mainly from L cells in the lower small intestine in response to a meal. GLP-1 binds to the G protein coupled receptor, GLP-1 receptor, and performs signal transduction by promoting the production of cAMP from ATP produced by glucose metabolism. GLP-1 receptors have the effect of enhancing insulin secretion and suppressing appetite in a glucose concentration-dependent manner, so that the agonist has been used to prevent or treat obesity, and to prevent or treat diabetes It has been studied to use for (non-patent documents 4-6).
  • liraglutide (trade name: Victoza), which is a human GLP-1 analogue preparation having GLP-1 receptor agonist activity, acylates endogenous GLP-1 which is easily degraded in vivo by long chain fatty acid, and its half life
  • the drug has been shown to be an extended drug, but has been shown to lower HbA1c, which is used as an indicator of glycemic control in clinical trials for patients with type 2 diabetes, and is marketed as a pharmaceutical in Japan, Europe and the United States.
  • HbA1c which is used as an indicator of glycemic control in clinical trials for patients with type 2 diabetes
  • liraglutide has been approved in Europe and the United States as a drug for overweight patients with obesity or complications associated with obesity.
  • GLP-1 analogues typified by liraglutide have poor oral absorbability because the active substance is a peptide or a derivative thereof, and most analogs thereof are developed and marketed as injections. Since the injections are seldom convenient for administration and accompanied by pain in administration, an orally administered GLP-1 receptor agonist which can be more easily taken is desired.
  • production of GLP-1 analogue preparations such as liraglutide is expensive compared to conventional low-molecular-weight drugs, development of non-peptide low-molecular-weight GLP-1 receptor agonists that can be manufactured more inexpensively It is desired.
  • An object of the present invention is to provide a small molecule GLP-1 receptor agonist having a novel skeleton. Another object of the present invention is to provide a low molecular weight GLP-1 receptor agonist which has excellent physical properties and is excellent in mammals (especially human).
  • the present inventors have created a compound having an agonist activity for the GLP-1 receptor and having a novel tricyclic skeleton having excellent properties as a pharmaceutical. And completed the present invention.
  • the present invention relates to [1] to [22] described below.
  • R 1 C3-C6 cycloalkyl group, phenyl group optionally substituted by 1 or 2 halogen atoms, or 6-membered ring heteroaryl group optionally substituted by 1 or 2 halogen atoms (wherein When R 1 is a phenyl group which may be substituted by one or two halogen atoms, the phenyl group is bonded at the ortho position to the end of the C 1 -C 6 alkyl group of R 2 to form a ring, R 1 and R 2 may form an indane ring or a tetralin ring containing a carbon atom directly bonded to each other)
  • R 2 hydrogen atom, C1-C6 alkyl group, C3-C6 cycloalkyl group, hydroxy C1-C6 alkyl group, C1-C6 alkoxy C1-C6 alkyl group, or C3-C5 saturated cyclic ether group
  • R 3 saturated cyclic ether group
  • R 7 is a pyridyl group substituted with one or two C 1 -C 6 alkyl groups, or a pharmacologically acceptable salt thereof.
  • R 5 may be substituted with a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a (C3-C6 cycloalkyl) methyl group, or one or two C1-C6 alkyl groups A 6-membered ring heteroaryl C1-C6 alkyl group, or a phenyl C1-C6 alkyl group optionally substituted by one or two C1-C6 alkyl groups or one or two halogen atoms [1] to [6] 3] The compound according to any one of the above, or a pharmacologically acceptable salt thereof.
  • R 1 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, 3,4-difluorophenyl group, 3,5-difluorophenyl group, 3-chloro-4-fluorophenyl group, or 4-chloro-3- Fluorophenyl group
  • R 2 hydrogen atom, methyl group, ethyl group, propyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group, oxetanyl group, tetrahydropyranyl group, or hydroxymethyl group
  • R 3 a hydrogen atom or a methyl group (however, R 2 and R 3 may be bonded at an end to form an oxetane ring containing a carbon atom to which they are directly bonded)
  • R 4 hydrogen atom
  • a pharmaceutical composition comprising the compound according to any one of [1] to [13] or a pharmacologically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition according to [14] for preventing or treating obesity.
  • the compound according to any one of [1] to [13] or a pharmacologically acceptable salt thereof for use in the prevention or treatment of obesity.
  • a method for the prophylaxis or treatment of obesity by administering an effective amount of the compound according to any one of [1] to [13] or a pharmacologically acceptable salt thereof.
  • [twenty two] A method for preventing or treating type 2 diabetes by administering an effective amount of the compound according to any one of [1] to [13] or a pharmacologically acceptable salt thereof.
  • the present invention relates, in another aspect, to the following [A-1] to [A-25].
  • R 1 C3-C6 cycloalkyl group, phenyl group optionally substituted by 1 or 2 halogen atoms, or 6-membered ring heteroaryl group optionally substituted by 1 or 2 halogen atoms (wherein When R 1 is a phenyl group which may be substituted by one or two halogen atoms, the phenyl group is bonded at the ortho position to the end of the C 1 -C 6 alkyl group of R 2 to form a ring, R 1 and R 2 may form an indane ring or a tetralin ring containing a carbon atom directly bonded to each other)
  • R 2 hydrogen atom, C1-C6 alkyl group, C3-C6 cycloalkyl group, hydroxy C1-C6 alkyl group, C1-C6 alkoxy C1-C6 alkyl group, or C3-C5 saturated cyclic ether group
  • R 3 saturated cyclic ether group
  • [A-3] The compound according to [A-1] or [A-2], wherein R 7 is a pyridyl group substituted with one or two C1-C6 alkyl groups, or a pharmacologically acceptable salt thereof.
  • R 5 may be substituted with a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a (C3-C6 cycloalkyl) methyl group, or one or two C1-C6 alkyl groups 6-membered ring heteroaryl C1-C6 alkyl group, or phenyl C1-C6 alkyl group optionally substituted with 1 or 2 C1-C6 alkyl groups or 1 or 2 halogen atoms [A-1] Or a compound according to any one of [A-3], or a pharmacologically acceptable salt thereof.
  • R 1 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, 3,4-difluorophenyl group, 3,5-difluorophenyl group, 3-chloro-4-fluorophenyl group, or 4-chloro-3- Fluorophenyl group
  • R 2 hydrogen atom, methyl group, ethyl group, propyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group, oxetanyl group, tetrahydropyranyl group, or hydroxymethyl group
  • R 3 a hydrogen atom or a methyl group (however, R 2 and R 3 may be bonded at an end to form an oxetane ring containing a carbon atom to which they are directly bonded)
  • R 4 hydrogen
  • [A-17] A pharmaceutical composition comprising the compound according to any one of [A-1] to [A-16] or a pharmacologically acceptable salt thereof as an active ingredient.
  • [A-18] The pharmaceutical composition according to [A-17] for preventing or treating obesity.
  • [A-19] Use of a compound of any one of [A-1] to [A-16] or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition for preventing or treating obesity.
  • A-20] A compound of any one of [A-1] to [A-16] or a pharmacologically acceptable salt thereof for use in the prevention or treatment of obesity.
  • [A-21] A method of preventing or treating obesity by administering an effective amount of the compound according to any one of [A-1] to [A-16] or a pharmacologically acceptable salt thereof.
  • [A-22] The pharmaceutical composition according to [A-17] for preventing or treating type 2 diabetes.
  • [A-23] Use of a compound of any one of [A-1] to [A-16] or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition for preventing or treating type 2 diabetes.
  • [A-24] A compound of any one of [A-1] to [A-16] or a pharmacologically acceptable salt thereof for use in the prevention or treatment of type 2 diabetes.
  • [A-25] A method for preventing or treating type 2 diabetes by administering an effective amount of the compound according to any one of [A-1] to [A-16] or a pharmacologically acceptable salt thereof.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has affinity for the GLP-1 receptor, hypoglycemic action, body weight reducing action, antifeedant action, rapid onset of drug efficacy, Sustained efficacy, physical stability, solubility, oral absorption, blood concentration, cell membrane permeability, metabolic stability, tissue transferability, bioavailability (BA), drug interaction, safety, etc. It has excellent properties and is useful as a pharmaceutical for mammals (especially for humans). Therefore, a medicament containing the compound of the present invention as an active ingredient can be used for the purpose of preventing or treating obesity or preventing or treating type 2 diabetes.
  • 1,2,3,4,7,8,9,10-octahydro [1,4] oxazepino [3,2-g] isoquinoline skeleton possessed by the compounds of the present invention
  • 2,3,4,5,7 2,8,9,10-octahydro [1,4] oxazepino [6,7-g] isoquinoline skeleton
  • the -g] isoquinoline skeleton is difficult to synthesize and there is no synthetic example so far.
  • C3-C6 cycloalkyl group a 3- to 6-membered ring alkyl group, specifically a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • Halogen atom a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • Phenyl group optionally substituted by one or two halogen atoms phenyl group, or substituted by one or two halogen atoms wherein the benzene ring is independently selected (the same applies to the following groups) Specific phenyl groups, such as phenyl, chlorophenyl (including ortho, meta and para substitution), fluorophenyl (including ortho, meta and para substitution), dichlorophenyl (all substitution patterns) , Difluorophenyl group (including all substitution patterns), or chlorofluorophenyl group (including all substitution patterns).
  • “Six-membered ring heteroaryl group” a six-membered ring aromatic group constituted by one or more hetero atoms independently selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms in addition to carbon atoms, Specifically, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group and the like.
  • a 6-membered ring heteroaryl group optionally substituted by 1 or 2 halogen atoms an unsubstituted 6-membered ring heteroaryl group, or a heteroaryl ring substituted by 1 or 2 halogen atoms 6
  • Membered ring heteroaryl group such as fluoropyridyl group, difluoropyridyl group, chloropyridyl group, dichloropyridyl group and the like.
  • a dichloropyridyl group including all substitution patterns but preferably a 5,6-dichloro-3-pyridyl group
  • a chloropyridyl group including all substitution patterns but preferably 5- Chloro-3-pyridyl group.
  • C1-C6 alkyl group a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, an isopropyl group, a butyl group, an isobutyl group and a sec- Butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl Group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, or 1,2-dimethylbutyl group.
  • “Hydroxy C1-C6 alkyl group” A group in which one C-C6 alkyl group is substituted with one hydroxy group, and specifically, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, a hydroxypentyl group And a hydroxyhexyl group.
  • C 1 -C 6 alkoxy group A group in which the above C 1 -C 6 alkyl group is bonded to an oxygen atom, and specifically, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, sec -Butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, isohexyloxy and the like.
  • C 1 -C 6 alkoxy C 1 -C 6 alkyl group a group in which one C 1 -C 6 alkoxy group is substituted to the C 1 -C 6 alkyl group, and specifically, a methoxymethyl group, an ethoxymethyl group, a propoxymethyl group Group, isopropoxymethyl group, methoxyethyl group, ethoxyethyl group, propoxyethyl group, isopropoxyethyl group and the like.
  • C3-C5 saturated cyclic ether group a 4- to 6-membered saturated ring which is a monovalent group containing one oxygen atom as a constituent atom in the ring, and more specifically a 2-oxetanyl group, Examples thereof include 3-oxetanyl group, 2-tetrahydrofuranyl group, 3-tetrahydrofuranyl group, 2-tetrahydropyranyl group, 3-tetrahydropyranyl group, and 4-tetrahydropyranyl group.
  • Halogeno C1-C6 alkyl group a group in which 1 to 5 halogen atoms are substituted to the above C1-C6 alkyl group, and more specifically, trifluoromethyl group, difluoromethyl group, 1,1-difluoroethyl group , 2,2-difluoroethyl group, or 2,2,2-trifluoroethyl group.
  • C 3 -C 6 cycloalkylmethyl group a group in which a methyl group is substituted with one of the aforementioned C 3 -C 6 cycloalkyl groups, and more specifically a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, or A cyclohexylmethyl group and the like.
  • C3-C5 saturated cyclic ether-substituted methyl group a group in which the C3-C5 saturated cyclic ether is substituted to a methyl group, and more specifically, 2-oxetanylmethyl group, 3-oxetanylmethyl group, 2- And the like. Tetrahydrofuranylmethyl group, 3-tetrahydrofuranylmethyl group, 2-tetrahydropyranylmethyl group, 3-tetrahydropyranylmethyl group, 4-tetrahydropyranylmethyl group and the like.
  • “Di (C 1 -C 6 alkyl) carbamoyl methyl group” A group in which a carbamoyl group substituted by two C 1 -C 6 alkyl groups on the N atom is bonded to a methyl group, specifically a dimethyl carbamoyl methyl group, diethyl And a carbamoylmethyl group, a dipropylcarbamoylmethyl group, or a dibutylcarbamoylmethyl group.
  • “5-membered ring heteroaryl group” a 5-membered ring aromatic group constituted by one or more hetero atoms independently selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms in addition to carbon atoms, Specific examples thereof include pyrrolyl group, pyrazolyl group, imidazolyl group, triazolyl group, tetrazolyl group, furyl group, thienyl group, oxazolyl group, isoxazolyl group, oxadiazolyl group, thiazolyl group, and thiadiazolyl group.
