WO2016084866A1 - Novel diazabicyclo derivative - Google Patents
Novel diazabicyclo derivative Download PDFInfo
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- WO2016084866A1 WO2016084866A1 PCT/JP2015/083128 JP2015083128W WO2016084866A1 WO 2016084866 A1 WO2016084866 A1 WO 2016084866A1 JP 2015083128 W JP2015083128 W JP 2015083128W WO 2016084866 A1 WO2016084866 A1 WO 2016084866A1
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- 0 C*(CC1CN(C2)C(/C3=C(\C)/C=C/C=C/C=C3)=O)C2N1C1=CC=CC=CC=CC=C1 Chemical compound C*(CC1CN(C2)C(/C3=C(\C)/C=C/C=C/C=C3)=O)C2N1C1=CC=CC=CC=CC=C1 0.000 description 5
- IHIFFZUDWSAROU-UHFFFAOYSA-N N#Cc(cc1)n[n]1-c1ccccn1 Chemical compound N#Cc(cc1)n[n]1-c1ccccn1 IHIFFZUDWSAROU-UHFFFAOYSA-N 0.000 description 1
- NYZGZKIPTHTZOF-UHFFFAOYSA-N N#Cc(cc1C(O)=O)n[n]1-c1ccccn1 Chemical compound N#Cc(cc1C(O)=O)n[n]1-c1ccccn1 NYZGZKIPTHTZOF-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
- A61K31/495—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
- A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention relates to a compound having an orexin receptor antagonism, particularly a compound having a diazabicyclo structure represented by the following formula (I), or a pharmaceutically acceptable salt thereof, or a compound thereof:
- the present invention relates to a solvate and a pharmaceutical composition containing them as an active ingredient.
- the present invention also relates to diseases involving orexin receptors, sleep disorders (insomnia, circadian rhythm sleep disorders, sleep-related complications), mental disorders (depression, anxiety disorders, bipolar disorders, attention deficit hyperactivity) Sexual disorders, autism, autism spectrum disorder, drug dependence, etc.), neurodegenerative diseases (Alzheimer's disease, etc.), memory disorders (dementia, etc.) and eating disorders (eg, bulimia), especially insomnia
- sleep disorders insomnia, circadian rhythm sleep disorders, sleep-related complications
- mental disorders depression, anxiety disorders, bipolar disorders, attention deficit hyperactivity
- sexual disorders autism, autism spectrum disorder, drug dependence, etc.
- neurodegenerative diseases Alzheimer's disease, etc.
- memory disorders eg, bulimia
- eating disorders eg, bulimia
- the present invention relates to a preventive and / or therapeutic agent for sleep disorders.
- Orexin is a neuropeptide specifically expressed in neurons existing in the lateral hypothalamic area, OX-A consisting of 33 amino acids and 28 OX-B consisting of the following amino acids has been identified.
- the orexin receptor which is a specific receptor for these peptides, has been reported in two subtypes, the OX1 receptor and the OX2 receptor.
- Each receptor is a seven-transmembrane G protein-coupled receptor expressed in the central nervous system, but the tissue distribution differs depending on the subtype and has various effects on various nerves. Has been suggested to have complex physiological activities.
- Non-patent Documents 1 and 2 By administering orexin into the rat ventricle, wakefulness-promoting effects such as increased spontaneous momentum and prolonged wakefulness are observed (Non-patent Documents 1 and 2). In addition, inhibition of arousal is observed in orexin KO mice and OX2 receptor KO mice (Non-patent Document 3). From these findings, orexin receptor antagonists are considered to be excellent insomnia treatments as sleep-inducing agents that induce sleep by suppressing wakefulness. Almorexant and suvorexant are known as orexin receptor antagonists.
- Non-patent Documents 4 and 5 Suvorexant has been approved for manufacture and sale as a therapeutic agent for insomnia (Belsomura (registered trademark)).
- Side effects such as daytime sleepiness (carry-over effect) and sleep behavior disorder are concerned.
- OX2 receptor selective antagonists induces physiological sleep and may be a therapeutic agent for insomnia with a low risk of side effects.
- MIN-202 and MK-1064 Non-patent Document 7
- WO2008 / 008517 pamphlet includes a compound having a diazabicyclo structure such as a diazabicyclo [4.2.1] nonane derivative, WO2011 / 050198 pamphlet (Patent Document 2).
- a diazabicyclo structure such as a diazabicyclo [4.2.1] nonane derivative, WO2011 / 050198 pamphlet (Patent Document 2).
- WO2012 / 085852 pamphlet for diazabicyclo [4.2.0] octane derivative
- WO2013 / 0500938 pamphlet includes diazabicyclo [3.3.1] nonane derivatives, respectively.
- the derivatives disclosed therein are different in basic skeleton from compounds having a diazabicyclo [3.2.1] octane or diazabicyclo [3.1.1] heptane structure, and diazabicyclo [3.2.1] octane.
- diazabicyclo [3.2.1] octane there is no disclosure or suggestion about a compound having a diazabicyclo [3.1.1] heptane structure.
- a piperidine derivative is disclosed as a compound having an orexin receptor antagonistic activity in WO 2014/066196 pamphlet (Patent Document 5), but diazabicyclo [3.2.1] octane or diazabicyclo [3.1. 1]
- the basic skeleton is different from a compound having a heptane structure.
- Patent Document 6 a diazabicyclo [3.2.1] octane derivative is disclosed as a compound having an anxiolytic action, but the disclosure of the specific compound of the present invention as shown below is disclosed. Absent. In WO2011 / 090935 (Patent Document 7), as a compound having an mTOR inhibitory action, and in WO2002 / 102778 (Patent Document 8), as a compound having a PDEIV inhibitory action, diazabicyclo [3.2.1]. Although a group of compounds containing an octane derivative is disclosed, there is no disclosure of specific compounds of the present invention as shown below.
- insomnia drugs are available for pharmacotherapy of sleep disorders such as insomnia, but the treatment satisfaction is low and the development of new insomnia drugs with better side effect profile There is still a need.
- the present inventors have conducted extensive research to obtain an orexin receptor antagonist that is highly safe and / or excellent in effectiveness. It was found that a compound having a diazabicyclo structure or a pharmaceutically acceptable salt thereof or a solvate thereof has an orexin receptor antagonistic action.
- the compound of the present invention has an orexin receptor antagonistic action, and has an action of improving psychiatric and neurological disorders including sleep disorders such as insomnia.
- the present invention contains a compound having a diazabicyclo structure represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, and an active ingredient thereof.
- the compound of the present invention is a compound having an orexin receptor antagonistic action, and has an action of improving psychiatric and neurological disorders including sleep disorders such as insomnia.
- the pharmaceutical composition containing the compound of the present invention as an active ingredient can be administered orally, and sleep such as orexin receptor antagonists, diseases involving orexin receptor, psychiatric and neurological disorders, especially insomnia It is expected as a preventive and / or therapeutic agent for disorders.
- the compound group of the present invention has at least one or more characteristics such as good solubility, high metabolic stability, excellent oral absorbability, and little hERG channel inhibitory action. Since it also has, it is highly useful.
- the present invention relates to a compound having a diazabicyclo structure represented by the following formula (I) shown in the following embodiment, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and A pharmaceutical composition characterized by containing them as an active ingredient, as well as their pharmaceutical use, orexin receptor antagonist.
- the present invention includes the following embodiments [1] to [14].
- the first aspect of the present invention is Formula (I) (Where n represents 1 or 2; Ring A represents a C 6 ⁇ 14 aryl group or a 5-14 membered heteroaryl group, in the ring A, the C 6 ⁇ 14 aryl group or a 5-14 membered heteroaryl group, respectively, 1-5 R Optionally substituted by 1 ; Ring B represents a phenyl group or a monocyclic heteroaryl group, and the phenyl group or monocyclic heteroaryl group in Ring B may each be substituted with 1 to 4 R 2 ; L is a halogen atom, C 3 ⁇ 8 cycloalkyl group, C 1 ⁇ 6 alkoxyl group, a halogenated C 1 ⁇ 6 alkoxy group, a phenoxy group, a monocyclic non-aromatic heterocyclic group, a phenyl group or a monocyclic heteroary
- L on ring B is a substituent adjacent to the bond position of ring A-bicycloring-CO—;
- R 1 is, each independently, a halogen atom, C 1 ⁇ 6 alkyl group, C 2 ⁇ 6 alkenyl group, C 2 ⁇ 6 alkynyl group, C 3 ⁇ 8 cycloalkyl group, C 1 ⁇ 6 alkoxy group, C 2 ⁇ 6 alkenyloxy group, C 2 ⁇ 6 alkynyloxy group, C 2 ⁇ 7 alkanoyl group, C 1 ⁇ 6 alkoxycarbonyl group, C 1 ⁇ 6 alkylthio group, -NR a R b group, optionally cyano group and oxo group represents a group selected, the C 1 ⁇ 6 alkyl group in R 1, C 2 ⁇ 6 alkenyl group, C 2 ⁇ 6 alkynyl group, C 3 ⁇ 8 cycloalkyl group, C 1 ⁇ 6 alkoxy group, C 2
- C 1-6 means that the number of constituent carbon atoms is 1 to 6, and unless otherwise specified, carbon atoms of a linear, branched or cyclic group Represents a number.
- the chain group means “straight or branched chain having 1 to 6 carbon atoms”.
- the cyclic group means “a cyclic group having 1 to 6 carbon atoms in the ring”.
- the group containing a chain group and a cyclic group means “a group having 1 to 6 total carbon atoms”.
- examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
- halogenated means having 1 to 5 “halogen atoms” as a substituent.
- Halogenation is also referred to as “halogeno”.
- examples of the “C 1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, hexyl and the like. .
- C 1-4 alkyl group examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and “C 1-2 alkyl group” includes Methyl and ethyl are mentioned.
- the “halogenated C 1-6 alkyl group” means a group in which the “C 1-6 alkyl group” is optionally substituted with 1 to 5 halogen atoms. Meaning, for example, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl and the like.
- “may be substituted with 1 to 5 substituents RI” means that the corresponding substituent (for example, an alkyl group) is 1 to 5 substituents RI.
- a C 1-6 alkyl group substituted with 1 to 5 substituents RI means that the “C 1-6 alkyl group” is 1 to 5 substituents RI, That is, a group optionally substituted with 1 to 5 halogen atoms or hydroxyl groups.
- the “C 1-6 alkyl group substituted with a hydroxyl group” is hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxy- Examples include 2-methyl-ethyl and the like, and 2,2,2-trifluoro-1-hydroxyethyl which is a “C 1-6 alkyl group substituted with a halogen atom and a hydroxyl group”.
- the "1 to 5 substituents RI group which may be substituted with” in addition to the C 1 ⁇ 6 alkyl groups, C 2 ⁇ 6 alkenyl groups, C 2 ⁇ 6 alkynyl groups, C 3-8 cycloalkyl group, C 1 ⁇ 6 alkoxy group, C 2 ⁇ 6 alkenyloxy group, C 2 ⁇ 6 alkynyloxy group, C 2 ⁇ 7 alkanoyl group, C 1 ⁇ 6 alkoxycarbonyl group, C 1 ⁇ 6 alkylthio Or a monocyclic heteroaryl group, in addition to each corresponding unsubstituted substituent, in addition to the aforementioned “C 1-6 alkyl group substituted by 1 to 5 substituents RI” ”Means a corresponding substituent optionally substituted with 1 to 5 substituents RI.
- C 2 ⁇ 6 alkenyl group for example, vinyl, allyl, isopropenyl, 1-propen-1-yl, butenyl, pentenyl, isopentenyl, and hexenyl and the like Can be mentioned.
- C 3 ⁇ 8 cycloalkyl group for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclic alkyl groups such as cycloheptyl and cyclooctyl.
- the “aryl group” means “monocyclic aryl group”, “condensed aryl group (including bicyclic or tricyclic)” or “partially A hydrogenated fused-ring aryl group ".
- the “partially hydrogenated condensed aryl group” means any hydrogen from a partially hydrogenated condensed ring in the “condensed aryl group”. It means a monovalent group formed by removing an atom, and either a hydrogen atom in an aromatic ring part of a condensed ring or a hydrogen atom in a hydrogenated part may be removed.
- C 6 ⁇ 14 aryl group for example, phenyl, 1-naphthyl, 2-naphthyl, 2-, 3-, 4-biphenyl anthryl, phenanthryl, acenaphthyl, Indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl and the like can be mentioned.
- the “heterocyclic group” means a 3 to 14-membered monocyclic or condensed ring containing 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. A monovalent group formed by removing any hydrogen atom from a cyclic ring.
- examples of the “heterocyclic group” include “heteroaryl group” and “non-aromatic heterocyclic group”.
- heteroaryl group refers to a 5- to 14-membered heteroaryl ring group containing 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. means.
- examples of the “heteroaryl group” include “monocyclic heteroaryl group”, “condensed heteroaryl group”, and “partially hydrogenated fused ring”.
- Formula heteroaryl group ".
- the “monocyclic heteroaryl group” preferably has 5 to 7 ring members.
- the “condensed heteroaryl group” means “heterocyclic group” and “aryl group”, or “heterocyclic group” and “monocyclic heteroaryl group”. Means a monovalent group formed by removing an arbitrary hydrogen atom from a condensed ring formed by condensation, and the arbitrary hydrogen atom may be removed from any condensed ring.
- the “condensed heteroaryl group” is preferably one having 8 to 12 ring members, for example, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, iso Benzothienyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzimidazolyl, 1H-indazolyl, 1H-benzotriazolyl, chromenyl, isochromenyl, quinolyl , Isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, benzoxazepinyl, benzoazepinyl, benzodiazepinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, carbolinyl,
- the “partially hydrogenated condensed heteroaryl group” means “heterocyclic group” and “aryl group”, or “heterocyclic group” and “heterocyclic group”.
- a condensed ring formed by condensing an “aryl group” it means a monovalent group formed by removing any hydrogen atom from a partially hydrogenated condensed ring.
- the arbitrary hydrogen atom is a hydrogen atom in any of the "heterocyclic group", “aryl group” and “heteroaryl group” in the condensed ring, or a hydrogen atom in the hydrogenated ring part.
- quinoline is partially hydrogenated tetrahydroquinolyl
- 5,6,7,8-tetrahydroquinolyl, 1,2,3,4-tetrahydroquinolyl and the like can be mentioned.
- these groups can be, for example, 5,6,7,8-tetrahydroquinolyl-2-yl, -3-yl, -4-yl, -5-yl.
- -6-yl, -7-yl, -8-yl and the like 1,2,3,4-tetrahydroquinolyl, for example, -1-yl, -2-yl, -3- Il, -4-yl, -5-yl, -6-yl, -7-yl, -8-yl and the like are exemplified.
- the “partially hydrogenated condensed heteroaryl group” preferably has 8 to 12 ring members, such as indolinyl, 4, 5, 6, 7 -Tetrahydro-1H-indonyl, 2,3-dihydrobenzofuranyl, 4,5,6,7-tetrahydro-benzofuranyl, 2,3-dihydrobenzo [d] oxazolyl, 2,3-dihydrobenzo [d] thiazolyl, 4,5,6,7-tetrahydro-1H-indazolyl, chromanyl, 2H-chromenyl, 4H-chromenyl, isochromanyl, 1H-isochromenyl, 1,3-benzodioxolyl, 2,3-dihydrofuro [3,2-c ] Pyridyl etc. are mentioned.
- the “monocyclic non-aromatic heterocyclic group” means a 3 to 8-membered member containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom.
- examples of the “monocyclic non-aromatic heterocyclic group” include aziridinyl, azetidinyl, oxiranyl, thiranyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, thiolanyl, and pyrazolinyl.
- the “C 1-6 alkoxyl group” means a group in which the “C 1-6 alkyl group” is substituted with an oxygen atom.
- examples of the “C 1-6 alkoxyl group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyl. Examples include oxy.
- C 1-4 alkoxyl group examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like, and “C 1-2 alkoxyl group” , Methoxy and ethoxy.
- the “halogenated C 1-6 alkoxyl group” means a halogen having 1 to 5 “C 1-6 alkyl groups” in the “C 1-6 alkoxyl group”. Means a group optionally substituted with atoms, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy Etc.
- the term "C 2 ⁇ 6 alkenyloxy group” means a group wherein the above "C 2 ⁇ 6 alkenyl group” is substituted with an oxygen atom.
- C 2 ⁇ 6 alkenyloxy group for example, vinyloxy, allyloxy, isopropenyloxy, butenyloxy, and pentenyloxy, and hexenyloxy and the like.
- C 2 ⁇ 6 alkynyloxy group means a group wherein the above “C 2 ⁇ 6 alkynyl group” is substituted with an oxygen atom.
- C 2 ⁇ 6 alkynyloxy group for example, ethynyloxy, 1-propynyloxy, 2-propynyloxy, butynyloxy, pentynyloxy, hexynyloxy, and the like.
- C 2 ⁇ 7 alkanoyl group the carbonyl group in the “C 1 ⁇ 6 alkyl group” bonded, means “C 1 ⁇ 6 alkyl group” .
- the “C 2 ⁇ 7 alkanoyl group” for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, cyclopropylcarbonyl, cyclobutylcarbonyl, Examples include cyclopentylcarbonyl, cyclohexylcarbonyl, cyclopropylmethylcarbonyl, 2-methylcyclopropylcarbonyl and the like.
- C 1-6 alkylthio group means a group in which the hydrogen atom of “thiol group (—SH)” is substituted with the above “C 1-6 alkyl group”.
- examples of the “C 1-6 alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio.
- the “—NR a R b group” means a group in which two hydrogen atoms on the nitrogen atom of the “amino group” are substituted with R a and R b . That is, “- NR a R b group” refers to two hydrogen atoms on the nitrogen atom of the “amino group” is, independently, “C 1 ⁇ 6 alkyl group", “halogenated C 1 ⁇ 6 alkyl group “means” C 2 ⁇ 6 alkenyl group "and” C 2 ⁇ 6 alkynyl group "which is substituted in the group selected arbitrarily from the base, for example, such as” di C 1 ⁇ 6 alkyl group "can be mentioned It is done.
- examples of the “di-C 1-6 alkylamino group” include dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, ethylmethylamino, propylmethylamino and the like. Is mentioned.
- Examples of “monocyclic non-aromatic heterocyclic group” in “R a and R b may form a monocyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded” include: Means a monovalent cyclic group formed by removing a hydrogen atom bonded to a nitrogen atom in the “monocyclic non-aromatic heterocyclic group”, specifically, for example, aziridinyl, azetidinyl, pyrrolidinyl , Piperidinyl, azepanyl, azocanyl and the like.
- heterocyclic group in the monocyclic non-aromatic heterocyclic group, at least one of the carbon atoms in the ring is replaced with an atom or carbonyl group arbitrarily selected from an oxygen atom, a sulfur atom and a nitrogen atom
- the heterocyclic group as ⁇ optionally '' may include, for example, oxazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, morpholinyl, thiomorpholinyl, 2-oxo Examples include pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperazinyl, oxadiazolinyl, oxadiazolidinyl and the like.
- R a and R b “in the monocyclic non-aromatic heterocyclic group, at least one of the carbon atoms in the ring is a nitrogen atom (the nitrogen atom is substituted with a C 1-6 alkyl group).
- Specific examples of the heterocyclic group as “which may be substituted” may include 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-propylpiperazine-1 -Yl and the like.
- C 1-6 alkoxylcarbonyl group means a group in which a hydrogen atom of “carboxy group (—COOH)” is substituted with the above “C 1-6 alkyl group”, that is, “Ester group” means.
- examples of the “C 1-6 alkoxylcarbonyl group” include methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and the like.
- L may be bonded to R 2 to form a condensed ring group together with a part of ring B. That is, as shown in the following partial structural formula, L, R 2 and ring B (part) can be bonded together to form a condensed ring D.
- the formed condensed ring D forms a condensed cyclic group together with a part of the adjacent ring B.
- the condensed ring D is a 5- to 7-membered heterocyclic group which may be substituted with a halogen atom, and forms a condensed heterocyclic group together with a part of the adjacent ring B.
- the “fused ring” in “L may bind to R 2 and form a condensed ring group together with a part of ring B”, that is, the condensed ring D is the “heterocyclic group” It means a monocyclic cyclic group, and specific examples include a cyclic group containing an oxygen atom, and a cyclic group containing an oxygen atom is preferred.
- the condensed heterocyclic group composed of the ring B adjacent to the condensed ring D means a condensed cyclic group in the “heterocyclic group”, specifically, the “condensed heteroaryl group”
- a condensed cyclic group containing an oxygen atom is preferable, and a condensed cyclic group containing an oxygen atom is preferable. More specifically, for example, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like can be mentioned.
- L is a substituent adjacent to the bonding position of ring A-bicycloring-CO—. That is, in formula (I), the carbon atom or heteroatom on ring B to which ring A-bicycloring-CO— is bonded and the carbon atom or heteroatom on ring B to which L is bonded are adjacent to each other. .
- n is preferably 2.
- the ring A is preferably a phenyl group or a 5- to 10-membered heteroaryl group, and the phenyl group or heteroaryl group is It may be substituted with 1 to 5 R 1 .
- R 1 is preferably a halogen atom, C 1 ⁇ 6 alkyl group, C 3 ⁇ 8 cycloalkyl group, C 1 ⁇ 6 alkoxy group, C 2 ⁇ 7 alkanoyl group, C 1 ⁇ 6 alkylthio group, -NR a R b group (wherein R a and R b represent a C 1-6 alkyl group, and R a and R b may form a monocyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded).
- the monocyclic non-aromatic heterocyclic group in R a and R b may be such that at least one carbon atom in the ring is substituted with an oxygen atom, a sulfur atom and a C 1-6 alkyl group. it may be replaced by atoms selected arbitrarily from a nitrogen atom which), a cyano group or an oxo group, more preferably a halogen atom, C 1 ⁇ 4 alkyl group, C 3 ⁇ 6 cycloalkyl group, C 1 ⁇ 4 alkoxyl group, C 2 ⁇ 5 alkanoyl group, C 1 ⁇ 4 alkylthio A group, —NR a R b group (wherein R a and R b represent a C 1-4 alkyl group, and R a and R b together with the nitrogen atom to which they are attached are monocyclic non-aromatic heterocycles) A cyano group or an oxo group, more preferably a halogen atom, a C
- a cyano group or an oxo group, which may form a 6-membered non-aromatic heterocyclic group) the alkyl group, cycloalkyl group, alkoxyl group, alkanoyl group or alkylthio group in R 1 above. Are each substituted with 1 to 5 substituents RI May be.
- the ring A is more preferably the following partial structural formula (a1), (a2), (a3) or (a4): (In the formula (a1), (a2), (a3) or (a4), Ring A1 together with the adjacent pyridine ring forms a 9 to 10 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, and the ring A1 is composed of 1 to 2 halogen atoms.
- Ring A2 together with the adjacent pyrazole ring forms an 8- to 9-membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, and the ring A2 is composed of 1 to 2 halogen atoms.
- Ring A3 together with the adjacent imidazole ring forms an 8- to 9-membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, and the ring A3 is composed of 1 to 2 halogen atoms.
- X 1 represents a nitrogen atom, C—H or C—R 1a
- X 2 represents a nitrogen atom, C—H or C—R 1d , provided that when X 1 is a nitrogen atom, X 2 is C—H or C—R 1d
- R 1a represents C 1 ⁇ 6 alkyl group, C 3 ⁇ 8 cycloalkyl group, C 1 ⁇ 6 alkoxy group, a C 2 ⁇ 7 alkanoyl group or a cyano group
- R 1b and R 1c each independently represents a hydrogen atom or a C 1-6 alkyl group
- R 1d represents a halogen atom, C 1 ⁇ 6 alkyl group, C 3 ⁇ 8 cycloalkyl group, C 1 ⁇ 6 alkoxy group, C 1 ⁇ 6 alkylthio group, a -NR a R b group or an oxo group, provided that, When R 1d is an oxo group, X 1 is a
- the ring A is preferably the partial structural formula (a1).
- the ring A1 preferably contains one oxygen atom in the ring A1.
- the ring A1 preferably forms a 9-membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group together with the adjacent pyridine ring.
- a condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group formed by ring A1 with an adjacent pyridine ring is the above-mentioned “condensed heteroaryl group” or “partially hydrogenated”.
- Examples of the “condensed heteroaryl group” include cyclic groups containing a pyridine ring, specifically, isoquinolin-1-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl, furo [ 2,3-c] pyridin-7-yl, furo [3,2-c] pyridin-4-yl, 2,3-dihydrofuro [2,3-c] pyridin-7-yl, 2,3-dihydrofuro [ 3,2-c] pyridin-4-yl and the like, preferably, furo [2,3-c] pyridin-7-yl, furo [3,2-c] pyridin-4-yl, 2,3 -Dihydrofuro [2,3-c] pyridine-7- It is suitably a le or 2,3-dihydrofuro [3,2-c] pyridin-4-yl.
- Said ring A2 preferably forms a 9-membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group with the adjacent pyrazole ring.
- a condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group formed by ring A2 with an adjacent pyrazole ring is the above-mentioned “condensed heteroaryl group” or “partially hydrogenated”.
- Examples of the “condensed heteroaryl group” include cyclic groups containing a pyrazole ring, specifically, 1H-indazol-3-yl, 4,5,6,7-tetrahydro-1H-indazole-3 -Yl, 1H-pyrazolo [3,4-c] pyridin-3-yl, 1H-pyrazolo [4,3-c] pyridin-3-yl, 1H-pyrazolo [3,4-b] pyridin-3-yl 1H-pyrazolo [4,3-b] pyridin-3-yl, 6,7-dihydro-1H-pyrazolo [4,3-c] pyridin-3-yl, 6,7-dihydro-1H-pyrazolo [4 , 3-b] pyridin-3-yl
- the ring A3 preferably forms a 9-membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group with an adjacent imidazole ring.
- a condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group formed by ring A3 with an adjacent imidazole ring is the above-mentioned “condensed heteroaryl group” or “partially hydrogenated”.
- Examples of the “condensed heteroaryl group” include cyclic groups containing an imidazole ring, specifically, imidazo [1,5-a] pyridin-1-yl, imidazo [1,5-a] pyrimidine -8-yl, imidazo [1,5-a] pyrazin-1-yl, 5,6-dihydro-imidazo [1,5-a] pyrazin-1-yl, and the like, preferably imidazo [1, 5-a] pyrazin-1-yl is suitable.
- X 1 is preferably C—H or C—R 1a , more preferably C—R 1a .
- R 1a is preferably C 1 ⁇ 4 alkyl group, C 3 ⁇ 6 cycloalkyl group, C 1 ⁇ 4 alkoxyl group, C 2 ⁇ 5 alkanoyl group or a cyano group, more preferably C 1 ⁇ 2 alkyl groups
- Each of the alkyl group, cycloalkyl group, alkoxyl group or alkanoyl group in 1a may be substituted with 1 to 5 substituents RI.
- R 1b and R 1c are preferably a hydrogen atom or a C 1-4 alkyl group, and more preferably a hydrogen atom or a C 1-2 alkyl group. More preferably, R 1b is a hydrogen atom, and R 1c is a hydrogen atom or a C 1-2 alkyl group.
- the R 1d is preferably a halogen atom, C 1 ⁇ 4 alkyl group, C 3 ⁇ 6 cycloalkyl group, C 1 ⁇ 4 alkoxyl group, C 1 ⁇ 4 alkylthio group, with -NR a R b group (wherein the R a and R b represent a C 1-4 alkyl group, and R a and R b may form a monocyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bound) or an oxo group More preferably, a halogen atom, a C 1-2 alkyl group, a C 3-4 cycloalkyl group, a C 1-2 alkoxyl group, a C 1-2 alkylthio group, a —NR a R b group (wherein the R a and R b represents a C 1-2 alkyl group, and R a and R b together with the nitrogen atom to which they are attached may form a 5-6 membere
- R 1d is an oxo group
- X 1 is a nitrogen atom which may be substituted with a C 1-6 alkyl group, preferably a C 1-4 alkyl group, more preferably a C 1-2 alkyl group.
- R 1e and R 1f are preferably a hydrogen atom or a C 1-4 alkyl group, more preferably a hydrogen atom or a C 1-2 alkyl group, and still more preferably a C 1-2 alkyl group. Is appropriate.
- X 2 is a nitrogen atom
- X 1 is C—R 1a and R 1c is other than a hydrogen atom.
- X 1 is preferably C—R 1a
- R 1b and R 1c are preferably hydrogen atoms.
- the ring A is more preferably the partial structural formula (a1), wherein X 1 is C—R 1a X 2 is a nitrogen atom, C—H or C—R 1d .
- the R 1d represents a halogen atom, C 1 ⁇ 6 alkyl group, C 3 ⁇ 8 cycloalkyl group, C 1 ⁇ 6 alkoxy group, C 1 ⁇ 6 alkylthio group or -NR a R b group.
- the definitions and preferred ranges of R 1a , R 1b and R 1c when ring A is the partial structural formula (a1) are as described above in the above embodiment [1-2-a].
- the R 1d is preferably a halogen atom, C 1 ⁇ 4 alkyl group, C 3 ⁇ 6 cycloalkyl group, C 1 ⁇ 4 alkoxyl group, C 1 ⁇ 4 alkylthio or -NR a R b group (wherein the R a and R b represent a C 1-4 alkyl group, and R a and R b may form a monocyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded, and more preferably Is a halogen atom, a C 1-2 alkyl group, a C 3-4 cycloalkyl group, a C 1-2 alkoxyl group, a C 1-2 alkylthio group, or a —NR a R b group (where R a and R b are A C 1-2 alkyl group, and R a and R b may form a 5- to 6-membered non-aromatic heterocyclic group together with the nitrogen atom to which
- the alkyl group, cycloalkyl group, alkoxyl group, and alkylthio group in R 1d above may each be substituted with 1 to 5 substituents RI.
- the X 2 is a nitrogen atom, preferably it said R 1c is other than a hydrogen atom, that is, C 1 ⁇ 6 alkyl group, more preferably a C 1 ⁇ 4 alkyl groups, more preferably C 1 ⁇ 2 alkyl Suitably the group.
- R 1b and R 1c are preferably hydrogen atoms.
- the ring A is particularly preferably the partial structural formula (a1), wherein X 1 is C—R 1a X 2 is a nitrogen atom, C—H or C—R 1d , R 1a represents a C 1-6 alkyl group or a cyano group, R 1b represents a hydrogen atom, and R 1c represents a hydrogen atom Or a C 1-6 alkyl group, R 1d represents a C 1-6 alkoxyl group, and the alkyl group or alkoxyl group in R 1a , R 1b , R 1c and R 1d is 1-5 It may be substituted with a halogen atom.
- R 1a is preferably a C 1-4 alkyl group or a cyano group, and more preferably a C 1-2 alkyl group or a cyano group.
- R 1c is preferably a hydrogen atom or a C 1-4 alkyl group, and more preferably a hydrogen atom or a C 1-2 alkyl group.
- R 1d is preferably a C 1-4 alkoxyl group, more preferably a C 1-2 alkoxyl group. If the X 2 is a nitrogen atom, the R 1a, R 1c is preferably each independently C 1 ⁇ 6 alkyl group, a C 1 ⁇ 4 alkyl groups each independently more preferably, more preferably Suitably each is independently a C 1-2 alkyl group.
- R 1a is a halogenated C 1-6 alkyl group or a cyano group, more preferably R 1a is a halogenated C 1-4 alkyl.
- R 1a is preferably a halogenated C 1-2 alkyl group or a cyano group.
- R 1c is suitably a hydrogen atom.
- the ring B preferably represents a phenyl group or a 5- to 6-membered monocyclic heteroaryl group, and the phenyl group in the ring B Alternatively, each heteroaryl group may be substituted with 1 to 4 R 2 .
- R 2 is preferably a halogen atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 alkoxyl group, a halogenated C 1-6 alkoxyl group, a cyano group or a monocyclic heteroaryl.
- a group (the heteroaryl group may be substituted with one halogen atom), more preferably a halogen atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a C 1-4 alkoxyl.
- a halogenated C 1-4 alkoxyl group, a cyano group or a 5- to 6-membered heteroaryl group (the heteroaryl group may be substituted with one halogen atom), more preferably a halogen atom, C 1-2 alkyl group, halogenated C 1-2 alkyl group, C 1-2 alkoxyl group, a halogenated C 1-2 alkoxy group, a cyano group or a 5-6 membered heteroaryl group (said heteroar- Lumpur groups are optionally substituted with one halogen atom), especially preferably a halogen atom, C 1 ⁇ 2 alkyl group, a halogenated C 1 ⁇ 2 alkyl group, C 1 ⁇ 2 alkoxy group or cyano It is appropriate that there is a group.
- the ring B more preferably represents a phenyl group or a 5- to 6-membered heteroaryl group, and the phenyl group in the ring B or Each heteroaryl group may be substituted with one R 2 .
- the definition and preferred range of R 2 are as described above in the above embodiment [1-3].
- the ring B is more preferably the following partial structural formula (b1) or (b2):
- Y represents a nitrogen atom, C—H or C—R 2b
- R 2a represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxyl group or a monocyclic heteroaryl group, provided that when Y is C—R 2b , R 2a is a hydrogen atom
- R 2b represents a halogen atom
- R 2c represents a hydrogen atom, a C 1-6 alkyl group or a cyano group
- the alkyl group and alkoxyl group in R 2a and R 2c may each be substituted with 1 to 5 substituents RI, 1 to 6 represent positions in the ring).
- the monocyclic heteroaryl group in R 2a is preferably located in the para position with respect to the bonding position of L, that is, in the formula (b1), the position of Y in the ring is the first position and the bonding of L If the position is 2nd, it is appropriate to be 5th.
- R 2a is preferably a hydrogen atom, a halogen atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a C 1-4 alkoxyl group, a halogenated C 1-4 alkoxyl group, or a 5- to 6-membered hetero group.
- R 2c is preferably a hydrogen atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group or a cyano group, more preferably a hydrogen atom, a C 1-2 alkyl group, a halogenated C 1-2 Suitably an alkyl group or a cyano group.
- the ring B is particularly preferably the partial structural formula (b1) or (b2), where Y is nitrogen.
- Y represents an atom, C—H or C—R 2b
- R 2a represents a hydrogen atom or a halogen atom, provided that when Y is C—R 2b , R 2a is a hydrogen atom and R 2b is a halogen atom
- R 2c represents a hydrogen atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, or a cyano group.
- R 2c is preferably a hydrogen atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group or a cyano group, more preferably a hydrogen atom, a C 1-2 alkyl group, a halogenated C 1-2 Suitably an alkyl group or a cyano group.
- L is preferably, C 3 ⁇ 8 cycloalkyl group, C 1 ⁇ 6 alkoxyl group, a halogenated C 1 ⁇ 6 alkoxy group, Represents a phenyl group or a 5- to 6-membered monocyclic heteroaryl group, and the phenyl group or heteroaryl group in L may each be substituted with 1 to 5 R 3 , or L and R When 2 is a substituent adjacent to each other on ring B, L may be bonded to R 2 to form a condensed ring group together with part of ring B.
- Ring D ′ may be formed.
- the formed condensed ring D ′ forms a condensed cyclic group together with a part of the adjacent ring B.
- the condensed ring D ′ is a 5- to 7-membered monocyclic non-aromatic heterocyclic group which may be substituted with a halogen atom, and a condensed heterocyclic group together with a part of the adjacent ring B Form.
- R 3 is preferably a halogen atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 alkoxyl group, a halogenated C 1-6 alkoxyl group or a cyano group, more preferably A halogen atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a C 1-4 alkoxyl group, a halogenated C 1-4 alkoxyl group or a cyano group, more preferably a halogen atom, C 1-2 An alkyl group, a halogenated C 1-2 alkyl group, a C 1-2 alkoxyl group, a halogenated C 1-2 alkoxyl group or a cyano group, particularly preferably a halogen atom
- L preferably represents a phenyl group or a 5- to 6-membered heteroaryl group, and the phenyl group or heteroaryl in L Each group may be substituted with one R 3 .
- R 3 The definition and preferred range of R 3 are as described above in the above embodiment [1-4].
- L preferably represents a phenyl group or a 5- to 6-membered heteroaryl group, and the phenyl group or heteroaryl in L Each group may be substituted with one R 3 , where R 3 represents a C 1-6 alkyl group, a C 1-6 alkoxyl group or a cyano group, wherein R 3 The alkyl group or alkoxyl group may each be substituted with 1 to 5 substituents RI.
- R 3 is preferably a C 1-4 alkyl group, a C 1-4 alkoxyl group or a cyano group, more preferably a C 1-2 alkyl group, a C 1-2 alkoxyl group or a cyano group, still more preferably. Is suitably a C 1-2 alkyl group or a cyano group.
- L is particularly preferably the following partial structural formula (c1), (c2) or (c3): (In the formula (c1), (c2) or (c3), Z 1 , Z 2 , and Z 3 each independently represent a nitrogen atom or C—H, provided that when Z 2 is C—H, Z 1 is C—H; Z 4 represents an oxygen atom or a sulfur atom, R 3a , R 3b and R 3c each independently represents a hydrogen atom, a C 1-6 alkyl group or a cyano group. Z 4 is preferably a sulfur atom.
- R 3a , R 3b and R 3c are each independently preferably a hydrogen atom, a C 1-4 alkyl group or a cyano group, more preferably a hydrogen atom, a C 1-2 alkyl group or a cyano group, More preferably, it is a hydrogen atom.
- R a and R b are preferably each independently a C 1-6 alkyl group, and R a and R b are A monocyclic non-aromatic heterocyclic group may be formed together with a nitrogen atom to which they are bonded, and the monocyclic non-aromatic heterocyclic group in R a and R b is at least one of carbon atoms in the ring. May be replaced with an atom arbitrarily selected from an oxygen atom, a sulfur atom and a nitrogen atom which may be substituted with a C 1-6 alkyl group.
- R a and R b more preferably each independently represent a C 1-4 alkyl group, and R a and R b together with the nitrogen atom to which they are attached form a monocyclic non-aromatic heterocyclic group More preferably, each independently represents a C 1-2 alkyl group, and R a and R b together with the nitrogen atom to which they are attached form a 5-6 membered non-aromatic heterocyclic group. Also good. [1-6]
- the substituents RI are preferably each independently a halogen atom.
- Ring A represents a phenyl group or a 5- to 10-membered heteroaryl group, and the phenyl group or heteroaryl group in Ring A may each be substituted with 1 to 5 R 1 ;
- Ring B represents a phenyl group or a 5- to 6-membered monocyclic heteroaryl group, and the phenyl group or heteroaryl group in Ring B may each be substituted with 1 to 4 R 2 ;
- L is, C 3 ⁇ 8 cycloalkyl group, C 1 ⁇ 6 alkoxyl group, a halogenated C 1 ⁇ 6 alkoxy group, a monocyclic heteroaryl group phenyl group or a 5-6-membered, or the phenyl group in L
- Each heteroaryl group may be substituted with 1 to 5 R 3 , or when L and R 2
- a condensed ring group may be formed together with a part of ring B, and the condensed ring group is a 5- to 7-membered monocyclic non-aromatic heterocyclic group which may be substituted with a halogen atom.
- n is 2.
- the definition and preferred range of ring A, ring B, L, R 1 , R 2 , R 3 , R a , R b and substituent RI are as described in the above embodiments [1-2] to As described above in [1-6].
- a condensed ring group may be formed together with a part of ring B, and the condensed ring group is a 5- to 7-membered monocyclic non-aromatic heterocyclic group which may be substituted with a halogen atom, L on B is a substituent adjacent to the bonding position of ring A-bicycloring-CO-).
- n is preferably 2.
- a more preferred embodiment is that in the formula (I), the ring A is The following partial structural formula (a1), (a2), (a3) or (a4): (In the formula (a1), (a2), (a3) or (a4), Ring A1 together with the adjacent pyridine ring forms a 9-10 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A1 is composed of 1 to 2 halogen atoms May be replaced, Ring A2 together with the adjacent pyrazole ring forms an 8-9 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A2 is composed of 1 to 2 halogen atoms May be replaced, Ring A3 together with the adjacent imidazole ring forms an 8-9 membered condensed heteroaryl group or a partially hydrogenated conden
- Ring B represents a phenyl group or a 5- to 6-membered heteroaryl group, and each of the phenyl group or heteroaryl group in Ring B may be substituted with one R 2
- L represents a phenyl group or a 5- to 6-membered heteroaryl group, and each of the phenyl group or heteroaryl group in L may be substituted with one R 3 .
- n is 2.
- R 1b is a hydrogen atom
- R 1c is a hydrogen atom or a C 1-2 alkyl group
- R 1d represents a halogen atom, C 1 ⁇ 6 alkyl group, C 3 ⁇ 8 cycloalkyl group, C 1 ⁇ 6 alkoxy group, C 1 ⁇ 6 alkylthio group, a -NR a R b group or an oxo group
- R 1d is preferably a halogen atom, C 1 ⁇ 4 alkyl group, C 3 ⁇ 6 cycloalkyl group, C 1 ⁇ 4 alkoxyl group, C 1 ⁇ 4 alkylthio group, -NR a R b group or an oxo group
- more Preferred are a halogen atom, a C 1-2 alkyl group, a C 3-4 cycloalkyl group, a C 1-2 alkoxyl group, a C 1-2 alkylthio group
- Ring B represents a phenyl group or a 5- to 6-membered heteroaryl group, and each of the phenyl group or heteroaryl group in Ring B may be substituted with one R 2
- Ring C represents a phenyl group or a 5- to 6-membered heteroaryl group, and each of the phenyl group or heteroaryl group in Ring C may be substituted with one R 3
- ring C is a substituent adjacent to the bonding position of ring A-bicycloring-CO—.
- n is preferably 2.
- ring A, ring A1, ring A2, ring A3, X 1, X 2, ring B, R 1, R 1a, R 1b, R 1c, R 1d, R 1e, R 1f , R 2 , R 3 , R a , R b and the substituent RI are as defined above and in the preferred embodiments [1-2] to [1-6].
- a further preferred embodiment is that in the formula (I), the ring A is In the partial structural formula (a1), X 1 is C—R 1a , X 2 is a nitrogen atom, C—H or C—R 1d , R 1d is a halogen atom, C 1-6 alkyl group, C 3 ⁇ 8 cycloalkyl group, C 1 ⁇ 6 alkoxy group, C 1 ⁇ 6 alkylthio group or -NR a R b group; Ring B has the following partial structural formula (b1) or (b2): (In the formula (b1) or (b2), Y represents a nitrogen atom, C—H or C—R 2b , R 2a represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxyl group or a monocyclic heteroaryl group, provided
- R a and R b each independently represent a C 1-6 alkyl group, R a and R b together with the nitrogen atom to which they are attached may form a monocyclic non-aromatic heterocyclic group;
- the monocyclic non-aromatic heterocyclic group for R a and R b is a nitrogen in which at least one of the carbon atoms in the ring may be substituted with an oxygen atom, a sulfur atom and a C 1-6 alkyl group It may be replaced with an atom arbitrarily selected from atoms, A compound, or a pharmaceutically acceptable salt or solvate thereof.
- n is 2.
- R 1b is a hydrogen atom
- R 1c is a hydrogen atom or a C 1-2 alkyl group
- R 1d represents a halogen atom, C 1 ⁇ 6 alkyl group, C 3 ⁇ 8 cycloalkyl group, C 1 ⁇ 6 alkoxy group, a C 1 ⁇ 6 alkylthio group or -NR a R b group
- R 1d is preferably a halogen atom, C 1 ⁇ 4 alkyl group, C 3 ⁇ 6 cycloalkyl group, C 1 ⁇ 4 alkoxyl group, C 1 ⁇ 4 alkylthio group or -NR a R b group, more preferably a halogen atom, C A 1-2 alkyl group, a C 3-4 cycloalkyl group, a C 1-2 alkoxyl group, a C 1-2 alkylthio group, or a —NR a R b group, more
- a 5- or 6-membered heteroaryl group more preferably a hydrogen atom, a halogen atom, a C 1-2 alkyl group, a C 1-2 alkoxyl group or a 5- or 6-membered heteroaryl group, and more preferably a hydrogen atom.
- Is suitably an atom or a halogen atom, provided that when Y is C—R 2b , R 2a is a hydrogen atom; R 2b represents a halogen atom, R 2c represents a hydrogen atom, a C 1-6 alkyl group or a cyano group, and R 2c is preferably a hydrogen atom, a C 1-4 alkyl group or a cyano group, more preferably a hydrogen atom, C 1- 2 is suitably an alkyl group or a cyano group, Each of the alkyl group and alkoxyl group in R 2a and R 2c may be substituted with 1 to 5 substituents RI; R 3 represents a C 1-6 alkyl group, a C 1-6 alkoxyl group or a cyano group, wherein the alkyl group or alkoxyl group in R 3 is each substituted with 1 to 5 substituents RI.
- R 3 is preferably a C 1-4 alkyl group, a C 1-4 alkoxyl group or a cyano group, more preferably a C 1-2 alkyl group, a C 1-2 alkoxyl group or a cyano group.
- R a and R b each independently represent a C 1-6 alkyl group, R a and R b together with the nitrogen atom to which they are attached may form a monocyclic non-aromatic heterocyclic group;
- the monocyclic non-aromatic heterocyclic group for R a and R b is a nitrogen in which at least one of the carbon atoms in the ring may be substituted with an oxygen atom, a sulfur atom and a C 1-6 alkyl group
- R a and R b may be optionally substituted with atoms arbitrarily selected from atoms, and more preferably each independently represents a C 1-4 alkyl group, and R a and R b are bonded to each other.
- the substituents RI each independently represent a halogen atom or a hydroxyl group, preferably a halogen atom.
- n is preferably 2.
- the definition and preferred range of the substituent RI are as described above in the above embodiments [1-2] to [1-6].
- a particularly preferred embodiment is represented by the formula (I):
- R 1a represents a C 1-6 alkyl group or a cyano group
- R 1b represents a hydrogen atom
- R 1c represents a hydrogen atom or a C 1-6 alkyl group
- R 1d represents a C 1-6 alkoxyl.
- Each of the alkyl group or alkoxyl group in R 1a , R 1b , R 1c and R 1d may be substituted with 1 to 5 halogen atoms
- R 2a represents a hydrogen atom or a halogen atom, provided that when Y is C—R 2b , R 2a is a hydrogen atom
- R 2c is preferably a hydrogen atom, a C 1-4 alkyl group, a halogenated group.
- a C 1-4 alkyl group or a cyano group, more preferably a hydrogen atom, a C 1-2 alkyl group, a halogenated C 1-2 alkyl group or a cyano group, L is the following partial structural formula (c1), (c2) or (c3): (In the formula (c1), (c2) or (c3), Z 1 , Z 2 , and Z 3 each independently represent a nitrogen atom or C—H, provided that when Z 2 is C—H, Z 1 is C—H; Z 4 represents an oxygen atom or a sulfur atom, R 3a , R 3b and R 3c each independently represents a hydrogen atom, a C 1-6 alkyl group or a cyano group) A compound, or a pharmaceutically acceptable salt or solvate thereof.
- n is 2.
- ring A, X 1 , X 2 , ring B, Y, L, Z 1 , Z 2 , Z 3 , Z 4 , R 1 , R 1a , R 1b , R 1c , R Definitions and preferred ranges of 1d , R 2 , R 2a , R 2b , R 2c , R 3 , R 3a , R 3b , R 3c , R a , R b and the substituent RI are the above-mentioned embodiments [1-2] to As described above in [1-6].
- R 1d represents a C 1-6 alkoxyl group, and R 1d is preferably a C 1-4 alkoxyl group, more preferably a C 1-2 alkoxyl group, and R 1a , R 1b , Each of the alkyl group or alkoxyl group in R 1c and R 1d may be substituted with 1 to 5 halogen atoms
- Ring B has the following partial structural formula (b1) -1 or (b2) -1: (In the formula (b1) -1 or (b2) -1, Y represents a nitrogen atom, C—H or C—R 2b , R 2a represents a hydrogen atom or a halogen atom, provided that when Y is C—R 2b , R 2a is a hydrogen atom; R 2b represents a halogen atom, R 2c represents a hydrogen atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group or a cyano group, Ring C has the following partial structural formula (
- n is preferably 2.
- the definitions and preferred ranges of 2b , R 2c , R 3 , R 3a , R 3b , R 3c , R a , R b and the substituent RI are as described above in the above embodiments [1-2] to [1-6]. It is.
- R 1d represents a C 1-6 alkoxyl group, and R 1d is preferably a C 1-4 alkoxyl group, more preferably a C 1-2 alkoxyl group, and R 1a , R 1b , Each of the alkyl group or alkoxyl group in R 1c and R 1d may be substituted with 1 to 5 halogen atoms
- Y represents a nitrogen atom, C—H or C—R 2b
- R 2a represents a hydrogen atom or a halogen atom, provided that when Y is C—R 2b , R 2a is a hydrogen atom
- R 2b represents a halogen atom
- Ring C has the following partial structural formula (c1), (c2) or (c3): (In the formula (c1), (c2) or (c3), Z 1 , Z 2 , and Z 3 each independently represent a nitrogen atom or C—H, provided that when Z 2 is C—H, Z 1 is C—H;
- Z 4 represents an oxygen
- n is preferably 2.
- R 3a , R 3b , R 3c , R a , R b and the substituent RI are as described above in the above embodiments [1-2] to [1-6].
- R 1d represents a C 1-6 alkoxyl group, and R 1d is preferably a C 1-4 alkoxyl group, more preferably a C 1-2 alkoxyl group, and R 1a , R 1b , Each of the alkyl group or alkoxyl group in R 1c and R 1d may be substituted with 1 to 5 halogen atoms
- R 2c represents a hydrogen atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group or a cyano group
- R 2c is preferably a hydrogen atom, a C 1-4 alkyl group, a halogenated C 1- 4 alkyl group or cyano group, more preferably a hydrogen atom, C 1-2 alkyl group, halogenated C 1-2 alkyl group or cyano group
- Ring C has the following partial structural formula (c1) or (c3): (In the formula (c1) or (c3), Z 1 and Z 2 each independently represents a nitrogen atom
- n is preferably 2.
- Z 1 , Z 2 , Z 4 , R 1 , R 1a , R 1b , R 1c , R 1d , R 2 , R 2c , R 3 , R 3a , R 3c , R a , R b and the substituent RI are as defined above and in the preferred embodiments [1-2] to [1-6].
- the preferred embodiments can be arbitrarily formed.
- more preferred substituents in the above formula (I) or a combination thereof are in accordance with the explanation described in the first embodiment.
- the sixth aspect of the present invention is the compound of the formula (I) of the aspect [1], wherein the preferred compounds are the compounds listed below, or pharmaceutically acceptable salts thereof, or those: Solvates thereof, or optical isomers thereof.
- the names of the compounds shown below are based on English names obtained according to the compound name naming program of ChemBioDraw (registered trademark) Ultra 14 (CambridgeSoft).
- a seventh aspect of the present invention contains at least one of the compound represented by the above formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. It is a pharmaceutical composition characterized by these.
- An eighth aspect of the present invention contains at least one of the compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
- Diseases involving orexin receptors include sleep disorders such as insomnia, circadian rhythm sleep disorder, and sleep-related sleep disorder; depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, autism, autism Spectrum disorders, mental disorders such as drug dependence; neurodegenerative diseases such as Alzheimer's disease; memory disorders such as dementia; and eating disorders such as bulimia.
- a ninth aspect of the present invention contains at least one of the compound represented by the above formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
- at least one of the compound represented by the above formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof is contained as an active ingredient, thereby preventing sleep disorder And / or a therapeutic agent, more preferably a prophylactic and / or therapeutic agent for insomnia.
- sleep disorder include insomnia, circadian rhythm sleep disorder, and sleep-related complications.
- insomnia More specific examples of insomnia include primary insomnia, insomnia due to mental illness, insomnia due to physical disease, insomnia due to drugs, and the like. However, it is not limited to these.
- a “mental disorder”, specifically, depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, autism, autism spectrum disorder, drug Addiction etc. are mentioned. However, it is not limited to these.
- examples of the “neurodegenerative disease” include Alzheimer's disease. However, it is not limited to these.
- the “memory disorder” specifically includes dementia and the like. However, it is not limited to these.
- “eating disorders” specifically includes bulimia and the like. However, it is not limited to these.
- a tenth aspect of the present invention is an orexin receptor antagonist comprising one or more of the compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof. It is.
- Another aspect of the present invention is an orexin 2 receptor selective antagonist comprising one or more of the compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof. is there.
- Another aspect of the present invention is an orexin receptor dual antagonist comprising one or more of the compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof. is there.
- the “orexin receptor dual antagonist” means an orexin receptor antagonist having an orexin 1 receptor antagonistic action and an orexin 2 receptor antagonistic action.
- An eleventh aspect of the present invention is the use of at least one pharmaceutical composition of a compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof. is there.
- a twelfth aspect of the present invention is the use of a compound represented by the above formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof as at least one orexin receptor antagonist. is there.
- a thirteenth aspect of the present invention is a method for treating a disease selected from sleep disorder, mental disorder, neurodegenerative disorder, memory disorder and eating disorder, and is represented by the above formula (I) Administering at least one of a compound, or a pharmaceutically acceptable salt or solvate thereof, to a subject in need of treatment of said disease or condition.
- a method for treating a sleep disorder wherein at least one of the compound represented by the above formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof is administered in the disease or condition.
- a method comprising administering to a subject in need of treatment, more preferably a method of treating insomnia.
- treatment refers to the progression of a “disease or condition” or one or more “diseases or conditions”. Means to mitigate, or suppress. Further, in the present specification, “treatment” refers to “disease” including preventing the onset of “disease or condition” or any symptoms related to “disease or condition” depending on the condition of the patient. Or prevention of “a condition” as well as reducing the severity of a “disease or condition” or any symptom thereof before onset. As used herein, “treating” is intended to include preventing and ameliorating the recurrence of a “disease or condition”.
- the disease is insomnia, circadian rhythm sleep disorder, parasomnia, depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, autism A prophylactic and / or therapeutic agent according to aspect [9] or a method according to aspect [13], selected from the group of: autism spectrum disorder, drug dependence, Alzheimer's disease, dementia, bulimia.
- the compound of the present invention has an IC 50 value of 1 ⁇ M or less for the orexin receptor when measured by a method in which orexin receptor antagonism is appropriately selected, for example, Pharmacological Experiment Example 1 (orexin receptor antagonism evaluation) described later. Compounds are preferred.
- a compound having a orexin 2 receptor antagonism is preferably a compound an IC 50 value is less than 1 ⁇ M for the orexin 2 receptor, more preferably 200nM or less, more preferably a compound or less 40 nM.
- the compound having such an activity is a compound having an orexin receptor antagonistic action, particularly an orexin 2 receptor antagonistic action, and can be used as an orexin receptor antagonist, particularly an orexin 2 receptor antagonist or a pharmaceutical composition It is.
- diseases involving orexin receptors sleep disorders (insomnia, circadian rhythm sleep disorders, sleep-related complications, etc.), mental disorders (depression, anxiety disorders, bipolar disorders, attention deficit hyperactivity disorder, self Autism, autism spectrum disorder, drug dependence, etc.), neurodegenerative diseases (such as Alzheimer's disease), memory disorders (such as dementia) or eating disorders (such as bulimia), especially diseases involving the orexin 2 receptor Or as an agent for preventing and / or treating sleep disorders such as insomnia.
- the compounds of the present invention include compounds having orexin 2 receptor antagonistic activity but not having orexining orexin 1 receptor antagonistic activity.
- Such compounds include orexin 2 receptor. It can be used as a compound having a selective antagonism or an orexin 2 receptor selective antagonist.
- a compound having an IC 50 value for orexin 1 receptor of 10 times or more, 20 times or more, 50 times or more, or 100 times or more of the IC 50 value for orexin 2 receptor can be mentioned.
- a compound having an orexin 2 receptor selective antagonism is useful as a pharmaceutical composition having no side effects due to orexin 1 receptor antagonism.
- diseases involving orexin 2 receptor sleep disorders (insomnia, circadian rhythm sleep disorders, sleep-related complications, etc.), mental disorders (depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, Autism, autism spectrum disorder, drug addiction, etc.), neurodegenerative diseases (Alzheimer's disease, etc.), memory disorders (dementia, etc.) or eating disorders (eg, bulimia), especially sleep disorders such as insomnia It can be used as a preventive and / or therapeutic agent.
- the compounds of the present invention include compounds having orexin 2 receptor antagonism as well as orexin 1 receptor antagonism, and such compounds are compounds having orexin receptor dual antagonism, It can be used as an orexin receptor dual antagonist or a pharmaceutical composition. Moreover, it can utilize as a preventive and / or therapeutic agent of the disease in which the above orexin receptor is involved.
- the compound of the present invention may form an acid addition salt or a salt with a base depending on the type of substituent.
- a salt is not particularly limited as long as it is a pharmaceutically acceptable salt.
- metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basics, Or the salt with an acidic amino acid etc. are mentioned.
- the metal salt include alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt, alkaline earth metal salts such as calcium salt, magnesium salt and barium salt, and aluminum salt. (For example, besides a mono salt, a disodium salt and a dipotassium salt are also included).
- the salt with an organic base include, for example, methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine, diethanolamine, triamine.
- the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
- the salt with an organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acids such as citric acid Salts with acids, salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid, salts of aromatic dicarboxylic acids such as phthalic acid, cinnamic acid, glycolic acid, pyruvic acid, oxylic acid, salicylic acid, N-acetylcysteine, etc.
- Salt with organic carboxylic acid salt with organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, gluta Acid addition salts with acidic amino acids such as phosphate and the like.
- Preferable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine
- preferable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred.
- an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt)
- an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
- examples thereof include salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
- the salt is formed by mixing the compound of the present invention with a solution containing an appropriate amount of acid or base to form the desired salt, and then separated by filtration, or the mixed solvent is distilled off. Can be obtained.
- the compound of the present invention or a salt thereof can form a solvate with a solvent such as water, ethanol or glycerol.
- solvate means a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules (eg, water, ethanol, etc.). When the solvent molecule is water, it is specifically called “hydrate”.
- solvent molecules eg, water, ethanol, etc.
- Prodrugs of the compounds of the present invention are also encompassed by the compounds of the present invention.
- a “prodrug” is, for example, when a certain derivative of a compound of the invention, which may exhibit little or no desired pharmacological activity, is administered in or on the body, eg, hydrolysis. When converted to the compound of the present invention having the desired pharmacological activity by the like, the compound before administration is called “prodrug”.
- “Prodrugs” of the compounds of the present invention may be prepared, for example, by combining suitable functional groups present in the compounds of the present invention with methods known in the literature, such as Design of Prodrugs, H. et al. It can be produced according to the method described in Bundgaard (Elsevier, 1985). Specific examples of the “prodrug” of the compound of the present invention include the following (1) to (3), but are not limited thereto.
- any one isomer And mixtures thereof are encompassed by the compounds of the present invention.
- the optical isomer resolved from the racemate is also encompassed in the compound of the present invention.
- the compound of the present invention has one or more asymmetric carbon atoms, two or more stereoisomers can exist.
- the compounds of the present invention if it contains "C 2 ⁇ 6 alkenyl group", geometric isomers (cis / trans or Z / E,) can be present.
- tautomerism can occur when structural isomers can be interconverted by a low energy barrier. Examples of tautomerism include proton tautomerism in compounds having an imino, keto, or oxime group.
- each can be isolated by known means.
- the racemate may be separated into a (+) form or a ( ⁇ ) form [(D) form or (L) form] by a conventional optical resolution means. it can.
- the compound of the present invention contains optical isomers, stereoisomers, positional isomers, rotational isomers, and tautomers, each isomer is converted to a single isomer by a known synthesis method or separation method. It can be obtained as a compound.
- the optical resolution method include methods known per se, such as (1) fractional recrystallization method, (2) diastereomer method, (3) chiral column method and the like.
- Fractionation recrystallization method After obtaining a crystalline diastereomer by ion-bonding an optical resolving agent to a racemate, it is separated by a fractional recrystallization method and, if desired, a neutralization step is performed. This is a method for obtaining a free optically pure compound.
- the optical resolution agent include (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, ( ⁇ )-1-phenethylamine, Examples include cinchonine, ( ⁇ )-cinchonidine, brucine and the like.
- Diastereomer method An optical resolution agent is covalently bonded (reacted) to a racemic mixture to obtain a mixture of diastereomers, which is then subjected to usual separation means (eg, fractional recrystallization, silica gel column chromatography). , High-performance liquid chromatography (HPLC), etc.) and then optically pure by removing the optical resolving agent by chemical treatment such as hydrolysis reaction. To obtain an optical isomer.
- separation means eg, fractional recrystallization, silica gel column chromatography). , High-performance liquid chromatography (HPLC), etc.
- the compound of the present invention when the compound of the present invention has an intramolecular hydroxyl group or a primary or secondary amino group, the compound and an optically active organic acid (eg, MTPA [ ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid], (-)-Menthoxyacetic acid and the like) are subjected to a condensation reaction to obtain ester or amide diastereomers, respectively.
- an amide or ester diastereomer can be obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. Each of the separated diastereomers is converted to an optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.
- Chiral column method A method in which a racemate or a salt thereof is subjected to direct optical resolution by subjecting it to chromatography on a chiral column (optical isomer separation column).
- a chiral column such as CHIRAL series (Daicel), water, various buffers (eg, phosphate buffer), organic solvents (eg, ethanol, methanol) , Isopropanol, acetonitrile, trifluoroacetic acid, diethylamine) alone or as a mixed solution, the optical isomers can be separated by development.
- the compound of the present invention may be a crystal, and a single crystal form or a crystal form mixture is included in the compound of the present invention.
- the compound of the present invention may be a pharmaceutically acceptable cocrystal or cocrystal salt.
- co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid.
- the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
- Compounds of the present invention include isotopes (eg, hydrogen isotopes, 2 H and 3 H, carbon isotopes, 11 C, 13 C, and 14 C, chlorine isotopes, 36 Cl, etc., fluorine Isotopes, 18 F, iodine isotopes, 123 I and 125 I, nitrogen isotopes, 13 N and 15 N, oxygen isotopes, 15 O, 17 O, and 18 O, phosphorus Also included are compounds labeled or substituted with isotopes, 32 P and the like, as well as sulfur isotopes, 35 S and the like.
- isotopes eg, hydrogen isotopes, 2 H and 3 H, carbon isotopes, 11 C, 13 C, and 14 C, chlorine isotopes, 36 Cl, etc.
- fluorine Isotopes, 18 F iodine isotopes, 123 I and 125 I
- Compounds of the invention labeled or substituted with certain isotopes can be synthesized, for example, by Positron Emission Tomography; PET ) Can be used as a tracer (PET tracer) for use in medical diagnosis and the like.
- Compounds of the invention labeled or substituted with certain isotopic labels are useful in drug and / or substrate tissue distribution studies. For example, 3 H and 14 C are useful for this research purpose because they are easy to label or displace and easy to detect.
- a compound labeled or substituted with 2 H (or sometimes referred to as D or deuterium) (D compound, deuterated compound) is expected to have high stability and is useful as an active compound itself. is there.
- a compound in which a hydrogen atom at a position to undergo metabolism is substituted with 2 H can be mentioned, and the metabolic reaction rate can be reduced with little influence on the properties of the compound.
- a compound in which the position of irreversibly binding to a metabolic enzyme is substituted with 2 H can suppress the inhibition of the action of the metabolic enzyme, and can reduce the drug interaction at the time of combined use.
- Isotopically-labeled compounds of the invention can be obtained by conventional techniques known to those skilled in the art or by methods analogous to the synthetic methods described in the examples below.
- the obtained isotope-labeled compound can be used for pharmacological experiments instead of the unlabeled compound.
- Definitions appearing in formula (I) such as L, ring A, ring B, R a , and R b in each formula of the following production methods are those of formula (I) described in the above embodiment unless otherwise specified. Each definition is the same.
- the definitions of L ′ and L ′′ in the production method are included in the definition of L in formula (I) and are defined in each production method.
- the definition of M in the production method is a metal such as lithium, sodium and potassium unless otherwise specified.
- the definition of X in the production method is a halogen atom or trifluoromethanesulfonate (OTf) unless otherwise specified.
- the definition of B in the production method is boronic acid ester, boronic acid, trifluoroborate salt, or boronic acid N-methyliminodiacetic acid ester unless otherwise specified.
- the definitions of P 1 and P 2 in the production method are a protecting group for a hydrogen atom or an imino group.
- Definition of R A in the manufacturing method is a C 1 ⁇ 6 alkyl group, C 6 ⁇ 14 aryl group or a C 7 ⁇ 20 aralkyl group.
- Definition of R B in the production process is a C 1 ⁇ 6 alkyl group or a C 3 ⁇ 8 cycloalkyl group.
- R C during manufacturing process, unless otherwise specified, C 3 ⁇ 8 cycloalkyl group, C 1 ⁇ 6 alkoxy group, C 1 ⁇ 6 alkylthio group, non-aromatic heterocyclic group or -NR a R b, It is a group.
- each raw material compound used for the production of formula (I) may form a salt, and as such a salt, the same salts as those of the aforementioned formula (I) can be mentioned. Can be mentioned.
- Each raw material compound used in the production of formula (I) can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from a reaction mixture according to a conventional method. It can be easily purified by known means, for example, separation means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, chromatography and the like.
- Examples of the solvent used for the recrystallization include water; alcohols such as methanol, ethanol, 2-propanol and butanol; ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; n-hexane, cyclohexane and heptane.
- Hydrocarbons such as benzene, toluene, xylene, etc .; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone; chloroform , Halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane; nitriles such as acetonitrile; ketones such as acetone and diphenyl ketone; esters such as methyl acetate and ethyl acetate; sulfoxides such as dimethyl sulfoxide; , Trifluoroacetic acid, methanesulfur Phosphate, organic acids such as p- toluenesulfonic acid; and the like.
- solvents can be used alone, or two or more kinds of solvents can be mixed at an appropriate ratio, for example, a ratio of 1: 1 to 1:10.
- a ratio of 1: 1 to 1:10 can be used when the compound in a formula is marketed, a commercial item can also be used as it is, and what was manufactured by the method known per se or a method according to it can also be used.
- substituent having the formula (I) is transformable functional group (e.g., carboxyl group, an amino group, a hydroxyl group, a carbonyl group, a mercapto groups, C 1 ⁇ 6 alkoxycarbonyl groups, C 6 ⁇ 14 aryloxycarbonyl groups, C In the case of containing 7-20 aralkyloxycarbonyl groups, sulfo groups (—SO 2 OH), halogen atoms, etc.), various compounds can be produced by converting these functional groups by a method known per se or a method analogous thereto. Can do.
- transformable functional group e.g., carboxyl group, an amino group, a hydroxyl group, a carbonyl group, a mercapto groups, C 1 ⁇ 6 alkoxycarbonyl groups, C 6 ⁇ 14 aryloxycarbonyl groups, C
- various compounds can be produced by converting these functional groups by a method known per se or a method analogous thereto. Can do.
- a “carboxy group” it can be converted by a reaction such as esterification, reduction, amidation, or a conversion reaction to an optionally protected amino group.
- an “amino group” it can be converted by a reaction such as amidation, sulfonylation, nitrosation, alkylation, arylation, imidation and the like.
- hydroxyl group it can be converted by a reaction such as esterification, carbamoylation, sulfonylation, alkylation, arylation, oxidation, halogenation and the like.
- carbonyl group it can be converted by a reaction such as reduction, oxidation, imination (including oximation and hydrazone formation), (thio) ketalization, alkylidene formation, thiocarbonylation and the like.
- a “mercapto group” it can be converted by a reaction such as alkylation or oxidation.
- the reduction can be converted by reaction such as hydrolysis.
- a “sulfo group” it can be converted by a reaction such as sulfonamidation or reduction.
- halogen atom it can be converted by, for example, various nucleophilic substitution reactions, various coupling reactions and the like.
- the compound when it is obtained in a free state, it may be converted into a salt according to a conventional method.
- salt When it is obtained as a salt, it is converted into a free form or other salt according to a conventional method.
- You can also These functional groups can be converted in accordance with, for example, the method described in the book of Larock et al., Comprehensive Organic Transformations, 2nd edition, October 1999, Wiley-VCH.
- a hydroxyl group an alcoholic hydroxyl group, a phenolic hydroxyl group, a heterocyclic hydroxyl group, etc.
- an amino group as a substituent
- Examples of the protective group for the hydroxyl group include C 1-6 represented by methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and the like.
- Examples of the protecting group for the amino group (—NH 2 group) or imino group (—NH— group) include alkanoyl groups represented by acetyl, ethylcarbonyl, pivaloyl, etc .; methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl Allyloxycarbonyl group; fluorenylmethoxycarbonyl group; phenyloxycarbonyl; aralkyloxycarbonyl group represented by benzyloxycarbonyl, paramethoxybenzyloxycarbonyl, paranitrobenzyloxycarbonyl and the like; Aralkyl groups typified by benzyl, triphenylmethyl, etc .; aroyl groups typified by benzoyl, etc .; aralkylcarbonyl groups typified by benzylcarbonyl, etc .; methanesulfonyl, p-toluenesulfonate , 2,4
- Examples of the protecting group for the carboxy group include alkyl groups typified by methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc .; alkenyl groups typified by allyl; An aryl group typified by phenyl or the like; an aralkyl group typified by benzyl, triphenylmethyl or the like; a silyl group typified by trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl or the like is used.
- Examples of the protecting group for the thiol group include alkyl groups typified by methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and the like; benzyl, triphenylmethyl and the like.
- Aralkyl groups represented by acetyl, ethylcarbonyl, pivaloyl and the like; aroyl groups represented by benzoyl and the like are used.
- Such a method for introducing / removing a protecting group is appropriately performed depending on the group to be protected or the type of protecting group. For example, Greene et al., Protective Groups in Organic Synthesis 4th Edition, 2007, John Wiley & Sons. It can be performed by the method described in the book.
- Examples of the deprotection method of the protecting group include alkanoyl groups represented by acetyl, ethylcarbonyl, pivaloyl, etc .; alkoxylcarbonyl groups represented by methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc .; benzoyl, etc.
- An acyl-type protecting group such as an aroyl group can be hydrolyzed and deprotected by using an appropriate base such as an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
- Alkoxylalkyl-type protecting groups represented by methoxymethyl, methoxyethoxymethyl, tetrahydropyranyl, etc .; Alkoxylcarbonyl-type protecting groups represented by t-butoxycarbonyl, etc .; benzyloxycarbonyl, paramethoxybenzyloxycarbonyl, etc.
- Aralkyloxycarbonyl-type protecting groups represented by trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and the like include, for example, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethane Deprotection can be achieved by using an appropriate acid such as sulfonic acid or a combination thereof.
- the silyl-type protecting group can also be deprotected by using a suitable fluorine ion (F ⁇ ) generating reagent such as a reagent such as tetrabutylammonium fluoride and hydrogen fluoride.
- F ⁇ fluorine ion
- Aralkyloxycarbonyl groups typified by benzyloxycarbonyl, paramethoxybenzyloxycarbonyl, paranitrobenzyloxycarbonyl and the like and aralkyl groups typified by benzyl are, for example, hydrogenolysis using a palladium-carbon (Pd-C) catalyst.
- Pd-C palladium-carbon
- the benzyl group can also be deprotected by, for example, Birch reduction using metallic sodium in liquid ammonia.
- the triphenylmethyl group can be deprotected by using an appropriate acid, for example, an acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or a combination thereof. . It can also be deprotected by liquid Birch reduction using metallic sodium or metallic lithium or hydrogenolysis using a palladium carbon catalyst.
- an appropriate acid for example, an acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or a combination thereof.
- an appropriate acid for example, an acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or a combination thereof.
- It can also be deprotected by liquid Birch reduction using metallic
- the sulfonyl group can be deprotected by, for example, one-electron reduction using Na / anthracene or Na / naphthalene at low temperature or Birch reduction using metallic sodium or metallic lithium in liquid ammonia.
- the 2-nitrobenzenesulfonyl group can be deprotected under mild conditions in which a thiol is reacted in the presence of a basic reagent such as potassium carbonate or triethylamine.
- the protecting group deprotection method shown here is only one example.
- reaction temperature is in the range from ⁇ 78 ° C. to the temperature at which the solvent is refluxed.
- the temperature is not described, it is room temperature (0 to 35 ° C.), and the reaction time is the time for which the reaction proceeds sufficiently. .
- each step in the production method can be performed without solvent or by dissolving or suspending the raw material compound in a solvent not involved in an appropriate reaction before the reaction.
- solvents that do not participate in the reaction include water; saturated hydrocarbon solvents such as cyclohexane and hexane; aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene, and xylene; methanol, ethanol, 1-propanol, 2 Alcohol solvents such as propanol, tert-butyl alcohol, 2-methoxyethanol; N, N-dimethylformamide (DMF), N, N-dimethylacetamide, hexamethylphosphoric triamide, 1,3-dimethyl-2- Polar amide solvents such as imidazolidinone: sulfoxide solvents such as dimethyl sulfoxide (DMSO); nitrile solvents such as acetonitrile and propionitrile; diethyl ether, diisopropyl
- the base (or deoxidizer) used in the production method of the compound of the present invention include lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, and carbonate.
- Inorganic bases such as cesium, calcium carbonate, sodium bicarbonate; triethylamine, N, N-diisopropylethylamine (DIPEA), tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4-dimethylaminopyridine (DMAP), N, N-dimethyl Aniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,4-diazabicyclo [2.2.2] octane, 1, 8-Diazabicyclo [5.4.0] -7-undecene
- Organic bases such as imidazole; metal alkoxid
- inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid; acetic acid, trifluoroacetic acid, oxalic acid, Organic acids such as phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid; boron trifluoride ether complex, zinc iodide, anhydrous chloride Lewis acids such as aluminum, anhydrous zinc chloride, and anhydrous iron chloride.
- inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid
- acetic acid trifluoroacetic acid, oxalic acid
- Organic acids such as phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic
- the salt of the formula (I) is prepared according to a method known per se.
- an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
- organic acids such as formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid
- formula (I) is an acidic compound, ammonia, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N -Diisopropylethylamine, N, N'-dibenzylethylenediamine, N, N-dialkyl
- an organic base such as ruaniline or an inorganic base such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide
- Solvent solvent such as benzene, toluene, polar solvents such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, etc., or a mixed solvent of these solvents are used.
- the reaction can be performed at a refluxing temperature to produce a compound represented by the formula (AM-3).
- ⁇ Step 2> [Production Method A] Using a compound represented by the formula (AM-3) obtained in ⁇ Step 1>, a method known in the literature, for example, “Protective Groups in Organic Synthesis 4th, 2007, John Wiley & Sons, Greene” In accordance with the method described in the book of the et al., The P 2 group is deprotected by reacting the protecting group P 2 with a method according to the type of the protecting group, and the formula (AM-4) Can be produced.
- a method described in “Experimental Chemistry Course 4th edition 22 Organic Synthesis IV Acid / Amino Acid / Peptide, 191-309, 1992, Maruzen” and the like 1,3-dicyclohexylcarbodiimide ( DCC), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBT), benzotriazol -1-Iroxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent), bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOP-Cl), 2-chloro-1,3-di
- the compound of formula (CA) can be prepared according to methods known in the literature, for example, “Journal of the American Chemical Society, 109 (24), p7488-7494, 1987”. Halogenation of thionyl chloride, oxalyl chloride, phosphoryl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide in the presence or absence of bases such as N-diisopropylethylamine and N, N-dimethylaminopyridine The reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C.
- ⁇ Step 2> [Production Method B] Using a compound of formula (AM-5) obtained in ⁇ Step 1>, a method known in the literature, for example, “Protective Groups in Organic Synthesis 4th, 2007, John Wiley & Sons, Green et al.” A compound represented by the formula (AM-6), wherein the P 1 group is deprotected by reacting the protecting group P 1 according to the method according to the type of the protecting group in accordance with the method described in the document Can be manufactured.
- a palladium catalyst such as (tetrakis triphenylphosphine palladium (Pd (PPh 3) 4
- a copper reagent such as copper iodide (CuI)
- CuI copper iodide
- a salt such as cesium fluoride and lithium chloride
- toluene, tetrahydrofuran, N, N-dimethyl Using a solvent such as formamide, 1,4-dioxane, or a solvent not involved in the reaction, or a mixed solvent thereof, the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C
- a solvent that does not participate in the reaction such as toluene, N, N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, or a mixed solvent thereof in the presence or absence of
- a solvent that does not participate in the reaction such as toluene, N, N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, or a mixed solvent thereof in the presence or absence of
- Trialkylborate such as trimethylborate and triisopropylborate is added in the presence of a reagent or magnesium metal, and the reaction is carried out at ⁇ 78 ° C. to room temperature, then an acid such as hydrochloric acid and sulfuric acid is added, and the solvent is refluxed from 0 ° C. Reaction at a temperature to produce a boronic acid of formula (IM-1) Can.
- a solvent that does not participate in the reaction such as water, N, N-dimethylformamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, in the presence or absence of a base such as diisopropylethylamine or triethylamine.
- the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. It can be produced compound.
- ⁇ Step 4> The compound of formula (AR-2-2), and the compound of formula (AM-1) (formula (AR-2-2) and compound of formula (AM-1) are commercially available compounds, or prepared from commercially available compounds in the literature
- the compound of formula (AM-3-2) can be produced by carrying out a reaction according to [Production Method A] ⁇ Step 1> using a compound of (a compound that can be produced by the method).
- ⁇ Step 5> [Production Method D] Using the compound of formula (AM-3-2) obtained in ⁇ Step 4> and trifluoroacetic anhydride (TFAA), a method known in the literature, for example, “WO2007 / 043677 pamphlet”.
- a compound of formula (E-1) (the compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature), and a compound of formula (RG-2) or formula (RG-3)
- the compound of formula (E-2) can be produced by carrying out a reaction according to [Production method C] ⁇ Step 4>.
- the compound of the formula (CA-3) can be produced by performing the reaction at a temperature at which the solvent is refluxed from 0 ° C. using a solvent inert to the reaction such as 4-dioxane and tetrahydrofuran, or a mixed solvent thereof. .
- Alcohol solvents such as methanol, ethanol, 2-propanol, ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, polar solvents such as ethyl acetate, methyl acetate, etc.
- the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. using a solvent that does not react or a mixture thereof. -3) can be produced.
- Step 1> Using a compound of the formula (G-1) (the compound is a commercially available compound or a compound that can be produced from a commercially available compound by a method known in the literature) and 2-hydrazinopyridine, a method known in the literature, for example,
- the reaction is performed in the presence of acetic acid using a solvent that does not participate in the reaction, such as tetrahydrofuran and 2-methoxyethanol, at a temperature at which the solvent refluxes from 0 ° C.
- a compound of the formula (G-2) can be produced.
- Step 1> Using the compound of formula (H-1) (the compound is a commercially available compound or a compound that can be produced from a commercially available compound by a production method known in the literature) and 2-hydrazinopyridine, [Production Method G] ⁇ Step The compound of the formula (H-2) can be produced by performing a reaction according to 1>.
- Combination agent containing the compound of the present invention can be used in combination with other drugs or drugs by a general method performed in the medical field.
- Examples of the drug that can be combined or used in combination with the compound of the present invention include (A) a sleep disorder-related drug, (B) a therapeutic drug for a disease that easily causes sleep disorder, and the like.
- Examples of the drug (A) include: (1) a sleep inducer ((i) a benzodiazepine sleep inducer [specifically, nitrazepam, estazolam, flurazepam hydrochloride, nimetazepam, flurazepam, haloxazolam, flunitrazepam, rilmazapine hydrochloride, Lormetazepam, triazolam, etc.], (ii) thienodiazepine sleep inducer [specifically, brotizolam, etc.], (iii) non-benzodiazepine sleep inducer [specifically, zolpidem, etc.], (iv) melatonin receptor operation Drugs (specifically, ramelteon, etc.), (v) cyclopyrrolone sleep inducers [specifically, zopiclone, etc.], (vi) orexin receptor antagonists [specifically, suvorexant, etc.], ( 2) Drugs prescribed for sleep apnea
- Examples of the drug of (B) include (4) atypical antipsychotic drugs [specifically, olanzapine, quetiapine, clozapine, ziprasidone, risperidone, paliperidone, perospirone, blonanserin, lurasidone, aripiprazole, sertindole, amisulpride, Iloperidone, bifeprunox, asenapine, melperone, brexpiprazole, zotepine, etc.], (5) typical antipsychotics [specifically, chlorpromazine, pchlorperazine, perphenazine, levomepromazine, fluphenazine, thioridazine, propericazine, spiperone] , Moperon, haloperidol, timiperone, bromperidol, pimozide, fluropipamide, sulpiride, thioprid, s
- Muscarinic M1 acetylcholine receptor activity modulator (21) Muscarinic M2 acetylcholine receptor activity modulator, (22) Adenosine receptor modulator, (23) Muscarinic M4 acetylcholine receptor activity regulator, (24 ) Muscarinic M5 acetylcholine receptor activity modulator, (25) adenosine receptor modulator, (26) glycine transporter 1 (GlyT1) inhibitor [specifically, ALX5407, SSR504734, etc.], (27) glutamate enhancer [Specifically, ampakine], (28) NMDA receptor inhibitor [specifically, memantine hydrochloride and the like], (29) metabolic glutamate receptor modulator (mGlu) [specifically, CDPPB, MPEP Etc.], (30) Anti-anxiety drugs ((i) benzodiazepine anxiolytic drugs [specifically Chlordiazepoxide, diazepam, oxazolam, medazep
- Antidiabetic agent ((i) PPAR ⁇ agonist (agonist, inhibitor) [specifically, pioglitazone, rosiglitazone, troglitazone, siglitazone, darglitazone, englitazone, netoglitazone, etc.], (ii) insulin Secretion enhancer [(a) sulfonylurea (specifically, tolbutamide, acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, glimepiride, glipentide, glyquidone, glisolamide, tolazamide, etc.), (b) non-sulfonylurea Agents, etc.], (iii) fast-acting insulin secretagogues (specifically, nateglinide, mitiglinide, repaglinide, etc.), (iv) ⁇ -glucosidase inhibitors [specifically, acarbose, a
- GPR40 agonists GPR40 agonists, (g) GPR119 agonists, (h) GPR120 agonists], (vi) hepatic gluconeogenesis inhibitors [specifically, glucagon antagonists, etc.], vii) biguanides [specifically, metformin, buformin, phenformin, etc.], (viii) insulin or insulin derivatives [specifically, insulin Phosphorus zinc suspension, insulin lispro, insulin aspart, regular insulin, NPH insulin, insulin glargine, insulin detemir, mixed insulin, etc.], (ix) ⁇ 2 antagonist [specifically, midaglyzol, isagridol, deliglidol, idazoxan , Efaloxane, etc.]),
- anti-obesity drugs ((i) adrenergic ⁇ 3 receptor agonists [specifically, KRP-204, TRK-380 / TAC-301, etc.], (ii) CB-1 receptor antagonists [specifically Rimonabant, SR-147778, BAY-65-2520 etc.], (iii) Neuropeptide Y (NPY) receptor antagonist [specifically, S-2367 etc.], (iv) Antifeedant [monoamine] Reuptake inhibitors [specifically sibutramine, mazindol, etc.]], (v) lipase inhibitors [specifically, orlistat, cetiristat, etc.], (vi) peptide YY (PYY) receptor antagonists, etc.), (40) Antihyperlipidemic drugs such as cholesterol-lowering drugs ((i) ⁇ 3 fatty acids [specifically, ethyl icosapentate (EPA-E preparation, for example, product name: Epadale (registered trademark) ), Docos,
- Antihypertensive agent (i) diuretic [specifically, trichlormethiazide, hydrochlorothiazide, mefluside, indapamide, methiclan, chlorthalidone, tripamide, furosemide, torasemide, bumetanide, ethacrynic acid, spironolactone, triamterene, eplerenone, etc.]
- (Ii) Calcium receptor antagonists [specifically, amlodipine, felodipine, nicardipine, nifedipine, nimodipine, nitrendipine, nilvadipine, alanidipine, azelnidipine, manidipine, varnidipine, efonidipine, cilnidipine, benidipine, diltiazem etc.], (synten) Converting enzyme inhibitors [specifically, captopril, lisinopril,
- Non-steroidal anti-inflammatory drugs [specifically, meloxicam, teoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin, etc.], (43) disease-modifying anti-rheumatic drugs, (44) anti-cytokine drugs [44] Specifically, TNF inhibitors, MAP kinase inhibitors], (45) steroid drugs [specifically, dexamethasone, hexestrol, cortisone acetate, etc.], (46) sex hormones or derivatives thereof [specifically, , Progesterone, estradiol, estradiol benzoate, etc.], (47) parathyroid hormone, (48) opioid agonist [specifically, morphine, pentazocine, tramadol], (49) pilin antipyretic analgesic [specifically, Sulpyrine], (50) non-pyrine antipyretic analgesics [specific Acetamin
- the dosage of existing drugs can be reduced, and the side effects of existing drugs can be reduced.
- the combination method using the said drug is not limited to the said disease, and the drug used together is not limited to the compound illustrated above.
- the compound of the present invention when used in combination with a drug used in combination, it may be a separate preparation or a combination. Moreover, in separate preparations, both can be taken simultaneously or can be administered at different times.
- the compounds of the present invention can be administered either alone or in combination with a pharmaceutically acceptable carrier, either single or multiple doses.
- suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution, and various organic solvents.
- the pharmaceutical composition thereby formed can then be easily administered in various dosage forms such as tablets, powders, lozenges, liquid preparations, syrups, injection solutions and the like.
- These pharmaceutical compositions can optionally contain additional ingredients such as flavoring agents, binders, excipients and the like.
- the compounds of the present invention may be used for oral, buccal, nasal, parenteral (eg, intravenous, intramuscular, or subcutaneous), transdermal (eg, patch), or rectal administration, or by inhalation or insufflation.
- parenteral eg, intravenous, intramuscular, or subcutaneous
- transdermal eg, patch
- rectal administration or by inhalation or insufflation.
- the administration mode of the compound of the present invention and the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
- Such dosage forms include, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, (2) Simultaneous administration by the same route of administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug, (3) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at the same administration route with a time difference, (4) Simultaneous administration of two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes, (5) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at different time intervals in different administration routes (for example, administration in the
- the concomitant drug and the compound of the present invention may be administered at the same time, but after administering the concomitant drug, the compound of the present invention may be administered.
- a concomitant drug may be administered after administration of the compound of the invention.
- the time difference varies depending on the active ingredient to be administered, dosage form, and administration method.
- administering the concomitant drug first preferably within 1 minute to 3 days after administering the concomitant drug.
- the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after the administration of the compound of the present invention. The method of doing is mentioned.
- the daily dose as a concomitant drug varies depending on the administration subject, administration route, target disease, symptom, etc., for example, when orally administered to a patient with schizophrenia (adult, body weight about 60 kg), Usually, the dose is about 0.1 to about 20 mg / kg body weight, preferably about 0.2 to about 10 mg / kg body weight, more preferably about 0.5 to about 10 mg / kg body weight. It is desirable to administer once to several times (eg, 2, 3, 4 or 8 times). When the compound of the present invention is used in combination with a concomitant drug, the amount of each agent can be reduced within a safe range in consideration of the opposite effect of those agents.
- the concomitant drug of the present invention has low toxicity.
- the compound of the present invention, or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a known method, for example, a pharmaceutical composition such as a tablet.
- a pharmaceutical composition such as a tablet.
- a pharmaceutical composition such as a tablet.
- a pharmaceutical composition such as a tablet.
- a pharmaceutical composition such as a tablet.
- a pharmaceutical composition such as a tablet.
- a pharmaceutical composition such as a tablet.
- a pharmaceutical composition such as a tablet.
- a pharmaceutical composition such as a tablet.
- a pharmaceutical composition such as a tablet.
- a pharmaceutical composition such as a tablet.
- powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release agents, and the like which can be oral or parenteral (Eg, topical, rectal, intravenous, etc.).
- the same carriers as those used for the pharmaceutical composition of the present invention described above can be used.
- the compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like. Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
- the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
- the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
- the administration subject is a human
- 0.01 to 100 parts by mass of the concomitant drug may be used per 1 part by mass of the compound of the present invention.
- the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by mass, preferably about 0, based on the whole preparation. The range is from 1 to 50% by mass, and more preferably from about 0.5 to 20% by mass.
- the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by mass, preferably about 0.1 to about It is in the range of 50% by weight, more preferably in the range of about 0.5 to about 20% by weight.
- the content of an additive such as a carrier in the combination agent of the present invention varies depending on the form of the preparation, but is usually in the range of about 1 to 99.99% by mass, preferably about 10 to about 90% with respect to the whole preparation. It is the range of mass%.
- the same content may be used when the compound of the present invention and the concomitant drug are formulated separately. As described above, since the dosage varies depending on various conditions, an amount smaller than the above dosage may be sufficient, and it may be necessary to administer beyond the range.
- the medicament of the present invention is administered in the form of a pharmaceutical composition.
- the pharmaceutical composition of the present invention only needs to contain at least one of the compounds represented by the formula (I) of the present invention, and is optionally combined with a pharmaceutically acceptable additive.
- excipients eg; lactose, sucrose, mannitol, crystalline cellulose, silicic acid, corn starch, potato starch
- binders eg; celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC)), crystalline cellulose, saccharides (lactose, mannitol, sucrose, sorbitol, erythritol, xylitol), starches (corn starch, potato starch), pregelatinized starch, dextrin, polyvinylpyrrolidone (PVP), macrogol, polyvinyl Alcohol (PVA)), lubricants (eg; magnesium stearate, calcium stearate, talc, carboxymethylcellulose), disintegrants (eg; starches (corn starch, potato starch), carboxymethyl starch sodium, potassium Lumellose, carmellose calcium, croscarmellose sodium, crospovidone), coating agent (eg, cellulose
- triethyl citrate, macrogol masking agents (e.g. titanium oxide), colorants, flavoring agents, preservatives (e.g. benzalkonium chloride, paraoxybenzoate), isotonic agents (e.g .; Glycerin, sodium chloride, calcium chloride, mannitol, glucose), pH adjuster (eg; buffer solution such as sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid, sulfuric acid, phosphate buffer), stabilizer (eg; Sugar, sugar alcohol, xanthan gum), dispersant, antioxidant (eg Asco Binic acid, butylhydroxyanisole (BHA), propyl gallate, dl- ⁇ -tocopherol), buffer, preservative (eg, paraben, benzyl alcohol, benzalkonium chloride), fragrance (eg, vanillin, l-menthol) , Rose oil), solubilizers (eg, polyoxyethylene hydrogenated castor oil, polysorbate 80, polyethylene
- Various dosage forms include, for example, tablets, capsules, granules, powders, pills, aerosols, inhalants, ointments, patches, suppositories, injections, troches, liquids, spirits, suspensions Agents, extracts, elixirs and the like.
- the medicament of the present invention is, for example, oral, subcutaneous administration, intramuscular administration, intranasal administration, transdermal administration, intravenous administration, intraarterial administration, perineural administration, epidural administration, intradural administration. It can be administered to patients by intraventricular administration, rectal administration, inhalation and the like.
- the compounds of the present invention can be formulated for parenteral administration by injection, including using conventional catheter techniques or infusion.
- injectable formulations may be presented as unit dosage forms, for example, in ampoules or multi-dose containers, with the addition of preservatives.
- These formulations can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and contain formulation agents such as suspending, stabilizing, and / or dispersing agents. be able to.
- the active ingredient can be in powder form for reconstitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.
- the product solution is isolated and included in water (or other aqueous medium) in an amount sufficient to produce a solution of the strength required for oral or parenteral administration to the patient. It can be produced by dissolving the complex.
- These compounds can be formulated into rapidly dispersed dosage forms (fddf) that are designed to release the active ingredient in the oral cavity. These formulations are often formulated using a matrix based on fast dissolving gelatin. These dosage forms are well known and can be used to deliver a wide range of drugs. Most rapid dispersion dosage forms utilize gelatin as a carrier or structure-forming agent. Gelatin is typically used to give a dosage form sufficient strength to prevent breakage when removed from the package, but once in the mouth, gelatin allows the dosage form to break down immediately. . Alternatively, various starches are used to achieve the same effect.
- the compounds of the invention can also be formulated in rectal compositions such as suppositories or retention enemas, eg containing conventional suppository bases such as cocoa butter or other glycerides.
- the compounds of the invention may be administered in the form of a solution or suspension from a pump spray container which is squeezed or pumped by the patient, or a suitable propellant such as dichloromethane.
- a suitable propellant such as dichloromethane.
- the dosage unit can be determined by providing a valve that delivers a metered amount.
- a pressurized container or nebulizer can contain a solution or suspension of the active compound.
- Capsules and cartridges for use in an inhaler or insufflator should be formulated containing a mixed powder of a compound of the invention and a suitable powder base such as lactose or starch. Can do.
- Aerosol formulations for treating the above-described conditions (eg, migraine) in the average adult preferably each metered dose or “puff” of the aerosol contains from about 20 mg to about 1000 mg of the compound of the invention. Is set as follows.
- the total daily dose with an aerosol will be within the range of about 100 mg to about 10 mg.
- Administration can be several times daily, for example 2, 3, 4 or 8 times, for example 1, 2 or 3 doses each time.
- Proposed daily doses of the compounds of the invention administered orally, parenterally, rectally, or buccally to the average adult to treat the above conditions are, for example, units that can be administered 1 to 4 times daily From about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg, of the active ingredient of formula (I) per dose.
- Orexin receptor antagonistic activity of the test compounds are expressed as an IC 50 value, an IC 50 value is +++
- ADL-OXB is a peptide in which two amino acids of human orexin B are substituted, and has a 400 times higher affinity for OX2R than OX1R.
- rats are cannulated and kept for at least 1 week as a recovery period.
- 100 ng / 5 ⁇ L of angiotensin 2 (Peptide Institute) is administered intraventricularly as a preliminary test, and the amount of water consumed for 30 minutes after the administration is measured. Only rats that have reached 5 g of drinking water are used in this study. Rats are acclimated for at least 120 minutes in the measurement cage until this test.
- either vehicle or test compound is administered and immediately returned to the measurement cage.
- 30 to 120 minutes after administration of the test compound the rat is again taken out from the housing cage, and the solvent (saline) or ADL-OXB (3 nmol / 5 ⁇ L / rat) is administered into the ventricle and immediately returned to the measurement cage.
- Spontaneous momentum is measured in a spontaneous momentum measurement chamber (Muromachi Kikai) equipped with an infrared sensor. Spontaneous exercise is counted every 10 minutes, and cumulative counts for 30, 60, 120 minutes after ADL-OXB administration are calculated for each treatment group. All data are expressed as mean and standard error of the mean.
- comparison between the control group and ADL-OXB single administration group was performed using Student's t-test (significant difference at p ⁇ 0.05), and comparison between ADL-OXB single administration group and test compound administration group Uses Dunnett's test (significantly different at p ⁇ 0.05).
- Pharmacological experiment example 3 Sleep EEG measurement test After purchasing male Sprague-Dawley rats and arriving at the breeding facility, the animals are used for experiments with an acclimatization period of at least one week. Animals are housed in a laboratory with controlled temperature and humidity under a 12 hour light / dark cycle, with free access to food and water. In order to confirm the effect on sleep, a sleep electroencephalogram test in rats is performed. Rats are subjected to EEG and EMG electrode implantation surgery for electroencephalogram (EEG) and electromyogram (EMG) measurement, and are kept for at least 1 week as a recovery period. After administration of vehicle or test compound, EEG and EMG signals are recorded for 6-12 hours.
- EEG electroencephalogram
- EMG electromyogram
- the analysis is performed by using an automatic analysis software SleepSign (registered trademark) (Kissei Comtech) to analyze an electroencephalogram frequency and an electromyogram activity signal to classify one of three stages of arousal, REM sleep, and NREM sleep.
- the cumulative time of each stage is calculated, and the sleep action of the test compound is confirmed from the decrease in the awakening time and the increase in the total sleep time (REM sleep + NREM sleep).
- the percentage of REM sleep with respect to the total sleep time is calculated, and it is examined whether a physiological sleep pattern is shown by comparing with the result of the control group.
- DMSO Precipitation Solubility (Kinetic Solubility) A 10 mM DMSO solution of the compound of the present invention is added to a 50 mM phosphate buffer (pH 7.4) to a final concentration of 100 ⁇ M. The solution was incubated at 600 rpm with stirring at room temperature for 1.5 hours, then filtered through a filter plate (MultiScreen HTS- PCF filter plate (Merck Millipore)), and using a plate reader (Powerscan HT (Dainippon Pharmaceutical)). Then, the absorbance of the filtrate is measured at the maximum absorption wavelength.
- a filter plate MultiScreen HTS- PCF filter plate (Merck Millipore)
- Powerscan HT Powerscan HT (Dainippon Pharmaceutical)
- the absorbance of each standard solution is measured using a DMSO solution to which a known concentration (1, 3, 10, 30, 100 ⁇ M) of the test compound is added as a calibration curve standard solution, and a calibration curve is created.
- the solubility ( ⁇ M) of the compound is calculated from the absorbance values of the filtrate and standard solution.
- Crystal solubility Thermodynamic Solubility
- the compound of the present invention is added to a solvent (for example, water, buffer) so as to be 1 mg / mL. The solution is incubated with stirring at 1000 rpm for 24 hours at 25 ° C. or 37 ° C. and then filtered through a filter plate.
- the filtrate is analyzed by HPLC, the peak is detected at the maximum absorption wavelength, and the peak area is measured.
- a solution eg, DMSO solution, 1,4-dioxane solution
- a known concentration of the test compound eg, 0.01, 0.03, 0.1, 0.3, 1, 3, 10 ⁇ g / mL
- Methanol solution is used as a standard curve standard solution to measure each peak area, and the solubility ( ⁇ g / mL) of the compound is calculated from the peak area of the standard curve.
- Metabolic stability test (1) Liver microsome solution (human, rat, mouse, dog or monkey; XenoTech), NADPH generating solution ( ⁇ -NADP, Glucose-6-phosphate, G-6) -PDH (Y), water containing MgCl 2 ). The solution is incubated at 37 ° C. for 5, 10, 20 or 30 minutes and then quenched with acetonitrile. The reaction solution is centrifuged through a filter plate (MultiScreen HTS- HV plate (Merck Millipore)), and the test compound in the filtrate is measured using high performance liquid chromatogram / mass spectrometry.
- a filter plate MultiScreen HTS- HV plate (Merck Millipore
- the reaction solution is centrifuged through a filter plate (MultiScreenHTS-HV plate (Merck Millipore)), and the test compound in the filtrate is measured using high performance liquid chromatogram / mass spectrometry.
- a sample with a reaction time of 0 minutes is measured as a control, and the residual rate (%) at each time point is calculated from the ratio of the hepatocyte reaction sample and the control.
- the reaction time is plotted on the horizontal axis and the residual ratio is plotted on the vertical axis, and the clearance ( ⁇ L / min / mg protein) is calculated from the slope.
- hERG Inhibition Test by Patch Clamp Method The effect on hERG (human ether-a-go related gene) channels is measured using a fully automatic patch clamp system (QPatch HT (Sophion Bioscience)).
- QPatch HT fully automatic patch clamp system
- the membrane potential is held at ⁇ 80 mV, followed by a depolarization pulse of ⁇ 50 mV, 0.02 seconds and 20 mV, 4.8 seconds. -50 mV, 5 seconds of repolarization pulse given once every 15 seconds.
- the effect of the test compound on the hERG channel is confirmed by the tail current change induced by the repolarization pulse.
- the measurement is performed at room temperature.
- the hERG channel inhibition rate is calculated as the reduction rate (suppression rate) of the tail current 4 minutes after the addition relative to the tail current peak value before the addition of the test compound. By calculating this suppression rate, the possibility of inducing QT prolongation by drugs and subsequent fatal side effects (such as ventricular tachycardia and sudden death) is shown.
- a standard solution to which a known concentration of a test compound (0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1 ⁇ g / mL) was added was measured, and a calibration curve was prepared.
- the plasma concentration ( ⁇ g / mL) is calculated, and the maximum plasma concentration is defined as Cmax ( ⁇ g / mL).
- test compound in plasma is measured by high performance liquid chromatogram / mass spectrometry.
- known concentrations of test compounds (0.001, 0.002, 0.005, 0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1, 2, 10 ⁇ g / (mL) is measured, the plasma concentration ( ⁇ g / mL) is calculated from the prepared calibration curve, and the maximum plasma concentration is defined as Cmax ( ⁇ g / mL).
- Pharmacological experiment example 9 Calculation of various parameters in pharmacokinetics test Model-independent analysis of time course of plasma concentration obtained by PK test in rat, dog and monkey animal species (pharmacological experiment example 7) Systemic clearance CLtot (L / kg / hr), distribution volume Vdss in steady state (L / kg), plasma concentration-time curve area AUC ( ⁇ g ⁇ hr / mL), half-life T1 / 2 (hr) Is calculated. In addition, the bioavailability is calculated by comparing the AUC at the time of intravenous administration with the AUC at the time of oral administration.
- Pharmacological experiment example 10 Prediction of pharmacokinetic parameters in humans Various parameters in animal pharmacokinetic tests, metabolic stability in in vitro tests, proteins obtained by the method described in pharmacological experiment examples 5, 7 or 8 Using parameters such as binding rate, pharmacokinetic parameters in humans are predicted by methods known to those skilled in the art such as allometric scaling or IVIVE (in vitro / in vivo extrapolation).
- Pharmacological Experiment Example 11 Safety test The compound of the present invention is orally administered to a mouse or rat once, and no deaths are observed, and no remarkable behavioral abnormality is observed, indicating the safety of the compound of the present invention.
- the compound of the present invention has an excellent orexin receptor antagonistic action. Furthermore, orexin antagonism is shown by an antagonism test against [Ala 11 , D-Leu 15 ] -orexin B-induced locomotor activity enhancement using rats, and sleep action is shown by a sleep electroencephalogram measurement test. In addition, no abnormality is observed in the safety test, indicating the low toxicity of the present invention. Furthermore, it is confirmed that the compound of the present invention is good in one point such as solubility, metabolic stability, pharmacokinetics, and avoidance of hERG channel inhibitory effect by conducting the above test.
- the compounds of the present invention are orexin receptor antagonists, such as sleep disorders (insomnia, circadian rhythm sleep disorders, sleep-related complications, etc.), mental disorders (depression, anxiety disorders, bipolar disorders, attention deficit hyperactivity) Prevention of diseases such as sexual disorders, autism, autism spectrum disorder, drug dependence), neurodegenerative diseases (Alzheimer's disease, etc.), memory disorders (dementia, etc.) and eating disorders (eg, bulimia) It is expected to be used as a therapeutic agent.
- the compound of the present invention is expected to show promising preventive or therapeutic effects for various diseases shown below.
- insomnia circadian rhythm sleep disorder
- sleep-related comorbidities depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, autism, autism spectrum disorder, drug addiction
- Promising therapeutic effects can be expected for Alzheimer's disease, dementia, bulimia and the like.
- JEOL JNM-ECX400 FT-NMR (JEOL) or JEOL JNM-ECX300 FT-NMR (JEOL) was used.
- Liquid chromatography-mass spectrometry spectrum (LC-Mass) was measured by one of the following methods.
- Step 2 Synthesis of 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 1) tert-butyl 8- (4,6-dimethyl Pyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 1-1) (1.6 g) in dichloromethane (5.0 mL) in trifluoroacetic acid ( 5.0 mL) was added and stirred at room temperature for 1 hour under a nitrogen atmosphere.
- Step 4 Synthesis of 8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 2) tert-butyl 8- To (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 2-3) (0.85 g) Trifluoroacetic acid (4.0 mL) was added, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere.
- reaction solution was evaporated under reduced pressure, an ethyl acetate-heptane mixed solvent (1: 1) was added to the resulting residue, and the mixture was extracted 3 times with 1N hydrochloric acid.
- a 1N aqueous sodium hydroxide solution and sodium chloride were added to the resulting aqueous layer, followed by extraction five times with ethyl acetate, and the extract was dried over anhydrous sodium sulfate.
- the solvent was distilled off under reduced pressure to obtain the title compound (0.56 g) as a pale purple liquid.
- Step 5 Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (Intermediate 3)
- the same method as in Step 4 of Production Example 2 Alternatively, tert-butyl 8- (4-cyano-3-methoxypyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 3- 4)
- the title compound (0.75 g) was obtained as a yellow liquid using (1.1 g).
- Step 2 Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (intermediate 4) tert-butyl 8- (4-cyanopyridin-2-yl ) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 4-1) (1.6 g) and 4M hydrogen chloride-ethyl acetate (25 mL) in a nitrogen atmosphere. Stir at room temperature for 10 minutes.
- Step 2 Synthesis of 8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 5) Similar to step 2 of Production Example 1 Tert-Butyl 8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (Intermediate 5) -1) The title compound (2.0 g) was obtained as a yellow solid using (2.9 g).
- Step 2 Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-chloroisonicotinonitrile (intermediate 6) tert obtained in Step 1 of Production Example 6 -Butyl 8- (3-chloro-4-cyanopyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 6-1) crude product (1 The crude product of the title compound (0.16 g) was obtained as a brown liquid in the same manner as in Step 4 of Production Example 2 or a method analogous thereto.
- Step 4 Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-fluoroisonicotinonitrile (Intermediate 7) The same method as in Step 4 of Production Example 2 Alternatively, tert-butyl 8- (4-cyano-3-fluoropyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 7- 3) The title compound (0.10 g) was obtained as a yellow liquid using (0.15 g). UPLC: 233 [M + H] + (retention time 0.67 minutes)
- Step 3> Synthesis of 8- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 9)
- the title compound (0.68 g) was obtained as a yellow liquid in the same manner as in Step 4 of Production Example 2 or a method analogous thereto.
- Step 2> 3-Benzyl-8- (3-methoxy-6-methylpyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 10-2) 3-benzyl-8- (6-bromo-3-methoxypyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 10-1) (0.40 g), trimethylboroxine (0.26 g), PdCl 2 (dppf) (38 mg), potassium carbonate (0.43 g) in DME (5.1 mL) was stirred at 90 ° C. for 14 hours under a nitrogen atmosphere.
- Step 3> Synthesis of 8- (3-methoxy-6-methylpyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 10) 3-Benzyl-8- (3- Methoxy-6-methylpyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 10-2) (0.30 g) and 10% Pd—C (18 mg) in methanol (9 .2 mL) The mixture was stirred under a hydrogen atmosphere at room temperature for 17 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (0.24 g) as a brown liquid.
- Step 2 Synthesis of 6-methoxy-2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 13) 6-methoxy-2- (1H-pyrazol-1-yl) methyl nicotinate (intermediate 13) -1)
- Sodium hydroxide 62 mg was added to a methanol-water (1.0 mL, 1: 1) mixed solution of (0.12 g), and the mixture was stirred at 50 ° C. for 1 hour. After cooling the reaction solution to room temperature, the solvent was evaporated under reduced pressure, ethyl acetate was added to the resulting residue, and the mixture was extracted 3 times with 1N aqueous sodium hydroxide solution.
- Step 2 Synthesis of 5-fluoro-3- (pyrimidin-2-yl) picolinic acid (intermediate 17) 5-Fluoro-3-yl by the same method as in Step 2 of Production Example 12 or a method analogous thereto.
- (pyrimidin-2-yl) methyl picolinate (intermediate 17-1) (0.17 g)
- the title compound (0.17 g) was obtained as a pale yellow amorphous product.
- Step 2 Synthesis of lithium 2- (1-methyl-1H-pyrazol-3-yl) nicotinate (intermediate 25) 2- (1-methyl-1H-pyrazol-3-yl) methyl nicotinate (intermediate) 25-1) (0.28 g) in methanol (1.0 mL) -THF (1.0 mL) was added an aqueous solution (0.50 mL) of lithium hydroxide monohydrate (60 mg) and stirred at 50 ° C. for 6 hours. Heated. A part of the solvent was distilled off, and the mixture was cooled to 0 ° C. and collected by filtration.
- Step 2 Synthesis of 3-methyl-1- (pyridin-2-yl) -1H-pyrazole-5-carboxylic acid (intermediate 26) 3-methyl-1- (pyridin-2-yl) -1H-pyrazole Lithium hydroxide monohydrate (25 mg) was added to a mixed solution of ethyl 5-carboxylate (intermediate 26-1) (0.11 g) in THF (1.5 mL) -water (0.5 mL), and a nitrogen atmosphere was added. The mixture was stirred overnight at room temperature.
- reaction solution was back-extracted with ethyl acetate, 1.0 M hydrochloric acid aqueous solution was added to the obtained aqueous layer, and the mixture was extracted with ethyl acetate and washed with saturated brine.
- the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (73 mg).
- Step 3> Synthesis of 4-ethoxy-2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 32)
- a mixed solution of (0.30 g) and lithium hydroxide (0.14 g) in THF (2.9 mL) -water (2.9 mL) was stirred at 50 ° C. for 3 days in a nitrogen atmosphere.
- the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove THF, and the aqueous layer was washed with MTBE (30 mL).
- Step 2 Synthesis of (2- (1H-pyrazol-1-yl) pyridin-3-yl) (3,6-diazabicyclo [3.1.1] heptan-3-yl) methanone (intermediate 43) tert -Butyl 3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate 43-1) (0.19 g) 2N Hydrochloric acid-ethyl acetate solution (4.0 mL) was added, and the mixture was stirred at 50 ° C. for 1 hr.
- Tetrakis (triphenylphosphine) palladium (0.10 g) was added to a mixed solution of 5N THF solution) (2.6 mL) in THF (0.73 mL), and a nitrogen atmosphere at 100 ° C. Stir for 3 days.
- the reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate.
- the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (77 mg) of the title compound as an orange liquid.
- Step 2 Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-cyclopropylisonicotinonitrile (Intermediate 44) Obtained in Step 1 of Preparation Example 44 Crude product of tert-butyl 8- (4-cyano-3-cyclopropylpyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 44-1) (77 mg) was added with trifluoroacetic acid and stirred at room temperature for 30 minutes.
- Example 1 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (5-methyl-2- (2H-1 , 2,3-Triazol-2-yl) phenyl) methanone 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 1) 22 mg), 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (20 mg), triethylamine (42 ⁇ L) in DMF (0.50 mL) mixed with HATU (46 mg).
- Examples 2 to 15 are the same as in Example 1 using any one of Intermediates 1 to 3 and any of Intermediates 12 to 14 or commercially available or known compounds, or It was synthesized by a method according to this.
- Example 16 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-methoxy-2- (1H-1 , 2,3-Triazol-1-yl) phenyl) methanone 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 1) 22 mg), 4-methoxy-2- (1H-1,2,3-triazol-1-yl) benzoic acid (22 mg), DIPEA (52 ⁇ L) in DMF (0.20 mL) mixed with HATU (46 mg).
- Example 17 to Example 55 were prepared using any of Intermediate 1 to Intermediate 8 and any of Intermediate 15, Intermediate 22 to Intermediate 28, Intermediate 29-1, or commercially available compounds or known compounds. This was synthesized by the same method as in Example 16 or a method analogous thereto.
- Example 57 to Example 76 are any of Intermediate 1, Intermediate 3 to Intermediate 5, Intermediate 29-1, Intermediate 29-2, Intermediate 30, and Intermediate 31 or commercially available compounds. Alternatively, synthesis was performed using a known compound by the same method as in Example 56 or a method analogous thereto.
- Example 78 to Example 87 are the same as or similar to Example 77, using any of Intermediate 1 to Intermediate 5, Intermediate 9 and Intermediate 28, or a commercially available or known compound. It was synthesized by the method.
- Example 88 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (1,1,2,2 Synthesis of -tetrafluoroethoxy) phenyl) methanone 2- (1,1,2,2-tetrafluoroethoxy) benzoic acid (28 mg) in dichloromethane (0.20 mL) in 1-chloro-N, N, 2-trimethyl -1-Propenylamine (17 ⁇ L) was added at room temperature under a nitrogen atmosphere.
- Example 90 3-Methoxy-2- (3- (4-methoxy-2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl ) Synthesis of isonicotionitrile Lithium 4-methoxy-2- (1H-pyrazol-1-yl) nicotinate (intermediate 33) (27 mg) and 2- (3,8-diazabicyclo [3.2.1] octane- EDCI (34 mg) was added to a mixed solution of 8-yl) -3-methoxyisonicotinonitrile (intermediate 3) (29 mg) and HOBT (28 mg) in DMF (0.60 mL), and the reaction solution was added at 50 ° C.
- Example 92 to Example 100 are any of Intermediate 1 to Intermediate 3, Intermediate 5, and Intermediate 10, and any of Intermediate 28, Intermediate 31, and Intermediate 32, or commercially available compounds or known compounds. And synthesized by the same method as in Example 91 or a method analogous thereto.
- Example 101 (4-Chloro-2- (pyrimidin-2-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane Synthesis of 3-yl) methanone 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 1) (28 mg), 4-chloro-2 A mixed solution of-(pyrimidin-2-yl) benzoic acid (intermediate 16) (30 mg), COMU (82 mg) and 2,6-lutidine (30 ⁇ L) in dichloromethane (0.64 mL) at room temperature under a nitrogen atmosphere Stir for hours.
- a saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction solution, extraction was performed with ethyl acetate (20 mL ⁇ 2), and the collected organic layer was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate.
- Example 102 to Example 104 were synthesized using any one of Intermediate 1 to Intermediate 3 and Intermediate 17 by the same method as in Example 101 or a method analogous thereto.
- Example 105 (4-Fluoro-2- (pyrimidin-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3 2.1] Synthesis of Octan-3-yl) methanone 4-Fluoro-2- (pyrimidin-2-yl) benzoic acid (40 mg), 8- (3-methoxy-4- (trifluoromethyl) pyridine-2 -Il) -3,8-diazabicyclo [3.2.1] octane (intermediate 2) (53 mg), T3P (0.11 mL), DIPEA (80 ⁇ L) in DMF (0.92 mL) mixed solution under nitrogen atmosphere And stirred at room temperature for 19 hours.
- Example 106 2- (3- (4-Fluoro-2- (pyrimidin-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyiso Synthesis of nicotinonitrile 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (in the same manner as in Example 105 or a method analogous thereto) Intermediate 3) (45 mg) was used to give the title compound (13 mg) as an orange solid.
- Example 107 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1- (thiazol-2-yl)- Synthesis of 1H-pyrazol-5-yl) methanone Methyl 1- (thiazol-2-yl) -1H-pyrazole-5-carboxylate (Intermediate 18) (14 mg) in methanol (0.10 mL) -THF (0. 10 mL) To the mixed solution was added 8N aqueous sodium hydroxide solution (13 ⁇ L), and the mixture was stirred at 50 ° C. for 1 hour.