  • “5-membered ring heteroaryl carbonyl group” a group in which one 5-membered ring heteroaryl group is bonded to a carbonyl group at any position, and specifically, a pyrrole carbonyl group, a pyrazolyl carbonyl group, an imidazolyl carbonyl group And furyl carbonyl group, thienyl carbonyl group, oxazolyl carbonyl group, or isoxazolyl carbonyl group.
  • “5- or 6-membered ring heteroaryl C1-C6 alkyl group” a group in which one C5-C6 alkyl group is substituted by one 5-membered ring heteroaryl group, or a group wherein the 6-membered ring heteroaryl group is substituted at any position
  • Specific examples thereof include pyrazolylmethyl group, imidazolylmethyl group, furylmethyl group, oxazolylmethyl group, oxazolylethyl group, isoxazolylmethyl group, pyridylmethyl group and the like.
  • Phenyl C1-C6 alkyl group a group wherein the above C1-C6 alkyl group is substituted with a phenyl group, and specific examples thereof include benzyl group, 1-phenylethyl group, 2-phenylethyl group, 1-phenylpropyl group And 2-phenylpropyl group, 3-phenylpropyl group, 1-phenylbutyl group, 2-phenylbutyl group, 3-phenylbutyl group, 4-phenylbutyl group and the like.
  • a carbonyl group to which the 5-membered ring heteroaryl group substituted by -C6 alkyl group is bonded and specific examples thereof include pyrazolyl carbonyl group, imidazolyl carbonyl group, oxazolyl carbonyl group, isoxazolyl carbonyl group, 1 -Methyl pyrazolyl carbonyl group, 1-methyl imidazolyl carbonyl group, methyl isoxazolyl carbonyl group, methyl oxazolyl carbonyl group, dimethyl oxazolyl carbonyl group, etc. 4-yl) carbonyl group.
  • a 5- or 6-membered ring heteroaryl C1-C6 alkyl optionally substituted with one or two C1-C6 alkyl groups the above-mentioned C1-C6 alkyl substituted with the aforementioned 5- or 6-membered ring heteroaryl group A C1-C6 alkyl group substituted by a group, or the above-mentioned 5- or 6-membered ring heteroaryl group substituted by one or two of the C1-C6 alkyl group, specifically a pyrazolylmethyl group, an imidazolyl group; Methyl group, oxazolyl methyl group, oxazolyl ethyl group, methyl oxazolyl methyl group, dimethyl oxazolyl methyl group, isoxazolyl methyl group, methyl isoxazolyl methyl group, pyridyl methyl group, or pyridazyl methyl And the like, preferably 2-pyridyl
  • Phenyl C1-C6 alkyl group optionally substituted by one or two C1-C6 alkyl groups or one or two halogen atoms the aforementioned C1-C6 alkyl group substituted by a phenyl group, or benzene ring Is a C1-C6 alkyl group substituted by one or two C1 to C6 alkyl groups or a phenyl group substituted by one or two of the halogen atoms, preferably a benzyl group, 1-phenyl group; Examples thereof include an ethyl group, a 2-phenylethyl group, a 1-phenylpropyl group, a 2-methylbenzyl group, a 2-fluorobenzyl group, a 3-fluorobenzyl group, and a 3-chlorobenzyl group.
  • a 6-membered ring heteroaryl group optionally substituted by 1 or 2 C1-C6 alkyl groups an unsubstituted 6-membered ring heteroaryl group, or one or two of the above-mentioned C1 ⁇ heteroaryl rings.
  • (C 1 -C 6 alkyl) carbonyl group a group in which one C 1 -C 6 alkyl group is bonded to a carbonyl group, and specifically, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, or a pivaloyl group And is preferably an acetyl group or a propionyl group.
  • a preferred substituent R 1 in the present invention is a phenyl group which may be substituted by one or two halogen atoms, more preferably a phenyl group substituted by one or two halogen atoms, More preferably, it is a phenyl group substituted by two halogen atoms, still more preferably, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, 3,4-difluorophenyl group, 3,5-difluoro It is a phenyl group, 3-chloro-4-fluorophenyl group or 4-chloro-3-fluorophenyl group. Particularly preferred is a 3,4-dichlorophenyl group.
  • the preferred substituent R 2 in the present invention is a hydrogen atom, methyl group, ethyl group, propyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group, oxetanyl group, tetrahydropyranyl group or hydroxymethyl group, and more preferred Is a hydrogen atom, a methyl group or an ethyl group.
  • the substituents R 1 and R 2 may be terminally bonded to form an indane ring or a tetralin ring containing a carbon atom to which R 1 and R 2 are directly bonded.
  • the preferred substituent R 3 in the present invention is a hydrogen atom or a C 1 -C 6 alkyl group, more preferably a hydrogen atom, a methyl group or an ethyl group, still more preferably a hydrogen atom or a methyl group .
  • the substituents R 2 and R 3 are terminally bonded to form a C3-C5 saturated cyclic ether (preferably an oxetane ring) containing a carbon atom to which R 2 and R 3 are directly bonded. May be
  • the preferred substituent R 4 in the present invention is a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, and still more preferably a hydrogen atom.
  • Preferred substituents R 5 in the present invention are methyl, ethyl, propyl, isopropyl, isobutyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo Propylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, benzyl group, 1-phenylpropyl group or 2-pyridylmethyl group, more preferably isobutyl group, cyclopentyl group, cyclohexyl group, cyclobutylmethyl group or It is a cyclopentyl methyl group.
  • the preferred substituent R 6 in the present invention is a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a chlorine atom, and still more preferably a hydrogen atom.
  • the preferred substituent R 7 in the present invention is a 6-membered ring heteroaryl group which may be substituted by one or two C 1 -C 6 alkyl groups, more preferably one or two C 1 -C 6 alkyl groups Is a pyridyl group substituted by and, more preferably, a 2,3-dimethyl-4-pyridyl group.
  • a substituent selected as X or Y a methylene group (-CH 2- ), a nitrogen atom substituted with a C 1 -C 6 alkyl group (-(C 1 -C 6 alkyl) N-), (C 1 -C 6)
  • a nitrogen atom substituted with a C 1 -C 6 alkyl group -(C 1 -C 6 alkyl) N-)
  • nitrogen atom (-((C1-C6 alkyl) carbonyl) N-) substituted with an alkyl) carbonyl group and an oxygen atom (-O-) are preferred, with the following substituents being preferred.
  • X -CH 2 -,-(CH 3 ) N-,-(CH 3 CH 2 ) N-,-(CH 3 CO) N-, or -O- Y: -CH 2 -,-(CH 3 ) N-,-(CH 3 CH 2 ) N-,-(CH 3 CO) N-, or -O-
  • an oxygen atom and an oxygen atom O—O
  • a nitrogen atom and an oxygen atom N—O
  • a single bond between hetero atoms such as a nitrogen atom and a nitrogen atom (N—N)
  • the combination of X and Y with is not included in the present invention.
  • Preferred Z in the present invention includes a methylene group (—CH 2 —) or an oxygen atom (—O—).
  • the combination of X, Y and Z in the present invention is preferably the following combination.
  • X -( CH 3) N-, Y: -CH 2 -, Z: -O-; (2) X :-( CH 3 CH 2) N-, Y: -CH 2 -, Z: -O-; (3) X :-( CH 3 CO ) N-, Y: -CH 2 -, Z: -O-; (4) X: -CH 2- , Y:-(CH 3 ) N-, Z: -O-; (5) X: -CH 2- , Y:-(CH 3 CH 2 ) N-, Z: -O-; (6) X: -CH 2- , Y:-(CH 3 CO) N-, Z: -O-; (7) X: -CH 2- , Y: -O-, Z:-CH 2-
  • the compounds represented by the general formula (I) are preferably the following compounds.
  • the pharmacologically acceptable salt indicates a salt that can be used as a pharmaceutical.
  • “salt with a base” or “acid addition salt” can be obtained by reacting with a base or an acid, and a salt thereof is shown.
  • “the pharmacologically acceptable salt” also includes the hydrate thereof.
  • the pharmacologically acceptable “salt with a base” of the compound is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; alkaline earth metal salt such as magnesium salt or calcium salt; -Methyl morpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, organic base salts such as picoline salt, or glycine salt, lysine It is a salt, arginine salt, ornithine salt, glutamate, amino acid salt such as aspartate, preferably alkali metal salt or alkaline earth metal salt.
  • alkali metal salt such as sodium salt, potassium salt or lithium salt
  • alkaline earth metal salt such as magnesium salt or calcium salt
  • -Methyl morpholine salt triethylamine salt, tributylamine salt
  • the pharmacologically acceptable “acid addition salt” of the compound is preferably a hydrofluoride, hydrochloride, hydrobromide, hydrohalide such as hydroiodide, nitrate, etc.
  • Inorganic acid salts such as perchlorate, sulfate and phosphate; methanesulfonate, trifluoromethanesulfonate, lower alkanesulfonate such as ethanesulfonate, benzenesulfonate, p-toluenesulfone
  • Aryl sulfonates such as acid salts, acetates, malates, fumarates, succinates, citrates, ascorbates, tartrates, tartrates, oxalates, maleates etc .
  • the compound of the present invention or a pharmacologically acceptable salt thereof may absorb moisture, adhere to adsorbed water, or become hydrate upon standing in the air or recrystallization.
  • the present invention also encompasses compounds of such various hydrates, solvates and crystalline polymorphs.
  • the compounds of the present invention also include labels, ie, compounds in which one or more atoms of the compound are substituted with an isotope (eg, 2 H, 3 H, 13 C, 14 C, 35 S, etc.).
  • labels ie, compounds in which one or more atoms of the compound are substituted with an isotope (eg, 2 H, 3 H, 13 C, 14 C, 35 S, etc.).
  • the invention also encompasses pharmacologically acceptable prodrugs of the compounds of the invention.
  • the pharmacologically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group or the like by solvolysis or under physiological conditions. Examples of groups forming a prodrug include the groups described in Prog. Med., 5, 2157-2161 (1985).
  • the prodrug more specifically, when an amino group is present in the compound, a compound in which the amino group is acylated or phosphorylated (for example, the amino group is eicosanoylated, alanylated, pentylaminocarbonyl And (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidinylmethylation, pivaloyloxymethylated compounds, etc.
  • the amino group is eicosanoylated, alanylated, pentylaminocarbonyl And (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidinylmethylation, pivaloyloxymethylated compounds, etc.
  • the hydroxyl group is acylated, alkylated, phosphorylated or borated (eg, the hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinyl) And the like.
  • the hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinyl
  • the hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinyl
  • a carboxy group is present in the compound, a compound in which the carboxy group is esterified and amidated (eg, the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pi And the like) and the like, and compounds such as baloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, amidated or methylamidated, and the like.
  • the compounds of the present invention and their pharmacologically acceptable salts can be produced by applying various known synthetic methods, using characteristics based on their basic structures or types of substituents. At that time, depending on the type of functional group, it may be effective in production technology to protect the functional group with an appropriate protecting group at the stage from the raw material to the intermediate.
  • protective groups there can be mentioned, for example, the protective groups described in Greene's Protective Groups in Organic Synthesis (5th Edition, 2014) by PGM Wuts and Greene (TW Greene), and these may be mentioned.
  • the protective groups may be selected appropriately depending on the reaction conditions of (1), and the optimum protective group may be appropriately selected by those skilled in the art.
  • the desired compound can be obtained by removing the protective group as necessary.
  • the prodrug of the compound of the present invention can be produced by introducing a specific group or performing further reaction using the obtained compound at the stage from the raw material to the intermediate, as in the above-mentioned protective group.
  • the reaction can be carried out by applying conventional esterification, amidation, dehydration and the like methods.
  • Each compound of the following methods A to W may be a salt of the compound.
  • hydrochloride or sulfate or the like, or sodium or potassium salt or the like can be mentioned.
  • solvent used in the reaction of each step of methods A to W described below is not particularly limited as long as it partially dissolves the starting material without inhibiting the reaction, and is selected from, for example, the following solvent group Ru.
  • Solvents include aliphatic hydrocarbons such as hexane, pentane, petroleum ether and cyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene; dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene Halogenated hydrocarbons such as: diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethers such as diethylene glycol dimethyl ether; acetone, methyl ethyl ketone, methyl isobutyl ketone, ketones such as cyclohexanone; ethyl a
  • the acid used in the reaction of each step of the following methods A to W is not particularly limited as long as it does not inhibit the reaction, and is selected from the following acid group.
  • the acid group includes inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid and nitric acid, organic acids such as acetic acid, propionic acid, trifluoroacetic acid and pentafluoropropionic acid, and methane It consists of an organic sulfonic acid such as sulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid and camphorsulfonic acid.
  • Base groups include alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; alkali metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; lithium hydroxide and sodium hydroxide , Alkali metal hydroxides such as potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; Alkali metal amides such as lithium amide, sodium amide, potassium amide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide; lithium such as lithium diisopropylamide Alkylamides; Silylamides such as lithium diisopropylamide Alkylamides; Silylamides such as lithium diisopropylamide Alkylamides; Silylamide
  • reaction temperature differs depending on the solvent, starting material, reagent and the like
  • reaction time varies depending on the solvent, starting material, reagent, reaction temperature and the like.
  • the target compound of each step is isolated from the reaction mixture according to a conventional method.
  • the target compound is, for example, (i) optionally filtering off insoluble matter such as a catalyst, and (ii) adding water and a water-immiscible solvent (eg methylene chloride, ethyl acetate etc.) to the reaction mixture.
  • a water-immiscible solvent eg methylene chloride, ethyl acetate etc.
  • the desired compound thus obtained can be further purified, if necessary, by conventional methods (eg, recrystallization, reprecipitation, silica gel column chromatography, etc.).
  • the target compound of each step can also be used for the next reaction without purification.
  • optical isomers by fractional recrystallization using an optically active amine such as (R) or (S) -phenethylamine or separation using an optically active column can be separated and purified.
  • Method A is a method of producing the compound (AV) of the present invention.
  • Step A1 Hydrolysis Reaction
  • the ester portion of compound (AI) is hydrolyzed by adding 1 equivalent or an excess of basic aqueous solution to obtain compound (A-II).
  • the base include inorganic bases such as lithium hydroxide, sodium hydroxide and potassium hydroxide.
  • the solvent is not particularly limited as long as it does not inhibit the reaction, and includes water, methanol, ethanol, tetrahydrofuran, dimethoxyethane, acetonitrile, or a mixture thereof.
  • the reaction temperature is usually about 0 to 60 ° C., and the reaction time is usually 0.5 to 24 hours. This process can be carried out by appropriately selecting reaction conditions described in P.G.M.Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis (5th Edition, 2014).
  • (A2 step) Amidation reaction (When using a condensing agent) In this step, compound (A-II) is amidated using one equivalent or an excess of the desired amine (A-III) and a condensing agent to obtain compound (A-IV).
  • DCC dicyclohexyl carbodiimide
  • EDCI 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • CDI 1,1′-carbonyldiimidazole
  • HATU O- (7-azabenzotriazole- 1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate
  • DTMM Methyl morpholinium chloride
  • the additive examples include N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt) and the like.
  • an organic base such as triethylamine or diisopropylethylamine, or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide, or sodium hydroxide may be advantageous in facilitating the reaction.
  • the solvent is not particularly limited as long as it is inert to the reaction, but N, N-dimethylformamide, dimethylacetamide, dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, or these And the like.
  • the reaction temperature is usually from room temperature to 120 ° C., and the reaction time is usually from 0.5 to 24 hours.
  • compound (A-II) is converted to a reactive derivative and then reacted with the desired amine (A-III) to obtain compound (A-IV).
  • acid halides obtained by reacting with halogenating agents such as oxalyl chloride and thionyl chloride, mixed acid anhydrides obtained by reacting with isobutyl chloroformate and the like, and condensation with 1-hydroxybenzotriazole and the like
  • an organic base such as triethylamine or diisopropylethylamine, or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide, or sodium hydroxide may be advantageous in facilitating the reaction.
  • the solvent any solvent inert to the reaction may be used, and halogenated hydrocarbons, aromatic hydrocarbons, ethers and the like can be mentioned.
  • the reaction temperature is usually ⁇ 20 to 60 ° C., and the reaction time is usually 0.5 to 24 hours.
  • Step A3 Hydrolysis reaction
  • the compound (A-IV) is added to an equal or excess amount of a basic aqueous solution in a solvent, and reacted under cooling or heating for 0.5 to 24 hours to obtain a compound of the present invention AV) is obtained.
  • This step can be carried out in the same manner as step A1.
  • Method B is a method of producing a compound (B-VI) (a compound corresponding to the compound (AI) of the method A).
  • R 1 to R 5 are as defined above, and R represents a C1-C6 alkyl group or a C1-C6 alkylcarbonyl group]
  • Step B1 Deprotection
  • the compound (B-II) is obtained by removing the Boc group from compound (BI) using trimethyliodosilane or 4N hydrochloric acid / 1,4-dioxane solution.
  • the reaction solvent may, for example, be dichloromethane, chloroform, acetonitrile or a mixture thereof.
  • the reaction temperature is usually 0-40 ° C., and the reaction time is usually 0.5-12 hours. Besides these conditions, this step can be carried out by appropriately selecting reaction conditions described in Greene's Protective Groups in Organic Synthesis (5th Edition, 2014) by PGM Wuts and Greene (TW Greene). .
  • Step B2 Deprotection
  • the benzyl group is removed from compound (B-II) using a metal catalyst under a hydrogen atmosphere to obtain compound (B-III).
  • a metal catalyst such as palladium carbon, palladium black, palladium hydroxide, platinum plate such as platinum plate, platinum oxide, nickel catalyst such as reduced nickel or raney nickel, rhodium catalyst such as tris (triphenylphosphine) chlororhodium And iron catalysts such as reduced iron.
  • reaction solvent alcohols such as methanol, ethanol and 2-propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, water, ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide or mixtures thereof It can be mentioned.
  • hydrogen gas it is also possible to use 1 equivalent to excess amount of formic acid or ammonium formate as a hydrogen source with respect to compound (B-II).
  • the reaction temperature is usually about 20 to 150 ° C., and the reaction time is about 1 hour to 5 days. Besides these conditions, this step can be carried out by appropriately selecting reaction conditions described in Greene's Protective Groups in Organic Synthesis (5th Edition, 2014) by PGM Wuts and Greene (TW Greene). .
  • Step B3 Introduction of Substituent to Nitrogen Atom
  • compound (B-IV) is obtained from compound (B-III) using the following method.
  • This step is a step of obtaining compound (B-IV) from compound (B-III) using a corresponding aldehyde and a reducing agent.
  • a reducing agent sodium cyanoborohydride, sodium triacetoxyborohydride, 2-picoline borane and the like can be used.
  • adding a small amount of an acid such as acetic acid, trifluoroacetic acid or hydrochloric acid may give better results.
  • the solvent is not particularly limited as long as it is inactive in the reaction, but alcohols such as methanol and ethanol, ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, halogen solvents such as dichloromethane and dichloroethane, or the like A mixture etc. are mentioned.
  • the reaction temperature is about 0 to 50 ° C., and the reaction time is usually about 0.1 hour to 3 days.
  • This step is a step of obtaining compound (B-IV) from compound (B-III) using an amidation reaction. This step can be carried out in the same manner as step A2.
  • Step B4 O-Alkylation This step is a step of subjecting compound (B-IV) to O-alkylation to obtain compound (B-VI).
  • compound (B-VI) is obtained from compound (B-IV) using alcohol (BV) in the presence of phosphine and azodicarboxylate, azodicarboxamide, or cyanomethylene trialkylphosphorane.
  • phosphine triphenyl phosphine, tri-n-butyl phosphine and the like can be mentioned.
  • Examples of the azodicarboxylate, azodicarboxamide or cyanomethylenetrialkylphosphorane include diethyl azodicarboxylate, di-tert-butyl azodicarboxylate, 1,1′-azobis (N, N-dimethylformamide), 1,1 Examples thereof include (-(azodicarbonyl) dipiperidine, cyanomethylenetributylphosphorane, cyanomethylenetrimethylphosphorane and the like.
  • the reaction solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, toluene, and mixtures thereof.
  • the reaction temperature is usually about 0 to 100 ° C., and the reaction time is usually about 0.5 to 24 hours.
  • Method C is a method of producing a compound (CV) (compound (BI) of Method B).
  • R 4 is as defined above, and R represents a C 1 -C 6 alkyl group or a C 1 -C 6 alkyl carbonyl group
  • Step C1 Deprotection
  • the compound (C-II) is obtained by removing the TBDMS group from compound (CI) using tetrabutylammonium fluoride. Adding acetic acid may give good results.
  • the reaction solvent is not particularly limited as long as it is inert to the reaction, and includes tetrahydrofuran and the like.
  • the reaction temperature is usually 0-70 ° C., and the reaction time is usually about 1 hour to 5 days. Besides these conditions, this step can be carried out by appropriately selecting reaction conditions described in Greene's Protective Groups in Organic Synthesis (5th Edition, 2014) by PGM Wuts and Greene (TW Greene). .
  • This step is a step of obtaining compound (C-III) from compound (C-II) using phosphine and azodicarboxylic acid ester or azodicarboxamide.
  • phosphine triphenyl phosphine, tri-n-butyl phosphine and the like can be mentioned.
  • azodicarboxylates or azodicarboxamides diethyl azodicarboxylate, di-tert-butyl azodicarboxylate, 1,1'-azobis (N, N-dimethylformamide), or 1,1 '-(azodicarbonyl) ) Dipiperidine and the like.
  • the reaction solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, toluene, and mixtures thereof.
  • the reaction temperature is usually about 0 to 100 ° C., and the reaction time is usually about 0.5 to 24 hours.
  • Step C3 Deprotection
  • 4-nitrobenzenesulfonyl group is removed from compound (C-III) using a base, 4-mercaptobenzoic acid to obtain compound (C-IV).
  • the base potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide and the like can be mentioned.
  • the reaction solvent is not particularly limited as long as it is inactive in this reaction, and dichloromethane, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, dimethyl sulfoxide, or a mixture of these, etc. may be mentioned.
  • the reaction time is about 1 hour to 3 days at about 0 to 60 ° C. Besides these conditions, this step can be carried out by appropriately selecting reaction conditions described in P.G.M.Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis (5th Edition, 2014).
  • Step C4 Introduction of Substituent on Nitrogen Atom
  • a substituent is introduced onto the nitrogen atom of the compound (C-IV) to obtain a compound (CV). This step can be carried out in the same manner as step B3.
  • Method D is a method of producing a compound (D-III) (compound (CI) of method C).
  • Step D1 N-Alkylation Reaction
  • compound (D-) is prepared from compound (DI) using 1- [4- (benzyloxy) phenyl] -2-propen-1-one or a derivative thereof in the presence of a base Step II).
  • a base triethylamine, diisopropylethylamine or the like is used. Ethanol or the like is used as a reaction solvent, the reaction temperature is usually 20 to 70 ° C., and the reaction time is usually 1 hour to 3 days.
  • Step D2 Asymmetric Reduction This step is a step of obtaining compound (D-III) from compound (D-II) using an asymmetric reducing agent.
  • an asymmetric reducing agent optically active oxazaborolidins such as (S) or (R) -5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine Cory-Baxe-Muta reducing agent prepared from C. and Borane.
  • the asymmetric reducing agent is appropriately selected by those skilled in the art according to the stereochemistry of the desired compound. These variations can also be used in this step as required.
  • the asymmetric reducing agent in this step is preferably prepared from (R) -5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine and dimethyl sulfide borane.
  • the solvent is not particularly limited as long as it is inert to the reaction, and includes tetrahydrofuran, toluene, dichloromethane, or a mixture thereof.
  • the reaction temperature is usually ⁇ 78 to 60 ° C., and the reaction time is about 0.5 to 24 hours.
  • Method D ′ is a method of producing compound (D′-VI) (compound (BI) of method B).
  • R 4 is as defined above, and R represents a C 1 -C 6 alkyl group or a C 1 -C 6 alkyl carbonyl group
  • Step D′ 1 N-Alkylation Reaction This step uses 1- [4- (benzyloxy) phenyl] -2-propen-1-one or a derivative thereof from compound (D′-I) in the presence of a base The step is to obtain a compound (D'-II). This step can be performed in the same manner as step D1.
  • Step D′ 2 Introduction of Substituent on Nitrogen Atom
  • a substituent is introduced from the compound (D′-II) onto the nitrogen atom to obtain a compound (D′-III).
  • This step can be carried out in the same manner as step B3.
  • Step D′ 3 Asymmetric Reduction This step is a step of obtaining compound (D′-IV) from compound (D′-III) using an asymmetric reducing agent. This step can be carried out in the same manner as step D2.
  • Step D′ 4 Deprotection In this step, the protective group is removed from compound (D′-IV) to give compound (D′-V). This step can be performed in the same manner as step C1.
  • Step D'5 Cyclization reaction This step is a step of obtaining compound (D'-VI) from compound (D'-V) using a phosphine and an azodicarboxylic acid ester or azodicarboxamide. This step can be performed in the same manner as step C2.
  • Method E is a method of producing a compound (E-VI) (a mixture of stereoisomers of a compound corresponding to the compound (AI) of the method A).
  • R 1 to R 5 are as defined above, and R represents a C1-C6 alkyl group or a C1-C6 alkylcarbonyl group]
  • Step E1 Deprotection
  • the Boc group is removed from compound (EI) to obtain compound (E-II).
  • This process can be performed by the method similar to B1 process.
  • Step E2 Introduction of Substituent to Nitrogen Atom
  • a substituent is introduced from the compound (E-II) onto the nitrogen atom to obtain a compound (E-III).
  • This process can be performed by the method similar to said B3 process.
  • Step E3 Deprotection
  • compound (E-IV) is obtained from compound (E-III) using a palladium catalyst and a nucleophile.
  • a palladium catalyst tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium, tris (dibenzylideneacetone) dipalladium, palladium acetate, palladium acetate, acetylacetone palladium, or bis (triphenyl) Phosphine) palladium dichloride and the like.
  • reaction solvent is not particularly limited as long as it is inert to the reaction, but tetrahydrofuran, N, N-dimethylformamide, dichloromethane, a mixture thereof or the like can be used.
  • the reaction temperature is usually about 20 to 100 ° C., and the reaction time is about 0.5 to 24 hours.