- Example 108 3-Methoxy-2- (3- (1- (thiazol-2-yl) -1H-pyrazole-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8- Yl) Synthesis of isonicotinonitrile 3-methoxy-2- (3- (1- (thiazol-2-yl) -1H-pyrazole-5-carbonyl) in the same manner as in Example 107 or a method analogous thereto ) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Intermediate 3) (16 mg) was used to obtain the title compound (7.0 mg) as a colorless amorphous.
- Example 109 (8- (3-Methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1- (thiazole Synthesis of -2-yl) -1H-pyrazol-5-yl) methanone
- Example 110 Synthesis of (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-iodophenyl) methanone 8- DME (2.0 mL) of (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 1) (0.20 g) and triethylamine (0.19 mL) 2-Iodobenzoyl chloride (0.24 g) was added to the mixed solution in several portions at room temperature, and the mixture was stirred at room temperature for 1 hour.
- Example 111 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (oxazol-2-yl) phenyl ) Synthesis of Methanone (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-iodophenyl) methanone (Example 110) (42 mg), 2- (tributyltin) oxazole (34 mg) and cesium fluoride (28 mg) in a mixed solution of DMF (0.50 mL) with tetrakis (triphenylphosphine) palladium (11 mg) and copper (I) iodide (1.
- Example 112 (2- (1H-pyrazol-3-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3 Synthesis of (-yl) methanone (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-iodophenyl) methanone (Examples) 110) (45 mg), (1H-pyrazol-3-yl) boronic acid (17 mg), PdCl 2 (dppf) (15 mg), potassium carbonate (41 mg) in DME (0.50 mL) -water (0.20 mL) The solution was stirred at 85 ° C.
- Example 113 (2- (1H-pyrazol-4-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3 Synthesis of -yl) methanone (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane) was carried out in the same manner as in Example 112 or a method analogous thereto.
- Example 114 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4′-fluoro- [1,1 ′ Synthesis of -biphenyl] -2-yl) methanone (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octan-3-yl) (2- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methanone (intermediate 11) (22 mg), 1-bromo-4-fluorobenzene (9.0 mg), PdCl 2 A mixture of (dppf) (7.3 mg) and potassium carbonate (21 mg) in DME (0.50 mL) -water (0.15 mL) was stirred at 80 ° C. for 1 hour under a nitrogen atmosphere. After the reaction solution was
- Example 115 to Example 126 were synthesized by the same method as in Example 114 or a method analogous thereto, using Intermediate 11 and a commercially available compound.
- Example 127 (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,6-dimethylpyridin-2-yl) -3,8-diazabicyclo [3.2 .1] Synthesis of octan-3-yl) methanone (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3-yl ) Methanone hydrochloride (intermediate 19) (38 mg), 2-bromo-4,6-dimethylpyridine (22 mg), sodium tert-butoxide (29 mg), ( ⁇ ) -BINAP (7.5 mg) in toluene (1.
- Example 128 to Example 129 were synthesized in the same manner as in Example 127 or a method analogous thereto, using any of Intermediate 19 to Intermediate 20 and commercially available compounds.
- Example 130 2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl)- Synthesis of 6-methylisonicotinonitrile (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3-yl) methanone hydrochloride Salt (intermediate 19) (42 mg), 2-chloro-6-methylisonicotinonitrile (20 mg), sodium tert-butoxide (31 mg), XPhos (6.8 mg) in toluene (1.0 mL) mixed with Pd 2 (dba) 3 (6.0 mg) was added, and the mixture was stirred at 100 ° C.
- Example 131 (8- (3,5-dimethylphenyl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-6- (2H-1,2,3 Synthesis of -triazol-2-yl) phenyl) methanone (3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-) by the same method as in Example 130 or a method analogous thereto Using 6- (2H-1,2,3-triazol-2-yl) phenyl) methanone hydrochloride (intermediate 20) (34 mg) and 1-bromo-3,5-dimethylbenzene (19 mg), the title compound ( 8.1 mg) was obtained as a colorless amorphous.
- Example 132 (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4- (difluoromethoxy) pyridin-2-yl) -3,8-diazabicyclo [3. 2.1] Synthesis of octan-3-yl) methanone (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3- Yl) methanone hydrochloride (intermediate 19) (64 mg), 2-chloro- (4-difluoromethoxy) pyridine (36 mg), sodium tert-butoxide (48 mg) in THF (1.5 mL) mixed with RuPhos Pd G2 ( 7.8 mg) was added, and the mixture was stirred at 85 ° C.
- Example 133 to Example 146 are the same as Example 132 using any of Intermediate 2-2, Intermediate 34 to Intermediate 36, or a commercially available compound or a known compound and Intermediate 19 or Intermediate 21. It was synthesized by the method or a method analogous thereto.
- Example 148 to Example 154 are the same as or similar to Example 147, using any of Intermediate 37 to Intermediate 38, commercially available compounds or known compounds, and Intermediate 19 or Intermediate 21. It was synthesized by the method.
- Example 155 (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4-ethyl-6-methylpyrimidin-2-yl) -3,8-diazabicyclo [3 Of 2.2.1] octan-3-yl) methanone (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3 2-yl-4-ethyl-6-methylpyrimidine in a mixed solution of -yl) methanone hydrochloride (intermediate 19) (40 mg), DIPEA (0.11 mL), DMAP (1.5 mg) in ethanol (1.0 mL) (20 mg) was added, and the mixture was stirred at 170 ° C.
- Examples 156 to 161 were synthesized by the same method as in Example 155 or a method analogous thereto, using Intermediate 19 or Intermediate 20, and commercially available compounds or known compounds.
- Example 162 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (3-methyl-1H-pyrazole Synthesis of (1-yl) pyridin-3-yl) methanone (2-chloropyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2. 1] Potassium carbonate (77 mg) was added to a mixed solution of octan-3-yl) methanone (intermediate 39) (50 mg) and 3-methyl-1H-pyrazole (34 mg) in DMSO (1.0 mL) at 200 ° C.
- DMSO 1.0 mL
- Examples 163 to 166 were synthesized in the same manner as in Example 162, or a method analogous thereto, using Intermediate 39 or Intermediate 40 and commercially available compounds.
- Example 167 (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (2,3-dihydrofuro [3,2-c] pyridin-4-yl) -3, Synthesis of 8-diazabicyclo [3.2.1] octane-3-yl) methanone (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (fur [3,2-c ] Pyridin-4-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 135) (30 mg) in ethanol (4.0 mL) was added to a flow hydrogenation reactor.
- Example 168 (2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (2,3-dihydrofuro [3,2-c] pyridin-4-yl) -3,8- Synthesis of diazabicyclo [3.2.1] octane-3-yl) methanone
- Compound (11 mg) was obtained as colorless amorphous.
- Tetrakis (triphenylphosphine) palladium (33 mg) was added to a mixed solution of (30 mg), cyclopropylzinc bromide (0.5N THF solution) (0.84 mL) in THF (0.4 mL), and nitrogen was added.
- Example 171 2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl)- Synthesis of 3-cyclopropylisonicotinonitrile 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-cyclopropyl by a method similar to that of Example 16 or a method analogous thereto. Isonicotinonitrile (intermediate 44) (12 mg) was used to give the title compound (12 mg) as a colorless solid. UPLC: 426 [M + H] + (retention time 1.09 minutes)
- Example 172 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (pyrrolidine-1 Synthesis of -yl) isonicotinonitrile 2- (3- (2- (1 (H) -pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- Pyrrolidine (8.9 ⁇ L) was added to a mixed solution of chloroisonicotinonitrile (Example 48) (30 mg) and DIPEA (20 ⁇ L) in NMP (0.5 mL), and the mixture was stirred at 150 ° C.
- Example 173 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (methylthio) iso Synthesis of nicotinonitrile 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-chloroisonicotino Sodium thiomethoxide (6.7 mg) was added to a solution of nitrile (Example 48) (27 mg) in DMF (2.0 mL), and the mixture was stirred at room temperature for 1 hour.
- Example 174 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (dimethylamino) Synthesis of isonicotinonitrile 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-fluoroisonicoti 9.5 M dimethylamine aqueous solution (1.0 mL) was added to nononitrile (Example 49) (15 mg), and the mixture was stirred at room temperature for 1 day.
- Example 175 (6- (4,6-Dimethylpyrimidin-2-yl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) (2-fluoro-6- (2H-1 , 2,3-Triazol-2-yl) phenyl) methanone tert-butyl 3- (2-fluoro-6- (2H-1,2,3-triazol-2-yl) benzoyl) -3,6-
- diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate 42) (39 mg) in dichloromethane (0.40 mL) was added trifluoroacetic acid (0.20 mL) at room temperature.
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Abstract
Provided are: compounds having orexin receptor antagonistic effects; a pharmaceutical composition characterized by comprising the compounds as an active ingredient; and medical applications thereof, particularly prophylactic and/or therapeutic agents for diseases relating to orexin receptors, sleep disorders, mental disorders, neurodegenerative diseases, memory disorders and eating disorders, particularly sleep disorders such as insomnia. Specifically, provided are compounds represented by formula (I), or pharmaceutically acceptable salts thereof, or solvates thereof.
Description
本発明は、オレキシン受容体拮抗作用を有する化合物、とりわけ、下記式(I)で表されるジアザビシクロ構造を持つことを特徴とする化合物、またはそれらの製薬学的に許容される塩、またはそれらの溶媒和物、および、それらを有効成分として含有することを特徴とする医薬組成物に関する。また、本発明は、オレキシン受容体が関与する疾患、睡眠障害(不眠症、概日リズム睡眠障害、睡眠時随伴症等)、精神疾患(うつ病、不安障害、双極性障害、注意欠陥多動性障害、自閉症、自閉症スペクトラム障害、薬物依存症等)、神経変性疾患(アルツハイマー病等)、記憶障害(認知症等)および摂食障害(過食症等)、とりわけ不眠症等の睡眠障害の予防及び/または治療剤に関する。
The present invention relates to a compound having an orexin receptor antagonism, particularly a compound having a diazabicyclo structure represented by the following formula (I), or a pharmaceutically acceptable salt thereof, or a compound thereof: The present invention relates to a solvate and a pharmaceutical composition containing them as an active ingredient. The present invention also relates to diseases involving orexin receptors, sleep disorders (insomnia, circadian rhythm sleep disorders, sleep-related complications), mental disorders (depression, anxiety disorders, bipolar disorders, attention deficit hyperactivity) Sexual disorders, autism, autism spectrum disorder, drug dependence, etc.), neurodegenerative diseases (Alzheimer's disease, etc.), memory disorders (dementia, etc.) and eating disorders (eg, bulimia), especially insomnia The present invention relates to a preventive and / or therapeutic agent for sleep disorders.
オレキシン(以下、「OX」と略記する場合がある)は、視床下部外側野に存在する神経細胞に特異的に発現している神経ペプチドであり、33個のアミノ酸からなるOX-Aおよび28個のアミノ酸からなるOX-Bが同定されている。これらペプチドの特異的受容体であるオレキシン受容体は、OX1受容体およびOX2受容体の2つのサブタイプが報告されている。いずれの受容体も中枢神経系に発現する7回膜貫通型のGタンパク質共役型受容体であるが、サブタイプによって組織分布は異なり、様々な神経に多様な影響を与えていることから、オレキシンが複雑な生理活性を有することが示唆されている。
オレキシンが同定された当初は、摂食行動の制御調節機能が注目されていたが、近年、オレキシンと睡眠・覚醒の制御調節との関連が注目されている。ラット脳室内にオレキシンを投与することにより、自発運動量の亢進、覚醒時間の延長等の覚醒促進作用が認められる(非特許文献1及び非特許文献2)。また、オレキシンKOマウスやOX2受容体KOマウスでは、覚醒阻害が認められる(非特許文献3)。このような知見から、オレキシン受容体拮抗剤は、覚醒状態を抑制することで睡眠を誘発する睡眠導入剤として、優れた不眠症治療薬になると考えられている。
オレキシン受容体拮抗剤として、アルモレキサントやスボレキサントが知られている。これら拮抗剤はOX1受容体及びOX2受容体を同程度に拮抗する物質(dual拮抗剤)であり、不眠症症状の改善が報告されている(非特許文献4及び非特許文献5)。スボレキサントは不眠症治療薬(ベルソムラ(登録商標))として製造販売承認を取得しているが、一方で日中の眠気(持ち越し効果)や睡眠時行動障害等の副作用が懸念されている。
KOマウスを用いた検討から、オレキシンによる覚醒作用やノンレム睡眠抑制作用は、主にOX2受容体を介していることが報告されている(非特許文献6)。よって、OX2受容体選択的拮抗剤は、生理的な睡眠を誘導し、副作用リスクが少ない不眠症治療薬となる可能性がある。OX2受容体選択的拮抗剤としては、MIN-202やMK-1064(非特許文献7)が不眠症治療薬として開発されている。 Orexin (hereinafter sometimes abbreviated as “OX”) is a neuropeptide specifically expressed in neurons existing in the lateral hypothalamic area, OX-A consisting of 33 amino acids and 28 OX-B consisting of the following amino acids has been identified. The orexin receptor, which is a specific receptor for these peptides, has been reported in two subtypes, the OX1 receptor and the OX2 receptor. Each receptor is a seven-transmembrane G protein-coupled receptor expressed in the central nervous system, but the tissue distribution differs depending on the subtype and has various effects on various nerves. Has been suggested to have complex physiological activities.
At the beginning of the identification of orexin, attention was focused on the regulation and regulation function of feeding behavior, but in recent years, the relationship between orexin and regulation of sleep / wakefulness has attracted attention. By administering orexin into the rat ventricle, wakefulness-promoting effects such as increased spontaneous momentum and prolonged wakefulness are observed (Non-patent Documents 1 and 2). In addition, inhibition of arousal is observed in orexin KO mice and OX2 receptor KO mice (Non-patent Document 3). From these findings, orexin receptor antagonists are considered to be excellent insomnia treatments as sleep-inducing agents that induce sleep by suppressing wakefulness.
Almorexant and suvorexant are known as orexin receptor antagonists. These antagonists are substances (dual antagonists) that antagonize the OX1 receptor and the OX2 receptor to the same extent, and improvement of insomnia symptoms has been reported (Non-patent Documents 4 and 5). Suvorexant has been approved for manufacture and sale as a therapeutic agent for insomnia (Belsomura (registered trademark)). On the other hand, side effects such as daytime sleepiness (carry-over effect) and sleep behavior disorder are concerned.
From studies using KO mice, it has been reported that the arousal action and non-REM sleep inhibitory action by orexin are mainly mediated by OX2 receptors (Non-patent Document 6). Therefore, an OX2 receptor selective antagonist induces physiological sleep and may be a therapeutic agent for insomnia with a low risk of side effects. As OX2 receptor selective antagonists, MIN-202 and MK-1064 (Non-patent Document 7) have been developed as therapeutic agents for insomnia.
オレキシンが同定された当初は、摂食行動の制御調節機能が注目されていたが、近年、オレキシンと睡眠・覚醒の制御調節との関連が注目されている。ラット脳室内にオレキシンを投与することにより、自発運動量の亢進、覚醒時間の延長等の覚醒促進作用が認められる(非特許文献1及び非特許文献2)。また、オレキシンKOマウスやOX2受容体KOマウスでは、覚醒阻害が認められる(非特許文献3)。このような知見から、オレキシン受容体拮抗剤は、覚醒状態を抑制することで睡眠を誘発する睡眠導入剤として、優れた不眠症治療薬になると考えられている。
オレキシン受容体拮抗剤として、アルモレキサントやスボレキサントが知られている。これら拮抗剤はOX1受容体及びOX2受容体を同程度に拮抗する物質(dual拮抗剤)であり、不眠症症状の改善が報告されている(非特許文献4及び非特許文献5)。スボレキサントは不眠症治療薬(ベルソムラ(登録商標))として製造販売承認を取得しているが、一方で日中の眠気(持ち越し効果)や睡眠時行動障害等の副作用が懸念されている。
KOマウスを用いた検討から、オレキシンによる覚醒作用やノンレム睡眠抑制作用は、主にOX2受容体を介していることが報告されている(非特許文献6)。よって、OX2受容体選択的拮抗剤は、生理的な睡眠を誘導し、副作用リスクが少ない不眠症治療薬となる可能性がある。OX2受容体選択的拮抗剤としては、MIN-202やMK-1064(非特許文献7)が不眠症治療薬として開発されている。 Orexin (hereinafter sometimes abbreviated as “OX”) is a neuropeptide specifically expressed in neurons existing in the lateral hypothalamic area, OX-A consisting of 33 amino acids and 28 OX-B consisting of the following amino acids has been identified. The orexin receptor, which is a specific receptor for these peptides, has been reported in two subtypes, the OX1 receptor and the OX2 receptor. Each receptor is a seven-transmembrane G protein-coupled receptor expressed in the central nervous system, but the tissue distribution differs depending on the subtype and has various effects on various nerves. Has been suggested to have complex physiological activities.
At the beginning of the identification of orexin, attention was focused on the regulation and regulation function of feeding behavior, but in recent years, the relationship between orexin and regulation of sleep / wakefulness has attracted attention. By administering orexin into the rat ventricle, wakefulness-promoting effects such as increased spontaneous momentum and prolonged wakefulness are observed (Non-patent Documents 1 and 2). In addition, inhibition of arousal is observed in orexin KO mice and OX2 receptor KO mice (Non-patent Document 3). From these findings, orexin receptor antagonists are considered to be excellent insomnia treatments as sleep-inducing agents that induce sleep by suppressing wakefulness.
Almorexant and suvorexant are known as orexin receptor antagonists. These antagonists are substances (dual antagonists) that antagonize the OX1 receptor and the OX2 receptor to the same extent, and improvement of insomnia symptoms has been reported (Non-patent Documents 4 and 5). Suvorexant has been approved for manufacture and sale as a therapeutic agent for insomnia (Belsomura (registered trademark)). On the other hand, side effects such as daytime sleepiness (carry-over effect) and sleep behavior disorder are concerned.
From studies using KO mice, it has been reported that the arousal action and non-REM sleep inhibitory action by orexin are mainly mediated by OX2 receptors (Non-patent Document 6). Therefore, an OX2 receptor selective antagonist induces physiological sleep and may be a therapeutic agent for insomnia with a low risk of side effects. As OX2 receptor selective antagonists, MIN-202 and MK-1064 (Non-patent Document 7) have been developed as therapeutic agents for insomnia.
オレキシン受容体拮抗作用を有する化合物として、WO2008/008517号パンフレット(特許文献1)には、ジアザビシクロ[4.2.1]ノナン誘導体等のジアザビシクロ構造を有する化合物、WO2011/050198号パンフレット(特許文献2)には、ジアザビシクロ[3.3.0]オクタン誘導体、WO2012/085852号パンフレット(特許文献3)には、ジアザビシクロ[4.2.0]オクタン誘導体、及びWO2013/050938号パンフレット(特許文献4)には、ジアザビシクロ[3.3.1]ノナン誘導体が各々開示されている。しかしながら、これらに開示の誘導体は、ジアザビシクロ[3.2.1]オクタンまたはジアザビシクロ[3.1.1]ヘプタン構造を持つ化合物とは基本骨格が異なっており、ジアザビシクロ[3.2.1]オクタンまたはジアザビシクロ[3.1.1]ヘプタン構造を持つ化合物については、開示も示唆もない。
As compounds having an orexin receptor antagonistic activity, WO2008 / 008517 pamphlet (Patent Document 1) includes a compound having a diazabicyclo structure such as a diazabicyclo [4.2.1] nonane derivative, WO2011 / 050198 pamphlet (Patent Document 2). ) For diazabicyclo [3.3.0] octane derivative, WO2012 / 085852 pamphlet (patent document 3), for diazabicyclo [4.2.0] octane derivative, and WO2013 / 0500938 pamphlet (patent document 4). Discloses diazabicyclo [3.3.1] nonane derivatives, respectively. However, the derivatives disclosed therein are different in basic skeleton from compounds having a diazabicyclo [3.2.1] octane or diazabicyclo [3.1.1] heptane structure, and diazabicyclo [3.2.1] octane. Alternatively, there is no disclosure or suggestion about a compound having a diazabicyclo [3.1.1] heptane structure.
また、WO2014/066196号パンフレット(特許文献5)には、オレキシン受容体拮抗作用を有する化合物として、ピペリジン誘導体が開示されているが、ジアザビシクロ[3.2.1]オクタンまたはジアザビシクロ[3.1.1]ヘプタン構造を持つ化合物とは基本骨格が異なる。
In addition, a piperidine derivative is disclosed as a compound having an orexin receptor antagonistic activity in WO 2014/066196 pamphlet (Patent Document 5), but diazabicyclo [3.2.1] octane or diazabicyclo [3.1. 1] The basic skeleton is different from a compound having a heptane structure.
FR2531709号パンフレット(特許文献6)には、抗不安作用を有する化合物として、ジアザビシクロ[3.2.1]オクタン誘導体が開示されているが、以下で示すような本発明の特定の化合物の開示はない。
WO2011/090935号パンフレット(特許文献7)には、mTOR阻害作用を有する化合物として、またWO2002/102778号パンフレット(特許文献8)には、PDEIV阻害作用を有する化合物として、ジアザビシクロ[3.2.1]オクタン誘導体を含む化合物群が開示されているが、以下で示すような本発明の特定の化合物の開示はない。 In the FR2531709 pamphlet (Patent Document 6), a diazabicyclo [3.2.1] octane derivative is disclosed as a compound having an anxiolytic action, but the disclosure of the specific compound of the present invention as shown below is disclosed. Absent.
In WO2011 / 090935 (Patent Document 7), as a compound having an mTOR inhibitory action, and in WO2002 / 102778 (Patent Document 8), as a compound having a PDEIV inhibitory action, diazabicyclo [3.2.1]. Although a group of compounds containing an octane derivative is disclosed, there is no disclosure of specific compounds of the present invention as shown below.
WO2011/090935号パンフレット(特許文献7)には、mTOR阻害作用を有する化合物として、またWO2002/102778号パンフレット(特許文献8)には、PDEIV阻害作用を有する化合物として、ジアザビシクロ[3.2.1]オクタン誘導体を含む化合物群が開示されているが、以下で示すような本発明の特定の化合物の開示はない。 In the FR2531709 pamphlet (Patent Document 6), a diazabicyclo [3.2.1] octane derivative is disclosed as a compound having an anxiolytic action, but the disclosure of the specific compound of the present invention as shown below is disclosed. Absent.
In WO2011 / 090935 (Patent Document 7), as a compound having an mTOR inhibitory action, and in WO2002 / 102778 (Patent Document 8), as a compound having a PDEIV inhibitory action, diazabicyclo [3.2.1]. Although a group of compounds containing an octane derivative is disclosed, there is no disclosure of specific compounds of the present invention as shown below.
さて、医薬品開発においては、目的とする薬理活性のみでなく、吸収、分布、代謝、排泄等の各種の面で厳しいクライテリアを満たすことが要求される。例えば、薬物相互作用、脱感受性ないし耐性、経口投与時の消化管吸収、小腸内への移行速度、吸収速度と初回通過効果、臓器バリアー、蛋白結合、薬物代謝酵素の誘導や阻害、排泄経路や体内クリアランス、適用方法(適用部位、方法、目的)等において種々の検討課題が要求され、これらを満たすものはなかなか見出されない。しかしながら、医薬品における課題は常に生じるであろう。
Now, in drug development, it is required to satisfy severe criteria not only in the intended pharmacological activity but also in various aspects such as absorption, distribution, metabolism, and excretion. For example, drug interaction, desensitization or tolerance, digestive tract absorption after oral administration, transfer rate into the small intestine, absorption rate and first-pass effect, organ barrier, protein binding, induction and inhibition of drug metabolizing enzymes, excretion route and Various examination subjects are required in the body clearance, application method (application site, method, purpose) and the like, and it is difficult to find one that satisfies these. However, challenges in medicine will always arise.
現在、不眠症等の睡眠障害の薬物療法において、種々の不眠症治療薬が利用可能となっているが、その治療満足度は低く、より良い副作用プロファイルを有する新たな不眠症治療薬の開発が、なお求められている。
At present, various insomnia drugs are available for pharmacotherapy of sleep disorders such as insomnia, but the treatment satisfaction is low and the development of new insomnia drugs with better side effect profile There is still a need.
オレキシン受容体拮抗作用を有する化合物の報告例は複数あるが、前記の医薬品開発上の総合的課題は常にある。より具体的には、例えば、溶解性がよくないこと、代謝安定性が低く経口投与による全身曝露が困難であること、吸収性や持続性等の薬物動態が良好ではないこと、あるいは不整脈を起こす危険性があるhERG(human ether-a-go-go related gene)チャネルの阻害活性を示すこと、薬物代謝酵素(例えば、シトクロムP450等)の誘導あるいは阻害活性を示すことや高い蛋白結合率を示すなど、有用性や安全性の課題がある。これらの問題を可能な限り多く解決し、且つ有効性の高い化合物を見出すことが求められている。
Although there are multiple reports of compounds having orexin receptor antagonistic activity, there are always comprehensive issues in the development of the aforementioned drugs. More specifically, for example, poor solubility, low metabolic stability, difficulty in systemic exposure by oral administration, poor pharmacokinetics such as absorption and persistence, or arrhythmia It exhibits hERG (human ether-a-go related gene) channel inhibitory activity, induces or inhibits drug metabolizing enzymes (eg, cytochrome P450), and exhibits a high protein binding rate. There are problems of usefulness and safety. There is a need to solve these problems as much as possible and find highly effective compounds.
本発明者らは、上記の課題を解決すべく、安全性が高く、および/または有効性に優れたオレキシン受容体拮抗剤を得るべく、鋭意研究を重ねてきた結果、式(I)で表されるジアザビシクロ構造を持つことを特徴とする化合物またはそれらの製薬学的に許容される塩またはそれらの溶媒和物が、オレキシン受容体拮抗作用を有することを見出した。本発明化合物は、オレキシン受容体拮抗作用を有し、不眠症等の睡眠障害を始めとする精神学的及び神経学的障害の改善作用を有する。
In order to solve the above-mentioned problems, the present inventors have conducted extensive research to obtain an orexin receptor antagonist that is highly safe and / or excellent in effectiveness. It was found that a compound having a diazabicyclo structure or a pharmaceutically acceptable salt thereof or a solvate thereof has an orexin receptor antagonistic action. The compound of the present invention has an orexin receptor antagonistic action, and has an action of improving psychiatric and neurological disorders including sleep disorders such as insomnia.
本発明は、式(I)で表されるジアザビシクロ構造を持つことを特徴とする化合物、またはそれらの製薬学的に許容される塩、またはそれらの溶媒和物、および、それらを有効成分として含有することを特徴とする医薬組成物である。
本発明化合物は、オレキシン受容体拮抗作用を有する化合物であり、不眠症等の睡眠障害を始めとする精神学的及び神経学的障害の改善作用を有している。
本発明化合物を有効成分として含有する医薬組成物は、経口投与可能であり、オレキシン受容体拮抗剤や、オレキシン受容体が関与する疾患、精神学的及び神経学的障害、とりわけ不眠症等の睡眠障害の予防及び/または治療剤として期待される。
また、本発明化合物群は、溶解性が良好であること、代謝安定性が高いこと、優れた経口吸収性をもつこと、あるいはhERGチャネルの阻害作用が少ないこと、などの少なくとも一つ以上の特徴も有することから有用性が高い。
The present invention contains a compound having a diazabicyclo structure represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, and an active ingredient thereof. A pharmaceutical composition characterized by comprising:
The compound of the present invention is a compound having an orexin receptor antagonistic action, and has an action of improving psychiatric and neurological disorders including sleep disorders such as insomnia.
The pharmaceutical composition containing the compound of the present invention as an active ingredient can be administered orally, and sleep such as orexin receptor antagonists, diseases involving orexin receptor, psychiatric and neurological disorders, especially insomnia It is expected as a preventive and / or therapeutic agent for disorders.
In addition, the compound group of the present invention has at least one or more characteristics such as good solubility, high metabolic stability, excellent oral absorbability, and little hERG channel inhibitory action. Since it also has, it is highly useful.
本発明は、以下の態様に示される下記式(I)で表されるジアザビシクロ構造を持つことを特徴とする化合物、またはそれらの製薬学的に許容される塩、またはそれらの溶媒和物、および、それらを有効成分として含有することを特徴とする医薬組成物、ならびにそれらの医薬用途、オレキシン受容体拮抗剤である。
The present invention relates to a compound having a diazabicyclo structure represented by the following formula (I) shown in the following embodiment, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and A pharmaceutical composition characterized by containing them as an active ingredient, as well as their pharmaceutical use, orexin receptor antagonist.
[本発明の態様]
本発明は、以下の態様[1]~[14]を含む。
[1] 本発明の第1の態様は、
下記式(I)
(式中、
nは、1または2を表し;
環Aは、C6~14アリール基または5~14員ヘテロアリール基を表し、環Aにおける、当該C6~14アリール基または5~14員ヘテロアリール基は、それぞれ、1~5個のR1で置換されていてもよく;
環Bは、フェニル基または単環式ヘテロアリール基を表し、環Bにおける当該フェニル基または単環式ヘテロアリール基は、それぞれ、1~4個のR2で置換されていてもよく;
Lは、ハロゲン原子、C3~8シクロアルキル基、C1~6アルコキシル基、ハロゲン化C1~6アルコキシル基、フェノキシ基、単環式非芳香族複素環基、フェニル基または単環式ヘテロアリール基を表し、Lにおける、当該フェノキシ基、単環式非芳香族複素環基、フェニル基または単環式ヘテロアリール基は、それぞれ、1~5個のR3で置換されていてもよく、または、Lは、R2と結合し、環Bの一部とともに縮合環基を形成してもよく、前記縮合環基は、ハロゲン原子で置換されていてもよい5~7員複素環基であり;
環B上においてLは環A-ビシクロ環-CO-の結合位置に隣接する置換基であり;
R1は、各々独立に、ハロゲン原子、C1~6アルキル基、C2~6アルケニル基、C2~6アルキニル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~6アルケニルオキシ基、C2~6アルキニルオキシ基、C2~7アルカノイル基、C1~6アルコキシルカルボニル基、C1~6アルキルチオ基、-NRaRb基、シアノ基及びオキソ基から任意に選ばれる基を表し、R1における当該C1~6アルキル基、C2~6アルケニル基、C2~6アルキニル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~6アルケニルオキシ基、C2~6アルキニルオキシ基、C2~7アルカノイル基、C1~6アルコキシルカルボニル基またはC1~6アルキルチオ基は、それぞれ、1~5個の置換基RIで置換されていてもよく;
R2は、各々独立に、ハロゲン原子、C1~6アルキル基、C2~6アルケニル基、C2~6アルキニル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~6アルケニルオキシ基、C2~6アルキニルオキシ基、シアノ基及び単環式ヘテロアリール基から任意に選ばれる基を表し、R2における当該C1~6アルキル基、C2~6アルケニル基、C2~6アルキニル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~6アルケニルオキシ基、C2~6アルキニルオキシ基または単環式ヘテロアリール基は、それぞれ、1~5個の置換基RIで置換されていてもよく;
R3は、各々独立に、ハロゲン原子、C1~6アルキル基、C2~6アルケニル基、C2~6アルキニル基、C1~6アルコキシル基、C2~6アルケニルオキシ基、C2~6アルキニルオキシ基及びシアノ基から任意に選ばれる基を表し、R3における当該C1~6アルキル基、C2~6アルケニル基、C2~6アルキニル基、C1~6アルコキシル基、C2~6アルケニルオキシ基またはC2~6アルキニルオキシ基は、それぞれ、1~5個の置換基RIで置換されていてもよく;
Ra及びRbは、各々独立に、C1~6アルキル基、ハロゲン化C1~6アルキル基、C2~6アルケニル基及びC2~6アルキニル基から任意に選ばれる基を表し、RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよく、RaおよびRbにおける当該単環式非芳香族複素環基は、その環内の炭素原子の少なくとも1個が、酸素原子、硫黄原子及びC1~6アルキル基で置換されていてもよい窒素原子から任意に選ばれる原子またはカルボニル基で置き換えられていてもよく;
置換基RIは、各々独立に、ハロゲン原子または水酸基を表す)
で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。 [Aspect of the Invention]
The present invention includes the following embodiments [1] to [14].
[1] The first aspect of the present invention is
Formula (I)
(Where
n represents 1 or 2;
Ring A represents a C 6 ~ 14 aryl group or a 5-14 membered heteroaryl group, in the ring A, the C 6 ~ 14 aryl group or a 5-14 membered heteroaryl group, respectively, 1-5 R Optionally substituted by 1 ;
Ring B represents a phenyl group or a monocyclic heteroaryl group, and the phenyl group or monocyclic heteroaryl group in Ring B may each be substituted with 1 to 4 R 2 ;
L is a halogen atom, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxyl group, a halogenated C 1 ~ 6 alkoxy group, a phenoxy group, a monocyclic non-aromatic heterocyclic group, a phenyl group or a monocyclic heteroaryl Represents an aryl group, and the phenoxy group, monocyclic non-aromatic heterocyclic group, phenyl group or monocyclic heteroaryl group in L may each be substituted with 1 to 5 R 3 , Alternatively, L may be bonded to R 2 to form a condensed ring group together with a part of the ring B, and the condensed ring group is a 5- to 7-membered heterocyclic group which may be substituted with a halogen atom. Yes;
L on ring B is a substituent adjacent to the bond position of ring A-bicycloring-CO—;
R 1 is, each independently, a halogen atom, C 1 ~ 6 alkyl group, C 2 ~ 6 alkenyl group, C 2 ~ 6 alkynyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 2 ~ 6 alkenyloxy group, C 2 ~ 6 alkynyloxy group, C 2 ~ 7 alkanoyl group, C 1 ~ 6 alkoxycarbonyl group, C 1 ~ 6 alkylthio group, -NR a R b group, optionally cyano group and oxo group represents a group selected, the C 1 ~ 6 alkyl group in R 1, C 2 ~ 6 alkenyl group, C 2 ~ 6 alkynyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 2 ~ 6 alkenyloxy group, C 2 ~ 6 alkynyloxy group, C 2 ~ 7 alkanoyl group, C 1 ~ 6 alkoxycarbonyl group, or a C 1 ~ 6 alkylthio group, respectively, substituted with 1 to 5 substituents RI Well;
R 2 are each independently a halogen atom, C 1 ~ 6 alkyl group, C 2 ~ 6 alkenyl group, C 2 ~ 6 alkynyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 2 ~ 6 alkenyloxy groups, C 2 ~ 6 alkynyloxy group, a chosen group optionally cyano group and a monocyclic heteroaryl group, said C 1 ~ 6 alkyl group in R 2, C 2 ~ 6 alkenyl groups, C 2-6 alkynyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 2-6 alkenyloxy group, C 2-6 alkynyloxy group or a monocyclic heteroaryl group, respectively, 1-5 Optionally substituted by one substituent RI;
R 3 are each independently a halogen atom, C 1 ~ 6 alkyl group, C 2 ~ 6 alkenyl group, C 2 ~ 6 alkynyl group, C 1 ~ 6 alkoxy group, C 2 ~ 6 alkenyloxy group, C 2 ~ represents 6 alkynyloxy group and chosen group optionally cyano group, the C 1 ~ 6 alkyl group in R 3, C 2 ~ 6 alkenyl group, C 2 ~ 6 alkynyl group, C 1 ~ 6 alkoxy group, C 2 1-6 alkenyloxy group or a C 2 - 6 alkynyloxy groups may each be substituted with 1 to 5 substituents RI;
R a and R b represent each independently, C 1 ~ 6 alkyl group, a halogenated C 1 ~ 6 alkyl group, a chosen group optionally from C 2 ~ 6 alkenyl group and C 2 ~ 6 alkynyl radical, R a and R b together with the nitrogen atom to which they are attached may form a monocyclic non-aromatic heterocyclic group, and the monocyclic non-aromatic heterocyclic group in R a and R b At least one of the carbon atoms may be replaced with an atom or carbonyl group arbitrarily selected from an oxygen atom, a sulfur atom and a nitrogen atom optionally substituted with a C 1-6 alkyl group;
Each of the substituents RI independently represents a halogen atom or a hydroxyl group)
Or a pharmaceutically acceptable salt or solvate thereof.
本発明は、以下の態様[1]~[14]を含む。
[1] 本発明の第1の態様は、
下記式(I)
nは、1または2を表し;
環Aは、C6~14アリール基または5~14員ヘテロアリール基を表し、環Aにおける、当該C6~14アリール基または5~14員ヘテロアリール基は、それぞれ、1~5個のR1で置換されていてもよく;
環Bは、フェニル基または単環式ヘテロアリール基を表し、環Bにおける当該フェニル基または単環式ヘテロアリール基は、それぞれ、1~4個のR2で置換されていてもよく;
Lは、ハロゲン原子、C3~8シクロアルキル基、C1~6アルコキシル基、ハロゲン化C1~6アルコキシル基、フェノキシ基、単環式非芳香族複素環基、フェニル基または単環式ヘテロアリール基を表し、Lにおける、当該フェノキシ基、単環式非芳香族複素環基、フェニル基または単環式ヘテロアリール基は、それぞれ、1~5個のR3で置換されていてもよく、または、Lは、R2と結合し、環Bの一部とともに縮合環基を形成してもよく、前記縮合環基は、ハロゲン原子で置換されていてもよい5~7員複素環基であり;
環B上においてLは環A-ビシクロ環-CO-の結合位置に隣接する置換基であり;
R1は、各々独立に、ハロゲン原子、C1~6アルキル基、C2~6アルケニル基、C2~6アルキニル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~6アルケニルオキシ基、C2~6アルキニルオキシ基、C2~7アルカノイル基、C1~6アルコキシルカルボニル基、C1~6アルキルチオ基、-NRaRb基、シアノ基及びオキソ基から任意に選ばれる基を表し、R1における当該C1~6アルキル基、C2~6アルケニル基、C2~6アルキニル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~6アルケニルオキシ基、C2~6アルキニルオキシ基、C2~7アルカノイル基、C1~6アルコキシルカルボニル基またはC1~6アルキルチオ基は、それぞれ、1~5個の置換基RIで置換されていてもよく;
R2は、各々独立に、ハロゲン原子、C1~6アルキル基、C2~6アルケニル基、C2~6アルキニル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~6アルケニルオキシ基、C2~6アルキニルオキシ基、シアノ基及び単環式ヘテロアリール基から任意に選ばれる基を表し、R2における当該C1~6アルキル基、C2~6アルケニル基、C2~6アルキニル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~6アルケニルオキシ基、C2~6アルキニルオキシ基または単環式ヘテロアリール基は、それぞれ、1~5個の置換基RIで置換されていてもよく;
R3は、各々独立に、ハロゲン原子、C1~6アルキル基、C2~6アルケニル基、C2~6アルキニル基、C1~6アルコキシル基、C2~6アルケニルオキシ基、C2~6アルキニルオキシ基及びシアノ基から任意に選ばれる基を表し、R3における当該C1~6アルキル基、C2~6アルケニル基、C2~6アルキニル基、C1~6アルコキシル基、C2~6アルケニルオキシ基またはC2~6アルキニルオキシ基は、それぞれ、1~5個の置換基RIで置換されていてもよく;
Ra及びRbは、各々独立に、C1~6アルキル基、ハロゲン化C1~6アルキル基、C2~6アルケニル基及びC2~6アルキニル基から任意に選ばれる基を表し、RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよく、RaおよびRbにおける当該単環式非芳香族複素環基は、その環内の炭素原子の少なくとも1個が、酸素原子、硫黄原子及びC1~6アルキル基で置換されていてもよい窒素原子から任意に選ばれる原子またはカルボニル基で置き換えられていてもよく;
置換基RIは、各々独立に、ハロゲン原子または水酸基を表す)
で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。 [Aspect of the Invention]
The present invention includes the following embodiments [1] to [14].
[1] The first aspect of the present invention is
Formula (I)
n represents 1 or 2;
Ring A represents a C 6 ~ 14 aryl group or a 5-14 membered heteroaryl group, in the ring A, the C 6 ~ 14 aryl group or a 5-14 membered heteroaryl group, respectively, 1-5 R Optionally substituted by 1 ;
Ring B represents a phenyl group or a monocyclic heteroaryl group, and the phenyl group or monocyclic heteroaryl group in Ring B may each be substituted with 1 to 4 R 2 ;
L is a halogen atom, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxyl group, a halogenated C 1 ~ 6 alkoxy group, a phenoxy group, a monocyclic non-aromatic heterocyclic group, a phenyl group or a monocyclic heteroaryl Represents an aryl group, and the phenoxy group, monocyclic non-aromatic heterocyclic group, phenyl group or monocyclic heteroaryl group in L may each be substituted with 1 to 5 R 3 , Alternatively, L may be bonded to R 2 to form a condensed ring group together with a part of the ring B, and the condensed ring group is a 5- to 7-membered heterocyclic group which may be substituted with a halogen atom. Yes;
L on ring B is a substituent adjacent to the bond position of ring A-bicycloring-CO—;
R 1 is, each independently, a halogen atom, C 1 ~ 6 alkyl group, C 2 ~ 6 alkenyl group, C 2 ~ 6 alkynyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 2 ~ 6 alkenyloxy group, C 2 ~ 6 alkynyloxy group, C 2 ~ 7 alkanoyl group, C 1 ~ 6 alkoxycarbonyl group, C 1 ~ 6 alkylthio group, -NR a R b group, optionally cyano group and oxo group represents a group selected, the C 1 ~ 6 alkyl group in R 1, C 2 ~ 6 alkenyl group, C 2 ~ 6 alkynyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 2 ~ 6 alkenyloxy group, C 2 ~ 6 alkynyloxy group, C 2 ~ 7 alkanoyl group, C 1 ~ 6 alkoxycarbonyl group, or a C 1 ~ 6 alkylthio group, respectively, substituted with 1 to 5 substituents RI Well;
R 2 are each independently a halogen atom, C 1 ~ 6 alkyl group, C 2 ~ 6 alkenyl group, C 2 ~ 6 alkynyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 2 ~ 6 alkenyloxy groups, C 2 ~ 6 alkynyloxy group, a chosen group optionally cyano group and a monocyclic heteroaryl group, said C 1 ~ 6 alkyl group in R 2, C 2 ~ 6 alkenyl groups, C 2-6 alkynyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 2-6 alkenyloxy group, C 2-6 alkynyloxy group or a monocyclic heteroaryl group, respectively, 1-5 Optionally substituted by one substituent RI;
R 3 are each independently a halogen atom, C 1 ~ 6 alkyl group, C 2 ~ 6 alkenyl group, C 2 ~ 6 alkynyl group, C 1 ~ 6 alkoxy group, C 2 ~ 6 alkenyloxy group, C 2 ~ represents 6 alkynyloxy group and chosen group optionally cyano group, the C 1 ~ 6 alkyl group in R 3, C 2 ~ 6 alkenyl group, C 2 ~ 6 alkynyl group, C 1 ~ 6 alkoxy group, C 2 1-6 alkenyloxy group or a C 2 - 6 alkynyloxy groups may each be substituted with 1 to 5 substituents RI;
R a and R b represent each independently, C 1 ~ 6 alkyl group, a halogenated C 1 ~ 6 alkyl group, a chosen group optionally from C 2 ~ 6 alkenyl group and C 2 ~ 6 alkynyl radical, R a and R b together with the nitrogen atom to which they are attached may form a monocyclic non-aromatic heterocyclic group, and the monocyclic non-aromatic heterocyclic group in R a and R b At least one of the carbon atoms may be replaced with an atom or carbonyl group arbitrarily selected from an oxygen atom, a sulfur atom and a nitrogen atom optionally substituted with a C 1-6 alkyl group;
Each of the substituents RI independently represents a halogen atom or a hydroxyl group)
Or a pharmaceutically acceptable salt or solvate thereof.
以下に、上記態様[1]の上記式(I)中の各基について具体的に説明する。
本発明の化合物に関する説明において、例えば「C1~6」とは、構成炭素原子数が1から6であることを示し、特に断らない限り、直鎖、分枝鎖または環状の基の炭素原子数を表す。鎖状の基については「構成炭素原子数が1ないし6の直鎖または分枝鎖」を意味する。また、環状の基については「環の構成炭素員数が1ないし6の環状基」を意味する。鎖状の基と環状の基を含む基については「総炭素原子数が1ないし6の基」を意味する。 Below, each group in the said formula (I) of the said aspect [1] is demonstrated concretely.
In the description of the compounds of the present invention, for example, “C 1-6 ” means that the number of constituent carbon atoms is 1 to 6, and unless otherwise specified, carbon atoms of a linear, branched or cyclic group Represents a number. The chain group means “straight or branched chain having 1 to 6 carbon atoms”. Further, the cyclic group means “a cyclic group having 1 to 6 carbon atoms in the ring”. The group containing a chain group and a cyclic group means “a group having 1 to 6 total carbon atoms”.
本発明の化合物に関する説明において、例えば「C1~6」とは、構成炭素原子数が1から6であることを示し、特に断らない限り、直鎖、分枝鎖または環状の基の炭素原子数を表す。鎖状の基については「構成炭素原子数が1ないし6の直鎖または分枝鎖」を意味する。また、環状の基については「環の構成炭素員数が1ないし6の環状基」を意味する。鎖状の基と環状の基を含む基については「総炭素原子数が1ないし6の基」を意味する。 Below, each group in the said formula (I) of the said aspect [1] is demonstrated concretely.
In the description of the compounds of the present invention, for example, “C 1-6 ” means that the number of constituent carbon atoms is 1 to 6, and unless otherwise specified, carbon atoms of a linear, branched or cyclic group Represents a number. The chain group means “straight or branched chain having 1 to 6 carbon atoms”. Further, the cyclic group means “a cyclic group having 1 to 6 carbon atoms in the ring”. The group containing a chain group and a cyclic group means “a group having 1 to 6 total carbon atoms”.
本明細書中、特に断りのない限り、「ハロゲン原子」としては、例えば、フッ素原子、塩素原子、臭素原子、およびヨウ素原子等が挙げられる。
本明細書中、特に断りのない限り、「ハロゲン化」とは、置換基として1~5個の前記「ハロゲン原子」を有することを意味する。また、「ハロゲン化」は「ハロゲノ」と言い換えられる。
本明細書中、特に断りのない限り、「C1~6アルキル基」としては、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチル、tert-ブチル、およびヘキシル等が挙げられる。また、「C1~4アルキル基」としては、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチルおよびtert-ブチル等が挙げられ、「C1~2アルキル基」としては、メチルおよびエチルが挙げられる。 In the present specification, unless otherwise specified, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
In the present specification, unless otherwise specified, “halogenated” means having 1 to 5 “halogen atoms” as a substituent. “Halogenation” is also referred to as “halogeno”.
In the present specification, unless otherwise specified, examples of the “C 1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, hexyl and the like. . Examples of the “C 1-4 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and “C 1-2 alkyl group” includes Methyl and ethyl are mentioned.
本明細書中、特に断りのない限り、「ハロゲン化」とは、置換基として1~5個の前記「ハロゲン原子」を有することを意味する。また、「ハロゲン化」は「ハロゲノ」と言い換えられる。
本明細書中、特に断りのない限り、「C1~6アルキル基」としては、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチル、tert-ブチル、およびヘキシル等が挙げられる。また、「C1~4アルキル基」としては、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチルおよびtert-ブチル等が挙げられ、「C1~2アルキル基」としては、メチルおよびエチルが挙げられる。 In the present specification, unless otherwise specified, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
In the present specification, unless otherwise specified, “halogenated” means having 1 to 5 “halogen atoms” as a substituent. “Halogenation” is also referred to as “halogeno”.
In the present specification, unless otherwise specified, examples of the “C 1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, hexyl and the like. . Examples of the “C 1-4 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and “C 1-2 alkyl group” includes Methyl and ethyl are mentioned.
本明細書中、特に断りのない限り、「ハロゲン化C1~6アルキル基」とは、前記「C1~6アルキル基」が1~5個のハロゲン原子で任意に置換されている基を意味し、例えば、ジフルオロメチル、トリフルオロメチル、2,2,2-トリフルオロエチル、1,1,2,2-テトラフルオロエチル、ペンタフルオロエチル等が挙げられる。
本明細書中、特に断りのない限り、「1~5個の置換基RIで置換されていてもよく」とは、該当する置換基(例えば、アルキル基)が置換基RIで1~5個任意に置換されていてもよいことを意味し、該当する無置換の置換基(例えば、無置換のアルキル基)に加えて、1~5個の置換基RIで置換されている該当基(例えば、アルキル基)を含むことを意味する。
具体的には、例えば、「1~5個の置換基RIで置換されているC1~6アルキル基」とは、前記「C1~6アルキル基」が1~5個の置換基RI、すなわち1~5個のハロゲン原子または水酸基、で任意に置換されている基を意味している。例えば、前記「ハロゲン化C1~6アルキル基」として挙げた基に加えて、「水酸基で置換されているC1~6アルキル基」であるヒドロキシメチル、ヒドロキシエチル、ヒドロキシプロピル、2-ヒドロキシ-2-メチル-エチル等、および「ハロゲン原子と水酸基で置換されているC1~6アルキル基」である2,2,2-トリフルオロ-1-ヒドロキシエチル等が挙げられる。 In the present specification, unless otherwise specified, the “halogenated C 1-6 alkyl group” means a group in which the “C 1-6 alkyl group” is optionally substituted with 1 to 5 halogen atoms. Meaning, for example, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl and the like.
In the present specification, unless otherwise specified, “may be substituted with 1 to 5 substituents RI” means that the corresponding substituent (for example, an alkyl group) is 1 to 5 substituents RI. It means that it may be optionally substituted, and in addition to the corresponding unsubstituted substituent (eg, unsubstituted alkyl group), the corresponding group (eg, , An alkyl group).
Specifically, for example, “a C 1-6 alkyl group substituted with 1 to 5 substituents RI” means that the “C 1-6 alkyl group” is 1 to 5 substituents RI, That is, a group optionally substituted with 1 to 5 halogen atoms or hydroxyl groups. For example, in addition to the groups mentioned as the above “halogenated C 1-6 alkyl group”, the “C 1-6 alkyl group substituted with a hydroxyl group” is hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxy- Examples include 2-methyl-ethyl and the like, and 2,2,2-trifluoro-1-hydroxyethyl which is a “C 1-6 alkyl group substituted with a halogen atom and a hydroxyl group”.
本明細書中、特に断りのない限り、「1~5個の置換基RIで置換されていてもよく」とは、該当する置換基(例えば、アルキル基)が置換基RIで1~5個任意に置換されていてもよいことを意味し、該当する無置換の置換基(例えば、無置換のアルキル基)に加えて、1~5個の置換基RIで置換されている該当基(例えば、アルキル基)を含むことを意味する。
具体的には、例えば、「1~5個の置換基RIで置換されているC1~6アルキル基」とは、前記「C1~6アルキル基」が1~5個の置換基RI、すなわち1~5個のハロゲン原子または水酸基、で任意に置換されている基を意味している。例えば、前記「ハロゲン化C1~6アルキル基」として挙げた基に加えて、「水酸基で置換されているC1~6アルキル基」であるヒドロキシメチル、ヒドロキシエチル、ヒドロキシプロピル、2-ヒドロキシ-2-メチル-エチル等、および「ハロゲン原子と水酸基で置換されているC1~6アルキル基」である2,2,2-トリフルオロ-1-ヒドロキシエチル等が挙げられる。 In the present specification, unless otherwise specified, the “halogenated C 1-6 alkyl group” means a group in which the “C 1-6 alkyl group” is optionally substituted with 1 to 5 halogen atoms. Meaning, for example, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl and the like.
In the present specification, unless otherwise specified, “may be substituted with 1 to 5 substituents RI” means that the corresponding substituent (for example, an alkyl group) is 1 to 5 substituents RI. It means that it may be optionally substituted, and in addition to the corresponding unsubstituted substituent (eg, unsubstituted alkyl group), the corresponding group (eg, , An alkyl group).
Specifically, for example, “a C 1-6 alkyl group substituted with 1 to 5 substituents RI” means that the “C 1-6 alkyl group” is 1 to 5 substituents RI, That is, a group optionally substituted with 1 to 5 halogen atoms or hydroxyl groups. For example, in addition to the groups mentioned as the above “halogenated C 1-6 alkyl group”, the “C 1-6 alkyl group substituted with a hydroxyl group” is hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxy- Examples include 2-methyl-ethyl and the like, and 2,2,2-trifluoro-1-hydroxyethyl which is a “C 1-6 alkyl group substituted with a halogen atom and a hydroxyl group”.
本明細書中、「1~5個の置換基RIで置換されていてもよい基」として、C1~6アルキル基に加えて、C2~6アルケニル基、C2~6アルキニル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~6アルケニルオキシ基、C2~6アルキニルオキシ基、C2~7アルカノイル基、C1~6アルコキシルカルボニル基、C1~6アルキルチオ基、または単環式ヘテロアリール基が示されており、各々の該当する無置換の置換基に加えて、前記の「1~5個の置換基RIで置換されているC1~6アルキル基」と同様に、1~5個の置換基RIで任意に置換されている該当置換基を意味している。
本明細書中、特に断りのない限り、「C2~6アルケニル基」としては、例えば、ビニル、アリル、イソプロペニル、1-プロペン-1-イル、ブテニル、ペンテニル、イソペンテニル、およびヘキセニル等が挙げられる。
本明細書中、特に断りのない限り、「C2~6アルキニル基」としては、例えば、エチニル、1-プロピニル(=1-プロピン-1-イル)、2-プロピニル(=2-プロピン-1-イル)、ブチニル、ペンチニル(=4-ペンチン-1-イル)、およびヘキシニル(=5-ヘキシン-1-イル)等が挙げられる。 In the specification, the "1 to 5 substituents RI group which may be substituted with", in addition to the C 1 ~ 6 alkyl groups, C 2 ~ 6 alkenyl groups, C 2 ~ 6 alkynyl groups, C 3-8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 2 ~ 6 alkenyloxy group, C 2 ~ 6 alkynyloxy group, C 2 ~ 7 alkanoyl group, C 1 ~ 6 alkoxycarbonyl group, C 1 ~ 6 alkylthio Or a monocyclic heteroaryl group, in addition to each corresponding unsubstituted substituent, in addition to the aforementioned “C 1-6 alkyl group substituted by 1 to 5 substituents RI” ”Means a corresponding substituent optionally substituted with 1 to 5 substituents RI.
Herein, unless otherwise specified, as the "C 2 ~ 6 alkenyl group", for example, vinyl, allyl, isopropenyl, 1-propen-1-yl, butenyl, pentenyl, isopentenyl, and hexenyl and the like Can be mentioned.
Herein, unless otherwise specified, as the "C 2 ~ 6 alkynyl group", for example, ethynyl, 1-propynyl (= 1-propyn-1-yl), 2-propynyl (= 2-propyn -1 -Yl), butynyl, pentynyl (= 4-pentyn-1-yl), hexynyl (= 5-hexyn-1-yl) and the like.
本明細書中、特に断りのない限り、「C2~6アルケニル基」としては、例えば、ビニル、アリル、イソプロペニル、1-プロペン-1-イル、ブテニル、ペンテニル、イソペンテニル、およびヘキセニル等が挙げられる。
本明細書中、特に断りのない限り、「C2~6アルキニル基」としては、例えば、エチニル、1-プロピニル(=1-プロピン-1-イル)、2-プロピニル(=2-プロピン-1-イル)、ブチニル、ペンチニル(=4-ペンチン-1-イル)、およびヘキシニル(=5-ヘキシン-1-イル)等が挙げられる。 In the specification, the "1 to 5 substituents RI group which may be substituted with", in addition to the C 1 ~ 6 alkyl groups, C 2 ~ 6 alkenyl groups, C 2 ~ 6 alkynyl groups, C 3-8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 2 ~ 6 alkenyloxy group, C 2 ~ 6 alkynyloxy group, C 2 ~ 7 alkanoyl group, C 1 ~ 6 alkoxycarbonyl group, C 1 ~ 6 alkylthio Or a monocyclic heteroaryl group, in addition to each corresponding unsubstituted substituent, in addition to the aforementioned “C 1-6 alkyl group substituted by 1 to 5 substituents RI” ”Means a corresponding substituent optionally substituted with 1 to 5 substituents RI.
Herein, unless otherwise specified, as the "C 2 ~ 6 alkenyl group", for example, vinyl, allyl, isopropenyl, 1-propen-1-yl, butenyl, pentenyl, isopentenyl, and hexenyl and the like Can be mentioned.
Herein, unless otherwise specified, as the "C 2 ~ 6 alkynyl group", for example, ethynyl, 1-propynyl (= 1-propyn-1-yl), 2-propynyl (= 2-propyn -1 -Yl), butynyl, pentynyl (= 4-pentyn-1-yl), hexynyl (= 5-hexyn-1-yl) and the like.
本明細書中、特に断りのない限り、「C3~8シクロアルキル基」としては、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチルおよびシクロオクチル等の環状アルキル基が挙げられる。
本明細書中、特に断りのない限り、「アリール基」は、「単環式アリール基」、「縮環式アリール基(2環式、または3環式が含まれる)」または「部分的に水素化された縮環式アリール基」を包含する。
本明細書中、特に断りのない限り、「部分的に水素化された縮環式アリール基」とは、前記「縮環式アリール基」において、部分的水素化された縮合環から任意の水素原子を除いてできる1価の基を意味し、縮合環の芳香環部分の水素原子あるいは水素化された部分の水素原子のどちらが除かれてもよい。
本明細書中、特に断りのない限り、「C6~14アリール基」としては、例えば、フェニル、1-ナフチル、2-ナフチル、2-,3-,4-ビフェニルアンスリル、フェナンスリル、アセナフチル、インダニル、インデニル、および1,2,3,4-テトラヒドロナフチル等が挙げられる。 Herein, unless otherwise specified, as the "C 3 ~ 8 cycloalkyl group", for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclic alkyl groups such as cycloheptyl and cyclooctyl.