  • this step can be carried out by appropriately selecting reaction conditions described in P.G.M.Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis (5th Edition, 2014).
  • Step E4 O-Alkylation This step is a step for obtaining compound (E-VI) by subjecting compound (E-IV) to O-alkylation. This step can be carried out in the same manner as step B4.
  • Method F is a method of producing a compound (FV) (compound (EI) of method E).
  • R 4 is as defined above, and R represents a C 1 -C 6 alkyl group or a C 1 -C 6 alkyl carbonyl group
  • Step F1 Deprotection
  • the protective group is removed from compound (FI) to obtain compound (F-II).
  • This step can be performed in the same manner as step C1.
  • Step F2 Cyclization reaction
  • compound (F-III) is obtained from compound (F-II) using (cyanomethylene) trialkylphosphorane, or phosphine and azodicarboxylic acid ester or azodicarboxamide to obtain compound (F-III).
  • (cyanomethylene) trialkylphosphoranes include (cyanomethylene) trimethylphosphorane, (cyanomethylene) tributylphosphorane and the like.
  • phosphine triphenyl phosphine, tri-n-butyl phosphine and the like can be mentioned.
  • reaction solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, toluene, and mixtures thereof.
  • the reaction temperature is usually about 0 to 100 ° C., and the reaction time is usually about 0.5 to 24 hours.
  • Step F3 Deprotection
  • compound (F-IV) is obtained by removing 4-nitrobenzenesulfonyl group from compound (F-III). This step can be carried out in the same manner as step C3.
  • Step F4 Introduction of Substituent on Nitrogen Atom
  • a substituent is introduced from the compound (F-IV) onto the nitrogen atom to obtain a compound (FV).
  • This process can be performed by the method similar to said B3 process.
  • Method G is a method of producing a compound (GV) (compound (FI) of Method F).
  • Step G1 O-Alkylation This step is a step of obtaining compound (G-III) from compound (GI) by O-alkylation using compound (G-II). This step can be carried out in the same manner as step B4.
  • Step G2 Reduction of Nitro Group
  • This step is a step of obtaining compound (G-IV) from compound (G-III) using iron powder and ammonium chloride.
  • a reaction solvent ethanol, water, acetic acid or the like can be used.
  • the reaction temperature is usually about 0 to 150 ° C., and the reaction time is about 1 hour to 3 days.
  • Step G3 Introduction of Protecting Group
  • This step is a step of obtaining compound (GV) from compound (G-IV) using pyridine and 4-nitrobenzenesulfonyl chloride.
  • the reaction solvent is not particularly limited as long as it is inert to the reaction, but tetrahydrofuran, dichloromethane or the like can be used.
  • the reaction temperature is usually about 20 to 60 ° C., and the reaction time is usually about 0.5 to 24 hours. Besides these conditions, this step can be carried out by appropriately selecting reaction conditions described in Greene's Protective Groups in Organic Synthesis (5th Edition, 2014) by PGM Wuts and Greene (TW Greene). .
  • Method H is a method of producing a compound (H-IV) (compound of method G (G-II)). [Wherein, R 4 represents the same as the above]
  • This step is a step of obtaining compound (H-II) from compound (HI) using diethyl carbonate in the presence of a base.
  • a base sodium hydride, lithium diisopropylamide and the like can be mentioned.
  • the reaction solvent is not particularly limited as long as it is inert to the reaction, and includes tetrahydrofuran and the like.
  • the reaction temperature is usually about 0 to 70 ° C., and the reaction time is usually about 1 hour to 3 days.
  • Step H2 Reduction Reaction
  • This step is a step of obtaining compound (H-III) from compound (H-II) using a reducing agent.
  • a reducing agent sodium borohydride, lithium borohydride and the like can be mentioned.
  • the reaction solvent may, for example, be methanol, ethanol, water, tetrahydrofuran or a mixture thereof.
  • the reaction temperature is usually 0-70 ° C., and the reaction time is usually 0.5-24 hours.
  • Step H3 Introduction of Protecting Group
  • This step is a step of obtaining compound (H-IV) from compound (H-III) using tert-butyldiphenylchlorosilane in the presence of imidazole and 4-dimethylaminopyridine.
  • this step can be carried out by appropriately selecting reaction conditions described in P.G.M.Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis (5th Edition, 2014).
  • Method I comprises compound (I-IV) (compound (BV) of method B, compound (EV) of method E, compound (K-VI) of method K, compound (O-III) of method O, compound of method P (PI), a compound of the Q method (Q-II) or a compound of the S method (S-II) or a compound (IV) (compound of the S method (S-II)).
  • R 1 to R 3 are as defined above, and L is a halogen, a methanesulfonyloxy group or a p-toluenesulfonyloxy group]
  • Step I1 Condensation reaction
  • This step is a step of obtaining compound (I-II) from compound (II) using N, O-dimethylhydroxylamine hydrochloride and a condensing agent in the presence of a base.
  • the base include triethylamine, diisopropylethylamine and the like.
  • the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), 1,1′-carbonyldiimidazole (CDI) and the like.
  • the reaction solvent is not particularly limited as long as it is inert to the reaction, but N, N-dimethylformamide, dimethylacetamide, dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, or these And the like.
  • the reaction temperature is usually from room temperature to 120 ° C., and the reaction time is usually from 0.5 to 24 hours.
  • Step I2 Addition of Organometallic Reagent
  • This step is a step of obtaining Compound (I-III) from Compound (I-II) using the corresponding organometallic reagent (R 2 -M; M represents a metal).
  • the reaction solvent is not particularly limited as long as it is inert to the reaction, and examples include diethyl ether, tetrahydrofuran, toluene and the like.
  • the reaction temperature is usually about ⁇ 78 to 60 ° C., and the reaction time is 0.5 to 24 hours.
  • This step is a step of obtaining compound (I-IV) from compound (I-III) using any one of the following two steps.
  • an asymmetric reducing agent optically active oxazaborolidins such as (S) or (R) -5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine Cory-Baxe-Muta reducing agent prepared from C. and Borane.
  • This step can be carried out in the same manner as step D2 (step for obtaining a tertiary alcohol (when R 3 CC 1 -C 6 alkyl group))
  • This step is a step of obtaining compound (I-IV) from compound (I-III) using an organometallic reagent (R 3 -M; M represents a metal).
  • This step can be carried out in the same manner as step I2.
  • Step I4 Halogenation or sulfonylation (sulfonylation)
  • This step is a step of obtaining compound (IV) from compound (I-IV) using a sulfonylation reagent in the presence of a base.
  • the base include pyridine, 4-dimethylaminopyridine, triethylamine, or diisopropylethylamine.
  • a sulfonylation reagent methanesulfonyl chloride, p-toluenesulfonyl chloride and the like can be mentioned.
  • the reaction solvent is not particularly limited as long as it is inert to the reaction, and includes tetrahydrofuran, dichloromethane, 1,2-dichloroethane and the like.
  • the reaction temperature is usually about ⁇ 78 to 60 ° C., and the reaction time is about 0.5 to 24 hours.
  • (Halogenated) This step is a step of obtaining compound (IV) from compound (I-IV) using a halogenating reagent.
  • the halogenation reagent can include carbon tetrabromide, N-bromosuccinimide or bromine, and a combination of triphenylphosphine.
  • the reaction solvent includes acetonitrile, dichloromethane, dichloroethane and the like.
  • the reaction temperature is usually about ⁇ 40 to 50 ° C., and the reaction time is about 0.5 to 24 hours.
  • Method J comprises compound (J-II) (compound (BV) of method B, compound (EV) of method E, compound (K-VI) of method K, compound (O-III) of method O, compound of method P (PI), a compound of the Q method (Q-II) or a compound of the S method (S-II) or a compound (J-III) (the compound of the S method (S-II)).
  • R 1 to R 3 are as defined above, and L is a halogen, a methanesulfonyloxy group or a p-toluenesulfonyloxy group]
  • Step J1 Addition of Organometallic Reagent
  • This step is a step of obtaining compound (J-II) from compound (JI) using an organometallic reagent. This step can be carried out in the same manner as step I2.
  • Step J2 Halogenation or Sulfonylation
  • This step is a step of obtaining compound (J-III) from compound (J-II) using a sulfonylating reagent in the presence of a halogenating reagent or a base. This step can be carried out in the same manner as step I4.
  • Method K is a method of producing a compound (K-VII) (a compound corresponding to the compound (AI) of the method A).
  • R 1 to R 5 are as defined above, and R is a C 1 -C 6 alkyl group or a C 1 -C 6 alkyl carbonyl group.
  • Step K1 Deprotection
  • the compound (K-II) is obtained by removing the Boc group from the compound (KI). This process can be performed by the method similar to B1 process.
  • Step K2 Introduction of Substituent on Nitrogen Atom
  • a substituent is introduced from the compound (K-II) onto the nitrogen atom to obtain a compound (K-III).
  • This process can be performed by the method similar to said B3 process.
  • Step K3 Deprotection
  • the 2-nitrobenzenesulfonyl group is removed from compound (K-III) to obtain compound (K-IV).
  • This step can be carried out in the same manner as step C3.
  • Step K4 Introduction of Substituent on Nitrogen Atom
  • a substituent is introduced from the compound (K-IV) onto the nitrogen atom to obtain a compound (KV).
  • This step can be carried out in the same manner as step B3.
  • Step K5 O-Alkylation This step is a step of subjecting compound (KV) to O-alkylation to obtain compound (K-VII). This step can be carried out in the same manner as step B4.
  • Method L is a method of producing a compound (LV) (a compound (KI) of Method K).
  • Step L1 Alkylation Reaction This step is a step of obtaining compound (L-II) from compound (LI) using a 2-bromo-1- (4-hydroxyphenyl) ethanone derivative in the presence of a base.
  • the base include triethylamine, diisopropylethylamine, potassium carbonate and the like.
  • the reaction solvent is not particularly limited as long as it is inert to the reaction, but tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, N, N-dimethylformamide, or a mixture thereof can be mentioned.
  • the reaction temperature is usually about 0 to 100 ° C., and the reaction time is usually about 0.5 to 24 hours.
  • Step L2 Asymmetric Reduction This step is a step of obtaining compound (L-III) from compound (L-II) using an asymmetric reducing agent. This step can be carried out in the same manner as step D2.
  • Step L3 Deprotection In this step, the protective group is removed from compound (L-III) to give compound (L-IV). This step can be performed in the same manner as step C1.
  • step 4 cyclization reaction (Mitsunobu reaction) This step is a step of obtaining compound (LV) from compound (L-IV) using phosphine and azodicarboxylic acid ester or azodicarboxamide. This step can be performed in the same manner as step C2.
  • Method M is a method of producing a compound (M-IV) (a compound corresponding to the compound (AI) in the method A).
  • R 1 to R 5 are as defined above, and R is a C1-C6 alkyl group.
  • Step M1 Removal of Protecting Group This step is a step of removing the protecting group from compound (MI) to obtain compound (M-II). This step can be carried out in the same manner as step E3.
  • Step M2 Introduction of Substituent on Nitrogen Atom
  • a substituent is introduced from the compound (M-II) onto the nitrogen atom to obtain a compound (M-III).
  • This process can be performed by the method similar to said B3 process.
  • (M3 step) Reductive reaction of amide group This step is carried out from compound (M-III) with diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinecarboxylate (Hantzsch ester) and trifluoromethanesulfonic anhydride
  • the step is to obtain a compound (M-IV) using
  • the reaction solvent is not particularly limited as long as it is inert to the reaction, and examples include diethyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, dichloromethane, chloroform, or a mixture thereof.
  • the reaction temperature is usually about ⁇ 20 ° C. to 100 ° C., and the reaction time is about 0.5 to 24 hours.
  • Method N is a method of producing compound (N-IV) (compound of method M (MI)).
  • R 1 to R 4 are as defined above, and R is a C 1 -C 6 alkyl group.
  • Step N1 Amidation Reaction This step is a step of obtaining compound (N-III) from compound (NI) using a condensing agent in the presence of a base. This step can be performed under the same conditions as step A2.
  • N2 step cyclization reaction (Mitsunobu reaction)
  • This step is a step of obtaining compound (N-IV) from compound (N-III) using phosphine and azodicarboxylic acid ester or azodicarboxamide. This step can be performed in the same manner as step C2.
  • Method O is a method of producing a compound (O-VI) (compound (N-II) of Method N).
  • R 1 to R 4 are as defined above, and R represents the above C 1 -C 6 alkyl group.
  • Step O1 Alkylation
  • C1-C6 alkylamine (R-NH 2 ) with 2-bromo-1- (4-hydroxyphenyl) ethanone derivative (OI) in the presence of a base
  • N-trifluoroacetylation is carried out using trifluoroacetic anhydride to obtain a compound (O-II).
  • the base include triethylamine, diisopropylethylamine and the like.
  • the reaction solvent is not particularly limited as long as it is inert to the reaction, and includes tetrahydrofuran, 1,4-dioxane, dichloromethane, or a mixture thereof.
  • the reaction temperature is usually about 0 to 60 ° C., and the reaction time is usually about 0.5 to 12 hours.
  • Step O2 O-Alkylation This step is a step of subjecting compound (O-II) to O-alkylation to obtain compound (O-IV). This step can be carried out in the same manner as step B4.