In the present specification, unless otherwise specified, the “aryl group” means “monocyclic aryl group”, “condensed aryl group (including bicyclic or tricyclic)” or “partially A hydrogenated fused-ring aryl group ".
In the present specification, unless otherwise specified, the “partially hydrogenated condensed aryl group” means any hydrogen from a partially hydrogenated condensed ring in the “condensed aryl group”. It means a monovalent group formed by removing an atom, and either a hydrogen atom in an aromatic ring part of a condensed ring or a hydrogen atom in a hydrogenated part may be removed.
Herein, unless otherwise specified, as the "C 6 ~ 14 aryl group", for example, phenyl, 1-naphthyl, 2-naphthyl, 2-, 3-, 4-biphenyl anthryl, phenanthryl, acenaphthyl, Indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl and the like can be mentioned.
本明細書中、特に断りのない限り、「アリール基」は、「単環式アリール基」、「縮環式アリール基(2環式、または3環式が含まれる)」または「部分的に水素化された縮環式アリール基」を包含する。
本明細書中、特に断りのない限り、「部分的に水素化された縮環式アリール基」とは、前記「縮環式アリール基」において、部分的水素化された縮合環から任意の水素原子を除いてできる1価の基を意味し、縮合環の芳香環部分の水素原子あるいは水素化された部分の水素原子のどちらが除かれてもよい。
本明細書中、特に断りのない限り、「C6~14アリール基」としては、例えば、フェニル、1-ナフチル、2-ナフチル、2-,3-,4-ビフェニルアンスリル、フェナンスリル、アセナフチル、インダニル、インデニル、および1,2,3,4-テトラヒドロナフチル等が挙げられる。 Herein, unless otherwise specified, as the "C 3 ~ 8 cycloalkyl group", for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclic alkyl groups such as cycloheptyl and cyclooctyl.
In the present specification, unless otherwise specified, the “aryl group” means “monocyclic aryl group”, “condensed aryl group (including bicyclic or tricyclic)” or “partially A hydrogenated fused-ring aryl group ".
In the present specification, unless otherwise specified, the “partially hydrogenated condensed aryl group” means any hydrogen from a partially hydrogenated condensed ring in the “condensed aryl group”. It means a monovalent group formed by removing an atom, and either a hydrogen atom in an aromatic ring part of a condensed ring or a hydrogen atom in a hydrogenated part may be removed.
Herein, unless otherwise specified, as the "C 6 ~ 14 aryl group", for example, phenyl, 1-naphthyl, 2-naphthyl, 2-, 3-, 4-biphenyl anthryl, phenanthryl, acenaphthyl, Indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl and the like can be mentioned.
本明細書中、特に断りのない限り、「複素環基」とは、窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を1~5個含有する3~14員環の単環式もしくは縮環式の環から任意の水素原子を除いてできる1価の基を意味する。
本明細書中、特に断りのない限り、「複素環基」としては、例えば、「ヘテロアリール基」および「非芳香族複素環基」等が挙げられる。
本明細書中、特に断りのない限り、前記「ヘテロアリール基」とは、窒素原子、硫黄原子、および酸素原子から選ばれるヘテロ原子を1~5個含有する5~14員ヘテロアリール環基を意味する。
本明細書中、特に断りのない限り、前記「ヘテロアリール基」としては、例えば、「単環式ヘテロアリール基」、「縮環式ヘテロアリール基」、「部分的に水素化された縮環式ヘテロアリール基」が挙げられる。
本明細書中、特に断りのない限り、前記「単環式ヘテロアリール基」としては、環員数5~7のものが好ましく、例えば、ピロリル、フリル、チエニル、イミダゾリル、ピラゾリル、オキサゾリル、イソキサゾリル、チアゾリル、イソチアゾリル、1,2,3-トリアゾリル、1,2,4-トリアゾリル、1,2,3-オキサジアゾリル、1,2,4-オキサジアゾリル、1,3,4-オキサジアゾリル、テトラゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル等が挙げられる。 In the present specification, unless otherwise specified, the “heterocyclic group” means a 3 to 14-membered monocyclic or condensed ring containing 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. A monovalent group formed by removing any hydrogen atom from a cyclic ring.
In the present specification, unless otherwise specified, examples of the “heterocyclic group” include “heteroaryl group” and “non-aromatic heterocyclic group”.
In the present specification, unless otherwise specified, the “heteroaryl group” refers to a 5- to 14-membered heteroaryl ring group containing 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. means.
In the present specification, unless otherwise specified, examples of the “heteroaryl group” include “monocyclic heteroaryl group”, “condensed heteroaryl group”, and “partially hydrogenated fused ring”. Formula heteroaryl group ".
In the present specification, unless otherwise specified, the “monocyclic heteroaryl group” preferably has 5 to 7 ring members. For example, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl , Isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl , Pyrazinyl and the like.
本明細書中、特に断りのない限り、「複素環基」としては、例えば、「ヘテロアリール基」および「非芳香族複素環基」等が挙げられる。
本明細書中、特に断りのない限り、前記「ヘテロアリール基」とは、窒素原子、硫黄原子、および酸素原子から選ばれるヘテロ原子を1~5個含有する5~14員ヘテロアリール環基を意味する。
本明細書中、特に断りのない限り、前記「ヘテロアリール基」としては、例えば、「単環式ヘテロアリール基」、「縮環式ヘテロアリール基」、「部分的に水素化された縮環式ヘテロアリール基」が挙げられる。
本明細書中、特に断りのない限り、前記「単環式ヘテロアリール基」としては、環員数5~7のものが好ましく、例えば、ピロリル、フリル、チエニル、イミダゾリル、ピラゾリル、オキサゾリル、イソキサゾリル、チアゾリル、イソチアゾリル、1,2,3-トリアゾリル、1,2,4-トリアゾリル、1,2,3-オキサジアゾリル、1,2,4-オキサジアゾリル、1,3,4-オキサジアゾリル、テトラゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル等が挙げられる。 In the present specification, unless otherwise specified, the “heterocyclic group” means a 3 to 14-membered monocyclic or condensed ring containing 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. A monovalent group formed by removing any hydrogen atom from a cyclic ring.
In the present specification, unless otherwise specified, examples of the “heterocyclic group” include “heteroaryl group” and “non-aromatic heterocyclic group”.
In the present specification, unless otherwise specified, the “heteroaryl group” refers to a 5- to 14-membered heteroaryl ring group containing 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. means.
In the present specification, unless otherwise specified, examples of the “heteroaryl group” include “monocyclic heteroaryl group”, “condensed heteroaryl group”, and “partially hydrogenated fused ring”. Formula heteroaryl group ".
In the present specification, unless otherwise specified, the “monocyclic heteroaryl group” preferably has 5 to 7 ring members. For example, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl , Isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl , Pyrazinyl and the like.
本明細書中、特に断りのない限り、前記「縮環式ヘテロアリール基」とは、「複素環基」と「アリール基」、もしくは、「複素環基」と「単環式ヘテロアリール基」が縮合して形成された縮合環から、任意の水素原子を除いてできる1価の基を意味し、当該任意の水素原子は縮合したいずれの環から除かれてもよい。
本明細書中、特に断りのない限り、前記「縮環式ヘテロアリール基」としては、環員数8~12のものが好ましく、例えば、インドリル、イソインドリル、ベンゾフラニル、イソベンゾフラニル、ベンゾチエニル、イソベンゾチエニル、ベンゾオキサゾリル、1,2-ベンゾイソキサゾリル、ベンゾチアゾリル、1,2-ベンゾイソチアゾリル、1H-ベンズイミダゾリル、1H-インダゾリル、1H-ベンゾトリアゾリル、クロメニル、イソクロメニル、キノリル、イソキノリル、シンノリニル、キナゾリニル、キノキサリニル、フタラジニル、ベンゾオキサゼピニル、ベンゾアゼピニル、ベンゾジアゼピニル、ナフチリジニル、プリニル、プテリジニル、カルバゾリル、カルボリニル、アクリジニル、フェノキサジニル、フェノチアジニル、フェナジニル、フェノキサチイニル、チアンスレニル、チアントレニル、フェナンスリジニル、フェナンスロリニル、インドリジニル、フロ[2,3-c]ピリジル、フロ[3,2-c]ピリジル、イミダゾ[1,5-a]ピラジニル、1H-ピラゾロ[3,4-c]ピリジル、1H-ピラゾロ[4,3-c]ピリジル、1H-ピラゾロ[4,3-b]ピリジル等が挙げられる。 In the present specification, unless otherwise specified, the “condensed heteroaryl group” means “heterocyclic group” and “aryl group”, or “heterocyclic group” and “monocyclic heteroaryl group”. Means a monovalent group formed by removing an arbitrary hydrogen atom from a condensed ring formed by condensation, and the arbitrary hydrogen atom may be removed from any condensed ring.
In the present specification, unless otherwise specified, the “condensed heteroaryl group” is preferably one having 8 to 12 ring members, for example, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, iso Benzothienyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzimidazolyl, 1H-indazolyl, 1H-benzotriazolyl, chromenyl, isochromenyl, quinolyl , Isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, benzoxazepinyl, benzoazepinyl, benzodiazepinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl , Phenazinyl, phenoxathiinyl, thianthrenyl, thianthenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, furo [2,3-c] pyridyl, furo [3,2-c] pyridyl, imidazo [1,5- a] pyrazinyl, 1H-pyrazolo [3,4-c] pyridyl, 1H-pyrazolo [4,3-c] pyridyl, 1H-pyrazolo [4,3-b] pyridyl and the like.
本明細書中、特に断りのない限り、前記「縮環式ヘテロアリール基」としては、環員数8~12のものが好ましく、例えば、インドリル、イソインドリル、ベンゾフラニル、イソベンゾフラニル、ベンゾチエニル、イソベンゾチエニル、ベンゾオキサゾリル、1,2-ベンゾイソキサゾリル、ベンゾチアゾリル、1,2-ベンゾイソチアゾリル、1H-ベンズイミダゾリル、1H-インダゾリル、1H-ベンゾトリアゾリル、クロメニル、イソクロメニル、キノリル、イソキノリル、シンノリニル、キナゾリニル、キノキサリニル、フタラジニル、ベンゾオキサゼピニル、ベンゾアゼピニル、ベンゾジアゼピニル、ナフチリジニル、プリニル、プテリジニル、カルバゾリル、カルボリニル、アクリジニル、フェノキサジニル、フェノチアジニル、フェナジニル、フェノキサチイニル、チアンスレニル、チアントレニル、フェナンスリジニル、フェナンスロリニル、インドリジニル、フロ[2,3-c]ピリジル、フロ[3,2-c]ピリジル、イミダゾ[1,5-a]ピラジニル、1H-ピラゾロ[3,4-c]ピリジル、1H-ピラゾロ[4,3-c]ピリジル、1H-ピラゾロ[4,3-b]ピリジル等が挙げられる。 In the present specification, unless otherwise specified, the “condensed heteroaryl group” means “heterocyclic group” and “aryl group”, or “heterocyclic group” and “monocyclic heteroaryl group”. Means a monovalent group formed by removing an arbitrary hydrogen atom from a condensed ring formed by condensation, and the arbitrary hydrogen atom may be removed from any condensed ring.
In the present specification, unless otherwise specified, the “condensed heteroaryl group” is preferably one having 8 to 12 ring members, for example, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, iso Benzothienyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzimidazolyl, 1H-indazolyl, 1H-benzotriazolyl, chromenyl, isochromenyl, quinolyl , Isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, benzoxazepinyl, benzoazepinyl, benzodiazepinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl , Phenazinyl, phenoxathiinyl, thianthrenyl, thianthenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, furo [2,3-c] pyridyl, furo [3,2-c] pyridyl, imidazo [1,5- a] pyrazinyl, 1H-pyrazolo [3,4-c] pyridyl, 1H-pyrazolo [4,3-c] pyridyl, 1H-pyrazolo [4,3-b] pyridyl and the like.
本明細書中、特に断りのない限り、「部分的に水素化された縮環式ヘテロアリール基」とは、「複素環基」と「アリール基」、もしくは、「複素環基」と「ヘテロアリール基」が縮合して形成された縮合環において、部分的に水素化された縮合環から、任意の水素原子を除いてできる1価の基を意味する。当該任意の水素原子は、縮合環内における「複素環基」、「アリール基」および「ヘテロアリール基」の何れの環部の水素原子、あるいは水素化された環部の水素原子のどちらが除かれても良く、例えば、キノリンが部分的に水素化されたテトラヒドロキノリルであれば、5,6,7,8-テトラヒドロキノリルあるいは1,2,3,4-テトラヒドロキノリル等が挙げられる。これらの基は、任意の水素原子を除く位置により、例えば、5,6,7,8-テトラヒドロキノリルであれば、-2-イル、-3-イル、-4-イル、-5-イル、-6-イル、-7-イル、-8-イルなどが例示され、1,2,3,4-テトラヒドロキノリルであれば、例えば、-1-イル、-2-イル、-3-イル、-4-イル、-5-イル、-6-イル、-7-イル、-8-イルなどが例示される。
本明細書中、特に断りのない限り、「部分的に水素化された縮環式ヘテロアリール基」としては、環員数8~12のものが好ましく、例えば、インドリニル、4,5,6,7-テトラヒドロ-1H-インドニル、2,3-ジヒドロベンゾフラニル、4,5,6,7-テトラヒドロ-ベンゾフラニル、2,3-ジヒドロベンゾ[d]オキサゾリル、2,3-ジヒドロベンゾ[d]チアゾリル、4,5,6,7-テトラヒドロ-1H-インダゾリル、クロマニル、2H-クロメニル、4H-クロメニル、イソクロマニル、1H-イソクロメニル、1,3-ベンゾジオキソリル、2,3-ジヒドロフロ[3,2-c]ピリジル等が挙げられる。 In this specification, unless otherwise specified, the “partially hydrogenated condensed heteroaryl group” means “heterocyclic group” and “aryl group”, or “heterocyclic group” and “heterocyclic group”. In a condensed ring formed by condensing an “aryl group”, it means a monovalent group formed by removing any hydrogen atom from a partially hydrogenated condensed ring. The arbitrary hydrogen atom is a hydrogen atom in any of the "heterocyclic group", "aryl group" and "heteroaryl group" in the condensed ring, or a hydrogen atom in the hydrogenated ring part. For example, if the quinoline is partially hydrogenated tetrahydroquinolyl, 5,6,7,8-tetrahydroquinolyl, 1,2,3,4-tetrahydroquinolyl and the like can be mentioned. Depending on the position of any hydrogen atom, these groups can be, for example, 5,6,7,8-tetrahydroquinolyl-2-yl, -3-yl, -4-yl, -5-yl. , -6-yl, -7-yl, -8-yl and the like, and 1,2,3,4-tetrahydroquinolyl, for example, -1-yl, -2-yl, -3- Il, -4-yl, -5-yl, -6-yl, -7-yl, -8-yl and the like are exemplified.
In the present specification, unless otherwise specified, the “partially hydrogenated condensed heteroaryl group” preferably has 8 to 12 ring members, such as indolinyl, 4, 5, 6, 7 -Tetrahydro-1H-indonyl, 2,3-dihydrobenzofuranyl, 4,5,6,7-tetrahydro-benzofuranyl, 2,3-dihydrobenzo [d] oxazolyl, 2,3-dihydrobenzo [d] thiazolyl, 4,5,6,7-tetrahydro-1H-indazolyl, chromanyl, 2H-chromenyl, 4H-chromenyl, isochromanyl, 1H-isochromenyl, 1,3-benzodioxolyl, 2,3-dihydrofuro [3,2-c ] Pyridyl etc. are mentioned.
本明細書中、特に断りのない限り、「部分的に水素化された縮環式ヘテロアリール基」としては、環員数8~12のものが好ましく、例えば、インドリニル、4,5,6,7-テトラヒドロ-1H-インドニル、2,3-ジヒドロベンゾフラニル、4,5,6,7-テトラヒドロ-ベンゾフラニル、2,3-ジヒドロベンゾ[d]オキサゾリル、2,3-ジヒドロベンゾ[d]チアゾリル、4,5,6,7-テトラヒドロ-1H-インダゾリル、クロマニル、2H-クロメニル、4H-クロメニル、イソクロマニル、1H-イソクロメニル、1,3-ベンゾジオキソリル、2,3-ジヒドロフロ[3,2-c]ピリジル等が挙げられる。 In this specification, unless otherwise specified, the “partially hydrogenated condensed heteroaryl group” means “heterocyclic group” and “aryl group”, or “heterocyclic group” and “heterocyclic group”. In a condensed ring formed by condensing an “aryl group”, it means a monovalent group formed by removing any hydrogen atom from a partially hydrogenated condensed ring. The arbitrary hydrogen atom is a hydrogen atom in any of the "heterocyclic group", "aryl group" and "heteroaryl group" in the condensed ring, or a hydrogen atom in the hydrogenated ring part. For example, if the quinoline is partially hydrogenated tetrahydroquinolyl, 5,6,7,8-tetrahydroquinolyl, 1,2,3,4-tetrahydroquinolyl and the like can be mentioned. Depending on the position of any hydrogen atom, these groups can be, for example, 5,6,7,8-tetrahydroquinolyl-2-yl, -3-yl, -4-yl, -5-yl. , -6-yl, -7-yl, -8-yl and the like, and 1,2,3,4-tetrahydroquinolyl, for example, -1-yl, -2-yl, -3- Il, -4-yl, -5-yl, -6-yl, -7-yl, -8-yl and the like are exemplified.
In the present specification, unless otherwise specified, the “partially hydrogenated condensed heteroaryl group” preferably has 8 to 12 ring members, such as indolinyl, 4, 5, 6, 7 -Tetrahydro-1H-indonyl, 2,3-dihydrobenzofuranyl, 4,5,6,7-tetrahydro-benzofuranyl, 2,3-dihydrobenzo [d] oxazolyl, 2,3-dihydrobenzo [d] thiazolyl, 4,5,6,7-tetrahydro-1H-indazolyl, chromanyl, 2H-chromenyl, 4H-chromenyl, isochromanyl, 1H-isochromenyl, 1,3-benzodioxolyl, 2,3-dihydrofuro [3,2-c ] Pyridyl etc. are mentioned.
本明細書中、特に断りのない限り、「単環式非芳香族複素環基」とは、酸素原子、硫黄原子および窒素原子から選ばれるヘテロ原子を1~4個含有する3~8員の単環である飽和もしくは不飽和の複素環から、任意の水素原子を除いてできる1価の基を意味する。
本明細書中、特に断りのない限り、「単環式非芳香族複素環基」としては、例えば、アジリジニル、アゼチジニル、オキシラニル、チイラニル、オキセタニル、チエタニル、ピロリジニル、テトラヒドロフリル、ジヒドロフリル、チオラニル、ピラゾリニル、ピラゾリジニル、イミダゾリジニル、ピペリジニル、ジヒドロピラニル、テトラヒドロピラニル(オキサニル)、テトラヒドロチオピラニル、ピペラジニル、ジオキサニル、オキサゾリジニル、イソキサゾリニル、1,3-オキサゾリジニル、イソキサゾリジニル、チアゾリニル、イソチアゾリニル、1,3-チアゾリジニル、イソチアゾリジニル、オキサジアゾリニル、1,3,4-オキサジアゾリジニル、モルホリニル、チオモルホリニル、キヌクリジニル、アゼパニル、ジアゼピニル、オキセパニル等が挙げられる。
本明細書中、特に断りのない限り、「C1~6アルコキシル基」とは、前記「C1~6アルキル基」が酸素原子に置換した基を意味する。
本明細書中、特に断りのない限り、「C1~6アルコキシル基」としては、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、sec-ブトキシ、tert-ブトキシ、ペンチルオキシ、およびヘキシルオキシ等が挙げられる。また、「C1~4アルコキシル基」としては、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、sec-ブトキシおよびtert-ブトキシ等が挙げられ、「C1~2アルコキシル基」としては、メトキシおよびエトキシが挙げられる。 In the present specification, unless otherwise specified, the “monocyclic non-aromatic heterocyclic group” means a 3 to 8-membered member containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. A monovalent group formed by removing any hydrogen atom from a monocyclic saturated or unsaturated heterocyclic ring.
Unless otherwise specified, in this specification, examples of the “monocyclic non-aromatic heterocyclic group” include aziridinyl, azetidinyl, oxiranyl, thiranyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, thiolanyl, and pyrazolinyl. , Pyrazolidinyl, imidazolidinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl (oxanyl), tetrahydrothiopyranyl, piperazinyl, dioxanyl, oxazolidinyl, isoxazolinyl, 1,3-oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl, 1,3 -Thiazolidinyl, isothiazolidinyl, oxadiazolinyl, 1,3,4-oxadiazolidinyl, morpholinyl, thiomorpholinyl, quinuclidinyl, azepanyl, diaze Cycloalkenyl, oxepanyl, and the like.
In the present specification, unless otherwise specified, the “C 1-6 alkoxyl group” means a group in which the “C 1-6 alkyl group” is substituted with an oxygen atom.
In the present specification, unless otherwise specified, examples of the “C 1-6 alkoxyl group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyl. Examples include oxy. Examples of the “C 1-4 alkoxyl group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like, and “C 1-2 alkoxyl group” , Methoxy and ethoxy.
本明細書中、特に断りのない限り、「単環式非芳香族複素環基」としては、例えば、アジリジニル、アゼチジニル、オキシラニル、チイラニル、オキセタニル、チエタニル、ピロリジニル、テトラヒドロフリル、ジヒドロフリル、チオラニル、ピラゾリニル、ピラゾリジニル、イミダゾリジニル、ピペリジニル、ジヒドロピラニル、テトラヒドロピラニル(オキサニル)、テトラヒドロチオピラニル、ピペラジニル、ジオキサニル、オキサゾリジニル、イソキサゾリニル、1,3-オキサゾリジニル、イソキサゾリジニル、チアゾリニル、イソチアゾリニル、1,3-チアゾリジニル、イソチアゾリジニル、オキサジアゾリニル、1,3,4-オキサジアゾリジニル、モルホリニル、チオモルホリニル、キヌクリジニル、アゼパニル、ジアゼピニル、オキセパニル等が挙げられる。
本明細書中、特に断りのない限り、「C1~6アルコキシル基」とは、前記「C1~6アルキル基」が酸素原子に置換した基を意味する。
本明細書中、特に断りのない限り、「C1~6アルコキシル基」としては、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、sec-ブトキシ、tert-ブトキシ、ペンチルオキシ、およびヘキシルオキシ等が挙げられる。また、「C1~4アルコキシル基」としては、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、sec-ブトキシおよびtert-ブトキシ等が挙げられ、「C1~2アルコキシル基」としては、メトキシおよびエトキシが挙げられる。 In the present specification, unless otherwise specified, the “monocyclic non-aromatic heterocyclic group” means a 3 to 8-membered member containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. A monovalent group formed by removing any hydrogen atom from a monocyclic saturated or unsaturated heterocyclic ring.
Unless otherwise specified, in this specification, examples of the “monocyclic non-aromatic heterocyclic group” include aziridinyl, azetidinyl, oxiranyl, thiranyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, thiolanyl, and pyrazolinyl. , Pyrazolidinyl, imidazolidinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl (oxanyl), tetrahydrothiopyranyl, piperazinyl, dioxanyl, oxazolidinyl, isoxazolinyl, 1,3-oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl, 1,3 -Thiazolidinyl, isothiazolidinyl, oxadiazolinyl, 1,3,4-oxadiazolidinyl, morpholinyl, thiomorpholinyl, quinuclidinyl, azepanyl, diaze Cycloalkenyl, oxepanyl, and the like.
In the present specification, unless otherwise specified, the “C 1-6 alkoxyl group” means a group in which the “C 1-6 alkyl group” is substituted with an oxygen atom.
In the present specification, unless otherwise specified, examples of the “C 1-6 alkoxyl group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyl. Examples include oxy. Examples of the “C 1-4 alkoxyl group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like, and “C 1-2 alkoxyl group” , Methoxy and ethoxy.
本明細書中、特に断りのない限り、「ハロゲン化C1~6アルコキシル基」とは、前記「C1~6アルコキシル基」の「C1~6アルキル基」部が1~5個のハロゲン原子で任意に置換されている基を意味し、例えば、フルオロメトキシ、ジフルオロメトキシ、トリフルオロメトキシ、2,2,2-トリフルオロエトキシ、1,1,2,2-テトラフルオロエトキシ、ペンタフルオロエトキシ等が挙げられる。
本明細書中、特に断りのない限り、「C2~6アルケニルオキシ基」とは、前記「C2~6アルケニル基」が酸素原子に置換した基を意味する。
本明細書中、特に断りのない限り、「C2~6アルケニルオキシ基」としては、例えば、ビニルオキシ、アリルオキシ、イソプロペニルオキシ、ブテニルオキシ、ペンテニルオキシ、およびヘキセニルオキシ等が挙げられる。
本明細書中、特に断りのない限り、「C2~6アルキニルオキシ基」とは、前記「C2~6アルキニル基」が酸素原子に置換した基を意味する。
本明細書中、特に断りのない限り、「C2~6アルキニルオキシ基」としては、例えば、エチニルオキシ、1-プロピニルオキシ、2-プロピニルオキシ、ブチニルオキシ、ペンチニルオキシ、ヘキシニルオキシ等が挙げられる。 In the present specification, unless otherwise specified, the “halogenated C 1-6 alkoxyl group” means a halogen having 1 to 5 “C 1-6 alkyl groups” in the “C 1-6 alkoxyl group”. Means a group optionally substituted with atoms, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy Etc.
Herein, unless otherwise indicated, the term "C 2 ~ 6 alkenyloxy group" means a group wherein the above "C 2 ~ 6 alkenyl group" is substituted with an oxygen atom.
Herein, unless otherwise specified, as the "C 2 ~ 6 alkenyloxy group", for example, vinyloxy, allyloxy, isopropenyloxy, butenyloxy, and pentenyloxy, and hexenyloxy and the like.
Herein, unless otherwise indicated, the term "C 2 ~ 6 alkynyloxy group" means a group wherein the above "C 2 ~ 6 alkynyl group" is substituted with an oxygen atom.
Herein, unless otherwise specified, as the "C 2 ~ 6 alkynyloxy group", for example, ethynyloxy, 1-propynyloxy, 2-propynyloxy, butynyloxy, pentynyloxy, hexynyloxy, and the like.
本明細書中、特に断りのない限り、「C2~6アルケニルオキシ基」とは、前記「C2~6アルケニル基」が酸素原子に置換した基を意味する。
本明細書中、特に断りのない限り、「C2~6アルケニルオキシ基」としては、例えば、ビニルオキシ、アリルオキシ、イソプロペニルオキシ、ブテニルオキシ、ペンテニルオキシ、およびヘキセニルオキシ等が挙げられる。
本明細書中、特に断りのない限り、「C2~6アルキニルオキシ基」とは、前記「C2~6アルキニル基」が酸素原子に置換した基を意味する。
本明細書中、特に断りのない限り、「C2~6アルキニルオキシ基」としては、例えば、エチニルオキシ、1-プロピニルオキシ、2-プロピニルオキシ、ブチニルオキシ、ペンチニルオキシ、ヘキシニルオキシ等が挙げられる。 In the present specification, unless otherwise specified, the “halogenated C 1-6 alkoxyl group” means a halogen having 1 to 5 “C 1-6 alkyl groups” in the “C 1-6 alkoxyl group”. Means a group optionally substituted with atoms, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy Etc.
Herein, unless otherwise indicated, the term "C 2 ~ 6 alkenyloxy group" means a group wherein the above "C 2 ~ 6 alkenyl group" is substituted with an oxygen atom.
Herein, unless otherwise specified, as the "C 2 ~ 6 alkenyloxy group", for example, vinyloxy, allyloxy, isopropenyloxy, butenyloxy, and pentenyloxy, and hexenyloxy and the like.
Herein, unless otherwise indicated, the term "C 2 ~ 6 alkynyloxy group" means a group wherein the above "C 2 ~ 6 alkynyl group" is substituted with an oxygen atom.
Herein, unless otherwise specified, as the "C 2 ~ 6 alkynyloxy group", for example, ethynyloxy, 1-propynyloxy, 2-propynyloxy, butynyloxy, pentynyloxy, hexynyloxy, and the like.
本明細書中、特に断りのない限り、「C2~7アルカノイル基」とは、前記「C1~6アルキル基」にカルボニル基が結合した、「C1~6アルキルカルボニル基」を意味する。
本明細書中、特に断りのない限り、「C2~7アルカノイル基」としては、例えば、アセチル、プロピオニル、ブチリル、イソブチリル、バレリル、イソバレリル、ピバロイル、ヘキサノイル、ヘプタノイル、シクロプロピルカルボニル、シクロブチルカルボニル、シクロペンチルカルボニル、シクロヘキシルカルボニル、シクロプロピルメチルカルボニル、2-メチルシクロプロピルカルボニル等が挙げられる。
本明細書中、特に断りのない限り、「C1~6アルキルチオ基」とは、「チオール基(‐SH)」の水素原子が、前記「C1~6アルキル基」に置換した基を意味する。
本明細書中、特に断りのない限り、「C1~6アルキルチオ基」としては、例えば、メチルチオ、エチルチオ、プロピルチオ、イソプロピルチオ、ブチルチオ、イソブチルチオ、sec-ブチルチオ、tert-ブチルチオ、ペンチルチオ、およびヘキシルチオ等が挙げられる。
本明細書中、特に断りのない限り、「-NRaRb基」とは、「アミノ基」の窒素原子上の二つの水素原子がRa及びRbに置換された基を意味する。すなわち、「-NRaRb基」とは、「アミノ基」の窒素原子上の二つの水素原子が、各々独立に、「C1~6アルキル基」、「ハロゲン化C1~6アルキル基」、「C2~6アルケニル基」及び「C2~6アルキニル基」から任意に選ばれる基に置換されている基を意味し、例えば、「ジC1~6アルキルアミノ基」等が挙げられる。 Herein, unless otherwise indicated, the term "C 2 ~ 7 alkanoyl group", the carbonyl group in the "C 1 ~ 6 alkyl group" bonded, means "C 1 ~ 6 alkyl group" .
Herein, unless otherwise specified, as the "C 2 ~ 7 alkanoyl group", for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, cyclopropylcarbonyl, cyclobutylcarbonyl, Examples include cyclopentylcarbonyl, cyclohexylcarbonyl, cyclopropylmethylcarbonyl, 2-methylcyclopropylcarbonyl and the like.
Unless otherwise specified, in this specification, “C 1-6 alkylthio group” means a group in which the hydrogen atom of “thiol group (—SH)” is substituted with the above “C 1-6 alkyl group”. To do.
Unless otherwise specified, in this specification, examples of the “C 1-6 alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio. Etc.
In the present specification, unless otherwise specified, the “—NR a R b group” means a group in which two hydrogen atoms on the nitrogen atom of the “amino group” are substituted with R a and R b . That is, "- NR a R b group" refers to two hydrogen atoms on the nitrogen atom of the "amino group" is, independently, "C 1 ~ 6 alkyl group", "halogenated C 1 ~ 6 alkyl group "means" C 2 ~ 6 alkenyl group "and" C 2 ~ 6 alkynyl group "which is substituted in the group selected arbitrarily from the base, for example, such as" di C 1 ~ 6 alkyl group "can be mentioned It is done.
本明細書中、特に断りのない限り、「C2~7アルカノイル基」としては、例えば、アセチル、プロピオニル、ブチリル、イソブチリル、バレリル、イソバレリル、ピバロイル、ヘキサノイル、ヘプタノイル、シクロプロピルカルボニル、シクロブチルカルボニル、シクロペンチルカルボニル、シクロヘキシルカルボニル、シクロプロピルメチルカルボニル、2-メチルシクロプロピルカルボニル等が挙げられる。
本明細書中、特に断りのない限り、「C1~6アルキルチオ基」とは、「チオール基(‐SH)」の水素原子が、前記「C1~6アルキル基」に置換した基を意味する。
本明細書中、特に断りのない限り、「C1~6アルキルチオ基」としては、例えば、メチルチオ、エチルチオ、プロピルチオ、イソプロピルチオ、ブチルチオ、イソブチルチオ、sec-ブチルチオ、tert-ブチルチオ、ペンチルチオ、およびヘキシルチオ等が挙げられる。
本明細書中、特に断りのない限り、「-NRaRb基」とは、「アミノ基」の窒素原子上の二つの水素原子がRa及びRbに置換された基を意味する。すなわち、「-NRaRb基」とは、「アミノ基」の窒素原子上の二つの水素原子が、各々独立に、「C1~6アルキル基」、「ハロゲン化C1~6アルキル基」、「C2~6アルケニル基」及び「C2~6アルキニル基」から任意に選ばれる基に置換されている基を意味し、例えば、「ジC1~6アルキルアミノ基」等が挙げられる。 Herein, unless otherwise indicated, the term "C 2 ~ 7 alkanoyl group", the carbonyl group in the "C 1 ~ 6 alkyl group" bonded, means "C 1 ~ 6 alkyl group" .
Herein, unless otherwise specified, as the "C 2 ~ 7 alkanoyl group", for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, cyclopropylcarbonyl, cyclobutylcarbonyl, Examples include cyclopentylcarbonyl, cyclohexylcarbonyl, cyclopropylmethylcarbonyl, 2-methylcyclopropylcarbonyl and the like.
Unless otherwise specified, in this specification, “C 1-6 alkylthio group” means a group in which the hydrogen atom of “thiol group (—SH)” is substituted with the above “C 1-6 alkyl group”. To do.
Unless otherwise specified, in this specification, examples of the “C 1-6 alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio. Etc.
In the present specification, unless otherwise specified, the “—NR a R b group” means a group in which two hydrogen atoms on the nitrogen atom of the “amino group” are substituted with R a and R b . That is, "- NR a R b group" refers to two hydrogen atoms on the nitrogen atom of the "amino group" is, independently, "C 1 ~ 6 alkyl group", "halogenated C 1 ~ 6 alkyl group "means" C 2 ~ 6 alkenyl group "and" C 2 ~ 6 alkynyl group "which is substituted in the group selected arbitrarily from the base, for example, such as" di C 1 ~ 6 alkyl group "can be mentioned It is done.
本明細書中、特に断りのない限り、「ジC1~6アルキルアミノ基」としては、例えば、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、ジイソプロピルアミノ、ジブチルアミノ、エチルメチルアミノ、およびプロピルメチルアミノ等が挙げられる。
「RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよく」における「単環式非芳香族複素環基」の例としては、具体的には、前記「単環式非芳香族複素環基」のうち、窒素原子に結合する水素原子を除いてできる1価の環状基を意味し、具体的には、例えば、アジリジニル、アゼチジニル、ピロリジニル、ピペリジニル、アゼパニル、アゾカニル等が挙げられる。
Ra、Rbにおいて「当該単環式非芳香族複素環基は、その環内の炭素原子の少なくとも1個が、酸素原子、硫黄原子及び窒素原子から任意に選ばれる原子またはカルボニル基で置き換えられていてもよく」としての複素環基として、具体的には、例えば、オキサゾリニル、イソキサゾリニル、オキサゾリジニル、イソキサゾリジニル、チアゾリニル、イソチアゾリニル、チアゾリジニル、イソチアゾリジニル、モルホリニル、チオモルホリニル、2-オキソピロリジニル、ピラゾリニル、ピラゾリジニル、ピペラジニル、オキサジアゾリニル、オキサジアゾリジニル等が挙げられる。
Ra、Rbにおいて「当該単環式非芳香族複素環基は、その環内の炭素原子の少なくとも1個が、窒素原子(当該窒素原子は、C1~6アルキル基で置換されていてもよい)で置き換えられていてもよく」としての複素環基として、具体的には、例えば、4-メチルピペラジン-1-イル、4-エチルピぺラジン-1-イル、4-プロピルピペラジン-1-イル等が挙げられる。 In the present specification, unless otherwise specified, examples of the “di-C 1-6 alkylamino group” include dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, ethylmethylamino, propylmethylamino and the like. Is mentioned.
Examples of “monocyclic non-aromatic heterocyclic group” in “R a and R b may form a monocyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded” include: Means a monovalent cyclic group formed by removing a hydrogen atom bonded to a nitrogen atom in the “monocyclic non-aromatic heterocyclic group”, specifically, for example, aziridinyl, azetidinyl, pyrrolidinyl , Piperidinyl, azepanyl, azocanyl and the like.
In R a and R b , “in the monocyclic non-aromatic heterocyclic group, at least one of the carbon atoms in the ring is replaced with an atom or carbonyl group arbitrarily selected from an oxygen atom, a sulfur atom and a nitrogen atom” Specific examples of the heterocyclic group as `` optionally '' may include, for example, oxazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, morpholinyl, thiomorpholinyl, 2-oxo Examples include pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperazinyl, oxadiazolinyl, oxadiazolidinyl and the like.
In R a and R b , “in the monocyclic non-aromatic heterocyclic group, at least one of the carbon atoms in the ring is a nitrogen atom (the nitrogen atom is substituted with a C 1-6 alkyl group). Specific examples of the heterocyclic group as “which may be substituted” may include 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-propylpiperazine-1 -Yl and the like.
「RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよく」における「単環式非芳香族複素環基」の例としては、具体的には、前記「単環式非芳香族複素環基」のうち、窒素原子に結合する水素原子を除いてできる1価の環状基を意味し、具体的には、例えば、アジリジニル、アゼチジニル、ピロリジニル、ピペリジニル、アゼパニル、アゾカニル等が挙げられる。
Ra、Rbにおいて「当該単環式非芳香族複素環基は、その環内の炭素原子の少なくとも1個が、酸素原子、硫黄原子及び窒素原子から任意に選ばれる原子またはカルボニル基で置き換えられていてもよく」としての複素環基として、具体的には、例えば、オキサゾリニル、イソキサゾリニル、オキサゾリジニル、イソキサゾリジニル、チアゾリニル、イソチアゾリニル、チアゾリジニル、イソチアゾリジニル、モルホリニル、チオモルホリニル、2-オキソピロリジニル、ピラゾリニル、ピラゾリジニル、ピペラジニル、オキサジアゾリニル、オキサジアゾリジニル等が挙げられる。
Ra、Rbにおいて「当該単環式非芳香族複素環基は、その環内の炭素原子の少なくとも1個が、窒素原子(当該窒素原子は、C1~6アルキル基で置換されていてもよい)で置き換えられていてもよく」としての複素環基として、具体的には、例えば、4-メチルピペラジン-1-イル、4-エチルピぺラジン-1-イル、4-プロピルピペラジン-1-イル等が挙げられる。 In the present specification, unless otherwise specified, examples of the “di-C 1-6 alkylamino group” include dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, ethylmethylamino, propylmethylamino and the like. Is mentioned.
Examples of “monocyclic non-aromatic heterocyclic group” in “R a and R b may form a monocyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded” include: Means a monovalent cyclic group formed by removing a hydrogen atom bonded to a nitrogen atom in the “monocyclic non-aromatic heterocyclic group”, specifically, for example, aziridinyl, azetidinyl, pyrrolidinyl , Piperidinyl, azepanyl, azocanyl and the like.
In R a and R b , “in the monocyclic non-aromatic heterocyclic group, at least one of the carbon atoms in the ring is replaced with an atom or carbonyl group arbitrarily selected from an oxygen atom, a sulfur atom and a nitrogen atom” Specific examples of the heterocyclic group as `` optionally '' may include, for example, oxazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, morpholinyl, thiomorpholinyl, 2-oxo Examples include pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperazinyl, oxadiazolinyl, oxadiazolidinyl and the like.
In R a and R b , “in the monocyclic non-aromatic heterocyclic group, at least one of the carbon atoms in the ring is a nitrogen atom (the nitrogen atom is substituted with a C 1-6 alkyl group). Specific examples of the heterocyclic group as “which may be substituted” may include 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-propylpiperazine-1 -Yl and the like.
本明細書中、特に断りのない限り、「C1~6アルコキシルカルボニル基」とは、「カルボキシ基(-COOH)」の水素原子が前記「C1~6アルキル基」に置換した基、即ち「エステル基」を意味する。
本明細書中、特に断りのない限り、「C1~6アルコキシルカルボニル基」としては、例えば、メトキシカルボニル、エトキシカルボニル、tert-ブトキシカルボニル等が挙げられる。 In the present specification, unless otherwise specified, the “C 1-6 alkoxylcarbonyl group” means a group in which a hydrogen atom of “carboxy group (—COOH)” is substituted with the above “C 1-6 alkyl group”, that is, “Ester group” means.
In the present specification, unless otherwise specified, examples of the “C 1-6 alkoxylcarbonyl group” include methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and the like.
本明細書中、特に断りのない限り、「C1~6アルコキシルカルボニル基」としては、例えば、メトキシカルボニル、エトキシカルボニル、tert-ブトキシカルボニル等が挙げられる。 In the present specification, unless otherwise specified, the “C 1-6 alkoxylcarbonyl group” means a group in which a hydrogen atom of “carboxy group (—COOH)” is substituted with the above “C 1-6 alkyl group”, that is, “Ester group” means.
In the present specification, unless otherwise specified, examples of the “C 1-6 alkoxylcarbonyl group” include methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and the like.
Lは、R2と結合し、環Bの一部とともに縮合環基を形成してもよい。すなわち、以下の部分構造式に示すように、L、R2及び環B(一部)は共に結合して縮合環Dを形成し得る。
形成された縮合環Dは、隣接する環Bの一部とともに縮環式の環状基を形成する。
ここで、当該縮合環Dは、ハロゲン原子で置換されていてもよい5~7員複素環基であり、隣接する環Bの一部とともに縮環式複素環基を形成する。
Lにおいて「Lは、R2と結合し、環Bの一部とともに縮合環基を形成してもよく」における「縮合環」、すなわち前記縮合環Dとは、前記「複素環基」のうち単環式の環状基を意味し、具体的には、酸素原子を含む環状基等が挙げられ、好ましくは酸素原子を含む環状基である。縮合環Dと隣接する環Bからなる縮環式複素環基は、前記「複素環基」のうち縮環式の環状基を意味し、具体的には、前記「縮環式ヘテロアリール基」及び「部分的に水素化された縮環式ヘテロアリール基」のうち、酸素原子を含む縮環式の環状基等が挙げられ、好ましくは酸素原子を含む縮環式の環状基である。より具体的には、例えば、ベンゾフラニル、2,3-ジヒドロベンゾフラニル、1,3-ベンゾジオキソリル、1,4-ベンゾジオキサニル等が挙げられる。
環B上においてLは、環A-ビシクロ環-CO-の結合位置に隣接する置換基である。即ち、式(I)中、環A-ビシクロ環-CO-が結合する環B上の炭素原子又はヘテロ原子と、Lが結合する環B上の炭素原子又はヘテロ原子は、互いに隣接している。 L may be bonded to R 2 to form a condensed ring group together with a part of ring B. That is, as shown in the following partial structural formula, L, R 2 and ring B (part) can be bonded together to form a condensed ring D.
The formed condensed ring D forms a condensed cyclic group together with a part of the adjacent ring B.
Here, the condensed ring D is a 5- to 7-membered heterocyclic group which may be substituted with a halogen atom, and forms a condensed heterocyclic group together with a part of the adjacent ring B.
In L, the “fused ring” in “L may bind to R 2 and form a condensed ring group together with a part of ring B”, that is, the condensed ring D is the “heterocyclic group” It means a monocyclic cyclic group, and specific examples include a cyclic group containing an oxygen atom, and a cyclic group containing an oxygen atom is preferred. The condensed heterocyclic group composed of the ring B adjacent to the condensed ring D means a condensed cyclic group in the “heterocyclic group”, specifically, the “condensed heteroaryl group” In addition, among the “partially hydrogenated condensed heteroaryl group”, a condensed cyclic group containing an oxygen atom, and the like are preferable, and a condensed cyclic group containing an oxygen atom is preferable. More specifically, for example, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like can be mentioned.
On ring B, L is a substituent adjacent to the bonding position of ring A-bicycloring-CO—. That is, in formula (I), the carbon atom or heteroatom on ring B to which ring A-bicycloring-CO— is bonded and the carbon atom or heteroatom on ring B to which L is bonded are adjacent to each other. .
形成された縮合環Dは、隣接する環Bの一部とともに縮環式の環状基を形成する。
ここで、当該縮合環Dは、ハロゲン原子で置換されていてもよい5~7員複素環基であり、隣接する環Bの一部とともに縮環式複素環基を形成する。
Lにおいて「Lは、R2と結合し、環Bの一部とともに縮合環基を形成してもよく」における「縮合環」、すなわち前記縮合環Dとは、前記「複素環基」のうち単環式の環状基を意味し、具体的には、酸素原子を含む環状基等が挙げられ、好ましくは酸素原子を含む環状基である。縮合環Dと隣接する環Bからなる縮環式複素環基は、前記「複素環基」のうち縮環式の環状基を意味し、具体的には、前記「縮環式ヘテロアリール基」及び「部分的に水素化された縮環式ヘテロアリール基」のうち、酸素原子を含む縮環式の環状基等が挙げられ、好ましくは酸素原子を含む縮環式の環状基である。より具体的には、例えば、ベンゾフラニル、2,3-ジヒドロベンゾフラニル、1,3-ベンゾジオキソリル、1,4-ベンゾジオキサニル等が挙げられる。
環B上においてLは、環A-ビシクロ環-CO-の結合位置に隣接する置換基である。即ち、式(I)中、環A-ビシクロ環-CO-が結合する環B上の炭素原子又はヘテロ原子と、Lが結合する環B上の炭素原子又はヘテロ原子は、互いに隣接している。 L may be bonded to R 2 to form a condensed ring group together with a part of ring B. That is, as shown in the following partial structural formula, L, R 2 and ring B (part) can be bonded together to form a condensed ring D.
The formed condensed ring D forms a condensed cyclic group together with a part of the adjacent ring B.
Here, the condensed ring D is a 5- to 7-membered heterocyclic group which may be substituted with a halogen atom, and forms a condensed heterocyclic group together with a part of the adjacent ring B.
In L, the “fused ring” in “L may bind to R 2 and form a condensed ring group together with a part of ring B”, that is, the condensed ring D is the “heterocyclic group” It means a monocyclic cyclic group, and specific examples include a cyclic group containing an oxygen atom, and a cyclic group containing an oxygen atom is preferred. The condensed heterocyclic group composed of the ring B adjacent to the condensed ring D means a condensed cyclic group in the “heterocyclic group”, specifically, the “condensed heteroaryl group” In addition, among the “partially hydrogenated condensed heteroaryl group”, a condensed cyclic group containing an oxygen atom, and the like are preferable, and a condensed cyclic group containing an oxygen atom is preferable. More specifically, for example, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like can be mentioned.
On ring B, L is a substituent adjacent to the bonding position of ring A-bicycloring-CO—. That is, in formula (I), the carbon atom or heteroatom on ring B to which ring A-bicycloring-CO— is bonded and the carbon atom or heteroatom on ring B to which L is bonded are adjacent to each other. .
[1-1] 前記態様[1]の前記式(I)の化合物において、nは好ましくは2である。
[1-2] 前記態様[1]の前記式(I)の化合物において、環Aは、好ましくは、フェニル基または5~10員ヘテロアリール基であり、当該フェニル基またはヘテロアリール基はそれぞれ、1~5個のR1で置換されていてもよい。
上記R1は、好ましくはハロゲン原子、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~7アルカノイル基、C1~6アルキルチオ基、-NRaRb基(ここで、当該Ra及びRbはC1~6アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよく、RaおよびRbにおける前記単環式非芳香族複素環基は、その環内の炭素原子の少なくとも1個が、酸素原子、硫黄原子及びC1~6アルキル基で置換されていてもよい窒素原子から任意に選ばれる原子で置き換えられていてもよい)、シアノ基またはオキソ基であり、より好ましくはハロゲン原子、C1~4アルキル基、C3~6シクロアルキル基、C1~4アルコキシル基、C2~5アルカノイル基、C1~4アルキルチオ基、-NRaRb基(ここで、当該Ra及びRbはC1~4アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよい)、シアノ基またはオキソ基であり、更に好ましくはハロゲン原子、C1~2アルキル基、C3~4シクロアルキル基、C1~2アルコキシル基、C2~3アルカノイル基、C1~2アルキルチオ基、-NRaRb基(ここで、当該Ra及びRbはC1~2アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに5~6員非芳香族複素環基を形成してもよい)、シアノ基またはオキソ基であることが適当であり、上記R1における前記アルキル基、シクロアルキル基、アルコキシル基、アルカノイル基またはアルキルチオ基は、それぞれ、1~5個の置換基RIで置換されていてもよい。 [1-1] In the compound of the formula (I) of the embodiment [1], n is preferably 2.
[1-2] In the compound of the formula (I) of the embodiment [1], the ring A is preferably a phenyl group or a 5- to 10-membered heteroaryl group, and the phenyl group or heteroaryl group is It may be substituted with 1 to 5 R 1 .
The above R 1 is preferably a halogen atom, C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 2 ~ 7 alkanoyl group, C 1 ~ 6 alkylthio group, -NR a R b group (wherein R a and R b represent a C 1-6 alkyl group, and R a and R b may form a monocyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded). The monocyclic non-aromatic heterocyclic group in R a and R b may be such that at least one carbon atom in the ring is substituted with an oxygen atom, a sulfur atom and a C 1-6 alkyl group. it may be replaced by atoms selected arbitrarily from a nitrogen atom which), a cyano group or an oxo group, more preferably a halogen atom, C 1 ~ 4 alkyl group, C 3 ~ 6 cycloalkyl group, C 1 ~ 4 alkoxyl group, C 2 ~ 5 alkanoyl group, C 1 ~ 4 alkylthio A group, —NR a R b group (wherein R a and R b represent a C 1-4 alkyl group, and R a and R b together with the nitrogen atom to which they are attached are monocyclic non-aromatic heterocycles) A cyano group or an oxo group, more preferably a halogen atom, a C 1-2 alkyl group, a C 3-4 cycloalkyl group, a C 1-2 alkoxyl group, a C 2-3 alkanoyl. A group, C 1-2 alkylthio group, —NR a R b group (wherein R a and R b represent C 1-2 alkyl groups, and R a and R b are 5 together with the nitrogen atom to which they are bonded). A cyano group or an oxo group, which may form a 6-membered non-aromatic heterocyclic group), the alkyl group, cycloalkyl group, alkoxyl group, alkanoyl group or alkylthio group in R 1 above. Are each substituted with 1 to 5 substituents RI May be.
[1-2] 前記態様[1]の前記式(I)の化合物において、環Aは、好ましくは、フェニル基または5~10員ヘテロアリール基であり、当該フェニル基またはヘテロアリール基はそれぞれ、1~5個のR1で置換されていてもよい。
上記R1は、好ましくはハロゲン原子、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~7アルカノイル基、C1~6アルキルチオ基、-NRaRb基(ここで、当該Ra及びRbはC1~6アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよく、RaおよびRbにおける前記単環式非芳香族複素環基は、その環内の炭素原子の少なくとも1個が、酸素原子、硫黄原子及びC1~6アルキル基で置換されていてもよい窒素原子から任意に選ばれる原子で置き換えられていてもよい)、シアノ基またはオキソ基であり、より好ましくはハロゲン原子、C1~4アルキル基、C3~6シクロアルキル基、C1~4アルコキシル基、C2~5アルカノイル基、C1~4アルキルチオ基、-NRaRb基(ここで、当該Ra及びRbはC1~4アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよい)、シアノ基またはオキソ基であり、更に好ましくはハロゲン原子、C1~2アルキル基、C3~4シクロアルキル基、C1~2アルコキシル基、C2~3アルカノイル基、C1~2アルキルチオ基、-NRaRb基(ここで、当該Ra及びRbはC1~2アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに5~6員非芳香族複素環基を形成してもよい)、シアノ基またはオキソ基であることが適当であり、上記R1における前記アルキル基、シクロアルキル基、アルコキシル基、アルカノイル基またはアルキルチオ基は、それぞれ、1~5個の置換基RIで置換されていてもよい。 [1-1] In the compound of the formula (I) of the embodiment [1], n is preferably 2.
[1-2] In the compound of the formula (I) of the embodiment [1], the ring A is preferably a phenyl group or a 5- to 10-membered heteroaryl group, and the phenyl group or heteroaryl group is It may be substituted with 1 to 5 R 1 .
The above R 1 is preferably a halogen atom, C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 2 ~ 7 alkanoyl group, C 1 ~ 6 alkylthio group, -NR a R b group (wherein R a and R b represent a C 1-6 alkyl group, and R a and R b may form a monocyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded). The monocyclic non-aromatic heterocyclic group in R a and R b may be such that at least one carbon atom in the ring is substituted with an oxygen atom, a sulfur atom and a C 1-6 alkyl group. it may be replaced by atoms selected arbitrarily from a nitrogen atom which), a cyano group or an oxo group, more preferably a halogen atom, C 1 ~ 4 alkyl group, C 3 ~ 6 cycloalkyl group, C 1 ~ 4 alkoxyl group, C 2 ~ 5 alkanoyl group, C 1 ~ 4 alkylthio A group, —NR a R b group (wherein R a and R b represent a C 1-4 alkyl group, and R a and R b together with the nitrogen atom to which they are attached are monocyclic non-aromatic heterocycles) A cyano group or an oxo group, more preferably a halogen atom, a C 1-2 alkyl group, a C 3-4 cycloalkyl group, a C 1-2 alkoxyl group, a C 2-3 alkanoyl. A group, C 1-2 alkylthio group, —NR a R b group (wherein R a and R b represent C 1-2 alkyl groups, and R a and R b are 5 together with the nitrogen atom to which they are bonded). A cyano group or an oxo group, which may form a 6-membered non-aromatic heterocyclic group), the alkyl group, cycloalkyl group, alkoxyl group, alkanoyl group or alkylthio group in R 1 above. Are each substituted with 1 to 5 substituents RI May be.
[1-2-a] 前記態様[1]の前記式(I)の化合物において、環Aは、より好ましくは、下記部分構造式(a1)、(a2)、(a3)または(a4):
(式(a1)、(a2)、(a3)または(a4)中、
環A1は、隣接するピリジン環とともに9~10員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成し、当該環A1は1~2個のハロゲン原子で置換されていてもよく、
環A2は、隣接するピラゾール環とともに8~9員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成し、当該環A2は1~2個のハロゲン原子で置換されていてもよく、
環A3は、隣接するイミダゾール環とともに8~9員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成し、当該環A3は1~2個のハロゲン原子で置換されていてもよく、
X1は、窒素原子、C-HまたはC-R1aを表し、
X2は、窒素原子、C-HまたはC-R1dを表し、但し、X1が窒素原子の場合は、X2はC-HまたはC-R1dであり、
R1aは、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~7アルカノイル基またはシアノ基を表し、
R1b及びR1cは、各々独立に、水素原子またはC1~6アルキル基を表し、
R1dは、ハロゲン原子、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C1~6アルキルチオ基、-NRaRb基またはオキソ基を表し、但し、R1dがオキソ基の場合は、X1はC1~6アルキル基で置換されていてもよい窒素原子であり、
R1e及びR1fは、各々独立に、水素原子またはC1~6アルキル基を表し、
R1a、R1b、R1c、R1d、R1e及びR1fにおける前記アルキル基、シクロアルキル基、アルコキシル基、アルカノイル基またはアルキルチオ基は、それぞれ、1~5個の置換基RIで置換されていてもよい)が挙げられる。 [1-2-a] In the compound of the formula (I) of the embodiment [1], the ring A is more preferably the following partial structural formula (a1), (a2), (a3) or (a4):
(In the formula (a1), (a2), (a3) or (a4),
Ring A1 together with the adjacent pyridine ring forms a 9 to 10 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, and the ring A1 is composed of 1 to 2 halogen atoms. May be replaced,
Ring A2 together with the adjacent pyrazole ring forms an 8- to 9-membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, and the ring A2 is composed of 1 to 2 halogen atoms. May be replaced,
Ring A3 together with the adjacent imidazole ring forms an 8- to 9-membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, and the ring A3 is composed of 1 to 2 halogen atoms. May be replaced,
X 1 represents a nitrogen atom, C—H or C—R 1a ,
X 2 represents a nitrogen atom, C—H or C—R 1d , provided that when X 1 is a nitrogen atom, X 2 is C—H or C—R 1d ,
R 1a represents C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, a C 2 ~ 7 alkanoyl group or a cyano group,
R 1b and R 1c each independently represents a hydrogen atom or a C 1-6 alkyl group,
R 1d represents a halogen atom, C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 1 ~ 6 alkylthio group, a -NR a R b group or an oxo group, provided that, When R 1d is an oxo group, X 1 is a nitrogen atom which may be substituted with a C 1-6 alkyl group,
R 1e and R 1f each independently represents a hydrogen atom or a C 1-6 alkyl group,
The alkyl group, cycloalkyl group, alkoxyl group, alkanoyl group or alkylthio group in R 1a , R 1b , R 1c , R 1d , R 1e and R 1f is each substituted with 1 to 5 substituents RI. May be included).