  • Step O3 Asymmetric Reduction This step is a step of obtaining compound (OV) from compound (O-IV) using an asymmetric reducing agent. This step can be carried out in the same manner as step D2.
  • the asymmetric reducing agent (R) -5,5-diphenyl-2-methyl-3,4-propano-1,3,2 is preferably used. -Prepared from oxazaborolidine and dimethyl sulfide borane.
  • Step O4 Deprotection This step is a step of obtaining compound (O-VI) from compound (OV) using an alkaline aqueous solution.
  • the alkali include inorganic bases such as potassium carbonate and sodium carbonate.
  • the solvent is not particularly limited as long as it does not inhibit the reaction, and methanol, ethanol, tetrahydrofuran, dimethoxyethane, acetonitrile, or a mixture of these, and the like can be mentioned.
  • the reaction temperature is usually about 20 to 100 ° C., and the reaction time is usually 0.5 to 12 hours. This process can be carried out by appropriately selecting reaction conditions described in P.G.M.Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis (5th Edition, 2014).
  • Method P is a method of producing a compound (P-II) (optically active alcohol (I-IV) or (J-II)).
  • (P1 step) Optical resolution
  • compound (PI) is condensed with an optically active amino acid derivative to convert it into the corresponding ester, and the obtained diastereomer is separated by chromatography, and the desired stereochemistry is obtained.
  • the step is to obtain an optically active compound (P-II) by hydrolyzing the ester.
  • the optically active amino acid derivative preferably includes L-form or D-form N-Boc proline.
  • the esterification reaction in this step can be carried out using a general condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), 1,1'-carbonyldiimidazole (CDI), etc. .
  • an organic base such as 4-dimethylaminopyridine may be advantageous in order to allow the reaction to proceed smoothly.
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction, but N, N-dimethylformamide, dimethylacetamide, dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, Or a mixture of these.
  • the reaction temperature is usually from room temperature to 120 ° C., and the reaction time is usually from 0.5 to 24 hours.
  • the hydrolysis reaction in this step can use one equivalent or an excess of basic aqueous solution, and as a base, lithium hydroxide, sodium hydroxide, potassium hydroxide And inorganic bases such as
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction, and methanol, ethanol, tetrahydrofuran, dimethoxyethane, acetonitrile, or a mixture thereof, and the like can be mentioned.
  • the reaction temperature is usually about 0 to 60 ° C., and the reaction time is usually about 0.5 to 12 hours.
  • Method Q is a method of producing a compound (QV) (a compound corresponding to the compound (AI) in the method A).
  • Step Q1 O-Alkylation This step is a step of subjecting compound (QI) to O-alkylation to obtain compound (Q-III). This step can be carried out in the same manner as step B4.
  • Step Q2 Deprotection In this step, the Boc group of compound (Q-III) is removed to obtain compound (Q-IV). This step can be carried out in the same manner as step B1.
  • Step Q3 Introduction of Substituent on Nitrogen Atom
  • a substituent is introduced from the compound (Q-IV) onto the nitrogen atom to obtain a compound (QV).
  • This process can be performed by the method similar to said B3 process.
  • Method R is a method of producing a compound (R-IV) (compound (QI) of Method Q).
  • Step R1 Addition Reaction to Alkyne
  • a desired arylboronic acid from compound (RI) in the presence of a base in the formula, 4- (benzyloxy) phenylboronic acid in which a phenyl group is substituted with a substituent R 4
  • a base in the formula, 4- (benzyloxy) phenylboronic acid in which a phenyl group is substituted with a substituent R 4
  • rhodium catalyst examples include hydroxy (cyclooctadiene) rhodium (I) dimer, chloro (1,5-cyclooctadiene) rhodium (I) dimer, acetylacetonatobis (ethylene) rhodium (I) and the like.
  • a phosphine ligand 1,3-bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane, 1,1′-bis (diphenylphosphino) ferrocene, 2,2′-bis ( Diphenylphosphino) -1,1'-binaphthalene and the like can be mentioned.
  • the base examples include inorganic bases such as sodium carbonate, potassium carbonate, lithium hydroxide and sodium hydroxide.
  • the reaction solvent is not particularly limited as long as it does not inhibit the present reaction, and includes 1,4-dioxane, 1,2-dimethoxyethane, water, toluene or a mixture thereof.
  • the reaction temperature is usually about 20 to 100 ° C., and the reaction time is usually about 1 to 24 hours.
  • Step R2 Deprotection and Hydrogenation
  • a compound (R-III) is obtained by removing a benzyl group and hydrogenating an olefin from compound (R-II) using a metal catalyst under a hydrogen atmosphere. It is.
  • This step can be carried out in the same manner as step B2.
  • step 3 cyclization reaction
  • This step is a step of obtaining compound (R-IV) from compound (R-III) using phosphine and azodicarboxylic acid ester or azodicarboxamide. This step can be performed in the same manner as step C2.
  • Method S is a method of producing a compound (SV) (a compound corresponding to the compound (AI) in the method A).
  • R 1 to R 5 are as defined above, and L is a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group]
  • Step S1 O-alkylation (when using Mitsunobu reaction)
  • This step is a step of subjecting compound (SI) to O-alkylation using alcohol (S-II) to obtain compound (S-III).
  • This step can be carried out in the same manner as step B4.
  • This step is a step of subjecting compound (SI) to O-alkylation using alkylation reagent (S-II ') in the presence of a base to obtain compound (S-III).
  • alkylation reagent alkylsulfonic acid esters prepared by Method I or Method J can be used.
  • organic bases such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate and sodium carbonate can be used.
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction, but tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, N, N-dimethylformamide, dimethyl sulfoxide, or a mixture thereof may be mentioned.
  • the reaction temperature is usually about 0 to 100 ° C., and the reaction time is usually about 0.5 to 24 hours.
  • Step S2 Deprotection This step is a step of removing a Boc group from compound (S-III) to obtain compound (S-IV). This step can be carried out in the same manner as step B1.
  • Step S3 Introduction of Substituent on Nitrogen Atom
  • a substituent is introduced from the compound (S-IV) onto the nitrogen atom to obtain a compound (SV).
  • This process can be performed by the method similar to said B3 process.
  • Method T is a method of producing a compound (TV) (compound (SI) of method S).
  • Step T1 Coupling Reaction
  • Metal catalysts include palladium catalysts or nickel catalysts.
  • a palladium catalyst tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium, tris (dibenzylideneacetone) dipalladium, palladium acetate, palladium acetate, acetylacetone palladium, or bis (triphenyl) Phosphine) palladium dichloride and the like
  • the nickel catalyst include [1,1′-bis (diphenylphosphino) ferrocene] nickel dichloride, or bis (triphenylphosphine) nickel dichloride and the like.
  • the addition of lithium chloride may give good results.
  • the organozinc reagent is obtained from zinc powder activated with iodine or trimethyl chloride chloride and the like and alkyl iodide (T-II).
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction, but tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, toluene or the like A mixture etc. are mentioned.
  • the reaction temperature is usually about 20 to 150 ° C., and the reaction time is usually about 1 hour to 3 days.
  • Step T2 Deprotection This step is a step of removing a benzyl group from compound (T-III) using a metal catalyst under a hydrogen atmosphere to obtain compound (T-IV). This step can be carried out in the same manner as step B2.
  • Step T3 Cyclization reaction This step is a step of obtaining compound (TV) from compound (T-IV) using phosphine and azodicarboxylic acid ester or azodicarboxamide. This step can be performed in the same manner as step C2.
  • Method U is a method of producing compound (UV) (compound of method T (T-II)).
  • Step U1 Introduction of Asymmetric Auxiliary Group
  • This step is a step of introducing an asymmetric auxiliary group into a compound (UI) to obtain a compound (U-II).
  • the compound (UI) is first converted to the corresponding acid chloride with catalytic amounts of N, N-dimethylformamide and oxalyl chloride in dichloromethane.
  • the reaction temperature is about 20 to 40 ° C., and the reaction time is about 1 to 12 hours.
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction, but is preferably tetrahydrofuran or the like, and the reaction time is usually about 0.5 to 12 hours.
  • Step U2 Alkylation Reaction
  • This step is a step of obtaining compound (U-III) from compound (U-II) using 2- (benzyloxy) ethyl trifluoromethanesulfonate in the presence of a base.
  • a base sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, lithium diisopropylamide and the like are used.
  • the reaction solvent is not particularly limited as long as it does not inhibit the present reaction, and examples thereof include diethyl ether and tetrahydrofuran.
  • the reaction temperature is usually about ⁇ 78 to 20 ° C., and the reaction time is about 0.5 to 12 hours.
  • Step U3 Removal of Asymmetric Auxiliary Group
  • This step is a step of obtaining compound (U-IV) from compound (U-III) using a reducing agent.
  • the reducing agent include lithium aluminum hydride and lithium borohydride.
  • the reaction solvent is not particularly limited as long as it does not inhibit this reaction, and methanol, ethanol, water, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, or a mixture thereof, and the like can be mentioned.
  • the reaction temperature is usually about 0 to 60 ° C., and the reaction time is usually about 1 to 24 hours.
  • Step U4 Iodination This step is a step of obtaining a compound (UV) from compound (U-IV) using an iodination reagent and triphenylphosphine in the presence of a base.
  • a base include imidazole, pyridine and the like.
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include diethyl ether, acetonitrile, dichloromethane, hexane, toluene, N, N-dimethylformamide or a mixture thereof.
  • the reaction temperature is usually about 0 to 100 ° C., and the reaction time is usually about 1 to 24 hours.
  • Method V is a method of producing compound (V-III) (compound (A-III) of method A).
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction, but methanol, ethanol, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, water, N, N-dimethylformamide, dimethyl sulfoxide, benzene And toluene, xylene, and mixtures thereof.
  • a palladium catalyst As a palladium catalyst, tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium, tris (dibenzylideneacetone) dipalladium, palladium acetate, palladium acetate, acetylacetone palladium, or bis (triphenyl) Phosphine) palladium dichloride and the like.
  • the nickel catalyst include [1,1′-bis (diphenylphosphino) ferrocene] nickel dichloride, or bis (triphenylphosphine) nickel dichloride.
  • organic bases such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), or 1,5-diazabicyclo [4.3.0] -5-nonene (DBN) as a base
  • inorganic bases such as potassium hydrogen carbonate, sodium hydrogen carbonate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium phosphate, or sodium phosphate.
  • the reaction temperature is usually about 20 to 150 ° C., and the reaction time is about 1 hour to 2 days.
  • Step V2 Deprotection
  • the protective group is removed from compound (V-II) to obtain compound (V-III) or a salt thereof.
  • Various conditions can be applied depending on the protecting group used.
  • the reaction can be carried out by appropriately selecting the reaction conditions described in P.G.M.Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis (5th Edition, 2014).
  • Method W is a method of producing a compound (WV).
  • R 6 to R 7 are as defined above, and X is a halogen atom
  • Step W1 Cross Coupling Reaction This step is a step of obtaining a compound (W-II) from a compound (WI) using a coupling reaction. This process can be carried out in the same manner as the V1 process.
  • Step W2 Sandmeyer Reaction
  • This step is a step of obtaining a compound (W-III) from a compound (W-II) using nitrite or nitrite and a copper salt.
  • nitrites or nitrites include sodium nitrite, tert-butyl nitrite and isoamyl nitrite.
  • Copper salts include copper (II) bromide and the like.
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction, and methanol, ethanol, water, acetonitrile, a mixture thereof, and the like can be mentioned.
  • the reaction temperature is usually about 0 to 80 ° C., and the reaction time is usually about 0.5 to 24 hours.
  • Step W3 Cross Coupling
  • compound (W-IV) is obtained from compound (W-III) using an organozinc compound and a metal catalyst.
  • Organozinc compounds can be prepared from methyl (2R) -2- (tert-butoxycarbonylamino) -3-iodopropionate. This process can be carried out in the same manner as the T1 process.
  • Step W4 Deprotection
  • the compound (WV) or a salt thereof is obtained by removing the Boc group from the compound (W-IV). This step can be carried out in the same manner as step B1.
  • Administration is orally administered by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intraarticular, intravenous or intramuscular injections, suppositories, eye drops, eye ointments, solutions for transdermal use, It may be in any form of parenteral administration by ointment, transdermal patch, transmucosal liquid preparation, transmucosal patch, inhalant and the like.
  • solid compositions for oral administration tablets, powders, granules and the like are used.
  • Such solid compositions comprise one or more active ingredients and at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl piriddon And / or magnesium aluminometasilicate and the like.
  • the composition may contain an inert additive such as a lubricant such as magnesium stearate or a disintegrant such as sodium carboxymethyl starch or the like, a stabilizer and a solubilizer according to a conventional method.
  • the tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance, if necessary.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water Or contains ethanol.
  • the liquid composition may contain, in addition to inert diluents, solubilizers, wetting agents, adjuvants such as suspending agents, sweetening agents, flavoring agents, fragrances, preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions.
  • Aqueous solvents include, for example, distilled water for injection or physiological saline.
  • Nonaqueous solvents include, for example, vegetable oils such as propylene glycol, polyethylene glycol or olive oil, alcohols such as ethanol, or Polysorbate 80.