(式(a1)、(a2)、(a3)または(a4)中、
環A1は、隣接するピリジン環とともに9~10員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成し、当該環A1は1~2個のハロゲン原子で置換されていてもよく、
環A2は、隣接するピラゾール環とともに8~9員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成し、当該環A2は1~2個のハロゲン原子で置換されていてもよく、
環A3は、隣接するイミダゾール環とともに8~9員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成し、当該環A3は1~2個のハロゲン原子で置換されていてもよく、
X1は、窒素原子、C-HまたはC-R1aを表し、
X2は、窒素原子、C-HまたはC-R1dを表し、但し、X1が窒素原子の場合は、X2はC-HまたはC-R1dであり、
R1aは、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~7アルカノイル基またはシアノ基を表し、
R1b及びR1cは、各々独立に、水素原子またはC1~6アルキル基を表し、
R1dは、ハロゲン原子、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C1~6アルキルチオ基、-NRaRb基またはオキソ基を表し、但し、R1dがオキソ基の場合は、X1はC1~6アルキル基で置換されていてもよい窒素原子であり、
R1e及びR1fは、各々独立に、水素原子またはC1~6アルキル基を表し、
R1a、R1b、R1c、R1d、R1e及びR1fにおける前記アルキル基、シクロアルキル基、アルコキシル基、アルカノイル基またはアルキルチオ基は、それぞれ、1~5個の置換基RIで置換されていてもよい)が挙げられる。 [1-2-a] In the compound of the formula (I) of the embodiment [1], the ring A is more preferably the following partial structural formula (a1), (a2), (a3) or (a4):
(In the formula (a1), (a2), (a3) or (a4),
Ring A1 together with the adjacent pyridine ring forms a 9 to 10 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, and the ring A1 is composed of 1 to 2 halogen atoms. May be replaced,
Ring A2 together with the adjacent pyrazole ring forms an 8- to 9-membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, and the ring A2 is composed of 1 to 2 halogen atoms. May be replaced,
Ring A3 together with the adjacent imidazole ring forms an 8- to 9-membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, and the ring A3 is composed of 1 to 2 halogen atoms. May be replaced,
X 1 represents a nitrogen atom, C—H or C—R 1a ,
X 2 represents a nitrogen atom, C—H or C—R 1d , provided that when X 1 is a nitrogen atom, X 2 is C—H or C—R 1d ,
R 1a represents C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, a C 2 ~ 7 alkanoyl group or a cyano group,
R 1b and R 1c each independently represents a hydrogen atom or a C 1-6 alkyl group,
R 1d represents a halogen atom, C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 1 ~ 6 alkylthio group, a -NR a R b group or an oxo group, provided that, When R 1d is an oxo group, X 1 is a nitrogen atom which may be substituted with a C 1-6 alkyl group,
R 1e and R 1f each independently represents a hydrogen atom or a C 1-6 alkyl group,
The alkyl group, cycloalkyl group, alkoxyl group, alkanoyl group or alkylthio group in R 1a , R 1b , R 1c , R 1d , R 1e and R 1f is each substituted with 1 to 5 substituents RI. May be included).
上記環Aは、好ましくは上記部分構造式(a1)であることが適当である。
上記環A1は、好ましくは環A1内に1個の酸素原子を含有することが適当である。また、上記環A1は、好ましくは隣接するピリジン環とともに9員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成することが適当である。環A1が隣接するピリジン環とともに形成する縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基とは、前記「縮環式ヘテロアリール基」または「部分的に水素化された縮環式ヘテロアリール基」のうち、ピリジン環を含有する環状基が挙げられ、具体的には、イソキノリン-1-イル、5,6,7,8-テトラヒドロイソキノリン-1-イル、フロ[2,3-c]ピリジン-7-イル、フロ[3,2-c]ピリジン-4-イル、2,3-ジヒドロフロ[2,3-c]ピリジン-7-イル、2,3-ジヒドロフロ[3,2-c]ピリジン-4-イル等が挙げられ、好ましくは、フロ[2,3-c]ピリジン-7-イル、フロ[3,2-c]ピリジン-4-イル、2,3-ジヒドロフロ[2,3-c]ピリジン-7-イルまたは2,3-ジヒドロフロ[3,2-c]ピリジン-4-イルであることが適当である。
上記環A2は、好ましくは隣接するピラゾール環とともに9員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成することが適当である。環A2が隣接するピラゾール環とともに形成する縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基とは、前記「縮環式ヘテロアリール基」または「部分的に水素化された縮環式ヘテロアリール基」のうち、ピラゾール環を含有する環状基が挙げられ、具体的には、1H-インダゾール-3-イル、4,5,6,7-テトラヒドロ-1H-インダゾール-3-イル、1H-ピラゾロ[3,4-c]ピリジン-3-イル、1H-ピラゾロ[4,3-c]ピリジン-3-イル、1H-ピラゾロ[3,4-b]ピリジン-3-イル、1H-ピラゾロ[4,3-b]ピリジン-3-イル、6,7-ジヒドロ-1H-ピラゾロ[4,3-c]ピリジン-3-イル、6,7-ジヒドロ-1H-ピラゾロ[4,3-b]ピリジン-3-イル等が挙げられ、好ましくは、1H-インダゾール-3-イル、4,5,6,7-テトラヒドロ-1H-インダゾール-3-イル、1H-ピラゾロ[3,4-c]ピリジン-3-イル、1H-ピラゾロ[4,3-c]ピリジン-3-イル、1H-ピラゾロ[4,3-b]ピリジン-3-イルであることが適当である。 The ring A is preferably the partial structural formula (a1).
The ring A1 preferably contains one oxygen atom in the ring A1. The ring A1 preferably forms a 9-membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group together with the adjacent pyridine ring. A condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group formed by ring A1 with an adjacent pyridine ring is the above-mentioned “condensed heteroaryl group” or “partially hydrogenated”. Examples of the “condensed heteroaryl group” include cyclic groups containing a pyridine ring, specifically, isoquinolin-1-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl, furo [ 2,3-c] pyridin-7-yl, furo [3,2-c] pyridin-4-yl, 2,3-dihydrofuro [2,3-c] pyridin-7-yl, 2,3-dihydrofuro [ 3,2-c] pyridin-4-yl and the like, preferably, furo [2,3-c] pyridin-7-yl, furo [3,2-c] pyridin-4-yl, 2,3 -Dihydrofuro [2,3-c] pyridine-7- It is suitably a le or 2,3-dihydrofuro [3,2-c] pyridin-4-yl.
Said ring A2 preferably forms a 9-membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group with the adjacent pyrazole ring. A condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group formed by ring A2 with an adjacent pyrazole ring is the above-mentioned “condensed heteroaryl group” or “partially hydrogenated”. Examples of the “condensed heteroaryl group” include cyclic groups containing a pyrazole ring, specifically, 1H-indazol-3-yl, 4,5,6,7-tetrahydro-1H-indazole-3 -Yl, 1H-pyrazolo [3,4-c] pyridin-3-yl, 1H-pyrazolo [4,3-c] pyridin-3-yl, 1H-pyrazolo [3,4-b] pyridin-3-yl 1H-pyrazolo [4,3-b] pyridin-3-yl, 6,7-dihydro-1H-pyrazolo [4,3-c] pyridin-3-yl, 6,7-dihydro-1H-pyrazolo [4 , 3-b] pyridin-3-yl Preferably, 1H-indazol-3-yl, 4,5,6,7-tetrahydro-1H-indazol-3-yl, 1H-pyrazolo [3,4-c] pyridin-3-yl, 1H-pyrazolo [4,3-c] pyridin-3-yl, 1H-pyrazolo [4,3-b] pyridin-3-yl is suitable.
上記環A1は、好ましくは環A1内に1個の酸素原子を含有することが適当である。また、上記環A1は、好ましくは隣接するピリジン環とともに9員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成することが適当である。環A1が隣接するピリジン環とともに形成する縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基とは、前記「縮環式ヘテロアリール基」または「部分的に水素化された縮環式ヘテロアリール基」のうち、ピリジン環を含有する環状基が挙げられ、具体的には、イソキノリン-1-イル、5,6,7,8-テトラヒドロイソキノリン-1-イル、フロ[2,3-c]ピリジン-7-イル、フロ[3,2-c]ピリジン-4-イル、2,3-ジヒドロフロ[2,3-c]ピリジン-7-イル、2,3-ジヒドロフロ[3,2-c]ピリジン-4-イル等が挙げられ、好ましくは、フロ[2,3-c]ピリジン-7-イル、フロ[3,2-c]ピリジン-4-イル、2,3-ジヒドロフロ[2,3-c]ピリジン-7-イルまたは2,3-ジヒドロフロ[3,2-c]ピリジン-4-イルであることが適当である。
上記環A2は、好ましくは隣接するピラゾール環とともに9員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成することが適当である。環A2が隣接するピラゾール環とともに形成する縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基とは、前記「縮環式ヘテロアリール基」または「部分的に水素化された縮環式ヘテロアリール基」のうち、ピラゾール環を含有する環状基が挙げられ、具体的には、1H-インダゾール-3-イル、4,5,6,7-テトラヒドロ-1H-インダゾール-3-イル、1H-ピラゾロ[3,4-c]ピリジン-3-イル、1H-ピラゾロ[4,3-c]ピリジン-3-イル、1H-ピラゾロ[3,4-b]ピリジン-3-イル、1H-ピラゾロ[4,3-b]ピリジン-3-イル、6,7-ジヒドロ-1H-ピラゾロ[4,3-c]ピリジン-3-イル、6,7-ジヒドロ-1H-ピラゾロ[4,3-b]ピリジン-3-イル等が挙げられ、好ましくは、1H-インダゾール-3-イル、4,5,6,7-テトラヒドロ-1H-インダゾール-3-イル、1H-ピラゾロ[3,4-c]ピリジン-3-イル、1H-ピラゾロ[4,3-c]ピリジン-3-イル、1H-ピラゾロ[4,3-b]ピリジン-3-イルであることが適当である。 The ring A is preferably the partial structural formula (a1).
The ring A1 preferably contains one oxygen atom in the ring A1. The ring A1 preferably forms a 9-membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group together with the adjacent pyridine ring. A condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group formed by ring A1 with an adjacent pyridine ring is the above-mentioned “condensed heteroaryl group” or “partially hydrogenated”. Examples of the “condensed heteroaryl group” include cyclic groups containing a pyridine ring, specifically, isoquinolin-1-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl, furo [ 2,3-c] pyridin-7-yl, furo [3,2-c] pyridin-4-yl, 2,3-dihydrofuro [2,3-c] pyridin-7-yl, 2,3-dihydrofuro [ 3,2-c] pyridin-4-yl and the like, preferably, furo [2,3-c] pyridin-7-yl, furo [3,2-c] pyridin-4-yl, 2,3 -Dihydrofuro [2,3-c] pyridine-7- It is suitably a le or 2,3-dihydrofuro [3,2-c] pyridin-4-yl.
Said ring A2 preferably forms a 9-membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group with the adjacent pyrazole ring. A condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group formed by ring A2 with an adjacent pyrazole ring is the above-mentioned “condensed heteroaryl group” or “partially hydrogenated”. Examples of the “condensed heteroaryl group” include cyclic groups containing a pyrazole ring, specifically, 1H-indazol-3-yl, 4,5,6,7-tetrahydro-1H-indazole-3 -Yl, 1H-pyrazolo [3,4-c] pyridin-3-yl, 1H-pyrazolo [4,3-c] pyridin-3-yl, 1H-pyrazolo [3,4-b] pyridin-3-yl 1H-pyrazolo [4,3-b] pyridin-3-yl, 6,7-dihydro-1H-pyrazolo [4,3-c] pyridin-3-yl, 6,7-dihydro-1H-pyrazolo [4 , 3-b] pyridin-3-yl Preferably, 1H-indazol-3-yl, 4,5,6,7-tetrahydro-1H-indazol-3-yl, 1H-pyrazolo [3,4-c] pyridin-3-yl, 1H-pyrazolo [4,3-c] pyridin-3-yl, 1H-pyrazolo [4,3-b] pyridin-3-yl is suitable.
上記環A3は、好ましくは隣接するイミダゾール環とともに9員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成することが適当である。環A3が隣接するイミダゾール環とともに形成する縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基とは、前記「縮環式ヘテロアリール基」または「部分的に水素化された縮環式ヘテロアリール基」のうち、イミダゾール環を含有する環状基が挙げられ、具体的には、イミダゾ[1,5-a]ピリジン-1-イル、イミダゾ[1,5-a]ピリミジン-8-イル、イミダゾ[1,5-a]ピラジン-1-イル、5,6-ジヒドロ-イミダゾ[1,5-a]ピラジン-1-イル等が挙げられ、好ましくは、イミダゾ[1,5-a]ピラジン-1-イルであることが適当である。
上記X1は、好ましくはC-HまたはC-R1aであり、より好ましくは、C-R1aであることが適当である。 The ring A3 preferably forms a 9-membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group with an adjacent imidazole ring. A condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group formed by ring A3 with an adjacent imidazole ring is the above-mentioned “condensed heteroaryl group” or “partially hydrogenated”. Examples of the “condensed heteroaryl group” include cyclic groups containing an imidazole ring, specifically, imidazo [1,5-a] pyridin-1-yl, imidazo [1,5-a] pyrimidine -8-yl, imidazo [1,5-a] pyrazin-1-yl, 5,6-dihydro-imidazo [1,5-a] pyrazin-1-yl, and the like, preferably imidazo [1, 5-a] pyrazin-1-yl is suitable.
X 1 is preferably C—H or C—R 1a , more preferably C—R 1a .
上記X1は、好ましくはC-HまたはC-R1aであり、より好ましくは、C-R1aであることが適当である。 The ring A3 preferably forms a 9-membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group with an adjacent imidazole ring. A condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group formed by ring A3 with an adjacent imidazole ring is the above-mentioned “condensed heteroaryl group” or “partially hydrogenated”. Examples of the “condensed heteroaryl group” include cyclic groups containing an imidazole ring, specifically, imidazo [1,5-a] pyridin-1-yl, imidazo [1,5-a] pyrimidine -8-yl, imidazo [1,5-a] pyrazin-1-yl, 5,6-dihydro-imidazo [1,5-a] pyrazin-1-yl, and the like, preferably imidazo [1, 5-a] pyrazin-1-yl is suitable.
X 1 is preferably C—H or C—R 1a , more preferably C—R 1a .
上記R1aは、好ましくはC1~4アルキル基、C3~6シクロアルキル基、C1~4アルコキシル基、C2~5アルカノイル基またはシアノ基であり、より好ましくはC1~2アルキル基、C3~4シクロアルキル基、C1~2アルコキシル基、C2~3アルカノイル基またはシアノ基であり、更に好ましくはC1~2アルキル基またはシアノ基であることが適当であり、上記R1aにおける前記アルキル基、シクロアルキル基、アルコキシル基またはアルカノイル基は、それぞれ、1~5個の置換基RIで置換されていてもよい。
上記R1b及びR1cは、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であることが適当である。更に好ましくは、上記R1bは水素原子であり、R1cは水素原子またはC1~2アルキル基であることが適当である。
上記R1dは、好ましくはハロゲン原子、C1~4アルキル基、C3~6シクロアルキル基、C1~4アルコキシル基、C1~4アルキルチオ基、-NRaRb基(ここで、当該Ra及びRbはC1~4アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよい)またはオキソ基であり、より好ましくはハロゲン原子、C1~2アルキル基、C3~4シクロアルキル基、C1~2アルコキシル基、C1~2アルキルチオ基、-NRaRb基(ここで、当該Ra及びRbはC1~2アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに5~6員非芳香族複素環基を形成してもよい)またはオキソ基であり、更に好ましくはC1~2アルコキシル基であることが適当であり、上記R1dにおける前記アルキル基、シクロアルキル基、アルコキシル基またはアルキルチオ基は、それぞれ、1~5個の置換基RIで置換されていてもよい。
但し、R1dがオキソ基の場合、X1は、C1~6アルキル基、好ましくは、C1~4アルキル基、より好ましくはC1~2アルキル基で置換されていてもよい窒素原子である。
上記R1e及びR1fは、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であり、更に好ましくはC1~2アルキル基であることが適当である。
上記X2が窒素原子の場合は、好ましくは上記X1はC-R1aであり、R1cは水素原子以外であることが適当である。
上記X2がC-HまたはC-R1dの場合は、好ましくは上記X1はC-R1aであり、上記R1b、R1cは水素原子であることが適当である。 Said R 1a is preferably C 1 ~ 4 alkyl group, C 3 ~ 6 cycloalkyl group, C 1 ~ 4 alkoxyl group, C 2 ~ 5 alkanoyl group or a cyano group, more preferably C 1 ~ 2 alkyl groups A C 3-4 cycloalkyl group, a C 1-2 alkoxyl group, a C 2-3 alkanoyl group or a cyano group, more preferably a C 1-2 alkyl group or a cyano group. Each of the alkyl group, cycloalkyl group, alkoxyl group or alkanoyl group in 1a may be substituted with 1 to 5 substituents RI.
R 1b and R 1c are preferably a hydrogen atom or a C 1-4 alkyl group, and more preferably a hydrogen atom or a C 1-2 alkyl group. More preferably, R 1b is a hydrogen atom, and R 1c is a hydrogen atom or a C 1-2 alkyl group.
The R 1d is preferably a halogen atom, C 1 ~ 4 alkyl group, C 3 ~ 6 cycloalkyl group, C 1 ~ 4 alkoxyl group, C 1 ~ 4 alkylthio group, with -NR a R b group (wherein the R a and R b represent a C 1-4 alkyl group, and R a and R b may form a monocyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bound) or an oxo group More preferably, a halogen atom, a C 1-2 alkyl group, a C 3-4 cycloalkyl group, a C 1-2 alkoxyl group, a C 1-2 alkylthio group, a —NR a R b group (wherein the R a and R b represents a C 1-2 alkyl group, and R a and R b together with the nitrogen atom to which they are attached may form a 5-6 membered non-aromatic heterocyclic group) or an oxo group, preferably suitably be a C 1 ~ 2 alkoxy group, wherein in the above R 1d Alkyl group, a cycloalkyl group, an alkoxyl group or alkylthio group, each of which may be substituted with 1 to 5 substituents RI.
However, when R 1d is an oxo group, X 1 is a nitrogen atom which may be substituted with a C 1-6 alkyl group, preferably a C 1-4 alkyl group, more preferably a C 1-2 alkyl group. is there.
R 1e and R 1f are preferably a hydrogen atom or a C 1-4 alkyl group, more preferably a hydrogen atom or a C 1-2 alkyl group, and still more preferably a C 1-2 alkyl group. Is appropriate.
When X 2 is a nitrogen atom, preferably X 1 is C—R 1a and R 1c is other than a hydrogen atom.
When X 2 is C—H or C—R 1d , X 1 is preferably C—R 1a , and R 1b and R 1c are preferably hydrogen atoms.
上記R1b及びR1cは、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であることが適当である。更に好ましくは、上記R1bは水素原子であり、R1cは水素原子またはC1~2アルキル基であることが適当である。
上記R1dは、好ましくはハロゲン原子、C1~4アルキル基、C3~6シクロアルキル基、C1~4アルコキシル基、C1~4アルキルチオ基、-NRaRb基(ここで、当該Ra及びRbはC1~4アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよい)またはオキソ基であり、より好ましくはハロゲン原子、C1~2アルキル基、C3~4シクロアルキル基、C1~2アルコキシル基、C1~2アルキルチオ基、-NRaRb基(ここで、当該Ra及びRbはC1~2アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに5~6員非芳香族複素環基を形成してもよい)またはオキソ基であり、更に好ましくはC1~2アルコキシル基であることが適当であり、上記R1dにおける前記アルキル基、シクロアルキル基、アルコキシル基またはアルキルチオ基は、それぞれ、1~5個の置換基RIで置換されていてもよい。
但し、R1dがオキソ基の場合、X1は、C1~6アルキル基、好ましくは、C1~4アルキル基、より好ましくはC1~2アルキル基で置換されていてもよい窒素原子である。
上記R1e及びR1fは、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であり、更に好ましくはC1~2アルキル基であることが適当である。
上記X2が窒素原子の場合は、好ましくは上記X1はC-R1aであり、R1cは水素原子以外であることが適当である。
上記X2がC-HまたはC-R1dの場合は、好ましくは上記X1はC-R1aであり、上記R1b、R1cは水素原子であることが適当である。 Said R 1a is preferably C 1 ~ 4 alkyl group, C 3 ~ 6 cycloalkyl group, C 1 ~ 4 alkoxyl group, C 2 ~ 5 alkanoyl group or a cyano group, more preferably C 1 ~ 2 alkyl groups A C 3-4 cycloalkyl group, a C 1-2 alkoxyl group, a C 2-3 alkanoyl group or a cyano group, more preferably a C 1-2 alkyl group or a cyano group. Each of the alkyl group, cycloalkyl group, alkoxyl group or alkanoyl group in 1a may be substituted with 1 to 5 substituents RI.
R 1b and R 1c are preferably a hydrogen atom or a C 1-4 alkyl group, and more preferably a hydrogen atom or a C 1-2 alkyl group. More preferably, R 1b is a hydrogen atom, and R 1c is a hydrogen atom or a C 1-2 alkyl group.
The R 1d is preferably a halogen atom, C 1 ~ 4 alkyl group, C 3 ~ 6 cycloalkyl group, C 1 ~ 4 alkoxyl group, C 1 ~ 4 alkylthio group, with -NR a R b group (wherein the R a and R b represent a C 1-4 alkyl group, and R a and R b may form a monocyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bound) or an oxo group More preferably, a halogen atom, a C 1-2 alkyl group, a C 3-4 cycloalkyl group, a C 1-2 alkoxyl group, a C 1-2 alkylthio group, a —NR a R b group (wherein the R a and R b represents a C 1-2 alkyl group, and R a and R b together with the nitrogen atom to which they are attached may form a 5-6 membered non-aromatic heterocyclic group) or an oxo group, preferably suitably be a C 1 ~ 2 alkoxy group, wherein in the above R 1d Alkyl group, a cycloalkyl group, an alkoxyl group or alkylthio group, each of which may be substituted with 1 to 5 substituents RI.
However, when R 1d is an oxo group, X 1 is a nitrogen atom which may be substituted with a C 1-6 alkyl group, preferably a C 1-4 alkyl group, more preferably a C 1-2 alkyl group. is there.
R 1e and R 1f are preferably a hydrogen atom or a C 1-4 alkyl group, more preferably a hydrogen atom or a C 1-2 alkyl group, and still more preferably a C 1-2 alkyl group. Is appropriate.
When X 2 is a nitrogen atom, preferably X 1 is C—R 1a and R 1c is other than a hydrogen atom.
When X 2 is C—H or C—R 1d , X 1 is preferably C—R 1a , and R 1b and R 1c are preferably hydrogen atoms.
[1-2-b] 前記態様[1]の前記式(I)の化合物において、環Aは、更に好ましくは、前記部分構造式(a1)であり、ここでX1はC-R1aであり、X2は窒素原子、C-HまたはC-R1dである。ここで、当該R1dは、ハロゲン原子、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C1~6アルキルチオ基または-NRaRb基を表す。環Aが部分構造式(a1)である場合のR1a、R1b及びR1cの定義および好ましい範囲は、上記態様[1-2-a]で上述したとおりである。
上記R1dは、好ましくはハロゲン原子、C1~4アルキル基、C3~6シクロアルキル基、C1~4アルコキシル基、C1~4アルキルチオ基または-NRaRb基(ここで、当該Ra及びRbはC1~4アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよい)であり、より好ましくはハロゲン原子、C1~2アルキル基、C3~4シクロアルキル基、C1~2アルコキシル基、C1~2アルキルチオ基または-NRaRb基(ここで、当該Ra及びRbはC1~2アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに5~6員非芳香族複素環基を形成してもよい)であり、更に好ましくはC1~2アルコキシル基であることが適当である。上記R1dにおける、当該アルキル基、シクロアルキル基、アルコキシル基、アルキルチオ基は、それぞれ、1~5個の置換基RIで置換されていてもよい。
上記X2が窒素原子の場合は、好ましくは上記R1cは水素原子以外、すなわちC1~6アルキル基であり、より好ましくはC1~4アルキル基であり、更に好ましくはC1~2アルキル基であることが適当である。
上記X2がC-HまたはC-R1dの場合は、好ましくは上記R1b、R1cは水素原子であることが適当である。 [1-2-b] In the compound of the formula (I) of the embodiment [1], the ring A is more preferably the partial structural formula (a1), wherein X 1 is C—R 1a X 2 is a nitrogen atom, C—H or C—R 1d . Here, the R 1d represents a halogen atom, C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 1 ~ 6 alkylthio group or -NR a R b group. The definitions and preferred ranges of R 1a , R 1b and R 1c when ring A is the partial structural formula (a1) are as described above in the above embodiment [1-2-a].
The R 1d is preferably a halogen atom, C 1 ~ 4 alkyl group, C 3 ~ 6 cycloalkyl group, C 1 ~ 4 alkoxyl group, C 1 ~ 4 alkylthio or -NR a R b group (wherein the R a and R b represent a C 1-4 alkyl group, and R a and R b may form a monocyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded, and more preferably Is a halogen atom, a C 1-2 alkyl group, a C 3-4 cycloalkyl group, a C 1-2 alkoxyl group, a C 1-2 alkylthio group, or a —NR a R b group (where R a and R b are A C 1-2 alkyl group, and R a and R b may form a 5- to 6-membered non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded, and more preferably C 1-2 Suitably it is an alkoxyl group. The alkyl group, cycloalkyl group, alkoxyl group, and alkylthio group in R 1d above may each be substituted with 1 to 5 substituents RI.
If the X 2 is a nitrogen atom, preferably it said R 1c is other than a hydrogen atom, that is, C 1 ~ 6 alkyl group, more preferably a C 1 ~ 4 alkyl groups, more preferably C 1 ~ 2 alkyl Suitably the group.
When X 2 is C—H or C—R 1d , R 1b and R 1c are preferably hydrogen atoms.
上記R1dは、好ましくはハロゲン原子、C1~4アルキル基、C3~6シクロアルキル基、C1~4アルコキシル基、C1~4アルキルチオ基または-NRaRb基(ここで、当該Ra及びRbはC1~4アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよい)であり、より好ましくはハロゲン原子、C1~2アルキル基、C3~4シクロアルキル基、C1~2アルコキシル基、C1~2アルキルチオ基または-NRaRb基(ここで、当該Ra及びRbはC1~2アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに5~6員非芳香族複素環基を形成してもよい)であり、更に好ましくはC1~2アルコキシル基であることが適当である。上記R1dにおける、当該アルキル基、シクロアルキル基、アルコキシル基、アルキルチオ基は、それぞれ、1~5個の置換基RIで置換されていてもよい。
上記X2が窒素原子の場合は、好ましくは上記R1cは水素原子以外、すなわちC1~6アルキル基であり、より好ましくはC1~4アルキル基であり、更に好ましくはC1~2アルキル基であることが適当である。
上記X2がC-HまたはC-R1dの場合は、好ましくは上記R1b、R1cは水素原子であることが適当である。 [1-2-b] In the compound of the formula (I) of the embodiment [1], the ring A is more preferably the partial structural formula (a1), wherein X 1 is C—R 1a X 2 is a nitrogen atom, C—H or C—R 1d . Here, the R 1d represents a halogen atom, C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 1 ~ 6 alkylthio group or -NR a R b group. The definitions and preferred ranges of R 1a , R 1b and R 1c when ring A is the partial structural formula (a1) are as described above in the above embodiment [1-2-a].
The R 1d is preferably a halogen atom, C 1 ~ 4 alkyl group, C 3 ~ 6 cycloalkyl group, C 1 ~ 4 alkoxyl group, C 1 ~ 4 alkylthio or -NR a R b group (wherein the R a and R b represent a C 1-4 alkyl group, and R a and R b may form a monocyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded, and more preferably Is a halogen atom, a C 1-2 alkyl group, a C 3-4 cycloalkyl group, a C 1-2 alkoxyl group, a C 1-2 alkylthio group, or a —NR a R b group (where R a and R b are A C 1-2 alkyl group, and R a and R b may form a 5- to 6-membered non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded, and more preferably C 1-2 Suitably it is an alkoxyl group. The alkyl group, cycloalkyl group, alkoxyl group, and alkylthio group in R 1d above may each be substituted with 1 to 5 substituents RI.
If the X 2 is a nitrogen atom, preferably it said R 1c is other than a hydrogen atom, that is, C 1 ~ 6 alkyl group, more preferably a C 1 ~ 4 alkyl groups, more preferably C 1 ~ 2 alkyl Suitably the group.
When X 2 is C—H or C—R 1d , R 1b and R 1c are preferably hydrogen atoms.
[1-2-c] 前記態様[1]の前記式(I)の化合物において、環Aは、殊更好ましくは、前記部分構造式(a1)であり、ここでX1はC-R1aであり、X2は窒素原子、C-HまたはC-R1dであり、R1aは、C1~6アルキル基またはシアノ基を表し、R1bは、水素原子を表し、R1cは、水素原子またはC1~6アルキル基を表し、R1dは、C1~6アルコキシル基を表し、R1a、R1b、R1c及びR1dにおける前記アルキル基またはアルコキシル基は、それぞれ、1~5個のハロゲン原子で置換されていてもよい。
上記R1aは、好ましくはC1~4アルキル基またはシアノ基であり、より好ましくはC1~2アルキル基またはシアノ基であることが適当である。
上記R1cは、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であることが適当である。
上記R1dは、好ましくはC1~4アルコキシル基、より好ましくはC1~2アルコキシル基であることが適当である。
上記X2が窒素原子の場合は、上記R1a、R1cは、好ましくは各々独立にC1~6アルキル基であり、より好ましくは各々独立にC1~4アルキル基であり、更に好ましくは各々独立にC1~2アルキル基であることが適当である。
上記X2がC-HまたはC-R1dの場合は、好ましくは上記R1aはハロゲン化C1~6アルキル基またはシアノ基であり、より好ましくは上記R1aはハロゲン化C1~4アルキル基またはシアノ基であり、更に好ましくは上記R1aはハロゲン化C1~2アルキル基またはシアノ基であることが適当である。
上記X2がC-HまたはC-R1dの場合は、上記R1cは水素原子であることが適当である。 [1-2-c] In the compound of the formula (I) of the embodiment [1], the ring A is particularly preferably the partial structural formula (a1), wherein X 1 is C—R 1a X 2 is a nitrogen atom, C—H or C—R 1d , R 1a represents a C 1-6 alkyl group or a cyano group, R 1b represents a hydrogen atom, and R 1c represents a hydrogen atom Or a C 1-6 alkyl group, R 1d represents a C 1-6 alkoxyl group, and the alkyl group or alkoxyl group in R 1a , R 1b , R 1c and R 1d is 1-5 It may be substituted with a halogen atom.
R 1a is preferably a C 1-4 alkyl group or a cyano group, and more preferably a C 1-2 alkyl group or a cyano group.
R 1c is preferably a hydrogen atom or a C 1-4 alkyl group, and more preferably a hydrogen atom or a C 1-2 alkyl group.
R 1d is preferably a C 1-4 alkoxyl group, more preferably a C 1-2 alkoxyl group.
If the X 2 is a nitrogen atom, the R 1a, R 1c is preferably each independently C 1 ~ 6 alkyl group, a C 1 ~ 4 alkyl groups each independently more preferably, more preferably Suitably each is independently a C 1-2 alkyl group.
When X 2 is C—H or C—R 1d , preferably R 1a is a halogenated C 1-6 alkyl group or a cyano group, more preferably R 1a is a halogenated C 1-4 alkyl. R 1a is preferably a halogenated C 1-2 alkyl group or a cyano group.
When X 2 is C—H or C—R 1d , R 1c is suitably a hydrogen atom.
上記R1aは、好ましくはC1~4アルキル基またはシアノ基であり、より好ましくはC1~2アルキル基またはシアノ基であることが適当である。
上記R1cは、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であることが適当である。
上記R1dは、好ましくはC1~4アルコキシル基、より好ましくはC1~2アルコキシル基であることが適当である。
上記X2が窒素原子の場合は、上記R1a、R1cは、好ましくは各々独立にC1~6アルキル基であり、より好ましくは各々独立にC1~4アルキル基であり、更に好ましくは各々独立にC1~2アルキル基であることが適当である。
上記X2がC-HまたはC-R1dの場合は、好ましくは上記R1aはハロゲン化C1~6アルキル基またはシアノ基であり、より好ましくは上記R1aはハロゲン化C1~4アルキル基またはシアノ基であり、更に好ましくは上記R1aはハロゲン化C1~2アルキル基またはシアノ基であることが適当である。
上記X2がC-HまたはC-R1dの場合は、上記R1cは水素原子であることが適当である。 [1-2-c] In the compound of the formula (I) of the embodiment [1], the ring A is particularly preferably the partial structural formula (a1), wherein X 1 is C—R 1a X 2 is a nitrogen atom, C—H or C—R 1d , R 1a represents a C 1-6 alkyl group or a cyano group, R 1b represents a hydrogen atom, and R 1c represents a hydrogen atom Or a C 1-6 alkyl group, R 1d represents a C 1-6 alkoxyl group, and the alkyl group or alkoxyl group in R 1a , R 1b , R 1c and R 1d is 1-5 It may be substituted with a halogen atom.
R 1a is preferably a C 1-4 alkyl group or a cyano group, and more preferably a C 1-2 alkyl group or a cyano group.
R 1c is preferably a hydrogen atom or a C 1-4 alkyl group, and more preferably a hydrogen atom or a C 1-2 alkyl group.
R 1d is preferably a C 1-4 alkoxyl group, more preferably a C 1-2 alkoxyl group.
If the X 2 is a nitrogen atom, the R 1a, R 1c is preferably each independently C 1 ~ 6 alkyl group, a C 1 ~ 4 alkyl groups each independently more preferably, more preferably Suitably each is independently a C 1-2 alkyl group.
When X 2 is C—H or C—R 1d , preferably R 1a is a halogenated C 1-6 alkyl group or a cyano group, more preferably R 1a is a halogenated C 1-4 alkyl. R 1a is preferably a halogenated C 1-2 alkyl group or a cyano group.
When X 2 is C—H or C—R 1d , R 1c is suitably a hydrogen atom.
[1-3] 前記態様[1]の前記式(I)の化合物において、環Bは、好ましくは、フェニル基または5~6員の単環式ヘテロアリール基を表し、環Bにおける当該フェニル基またはヘテロアリール基は、それぞれ、1~4個のR2で置換されていてもよい。
上記R2は、好ましくはハロゲン原子、C1~6アルキル基、ハロゲン化C1~6アルキル基、C1~6アルコキシル基、ハロゲン化C1~6アルコキシル基、シアノ基または単環式ヘテロアリール基(当該ヘテロアリール基は1個のハロゲン原子で置換されていてもよい)であり、より好ましくはハロゲン原子、C1~4アルキル基、ハロゲン化C1~4アルキル基、C1~4アルコキシル基、ハロゲン化C1~4アルコキシル基、シアノ基または5~6員ヘテロアリール基(当該ヘテロアリール基は1個のハロゲン原子で置換されていてもよい)であり、更に好ましくはハロゲン原子、C1~2アルキル基、ハロゲン化C1~2アルキル基、C1~2アルコキシル基、ハロゲン化C1~2アルコキシル基、シアノ基または5~6員ヘテロアリール基(当該ヘテロアリール基は1個のハロゲン原子で置換されていてもよい)であり、殊更好ましくはハロゲン原子、C1~2アルキル基、ハロゲン化C1~2アルキル基、C1~2アルコキシル基またはシアノ基あることが適当である。 [1-3] In the compound of the formula (I) of the embodiment [1], the ring B preferably represents a phenyl group or a 5- to 6-membered monocyclic heteroaryl group, and the phenyl group in the ring B Alternatively, each heteroaryl group may be substituted with 1 to 4 R 2 .
R 2 is preferably a halogen atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 alkoxyl group, a halogenated C 1-6 alkoxyl group, a cyano group or a monocyclic heteroaryl. A group (the heteroaryl group may be substituted with one halogen atom), more preferably a halogen atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a C 1-4 alkoxyl. A halogenated C 1-4 alkoxyl group, a cyano group or a 5- to 6-membered heteroaryl group (the heteroaryl group may be substituted with one halogen atom), more preferably a halogen atom, C 1-2 alkyl group, halogenated C 1-2 alkyl group, C 1-2 alkoxyl group, a halogenated C 1-2 alkoxy group, a cyano group or a 5-6 membered heteroaryl group (said heteroar- Lumpur groups are optionally substituted with one halogen atom), especially preferably a halogen atom, C 1 ~ 2 alkyl group, a halogenated C 1 ~ 2 alkyl group, C 1 ~ 2 alkoxy group or cyano It is appropriate that there is a group.
上記R2は、好ましくはハロゲン原子、C1~6アルキル基、ハロゲン化C1~6アルキル基、C1~6アルコキシル基、ハロゲン化C1~6アルコキシル基、シアノ基または単環式ヘテロアリール基(当該ヘテロアリール基は1個のハロゲン原子で置換されていてもよい)であり、より好ましくはハロゲン原子、C1~4アルキル基、ハロゲン化C1~4アルキル基、C1~4アルコキシル基、ハロゲン化C1~4アルコキシル基、シアノ基または5~6員ヘテロアリール基(当該ヘテロアリール基は1個のハロゲン原子で置換されていてもよい)であり、更に好ましくはハロゲン原子、C1~2アルキル基、ハロゲン化C1~2アルキル基、C1~2アルコキシル基、ハロゲン化C1~2アルコキシル基、シアノ基または5~6員ヘテロアリール基(当該ヘテロアリール基は1個のハロゲン原子で置換されていてもよい)であり、殊更好ましくはハロゲン原子、C1~2アルキル基、ハロゲン化C1~2アルキル基、C1~2アルコキシル基またはシアノ基あることが適当である。 [1-3] In the compound of the formula (I) of the embodiment [1], the ring B preferably represents a phenyl group or a 5- to 6-membered monocyclic heteroaryl group, and the phenyl group in the ring B Alternatively, each heteroaryl group may be substituted with 1 to 4 R 2 .
R 2 is preferably a halogen atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 alkoxyl group, a halogenated C 1-6 alkoxyl group, a cyano group or a monocyclic heteroaryl. A group (the heteroaryl group may be substituted with one halogen atom), more preferably a halogen atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a C 1-4 alkoxyl. A halogenated C 1-4 alkoxyl group, a cyano group or a 5- to 6-membered heteroaryl group (the heteroaryl group may be substituted with one halogen atom), more preferably a halogen atom, C 1-2 alkyl group, halogenated C 1-2 alkyl group, C 1-2 alkoxyl group, a halogenated C 1-2 alkoxy group, a cyano group or a 5-6 membered heteroaryl group (said heteroar- Lumpur groups are optionally substituted with one halogen atom), especially preferably a halogen atom, C 1 ~ 2 alkyl group, a halogenated C 1 ~ 2 alkyl group, C 1 ~ 2 alkoxy group or cyano It is appropriate that there is a group.
[1-3-a] 前記態様[1]の前記式(I)の化合物において、環Bは、より好ましくは、フェニル基または5~6員ヘテロアリール基を表し、環Bにおける当該フェニル基またはヘテロアリール基は、それぞれ、1個のR2で置換されていてもよい。
R2の定義および好ましい範囲は、上記態様[1-3]で上述したとおりである。
[1-3-b] 前記態様[1]の前記式(I)の化合物において、環Bは、更に好ましくは、下記部分構造式(b1)または(b2):
(式(b1)または(b2)中、
Yは、窒素原子、C-HまたはC-R2bを表し、
R2aは、水素原子、ハロゲン原子、C1~6アルキル基、C1~6アルコキシル基または単環式ヘテロアリール基を表し、但し、YがC-R2bの場合は、R2aは水素原子であり、
R2bは、ハロゲン原子を表し、
R2cは、水素原子、C1~6アルキル基またはシアノ基を表し、
R2a及びR2cにおける前記アルキル基、アルコキシル基は、それぞれ、1~5個の置換基RIで置換されていてもよく、
1ないし6の数字は、環内における位置を表す)が挙げられる。
上記R2aにおける当該単環式ヘテロアリール基は、好ましくはLの結合位置に対してパラ位に位置すること、すなわち上記式(b1)において、環内におけるYの位置を1位、Lの結合位置を2位とした場合、5位に位置することが適当である。
上記R2aは、好ましくは水素原子、ハロゲン原子、C1~4アルキル基、ハロゲン化C1~4アルキル基、C1~4アルコキシル基、ハロゲン化C1~4アルコキシル基または5~6員ヘテロアリール基であり、より好ましくは水素原子、ハロゲン原子、C1~2アルキル基、C1~2アルコキシル基または5~6員ヘテロアリール基であり、更に好ましくは水素原子またはハロゲン原子であることが適当である。
上記R2cは、好ましくは水素原子、C1~4アルキル基、ハロゲン化C1~4アルキル基またはシアノ基であり、より好ましくは水素原子、C1~2アルキル基、ハロゲン化C1~2アルキル基またはシアノ基であることが適当である。 [1-3-a] In the compound of the formula (I) of the embodiment [1], the ring B more preferably represents a phenyl group or a 5- to 6-membered heteroaryl group, and the phenyl group in the ring B or Each heteroaryl group may be substituted with one R 2 .
The definition and preferred range of R 2 are as described above in the above embodiment [1-3].
[1-3-b] In the compound of the formula (I) of the embodiment [1], the ring B is more preferably the following partial structural formula (b1) or (b2):
(In the formula (b1) or (b2),
Y represents a nitrogen atom, C—H or C—R 2b ,
R 2a represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxyl group or a monocyclic heteroaryl group, provided that when Y is C—R 2b , R 2a is a hydrogen atom And
R 2b represents a halogen atom,
R 2c represents a hydrogen atom, a C 1-6 alkyl group or a cyano group,
The alkyl group and alkoxyl group in R 2a and R 2c may each be substituted with 1 to 5 substituents RI,
1 to 6 represent positions in the ring).
The monocyclic heteroaryl group in R 2a is preferably located in the para position with respect to the bonding position of L, that is, in the formula (b1), the position of Y in the ring is the first position and the bonding of L If the position is 2nd, it is appropriate to be 5th.
R 2a is preferably a hydrogen atom, a halogen atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a C 1-4 alkoxyl group, a halogenated C 1-4 alkoxyl group, or a 5- to 6-membered hetero group. An aryl group, more preferably a hydrogen atom, a halogen atom, a C 1-2 alkyl group, a C 1-2 alkoxyl group or a 5- to 6-membered heteroaryl group, and still more preferably a hydrogen atom or a halogen atom. Is appropriate.
R 2c is preferably a hydrogen atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group or a cyano group, more preferably a hydrogen atom, a C 1-2 alkyl group, a halogenated C 1-2 Suitably an alkyl group or a cyano group.
R2の定義および好ましい範囲は、上記態様[1-3]で上述したとおりである。
[1-3-b] 前記態様[1]の前記式(I)の化合物において、環Bは、更に好ましくは、下記部分構造式(b1)または(b2):
(式(b1)または(b2)中、
Yは、窒素原子、C-HまたはC-R2bを表し、
R2aは、水素原子、ハロゲン原子、C1~6アルキル基、C1~6アルコキシル基または単環式ヘテロアリール基を表し、但し、YがC-R2bの場合は、R2aは水素原子であり、
R2bは、ハロゲン原子を表し、
R2cは、水素原子、C1~6アルキル基またはシアノ基を表し、
R2a及びR2cにおける前記アルキル基、アルコキシル基は、それぞれ、1~5個の置換基RIで置換されていてもよく、
1ないし6の数字は、環内における位置を表す)が挙げられる。
上記R2aにおける当該単環式ヘテロアリール基は、好ましくはLの結合位置に対してパラ位に位置すること、すなわち上記式(b1)において、環内におけるYの位置を1位、Lの結合位置を2位とした場合、5位に位置することが適当である。
上記R2aは、好ましくは水素原子、ハロゲン原子、C1~4アルキル基、ハロゲン化C1~4アルキル基、C1~4アルコキシル基、ハロゲン化C1~4アルコキシル基または5~6員ヘテロアリール基であり、より好ましくは水素原子、ハロゲン原子、C1~2アルキル基、C1~2アルコキシル基または5~6員ヘテロアリール基であり、更に好ましくは水素原子またはハロゲン原子であることが適当である。
上記R2cは、好ましくは水素原子、C1~4アルキル基、ハロゲン化C1~4アルキル基またはシアノ基であり、より好ましくは水素原子、C1~2アルキル基、ハロゲン化C1~2アルキル基またはシアノ基であることが適当である。 [1-3-a] In the compound of the formula (I) of the embodiment [1], the ring B more preferably represents a phenyl group or a 5- to 6-membered heteroaryl group, and the phenyl group in the ring B or Each heteroaryl group may be substituted with one R 2 .
The definition and preferred range of R 2 are as described above in the above embodiment [1-3].
[1-3-b] In the compound of the formula (I) of the embodiment [1], the ring B is more preferably the following partial structural formula (b1) or (b2):
(In the formula (b1) or (b2),
Y represents a nitrogen atom, C—H or C—R 2b ,
R 2a represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxyl group or a monocyclic heteroaryl group, provided that when Y is C—R 2b , R 2a is a hydrogen atom And
R 2b represents a halogen atom,
R 2c represents a hydrogen atom, a C 1-6 alkyl group or a cyano group,
The alkyl group and alkoxyl group in R 2a and R 2c may each be substituted with 1 to 5 substituents RI,
1 to 6 represent positions in the ring).
The monocyclic heteroaryl group in R 2a is preferably located in the para position with respect to the bonding position of L, that is, in the formula (b1), the position of Y in the ring is the first position and the bonding of L If the position is 2nd, it is appropriate to be 5th.
R 2a is preferably a hydrogen atom, a halogen atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a C 1-4 alkoxyl group, a halogenated C 1-4 alkoxyl group, or a 5- to 6-membered hetero group. An aryl group, more preferably a hydrogen atom, a halogen atom, a C 1-2 alkyl group, a C 1-2 alkoxyl group or a 5- to 6-membered heteroaryl group, and still more preferably a hydrogen atom or a halogen atom. Is appropriate.
R 2c is preferably a hydrogen atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group or a cyano group, more preferably a hydrogen atom, a C 1-2 alkyl group, a halogenated C 1-2 Suitably an alkyl group or a cyano group.
[1-3-c] 前記態様[1]の前記式(I)の化合物において、環Bは、殊更好ましくは、上記部分構造式(b1)または(b2)であり、ここでYは、窒素原子、C-HまたはC-R2bを表し、R2aは、水素原子またはハロゲン原子を表し、但し、YがC-R2bの場合は、R2aは水素原子であり、R2bは、ハロゲン原子を表し、R2cは、水素原子、C1~6アルキル基、ハロゲン化C1~6アルキル基またはシアノ基を表す。
上記R2cは、好ましくは水素原子、C1~4アルキル基、ハロゲン化C1~4アルキル基またはシアノ基であり、より好ましくは水素原子、C1~2アルキル基、ハロゲン化C1~2アルキル基またはシアノ基であることが適当である。 [1-3-c] In the compound of the formula (I) of the embodiment [1], the ring B is particularly preferably the partial structural formula (b1) or (b2), where Y is nitrogen. Represents an atom, C—H or C—R 2b , R 2a represents a hydrogen atom or a halogen atom, provided that when Y is C—R 2b , R 2a is a hydrogen atom and R 2b is a halogen atom R 2c represents a hydrogen atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, or a cyano group.
R 2c is preferably a hydrogen atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group or a cyano group, more preferably a hydrogen atom, a C 1-2 alkyl group, a halogenated C 1-2 Suitably an alkyl group or a cyano group.
上記R2cは、好ましくは水素原子、C1~4アルキル基、ハロゲン化C1~4アルキル基またはシアノ基であり、より好ましくは水素原子、C1~2アルキル基、ハロゲン化C1~2アルキル基またはシアノ基であることが適当である。 [1-3-c] In the compound of the formula (I) of the embodiment [1], the ring B is particularly preferably the partial structural formula (b1) or (b2), where Y is nitrogen. Represents an atom, C—H or C—R 2b , R 2a represents a hydrogen atom or a halogen atom, provided that when Y is C—R 2b , R 2a is a hydrogen atom and R 2b is a halogen atom R 2c represents a hydrogen atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, or a cyano group.
R 2c is preferably a hydrogen atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group or a cyano group, more preferably a hydrogen atom, a C 1-2 alkyl group, a halogenated C 1-2 Suitably an alkyl group or a cyano group.
[1-4] 前記態様[1]の前記式(I)の化合物において、Lは、好ましくは、C3~8シクロアルキル基、C1~6アルコキシル基、ハロゲン化C1~6アルコキシル基、フェニル基または5~6員の単環式ヘテロアリール基を表し、Lにおける当該フェニル基またはヘテロアリール基は、それぞれ、1~5個のR3で置換されていてもよく、または、LとR2が環B上で互いに隣接する置換基である場合、Lは、R2と結合し、環Bの一部とともに縮合環基を形成してもよい。すなわち、以下の部分構造式に示すように、L及びR2は、環B上で互いに隣接している(オルト位)場合、L、R2及び環B(一部)は共に結合して縮合環D’を形成し得る。
形成された上記縮合環D’は、隣接する環Bの一部とともに縮環式の環状基を形成する。
ここで、当該縮合環D’は、ハロゲン原子で置換されていてもよい5~7員の単環式非芳香族複素環基であり、隣接する環Bの一部とともに縮環式複素環基を形成する。縮合環D’と環Bからなる縮環式複素環基の定義および好ましい範囲は、前記態様[1]で上述したとおりである。
上記R3は、好ましくはハロゲン原子、C1~6アルキル基、ハロゲン化C1~6アルキル基、C1~6アルコキシル基、ハロゲン化C1~6アルコキシル基またはシアノ基であり、より好ましくはハロゲン原子、C1~4アルキル基、ハロゲン化C1~4アルキル基、C1~4アルコキシル基、ハロゲン化C1~4アルコキシル基またはシアノ基であり、更に好ましくはハロゲン原子、C1~2アルキル基、ハロゲン化C1~2アルキル基、C1~2アルコキシル基、ハロゲン化C1~2アルコキシル基またはシアノ基であり、殊更に好ましくはハロゲン原子、C1~2アルキル基またはシアノ基であることが適当である。 [1-4] In the compound of formula (I) of the embodiment [1], L is preferably, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxyl group, a halogenated C 1 ~ 6 alkoxy group, Represents a phenyl group or a 5- to 6-membered monocyclic heteroaryl group, and the phenyl group or heteroaryl group in L may each be substituted with 1 to 5 R 3 , or L and R When 2 is a substituent adjacent to each other on ring B, L may be bonded to R 2 to form a condensed ring group together with part of ring B. That is, as shown in the following partial structural formula, when L and R 2 are adjacent to each other on the ring B (ortho position), L, R 2 and ring B (part) are bonded together and condensed. Ring D ′ may be formed.
The formed condensed ring D ′ forms a condensed cyclic group together with a part of the adjacent ring B.
Here, the condensed ring D ′ is a 5- to 7-membered monocyclic non-aromatic heterocyclic group which may be substituted with a halogen atom, and a condensed heterocyclic group together with a part of the adjacent ring B Form. The definition and preferred range of the condensed heterocyclic group consisting of the condensed ring D ′ and the ring B are as described above in the embodiment [1].
R 3 is preferably a halogen atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 alkoxyl group, a halogenated C 1-6 alkoxyl group or a cyano group, more preferably A halogen atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a C 1-4 alkoxyl group, a halogenated C 1-4 alkoxyl group or a cyano group, more preferably a halogen atom, C 1-2 An alkyl group, a halogenated C 1-2 alkyl group, a C 1-2 alkoxyl group, a halogenated C 1-2 alkoxyl group or a cyano group, particularly preferably a halogen atom, a C 1-2 alkyl group or a cyano group It is appropriate to be.
形成された上記縮合環D’は、隣接する環Bの一部とともに縮環式の環状基を形成する。
ここで、当該縮合環D’は、ハロゲン原子で置換されていてもよい5~7員の単環式非芳香族複素環基であり、隣接する環Bの一部とともに縮環式複素環基を形成する。縮合環D’と環Bからなる縮環式複素環基の定義および好ましい範囲は、前記態様[1]で上述したとおりである。
上記R3は、好ましくはハロゲン原子、C1~6アルキル基、ハロゲン化C1~6アルキル基、C1~6アルコキシル基、ハロゲン化C1~6アルコキシル基またはシアノ基であり、より好ましくはハロゲン原子、C1~4アルキル基、ハロゲン化C1~4アルキル基、C1~4アルコキシル基、ハロゲン化C1~4アルコキシル基またはシアノ基であり、更に好ましくはハロゲン原子、C1~2アルキル基、ハロゲン化C1~2アルキル基、C1~2アルコキシル基、ハロゲン化C1~2アルコキシル基またはシアノ基であり、殊更に好ましくはハロゲン原子、C1~2アルキル基またはシアノ基であることが適当である。 [1-4] In the compound of formula (I) of the embodiment [1], L is preferably, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxyl group, a halogenated C 1 ~ 6 alkoxy group, Represents a phenyl group or a 5- to 6-membered monocyclic heteroaryl group, and the phenyl group or heteroaryl group in L may each be substituted with 1 to 5 R 3 , or L and R When 2 is a substituent adjacent to each other on ring B, L may be bonded to R 2 to form a condensed ring group together with part of ring B. That is, as shown in the following partial structural formula, when L and R 2 are adjacent to each other on the ring B (ortho position), L, R 2 and ring B (part) are bonded together and condensed. Ring D ′ may be formed.
The formed condensed ring D ′ forms a condensed cyclic group together with a part of the adjacent ring B.
Here, the condensed ring D ′ is a 5- to 7-membered monocyclic non-aromatic heterocyclic group which may be substituted with a halogen atom, and a condensed heterocyclic group together with a part of the adjacent ring B Form. The definition and preferred range of the condensed heterocyclic group consisting of the condensed ring D ′ and the ring B are as described above in the embodiment [1].
R 3 is preferably a halogen atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 alkoxyl group, a halogenated C 1-6 alkoxyl group or a cyano group, more preferably A halogen atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a C 1-4 alkoxyl group, a halogenated C 1-4 alkoxyl group or a cyano group, more preferably a halogen atom, C 1-2 An alkyl group, a halogenated C 1-2 alkyl group, a C 1-2 alkoxyl group, a halogenated C 1-2 alkoxyl group or a cyano group, particularly preferably a halogen atom, a C 1-2 alkyl group or a cyano group It is appropriate to be.
[1-4-a] 前記態様[1]の前記式(I)の化合物において、Lは、より好ましくは、フェニル基または5~6員ヘテロアリール基を表し、Lにおける前記フェニル基またはヘテロアリール基は、それぞれ、1個のR3で置換されていてもよい。
R3の定義および好ましい範囲は、上記態様[1-4]で上述したとおりである。 [1-4-a] In the compound of the formula (I) of the embodiment [1], L preferably represents a phenyl group or a 5- to 6-membered heteroaryl group, and the phenyl group or heteroaryl in L Each group may be substituted with one R 3 .
The definition and preferred range of R 3 are as described above in the above embodiment [1-4].
R3の定義および好ましい範囲は、上記態様[1-4]で上述したとおりである。 [1-4-a] In the compound of the formula (I) of the embodiment [1], L preferably represents a phenyl group or a 5- to 6-membered heteroaryl group, and the phenyl group or heteroaryl in L Each group may be substituted with one R 3 .
The definition and preferred range of R 3 are as described above in the above embodiment [1-4].
[1-4-b] 前記態様[1]の前記式(I)の化合物において、Lは、更に好ましくは、フェニル基または5~6員ヘテロアリール基を表し、Lにおける前記フェニル基またはヘテロアリール基は、それぞれ、1個のR3で置換されていてもよく、ここで、当該R3は、C1~6アルキル基、C1~6アルコキシル基またはシアノ基を表し、ここでR3における前記アルキル基またはアルコキシル基は、それぞれ、1~5個の置換基RIで置換されていてもよい。
上記R3は、好ましくはC1~4アルキル基、C1~4アルコキシル基またはシアノ基であり、より好ましくはC1~2アルキル基、C1~2アルコキシル基またはシアノ基であり、更に好ましくはC1~2アルキル基またはシアノ基であることが適当である。 [1-4-b] In the compound of the formula (I) of the embodiment [1], L preferably represents a phenyl group or a 5- to 6-membered heteroaryl group, and the phenyl group or heteroaryl in L Each group may be substituted with one R 3 , where R 3 represents a C 1-6 alkyl group, a C 1-6 alkoxyl group or a cyano group, wherein R 3 The alkyl group or alkoxyl group may each be substituted with 1 to 5 substituents RI.
R 3 is preferably a C 1-4 alkyl group, a C 1-4 alkoxyl group or a cyano group, more preferably a C 1-2 alkyl group, a C 1-2 alkoxyl group or a cyano group, still more preferably. Is suitably a C 1-2 alkyl group or a cyano group.
上記R3は、好ましくはC1~4アルキル基、C1~4アルコキシル基またはシアノ基であり、より好ましくはC1~2アルキル基、C1~2アルコキシル基またはシアノ基であり、更に好ましくはC1~2アルキル基またはシアノ基であることが適当である。 [1-4-b] In the compound of the formula (I) of the embodiment [1], L preferably represents a phenyl group or a 5- to 6-membered heteroaryl group, and the phenyl group or heteroaryl in L Each group may be substituted with one R 3 , where R 3 represents a C 1-6 alkyl group, a C 1-6 alkoxyl group or a cyano group, wherein R 3 The alkyl group or alkoxyl group may each be substituted with 1 to 5 substituents RI.