  • Such compositions may further comprise tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers or solubilizers. These are sterilized, for example, by filtration through a bacteria retention filter, formulation of germicides or irradiation. They can also be used to prepare sterile solid compositions and be dissolved or suspended in sterile water or sterile injectable solvent prior to use.
  • the external preparation includes ointments, plasters, creams, jellies, patches, sprays, lotions, eye drops, eye ointments and the like.
  • These dosage forms contain generally used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions and the like.
  • ointment or lotion base polyethylene glycol, propylene glycol, white petrolatum, bleached beeswax, polyoxyethylene hydrogenated castor oil, glycerin monostearate, stearyl alcohol, cetyl alcohol, lauro macrogol, sorbitan sesquioleate, etc. Can be mentioned.
  • Transmucosal agents such as inhalants and transnasal agents are used in solid, liquid or semi-solid form, and can be produced according to conventionally known methods. For example, known excipients, pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be added as appropriate. Administration can use devices for appropriate inhalation or insufflation. For example, the compounds may be administered alone or as a powder of a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using known devices and nebulizers, such as metered dose inhalation devices. be able to.
  • the dry powder inhaler or the like may be for single or multiple administration, and dry powder or powder-containing capsules can be used.
  • it may be in the form of a suitable aerosol, such as a pressurized aerosol spray using a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
  • the daily dose is suitably about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, and more preferably 0.1 to 10 mg / kg of body weight. It is given once or in two or more divided doses.
  • the appropriate daily dose is about 0.0001-10 mg / kg of body weight, which is administered once or several times a day.
  • about 0.001 to 100 mg / kg of body weight is administered in one or more divided doses a day. The dose is appropriately determined depending on the individual case in consideration of symptoms, age, sex and the like.
  • combination In the present invention, it can be used in combination with various therapeutic or preventive agents for diseases which are considered to show its efficacy.
  • the combination may be administered simultaneously, or separately separately, continuously, or at desired time intervals.
  • Co-administered formulations may be formulated or formulated separately.
  • Powder Powder A powder is obtained by mixing 5 g of the compound of the present invention or a pharmacologically acceptable salt thereof, 895 g of lactose and 100 g of corn starch in a blender.
  • Formulation Example 2 Granules After mixing 5 g of the compound of the present invention or a pharmacologically acceptable salt thereof, 865 g of lactose and 100 g of low substituted hydroxypropyl cellulose, 300 g of a 10% aqueous solution of hydroxypropyl cellulose is added thereto. Mix up. This is granulated using an extrusion granulator and dried to obtain granules.
  • Formulation Example 3 Tablet A tableting machine after mixing 5 g of the compound of the present invention or a pharmacologically acceptable salt thereof, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate in a blender. The tablet is obtained by tableting with
  • the cells were cultured overnight in an incubator at 37 ° C., 95% O 2 , 5% CO 2 , the medium was removed, and Hanks' Balanced Salt solution (HBSS) (LIFE TECHNOLOGIES) medium (final concentration 100 ⁇ L)
  • HBSS Hanks' Balanced Salt solution
  • the compounds were treated on cells in 100 ⁇ M PDE inhibitors IBMX, 0.1% BSA, 1% DMSO) and cultured in an incubator for 1 hour.
  • the cAMP was quantified by reading the chemiluminescence signal by the Rubystar using a competitive immunoassay (cAMP-Gs HiRange kit, Cisbio) based on HTRF® technology.
  • the EC50 of each compound was determined from the analysis of chemiluminescence, and the Emax was determined using a dose response curve of GLP-1.
  • Table 1 shows the average EC50 (nM) and Emax (%) of the example compounds.
  • the specificity of the GLP-1 receptor agonist for the GLP-1 receptor was confirmed by performing the same evaluation using human glucagon receptor and GIP receptor.
  • mice feeding suppression test (1) Animal Used A commercially available mouse (C57BL / 6N mouse, male, 8 to 10 weeks old when used, sold by Japan Charles River Co., Ltd.) was used.
  • test compound (example compound, comparative compound 1 (compound described in WO2009 / 111700) or comparative compound 2 (compound described in WO2010 / 114824 example 216) is 0.5% methylcellulose (Wako Pure Chemical Industries, Ltd.) Company) or a mixed solution of sodium carbonate and sodium hydrogen carbonate, and prepared by adding polyethylene glycol 400 and Tween 80 as needed.
  • the prepared administration solutions control group (administered vehicle without test compound) and test compound group) were orally administered orally to 5 to 6 mice in each group. Thirty minutes after administration of the test compound, the motorized shutter was opened, and the amount of food consumed for 24 hours after refeeding was measured and analyzed by the software for controlling feeding and measuring the amount of food intake.
  • the compound of the present invention exhibits a remarkable antifeedant effect. Therefore, the compound of the present invention or a pharmacologically acceptable salt thereof can be administered to mammals (particularly humans) for the purpose of preventing or treating obesity, and is useful as a medicine.
  • mice Female oral glucose tolerance test (1) Animals used Commercially available mice (C57BL / 6N mice, male, 7 to 9 weeks old at the time of use, sold by Japan Charles River Co., Ltd.) were used.
  • test compound (Example compound, Comparative compound 1 or Comparative compound 2) was prepared using 0.5% methylcellulose (Wako Pure Chemical Industries, Ltd.) or a mixed solution of sodium carbonate and sodium hydrogen carbonate and, if necessary, polyethylene glycol 400 and Tween 80. It prepared by adding.
  • the dose of the prepared solution was 50 mg / kg for the example compound against each of 5 to 6 mice in each group, and comparative compound 1 and comparison Compound 2 was orally administered at 200 mg / kg, respectively.
  • the glucose load was orally administered at a dose of 2 g / kg of glucose solution (Otsuka sugar solution) 30 minutes after administration of the test compound.
  • the compound of the present invention exhibits a remarkable hypoglycemic action. Therefore, the compound of the present invention or a pharmacologically acceptable salt thereof can be administered to mammals (particularly humans) for the purpose of preventing or treating diabetes, and is useful as a medicine.
  • diethyl carbonate (340 ⁇ L, 2.84 mL) and sodium hydride (60 wt%, 136 mg, 3.12 mmol) were added, and the mixture was stirred at room temperature for 4 hours.
  • Saturated aqueous ammonium chloride solution was added to the reaction solution, and extracted with ethyl acetate ( ⁇ 2).
  • the organic layer was combined and washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure.
  • the reaction solution was diluted with ethyl acetate and the insoluble matter was filtered off.
  • the filtrate was washed with saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with ethyl acetate.
  • the organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure.
  • reaction solution is filtered through Celite, the solvent is evaporated under reduced pressure, the obtained residue is suspended in ethyl acetate / diethyl ether, collected by filtration, and 1.01 g of the title compound (yield 96%) as a white solid Got as.
  • the reaction solution was allowed to cool to room temperature, methylene chloride (500 mL) and paraformaldehyde (12.6 g, 0.42 mol) were added, and the mixture was stirred at room temperature for 2 hours.
  • the solvent was distilled off under reduced pressure and trifluoroacetic acid was removed azeotropically using ethyl acetate.
  • the obtained residue was suspended in ethyl acetate (300 mL) and water (200 mL), and sodium bicarbonate (58 g, 0.70 mol) was gradually added to neutralize. Then, di-tert-butyl dicarbonate (38 mL, 0.17 mol) was added and stirred at room temperature for 16 hours.
  • reaction mixture was diluted with ethyl acetate / n-hexane, washed with water and saturated brine, and dried over sodium sulfate.
  • aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain an oxime intermediate as a colorless oil .
  • a solution of the obtained oxime intermediate in acetic acid (102 mL) was heated to 40 ° C., finely ground zinc powder (16.0 g, 244 mmol) was divided into 4 portions, added over 10 minutes, and further 20 minutes at 40 ° C. Heated.
  • the reaction solution was diluted with ethyl acetate and poured into ice-cold aqueous ammonia solution.
  • reaction solution was allowed to cool to room temperature, the insoluble matter was filtered off, and the solvent was evaporated under reduced pressure.
  • the residue was dissolved in ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 806 mg of the title compound (quantitative) as a colorless amorphous substance .
  • the reaction solution was diluted with methylene chloride, the organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • reaction solution was cooled to room temperature, diluted with ethyl acetate, saturated aqueous ammonium chloride solution (30 mL) was added, and the mixture was filtered through Celite, and washed with ethyl acetate. The filtrate was separated, the aqueous layer was extracted with ethyl acetate (200 mL), the organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the reaction mixture was diluted with ethyl acetate (200 mL), washed with water (x 2) and saturated brine (x 1), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the reaction mixture was diluted with methylene chloride, washed with a 10% aqueous sodium bisulfite solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the reaction mixture was diluted with methylene chloride and washed with saturated aqueous sodium bicarbonate, and then washed with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the reaction solution was diluted with methylene chloride, washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 3 N- ⁇ (9S) -4- ⁇ 4- [1- (3,4-dichlorophenyl) -2-methoxyethoxy] phenyl ⁇ -1-methyl-8-[(pyridin-2-yl) methyl] -1, 2,3,4,7,8,9,10-octahydro [1,4] oxazepino [3,2-g] isoquinolin-9-carbonyl ⁇ -4- (2,3-dimethylpyridin-4-yl)- L-phenylalanine (3a) methyl (9S) -4- ⁇ 4- [1- (3,4-dichlorophenyl) -2-methoxyethoxy] phenyl ⁇ -1-methyl-8-[(pyridin-2-yl) methyl ] -1,2,3,4,4,7,8,9,10-octahydro [1,4] oxazepino [3,2-g] isoquinolin-9-carboxylate The methyl obtained in
  • the reaction mixture was adjusted to pH 6 by adding 1N hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 6 Sodium (2S) -2-( ⁇ [(4R, 9S) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -8-[(3-fluorophenyl) methyl] ] -1-Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepino [3,2-g] isoquinoline-9-carbonyl ⁇ amino) -3- [4-] (2,3-Dimethylpyridin-4-yl) phenyl] propanoate The methyl N- ⁇ (4R, 9S) -4- ⁇ 4-[(1R) -1- (3,) obtained in Example 5 (5d) 4-Dichlorophenyl) propoxy] phenyl ⁇ -8-[(3-fluorophenyl) methyl] -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,
  • Example 7 N- ⁇ (4R, 9S) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -8- [3-fluorophenyl) methyl] -1-methyl-1, 2,3,4,7,8,9,10-Octahydro [1,4] oxazepino [3,2-g] isoquinoline-9-carbonyl ⁇ -4- (2,3-dimethylpyridin-4-yl)- L-Phenylalanine hydrochloride Methyl N- ⁇ (4R, 9S) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -8 obtained in Example 5 (5d) -[(3-Fluorophenyl) methyl] -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepino [3,2-
  • Example 8 N- ⁇ (4R, 9S) -4- ⁇ 4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl ⁇ -8-[(3-fluorophenyl) methyl] -1-methyl- 1,2,3,4,7,8,9,10-octahydro [1,4] oxazepino [3,2-g] isoquinoline-9-carbonyl ⁇ -4- (2,3-dimethylpyridin-4-yl ) -L-Phenylalanine (8a) methyl (4R, 9S) -4- ⁇ 4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl ⁇ -8-[(3-fluorophenyl) methyl ] -1-Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepino [3,2-g] isoquinolin-9
  • Example 9 N-[(4R, 9S) -8- (cyclobutylmethyl) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -1-methyl-1,2,3 , 4,7,8,9,10-Octahydro [1,4] oxazepino [3,2-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (9a) Methyl (4R, 9S) -8- (cyclobutylmethyl) -4- (4-hydroxyphenyl) -1-methyl-1,2,3,4,7,8,9,10-octahydro [1 , 4] Oxazepino [3,2-g] isoquinoline-9-carboxylate The methyl (4R, 9S) -4- (4-hydroxyphenyl) -1-methyl obtained in Reference Example 3 (3k) under nitrogen atmosphere.
  • the reaction mixture was adjusted to pH 6 by adding 1N hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 10 N-[(4R, 9S) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -1-methyl-8- (2-methylpropyl) -1,2, 3,4,7,8,9,10-Octahydro [1,4] oxazepino [3,2-g] isoquinoline-9-carbonyl ⁇ -4- (2,3-dimethylpyridin-4-yl) -L- Phenylalanine (10a) methyl (4R, 9S) -4- (4-hydroxyphenyl) -1-methyl-8- (2-methylpropyl) -1,2,3,4,7,8,9,10-octahydro [1,4] Oxazepino [3,2-g] isoquinoline-9-carboxylate The reaction is carried out in the same manner as described in Example 5 (5a) using isobutyraldehyde to give the title compound (yield 70%) Was obtained as a white
  • Example 11 N-[(4R, 9S) -8-cyclopentyl-4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -1-methyl-1,2,3,4,7 , 8,9,10-Octahydro [1,4] oxazepino [3,2-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (11a) methyl (4R, 9S) -8-Cyclopentyl-4- (4-hydroxyphenyl) -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepino [3,2 -g] Isoquinoline-9-carboxylate Methyl (4R, 9S) -4- (4-hydroxyphenyl) -1-methyl-1,2,3,4 obtained in Reference Example 3 (3k) under nitrogen atmosphere Acetic
  • the reaction mixture was adjusted to pH 6 by adding 1N hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 12 N-[(4R, 9S) -8- (Cyclopentylmethyl) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -1-methyl-1,2,3, 4,7,8,9,10-octahydro [1,4] oxazepino [3,2-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine ( 12a) Methyl (4R, 9S) -4- [4- (benzyloxy) phenyl] -8- (cyclopentylmethyl) -1-methyl-1,2,3,4,7,8,9,10-octahydro [ 1,4] Oxazepino [3,2-g] isoquinoline-9-carboxylate The methyl (4R, 9S) -4- [4- (benzyloxy) phenyl] -1-methyl obtained
  • reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, then washed three times with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 14 N-[(4R, 9S) -8- (cyclopentylmethyl) -4- ⁇ 4-[(1R) -1- (5,6-dichloropyridin-3-yl) propoxy] phenyl ⁇ -1-methyl-1 2,2,3,4,7,8,9,10-octahydro [1,4] oxazepino [3,2-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (14a) methyl (4R, 9S) -8- (cyclopentylmethyl) -4- ⁇ 4-[(1R) -1- (5,6-dichloropyridin-3-yl) propoxy] phenyl ⁇ - 1-Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepino [3,2-g] isoquinoline-9-carboxylate Obtained in Example 12
  • diallyl dicarbonate (1.58 mL, 9.50 mmol) was added, and the mixture was stirred at room temperature for 2 hours.