R 3 is preferably a C 1-4 alkyl group, a C 1-4 alkoxyl group or a cyano group, more preferably a C 1-2 alkyl group, a C 1-2 alkoxyl group or a cyano group, still more preferably. Is suitably a C 1-2 alkyl group or a cyano group.
[1-4-c] 前記態様[1]の前記式(I)の化合物において、Lは、殊更好ましくは、下記部分構造式(c1)、(c2)または(c3):
(式(c1)、(c2)または(c3)中、
Z1、Z2、Z3は、各々独立に、窒素原子またはC-Hを表し、但し、Z2がC-Hの場合は、Z1はC-Hであり、
Z4は、酸素原子または硫黄原子を表し、
R3a、R3b及びR3cは、各々独立に、水素原子、C1~6アルキル基またはシアノ基を表す)が挙げられる。
上記Z4は、好ましくは硫黄原子であることが適当である。
上記R3a、R3b、R3cは、各々独立に、好ましくは水素原子、C1~4アルキル基またはシアノ基であり、より好ましくは水素原子、C1~2アルキル基またはシアノ基であり、更に好ましくは水素原子であることが適当である。 [1-4-c] In the compound of the formula (I) of the embodiment [1], L is particularly preferably the following partial structural formula (c1), (c2) or (c3):
(In the formula (c1), (c2) or (c3),
Z 1 , Z 2 , and Z 3 each independently represent a nitrogen atom or C—H, provided that when Z 2 is C—H, Z 1 is C—H;
Z 4 represents an oxygen atom or a sulfur atom,
R 3a , R 3b and R 3c each independently represents a hydrogen atom, a C 1-6 alkyl group or a cyano group.
Z 4 is preferably a sulfur atom.
R 3a , R 3b and R 3c are each independently preferably a hydrogen atom, a C 1-4 alkyl group or a cyano group, more preferably a hydrogen atom, a C 1-2 alkyl group or a cyano group, More preferably, it is a hydrogen atom.
(式(c1)、(c2)または(c3)中、
Z1、Z2、Z3は、各々独立に、窒素原子またはC-Hを表し、但し、Z2がC-Hの場合は、Z1はC-Hであり、
Z4は、酸素原子または硫黄原子を表し、
R3a、R3b及びR3cは、各々独立に、水素原子、C1~6アルキル基またはシアノ基を表す)が挙げられる。
上記Z4は、好ましくは硫黄原子であることが適当である。
上記R3a、R3b、R3cは、各々独立に、好ましくは水素原子、C1~4アルキル基またはシアノ基であり、より好ましくは水素原子、C1~2アルキル基またはシアノ基であり、更に好ましくは水素原子であることが適当である。 [1-4-c] In the compound of the formula (I) of the embodiment [1], L is particularly preferably the following partial structural formula (c1), (c2) or (c3):
(In the formula (c1), (c2) or (c3),
Z 1 , Z 2 , and Z 3 each independently represent a nitrogen atom or C—H, provided that when Z 2 is C—H, Z 1 is C—H;
Z 4 represents an oxygen atom or a sulfur atom,
R 3a , R 3b and R 3c each independently represents a hydrogen atom, a C 1-6 alkyl group or a cyano group.
Z 4 is preferably a sulfur atom.
R 3a , R 3b and R 3c are each independently preferably a hydrogen atom, a C 1-4 alkyl group or a cyano group, more preferably a hydrogen atom, a C 1-2 alkyl group or a cyano group, More preferably, it is a hydrogen atom.
[1-5] 前記態様[1]の前記式(I)の化合物において、Ra及びRbは、好ましくは、各々独立に、C1~6アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよく、RaおよびRbにおける前記単環式非芳香族複素環基は、その環内の炭素原子の少なくとも1個が、酸素原子、硫黄原子及びC1~6アルキル基で置換されていてもよい窒素原子から任意に選ばれる原子で置き換えられていてもよい。
上記Ra及びRbは、より好ましくは、各々独立に、C1~4アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよく、更に好ましくは、各々独立に、C1~2アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに5~6員非芳香族複素環基を形成してもよい。
[1-6] 前記態様[1]の前記式(I)の化合物において、置換基RIは、好ましくは、各々独立に、ハロゲン原子である。 [1-5] In the compound of the formula (I) of the embodiment [1], R a and R b are preferably each independently a C 1-6 alkyl group, and R a and R b are A monocyclic non-aromatic heterocyclic group may be formed together with a nitrogen atom to which they are bonded, and the monocyclic non-aromatic heterocyclic group in R a and R b is at least one of carbon atoms in the ring. May be replaced with an atom arbitrarily selected from an oxygen atom, a sulfur atom and a nitrogen atom which may be substituted with a C 1-6 alkyl group.
R a and R b more preferably each independently represent a C 1-4 alkyl group, and R a and R b together with the nitrogen atom to which they are attached form a monocyclic non-aromatic heterocyclic group More preferably, each independently represents a C 1-2 alkyl group, and R a and R b together with the nitrogen atom to which they are attached form a 5-6 membered non-aromatic heterocyclic group. Also good.
[1-6] In the compound of the formula (I) of the embodiment [1], the substituents RI are preferably each independently a halogen atom.
上記Ra及びRbは、より好ましくは、各々独立に、C1~4アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよく、更に好ましくは、各々独立に、C1~2アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに5~6員非芳香族複素環基を形成してもよい。
[1-6] 前記態様[1]の前記式(I)の化合物において、置換基RIは、好ましくは、各々独立に、ハロゲン原子である。 [1-5] In the compound of the formula (I) of the embodiment [1], R a and R b are preferably each independently a C 1-6 alkyl group, and R a and R b are A monocyclic non-aromatic heterocyclic group may be formed together with a nitrogen atom to which they are bonded, and the monocyclic non-aromatic heterocyclic group in R a and R b is at least one of carbon atoms in the ring. May be replaced with an atom arbitrarily selected from an oxygen atom, a sulfur atom and a nitrogen atom which may be substituted with a C 1-6 alkyl group.
R a and R b more preferably each independently represent a C 1-4 alkyl group, and R a and R b together with the nitrogen atom to which they are attached form a monocyclic non-aromatic heterocyclic group More preferably, each independently represents a C 1-2 alkyl group, and R a and R b together with the nitrogen atom to which they are attached form a 5-6 membered non-aromatic heterocyclic group. Also good.
[1-6] In the compound of the formula (I) of the embodiment [1], the substituents RI are preferably each independently a halogen atom.
[2] 前記態様[1]の前記式(I)の化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物において、好ましい態様は、式(I)中、
環Aは、フェニル基または5~10員ヘテロアリール基を表し、環Aにおける前記フェニル基またはヘテロアリール基は、それぞれ、1~5個のR1で置換されていてもよく;
環Bは、フェニル基または5~6員の単環式ヘテロアリール基を表し、環Bにおける当該フェニル基またはヘテロアリール基は、それぞれ、1~4個のR2で置換されていてもよく;
Lは、C3~8シクロアルキル基、C1~6アルコキシル基、ハロゲン化C1~6アルコキシル基、フェニル基または5~6員の単環式ヘテロアリール基を表し、Lにおける当該フェニル基またはヘテロアリール基は、それぞれ、1~5個のR3で置換されていてもよく、または、LとR2が環B上で互いに隣接する置換基である場合、Lは、R2と結合し、環Bの一部とともに縮合環基を形成してもよく、当該縮合環基は、ハロゲン原子で置換されていてもよい5~7員の単環式非芳香族複素環基である、
化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。
上記式(I)の化合物において、より好ましくは、nは2である。
上記式(I)の化合物において、環A、環B、L、R1、R2、R3、Ra、Rb及び置換基RIの定義および好ましい範囲は、上記態様[1-2]~[1-6]で上述したとおりである。 [2] In the compound of the above formula (I) of the above embodiment [1], or a pharmaceutically acceptable salt thereof or a solvate thereof, a preferred embodiment is represented by the formula (I):
Ring A represents a phenyl group or a 5- to 10-membered heteroaryl group, and the phenyl group or heteroaryl group in Ring A may each be substituted with 1 to 5 R 1 ;
Ring B represents a phenyl group or a 5- to 6-membered monocyclic heteroaryl group, and the phenyl group or heteroaryl group in Ring B may each be substituted with 1 to 4 R 2 ;
L is, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxyl group, a halogenated C 1 ~ 6 alkoxy group, a monocyclic heteroaryl group phenyl group or a 5-6-membered, or the phenyl group in L Each heteroaryl group may be substituted with 1 to 5 R 3 , or when L and R 2 are substituents adjacent to each other on ring B, L is bonded to R 2. A condensed ring group may be formed together with a part of ring B, and the condensed ring group is a 5- to 7-membered monocyclic non-aromatic heterocyclic group which may be substituted with a halogen atom.
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (I), more preferably, n is 2.
In the compound of the above formula (I), the definition and preferred range of ring A, ring B, L, R 1 , R 2 , R 3 , R a , R b and substituent RI are as described in the above embodiments [1-2] to As described above in [1-6].
環Aは、フェニル基または5~10員ヘテロアリール基を表し、環Aにおける前記フェニル基またはヘテロアリール基は、それぞれ、1~5個のR1で置換されていてもよく;
環Bは、フェニル基または5~6員の単環式ヘテロアリール基を表し、環Bにおける当該フェニル基またはヘテロアリール基は、それぞれ、1~4個のR2で置換されていてもよく;
Lは、C3~8シクロアルキル基、C1~6アルコキシル基、ハロゲン化C1~6アルコキシル基、フェニル基または5~6員の単環式ヘテロアリール基を表し、Lにおける当該フェニル基またはヘテロアリール基は、それぞれ、1~5個のR3で置換されていてもよく、または、LとR2が環B上で互いに隣接する置換基である場合、Lは、R2と結合し、環Bの一部とともに縮合環基を形成してもよく、当該縮合環基は、ハロゲン原子で置換されていてもよい5~7員の単環式非芳香族複素環基である、
化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。
上記式(I)の化合物において、より好ましくは、nは2である。
上記式(I)の化合物において、環A、環B、L、R1、R2、R3、Ra、Rb及び置換基RIの定義および好ましい範囲は、上記態様[1-2]~[1-6]で上述したとおりである。 [2] In the compound of the above formula (I) of the above embodiment [1], or a pharmaceutically acceptable salt thereof or a solvate thereof, a preferred embodiment is represented by the formula (I):
Ring A represents a phenyl group or a 5- to 10-membered heteroaryl group, and the phenyl group or heteroaryl group in Ring A may each be substituted with 1 to 5 R 1 ;
Ring B represents a phenyl group or a 5- to 6-membered monocyclic heteroaryl group, and the phenyl group or heteroaryl group in Ring B may each be substituted with 1 to 4 R 2 ;
L is, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxyl group, a halogenated C 1 ~ 6 alkoxy group, a monocyclic heteroaryl group phenyl group or a 5-6-membered, or the phenyl group in L Each heteroaryl group may be substituted with 1 to 5 R 3 , or when L and R 2 are substituents adjacent to each other on ring B, L is bonded to R 2. A condensed ring group may be formed together with a part of ring B, and the condensed ring group is a 5- to 7-membered monocyclic non-aromatic heterocyclic group which may be substituted with a halogen atom.
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (I), more preferably, n is 2.
In the compound of the above formula (I), the definition and preferred range of ring A, ring B, L, R 1 , R 2 , R 3 , R a , R b and substituent RI are as described in the above embodiments [1-2] to As described above in [1-6].
[2-1] 前記態様[1]の前記式(I)の化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物において、好ましい別の態様は、下記式(I)-1:
(式(I)-1中、n、R1、R2、R3、Ra、Rb及び置換基RIの定義は上記態様[1]中の定義と同じであり;
環Aは、フェニル基または5~10員ヘテロアリール基を表し、環Aにおける前記フェニル基またはヘテロアリール基は、それぞれ、1~5個のR1で置換されていてもよく;
環Bは、フェニル基または5~6員の単環式ヘテロアリール基を表し、環Bにおける当該フェニル基またはヘテロアリール基は、それぞれ、1~4個のR2で置換されていてもよく;
Lは、C3~8シクロアルキル基、C1~6アルコキシル基、ハロゲン化C1~6アルコキシル基、フェニル基または5~6員の単環式ヘテロアリール基を表し、Lにおける当該フェニル基またはヘテロアリール基は、それぞれ、1~5個のR3で置換されていてもよく、または、LとR2が環B上で互いに隣接する置換基である場合、Lは、R2と結合し、環Bの一部とともに縮合環基を形成してもよく、当該縮合環基は、ハロゲン原子で置換されていてもよい5~7員の単環式非芳香族複素環基であり、環B上においてLは環A-ビシクロ環-CO-の結合位置に隣接する置換基である)で表される、
化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。
上記式(I)-1の化合物において、nは好ましくは2である。
上記式(I)-1の化合物において、環A、環B、L、R1、R2、R3、Ra、Rb及び置換基RIの定義および好ましい範囲は、上記態様[1-2]~[1-6]で上述したとおりである。 [2-1] In the compound of the above formula (I) of the above embodiment [1], or a pharmaceutically acceptable salt or solvate thereof, another preferred embodiment is represented by the following formula (I) -1 :
(In the formula (I) -1, the definitions of n, R 1 , R 2 , R 3 , R a , R b and the substituent RI are the same as those defined in the above embodiment [1];
Ring A represents a phenyl group or a 5- to 10-membered heteroaryl group, and the phenyl group or heteroaryl group in Ring A may each be substituted with 1 to 5 R 1 ;
Ring B represents a phenyl group or a 5- to 6-membered monocyclic heteroaryl group, and the phenyl group or heteroaryl group in Ring B may each be substituted with 1 to 4 R 2 ;
L is, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxyl group, a halogenated C 1 ~ 6 alkoxy group, a monocyclic heteroaryl group phenyl group or a 5-6-membered, or the phenyl group in L Each heteroaryl group may be substituted with 1 to 5 R 3 , or when L and R 2 are substituents adjacent to each other on ring B, L is bonded to R 2. A condensed ring group may be formed together with a part of ring B, and the condensed ring group is a 5- to 7-membered monocyclic non-aromatic heterocyclic group which may be substituted with a halogen atom, L on B is a substituent adjacent to the bonding position of ring A-bicycloring-CO-).
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (I) -1, n is preferably 2.
In the compound of the formula (I) -1, the definition and preferred range of the ring A, ring B, L, R 1 , R 2 , R 3 , R a , R b and the substituent RI are as defined in the above embodiment [1-2 ] To [1-6] as described above.
(式(I)-1中、n、R1、R2、R3、Ra、Rb及び置換基RIの定義は上記態様[1]中の定義と同じであり;
環Aは、フェニル基または5~10員ヘテロアリール基を表し、環Aにおける前記フェニル基またはヘテロアリール基は、それぞれ、1~5個のR1で置換されていてもよく;
環Bは、フェニル基または5~6員の単環式ヘテロアリール基を表し、環Bにおける当該フェニル基またはヘテロアリール基は、それぞれ、1~4個のR2で置換されていてもよく;
Lは、C3~8シクロアルキル基、C1~6アルコキシル基、ハロゲン化C1~6アルコキシル基、フェニル基または5~6員の単環式ヘテロアリール基を表し、Lにおける当該フェニル基またはヘテロアリール基は、それぞれ、1~5個のR3で置換されていてもよく、または、LとR2が環B上で互いに隣接する置換基である場合、Lは、R2と結合し、環Bの一部とともに縮合環基を形成してもよく、当該縮合環基は、ハロゲン原子で置換されていてもよい5~7員の単環式非芳香族複素環基であり、環B上においてLは環A-ビシクロ環-CO-の結合位置に隣接する置換基である)で表される、
化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。
上記式(I)-1の化合物において、nは好ましくは2である。
上記式(I)-1の化合物において、環A、環B、L、R1、R2、R3、Ra、Rb及び置換基RIの定義および好ましい範囲は、上記態様[1-2]~[1-6]で上述したとおりである。 [2-1] In the compound of the above formula (I) of the above embodiment [1], or a pharmaceutically acceptable salt or solvate thereof, another preferred embodiment is represented by the following formula (I) -1 :
(In the formula (I) -1, the definitions of n, R 1 , R 2 , R 3 , R a , R b and the substituent RI are the same as those defined in the above embodiment [1];
Ring A represents a phenyl group or a 5- to 10-membered heteroaryl group, and the phenyl group or heteroaryl group in Ring A may each be substituted with 1 to 5 R 1 ;
Ring B represents a phenyl group or a 5- to 6-membered monocyclic heteroaryl group, and the phenyl group or heteroaryl group in Ring B may each be substituted with 1 to 4 R 2 ;
L is, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxyl group, a halogenated C 1 ~ 6 alkoxy group, a monocyclic heteroaryl group phenyl group or a 5-6-membered, or the phenyl group in L Each heteroaryl group may be substituted with 1 to 5 R 3 , or when L and R 2 are substituents adjacent to each other on ring B, L is bonded to R 2. A condensed ring group may be formed together with a part of ring B, and the condensed ring group is a 5- to 7-membered monocyclic non-aromatic heterocyclic group which may be substituted with a halogen atom, L on B is a substituent adjacent to the bonding position of ring A-bicycloring-CO-).
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (I) -1, n is preferably 2.
In the compound of the formula (I) -1, the definition and preferred range of the ring A, ring B, L, R 1 , R 2 , R 3 , R a , R b and the substituent RI are as defined in the above embodiment [1-2 ] To [1-6] as described above.
[3] 前記態様[1]の前記式(I)の化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物において、より好ましい態様は、式(I)中、環Aは、下記部分構造式(a1)、(a2)、(a3)または(a4):
(式(a1)、(a2)、(a3)または(a4)中、
環A1は、隣接するピリジン環とともに9~10員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成し、前記環A1は1~2個のハロゲン原子で置換されていてもよく、
環A2は、隣接するピラゾール環とともに8~9員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成し、前記環A2は1~2個のハロゲン原子で置換されていてもよく、
環A3は、隣接するイミダゾール環とともに8~9員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成し、前記環A3は1~2個のハロゲン原子で置換されていてもよく、
X1は、窒素原子、C-HまたはC-R1aを表し、
X2は、窒素原子、C-HまたはC-R1dを表し、但し、X1が窒素原子の場合は、X2はC-HまたはC-R1dであり、
R1aは、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~7アルカノイル基またはシアノ基を表し、
R1b及びR1cは、各々独立に、水素原子またはC1~6アルキル基を表し、
R1dは、ハロゲン原子、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C1~6アルキルチオ基、-NRaRb基またはオキソ基を表し、但し、R1dがオキソ基の場合は、X1はC1~6アルキル基で置換されていてもよい窒素原子であり、
R1e及びR1fは、各々独立に、水素原子またはC1~6アルキル基を表し、
R1a、R1b、R1c、R1d、R1e及びR1fにおける前記アルキル基、シクロアルキル基、アルコキシル基、アルカノイル基またはアルキルチオ基は、それぞれ、1~5個の置換基RIで置換されていてもよい)を表し、
環Bは、フェニル基または5~6員ヘテロアリール基を表し、環Bにおける前記フェニル基またはヘテロアリール基は、それぞれ、1個のR2で置換されていてもよく、
Lは、フェニル基または5~6員ヘテロアリール基を表し、Lにおける前記フェニル基またはヘテロアリール基は、それぞれ、1個のR3で置換されていてもよい、
化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。
上記式(I)の化合物において、より好ましくは、nは2である。
上記式(I)の化合物において、環A、環A1、環A2、環A3、X1、X2、環B、L、R1、R1a、R1b、R1c、R1d、R1e、R1f、R2、R3、Ra、Rb及び置換基RIの定義および好ましい範囲は、上記態様[1-2]~[1-6]で上述したとおりである。 [3] In the compound of the above formula (I) of the above embodiment [1], or a pharmaceutically acceptable salt or solvate thereof, a more preferred embodiment is that in the formula (I), the ring A is The following partial structural formula (a1), (a2), (a3) or (a4):
(In the formula (a1), (a2), (a3) or (a4),
Ring A1 together with the adjacent pyridine ring forms a 9-10 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A1 is composed of 1 to 2 halogen atoms May be replaced,
Ring A2 together with the adjacent pyrazole ring forms an 8-9 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A2 is composed of 1 to 2 halogen atoms May be replaced,
Ring A3 together with the adjacent imidazole ring forms an 8-9 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A3 is composed of 1 to 2 halogen atoms May be replaced,
X 1 represents a nitrogen atom, C—H or C—R 1a ,
X 2 represents a nitrogen atom, C—H or C—R 1d , provided that when X 1 is a nitrogen atom, X 2 is C—H or C—R 1d ,
R 1a represents C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, a C 2 ~ 7 alkanoyl group or a cyano group,
R 1b and R 1c each independently represents a hydrogen atom or a C 1-6 alkyl group,
R 1d represents a halogen atom, C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 1 ~ 6 alkylthio group, a -NR a R b group or an oxo group, provided that, When R 1d is an oxo group, X 1 is a nitrogen atom which may be substituted with a C 1-6 alkyl group,
R 1e and R 1f each independently represents a hydrogen atom or a C 1-6 alkyl group,
The alkyl group, cycloalkyl group, alkoxyl group, alkanoyl group or alkylthio group in R 1a , R 1b , R 1c , R 1d , R 1e and R 1f is each substituted with 1 to 5 substituents RI. May represent)
Ring B represents a phenyl group or a 5- to 6-membered heteroaryl group, and each of the phenyl group or heteroaryl group in Ring B may be substituted with one R 2 ,
L represents a phenyl group or a 5- to 6-membered heteroaryl group, and each of the phenyl group or heteroaryl group in L may be substituted with one R 3 .
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (I), more preferably, n is 2.
In the compounds of the formula (I), ring A, ring A1, ring A2, ring A3, X 1, X 2, ring B, L, R 1, R 1a, R 1b, R 1c, R 1d, R 1e, The definitions and preferred ranges of R 1f , R 2 , R 3 , R a , R b and the substituent RI are as described above in the above embodiments [1-2] to [1-6].
(式(a1)、(a2)、(a3)または(a4)中、
環A1は、隣接するピリジン環とともに9~10員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成し、前記環A1は1~2個のハロゲン原子で置換されていてもよく、
環A2は、隣接するピラゾール環とともに8~9員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成し、前記環A2は1~2個のハロゲン原子で置換されていてもよく、
環A3は、隣接するイミダゾール環とともに8~9員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成し、前記環A3は1~2個のハロゲン原子で置換されていてもよく、
X1は、窒素原子、C-HまたはC-R1aを表し、
X2は、窒素原子、C-HまたはC-R1dを表し、但し、X1が窒素原子の場合は、X2はC-HまたはC-R1dであり、
R1aは、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~7アルカノイル基またはシアノ基を表し、
R1b及びR1cは、各々独立に、水素原子またはC1~6アルキル基を表し、
R1dは、ハロゲン原子、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C1~6アルキルチオ基、-NRaRb基またはオキソ基を表し、但し、R1dがオキソ基の場合は、X1はC1~6アルキル基で置換されていてもよい窒素原子であり、
R1e及びR1fは、各々独立に、水素原子またはC1~6アルキル基を表し、
R1a、R1b、R1c、R1d、R1e及びR1fにおける前記アルキル基、シクロアルキル基、アルコキシル基、アルカノイル基またはアルキルチオ基は、それぞれ、1~5個の置換基RIで置換されていてもよい)を表し、
環Bは、フェニル基または5~6員ヘテロアリール基を表し、環Bにおける前記フェニル基またはヘテロアリール基は、それぞれ、1個のR2で置換されていてもよく、
Lは、フェニル基または5~6員ヘテロアリール基を表し、Lにおける前記フェニル基またはヘテロアリール基は、それぞれ、1個のR3で置換されていてもよい、
化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。
上記式(I)の化合物において、より好ましくは、nは2である。
上記式(I)の化合物において、環A、環A1、環A2、環A3、X1、X2、環B、L、R1、R1a、R1b、R1c、R1d、R1e、R1f、R2、R3、Ra、Rb及び置換基RIの定義および好ましい範囲は、上記態様[1-2]~[1-6]で上述したとおりである。 [3] In the compound of the above formula (I) of the above embodiment [1], or a pharmaceutically acceptable salt or solvate thereof, a more preferred embodiment is that in the formula (I), the ring A is The following partial structural formula (a1), (a2), (a3) or (a4):
(In the formula (a1), (a2), (a3) or (a4),
Ring A1 together with the adjacent pyridine ring forms a 9-10 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A1 is composed of 1 to 2 halogen atoms May be replaced,
Ring A2 together with the adjacent pyrazole ring forms an 8-9 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A2 is composed of 1 to 2 halogen atoms May be replaced,
Ring A3 together with the adjacent imidazole ring forms an 8-9 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A3 is composed of 1 to 2 halogen atoms May be replaced,
X 1 represents a nitrogen atom, C—H or C—R 1a ,
X 2 represents a nitrogen atom, C—H or C—R 1d , provided that when X 1 is a nitrogen atom, X 2 is C—H or C—R 1d ,
R 1a represents C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, a C 2 ~ 7 alkanoyl group or a cyano group,
R 1b and R 1c each independently represents a hydrogen atom or a C 1-6 alkyl group,
R 1d represents a halogen atom, C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 1 ~ 6 alkylthio group, a -NR a R b group or an oxo group, provided that, When R 1d is an oxo group, X 1 is a nitrogen atom which may be substituted with a C 1-6 alkyl group,
R 1e and R 1f each independently represents a hydrogen atom or a C 1-6 alkyl group,
The alkyl group, cycloalkyl group, alkoxyl group, alkanoyl group or alkylthio group in R 1a , R 1b , R 1c , R 1d , R 1e and R 1f is each substituted with 1 to 5 substituents RI. May represent)
Ring B represents a phenyl group or a 5- to 6-membered heteroaryl group, and each of the phenyl group or heteroaryl group in Ring B may be substituted with one R 2 ,
L represents a phenyl group or a 5- to 6-membered heteroaryl group, and each of the phenyl group or heteroaryl group in L may be substituted with one R 3 .
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (I), more preferably, n is 2.
In the compounds of the formula (I), ring A, ring A1, ring A2, ring A3, X 1, X 2, ring B, L, R 1, R 1a, R 1b, R 1c, R 1d, R 1e, The definitions and preferred ranges of R 1f , R 2 , R 3 , R a , R b and the substituent RI are as described above in the above embodiments [1-2] to [1-6].
[3-1]前記態様[1]の前記式(I)の化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物において、より好ましい別の態様は、下記式(II):
(式(II)中、n、R2、R3、Ra及びRbの定義は上記態様[1]中の定義と同じであり、
環Aは、下記部分構造式(a1)、(a2)、(a3)または(a4):
(式(a1)、(a2)、(a3)または(a4)中、
環A1は、隣接するピリジン環とともに9~10員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成し、前記環A1は1~2個のハロゲン原子で置換されていてもよく、
環A2は、隣接するピラゾール環とともに8~9員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成し、前記環A2は1~2個のハロゲン原子で置換されていてもよく、
環A3は、隣接するイミダゾール環とともに8~9員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成し、前記環A3は1~2個のハロゲン原子で置換されていてもよく、
X1は、窒素原子、C-HまたはC-R1aを表し、
X2は、窒素原子、C-HまたはC-R1dを表し、但し、X1が窒素原子の場合は、X2はC-HまたはC-R1dであり、
R1aは、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~7アルカノイル基またはシアノ基を表し、さらにR1aは、好ましくはC1~4アルキル基、C3~6シクロアルキル基、C1~4アルコキシル基、C2~5アルカノイル基またはシアノ基であり、より好ましくはC1~2アルキル基、C3~4シクロアルキル基、C1~2アルコキシル基、C2~3アルカノイル基またはシアノ基であり、更に好ましくはC1~2アルキル基またはシアノ基であり、
R1b及びR1cは、各々独立に、水素原子またはC1~6アルキル基を表し、さらにR1b及びR1cは、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であり、更に好ましくはR1bは水素原子でありR1cは水素原子またはC1~2アルキル基であり、
R1dは、ハロゲン原子、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C1~6アルキルチオ基、-NRaRb基またはオキソ基を表し、さらにR1dは、好ましくはハロゲン原子、C1~4アルキル基、C3~6シクロアルキル基、C1~4アルコキシル基、C1~4アルキルチオ基、-NRaRb基またはオキソ基であり、より好ましくはハロゲン原子、C1~2アルキル基、C3~4シクロアルキル基、C1~2アルコキシル基、C1~2アルキルチオ基、-NRaRb基またはオキソ基であり、更に好ましくはC1~2アルコキシル基であり、但し、R1dがオキソ基の場合は、X1はC1~6アルキル基で置換されていてもよい窒素原子であり、
R1e及びR1fは、各々独立に、水素原子またはC1~6アルキル基を表し、さらにR1e及びR1fは、各々独立に、好ましくはC1~4アルキル基であり、より好ましくはC1~2アルキル基であり、
R1a、R1b、R1c、R1d、R1e及びR1fにおける前記アルキル基、シクロアルキル基、アルコキシル基、アルカノイル基またはアルキルチオ基は、それぞれ、1~5個の置換基RIで置換されていてもよい)を表し、
環Bは、フェニル基または5~6員ヘテロアリール基を表し、環Bにおける前記フェニル基またはヘテロアリール基は、それぞれ、1個のR2で置換されていてもよく、
環Cは、フェニル基または5~6員ヘテロアリール基を表し、環Cにおける前記フェニル基またはヘテロアリール基は、それぞれ、1個のR3で置換されていてもよく、
環B上において環Cは環A-ビシクロ環-CO-の結合位置に隣接する置換基である、
化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。
上記式(II)の化合物において、nは好ましくは2である。
上記式(II)の化合物において、環A、環A1、環A2、環A3、X1、X2、環B、R1、R1a、R1b、R1c、R1d、R1e、R1f、R2、R3、Ra、Rb及び置換基RIの定義および好ましい範囲は、上記態様[1-2]~[1-6]で上述したとおりである。 [3-1] In the compound of the above formula (I) of the above embodiment [1], or a pharmaceutically acceptable salt thereof or a solvate thereof, another more preferable embodiment is represented by the following formula (II):
(In the formula (II), the definitions of n, R 2 , R 3 , R a and R b are the same as defined in the above embodiment [1];
Ring A has the following partial structural formula (a1), (a2), (a3) or (a4):
(In the formula (a1), (a2), (a3) or (a4),
Ring A1 together with the adjacent pyridine ring forms a 9-10 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A1 is composed of 1 to 2 halogen atoms May be replaced,
Ring A2 together with the adjacent pyrazole ring forms an 8-9 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A2 is composed of 1 to 2 halogen atoms May be replaced,
Ring A3 together with the adjacent imidazole ring forms an 8-9 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A3 is composed of 1 to 2 halogen atoms May be replaced,
X 1 represents a nitrogen atom, C—H or C—R 1a ,
X 2 represents a nitrogen atom, C—H or C—R 1d , provided that when X 1 is a nitrogen atom, X 2 is C—H or C—R 1d ,
R 1a represents C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, a C 2 ~ 7 alkanoyl group or a cyano group, further R 1a is preferably C 1 ~ 4 alkyl group, C 3 ~ 6 cycloalkyl group, C 1 ~ 4 alkoxyl group, a C 2 ~ 5 alkanoyl group or a cyano group, more preferably C 1 ~ 2 alkyl group, C 3 ~ 4 cycloalkyl group, C 1 ~ A 2 alkoxyl group, a C 2-3 alkanoyl group or a cyano group, more preferably a C 1-2 alkyl group or a cyano group,
R 1b and R 1c each independently represents a hydrogen atom or a C 1-6 alkyl group, and R 1b and R 1c are preferably a hydrogen atom or a C 1-4 alkyl group, more preferably a hydrogen atom. Or a C 1-2 alkyl group, more preferably R 1b is a hydrogen atom, R 1c is a hydrogen atom or a C 1-2 alkyl group,
R 1d represents a halogen atom, C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 1 ~ 6 alkylthio group, a -NR a R b group or an oxo group, further R 1d is preferably a halogen atom, C 1 ~ 4 alkyl group, C 3 ~ 6 cycloalkyl group, C 1 ~ 4 alkoxyl group, C 1 ~ 4 alkylthio group, -NR a R b group or an oxo group, more Preferred are a halogen atom, a C 1-2 alkyl group, a C 3-4 cycloalkyl group, a C 1-2 alkoxyl group, a C 1-2 alkylthio group, a —NR a R b group or an oxo group, and more preferred is C 1 to 2 alkoxyl group, provided that when R 1d is an oxo group, X 1 is a nitrogen atom which may be substituted with a C 1-6 alkyl group;
R 1e and R 1f each independently represents a hydrogen atom or a C 1-6 alkyl group, and R 1e and R 1f are each independently preferably a C 1-4 alkyl group, more preferably C 1 1 to 2 alkyl groups,
The alkyl group, cycloalkyl group, alkoxyl group, alkanoyl group or alkylthio group in R 1a , R 1b , R 1c , R 1d , R 1e and R 1f is each substituted with 1 to 5 substituents RI. May represent)
Ring B represents a phenyl group or a 5- to 6-membered heteroaryl group, and each of the phenyl group or heteroaryl group in Ring B may be substituted with one R 2 ,
Ring C represents a phenyl group or a 5- to 6-membered heteroaryl group, and each of the phenyl group or heteroaryl group in Ring C may be substituted with one R 3 ,
On ring B, ring C is a substituent adjacent to the bonding position of ring A-bicycloring-CO—.
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (II), n is preferably 2.
In the compounds of above-mentioned formula (II), ring A, ring A1, ring A2, ring A3, X 1, X 2, ring B, R 1, R 1a, R 1b, R 1c, R 1d, R 1e, R 1f , R 2 , R 3 , R a , R b and the substituent RI are as defined above and in the preferred embodiments [1-2] to [1-6].
(式(II)中、n、R2、R3、Ra及びRbの定義は上記態様[1]中の定義と同じであり、
環Aは、下記部分構造式(a1)、(a2)、(a3)または(a4):
(式(a1)、(a2)、(a3)または(a4)中、
環A1は、隣接するピリジン環とともに9~10員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成し、前記環A1は1~2個のハロゲン原子で置換されていてもよく、
環A2は、隣接するピラゾール環とともに8~9員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成し、前記環A2は1~2個のハロゲン原子で置換されていてもよく、
環A3は、隣接するイミダゾール環とともに8~9員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成し、前記環A3は1~2個のハロゲン原子で置換されていてもよく、
X1は、窒素原子、C-HまたはC-R1aを表し、
X2は、窒素原子、C-HまたはC-R1dを表し、但し、X1が窒素原子の場合は、X2はC-HまたはC-R1dであり、
R1aは、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~7アルカノイル基またはシアノ基を表し、さらにR1aは、好ましくはC1~4アルキル基、C3~6シクロアルキル基、C1~4アルコキシル基、C2~5アルカノイル基またはシアノ基であり、より好ましくはC1~2アルキル基、C3~4シクロアルキル基、C1~2アルコキシル基、C2~3アルカノイル基またはシアノ基であり、更に好ましくはC1~2アルキル基またはシアノ基であり、
R1b及びR1cは、各々独立に、水素原子またはC1~6アルキル基を表し、さらにR1b及びR1cは、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であり、更に好ましくはR1bは水素原子でありR1cは水素原子またはC1~2アルキル基であり、
R1dは、ハロゲン原子、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C1~6アルキルチオ基、-NRaRb基またはオキソ基を表し、さらにR1dは、好ましくはハロゲン原子、C1~4アルキル基、C3~6シクロアルキル基、C1~4アルコキシル基、C1~4アルキルチオ基、-NRaRb基またはオキソ基であり、より好ましくはハロゲン原子、C1~2アルキル基、C3~4シクロアルキル基、C1~2アルコキシル基、C1~2アルキルチオ基、-NRaRb基またはオキソ基であり、更に好ましくはC1~2アルコキシル基であり、但し、R1dがオキソ基の場合は、X1はC1~6アルキル基で置換されていてもよい窒素原子であり、
R1e及びR1fは、各々独立に、水素原子またはC1~6アルキル基を表し、さらにR1e及びR1fは、各々独立に、好ましくはC1~4アルキル基であり、より好ましくはC1~2アルキル基であり、
R1a、R1b、R1c、R1d、R1e及びR1fにおける前記アルキル基、シクロアルキル基、アルコキシル基、アルカノイル基またはアルキルチオ基は、それぞれ、1~5個の置換基RIで置換されていてもよい)を表し、
環Bは、フェニル基または5~6員ヘテロアリール基を表し、環Bにおける前記フェニル基またはヘテロアリール基は、それぞれ、1個のR2で置換されていてもよく、
環Cは、フェニル基または5~6員ヘテロアリール基を表し、環Cにおける前記フェニル基またはヘテロアリール基は、それぞれ、1個のR3で置換されていてもよく、
環B上において環Cは環A-ビシクロ環-CO-の結合位置に隣接する置換基である、
化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。
上記式(II)の化合物において、nは好ましくは2である。
上記式(II)の化合物において、環A、環A1、環A2、環A3、X1、X2、環B、R1、R1a、R1b、R1c、R1d、R1e、R1f、R2、R3、Ra、Rb及び置換基RIの定義および好ましい範囲は、上記態様[1-2]~[1-6]で上述したとおりである。 [3-1] In the compound of the above formula (I) of the above embodiment [1], or a pharmaceutically acceptable salt thereof or a solvate thereof, another more preferable embodiment is represented by the following formula (II):
(In the formula (II), the definitions of n, R 2 , R 3 , R a and R b are the same as defined in the above embodiment [1];
Ring A has the following partial structural formula (a1), (a2), (a3) or (a4):
(In the formula (a1), (a2), (a3) or (a4),
Ring A1 together with the adjacent pyridine ring forms a 9-10 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A1 is composed of 1 to 2 halogen atoms May be replaced,
Ring A2 together with the adjacent pyrazole ring forms an 8-9 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A2 is composed of 1 to 2 halogen atoms May be replaced,
Ring A3 together with the adjacent imidazole ring forms an 8-9 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A3 is composed of 1 to 2 halogen atoms May be replaced,
X 1 represents a nitrogen atom, C—H or C—R 1a ,
X 2 represents a nitrogen atom, C—H or C—R 1d , provided that when X 1 is a nitrogen atom, X 2 is C—H or C—R 1d ,
R 1a represents C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, a C 2 ~ 7 alkanoyl group or a cyano group, further R 1a is preferably C 1 ~ 4 alkyl group, C 3 ~ 6 cycloalkyl group, C 1 ~ 4 alkoxyl group, a C 2 ~ 5 alkanoyl group or a cyano group, more preferably C 1 ~ 2 alkyl group, C 3 ~ 4 cycloalkyl group, C 1 ~ A 2 alkoxyl group, a C 2-3 alkanoyl group or a cyano group, more preferably a C 1-2 alkyl group or a cyano group,
R 1b and R 1c each independently represents a hydrogen atom or a C 1-6 alkyl group, and R 1b and R 1c are preferably a hydrogen atom or a C 1-4 alkyl group, more preferably a hydrogen atom. Or a C 1-2 alkyl group, more preferably R 1b is a hydrogen atom, R 1c is a hydrogen atom or a C 1-2 alkyl group,
R 1d represents a halogen atom, C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 1 ~ 6 alkylthio group, a -NR a R b group or an oxo group, further R 1d is preferably a halogen atom, C 1 ~ 4 alkyl group, C 3 ~ 6 cycloalkyl group, C 1 ~ 4 alkoxyl group, C 1 ~ 4 alkylthio group, -NR a R b group or an oxo group, more Preferred are a halogen atom, a C 1-2 alkyl group, a C 3-4 cycloalkyl group, a C 1-2 alkoxyl group, a C 1-2 alkylthio group, a —NR a R b group or an oxo group, and more preferred is C 1 to 2 alkoxyl group, provided that when R 1d is an oxo group, X 1 is a nitrogen atom which may be substituted with a C 1-6 alkyl group;
R 1e and R 1f each independently represents a hydrogen atom or a C 1-6 alkyl group, and R 1e and R 1f are each independently preferably a C 1-4 alkyl group, more preferably C 1 1 to 2 alkyl groups,
The alkyl group, cycloalkyl group, alkoxyl group, alkanoyl group or alkylthio group in R 1a , R 1b , R 1c , R 1d , R 1e and R 1f is each substituted with 1 to 5 substituents RI. May represent)
Ring B represents a phenyl group or a 5- to 6-membered heteroaryl group, and each of the phenyl group or heteroaryl group in Ring B may be substituted with one R 2 ,
Ring C represents a phenyl group or a 5- to 6-membered heteroaryl group, and each of the phenyl group or heteroaryl group in Ring C may be substituted with one R 3 ,
On ring B, ring C is a substituent adjacent to the bonding position of ring A-bicycloring-CO—.
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (II), n is preferably 2.
In the compounds of above-mentioned formula (II), ring A, ring A1, ring A2, ring A3, X 1, X 2, ring B, R 1, R 1a, R 1b, R 1c, R 1d, R 1e, R 1f , R 2 , R 3 , R a , R b and the substituent RI are as defined above and in the preferred embodiments [1-2] to [1-6].
[4] 前記態様[3]の前記式(I)の化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物において、さらに好ましい態様は、式(I)中、環Aは、前記部分構造式(a1)であり、ここでX1はC-R1aであり、X2は窒素原子、C-HまたはC-R1dであり、R1dは、ハロゲン原子、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C1~6アルキルチオ基または-NRaRb基を表し、;
環Bは、下記部分構造式(b1)または(b2):
(式(b1)または(b2)中、
Yは、窒素原子、C-HまたはC-R2bを表し、
R2aは、水素原子、ハロゲン原子、C1~6アルキル基、C1~6アルコキシル基または単環式ヘテロアリール基を表し、但し、YがC-R2bの場合は、R2aは水素原子であり、
R2bは、ハロゲン原子を表し、
R2cは、水素原子、C1~6アルキル基またはシアノ基を表し、
R2a及びR2cにおける前記アルキル基、アルコキシル基は、それぞれ、1~5個の置換基RIで置換されていてもよい)を表し;
R3は、C1~6アルキル基、C1~6アルコキシル基またはシアノ基を表し、ここでR3における前記アルキル基またはアルコキシル基は、それぞれ、1~5個の置換基RIで置換されていてもよく;
Ra及びRbは、各々独立に、C1~6アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよく、RaおよびRbにおける前記単環式非芳香族複素環基は、その環内の炭素原子の少なくとも1個が、酸素原子、硫黄原子及びC1~6アルキル基で置換されていてもよい窒素原子から任意に選ばれる原子で置き換えられていてもよい、
化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。
上記式(I)の化合物において、より好ましくは、nは2である。
上記式(I)の化合物において、環A、X1、X2、環B、Y、L、R1、R1a、R1b、R1c、R1d、R2、R2a、R2b、R2c、R3、Ra、Rb及び置換基RIの定義および好ましい範囲は、上記態様[1-2]~[1-6]で上述したとおりである。 [4] In the compound of the above formula (I) of the above embodiment [3], or a pharmaceutically acceptable salt or solvate thereof, a further preferred embodiment is that in the formula (I), the ring A is In the partial structural formula (a1), X 1 is C—R 1a , X 2 is a nitrogen atom, C—H or C—R 1d , R 1d is a halogen atom, C 1-6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 1 ~ 6 alkylthio group or -NR a R b group;
Ring B has the following partial structural formula (b1) or (b2):
(In the formula (b1) or (b2),
Y represents a nitrogen atom, C—H or C—R 2b ,
R 2a represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxyl group or a monocyclic heteroaryl group, provided that when Y is C—R 2b , R 2a is a hydrogen atom And
R 2b represents a halogen atom,
R 2c represents a hydrogen atom, a C 1-6 alkyl group or a cyano group,
Each of the alkyl group and alkoxyl group in R 2a and R 2c may be substituted with 1 to 5 substituents RI;
R 3 represents a C 1-6 alkyl group, a C 1-6 alkoxyl group or a cyano group, wherein the alkyl group or alkoxyl group in R 3 is each substituted with 1 to 5 substituents RI. May be;
R a and R b each independently represent a C 1-6 alkyl group, R a and R b together with the nitrogen atom to which they are attached may form a monocyclic non-aromatic heterocyclic group; The monocyclic non-aromatic heterocyclic group for R a and R b is a nitrogen in which at least one of the carbon atoms in the ring may be substituted with an oxygen atom, a sulfur atom and a C 1-6 alkyl group It may be replaced with an atom arbitrarily selected from atoms,
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (I), more preferably, n is 2.
In the compound of the above formula (I), ring A, X 1 , X 2 , ring B, Y, L, R 1 , R 1a , R 1b , R 1c , R 1d , R 2 , R 2a , R 2b , R The definitions and preferred ranges of 2c , R 3 , R a , R b and the substituent RI are as described above in the above embodiments [1-2] to [1-6].
環Bは、下記部分構造式(b1)または(b2):
(式(b1)または(b2)中、
Yは、窒素原子、C-HまたはC-R2bを表し、
R2aは、水素原子、ハロゲン原子、C1~6アルキル基、C1~6アルコキシル基または単環式ヘテロアリール基を表し、但し、YがC-R2bの場合は、R2aは水素原子であり、
R2bは、ハロゲン原子を表し、
R2cは、水素原子、C1~6アルキル基またはシアノ基を表し、
R2a及びR2cにおける前記アルキル基、アルコキシル基は、それぞれ、1~5個の置換基RIで置換されていてもよい)を表し;
R3は、C1~6アルキル基、C1~6アルコキシル基またはシアノ基を表し、ここでR3における前記アルキル基またはアルコキシル基は、それぞれ、1~5個の置換基RIで置換されていてもよく;
Ra及びRbは、各々独立に、C1~6アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよく、RaおよびRbにおける前記単環式非芳香族複素環基は、その環内の炭素原子の少なくとも1個が、酸素原子、硫黄原子及びC1~6アルキル基で置換されていてもよい窒素原子から任意に選ばれる原子で置き換えられていてもよい、
化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。
上記式(I)の化合物において、より好ましくは、nは2である。
上記式(I)の化合物において、環A、X1、X2、環B、Y、L、R1、R1a、R1b、R1c、R1d、R2、R2a、R2b、R2c、R3、Ra、Rb及び置換基RIの定義および好ましい範囲は、上記態様[1-2]~[1-6]で上述したとおりである。 [4] In the compound of the above formula (I) of the above embodiment [3], or a pharmaceutically acceptable salt or solvate thereof, a further preferred embodiment is that in the formula (I), the ring A is In the partial structural formula (a1), X 1 is C—R 1a , X 2 is a nitrogen atom, C—H or C—R 1d , R 1d is a halogen atom, C 1-6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 1 ~ 6 alkylthio group or -NR a R b group;
Ring B has the following partial structural formula (b1) or (b2):
(In the formula (b1) or (b2),
Y represents a nitrogen atom, C—H or C—R 2b ,
R 2a represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxyl group or a monocyclic heteroaryl group, provided that when Y is C—R 2b , R 2a is a hydrogen atom And
R 2b represents a halogen atom,
R 2c represents a hydrogen atom, a C 1-6 alkyl group or a cyano group,
Each of the alkyl group and alkoxyl group in R 2a and R 2c may be substituted with 1 to 5 substituents RI;
R 3 represents a C 1-6 alkyl group, a C 1-6 alkoxyl group or a cyano group, wherein the alkyl group or alkoxyl group in R 3 is each substituted with 1 to 5 substituents RI. May be;
R a and R b each independently represent a C 1-6 alkyl group, R a and R b together with the nitrogen atom to which they are attached may form a monocyclic non-aromatic heterocyclic group; The monocyclic non-aromatic heterocyclic group for R a and R b is a nitrogen in which at least one of the carbon atoms in the ring may be substituted with an oxygen atom, a sulfur atom and a C 1-6 alkyl group It may be replaced with an atom arbitrarily selected from atoms,
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (I), more preferably, n is 2.
In the compound of the above formula (I), ring A, X 1 , X 2 , ring B, Y, L, R 1 , R 1a , R 1b , R 1c , R 1d , R 2 , R 2a , R 2b , R The definitions and preferred ranges of 2c , R 3 , R a , R b and the substituent RI are as described above in the above embodiments [1-2] to [1-6].
[4-1]前記態様[3]の前記式(I)の化合物もしくは前記態様[3-1]の前記式(II)の化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物において、さらに好ましい別の態様は、下記式(III):
(式(III)中、n、R3、Ra及びRbの定義は上記態様[1]中の定義と同じであり、環Cの定義は上記式(II)の定義と同じであり;
Xは窒素原子、C-HまたはC-R1dであり、
R1aは、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~7アルカノイル基またはシアノ基を表し、さらにR1aは、好ましくはC1~4アルキル基、C3~6シクロアルキル基、C1~4アルコキシル基、C2~5アルカノイル基またはシアノ基であり、より好ましくはC1~2アルキル基、C3~4シクロアルキル基、C1~2アルコキシル基、C2~3アルカノイル基またはシアノ基であり、更に好ましくはC1~2アルキル基またはシアノ基であり、
R1b及びR1cは、各々独立に、水素原子またはC1~6アルキル基を表し、さらにR1b及びR1cは、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であり、更に好ましくはR1bは水素原子でありR1cは水素原子またはC1~2アルキル基であり、
R1dは、ハロゲン原子、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C1~6アルキルチオ基または-NRaRb基を表し、さらにR1dは、好ましくはハロゲン原子、C1~4アルキル基、C3~6シクロアルキル基、C1~4アルコキシル基、C1~4アルキルチオ基または-NRaRb基であり、より好ましくはハロゲン原子、C1~2アルキル基、C3~4シクロアルキル基、C1~2アルコキシル基、C1~2アルキルチオ基または-NRaRb基であり、更に好ましくはC1~2アルコキシル基であり、
R1a、R1b、R1c及びR1dにおける当該アルキル基、シクロアルキル基、アルコキシル基、アルカノイル基またはアルキルチオ基は、それぞれ、1~5個の置換基RIで置換されていてもよく;
環Bは、下記部分構造式(b1)または(b2):
(式(b1)または(b2)中、
Yは、窒素原子、C-HまたはC-R2bを表し、
R2aは、水素原子、ハロゲン原子、C1~6アルキル基、C1~6アルコキシル基または単環式ヘテロアリール基を表し、当該R2aにおける当該単環式ヘテロアリール基は、好ましくはフェニル基又は5~6員ヘテロアリール基である環Cのパラ位に位置することが適当であり、当該R2aは、好ましくは水素原子、ハロゲン原子、C1~4アルキル基、C1~4アルコキシル基または5または6員のヘテロアリール基であり、より好ましくは水素原子、ハロゲン原子、C1~2アルキル基、C1~2アルコキシル基または5または6員のヘテロアリール基であり、更に好ましくは水素原子またはハロゲン原子であることが適当であり、但し、YがC-R2bの場合は、R2aは水素原子であり、
R2bは、ハロゲン原子を表し、
R2cは、水素原子、C1~6アルキル基またはシアノ基を表し、当該R2cは、好ましくは水素原子、C1~4アルキル基またはシアノ基であり、より好ましくは水素原子、C1~2アルキル基またはシアノ基であることが適当であり、
R2a及びR2cにおける前記アルキル基、アルコキシル基は、それぞれ、1~5個の置換基RIで置換されていてもよい)を表し;
R3は、C1~6アルキル基、C1~6アルコキシル基またはシアノ基を表し、ここでR3における前記アルキル基またはアルコキシル基は、それぞれ、1~5個の置換基RIで置換されていてもよく、当該R3は、好ましくはC1~4アルキル基、C1~4アルコキシル基またはシアノ基であり、より好ましくはC1~2アルキル基、C1~2アルコキシル基またはシアノ基であり、更に好ましくはC1~2アルキル基またはシアノ基であることが適当であり;
Ra及びRbは、各々独立に、C1~6アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよく、RaおよびRbにおける前記単環式非芳香族複素環基は、その環内の炭素原子の少なくとも1個が、酸素原子、硫黄原子及びC1~6アルキル基で置換されていてもよい窒素原子から任意に選ばれる原子で置き換えられていてもよく、当該Ra及びRbは、より好ましくは、各々独立に、C1~4アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよく;
置換基RIは、各々独立に、ハロゲン原子または水酸基を表し、好ましくは、ハロゲン原子である、
化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。
上記式(III)の化合物において、nは好ましくは2である。
上記式(III)の化合物において、環B、Y、R1、R1a、R1b、R1c、R1d、R2、R2a、R2b、R2c、R3、Ra、Rb及び置換基RIの定義および好ましい範囲は、上記態様[1-2]~[1-6]で上述したとおりである。 [4-1] The compound of the formula (I) of the embodiment [3] or the compound of the formula (II) of the embodiment [3-1], or a pharmaceutically acceptable salt thereof, or a solvate thereof In the product, another preferred embodiment is the following formula (III):
(In formula (III), the definitions of n, R 3 , R a and R b are the same as those in the above embodiment [1], and the definition of ring C is the same as the definition of formula (II) above;
X is a nitrogen atom, C—H or C—R 1d ,
R 1a represents C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, a C 2 ~ 7 alkanoyl group or a cyano group, further R 1a is preferably C 1 ~ 4 alkyl group, C 3 ~ 6 cycloalkyl group, C 1 ~ 4 alkoxyl group, a C 2 ~ 5 alkanoyl group or a cyano group, more preferably C 1 ~ 2 alkyl group, C 3 ~ 4 cycloalkyl group, C 1 ~ A 2 alkoxyl group, a C 2-3 alkanoyl group or a cyano group, more preferably a C 1-2 alkyl group or a cyano group,
R 1b and R 1c each independently represents a hydrogen atom or a C 1-6 alkyl group, and R 1b and R 1c are preferably a hydrogen atom or a C 1-4 alkyl group, more preferably a hydrogen atom. Or a C 1-2 alkyl group, more preferably R 1b is a hydrogen atom, R 1c is a hydrogen atom or a C 1-2 alkyl group,
R 1d represents a halogen atom, C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, a C 1 ~ 6 alkylthio group or -NR a R b group, further R 1d is preferably a halogen atom, C 1 ~ 4 alkyl group, C 3 ~ 6 cycloalkyl group, C 1 ~ 4 alkoxyl group, C 1 ~ 4 alkylthio group or -NR a R b group, more preferably a halogen atom, C A 1-2 alkyl group, a C 3-4 cycloalkyl group, a C 1-2 alkoxyl group, a C 1-2 alkylthio group, or a —NR a R b group, more preferably a C 1-2 alkoxyl group,
The alkyl group, cycloalkyl group, alkoxyl group, alkanoyl group or alkylthio group in R 1a , R 1b , R 1c and R 1d may each be substituted with 1 to 5 substituents RI;
Ring B has the following partial structural formula (b1) or (b2):
(In the formula (b1) or (b2),
Y represents a nitrogen atom, C—H or C—R 2b ,
R 2a represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxyl group or a monocyclic heteroaryl group, and the monocyclic heteroaryl group in R 2a is preferably a phenyl group Or a 5- to 6-membered heteroaryl group is suitably located in the para position of ring C, and R 2a is preferably a hydrogen atom, a halogen atom, a C 1-4 alkyl group, or a C 1-4 alkoxyl group. Or a 5- or 6-membered heteroaryl group, more preferably a hydrogen atom, a halogen atom, a C 1-2 alkyl group, a C 1-2 alkoxyl group or a 5- or 6-membered heteroaryl group, and more preferably a hydrogen atom. Is suitably an atom or a halogen atom, provided that when Y is C—R 2b , R 2a is a hydrogen atom;
R 2b represents a halogen atom,
R 2c represents a hydrogen atom, a C 1-6 alkyl group or a cyano group, and R 2c is preferably a hydrogen atom, a C 1-4 alkyl group or a cyano group, more preferably a hydrogen atom, C 1- 2 is suitably an alkyl group or a cyano group,
Each of the alkyl group and alkoxyl group in R 2a and R 2c may be substituted with 1 to 5 substituents RI;
R 3 represents a C 1-6 alkyl group, a C 1-6 alkoxyl group or a cyano group, wherein the alkyl group or alkoxyl group in R 3 is each substituted with 1 to 5 substituents RI. R 3 is preferably a C 1-4 alkyl group, a C 1-4 alkoxyl group or a cyano group, more preferably a C 1-2 alkyl group, a C 1-2 alkoxyl group or a cyano group. More preferably a C 1-2 alkyl group or a cyano group;
R a and R b each independently represent a C 1-6 alkyl group, R a and R b together with the nitrogen atom to which they are attached may form a monocyclic non-aromatic heterocyclic group; The monocyclic non-aromatic heterocyclic group for R a and R b is a nitrogen in which at least one of the carbon atoms in the ring may be substituted with an oxygen atom, a sulfur atom and a C 1-6 alkyl group R a and R b may be optionally substituted with atoms arbitrarily selected from atoms, and more preferably each independently represents a C 1-4 alkyl group, and R a and R b are bonded to each other. May form a monocyclic non-aromatic heterocyclic group with the nitrogen atom
The substituents RI each independently represent a halogen atom or a hydroxyl group, preferably a halogen atom.
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (III), n is preferably 2.
In the compound of the above formula (III), ring B, Y, R 1 , R 1a , R 1b , R 1c , R 1d , R 2 , R 2a , R 2b , R 2c , R 3 , R a , R b and The definition and preferred range of the substituent RI are as described above in the above embodiments [1-2] to [1-6].
(式(III)中、n、R3、Ra及びRbの定義は上記態様[1]中の定義と同じであり、環Cの定義は上記式(II)の定義と同じであり;
Xは窒素原子、C-HまたはC-R1dであり、
R1aは、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~7アルカノイル基またはシアノ基を表し、さらにR1aは、好ましくはC1~4アルキル基、C3~6シクロアルキル基、C1~4アルコキシル基、C2~5アルカノイル基またはシアノ基であり、より好ましくはC1~2アルキル基、C3~4シクロアルキル基、C1~2アルコキシル基、C2~3アルカノイル基またはシアノ基であり、更に好ましくはC1~2アルキル基またはシアノ基であり、
R1b及びR1cは、各々独立に、水素原子またはC1~6アルキル基を表し、さらにR1b及びR1cは、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であり、更に好ましくはR1bは水素原子でありR1cは水素原子またはC1~2アルキル基であり、
R1dは、ハロゲン原子、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C1~6アルキルチオ基または-NRaRb基を表し、さらにR1dは、好ましくはハロゲン原子、C1~4アルキル基、C3~6シクロアルキル基、C1~4アルコキシル基、C1~4アルキルチオ基または-NRaRb基であり、より好ましくはハロゲン原子、C1~2アルキル基、C3~4シクロアルキル基、C1~2アルコキシル基、C1~2アルキルチオ基または-NRaRb基であり、更に好ましくはC1~2アルコキシル基であり、
R1a、R1b、R1c及びR1dにおける当該アルキル基、シクロアルキル基、アルコキシル基、アルカノイル基またはアルキルチオ基は、それぞれ、1~5個の置換基RIで置換されていてもよく;
環Bは、下記部分構造式(b1)または(b2):
(式(b1)または(b2)中、
Yは、窒素原子、C-HまたはC-R2bを表し、
R2aは、水素原子、ハロゲン原子、C1~6アルキル基、C1~6アルコキシル基または単環式ヘテロアリール基を表し、当該R2aにおける当該単環式ヘテロアリール基は、好ましくはフェニル基又は5~6員ヘテロアリール基である環Cのパラ位に位置することが適当であり、当該R2aは、好ましくは水素原子、ハロゲン原子、C1~4アルキル基、C1~4アルコキシル基または5または6員のヘテロアリール基であり、より好ましくは水素原子、ハロゲン原子、C1~2アルキル基、C1~2アルコキシル基または5または6員のヘテロアリール基であり、更に好ましくは水素原子またはハロゲン原子であることが適当であり、但し、YがC-R2bの場合は、R2aは水素原子であり、
R2bは、ハロゲン原子を表し、
R2cは、水素原子、C1~6アルキル基またはシアノ基を表し、当該R2cは、好ましくは水素原子、C1~4アルキル基またはシアノ基であり、より好ましくは水素原子、C1~2アルキル基またはシアノ基であることが適当であり、
R2a及びR2cにおける前記アルキル基、アルコキシル基は、それぞれ、1~5個の置換基RIで置換されていてもよい)を表し;
R3は、C1~6アルキル基、C1~6アルコキシル基またはシアノ基を表し、ここでR3における前記アルキル基またはアルコキシル基は、それぞれ、1~5個の置換基RIで置換されていてもよく、当該R3は、好ましくはC1~4アルキル基、C1~4アルコキシル基またはシアノ基であり、より好ましくはC1~2アルキル基、C1~2アルコキシル基またはシアノ基であり、更に好ましくはC1~2アルキル基またはシアノ基であることが適当であり;
Ra及びRbは、各々独立に、C1~6アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよく、RaおよびRbにおける前記単環式非芳香族複素環基は、その環内の炭素原子の少なくとも1個が、酸素原子、硫黄原子及びC1~6アルキル基で置換されていてもよい窒素原子から任意に選ばれる原子で置き換えられていてもよく、当該Ra及びRbは、より好ましくは、各々独立に、C1~4アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよく;
置換基RIは、各々独立に、ハロゲン原子または水酸基を表し、好ましくは、ハロゲン原子である、
化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。
上記式(III)の化合物において、nは好ましくは2である。
上記式(III)の化合物において、環B、Y、R1、R1a、R1b、R1c、R1d、R2、R2a、R2b、R2c、R3、Ra、Rb及び置換基RIの定義および好ましい範囲は、上記態様[1-2]~[1-6]で上述したとおりである。 [4-1] The compound of the formula (I) of the embodiment [3] or the compound of the formula (II) of the embodiment [3-1], or a pharmaceutically acceptable salt thereof, or a solvate thereof In the product, another preferred embodiment is the following formula (III):
(In formula (III), the definitions of n, R 3 , R a and R b are the same as those in the above embodiment [1], and the definition of ring C is the same as the definition of formula (II) above;
X is a nitrogen atom, C—H or C—R 1d ,
R 1a represents C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, a C 2 ~ 7 alkanoyl group or a cyano group, further R 1a is preferably C 1 ~ 4 alkyl group, C 3 ~ 6 cycloalkyl group, C 1 ~ 4 alkoxyl group, a C 2 ~ 5 alkanoyl group or a cyano group, more preferably C 1 ~ 2 alkyl group, C 3 ~ 4 cycloalkyl group, C 1 ~ A 2 alkoxyl group, a C 2-3 alkanoyl group or a cyano group, more preferably a C 1-2 alkyl group or a cyano group,
R 1b and R 1c each independently represents a hydrogen atom or a C 1-6 alkyl group, and R 1b and R 1c are preferably a hydrogen atom or a C 1-4 alkyl group, more preferably a hydrogen atom. Or a C 1-2 alkyl group, more preferably R 1b is a hydrogen atom, R 1c is a hydrogen atom or a C 1-2 alkyl group,
R 1d represents a halogen atom, C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, a C 1 ~ 6 alkylthio group or -NR a R b group, further R 1d is preferably a halogen atom, C 1 ~ 4 alkyl group, C 3 ~ 6 cycloalkyl group, C 1 ~ 4 alkoxyl group, C 1 ~ 4 alkylthio group or -NR a R b group, more preferably a halogen atom, C A 1-2 alkyl group, a C 3-4 cycloalkyl group, a C 1-2 alkoxyl group, a C 1-2 alkylthio group, or a —NR a R b group, more preferably a C 1-2 alkoxyl group,
The alkyl group, cycloalkyl group, alkoxyl group, alkanoyl group or alkylthio group in R 1a , R 1b , R 1c and R 1d may each be substituted with 1 to 5 substituents RI;
Ring B has the following partial structural formula (b1) or (b2):
(In the formula (b1) or (b2),
Y represents a nitrogen atom, C—H or C—R 2b ,
R 2a represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxyl group or a monocyclic heteroaryl group, and the monocyclic heteroaryl group in R 2a is preferably a phenyl group Or a 5- to 6-membered heteroaryl group is suitably located in the para position of ring C, and R 2a is preferably a hydrogen atom, a halogen atom, a C 1-4 alkyl group, or a C 1-4 alkoxyl group. Or a 5- or 6-membered heteroaryl group, more preferably a hydrogen atom, a halogen atom, a C 1-2 alkyl group, a C 1-2 alkoxyl group or a 5- or 6-membered heteroaryl group, and more preferably a hydrogen atom. Is suitably an atom or a halogen atom, provided that when Y is C—R 2b , R 2a is a hydrogen atom;
R 2b represents a halogen atom,
R 2c represents a hydrogen atom, a C 1-6 alkyl group or a cyano group, and R 2c is preferably a hydrogen atom, a C 1-4 alkyl group or a cyano group, more preferably a hydrogen atom, C 1- 2 is suitably an alkyl group or a cyano group,
Each of the alkyl group and alkoxyl group in R 2a and R 2c may be substituted with 1 to 5 substituents RI;
R 3 represents a C 1-6 alkyl group, a C 1-6 alkoxyl group or a cyano group, wherein the alkyl group or alkoxyl group in R 3 is each substituted with 1 to 5 substituents RI. R 3 is preferably a C 1-4 alkyl group, a C 1-4 alkoxyl group or a cyano group, more preferably a C 1-2 alkyl group, a C 1-2 alkoxyl group or a cyano group. More preferably a C 1-2 alkyl group or a cyano group;
R a and R b each independently represent a C 1-6 alkyl group, R a and R b together with the nitrogen atom to which they are attached may form a monocyclic non-aromatic heterocyclic group; The monocyclic non-aromatic heterocyclic group for R a and R b is a nitrogen in which at least one of the carbon atoms in the ring may be substituted with an oxygen atom, a sulfur atom and a C 1-6 alkyl group R a and R b may be optionally substituted with atoms arbitrarily selected from atoms, and more preferably each independently represents a C 1-4 alkyl group, and R a and R b are bonded to each other. May form a monocyclic non-aromatic heterocyclic group with the nitrogen atom
The substituents RI each independently represent a halogen atom or a hydroxyl group, preferably a halogen atom.
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (III), n is preferably 2.
In the compound of the above formula (III), ring B, Y, R 1 , R 1a , R 1b , R 1c , R 1d , R 2 , R 2a , R 2b , R 2c , R 3 , R a , R b and The definition and preferred range of the substituent RI are as described above in the above embodiments [1-2] to [1-6].
[5] 前記態様[4]の前記式(I)の化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物において、殊更好ましい態様は、式(I)中、
R1aは、C1~6アルキル基またはシアノ基を表し、R1bは、水素原子を表し、R1cは、水素原子またはC1~6アルキル基を表し、R1dは、C1~6アルコキシル基を表し、R1a、R1b、R1c及びR1dにおける前記アルキル基またはアルコキシル基は、それぞれ、1~5個のハロゲン原子で置換されていてもよく、
R2aは、水素原子またはハロゲン原子を表し、但し、YがC-R2bの場合は、R2aは水素原子であり、R2cは、好ましくは水素原子、C1~4アルキル基、ハロゲン化C1~4アルキル基またはシアノ基であり、より好ましくは水素原子、C1~2アルキル基、ハロゲン化C1~2アルキル基またはシアノ基であり、
Lは、下記部分構造式(c1)、(c2)または(c3):
(式(c1)、(c2)または(c3)中、
Z1、Z2、Z3は、各々独立に、窒素原子またはC-Hを表し、但し、Z2がC-Hの場合は、Z1はC-Hであり、
Z4は、酸素原子または硫黄原子を表し、
R3a、R3b及びR3cは、各々独立に、水素原子、C1~6アルキル基またはシアノ基を表す)を表す、
化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。
上記式(I)の化合物において、より好ましくは、nは2である。
上記式(I)の化合物において、環A、X1、X2、環B、Y、L、Z1、Z2、Z3、Z4、R1、R1a、R1b、R1c、R1d、R2、R2a、R2b、R2c、R3、R3a、R3b、R3c、Ra、Rb及び置換基RIの定義および好ましい範囲は、上記態様[1-2]~[1-6]で上述したとおりである。 [5] In the compound of the above formula (I) of the above embodiment [4], or a pharmaceutically acceptable salt thereof or a solvate thereof, a particularly preferred embodiment is represented by the formula (I):
R 1a represents a C 1-6 alkyl group or a cyano group, R 1b represents a hydrogen atom, R 1c represents a hydrogen atom or a C 1-6 alkyl group, and R 1d represents a C 1-6 alkoxyl. Each of the alkyl group or alkoxyl group in R 1a , R 1b , R 1c and R 1d may be substituted with 1 to 5 halogen atoms,
R 2a represents a hydrogen atom or a halogen atom, provided that when Y is C—R 2b , R 2a is a hydrogen atom, and R 2c is preferably a hydrogen atom, a C 1-4 alkyl group, a halogenated group. A C 1-4 alkyl group or a cyano group, more preferably a hydrogen atom, a C 1-2 alkyl group, a halogenated C 1-2 alkyl group or a cyano group,
L is the following partial structural formula (c1), (c2) or (c3):
(In the formula (c1), (c2) or (c3),
Z 1 , Z 2 , and Z 3 each independently represent a nitrogen atom or C—H, provided that when Z 2 is C—H, Z 1 is C—H;
Z 4 represents an oxygen atom or a sulfur atom,
R 3a , R 3b and R 3c each independently represents a hydrogen atom, a C 1-6 alkyl group or a cyano group)
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (I), more preferably, n is 2.
In the compound of the above formula (I), ring A, X 1 , X 2 , ring B, Y, L, Z 1 , Z 2 , Z 3 , Z 4 , R 1 , R 1a , R 1b , R 1c , R Definitions and preferred ranges of 1d , R 2 , R 2a , R 2b , R 2c , R 3 , R 3a , R 3b , R 3c , R a , R b and the substituent RI are the above-mentioned embodiments [1-2] to As described above in [1-6].
R1aは、C1~6アルキル基またはシアノ基を表し、R1bは、水素原子を表し、R1cは、水素原子またはC1~6アルキル基を表し、R1dは、C1~6アルコキシル基を表し、R1a、R1b、R1c及びR1dにおける前記アルキル基またはアルコキシル基は、それぞれ、1~5個のハロゲン原子で置換されていてもよく、
R2aは、水素原子またはハロゲン原子を表し、但し、YがC-R2bの場合は、R2aは水素原子であり、R2cは、好ましくは水素原子、C1~4アルキル基、ハロゲン化C1~4アルキル基またはシアノ基であり、より好ましくは水素原子、C1~2アルキル基、ハロゲン化C1~2アルキル基またはシアノ基であり、
Lは、下記部分構造式(c1)、(c2)または(c3):
(式(c1)、(c2)または(c3)中、
Z1、Z2、Z3は、各々独立に、窒素原子またはC-Hを表し、但し、Z2がC-Hの場合は、Z1はC-Hであり、
Z4は、酸素原子または硫黄原子を表し、
R3a、R3b及びR3cは、各々独立に、水素原子、C1~6アルキル基またはシアノ基を表す)を表す、
化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。
上記式(I)の化合物において、より好ましくは、nは2である。
上記式(I)の化合物において、環A、X1、X2、環B、Y、L、Z1、Z2、Z3、Z4、R1、R1a、R1b、R1c、R1d、R2、R2a、R2b、R2c、R3、R3a、R3b、R3c、Ra、Rb及び置換基RIの定義および好ましい範囲は、上記態様[1-2]~[1-6]で上述したとおりである。 [5] In the compound of the above formula (I) of the above embodiment [4], or a pharmaceutically acceptable salt thereof or a solvate thereof, a particularly preferred embodiment is represented by the formula (I):
R 1a represents a C 1-6 alkyl group or a cyano group, R 1b represents a hydrogen atom, R 1c represents a hydrogen atom or a C 1-6 alkyl group, and R 1d represents a C 1-6 alkoxyl. Each of the alkyl group or alkoxyl group in R 1a , R 1b , R 1c and R 1d may be substituted with 1 to 5 halogen atoms,
R 2a represents a hydrogen atom or a halogen atom, provided that when Y is C—R 2b , R 2a is a hydrogen atom, and R 2c is preferably a hydrogen atom, a C 1-4 alkyl group, a halogenated group. A C 1-4 alkyl group or a cyano group, more preferably a hydrogen atom, a C 1-2 alkyl group, a halogenated C 1-2 alkyl group or a cyano group,
L is the following partial structural formula (c1), (c2) or (c3):
(In the formula (c1), (c2) or (c3),
Z 1 , Z 2 , and Z 3 each independently represent a nitrogen atom or C—H, provided that when Z 2 is C—H, Z 1 is C—H;
Z 4 represents an oxygen atom or a sulfur atom,
R 3a , R 3b and R 3c each independently represents a hydrogen atom, a C 1-6 alkyl group or a cyano group)
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (I), more preferably, n is 2.
In the compound of the above formula (I), ring A, X 1 , X 2 , ring B, Y, L, Z 1 , Z 2 , Z 3 , Z 4 , R 1 , R 1a , R 1b , R 1c , R Definitions and preferred ranges of 1d , R 2 , R 2a , R 2b , R 2c , R 3 , R 3a , R 3b , R 3c , R a , R b and the substituent RI are the above-mentioned embodiments [1-2] to As described above in [1-6].
[5-1]前記態様[4]の前記式(I)の化合物もしくは前記態様[4-1]の前記式(III)の化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物において、殊更好ましい別の態様は、下記式(III)-1:
(式(III)-1中、n、Xの定義は上記式(III)の定義と同じであり、
R1aは、C1~6アルキル基またはシアノ基を表し、さらにR1aは、好ましくはC1~4アルキル基であり、より好ましくはC1~2アルキル基であり、R1bは、水素原子を表し、R1cは、水素原子またはC1~6アルキル基を表し、さらにR1cは、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であり、R1dは、C1~6アルコキシル基を表し、さらにR1dは、好ましくはC1~4アルコキシル基であり、より好ましくはC1~2アルコキシル基であり、R1a、R1b、R1c及びR1dにおける前記アルキル基またはアルコキシル基は、それぞれ、1~5個のハロゲン原子で置換されていてもよく、
環Bは、下記部分構造式(b1)-1または(b2)-1:
(式(b1)-1または(b2)-1中、
Yは、窒素原子、C-HまたはC-R2bを表し、
R2aは、水素原子またはハロゲン原子を表し、但し、YがC-R2bの場合は、R2aは水素原子であり、
R2bは、ハロゲン原子を表し、
R2cは、水素原子、C1~6アルキル基、ハロゲン化C1~6アルキル基またはシアノ基を表し、
環Cは、下記部分構造式(c1)、(c2)または(c3):
(式(c1)、(c2)または(c3)中、
Z1、Z2、Z3は、各々独立に、窒素原子またはC-Hを表し、但し、Z2がC-Hの場合は、Z1はC-Hであり、
Z4は、酸素原子または硫黄原子を表し、
R3a、R3b及びR3cは、各々独立に、水素原子、C1~6アルキル基またはシアノ基を表し、さらにR3a、R3b及びR3cは、各々独立に、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であり、更に好ましくは水素原子である)で表される、
化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。
上記式(III)-1の化合物において、nは好ましくは2である。
上記式(III)-1の化合物において、環B、Y、Z1、Z2、Z3、Z4、R1、R1a、R1b、R1c、R1d、R2、R2a、R2b、R2c、R3、R3a、R3b、R3c、Ra、Rb及び置換基RIの定義および好ましい範囲は、上記態様[1-2]~[1-6]で上述したとおりである。 [5-1] The compound of the formula (I) of the embodiment [4], the compound of the formula (III) of the embodiment [4-1], or a pharmaceutically acceptable salt thereof, or a solvate thereof In the product, another particularly preferred embodiment is represented by the following formula (III) -1:
(In formula (III) -1, the definitions of n and X are the same as those in formula (III) above,
R 1a represents a C 1-6 alkyl group or a cyano group, and R 1a is preferably a C 1-4 alkyl group, more preferably a C 1-2 alkyl group, and R 1b represents a hydrogen atom R 1c represents a hydrogen atom or a C 1-6 alkyl group, and R 1c is preferably a hydrogen atom or a C 1-4 alkyl group, more preferably a hydrogen atom or a C 1-2 alkyl group. R 1d represents a C 1-6 alkoxyl group, and R 1d is preferably a C 1-4 alkoxyl group, more preferably a C 1-2 alkoxyl group, and R 1a , R 1b , Each of the alkyl group or alkoxyl group in R 1c and R 1d may be substituted with 1 to 5 halogen atoms,
Ring B has the following partial structural formula (b1) -1 or (b2) -1:
(In the formula (b1) -1 or (b2) -1,
Y represents a nitrogen atom, C—H or C—R 2b ,
R 2a represents a hydrogen atom or a halogen atom, provided that when Y is C—R 2b , R 2a is a hydrogen atom;
R 2b represents a halogen atom,
R 2c represents a hydrogen atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group or a cyano group,
Ring C has the following partial structural formula (c1), (c2) or (c3):
(In the formula (c1), (c2) or (c3),
Z 1 , Z 2 , and Z 3 each independently represent a nitrogen atom or C—H, provided that when Z 2 is C—H, Z 1 is C—H;
Z 4 represents an oxygen atom or a sulfur atom,
R 3a , R 3b and R 3c each independently represents a hydrogen atom, a C 1-6 alkyl group or a cyano group, and R 3a , R 3b and R 3c are each independently preferably a hydrogen atom or C 1 to 4 alkyl group, more preferably a hydrogen atom or C 1-2 alkyl group, and still more preferably a hydrogen atom).
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (III) -1, n is preferably 2.
In the compound of the above formula (III) -1, rings B, Y, Z 1 , Z 2 , Z 3 , Z 4 , R 1 , R 1a , R 1b , R 1c , R 1d , R 2 , R 2a , R The definitions and preferred ranges of 2b , R 2c , R 3 , R 3a , R 3b , R 3c , R a , R b and the substituent RI are as described above in the above embodiments [1-2] to [1-6]. It is.
(式(III)-1中、n、Xの定義は上記式(III)の定義と同じであり、
R1aは、C1~6アルキル基またはシアノ基を表し、さらにR1aは、好ましくはC1~4アルキル基であり、より好ましくはC1~2アルキル基であり、R1bは、水素原子を表し、R1cは、水素原子またはC1~6アルキル基を表し、さらにR1cは、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であり、R1dは、C1~6アルコキシル基を表し、さらにR1dは、好ましくはC1~4アルコキシル基であり、より好ましくはC1~2アルコキシル基であり、R1a、R1b、R1c及びR1dにおける前記アルキル基またはアルコキシル基は、それぞれ、1~5個のハロゲン原子で置換されていてもよく、
環Bは、下記部分構造式(b1)-1または(b2)-1:
(式(b1)-1または(b2)-1中、
Yは、窒素原子、C-HまたはC-R2bを表し、
R2aは、水素原子またはハロゲン原子を表し、但し、YがC-R2bの場合は、R2aは水素原子であり、
R2bは、ハロゲン原子を表し、
R2cは、水素原子、C1~6アルキル基、ハロゲン化C1~6アルキル基またはシアノ基を表し、
環Cは、下記部分構造式(c1)、(c2)または(c3):
(式(c1)、(c2)または(c3)中、
Z1、Z2、Z3は、各々独立に、窒素原子またはC-Hを表し、但し、Z2がC-Hの場合は、Z1はC-Hであり、
Z4は、酸素原子または硫黄原子を表し、
R3a、R3b及びR3cは、各々独立に、水素原子、C1~6アルキル基またはシアノ基を表し、さらにR3a、R3b及びR3cは、各々独立に、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であり、更に好ましくは水素原子である)で表される、
化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。
上記式(III)-1の化合物において、nは好ましくは2である。
上記式(III)-1の化合物において、環B、Y、Z1、Z2、Z3、Z4、R1、R1a、R1b、R1c、R1d、R2、R2a、R2b、R2c、R3、R3a、R3b、R3c、Ra、Rb及び置換基RIの定義および好ましい範囲は、上記態様[1-2]~[1-6]で上述したとおりである。 [5-1] The compound of the formula (I) of the embodiment [4], the compound of the formula (III) of the embodiment [4-1], or a pharmaceutically acceptable salt thereof, or a solvate thereof In the product, another particularly preferred embodiment is represented by the following formula (III) -1:
(In formula (III) -1, the definitions of n and X are the same as those in formula (III) above,
R 1a represents a C 1-6 alkyl group or a cyano group, and R 1a is preferably a C 1-4 alkyl group, more preferably a C 1-2 alkyl group, and R 1b represents a hydrogen atom R 1c represents a hydrogen atom or a C 1-6 alkyl group, and R 1c is preferably a hydrogen atom or a C 1-4 alkyl group, more preferably a hydrogen atom or a C 1-2 alkyl group. R 1d represents a C 1-6 alkoxyl group, and R 1d is preferably a C 1-4 alkoxyl group, more preferably a C 1-2 alkoxyl group, and R 1a , R 1b , Each of the alkyl group or alkoxyl group in R 1c and R 1d may be substituted with 1 to 5 halogen atoms,
Ring B has the following partial structural formula (b1) -1 or (b2) -1:
(In the formula (b1) -1 or (b2) -1,
Y represents a nitrogen atom, C—H or C—R 2b ,
R 2a represents a hydrogen atom or a halogen atom, provided that when Y is C—R 2b , R 2a is a hydrogen atom;
R 2b represents a halogen atom,
R 2c represents a hydrogen atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group or a cyano group,
Ring C has the following partial structural formula (c1), (c2) or (c3):
(In the formula (c1), (c2) or (c3),
Z 1 , Z 2 , and Z 3 each independently represent a nitrogen atom or C—H, provided that when Z 2 is C—H, Z 1 is C—H;
Z 4 represents an oxygen atom or a sulfur atom,
R 3a , R 3b and R 3c each independently represents a hydrogen atom, a C 1-6 alkyl group or a cyano group, and R 3a , R 3b and R 3c are each independently preferably a hydrogen atom or C 1 to 4 alkyl group, more preferably a hydrogen atom or C 1-2 alkyl group, and still more preferably a hydrogen atom).
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (III) -1, n is preferably 2.
In the compound of the above formula (III) -1, rings B, Y, Z 1 , Z 2 , Z 3 , Z 4 , R 1 , R 1a , R 1b , R 1c , R 1d , R 2 , R 2a , R The definitions and preferred ranges of 2b , R 2c , R 3 , R 3a , R 3b , R 3c , R a , R b and the substituent RI are as described above in the above embodiments [1-2] to [1-6]. It is.
[5-1-a]前記態様[4]の前記式(I)の化合物もしくは前記態様[4-1]の前記式(III)の化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物において、殊更好ましい別の態様は、下記式(IV):
(式(IV)中、n、Xの定義は上記式(III)の定義と同じであり、
R1aは、C1~6アルキル基またはシアノ基を表し、さらにR1aは、好ましくはC1~4アルキル基であり、より好ましくはC1~2アルキル基であり、R1bは、水素原子を表し、R1cは、水素原子またはC1~6アルキル基を表し、さらにR1cは、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であり、R1dは、C1~6アルコキシル基を表し、さらにR1dは、好ましくはC1~4アルコキシル基であり、より好ましくはC1~2アルコキシル基であり、R1a、R1b、R1c及びR1dにおける前記アルキル基またはアルコキシル基は、それぞれ、1~5個のハロゲン原子で置換されていてもよく、
Yは、窒素原子、C-HまたはC-R2bを表し、
R2aは、水素原子またはハロゲン原子を表し、但し、YがC-R2bの場合は、R2aは水素原子であり、
R2bは、ハロゲン原子を表し、
環Cは、下記部分構造式(c1)、(c2)または(c3):
(式(c1)、(c2)または(c3)中、
Z1、Z2、Z3は、各々独立に、窒素原子またはC-Hを表し、但し、Z2がC-Hの場合は、Z1はC-Hであり、
Z4は、酸素原子または硫黄原子を表し、
R3a、R3b及びR3cは、各々独立に、水素原子、C1~6アルキル基またはシアノ基を表し、さらにR3a、R3b及びR3cは、各々独立に、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であり、更に好ましくは水素原子である)で表される、
化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。
上記式(IV)の化合物において、nは好ましくは2である。
上記式(IV)の化合物において、Y、Z1、Z2、Z3、Z4、R1、R1a、R1b、R1c、R1d、R2、R2a、R2b、R3、R3a、R3b、R3c、Ra、Rb及び置換基RIの定義および好ましい範囲は、上記態様[1-2]~[1-6]で上述したとおりである。 [5-1-a] The compound of the formula (I) of the embodiment [4], the compound of the formula (III) of the embodiment [4-1], or a pharmaceutically acceptable salt thereof, or a salt thereof In the solvate, another particularly preferable embodiment is the following formula (IV):
(In formula (IV), the definition of n and X is the same as the definition of said formula (III),
R 1a represents a C 1-6 alkyl group or a cyano group, and R 1a is preferably a C 1-4 alkyl group, more preferably a C 1-2 alkyl group, and R 1b represents a hydrogen atom R 1c represents a hydrogen atom or a C 1-6 alkyl group, and R 1c is preferably a hydrogen atom or a C 1-4 alkyl group, more preferably a hydrogen atom or a C 1-2 alkyl group. R 1d represents a C 1-6 alkoxyl group, and R 1d is preferably a C 1-4 alkoxyl group, more preferably a C 1-2 alkoxyl group, and R 1a , R 1b , Each of the alkyl group or alkoxyl group in R 1c and R 1d may be substituted with 1 to 5 halogen atoms,
Y represents a nitrogen atom, C—H or C—R 2b ,
R 2a represents a hydrogen atom or a halogen atom, provided that when Y is C—R 2b , R 2a is a hydrogen atom;
R 2b represents a halogen atom,
Ring C has the following partial structural formula (c1), (c2) or (c3):
(In the formula (c1), (c2) or (c3),
Z 1 , Z 2 , and Z 3 each independently represent a nitrogen atom or C—H, provided that when Z 2 is C—H, Z 1 is C—H;
Z 4 represents an oxygen atom or a sulfur atom,
R 3a , R 3b and R 3c each independently represents a hydrogen atom, a C 1-6 alkyl group or a cyano group, and R 3a , R 3b and R 3c are each independently preferably a hydrogen atom or C 1 to 4 alkyl group, more preferably a hydrogen atom or C 1-2 alkyl group, and still more preferably a hydrogen atom).
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (IV), n is preferably 2.
In the compound of the above formula (IV), Y, Z 1 , Z 2 , Z 3 , Z 4 , R 1 , R 1a , R 1b , R 1c , R 1d , R 2 , R 2a , R 2b , R 3 , The definitions and preferred ranges of R 3a , R 3b , R 3c , R a , R b and the substituent RI are as described above in the above embodiments [1-2] to [1-6].
(式(IV)中、n、Xの定義は上記式(III)の定義と同じであり、
R1aは、C1~6アルキル基またはシアノ基を表し、さらにR1aは、好ましくはC1~4アルキル基であり、より好ましくはC1~2アルキル基であり、R1bは、水素原子を表し、R1cは、水素原子またはC1~6アルキル基を表し、さらにR1cは、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であり、R1dは、C1~6アルコキシル基を表し、さらにR1dは、好ましくはC1~4アルコキシル基であり、より好ましくはC1~2アルコキシル基であり、R1a、R1b、R1c及びR1dにおける前記アルキル基またはアルコキシル基は、それぞれ、1~5個のハロゲン原子で置換されていてもよく、
Yは、窒素原子、C-HまたはC-R2bを表し、
R2aは、水素原子またはハロゲン原子を表し、但し、YがC-R2bの場合は、R2aは水素原子であり、
R2bは、ハロゲン原子を表し、
環Cは、下記部分構造式(c1)、(c2)または(c3):
(式(c1)、(c2)または(c3)中、
Z1、Z2、Z3は、各々独立に、窒素原子またはC-Hを表し、但し、Z2がC-Hの場合は、Z1はC-Hであり、
Z4は、酸素原子または硫黄原子を表し、
R3a、R3b及びR3cは、各々独立に、水素原子、C1~6アルキル基またはシアノ基を表し、さらにR3a、R3b及びR3cは、各々独立に、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であり、更に好ましくは水素原子である)で表される、
化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。
上記式(IV)の化合物において、nは好ましくは2である。
上記式(IV)の化合物において、Y、Z1、Z2、Z3、Z4、R1、R1a、R1b、R1c、R1d、R2、R2a、R2b、R3、R3a、R3b、R3c、Ra、Rb及び置換基RIの定義および好ましい範囲は、上記態様[1-2]~[1-6]で上述したとおりである。 [5-1-a] The compound of the formula (I) of the embodiment [4], the compound of the formula (III) of the embodiment [4-1], or a pharmaceutically acceptable salt thereof, or a salt thereof In the solvate, another particularly preferable embodiment is the following formula (IV):
(In formula (IV), the definition of n and X is the same as the definition of said formula (III),
R 1a represents a C 1-6 alkyl group or a cyano group, and R 1a is preferably a C 1-4 alkyl group, more preferably a C 1-2 alkyl group, and R 1b represents a hydrogen atom R 1c represents a hydrogen atom or a C 1-6 alkyl group, and R 1c is preferably a hydrogen atom or a C 1-4 alkyl group, more preferably a hydrogen atom or a C 1-2 alkyl group. R 1d represents a C 1-6 alkoxyl group, and R 1d is preferably a C 1-4 alkoxyl group, more preferably a C 1-2 alkoxyl group, and R 1a , R 1b , Each of the alkyl group or alkoxyl group in R 1c and R 1d may be substituted with 1 to 5 halogen atoms,
Y represents a nitrogen atom, C—H or C—R 2b ,
R 2a represents a hydrogen atom or a halogen atom, provided that when Y is C—R 2b , R 2a is a hydrogen atom;
R 2b represents a halogen atom,
Ring C has the following partial structural formula (c1), (c2) or (c3):
(In the formula (c1), (c2) or (c3),
Z 1 , Z 2 , and Z 3 each independently represent a nitrogen atom or C—H, provided that when Z 2 is C—H, Z 1 is C—H;
Z 4 represents an oxygen atom or a sulfur atom,
R 3a , R 3b and R 3c each independently represents a hydrogen atom, a C 1-6 alkyl group or a cyano group, and R 3a , R 3b and R 3c are each independently preferably a hydrogen atom or C 1 to 4 alkyl group, more preferably a hydrogen atom or C 1-2 alkyl group, and still more preferably a hydrogen atom).
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (IV), n is preferably 2.
In the compound of the above formula (IV), Y, Z 1 , Z 2 , Z 3 , Z 4 , R 1 , R 1a , R 1b , R 1c , R 1d , R 2 , R 2a , R 2b , R 3 , The definitions and preferred ranges of R 3a , R 3b , R 3c , R a , R b and the substituent RI are as described above in the above embodiments [1-2] to [1-6].
[5-1-b]前記態様[4]の前記式(I)の化合物もしくは前記態様[4-1]の前記式(III)の化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物において、殊更好ましい別の態様は、下記式(V):
(式(V)中、n、Xの定義は上記式(III)の定義と同じであり、
R1aは、C1~6アルキル基またはシアノ基を表し、さらにR1aは、好ましくはC1~4アルキル基であり、より好ましくはC1~2アルキル基であり、R1bは、水素原子を表し、R1cは、水素原子またはC1~6アルキル基を表し、さらにR1cは、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であり、R1dは、C1~6アルコキシル基を表し、さらにR1dは、好ましくはC1~4アルコキシル基であり、より好ましくはC1~2アルコキシル基であり、R1a、R1b、R1c及びR1dにおける前記アルキル基またはアルコキシル基は、それぞれ、1~5個のハロゲン原子で置換されていてもよく、
R2cは、水素原子、C1~6アルキル基、ハロゲン化C1~6アルキル基またはシアノ基を表し、さらにR2cは、好ましくは水素原子、C1~4アルキル基、ハロゲン化C1~4アルキル基またはシアノ基であり、より好ましくは水素原子、C1~2アルキル基、ハロゲン化C1~2アルキル基またはシアノ基であり、
環Cは、下記部分構造式(c1)または(c3):
(式(c1)または(c3)中、
Z1、Z2は、各々独立に、窒素原子またはC-Hを表し、但し、Z2がC-Hの場合は、Z1はC-Hであり、
Z4は、酸素原子または硫黄原子を表し、
R3a及びR3cは、各々独立に、水素原子、C1~6アルキル基またはシアノ基を表し、さらにR3a及びR3cは、各々独立に、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であり、更に好ましくは水素原子である)で表される、
化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。
上記式(V)の化合物において、nは好ましくは2である。
上記式(V)の化合物において、Z1、Z2、Z4、R1、R1a、R1b、R1c、R1d、R2、R2c、R3、R3a、R3c、Ra、Rb及び置換基RIの定義および好ましい範囲は、上記態様[1-2]~[1-6]で上述したとおりである。 [5-1-b] The compound of the formula (I) of the embodiment [4], the compound of the formula (III) of the embodiment [4-1], or a pharmaceutically acceptable salt thereof, or a compound thereof In the solvate, another particularly preferable embodiment is represented by the following formula (V):
(In formula (V), the definitions of n and X are the same as the definitions of formula (III) above,
R 1a represents a C 1-6 alkyl group or a cyano group, and R 1a is preferably a C 1-4 alkyl group, more preferably a C 1-2 alkyl group, and R 1b represents a hydrogen atom R 1c represents a hydrogen atom or a C 1-6 alkyl group, and R 1c is preferably a hydrogen atom or a C 1-4 alkyl group, more preferably a hydrogen atom or a C 1-2 alkyl group. R 1d represents a C 1-6 alkoxyl group, and R 1d is preferably a C 1-4 alkoxyl group, more preferably a C 1-2 alkoxyl group, and R 1a , R 1b , Each of the alkyl group or alkoxyl group in R 1c and R 1d may be substituted with 1 to 5 halogen atoms,
R 2c represents a hydrogen atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group or a cyano group, and R 2c is preferably a hydrogen atom, a C 1-4 alkyl group, a halogenated C 1- 4 alkyl group or cyano group, more preferably a hydrogen atom, C 1-2 alkyl group, halogenated C 1-2 alkyl group or cyano group,
Ring C has the following partial structural formula (c1) or (c3):
(In the formula (c1) or (c3),
Z 1 and Z 2 each independently represents a nitrogen atom or C—H, provided that when Z 2 is C—H, Z 1 is C—H;
Z 4 represents an oxygen atom or a sulfur atom,
R 3a and R 3c each independently represent a hydrogen atom, a C 1-6 alkyl group or a cyano group, and R 3a and R 3c each independently preferably represent a hydrogen atom or a C 1-4 alkyl group. More preferably a hydrogen atom or a C 1-2 alkyl group, still more preferably a hydrogen atom).
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (V), n is preferably 2.
In the compound of the above formula (V), Z 1 , Z 2 , Z 4 , R 1 , R 1a , R 1b , R 1c , R 1d , R 2 , R 2c , R 3 , R 3a , R 3c , R a , R b and the substituent RI are as defined above and in the preferred embodiments [1-2] to [1-6].
(式(V)中、n、Xの定義は上記式(III)の定義と同じであり、
R1aは、C1~6アルキル基またはシアノ基を表し、さらにR1aは、好ましくはC1~4アルキル基であり、より好ましくはC1~2アルキル基であり、R1bは、水素原子を表し、R1cは、水素原子またはC1~6アルキル基を表し、さらにR1cは、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であり、R1dは、C1~6アルコキシル基を表し、さらにR1dは、好ましくはC1~4アルコキシル基であり、より好ましくはC1~2アルコキシル基であり、R1a、R1b、R1c及びR1dにおける前記アルキル基またはアルコキシル基は、それぞれ、1~5個のハロゲン原子で置換されていてもよく、
R2cは、水素原子、C1~6アルキル基、ハロゲン化C1~6アルキル基またはシアノ基を表し、さらにR2cは、好ましくは水素原子、C1~4アルキル基、ハロゲン化C1~4アルキル基またはシアノ基であり、より好ましくは水素原子、C1~2アルキル基、ハロゲン化C1~2アルキル基またはシアノ基であり、
環Cは、下記部分構造式(c1)または(c3):
(式(c1)または(c3)中、
Z1、Z2は、各々独立に、窒素原子またはC-Hを表し、但し、Z2がC-Hの場合は、Z1はC-Hであり、
Z4は、酸素原子または硫黄原子を表し、
R3a及びR3cは、各々独立に、水素原子、C1~6アルキル基またはシアノ基を表し、さらにR3a及びR3cは、各々独立に、好ましくは水素原子またはC1~4アルキル基であり、より好ましくは水素原子またはC1~2アルキル基であり、更に好ましくは水素原子である)で表される、
化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物である。
上記式(V)の化合物において、nは好ましくは2である。
上記式(V)の化合物において、Z1、Z2、Z4、R1、R1a、R1b、R1c、R1d、R2、R2c、R3、R3a、R3c、Ra、Rb及び置換基RIの定義および好ましい範囲は、上記態様[1-2]~[1-6]で上述したとおりである。 [5-1-b] The compound of the formula (I) of the embodiment [4], the compound of the formula (III) of the embodiment [4-1], or a pharmaceutically acceptable salt thereof, or a compound thereof In the solvate, another particularly preferable embodiment is represented by the following formula (V):
(In formula (V), the definitions of n and X are the same as the definitions of formula (III) above,
R 1a represents a C 1-6 alkyl group or a cyano group, and R 1a is preferably a C 1-4 alkyl group, more preferably a C 1-2 alkyl group, and R 1b represents a hydrogen atom R 1c represents a hydrogen atom or a C 1-6 alkyl group, and R 1c is preferably a hydrogen atom or a C 1-4 alkyl group, more preferably a hydrogen atom or a C 1-2 alkyl group. R 1d represents a C 1-6 alkoxyl group, and R 1d is preferably a C 1-4 alkoxyl group, more preferably a C 1-2 alkoxyl group, and R 1a , R 1b , Each of the alkyl group or alkoxyl group in R 1c and R 1d may be substituted with 1 to 5 halogen atoms,
R 2c represents a hydrogen atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group or a cyano group, and R 2c is preferably a hydrogen atom, a C 1-4 alkyl group, a halogenated C 1- 4 alkyl group or cyano group, more preferably a hydrogen atom, C 1-2 alkyl group, halogenated C 1-2 alkyl group or cyano group,
Ring C has the following partial structural formula (c1) or (c3):
(In the formula (c1) or (c3),
Z 1 and Z 2 each independently represents a nitrogen atom or C—H, provided that when Z 2 is C—H, Z 1 is C—H;
Z 4 represents an oxygen atom or a sulfur atom,
R 3a and R 3c each independently represent a hydrogen atom, a C 1-6 alkyl group or a cyano group, and R 3a and R 3c each independently preferably represent a hydrogen atom or a C 1-4 alkyl group. More preferably a hydrogen atom or a C 1-2 alkyl group, still more preferably a hydrogen atom).
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (V), n is preferably 2.
In the compound of the above formula (V), Z 1 , Z 2 , Z 4 , R 1 , R 1a , R 1b , R 1c , R 1d , R 2 , R 2c , R 3 , R 3a , R 3c , R a , R b and the substituent RI are as defined above and in the preferred embodiments [1-2] to [1-6].
以上、本発明の態様[1]~[5]までの各々及びその好ましい態様を、更には置換基の定義を適宜組み合わせることにより、前記態様[1]の前記式(I)で表される化合物の好ましい態様を任意に形成しうる。
前記態様[1]~[5]およびそれらの下位態様において、上記式(I)におけるより好ましい置換基またはそれらの組み合わせは、第1の態様に記載されている説明に準ずる。 As described above, each of the embodiments [1] to [5] of the present invention and preferred embodiments thereof, and further by appropriately combining the definitions of substituents, the compound represented by the formula (I) of the embodiment [1] The preferred embodiments can be arbitrarily formed.
In the above-mentioned embodiments [1] to [5] and sub-embodiments thereof, more preferred substituents in the above formula (I) or a combination thereof are in accordance with the explanation described in the first embodiment.
前記態様[1]~[5]およびそれらの下位態様において、上記式(I)におけるより好ましい置換基またはそれらの組み合わせは、第1の態様に記載されている説明に準ずる。 As described above, each of the embodiments [1] to [5] of the present invention and preferred embodiments thereof, and further by appropriately combining the definitions of substituents, the compound represented by the formula (I) of the embodiment [1] The preferred embodiments can be arbitrarily formed.
In the above-mentioned embodiments [1] to [5] and sub-embodiments thereof, more preferred substituents in the above formula (I) or a combination thereof are in accordance with the explanation described in the first embodiment.
[6] 本発明の第6の態様は、前記態様[1]の前記式(I)の化合物において、好ましい化合物として、以下に列挙される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物、或いはそれらの光学異性体である。なお、以下に表される化合物の名称は、ChemBioDraw(登録商標) Ultra 14(CambridgeSoft)の化合物名称命名プログラムに従って得られる英語名称に基づくものである。
[6] The sixth aspect of the present invention is the compound of the formula (I) of the aspect [1], wherein the preferred compounds are the compounds listed below, or pharmaceutically acceptable salts thereof, or those: Solvates thereof, or optical isomers thereof. The names of the compounds shown below are based on English names obtained according to the compound name naming program of ChemBioDraw (registered trademark) Ultra 14 (CambridgeSoft).