  • the organic layer was separated, and the aqueous layer was extracted with ethyl acetate.
  • the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate aqueous solution, and then the solvent was evaporated under reduced pressure.
  • Example 17 N-[(4R, 9S) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -1-methyl-8-propyl-1,2,3,4,7 , 8,9,10-Octahydro [1,4] oxazepino [3,2-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (17a) methyl (4R, 9S) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -1-methyl-8-propyl-1,2,3,4,7,8, 9,10-Octahydro [1,4] oxazepino [3,2-g] isoquinoline-9-carboxylate The methyl 3-[(2R) -2- ⁇ 4 obtained in Example 16 (16c) under a nitrogen atmosphere.
  • Example 18 N-[(4R, 9S) -8- (Cyclopropylmethyl) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -1-methyl-1,2,3 , 4,7,8,9,10-Octahydro [1,4] oxazepino [3,2-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (18a) Methyl (4R, 9S) -8- (cyclopropylmethyl) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -1-methyl-1,2, 3,4,7,8,9,10-octahydro [1,4] oxazepino [3,2-g] isoquinolin-9-carboxylate The method described in Example 17 (17a) using
  • Example 20 N-[(4R, 9S) -8-Cyclobutyl-4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -1-methyl-1,2,3,4,7 2,8,9,10-octahydro [1,4] oxazepino [3,2-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (20a) methyl (4R, 9S) -8-Cyclobutyl-4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -1-methyl-1,2,3,4,7,8, 9,10-octahydro [1,4] oxazepino [3,2-g] isoquinolin-9-carboxylate The reaction was carried out in the same manner as described in Example 17 (17a) using cyclobut
  • Example 21 N-[(4R, 9S) -8-cyclopropyl-4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -1-methyl-1,2,3,4, 7,8,9,10-Octahydro [1,4] oxazepino [3,2-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (21a) Methyl (4R, 9S) -8-cyclopropyl-4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -1-methyl-1,2,3,4,7, 8,9,10-Octahydro [1,4] oxazepino [3,2-g] isoquinoline-9-carboxylate The methyl 3-[(2R)-obtained in Example 16 (16c) at room temperature
  • the reaction solution was allowed to cool to room temperature and then filtered, and the solvent was evaporated under reduced pressure.
  • the residue was dissolved in ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 22 N-[(4R, 9S) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -1-methyl-8- (propan-2-yl) -1,2 , 3,4,7,8,9,10-octahydro [1,4] oxazepino [3,2-g] isoquinolin-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L -Phenylalanine (22a) methyl (4R, 9S) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -1-methyl-8- (propan-2-yl)- 1,2,3,4,7,8,9,10-octahydro [1,4] oxazepino [3,2-g] isoquinoline-9-carboxylate Method described in Example 17 (17a) using ace
  • Example 23 N-[(4R, 9S) -8-cyclohexyl-4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -1-methyl-1,2,3,4,7 , 8,9,10-Octahydro [1,4] oxazepino [3,2-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (23a) methyl (4R, 9S) -8-Cyclohexyl-4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -1-methyl-1,2,3,4,7,8, 9,10-octahydro [1,4] oxazepino [3,2-g] isoquinolin-9-carboxylate The reaction was carried out in the same manner as described in Example 17 (17a) using
  • the reaction solution is allowed to cool to room temperature, diluted with ethyl acetate, washed once with saturated aqueous sodium hydrogen carbonate solution and once with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. did.
  • the obtained residue was dissolved in methanol (10 mL), potassium carbonate (124 mg, 0.89 mmol) was added under ice-cooling, and the mixture was stirred for 20 minutes with the same temperature.
  • the reaction solution was warmed to room temperature, and the solvent was evaporated under reduced pressure.
  • the residue was dissolved in ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 26 N-[(2S, 8S) -9-benzyl-2- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -4-methyl-2,3,4,5,7 , 8,9,10-Octahydro [1,4] oxazepino [6,7-g] isoquinoline-8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (26a) methyl (2S, 8S) -9-benzyl-2- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -4-methyl-5-oxo-2,3,4,5, 7,8,9,10-Octahydro [1,4] oxazepino [6,7-g] isoquinoline-8-carboxylate The methyl (2S, 8S) -2- ⁇ 4- obtained from Example 25
  • Example 28 4-Dichlorophenyl) propoxy] phenyl ⁇ -4-methyl-9-[(5-methyl-1,2-oxazol-3-yl) methyl] -2,3,4,5,7,8,9,10-
  • the reaction was carried out in the same manner as described in Example 25 (25j) using octahydro [1,4] oxazepino [6,7-g] isoquinoline-8-carboxylic acid to give the title compound (purity 85%, yield 99%) was obtained as a pale yellow amorphous.
  • Example 30 N-[(2S, 8S) -9- (Cyclopentylmethyl) -2- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -4-methyl-2,3,4, 5,7,8,9,10-Octahydro [1,4] oxazepino [6,7-g] isoquinoline-8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine ( 30a) Methyl (2S, 8S) -9- (cyclopentylmethyl) -2- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -4-methyl-5-oxo-2, 3,4,5,7,8,9,10-Octahydro [1,4] oxazepino [6,7-g] isoquinolin-8-carboxylate described in Example
  • the reaction mixture was diluted with methylene chloride, washed with a 10% aqueous potassium carbonate solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 32 N- ⁇ (2S, 8S) -2- ⁇ 4-[(R)-(3,4-dichlorophenyl) (oxane-4-yl) methoxy] phenyl ⁇ -9-[(3-fluorophenyl) methyl]- 4-Methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepino [6,7-g] isoquinoline-8-carbonyl ⁇ -4- (2,3-dimethylpyridine -4-yl) -L-phenylalanine (32a) 9-tert-butyl 8-methyl (2S, 8S) -2- ⁇ 4-[(R)-(3,4-dichlorophenyl) (oxane-4-yl) Methoxy] phenyl ⁇ -4-methyl-3,4,5,7,8,10-hexahydro [1,4] oxazepino [6,7-g] isoquinoline-8
  • Example 35 N-[(2S, 8S) -4-acetyl-2- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -9- (2,2,2-trifluoroethyl) -2,3,4,5,7,7,8,9,10-octahydro [1,4] oxazepino [6,7-g] isoquinoline-8-carbonyl] -4- (2,3-dimethylpyridine-4-) ) -L-phenylalanine (35a) methyl (2S, 8S) -4-acetyl-2- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -9- (2,2 2,2-Trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepino [6,7-g] isoquinoline-8
  • Example 36 N-[(2S, 8S) -4-acetyl-2- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -9- (2-methylpropyl) -2,3, 3 4,5,7,8,9,10-Octahydro [1,4] oxazepino [6,7-g] isoquinolin-8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L- Phenylalanine (36a) methyl (2S, 8S) -4-acetyl-2- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -9- (2-methylpropyl) -2, 3,4,5,7,8,9,10-Octahydro [1,4] oxazepino [6,7-g] isoquinolin-8-carboxylate The methyl (2
  • Example 38 N-[(2S, 8S) -2- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -4-methyl-9- (2,2,2-trifluoroethyl) -2,3,4,5,7,7,8,9,10-octahydro [1,4] oxazepino [6,7-g] isoquinoline-8-carbonyl] -4- (2,3-dimethylpyridine-4-) ) -L-phenylalanine (38a) methyl (2S, 8S) -4- (2-nitrobenzene-1-sulfonyl) -2- ⁇ 4- ⁇ [(2-nitrobenzene-1-sulfonyl) oxy] phenyl ⁇ -2 , 3,4,5,7,8,9,10-Octahydro [1,4] oxazepino [6,7-g] isoquinolin-8-carboxylate 9-tert
  • reaction solution is diluted with methylene chloride, washed with a 10% aqueous potassium carbonate solution and then dried over anhydrous sodium sulfate, and then the solvent is evaporated under reduced pressure to yield 372 mg of the title compound (yield 94%) as a colorless solid Got as.
  • the reaction mixture was diluted with methylene chloride, washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • reaction mixture was adjusted to pH 4-5 by adding 1N hydrochloric acid, extracted with chloroform, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and 157 mg of the title compound (quantitative) Was obtained as a colorless solid.
  • Example 40 N-[(2S, 8S) -2- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -4-methyl-9- (propan-2-yl) -2,3 , 4,5,7,8,9,10-octahydro [1,4] oxazepino [6,7-g] isoquinoline-8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L -Phenylalanine (40a) methyl (2S, 8S) -2- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -4-methyl-9- (propan-2-yl)- 2,3,4,5,7,7,8,9,10-octahydro [1,4] oxazepino [6,7-g] isoquinoline-8-carboxylate The methyl (2S, 8
  • Example 42 N-[(2S, 8S) -2- ⁇ 4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl ⁇ -4-methyl-9- (propan-2-yl) -2, 3,4,5,7,8,9,10-Octahydro [1,4] oxazepino [6,7-g] isoquinolin-8-carbonyl] -4- (2,3-dimethylpyridin-4-yl)- L-phenylalanine (42a) methyl (2S, 8S) -2- ⁇ 4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl ⁇ -4-methyl-9- (propan-2-yl )-2,3,4,5,7,8,9,10-Octahydro [1,4] oxazepino [6,7-g] isoquinolin-8-carboxylate The methyl obtained in Example 41 (41b
  • the reaction mixture was adjusted to pH 6 by adding 1N hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 48 N-[(2S, 8S) -9-Cyclohexyl-2- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -4-methyl-2,3,4,5,7 , 8,9,10-Octahydro [1,4] oxazepino [6,7-g] isoquinoline-8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (48a) methyl (2S, 8S) -9-Cyclohexyl-2- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -4-methyl-2,3,4,5,7,8, 9,10-Octahydro [1,4] oxazepino [6,7-g] isoquinoline-8-carboxylate The methyl (2S, 8S) -2- ⁇ 4-[
  • the reaction mixture was adjusted to pH 6 by adding 1N hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 50 N-[(4S, 9S) -8-Cyclopentyl-4- ⁇ 4-[(3,4-dichlorophenyl) methoxy] phenyl ⁇ -2,3,4,5,7,8,9,10-octahydrooxy Cepino [2,3-g] isoquinolin-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (50a) methyl (4S, 9S) -8-cyclopentyl-4- ⁇ 4-[(3,4-Dichlorophenyl) methoxy] phenyl ⁇ -2,3,4,5,7,8,9,10-Octahydrooxepino [2,3-g] isoquinoline-9-carboxylate The methyl (4S, 9S) -4- ⁇ 4-[(3,4-dichlorophenyl) methoxy] phenyl ⁇ -2,3,4,5,7,8,9,
  • Example 51 2-Chloro-N- ⁇ (9S) -4- ⁇ 4-[(3,4-dichlorophenyl) methoxy] -3-fluorophenyl ⁇ -8-[(pyridazin-3-yl) methyl] -2,3, 3 4,5,7,8,9,10-Octahydrooxepino [2,3-g] isoquinoline-9-carbonyl ⁇ -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine ( 51a) Methyl (9S) -4- ⁇ 4-[(3,4-dichlorophenyl) methoxy] -3-fluorophenyl ⁇ -8-[(pyridazin-3-yl) methyl] -2,3,4,5, 7,8,9,10-Octahydrooxepino [2,3-g] isoquinoline-9-carboxylate The methyl (9S) -4- ⁇ 4-[(3,
  • Example 54 2-Chloro-N- ⁇ (9S) -4- ⁇ 4- [1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -8-[(pyridin-2-yl) methyl] -2,3,4, 5,7,8,9,10-Octahydrooxepino [2,3-g] isoquinoline-9-carbonyl ⁇ -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (54a) Methyl (9S) -4- ⁇ 4- [1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -8-[(pyridin-2-yl) methyl] -2,3,4,5,7,8, 9,10-Octahydrooxepino [2,3-g] isoquinoline-9-carboxylate The methyl (9S) -4- ⁇ 4- [1- (3,4-) obtained in Reference Example 25 (25b) Dich
  • Example 56 N- ⁇ (9S) -4- ⁇ 4-[(3,4-dichlorophenyl) (oxane-4-yl) methoxy] phenyl ⁇ -8-[(5-methyl-1,2-oxazol-3-yl) Methyl] -2,3,4,5,7,8,9,10-Octahydrooxepino [2,3-g] isoquinoline-9-carbonyl ⁇ -4- (2,3-dimethylpyridine-4-) ) -L-phenylalanine (56a) methyl (9S) -4- ⁇ 4-[(3,4-dichlorophenyl) (oxan-4-yl) methoxy] phenyl ⁇ -8-[(5-methyl-1,2 -Oxazol-3-yl) methyl] -2,3,4,5,7,8,9,10-Octahydrooxepino [2,3-g] isoquinolin-9-carboxylate Reference Example
  • Example 58 N- ⁇ (4S, 9S) -4- ⁇ 4-[(R)-(3,4-dichlorophenyl) (oxane-4-yl) methoxy] phenyl ⁇ -8-[(3-fluorophenyl) methyl]- 2,3,4,5,7,8,9,10-Octahydrooxepino [2,3-g] isoquinolin-9-carbonyl ⁇ -4- (2,3-dimethylpyridin-4-yl)- L-phenylalanine (58a) methyl (4S, 9S) -4- ⁇ 4-[(R)-(3,4-dichlorophenyl) (oxane-4-yl) methoxy] phenyl ⁇ -8-[(3-fluorophenyl ) Methyl] -2,3,4,5,7,8,9,10-Octahydrooxepino [2,3-g] isoquinoline-9-carboxylate
  • Example 59 N- ⁇ (4S, 9S) -4- ⁇ 4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl ⁇ -8-[(3-fluorophenyl) methyl] -2,3, 4,5,7,8,9,10-Octahydrooxepino [2,3-g] isoquinoline-9-carbonyl ⁇ -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine ( 59a) Methyl (4S, 9S) -4- ⁇ 4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl ⁇ -8-[(3-fluorophenyl) methyl] -2,3, 4,5,7,8,9,10-Octahydrooxepino [2,3-g] isoquinoline-9-carboxylate The methyl (4S, 9S) -4
  • Example 60 N-[(4S, 9S) -8-cyclopentylmethyl-4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -2,3,4,5,7,8, 9,10-Octahydrooxepino [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (60a) methyl (4S, 9S) -8-Cyclopentylmethyl-4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -2,3,4,5,7,8,9,10-octahydroxose Pino [2,3-g] isoquinoline-9-carboxylate The methyl (4S, 9S) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl
  • Example 61 N-[(4S, 9S) -8-cyclopentylmethyl-4- ⁇ 4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl ⁇ -2,3,4,5,7,8 , 9, 10-Octahydrooxepino [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (61a) methyl (4S, 9S ) -8-Cyclopentylmethyl-4- ⁇ 4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl ⁇ -2,3,4,5,7,8,9,10-octahydro Oxepino [2,3-g] isoquinoline-9-carboxylate The methyl (4S, 9S) -4- ⁇ 4-[(1R) -1- (3,4-) obtained in Reference
  • Example 62 N-[(4S, 9S) -8- (Cyclobutylmethyl) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -2,3,4,5,7 2,8,9,10-Octahydrooxepino [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (62a) methyl (4S , 9S) -8- (Cyclobutylmethyl) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -2,3,4,5,7,8,9, 10-Octahydrooxepino [2,3-g] isoquinoline-9-carboxylate The methyl (4S, 9S) -4- ⁇ 4-[(1R) -1- (methyl) obtained
  • Example 63 N-[(4S, 9S) -8- (Cyclobutylmethyl) -4- ⁇ 4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl ⁇ -2,3,4,5, 7,8,9,10-octahydrooxepino [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (63a) methyl ( 4S, 9S) -8- (Cyclobutylmethyl) -4- ⁇ 4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl ⁇ -2,3,4,5,7,8, 9,10-Octahydrooxepino [2,3-g] isoquinoline-9-carboxylate The methyl (4S, 9S) -4- ⁇ 4-[(1R) -1 obtained in Reference Example
  • Example 64 N-[(4S, 9S) -8-cyclopentyl-4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -2,3,4,5,7,8,9 , 10-Octahydrooxepino [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (64a) methyl (4S, 9S)- 8-Cyclopentyl-4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -2,3,4,5,7,8,9,10-octahydro oxepino [ 2,3-g] isoquinoline-9-carboxylate The methyl (4S, 9S) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl)
  • Example 65 N-[(4S, 9S) -8-Cyclobutyl-4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -2,3,4,5,7,8,9 , 10-Octahydrooxepino [2,3-g] isoquinolin-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (65a) methyl (4S, 9S)- 8-Cyclobutyl-4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -2,3,4,5,7,8,9,10-octahydro oxepino [ 2,3-g] isoquinoline-9-carboxylate The methyl (4S, 9S) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl
  • Example 66 N-[(4S, 9S) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -8- (2-methylpropyl) -2,3,4,5, 7,8,9,10-Octahydrooxepino [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (66a) methyl ( 4S, 9S) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -8- (2-methylpropyl) -2,3,3,4,5,7,8, 9,10-Octahydrooxepino [2,3-g] isoquinoline-9-carboxylate The methyl (4S, 9S) -4- ⁇ 4-[(1R) -1 obtained in Reference Example 28 (28b)
  • Example 68 N-[(4S, 9S) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -8-propyl-2,3,4,5,7,8,9 , 10-Octahydrooxepino [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (68a) methyl (4S, 9S)- 4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -8-propyl-2,3,4,5,7,8,9,10-octahydro oxepino [ 2,3-g] isoquinoline-9-carboxylate The methyl (4S, 9S) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] obtained in Reference
  • Example 69 N-[(4S, 9S) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -8- (propan-2-yl) -2,3,4,5 , 7,8,9,10-Octahydrooxepino [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (69a) methyl (4S, 9S) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -8- (propan-2-yl) -2,3,4,5,7, 8,9,10-Octahydrooxepino [2,3-g] isoquinoline-9-carboxylate The methyl (4S, 9S) -4- ⁇ 4-[(1R) obtained in Reference Example 28 (28b)
  • Example 70 N-[(4S, 9S) -8-Cyclopropyl-4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -2,3,4,5,7,8, 9,10-Octahydrooxepino [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (70a) methyl (4S, 9S) -8-Cyclopropyl-4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl ⁇ -2,3,4,5,7,8,9,10-octahydroxose Pino [2,3-g] isoquinoline-9-carboxylate The methyl (4S, 9S) -4- ⁇ 4-[(1R) -1- (3,4-dichlorophenyl) obtained
  • Example 71 N-[(4S, 9S) -8- (Cyclobutylmethyl) -4- ⁇ 4-[(3,4-dichlorophenyl) methoxy] phenyl ⁇ -2,3,4,5,7,8,9,10 -Octahydrooxepino [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (71a) methyl (4S, 9S) -8- (Cyclobutylmethyl) -4- ⁇ 4-[(3,4-dichlorophenyl) methoxy] phenyl ⁇ -2,3,4,5,7,8,9,10-octahydrooxepino [2,3- g] Isoquinolin-9-carboxylate Methyl (4S, 9S) -4- ⁇ 4-[(3,4-dichlorophenyl) methoxy] phen
  • Example 72 N-[(4S, 9S) -4- ⁇ 4-[(3,4-dichlorophenyl) methoxy] phenyl ⁇ -8- (2-methylpropyl) -2,3,4,5,7,8,9, 10-Octahydrooxepino [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (72a) methyl (4S, 9S) -4 - ⁇ 4-[(3,4-dichlorophenyl) methoxy] phenyl ⁇ -8- (2-methylpropyl) -2,3,4,5,7,8,9,10-octahydro oxepino [2, 3- (g) isoquinoline-9-carboxylate The methyl (4S, 9S) -4- ⁇ 4-[(3,4-dichlorophenyl) methoxy] phenyl ⁇ -2,3 and 4 obtained
  • Example 73 N-[(4S, 9S) -8-Cyclobutyl-4- ⁇ 4-[(3,4-dichlorophenyl) methoxy] phenyl ⁇ -2,3,4,5,7,8,9,10-octahydrooxy Cepino [2,3-g] isoquinolin-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (73a) methyl (4S, 9S) -8-cyclobutyl-4- ⁇ 4-[(3,4-Dichlorophenyl) methoxy] phenyl ⁇ -2,3,4,5,7,8,9,10-Octahydrooxepino [2,3-g] isoquinoline-9-carboxylate The methyl (4S, 9S) -4- ⁇ 4-[(3,4-dichlorophenyl) methoxy] phenyl ⁇ -2,3,4,5,7,8,9,
  • Example 75 N- ⁇ (4S, 9S) -4- ⁇ 4-[(3,4-dichlorophenyl) methoxy] phenyl ⁇ -8-[(1S) -1-phenylpropyl] -2,3,4,5,7, 8,9,10-Octahydrooxepino [2,3-g] isoquinoline-9-carbonyl ⁇ -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine or N-( ⁇ (4S , 9S) -4- ⁇ 4-[(3,4-dichlorophenyl) methoxy] phenyl ⁇ -8-[(1R) -1-phenylpropyl] -2,3,4,5,7,8,9,10 -Octahydrooxepino [2,3-g] isoquinoline-9-carbonyl ⁇ -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine
  • Example 76 N- ⁇ (4S, 9S) -4- ⁇ 4-[(3,4-dichlorophenyl) methoxy] phenyl ⁇ -8-[(pyridin-2-yl) methyl] -2,3,4,5,7, 8,9,10-Octahydrooxepino [2,3-g] isoquinoline-9-carbonyl ⁇ -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (76a) methyl (4S, 9S) -4- ⁇ 4-[(3,4-dichlorophenyl) methoxy] phenyl ⁇ -8-[(pyridin-2-yl) methyl] -2,3,4,5,7,8,9,10- Octahydrooxepino [2,3-g] isoquinoline-9-carboxylate The methyl (4S, 9S) -4- ⁇ 4-[(3,4-dichlorophenyl) methoxy] obtained

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Abstract

La présente invention aborde le problème de la fourniture d'un médicament destiné à être utilisé pour prévenir ou traiter l'obésité ou pour prévenir ou traiter le diabète de type 2. La solution selon la présente invention porte sur un composé représenté par la formule générale (I) ou un sel pharmacologiquement acceptable de celui-ci. La description abrégée de chaque substituant est la suivante. Par exemple, R1 : représente un groupe phényle ou similaire, R2 : représente un atome d'hydrogène ou similaire, R3 : représente un atome d'hydrogène ou similaire, R4 : représente un atome d'hydrogène ou similaire, R5 : représente un groupe méthyle ou similaire, R6 : représente un atome d'hydrogène ou similaire, R7 : représente un groupe hétéroaryle ou similaire, X : représente CH2 ou similaire, Y : représente CH2 ou similaire, Z : représente CH2 ou similaire.
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WO2021238964A1 (fr) * 2020-05-28 2021-12-02 杭州中美华东制药有限公司 Procédé de préparation d'une base libre d'agoniste du récepteur glp-1
CN115667219A (zh) * 2020-05-28 2023-01-31 杭州中美华东制药有限公司 一种(s)-2-氨基-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸甲酯二酸盐的制备方法
WO2023038039A1 (fr) 2021-09-08 2023-03-16 塩野義製薬株式会社 Médicament destiné à la prévention et au traitement de maladies liées à l'activité anti-obésité
US12234236B1 (en) 2023-09-14 2025-02-25 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof
US12291530B1 (en) 2023-11-24 2025-05-06 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof

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WO2022262143A1 (fr) * 2021-06-17 2022-12-22 杭州中美华东制药有限公司 Procédé de préparation de borate de pyridine

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WO2021238964A1 (fr) * 2020-05-28 2021-12-02 杭州中美华东制药有限公司 Procédé de préparation d'une base libre d'agoniste du récepteur glp-1
CN115667219A (zh) * 2020-05-28 2023-01-31 杭州中美华东制药有限公司 一种(s)-2-氨基-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸甲酯二酸盐的制备方法
CN115667268A (zh) * 2020-05-28 2023-01-31 杭州中美华东制药有限公司 一种glp-1受体激动剂游离碱的制备方法
EP4159719A4 (fr) * 2020-05-28 2024-07-17 Hangzhou Zhongmeihuadong Pharmaceutical Co., Ltd. Procédé de préparation de sel de diacide de propanoate de méthyle (s)-2-amino-3-(4-(2,3-diméthylpyridine-4-yl)phényl)
CN115667268B (zh) * 2020-05-28 2024-09-24 杭州中美华东制药有限公司 一种glp-1受体激动剂游离碱的制备方法
WO2023038039A1 (fr) 2021-09-08 2023-03-16 塩野義製薬株式会社 Médicament destiné à la prévention et au traitement de maladies liées à l'activité anti-obésité
KR20240056719A (ko) 2021-09-08 2024-04-30 시오노기 앤드 컴파니, 리미티드 항비만 작용이 관여하는 질환의 예방 및 치료용 의약
US12234236B1 (en) 2023-09-14 2025-02-25 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof
US12291530B1 (en) 2023-11-24 2025-05-06 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof

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