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(5-メチル-2-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン(実施例1);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(3-メチル-1,2,4-オキサジアゾール-5-イル)フェニル)メタノン(実施例2);
(2-(1H-ピラゾール-1-イル)フェニル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例3);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(ピリミジン-2-イル)フェニル)メタノン(実施例4);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(トリフルオロメトキシ)フェニル)メタノン(実施例5); (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (5-methyl-2- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 1);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (3-methyl-1,2,4-oxadi Azol-5-yl) phenyl) methanone (Example 2);
(2- (1H-pyrazol-1-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone ( Example 3);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (pyrimidin-2-yl) phenyl) methanone (Examples) 4);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (trifluoromethoxy) phenyl) methanone (Example 5) ;
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(3-メチル-1,2,4-オキサジアゾール-5-イル)フェニル)メタノン(実施例2);
(2-(1H-ピラゾール-1-イル)フェニル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例3);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(ピリミジン-2-イル)フェニル)メタノン(実施例4);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(トリフルオロメトキシ)フェニル)メタノン(実施例5); (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (5-methyl-2- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 1);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (3-methyl-1,2,4-oxadi Azol-5-yl) phenyl) methanone (Example 2);
(2- (1H-pyrazol-1-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone ( Example 3);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (pyrimidin-2-yl) phenyl) methanone (Examples) 4);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (trifluoromethoxy) phenyl) methanone (Example 5) ;
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-フェノキシフェニル)メタノン(実施例6);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(6-メトキシ-2-(1H-ピラゾール-1-イル)ピリジン-3-イル)メタノン(実施例7);
(3-(2H-1,2,3-トリアゾール-2-イル)ピリジン-4-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例8);
(3-(1H-ピラゾール-1-イル)ピリダジン-4-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例9);
(4-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例10); (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-phenoxyphenyl) methanone (Example 6);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (6-methoxy-2- (1H-pyrazol-1-yl) Pyridin-3-yl) methanone (Example 7);
(3- (2H-1,2,3-triazol-2-yl) pyridin-4-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2. 1] Octane-3-yl) methanone (Example 8);
(3- (1H-pyrazol-1-yl) pyridazin-4-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3- Yl) methanone (Example 9);
(4-Fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8- Diazabicyclo [3.2.1] octane-3-yl) methanone (Example 10);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(6-メトキシ-2-(1H-ピラゾール-1-イル)ピリジン-3-イル)メタノン(実施例7);
(3-(2H-1,2,3-トリアゾール-2-イル)ピリジン-4-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例8);
(3-(1H-ピラゾール-1-イル)ピリダジン-4-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例9);
(4-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例10); (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-phenoxyphenyl) methanone (Example 6);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (6-methoxy-2- (1H-pyrazol-1-yl) Pyridin-3-yl) methanone (Example 7);
(3- (2H-1,2,3-triazol-2-yl) pyridin-4-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2. 1] Octane-3-yl) methanone (Example 8);
(3- (1H-pyrazol-1-yl) pyridazin-4-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3- Yl) methanone (Example 9);
(4-Fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8- Diazabicyclo [3.2.1] octane-3-yl) methanone (Example 10);
2-(3-(4-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例11);
(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(ピリミジン-2-イル)フェニル)メタノン(実施例12);
3-メトキシ-2-(3-(2-(ピリミジン-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例13);
2-(3-(3-(2H-1,2,3-トリアゾール-2-イル)イソニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例14);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-フルオロ-6-(ピリミジン-2-イル)フェニル)メタノン(実施例15); 2- (3- (4-Fluoro-2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3 -Methoxyisonicotinonitrile (Example 11);
(8- (3-Methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (pyrimidin-2-yl) Phenyl) methanone (Example 12);
3-methoxy-2- (3- (2- (pyrimidin-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Example 13);
2- (3- (3- (2H-1,2,3-triazol-2-yl) isonicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicoti Nononitrile (Example 14);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-6- (pyrimidin-2-yl) phenyl) Methanone (Example 15);
(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(ピリミジン-2-イル)フェニル)メタノン(実施例12);
3-メトキシ-2-(3-(2-(ピリミジン-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例13);
2-(3-(3-(2H-1,2,3-トリアゾール-2-イル)イソニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例14);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-フルオロ-6-(ピリミジン-2-イル)フェニル)メタノン(実施例15); 2- (3- (4-Fluoro-2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3 -Methoxyisonicotinonitrile (Example 11);
(8- (3-Methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (pyrimidin-2-yl) Phenyl) methanone (Example 12);
3-methoxy-2- (3- (2- (pyrimidin-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Example 13);
2- (3- (3- (2H-1,2,3-triazol-2-yl) isonicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicoti Nononitrile (Example 14);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-6- (pyrimidin-2-yl) phenyl) Methanone (Example 15);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(4-メトキシ-2-(1H-1,2,3-トリアゾール-1-イル)フェニル)メタノン(実施例16);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(4-メチル-2-(ピリミジン-2-イル)フェニル)メタノン(実施例17);
(2,2-ジフルオロベンゾ[d][1,3]ジオキソル-4-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例18);
(2-シクロプロピルフェニル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例19);
(2,6-ジエトキシフェニル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例20); (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-methoxy-2- (1H-1,2,3- Triazol-1-yl) phenyl) methanone (Example 16);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-methyl-2- (pyrimidin-2-yl) phenyl) Methanone (Example 17);
(2,2-difluorobenzo [d] [1,3] dioxol-4-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane -3-yl) methanone (Example 18);
(2-cyclopropylphenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 19);
(2,6-diethoxyphenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 20);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(4-メチル-2-(ピリミジン-2-イル)フェニル)メタノン(実施例17);
(2,2-ジフルオロベンゾ[d][1,3]ジオキソル-4-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例18);
(2-シクロプロピルフェニル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例19);
(2,6-ジエトキシフェニル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例20); (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-methoxy-2- (1H-1,2,3- Triazol-1-yl) phenyl) methanone (Example 16);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-methyl-2- (pyrimidin-2-yl) phenyl) Methanone (Example 17);
(2,2-difluorobenzo [d] [1,3] dioxol-4-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane -3-yl) methanone (Example 18);
(2-cyclopropylphenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 19);
(2,6-diethoxyphenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 20);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(5-メチル-2-フェニルフラン-3-イル)メタノン(実施例21);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-メチル-4-フェニルチアゾール-5-イル)メタノン(実施例22);
(2-シクロプロピル-4-フェニルチアゾール-5-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例23);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(3-メチル-1-フェニル-1H-ピラゾール-5-イル)メタノン(実施例24);
3-(5-(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボニル)-3-メチル-1H-ピラゾール-1-イル)ベンゾニトリル(実施例25); (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (5-methyl-2-phenylfuran-3-yl) methanone ( Example 21);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-methyl-4-phenylthiazol-5-yl) methanone ( Example 22);
(2-Cyclopropyl-4-phenylthiazol-5-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 23);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (3-methyl-1-phenyl-1H-pyrazol-5-yl ) Methanone (Example 24);
3- (5- (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carbonyl) -3-methyl-1H-pyrazole-1- Yl) benzonitrile (Example 25);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-メチル-4-フェニルチアゾール-5-イル)メタノン(実施例22);
(2-シクロプロピル-4-フェニルチアゾール-5-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例23);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(3-メチル-1-フェニル-1H-ピラゾール-5-イル)メタノン(実施例24);
3-(5-(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボニル)-3-メチル-1H-ピラゾール-1-イル)ベンゾニトリル(実施例25); (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (5-methyl-2-phenylfuran-3-yl) methanone ( Example 21);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-methyl-4-phenylthiazol-5-yl) methanone ( Example 22);
(2-Cyclopropyl-4-phenylthiazol-5-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 23);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (3-methyl-1-phenyl-1H-pyrazol-5-yl ) Methanone (Example 24);
3- (5- (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carbonyl) -3-methyl-1H-pyrazole-1- Yl) benzonitrile (Example 25);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(1-(ピリジン-2-イル)-1H-ピラゾール-5-イル)メタノン(実施例26);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(1-(ピリジン-2-イル)-3-(トリフルオロメチル)-1H-ピラゾール-5-イル)メタノン(実施例27);
5-(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボニル)-1-(ピリジン-2-イル)-1H-ピラゾール-3-カルボニトリル(実施例28);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(1-メチル-3-(ピリジン-2-イル)-1H-ピラゾール-4-イル)メタノン(実施例29);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(5-フルオロ-2-(1H-ピラゾール-1-イル)ピリジン-3-イル)メタノン(実施例30); (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1- (pyridin-2-yl) -1H-pyrazol-5 -Yl) methanone (Example 26);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1- (pyridin-2-yl) -3- (trifluoro Methyl) -1H-pyrazol-5-yl) methanone (Example 27);
5- (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carbonyl) -1- (pyridin-2-yl) -1H-pyrazole -3-carbonitrile (Example 28);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1-methyl-3- (pyridin-2-yl) -1H -Pyrazol-4-yl) methanone (Example 29);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (5-fluoro-2- (1H-pyrazol-1-yl) Pyridin-3-yl) methanone (Example 30);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(1-(ピリジン-2-イル)-3-(トリフルオロメチル)-1H-ピラゾール-5-イル)メタノン(実施例27);
5-(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボニル)-1-(ピリジン-2-イル)-1H-ピラゾール-3-カルボニトリル(実施例28);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(1-メチル-3-(ピリジン-2-イル)-1H-ピラゾール-4-イル)メタノン(実施例29);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(5-フルオロ-2-(1H-ピラゾール-1-イル)ピリジン-3-イル)メタノン(実施例30); (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1- (pyridin-2-yl) -1H-pyrazol-5 -Yl) methanone (Example 26);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1- (pyridin-2-yl) -3- (trifluoro Methyl) -1H-pyrazol-5-yl) methanone (Example 27);
5- (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carbonyl) -1- (pyridin-2-yl) -1H-pyrazole -3-carbonitrile (Example 28);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1-methyl-3- (pyridin-2-yl) -1H -Pyrazol-4-yl) methanone (Example 29);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (5-fluoro-2- (1H-pyrazol-1-yl) Pyridin-3-yl) methanone (Example 30);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(1-メチル-1H-ピラゾール-3-イル)ピリジン-3-イル)メタノン(実施例31);
[2,2’-ビピリジン]-3-イル(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例32);
(5’’-クロロ-[2,2’:5’,3’’-ターピリジン]-3’-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例33);
2-(3-(1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボニル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例34);
3-メトキシ-2-(3-(1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボニル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例35); (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (1-methyl-1H-pyrazol-3-yl) Pyridin-3-yl) methanone (Example 31);
[2,2′-bipyridin] -3-yl (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Examples) 32);
(5 ″ -chloro- [2,2 ′: 5 ′, 3 ″ -terpyridin] -3′-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [ 3.2.1] octane-3-yl) methanone (Example 33);
2- (3- (1- (Pyridin-2-yl) -1H-pyrazol-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Examples) 34);
3-methoxy-2- (3- (1- (pyridin-2-yl) -1H-pyrazol-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotino Nitrile (Example 35);
[2,2’-ビピリジン]-3-イル(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例32);
(5’’-クロロ-[2,2’:5’,3’’-ターピリジン]-3’-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例33);
2-(3-(1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボニル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例34);
3-メトキシ-2-(3-(1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボニル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例35); (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (1-methyl-1H-pyrazol-3-yl) Pyridin-3-yl) methanone (Example 31);
[2,2′-bipyridin] -3-yl (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Examples) 32);
(5 ″ -chloro- [2,2 ′: 5 ′, 3 ″ -terpyridin] -3′-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [ 3.2.1] octane-3-yl) methanone (Example 33);
2- (3- (1- (Pyridin-2-yl) -1H-pyrazol-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Examples) 34);
3-methoxy-2- (3- (1- (pyridin-2-yl) -1H-pyrazol-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotino Nitrile (Example 35);
(3-メチル-1-(ピリジン-2-イル)-1H-ピラゾール-5-イル)(8-(4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例36);
(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(3-メチル-1-(ピリジン-2-イル)-1H-ピラゾール-5-イル)メタノン(実施例37);
2-(3-(3-メチル-1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボニル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例38);
3-メトキシ-2-(3-(3-メチル-1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボニル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例39);
3-メトキシ-2-(3-(1-(ピリジン-2-イル)-3-(トリフルオロメチル)-1H-ピラゾール-5-カルボニル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例40); (3-Methyl-1- (pyridin-2-yl) -1H-pyrazol-5-yl) (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2 .1] octane-3-yl) methanone (Example 36);
(8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octan-3-yl) (3-methyl-1- (pyridine- 2-yl) -1H-pyrazol-5-yl) methanone (Example 37);
2- (3- (3-Methyl-1- (pyridin-2-yl) -1H-pyrazol-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotino Nitrile (Example 38);
3-Methoxy-2- (3- (3-methyl-1- (pyridin-2-yl) -1H-pyrazol-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl ) Isonicotinonitrile (Example 39);
3-methoxy-2- (3- (1- (pyridin-2-yl) -3- (trifluoromethyl) -1H-pyrazole-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane -8-yl) isonicotinonitrile (Example 40);
(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(3-メチル-1-(ピリジン-2-イル)-1H-ピラゾール-5-イル)メタノン(実施例37);
2-(3-(3-メチル-1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボニル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例38);
3-メトキシ-2-(3-(3-メチル-1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボニル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例39);
3-メトキシ-2-(3-(1-(ピリジン-2-イル)-3-(トリフルオロメチル)-1H-ピラゾール-5-カルボニル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例40); (3-Methyl-1- (pyridin-2-yl) -1H-pyrazol-5-yl) (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2 .1] octane-3-yl) methanone (Example 36);
(8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octan-3-yl) (3-methyl-1- (pyridine- 2-yl) -1H-pyrazol-5-yl) methanone (Example 37);
2- (3- (3-Methyl-1- (pyridin-2-yl) -1H-pyrazol-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotino Nitrile (Example 38);
3-Methoxy-2- (3- (3-methyl-1- (pyridin-2-yl) -1H-pyrazol-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl ) Isonicotinonitrile (Example 39);
3-methoxy-2- (3- (1- (pyridin-2-yl) -3- (trifluoromethyl) -1H-pyrazole-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane -8-yl) isonicotinonitrile (Example 40);
1-(ピリジン-2-イル)-5-(8-(4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボニル)-1H-ピラゾール-3-カルボニトリル(実施例41);
2-(3-(3-シアノ-1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボニル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例42);
3-メトキシ-2-(3-(1-(ピリダジン-3-イル)-1H-ピラゾール-5-カルボニル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例43);
(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(1-メチル-3-(ピリジン-2-イル)-1H-ピラゾール-4-イル)メタノン(実施例44);
2-(3-(2,6-ジエトキシベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例45); 1- (Pyridin-2-yl) -5- (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carbonyl) -1H -Pyrazole-3-carbonitrile (Example 41);
2- (3- (3-Cyano-1- (pyridin-2-yl) -1H-pyrazol-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- Methoxyisonicotinonitrile (Example 42);
3-methoxy-2- (3- (1- (pyridazin-3-yl) -1H-pyrazol-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotino Nitrile (Example 43);
(8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1-methyl-3- (pyridine- 2-yl) -1H-pyrazol-4-yl) methanone (Example 44);
2- (3- (2,6-diethoxybenzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (Example 45);
2-(3-(3-シアノ-1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボニル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例42);
3-メトキシ-2-(3-(1-(ピリダジン-3-イル)-1H-ピラゾール-5-カルボニル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例43);
(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(1-メチル-3-(ピリジン-2-イル)-1H-ピラゾール-4-イル)メタノン(実施例44);
2-(3-(2,6-ジエトキシベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例45); 1- (Pyridin-2-yl) -5- (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carbonyl) -1H -Pyrazole-3-carbonitrile (Example 41);
2- (3- (3-Cyano-1- (pyridin-2-yl) -1H-pyrazol-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- Methoxyisonicotinonitrile (Example 42);
3-methoxy-2- (3- (1- (pyridazin-3-yl) -1H-pyrazol-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotino Nitrile (Example 43);
(8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1-methyl-3- (pyridine- 2-yl) -1H-pyrazol-4-yl) methanone (Example 44);
2- (3- (2,6-diethoxybenzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (Example 45);
(2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例46);
2-(3-(2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例47);
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-クロロイソニコチノニトリル(実施例48);
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-フルオロイソニコチノニトリル(実施例49);
2-(3-(2-(1H-1,2,3-トリアゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例50); (2-Fluoro-6- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8- Diazabicyclo [3.2.1] octane-3-yl) methanone (Example 46);
2- (3- (2-Fluoro-6- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3 -Methoxyisonicotinonitrile (Example 47);
2- (3- (2- (1 (H) pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-chloroisonicotinonitrile (Example 48) );
2- (3- (2- (1 (H) pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-fluoroisonicotinonitrile (Example 49) );
2- (3- (2- (1- (1, H-1,2,3-triazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicoti Nononitrile (Example 50);
2-(3-(2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例47);
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-クロロイソニコチノニトリル(実施例48);
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-フルオロイソニコチノニトリル(実施例49);
2-(3-(2-(1H-1,2,3-トリアゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例50); (2-Fluoro-6- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8- Diazabicyclo [3.2.1] octane-3-yl) methanone (Example 46);
2- (3- (2-Fluoro-6- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3 -Methoxyisonicotinonitrile (Example 47);
2- (3- (2- (1 (H) pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-chloroisonicotinonitrile (Example 48) );
2- (3- (2- (1 (H) pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-fluoroisonicotinonitrile (Example 49) );
2- (3- (2- (1- (1, H-1,2,3-triazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicoti Nononitrile (Example 50);
[2,2’-ビピリジン]-3-イル(8-(4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例51);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル-2,2,4,4-d4)(1-(ピリジン-2-イル)-1H-ピラゾール-5-イル)メタノン(実施例52);
(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル-2,2,4,4-d4)メタノン(実施例53);
(2-メチル-4-フェニルチアゾール-5-イル)(8-(4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例54);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(1-メチル-3-(チアゾール-2-イル)-1H-ピラゾール-4-イル)メタノン(実施例55); [2,2′-bipyridin] -3-yl (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone ( Example 51);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl-2,2,4,4-d4) (1- (pyridine- 2-yl) -1H-pyrazol-5-yl) methanone (Example 52);
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3- Yl-2,2,4,4-d4) methanone (Example 53);
(2-Methyl-4-phenylthiazol-5-yl) (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) Methanone (Example 54);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1-methyl-3- (thiazol-2-yl) -1H -Pyrazol-4-yl) methanone (Example 55);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル-2,2,4,4-d4)(1-(ピリジン-2-イル)-1H-ピラゾール-5-イル)メタノン(実施例52);
(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル-2,2,4,4-d4)メタノン(実施例53);
(2-メチル-4-フェニルチアゾール-5-イル)(8-(4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例54);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(1-メチル-3-(チアゾール-2-イル)-1H-ピラゾール-4-イル)メタノン(実施例55); [2,2′-bipyridin] -3-yl (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone ( Example 51);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl-2,2,4,4-d4) (1- (pyridine- 2-yl) -1H-pyrazol-5-yl) methanone (Example 52);
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3- Yl-2,2,4,4-d4) methanone (Example 53);
(2-Methyl-4-phenylthiazol-5-yl) (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) Methanone (Example 54);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1-methyl-3- (thiazol-2-yl) -1H -Pyrazol-4-yl) methanone (Example 55);
(3-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例56);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(3-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン(実施例57);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(4-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン(実施例58);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(5-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン(実施例59);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン(実施例60); (3-Fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8- Diazabicyclo [3.2.1] octane-3-yl) methanone (Example 56);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (3-fluoro-2- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 57);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-fluoro-2- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 58);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (5-fluoro-2- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 59);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-6- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 60);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(3-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン(実施例57);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(4-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン(実施例58);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(5-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン(実施例59);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン(実施例60); (3-Fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8- Diazabicyclo [3.2.1] octane-3-yl) methanone (Example 56);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (3-fluoro-2- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 57);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-fluoro-2- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 58);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (5-fluoro-2- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 59);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-6- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 60);
(2-クロロ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例61);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(4-メチル-2-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン(実施例62);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-メトキシ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン(実施例63);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(4-メトキシ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン(実施例64);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(4-フルオロ-2-(ピリミジン-2-イル)フェニル)メタノン(実施例65); (2-Chloro-6- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2. 1] Octane-3-yl) methanone (Example 61);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-methyl-2- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 62);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-methoxy-6- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 63);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-methoxy-2- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 64);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-fluoro-2- (pyrimidin-2-yl) phenyl) Methanone (Example 65);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(4-メチル-2-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン(実施例62);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-メトキシ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン(実施例63);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(4-メトキシ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン(実施例64);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(4-フルオロ-2-(ピリミジン-2-イル)フェニル)メタノン(実施例65); (2-Chloro-6- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2. 1] Octane-3-yl) methanone (Example 61);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-methyl-2- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 62);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-methoxy-6- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 63);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-methoxy-2- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 64);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-fluoro-2- (pyrimidin-2-yl) phenyl) Methanone (Example 65);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(チアゾール-2-イル)ピリジン-3-イル)メタノン(実施例66);
(2-(1H-1,2,3-トリアゾール-1-イル)ピリジン-3-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例67);
(2-(2H-1,2,3-トリアゾール-2-イル)ピリジン-3-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例68);
(2-メトキシ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例69);
2-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例70); (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (thiazol-2-yl) pyridin-3-yl) Methanone (Example 66);
(2- (1H-1,2,3-triazol-1-yl) pyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2. 1] Octane-3-yl) methanone (Example 67);
(2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2. 1] Octane-3-yl) methanone (Example 68);
(2-Methoxy-6- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3. 2.1] octane-3-yl) methanone (Example 69);
2- (3- (2- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile Example 70);
(2-(1H-1,2,3-トリアゾール-1-イル)ピリジン-3-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例67);
(2-(2H-1,2,3-トリアゾール-2-イル)ピリジン-3-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例68);
(2-メトキシ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例69);
2-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例70); (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (thiazol-2-yl) pyridin-3-yl) Methanone (Example 66);
(2- (1H-1,2,3-triazol-1-yl) pyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2. 1] Octane-3-yl) methanone (Example 67);
(2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2. 1] Octane-3-yl) methanone (Example 68);
(2-Methoxy-6- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3. 2.1] octane-3-yl) methanone (Example 69);
2- (3- (2- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile Example 70);
2-(3-(2-メトキシ-6-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例71);
2-(3-(3-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例72);
3-メトキシ-2-(3-(2-メトキシ-6-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例73);
2-(3-(4-フルオロ-2-(ピリミジン-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例74);
2-(3-(2-(チアゾール-2-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例75); 2- (3- (2-Methoxy-6- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicoti Nononitrile (Example 71);
2- (3- (3-Fluoro-2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3 -Methoxyisonicotinonitrile (Example 72);
3-Methoxy-2- (3- (2-methoxy-6- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8- Yl) isonicotinonitrile (Example 73);
2- (3- (4-Fluoro-2- (pyrimidin-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Example 74);
2- (3- (2- (thiazol-2-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Example 75);
2-(3-(3-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例72);
3-メトキシ-2-(3-(2-メトキシ-6-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例73);
2-(3-(4-フルオロ-2-(ピリミジン-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例74);
2-(3-(2-(チアゾール-2-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例75); 2- (3- (2-Methoxy-6- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicoti Nononitrile (Example 71);
2- (3- (3-Fluoro-2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3 -Methoxyisonicotinonitrile (Example 72);
3-Methoxy-2- (3- (2-methoxy-6- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8- Yl) isonicotinonitrile (Example 73);
2- (3- (4-Fluoro-2- (pyrimidin-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Example 74);
2- (3- (2- (thiazol-2-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Example 75);
(2-(2H-テトラゾール-2-イル)フェニル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例76);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例77);
[1,1’-ビフェニル]-2-イル(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例78);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(6-メチル-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例79);
(4-クロロ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例80); (2- (2H-tetrazol-2-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone ( Example 76);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane- 3-yl) methanone (Example 77);
[1,1′-biphenyl] -2-yl (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Examples) 78);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3. 2.1] octane-3-yl) methanone (Example 79);
(4-Chloro-2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8- Diazabicyclo [3.2.1] octane-3-yl) methanone (Example 80);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例77);
[1,1’-ビフェニル]-2-イル(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例78);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(6-メチル-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例79);
(4-クロロ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例80); (2- (2H-tetrazol-2-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone ( Example 76);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane- 3-yl) methanone (Example 77);
[1,1′-biphenyl] -2-yl (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Examples) 78);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3. 2.1] octane-3-yl) methanone (Example 79);
(4-Chloro-2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8- Diazabicyclo [3.2.1] octane-3-yl) methanone (Example 80);
(4-メトキシ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例81);
2-(3-(4-クロロ-2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例82);
3-メトキシ-2-(3-(4-メトキシ-2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例83);
(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例84);
(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例85); (4-Methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8- Diazabicyclo [3.2.1] octane-3-yl) methanone (Example 81);
2- (3- (4-Chloro-2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3 -Methoxyisonicotinonitrile (Example 82);
3-methoxy-2- (3- (4-methoxy-2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8- Yl) isonicotinonitrile (Example 83);
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane- 3-yl) methanone (Example 84);
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2. 1] Octane-3-yl) methanone (Example 85);
2-(3-(4-クロロ-2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例82);
3-メトキシ-2-(3-(4-メトキシ-2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例83);
(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例84);
(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例85); (4-Methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8- Diazabicyclo [3.2.1] octane-3-yl) methanone (Example 81);
2- (3- (4-Chloro-2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3 -Methoxyisonicotinonitrile (Example 82);
3-methoxy-2- (3- (4-methoxy-2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8- Yl) isonicotinonitrile (Example 83);
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane- 3-yl) methanone (Example 84);
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2. 1] Octane-3-yl) methanone (Example 85);
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例86);
2-(3-([2,2’-ビピリジン]-3-カルボニル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例87);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(1,1,2,2-テトラフルオロエトキシ)フェニル)メタノン(実施例88);
2-(3-(2-(1,1,2,2-テトラフルオロエトキシ)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例89);
3-メトキシ-2-(3-(4-メトキシ-2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例90); 2- (3- (2- (1- (1-H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Example 86);
2- (3-([2,2′-bipyridine] -3-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (Example 87) );
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (1,1,2,2-tetrafluoroethoxy) Phenyl) methanone (Example 88);
2- (3- (2- (1,1,2,2-tetrafluoroethoxy) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Example 89) );
3-methoxy-2- (3- (4-methoxy-2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Example 90);
2-(3-([2,2’-ビピリジン]-3-カルボニル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例87);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(1,1,2,2-テトラフルオロエトキシ)フェニル)メタノン(実施例88);
2-(3-(2-(1,1,2,2-テトラフルオロエトキシ)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例89);
3-メトキシ-2-(3-(4-メトキシ-2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例90); 2- (3- (2- (1- (1-H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Example 86);
2- (3-([2,2′-bipyridine] -3-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (Example 87) );
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (1,1,2,2-tetrafluoroethoxy) Phenyl) methanone (Example 88);
2- (3- (2- (1,1,2,2-tetrafluoroethoxy) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Example 89) );
3-methoxy-2- (3- (4-methoxy-2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Example 90);
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例91);
(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例92);
(2-(チアゾール-2-イル)ピリジン-3-イル)(8-(4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例93);
(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(チアゾール-2-イル)ピリジン-3-イル)メタノン(実施例94);
3-メトキシ-2-(3-(2-(チアゾール-2-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例95); 2- (3- (2- (1 (H) pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (Example 91) );
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3- Yl) methanone (Example 92);
(2- (thiazol-2-yl) pyridin-3-yl) (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3- Yl) methanone (Example 93);
(8- (3-Methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (thiazol-2-yl) Pyridin-3-yl) methanone (Example 94);
3-methoxy-2- (3- (2- (2- (thiazol-2-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Example 95);
(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例92);
(2-(チアゾール-2-イル)ピリジン-3-イル)(8-(4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例93);
(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(チアゾール-2-イル)ピリジン-3-イル)メタノン(実施例94);
3-メトキシ-2-(3-(2-(チアゾール-2-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例95); 2- (3- (2- (1 (H) pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (Example 91) );
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3- Yl) methanone (Example 92);
(2- (thiazol-2-yl) pyridin-3-yl) (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3- Yl) methanone (Example 93);
(8- (3-Methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (thiazol-2-yl) Pyridin-3-yl) methanone (Example 94);
3-methoxy-2- (3- (2- (2- (thiazol-2-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Example 95);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(3-メトキシ-6-メチルピラジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例96);
(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(3-メトキシ-6-メチルピラジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例97);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(4-エトキシ-2-(1H-ピラゾール-1-イル)ピリジン-3-イル)メタノン(実施例98);
2-(3-(4-エトキシ-2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例99);
(4-エトキシ-2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例100); (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-6-methylpyrazin-2-yl) -3,8-diazabicyclo [3.2.1] Octan-3-yl) methanone (Example 96);
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (3-methoxy-6-methylpyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane- 3-yl) methanone (Example 97);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-ethoxy-2- (1H-pyrazol-1-yl) Pyridin-3-yl) methanone (Example 98);
2- (3- (4-Ethoxy-2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (Example 99);
(4-Ethoxy-2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2. 1] Octane-3-yl) methanone (Example 100);
(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(3-メトキシ-6-メチルピラジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例97);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(4-エトキシ-2-(1H-ピラゾール-1-イル)ピリジン-3-イル)メタノン(実施例98);
2-(3-(4-エトキシ-2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例99);
(4-エトキシ-2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例100); (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-6-methylpyrazin-2-yl) -3,8-diazabicyclo [3.2.1] Octan-3-yl) methanone (Example 96);
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (3-methoxy-6-methylpyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane- 3-yl) methanone (Example 97);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-ethoxy-2- (1H-pyrazol-1-yl) Pyridin-3-yl) methanone (Example 98);
2- (3- (4-Ethoxy-2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (Example 99);
(4-Ethoxy-2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2. 1] Octane-3-yl) methanone (Example 100);
(4-クロロ-2-(ピリミジン-2-イル)フェニル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例101);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(5-フルオロ-3-(ピリミジン-2-イル)ピリジン-2-イル)メタノン(実施例102);
(5-フルオロ-3-(ピリミジン-2-イル)ピリジン-2-イル)(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例103);
2-(3-(5-フルオロ-3-(ピリミジン-2-イル)ピコリノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例104);
(4-フルオロ-2-(ピリミジン-2-イル)フェニル)(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例105); (4-Chloro-2- (pyrimidin-2-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) Methanone (Example 101);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (5-fluoro-3- (pyrimidin-2-yl) pyridine- 2-yl) methanone (Example 102);
(5-Fluoro-3- (pyrimidin-2-yl) pyridin-2-yl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3. 2.1] octane-3-yl) methanone (Example 103);
2- (3- (5-Fluoro-3- (pyrimidin-2-yl) picolinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile Example 104);
(4-Fluoro-2- (pyrimidin-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] Octan-3-yl) methanone (Example 105);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(5-フルオロ-3-(ピリミジン-2-イル)ピリジン-2-イル)メタノン(実施例102);
(5-フルオロ-3-(ピリミジン-2-イル)ピリジン-2-イル)(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例103);
2-(3-(5-フルオロ-3-(ピリミジン-2-イル)ピコリノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例104);
(4-フルオロ-2-(ピリミジン-2-イル)フェニル)(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例105); (4-Chloro-2- (pyrimidin-2-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) Methanone (Example 101);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (5-fluoro-3- (pyrimidin-2-yl) pyridine- 2-yl) methanone (Example 102);
(5-Fluoro-3- (pyrimidin-2-yl) pyridin-2-yl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3. 2.1] octane-3-yl) methanone (Example 103);
2- (3- (5-Fluoro-3- (pyrimidin-2-yl) picolinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile Example 104);
(4-Fluoro-2- (pyrimidin-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] Octan-3-yl) methanone (Example 105);
2-(3-(4-フルオロ-2-(ピリミジン-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例106);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(1-(チアゾール-2-イル)-1H-ピラゾール-5-イル)メタノン(実施例107);
3-メトキシ-2-(3-(1-(チアゾール-2-イル)-1H-ピラゾール-5-カルボニル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例108);
(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(1-(チアゾール-2-イル)-1H-ピラゾール-5-イル)メタノン(実施例109);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-ヨードフェニル)メタノン(実施例110); 2- (3- (4-Fluoro-2- (pyrimidin-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile Example 106);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1- (thiazol-2-yl) -1H-pyrazol-5 -Yl) methanone (Example 107);
3-methoxy-2- (3- (1- (thiazol-2-yl) -1H-pyrazol-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotino Nitrile (Example 108);
(8- (3-Methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1- (thiazol-2-yl) -1H-pyrazol-5-yl) methanone (Example 109);
(8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-iodophenyl) methanone (Example 110);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(1-(チアゾール-2-イル)-1H-ピラゾール-5-イル)メタノン(実施例107);
3-メトキシ-2-(3-(1-(チアゾール-2-イル)-1H-ピラゾール-5-カルボニル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(実施例108);
(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(1-(チアゾール-2-イル)-1H-ピラゾール-5-イル)メタノン(実施例109);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-ヨードフェニル)メタノン(実施例110); 2- (3- (4-Fluoro-2- (pyrimidin-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile Example 106);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1- (thiazol-2-yl) -1H-pyrazol-5 -Yl) methanone (Example 107);
3-methoxy-2- (3- (1- (thiazol-2-yl) -1H-pyrazol-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotino Nitrile (Example 108);
(8- (3-Methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1- (thiazol-2-yl) -1H-pyrazol-5-yl) methanone (Example 109);
(8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-iodophenyl) methanone (Example 110);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(オキサゾール-2-イル)フェニル)メタノン(実施例111);
(2-(1H-ピラゾール-3-イル)フェニル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例112);
(2-(1H-ピラゾール-4-イル)フェニル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例113);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(4’-フルオロ-[1,1’-ビフェニル]-2-イル)メタノン(実施例114);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(3’-メトキシ-[1,1’-ビフェニル]-2-イル)メタノン(実施例115); (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (oxazol-2-yl) phenyl) methanone (Examples) 111);
(2- (1H-pyrazol-3-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone ( Example 112);
(2- (1H-pyrazol-4-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone ( Example 113);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4′-fluoro- [1,1′-biphenyl] -2 -Yl) methanone (Example 114);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (3′-methoxy- [1,1′-biphenyl] -2 -Yl) methanone (Example 115);
(2-(1H-ピラゾール-3-イル)フェニル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例112);
(2-(1H-ピラゾール-4-イル)フェニル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例113);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(4’-フルオロ-[1,1’-ビフェニル]-2-イル)メタノン(実施例114);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(3’-メトキシ-[1,1’-ビフェニル]-2-イル)メタノン(実施例115); (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (oxazol-2-yl) phenyl) methanone (Examples) 111);
(2- (1H-pyrazol-3-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone ( Example 112);
(2- (1H-pyrazol-4-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone ( Example 113);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4′-fluoro- [1,1′-biphenyl] -2 -Yl) methanone (Example 114);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (3′-methoxy- [1,1′-biphenyl] -2 -Yl) methanone (Example 115);
(3’-(ジフルオロメトキシ)-[1,1’-ビフェニル]-2-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例116);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(イソチアゾール-4-イル)フェニル)メタノン(実施例117);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(3-メチルイソチアゾール-5-イル)フェニル)メタノン(実施例118);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(チアゾール-4-イル)フェニル)メタノン(実施例119);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(チアゾール-5-イル)フェニル)メタノン(実施例120); (3 ′-(Difluoromethoxy)-[1,1′-biphenyl] -2-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] Octan-3-yl) methanone (Example 116);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (isothiazol-4-yl) phenyl) methanone Example 117);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (3-methylisothiazol-5-yl) phenyl) Methanone (Example 118);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (thiazol-4-yl) phenyl) methanone (Examples) 119);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (thiazol-5-yl) phenyl) methanone (Examples) 120);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(イソチアゾール-4-イル)フェニル)メタノン(実施例117);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(3-メチルイソチアゾール-5-イル)フェニル)メタノン(実施例118);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(チアゾール-4-イル)フェニル)メタノン(実施例119);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(チアゾール-5-イル)フェニル)メタノン(実施例120); (3 ′-(Difluoromethoxy)-[1,1′-biphenyl] -2-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] Octan-3-yl) methanone (Example 116);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (isothiazol-4-yl) phenyl) methanone Example 117);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (3-methylisothiazol-5-yl) phenyl) Methanone (Example 118);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (thiazol-4-yl) phenyl) methanone (Examples) 119);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (thiazol-5-yl) phenyl) methanone (Examples) 120);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(チアゾール-2-イル)フェニル)メタノン(実施例121);
2-(2-(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボニル)フェニル)チアゾール-4-カルボニトリル(実施例122);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(ピリジン-2-イル)フェニル)メタノン(実施例123);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(6-メチルピリジン-2-イル)フェニル)メタノン(実施例124);
6-(2-(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボニル)フェニル)ピコリノニトリル(実施例125); (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (thiazol-2-yl) phenyl) methanone (Examples) 121);
2- (2- (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carbonyl) phenyl) thiazole-4-carbonitrile (Examples) 122);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (pyridin-2-yl) phenyl) methanone (Examples) 123);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (6-methylpyridin-2-yl) phenyl) methanone (Example 124);
6- (2- (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carbonyl) phenyl) picolinonitrile (Example 125);
2-(2-(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボニル)フェニル)チアゾール-4-カルボニトリル(実施例122);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(ピリジン-2-イル)フェニル)メタノン(実施例123);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(6-メチルピリジン-2-イル)フェニル)メタノン(実施例124);
6-(2-(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボニル)フェニル)ピコリノニトリル(実施例125); (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (thiazol-2-yl) phenyl) methanone (Examples) 121);
2- (2- (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carbonyl) phenyl) thiazole-4-carbonitrile (Examples) 122);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (pyridin-2-yl) phenyl) methanone (Examples) 123);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (6-methylpyridin-2-yl) phenyl) methanone (Example 124);
6- (2- (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carbonyl) phenyl) picolinonitrile (Example 125);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(6-メトキシピリジン-2-イル)フェニル)メタノン(実施例126);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4,6-ジメチルピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例127);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例128);
(8-(4,5-ジメチルチアゾール-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン(実施例129);
2-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-6-メチルイソニコチノニトリル(実施例130); (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (6-methoxypyridin-2-yl) phenyl) methanone (Example 126);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,6-dimethylpyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane- 3-yl) methanone (Example 127);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] Octan-3-yl) methanone (Example 128);
(8- (4,5-Dimethylthiazol-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-6- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 129);
2- (3- (2- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -6-methylisonicoti Nononitrile (Example 130);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4,6-ジメチルピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例127);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例128);
(8-(4,5-ジメチルチアゾール-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン(実施例129);
2-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-6-メチルイソニコチノニトリル(実施例130); (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (6-methoxypyridin-2-yl) phenyl) methanone (Example 126);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,6-dimethylpyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane- 3-yl) methanone (Example 127);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] Octan-3-yl) methanone (Example 128);
(8- (4,5-Dimethylthiazol-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-6- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 129);
2- (3- (2- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -6-methylisonicoti Nononitrile (Example 130);
(8-(3,5-ジメチルフェニル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン(実施例131);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4-(ジフルオロメトキシ)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例132);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例133);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(3-メチル-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例134);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(フロ[3,2-c]ピリジン-4-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例135); (8- (3,5-Dimethylphenyl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-6- (2H-1,2,3-triazole-2- Yl) phenyl) methanone (Example 131);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4- (difluoromethoxy) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane -3-yl) methanone (Example 132);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3. 2.1] octane-3-yl) methanone (Example 133);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methyl-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3. 2.1] octane-3-yl) methanone (Example 134);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (furo [3,2-c] pyridin-4-yl) -3,8-diazabicyclo [3.2.1] ] Octane-3-yl) methanone (Example 135);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4-(ジフルオロメトキシ)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例132);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例133);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(3-メチル-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例134);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(フロ[3,2-c]ピリジン-4-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例135); (8- (3,5-Dimethylphenyl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-6- (2H-1,2,3-triazole-2- Yl) phenyl) methanone (Example 131);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4- (difluoromethoxy) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane -3-yl) methanone (Example 132);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3. 2.1] octane-3-yl) methanone (Example 133);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methyl-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3. 2.1] octane-3-yl) methanone (Example 134);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (furo [3,2-c] pyridin-4-yl) -3,8-diazabicyclo [3.2.1] ] Octane-3-yl) methanone (Example 135);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(フロ[2,3-c]ピリジン-7-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例136);
(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(フロ[3,2-c]ピリジン-4-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例137);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(1-メチル-1H-インダゾール-3-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例138);
(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(1-メチル-1H-インダゾール-3-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例139);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(1-メチル-1H-ピラゾロ[4,3-b]ピリジン-3-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例140); (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (furo [2,3-c] pyridin-7-yl) -3,8-diazabicyclo [3.2.1] ] Octane-3-yl) methanone (Example 136);
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (furo [3,2-c] pyridin-4-yl) -3,8-diazabicyclo [3.2.1] octane -3-yl) methanone (Example 137);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (1-methyl-1H-indazol-3-yl) -3,8-diazabicyclo [3.2.1] octane -3-yl) methanone (Example 138);
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (1-methyl-1H-indazol-3-yl) -3,8-diazabicyclo [3.2.1] octane-3 -Yl) methanone (Example 139);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (1-methyl-1H-pyrazolo [4,3-b] pyridin-3-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 140);
(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(フロ[3,2-c]ピリジン-4-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例137);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(1-メチル-1H-インダゾール-3-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例138);
(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(1-メチル-1H-インダゾール-3-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例139);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(1-メチル-1H-ピラゾロ[4,3-b]ピリジン-3-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例140); (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (furo [2,3-c] pyridin-7-yl) -3,8-diazabicyclo [3.2.1] ] Octane-3-yl) methanone (Example 136);
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (furo [3,2-c] pyridin-4-yl) -3,8-diazabicyclo [3.2.1] octane -3-yl) methanone (Example 137);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (1-methyl-1H-indazol-3-yl) -3,8-diazabicyclo [3.2.1] octane -3-yl) methanone (Example 138);
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (1-methyl-1H-indazol-3-yl) -3,8-diazabicyclo [3.2.1] octane-3 -Yl) methanone (Example 139);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (1-methyl-1H-pyrazolo [4,3-b] pyridin-3-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 140);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(1-メチル-1H-ピラゾロ[4,3-c]ピリジン-3-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例141);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(1-メチル-1H-ピラゾロ[3,4-c]ピリジン-3-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例142);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(1-メチル-4,5,6,7-テトラヒドロ-1H-インダゾール-3-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例143);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(3-メチルイミダゾ[1,5-a]ピラジン-1-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例144);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(6-フルオロ-1-メチル-1H-インダゾール-3-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例145); (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (1-methyl-1H-pyrazolo [4,3-c] pyridin-3-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 141);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (1-methyl-1H-pyrazolo [3,4-c] pyridin-3-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 142);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (1-methyl-4,5,6,7-tetrahydro-1H-indazol-3-yl) -3,8 -Diazabicyclo [3.2.1] octane-3-yl) methanone (Example 143);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methylimidazo [1,5-a] pyrazin-1-yl) -3,8-diazabicyclo [3. 2.1] octane-3-yl) methanone (Example 144);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (6-fluoro-1-methyl-1H-indazol-3-yl) -3,8-diazabicyclo [3.2 .1] octane-3-yl) methanone (Example 145);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(1-メチル-1H-ピラゾロ[3,4-c]ピリジン-3-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例142);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(1-メチル-4,5,6,7-テトラヒドロ-1H-インダゾール-3-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例143);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(3-メチルイミダゾ[1,5-a]ピラジン-1-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例144);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(6-フルオロ-1-メチル-1H-インダゾール-3-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例145); (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (1-methyl-1H-pyrazolo [4,3-c] pyridin-3-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 141);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (1-methyl-1H-pyrazolo [3,4-c] pyridin-3-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 142);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (1-methyl-4,5,6,7-tetrahydro-1H-indazol-3-yl) -3,8 -Diazabicyclo [3.2.1] octane-3-yl) methanone (Example 143);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methylimidazo [1,5-a] pyrazin-1-yl) -3,8-diazabicyclo [3. 2.1] octane-3-yl) methanone (Example 144);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (6-fluoro-1-methyl-1H-indazol-3-yl) -3,8-diazabicyclo [3.2 .1] octane-3-yl) methanone (Example 145);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(5-フルオロ-1-メチル-1H-インダゾール-3-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例146);
2-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例147);
2-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メチルイソニコチノニトリル(実施例148);
2-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-エトキシイソニコチノニトリル(実施例149);
2-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-(メトキシ-d3)イソニコチノニトリル(実施例150); (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (5-fluoro-1-methyl-1H-indazol-3-yl) -3,8-diazabicyclo [3.2 .1] octane-3-yl) methanone (Example 146);
2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicoti Nononitrile (Example 147);
2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methylisonicoti Nononitrile (Example 148);
2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-ethoxyisonicoti Nononitrile (Example 149);
2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (methoxy- d3) Isonicotinonitrile (Example 150);
2-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(実施例147);
2-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メチルイソニコチノニトリル(実施例148);
2-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-エトキシイソニコチノニトリル(実施例149);
2-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-(メトキシ-d3)イソニコチノニトリル(実施例150); (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (5-fluoro-1-methyl-1H-indazol-3-yl) -3,8-diazabicyclo [3.2 .1] octane-3-yl) methanone (Example 146);
2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicoti Nononitrile (Example 147);
2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methylisonicoti Nononitrile (Example 148);
2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-ethoxyisonicoti Nononitrile (Example 149);
2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (methoxy- d3) Isonicotinonitrile (Example 150);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4-(2,2,2-トリフルオロ-1-ヒドロキシエチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例151);
2-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチン酸メチル(実施例152);
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-(メトキシ-d3)イソニコチノニトリル(実施例153);
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-エトキシイソニコチノニトリル(実施例154);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4-エチル-6-メチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例155); (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4- (2,2,2-trifluoro-1-hydroxyethyl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 151);
2- (3- (2- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinate methyl Example 152);
2- (3- (2- (1 (H) pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (methoxy-d3) isonicotinonitrile (Example 153);
2- (3- (2- (1 (H) pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-ethoxyisonicotinonitrile (Example 154) );
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4-ethyl-6-methylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] Octan-3-yl) methanone (Example 155);
2-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチン酸メチル(実施例152);
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-(メトキシ-d3)イソニコチノニトリル(実施例153);
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-エトキシイソニコチノニトリル(実施例154);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4-エチル-6-メチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例155); (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4- (2,2,2-trifluoro-1-hydroxyethyl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 151);
2- (3- (2- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinate methyl Example 152);
2- (3- (2- (1 (H) pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (methoxy-d3) isonicotinonitrile (Example 153);
2- (3- (2- (1 (H) pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-ethoxyisonicotinonitrile (Example 154) );
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4-ethyl-6-methylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] Octan-3-yl) methanone (Example 155);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4,5-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例156);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4,5,6-トリメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例157);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4-シクロプロピル-6-メチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例158);
(2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4-メトキシ-6-メチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例159);
1-(2-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)ピリジン-4-イル)エタン-1-オン(実施例160); (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,5-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane- 3-yl) methanone (Example 156);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,5,6-trimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] Octan-3-yl) methanone (Example 157);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4-cyclopropyl-6-methylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1 ] Octane-3-yl) methanone (Example 158);
(2-Fluoro-6- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4-methoxy-6-methylpyrimidin-2-yl) -3,8-diazabicyclo [3. 2.1] octane-3-yl) methanone (Example 159);
1- (2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) pyridine-4 -Yl) ethane-1-one (Example 160);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4,5,6-トリメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例157);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4-シクロプロピル-6-メチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例158);
(2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4-メトキシ-6-メチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例159);
1-(2-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)ピリジン-4-イル)エタン-1-オン(実施例160); (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,5-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane- 3-yl) methanone (Example 156);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,5,6-trimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] Octan-3-yl) methanone (Example 157);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4-cyclopropyl-6-methylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1 ] Octane-3-yl) methanone (Example 158);
(2-Fluoro-6- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4-methoxy-6-methylpyrimidin-2-yl) -3,8-diazabicyclo [3. 2.1] octane-3-yl) methanone (Example 159);
1- (2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) pyridine-4 -Yl) ethane-1-one (Example 160);
2-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-クロロイソニコチノニトリル(実施例161);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(3-メチル-1H-ピラゾール-1-イル)ピリジン-3-イル)メタノン(実施例162);
1-(3-(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボニル)ピリジン-2-イル)-1H-ピラゾール-3-カルボニトリル(実施例163);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-モルホリノピリジン-3-イル)メタノン(実施例164);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(ピロリジン-1-イル)ピリジン-3-イル)メタノン(実施例165); 2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-chloroisonicoti Nononitrile (Example 161);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (3-methyl-1H-pyrazol-1-yl) Pyridin-3-yl) methanone (Example 162);
1- (3- (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carbonyl) pyridin-2-yl) -1H-pyrazole- 3-carbonitrile (Example 163);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-morpholinopyridin-3-yl) methanone (Example 164) ;
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (pyrrolidin-1-yl) pyridin-3-yl) Methanone (Example 165);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(3-メチル-1H-ピラゾール-1-イル)ピリジン-3-イル)メタノン(実施例162);
1-(3-(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボニル)ピリジン-2-イル)-1H-ピラゾール-3-カルボニトリル(実施例163);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-モルホリノピリジン-3-イル)メタノン(実施例164);
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(ピロリジン-1-イル)ピリジン-3-イル)メタノン(実施例165); 2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-chloroisonicoti Nononitrile (Example 161);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (3-methyl-1H-pyrazol-1-yl) Pyridin-3-yl) methanone (Example 162);
1- (3- (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carbonyl) pyridin-2-yl) -1H-pyrazole- 3-carbonitrile (Example 163);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-morpholinopyridin-3-yl) methanone (Example 164) ;
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (pyrrolidin-1-yl) pyridin-3-yl) Methanone (Example 165);
(2,5-ジ(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例166);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(2,3-ジヒドロフロ[3,2-c]ピリジン-4-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例167);
(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(2,3-ジヒドロフロ[3,2-c]ピリジン-4-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例168);
3-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-1,5-ジメチルピラジン-2(1H)-オン(実施例169);
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-シクロプロピルイソニコチノニトリル(実施例170); (2,5-di (1H-pyrazol-1-yl) pyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane -3-yl) methanone (Example 166);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (2,3-dihydrofuro [3,2-c] pyridin-4-yl) -3,8-diazabicyclo [3 2.1] octan-3-yl) methanone (Example 167);
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (2,3-dihydrofuro [3,2-c] pyridin-4-yl) -3,8-diazabicyclo [3.2 .1] octane-3-yl) methanone (Example 168);
3- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -1,5-dimethyl Pyrazin-2 (1H) -one (Example 169);
2- (3- (2- (1 (H) pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-cyclopropylisonicotinonitrile (Examples) 170);
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(2,3-ジヒドロフロ[3,2-c]ピリジン-4-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例167);
(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(2,3-ジヒドロフロ[3,2-c]ピリジン-4-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例168);
3-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-1,5-ジメチルピラジン-2(1H)-オン(実施例169);
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-シクロプロピルイソニコチノニトリル(実施例170); (2,5-di (1H-pyrazol-1-yl) pyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane -3-yl) methanone (Example 166);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (2,3-dihydrofuro [3,2-c] pyridin-4-yl) -3,8-diazabicyclo [3 2.1] octan-3-yl) methanone (Example 167);
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (2,3-dihydrofuro [3,2-c] pyridin-4-yl) -3,8-diazabicyclo [3.2 .1] octane-3-yl) methanone (Example 168);
3- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -1,5-dimethyl Pyrazin-2 (1H) -one (Example 169);
2- (3- (2- (1 (H) pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-cyclopropylisonicotinonitrile (Examples) 170);
2-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-シクロプロピルイソニコチノニトリル(実施例171);
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-(ピロリジン-1-イル)イソニコチノニトリル(実施例172);
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-(メチルチオ)イソニコチノニトリル(実施例173);
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-(ジメチルアミノ)イソニコチノニトリル(実施例174);
(6-(4,6-ジメチルピリミジン-2-イル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)(2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン(実施例175);
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-6-イル)-3-メトキシイソニコチノニトリル(実施例176)。 2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-cyclopropyliso Nicotinonitrile (Example 171);
2- (3- (2- (1 (H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (pyrrolidin-1-yl) isonicoti Nononitrile (Example 172);
2- (3- (2- (1- (1-H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (methylthio) isonicotinonitrile Example 173);
2- (3- (2- (1 (H) pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (dimethylamino) isonicotinonitrile ( Example 174);
(6- (4,6-Dimethylpyrimidin-2-yl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) (2-fluoro-6- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 175);
2- (3- (2- (1 (H-pyrazol-1-yl) nicotinoyl) -3,6-diazabicyclo [3.1.1] heptan-6-yl) -3-methoxyisonicotinonitrile (Example 176) ).
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-(ピロリジン-1-イル)イソニコチノニトリル(実施例172);
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-(メチルチオ)イソニコチノニトリル(実施例173);
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-(ジメチルアミノ)イソニコチノニトリル(実施例174);
(6-(4,6-ジメチルピリミジン-2-イル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)(2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン(実施例175);
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-6-イル)-3-メトキシイソニコチノニトリル(実施例176)。 2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-cyclopropyliso Nicotinonitrile (Example 171);
2- (3- (2- (1 (H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (pyrrolidin-1-yl) isonicoti Nononitrile (Example 172);
2- (3- (2- (1- (1-H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (methylthio) isonicotinonitrile Example 173);
2- (3- (2- (1 (H) pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (dimethylamino) isonicotinonitrile ( Example 174);
(6- (4,6-Dimethylpyrimidin-2-yl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) (2-fluoro-6- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 175);
2- (3- (2- (1 (H-pyrazol-1-yl) nicotinoyl) -3,6-diazabicyclo [3.1.1] heptan-6-yl) -3-methoxyisonicotinonitrile (Example 176) ).
[7]本発明の第7の態様は、上記式(I)で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも1つを有効成分として含有することを特徴とする、医薬組成物である。
[7] A seventh aspect of the present invention contains at least one of the compound represented by the above formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. It is a pharmaceutical composition characterized by these.
[8]本発明の第8の態様は、上記式(I)で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも1つを有効成分として含有することを特徴とする、オレキシン受容体が関与する疾患の予防及び/または治療剤である。
オレキシン受容体が関与する疾患として、不眠症、概日リズム睡眠障害、睡眠時随伴症等の睡眠障害;うつ病、不安障害、双極性障害、注意欠陥多動性障害、自閉症、自閉症スペクトラム障害、薬物依存症等の精神疾患;アルツハイマー病等の神経変性疾患;認知症等の記憶障害;および過食症等の摂食障害、等が挙げられる。 [8] An eighth aspect of the present invention contains at least one of the compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. Is a prophylactic and / or therapeutic agent for a disease involving orexin receptor.
Diseases involving orexin receptors include sleep disorders such as insomnia, circadian rhythm sleep disorder, and sleep-related sleep disorder; depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, autism, autism Spectrum disorders, mental disorders such as drug dependence; neurodegenerative diseases such as Alzheimer's disease; memory disorders such as dementia; and eating disorders such as bulimia.
オレキシン受容体が関与する疾患として、不眠症、概日リズム睡眠障害、睡眠時随伴症等の睡眠障害;うつ病、不安障害、双極性障害、注意欠陥多動性障害、自閉症、自閉症スペクトラム障害、薬物依存症等の精神疾患;アルツハイマー病等の神経変性疾患;認知症等の記憶障害;および過食症等の摂食障害、等が挙げられる。 [8] An eighth aspect of the present invention contains at least one of the compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. Is a prophylactic and / or therapeutic agent for a disease involving orexin receptor.
Diseases involving orexin receptors include sleep disorders such as insomnia, circadian rhythm sleep disorder, and sleep-related sleep disorder; depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, autism, autism Spectrum disorders, mental disorders such as drug dependence; neurodegenerative diseases such as Alzheimer's disease; memory disorders such as dementia; and eating disorders such as bulimia.
[9]本発明の第9の態様は、上記式(I)で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも1つを有効成分として含有することを特徴とする、睡眠障害、精神疾患、神経変性疾患、記憶障害または摂食障害の予防及び/または治療剤である。
好ましくは、上記式(I)で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも1つを有効成分として含有することを特徴とする、睡眠障害の予防及び/または治療剤であり、より好ましくは、不眠症の予防及び/または治療剤である。
本明細書中、特に断りのない限り、「睡眠障害」として、具体的には、不眠症、概日リズム睡眠障害、睡眠時随伴症等が挙げられる。不眠症として、より具体的には、原発性不眠症、精神疾患による不眠症、身体疾患による不眠症、薬物による不眠症等が挙げられる。但し、これらに限定されるものではない。
本明細書中、特に断りのない限り、「精神疾患」として、具体的には、うつ病、不安障害、双極性障害、注意欠陥多動性障害、自閉症、自閉症スペクトラム障害、薬物依存症等が挙げられる。但し、これらに限定されるものではない。
本明細書中、特に断りのない限り、「神経変性疾患」として、具体的には、アルツハイマー病等が挙げられる。但し、これらに限定されるものではない。
本明細書中、特に断りのない限り、「記憶障害」として、具体的には、認知症等が挙げられる。但し、これらに限定されるものではない。
本明細書中、特に断りのない限り、「摂食障害」として、具体的には、過食症等が挙げられる。但し、これらに限定されるものではない。 [9] A ninth aspect of the present invention contains at least one of the compound represented by the above formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. A prophylactic and / or therapeutic agent for sleep disorders, mental disorders, neurodegenerative diseases, memory disorders or eating disorders.
Preferably, at least one of the compound represented by the above formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof is contained as an active ingredient, thereby preventing sleep disorder And / or a therapeutic agent, more preferably a prophylactic and / or therapeutic agent for insomnia.
In the present specification, unless otherwise specified, examples of the “sleep disorder” include insomnia, circadian rhythm sleep disorder, and sleep-related complications. More specific examples of insomnia include primary insomnia, insomnia due to mental illness, insomnia due to physical disease, insomnia due to drugs, and the like. However, it is not limited to these.
In this specification, unless otherwise specified, as a “mental disorder”, specifically, depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, autism, autism spectrum disorder, drug Addiction etc. are mentioned. However, it is not limited to these.
In the present specification, unless otherwise specified, examples of the “neurodegenerative disease” include Alzheimer's disease. However, it is not limited to these.
In the present specification, unless otherwise specified, the “memory disorder” specifically includes dementia and the like. However, it is not limited to these.
Unless otherwise specified, in this specification, “eating disorders” specifically includes bulimia and the like. However, it is not limited to these.
好ましくは、上記式(I)で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも1つを有効成分として含有することを特徴とする、睡眠障害の予防及び/または治療剤であり、より好ましくは、不眠症の予防及び/または治療剤である。
本明細書中、特に断りのない限り、「睡眠障害」として、具体的には、不眠症、概日リズム睡眠障害、睡眠時随伴症等が挙げられる。不眠症として、より具体的には、原発性不眠症、精神疾患による不眠症、身体疾患による不眠症、薬物による不眠症等が挙げられる。但し、これらに限定されるものではない。
本明細書中、特に断りのない限り、「精神疾患」として、具体的には、うつ病、不安障害、双極性障害、注意欠陥多動性障害、自閉症、自閉症スペクトラム障害、薬物依存症等が挙げられる。但し、これらに限定されるものではない。
本明細書中、特に断りのない限り、「神経変性疾患」として、具体的には、アルツハイマー病等が挙げられる。但し、これらに限定されるものではない。
本明細書中、特に断りのない限り、「記憶障害」として、具体的には、認知症等が挙げられる。但し、これらに限定されるものではない。
本明細書中、特に断りのない限り、「摂食障害」として、具体的には、過食症等が挙げられる。但し、これらに限定されるものではない。 [9] A ninth aspect of the present invention contains at least one of the compound represented by the above formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. A prophylactic and / or therapeutic agent for sleep disorders, mental disorders, neurodegenerative diseases, memory disorders or eating disorders.
Preferably, at least one of the compound represented by the above formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof is contained as an active ingredient, thereby preventing sleep disorder And / or a therapeutic agent, more preferably a prophylactic and / or therapeutic agent for insomnia.
In the present specification, unless otherwise specified, examples of the “sleep disorder” include insomnia, circadian rhythm sleep disorder, and sleep-related complications. More specific examples of insomnia include primary insomnia, insomnia due to mental illness, insomnia due to physical disease, insomnia due to drugs, and the like. However, it is not limited to these.
In this specification, unless otherwise specified, as a “mental disorder”, specifically, depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, autism, autism spectrum disorder, drug Addiction etc. are mentioned. However, it is not limited to these.
In the present specification, unless otherwise specified, examples of the “neurodegenerative disease” include Alzheimer's disease. However, it is not limited to these.
In the present specification, unless otherwise specified, the “memory disorder” specifically includes dementia and the like. However, it is not limited to these.
Unless otherwise specified, in this specification, “eating disorders” specifically includes bulimia and the like. However, it is not limited to these.
[10]本発明の第10の態様は、上記式(I)で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の1つ以上からなるオレキシン受容体拮抗剤である。
本発明の別の態様は、上記式(I)で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の1つ以上からなるオレキシン2受容体選択的拮抗剤である。
また、本発明の別の態様は、上記式(I)で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の1つ以上からなるオレキシン受容体dual拮抗剤である。ここで、「オレキシン受容体dual拮抗剤」とは、オレキシン1受容体拮抗作用とオレキシン2受容体拮抗作用とを有するオレキシン受容体拮抗剤を意味する。 [10] A tenth aspect of the present invention is an orexin receptor antagonist comprising one or more of the compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof. It is.
Another aspect of the present invention is an orexin 2 receptor selective antagonist comprising one or more of the compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof. is there.
Another aspect of the present invention is an orexin receptor dual antagonist comprising one or more of the compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof. is there. Here, the “orexin receptor dual antagonist” means an orexin receptor antagonist having an orexin 1 receptor antagonistic action and an orexin 2 receptor antagonistic action.
本発明の別の態様は、上記式(I)で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の1つ以上からなるオレキシン2受容体選択的拮抗剤である。
また、本発明の別の態様は、上記式(I)で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の1つ以上からなるオレキシン受容体dual拮抗剤である。ここで、「オレキシン受容体dual拮抗剤」とは、オレキシン1受容体拮抗作用とオレキシン2受容体拮抗作用とを有するオレキシン受容体拮抗剤を意味する。 [10] A tenth aspect of the present invention is an orexin receptor antagonist comprising one or more of the compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof. It is.
Another aspect of the present invention is an orexin 2 receptor selective antagonist comprising one or more of the compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof. is there.
Another aspect of the present invention is an orexin receptor dual antagonist comprising one or more of the compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof. is there. Here, the “orexin receptor dual antagonist” means an orexin receptor antagonist having an orexin 1 receptor antagonistic action and an orexin 2 receptor antagonistic action.
[11]本発明の第11の態様は、上記式(I)で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも1つの医薬組成物としての使用である。
[12]本発明の第12の態様は、上記式(I)で表される化合物、または薬学的に許容できるその塩またはそれらの溶媒和物の少なくとも1つのオレキシン受容体拮抗剤としての使用である。 [11] An eleventh aspect of the present invention is the use of at least one pharmaceutical composition of a compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof. is there.
[12] A twelfth aspect of the present invention is the use of a compound represented by the above formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof as at least one orexin receptor antagonist. is there.
[12]本発明の第12の態様は、上記式(I)で表される化合物、または薬学的に許容できるその塩またはそれらの溶媒和物の少なくとも1つのオレキシン受容体拮抗剤としての使用である。 [11] An eleventh aspect of the present invention is the use of at least one pharmaceutical composition of a compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof. is there.
[12] A twelfth aspect of the present invention is the use of a compound represented by the above formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof as at least one orexin receptor antagonist. is there.
[13]本発明の第13の態様は、睡眠障害、精神疾患、神経変性疾患、記憶障害および摂食障害から選択される疾患を治療する方法であって、上記式(I)で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも1つを前記疾患または状態の治療を必要とする対象に投与することを含む方法である。
好ましくは、睡眠障害を治療する方法であって、上記式(I)で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも1つを前記疾患または状態の治療を必要とする対象に投与することを含む方法であり、より好ましくは不眠症を治療する方法である。
本明細書中、特に断りのない限り、「疾患または状態の治療」にあるような「治療」とは、「疾患または状態」の進行、または1つもしくは複数の「疾患または状態」を回復させる、緩和する、または抑制することを意味する。また、本明細書中、「治療」は、患者の状態に応じて、「疾患または状態」の発症またはその「疾患または状態」に関連する任意の症状の発症を予防することを包含する「疾患または状態」の予防、ならびに発症前に「疾患または状態」またはその任意の症状の重症度を低減することも包含する。本明細書では、「治療する」はある「疾患または状態」の再発を予防するおよび改善することも含むものとする。 [13] A thirteenth aspect of the present invention is a method for treating a disease selected from sleep disorder, mental disorder, neurodegenerative disorder, memory disorder and eating disorder, and is represented by the above formula (I) Administering at least one of a compound, or a pharmaceutically acceptable salt or solvate thereof, to a subject in need of treatment of said disease or condition.
Preferably, a method for treating a sleep disorder, wherein at least one of the compound represented by the above formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof is administered in the disease or condition. A method comprising administering to a subject in need of treatment, more preferably a method of treating insomnia.
In this specification, unless stated otherwise, “treatment” as in “treatment of a disease or condition” refers to the progression of a “disease or condition” or one or more “diseases or conditions”. Means to mitigate, or suppress. Further, in the present specification, “treatment” refers to “disease” including preventing the onset of “disease or condition” or any symptoms related to “disease or condition” depending on the condition of the patient. Or prevention of “a condition” as well as reducing the severity of a “disease or condition” or any symptom thereof before onset. As used herein, “treating” is intended to include preventing and ameliorating the recurrence of a “disease or condition”.
好ましくは、睡眠障害を治療する方法であって、上記式(I)で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも1つを前記疾患または状態の治療を必要とする対象に投与することを含む方法であり、より好ましくは不眠症を治療する方法である。
本明細書中、特に断りのない限り、「疾患または状態の治療」にあるような「治療」とは、「疾患または状態」の進行、または1つもしくは複数の「疾患または状態」を回復させる、緩和する、または抑制することを意味する。また、本明細書中、「治療」は、患者の状態に応じて、「疾患または状態」の発症またはその「疾患または状態」に関連する任意の症状の発症を予防することを包含する「疾患または状態」の予防、ならびに発症前に「疾患または状態」またはその任意の症状の重症度を低減することも包含する。本明細書では、「治療する」はある「疾患または状態」の再発を予防するおよび改善することも含むものとする。 [13] A thirteenth aspect of the present invention is a method for treating a disease selected from sleep disorder, mental disorder, neurodegenerative disorder, memory disorder and eating disorder, and is represented by the above formula (I) Administering at least one of a compound, or a pharmaceutically acceptable salt or solvate thereof, to a subject in need of treatment of said disease or condition.
Preferably, a method for treating a sleep disorder, wherein at least one of the compound represented by the above formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof is administered in the disease or condition. A method comprising administering to a subject in need of treatment, more preferably a method of treating insomnia.
In this specification, unless stated otherwise, “treatment” as in “treatment of a disease or condition” refers to the progression of a “disease or condition” or one or more “diseases or conditions”. Means to mitigate, or suppress. Further, in the present specification, “treatment” refers to “disease” including preventing the onset of “disease or condition” or any symptoms related to “disease or condition” depending on the condition of the patient. Or prevention of “a condition” as well as reducing the severity of a “disease or condition” or any symptom thereof before onset. As used herein, “treating” is intended to include preventing and ameliorating the recurrence of a “disease or condition”.
[14]本発明の第14の態様は、前記疾患が、不眠症、概日リズム睡眠障害、睡眠時随伴症、うつ病、不安障害、双極性障害、注意欠陥多動性障害、自閉症、自閉症スペクトラム障害、薬物依存症、アルツハイマー病、認知症、過食症の群から選択される態様[9]に記載の予防及び/または治療剤又は態様[13]に記載の方法である。
本発明の化合物は、オレキシン受容体拮抗作用を適宜選択した方法、例えば、後述の薬理実験例1(オレキシン受容体拮抗活性評価)で測定した場合、オレキシン受容体に対するIC50値が1μM以下である化合物が好ましい。より好ましくは、オレキシン受容体に対するIC50値が200nM以下、更に好ましくは40nM以下である化合物である。また、オレキシン2受容体拮抗作用を有する化合物として、オレキシン2受容体に対するIC50値が1μM以下である化合物が好ましく、より好ましくは200nM以下、更に好ましくは40nM以下である化合物である。このような活性を有する化合物は、オレキシン受容体拮抗作用、とりわけオレキシン2受容体拮抗作用を有する化合物であり、オレキシン受容体拮抗剤、とりわけオレキシン2受容体拮抗剤、または医薬組成物として、利用可能である。また、オレキシン受容体が関与する疾患、睡眠障害(不眠症、概日リズム睡眠障害、睡眠時随伴症等)、精神疾患(うつ病、不安障害、双極性障害、注意欠陥多動性障害、自閉症、自閉症スペクトラム障害、薬物依存症等)、神経変性疾患(アルツハイマー病等)、記憶障害(認知症等)または摂食障害(過食症等)、とりわけオレキシン2受容体が関与する疾患、または不眠症等の睡眠障害の予防及び/または治療剤として、利用可能である。 [14] In a fourteenth aspect of the present invention, the disease is insomnia, circadian rhythm sleep disorder, parasomnia, depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, autism A prophylactic and / or therapeutic agent according to aspect [9] or a method according to aspect [13], selected from the group of: autism spectrum disorder, drug dependence, Alzheimer's disease, dementia, bulimia.
The compound of the present invention has an IC 50 value of 1 μM or less for the orexin receptor when measured by a method in which orexin receptor antagonism is appropriately selected, for example, Pharmacological Experiment Example 1 (orexin receptor antagonism evaluation) described later. Compounds are preferred. More preferred is a compound having an IC 50 value for the orexin receptor of 200 nM or less, more preferably 40 nM or less. Further, as a compound having a orexin 2 receptor antagonism is preferably a compound an IC 50 value is less than 1μM for the orexin 2 receptor, more preferably 200nM or less, more preferably a compound or less 40 nM. The compound having such an activity is a compound having an orexin receptor antagonistic action, particularly an orexin 2 receptor antagonistic action, and can be used as an orexin receptor antagonist, particularly an orexin 2 receptor antagonist or a pharmaceutical composition It is. In addition, diseases involving orexin receptors, sleep disorders (insomnia, circadian rhythm sleep disorders, sleep-related complications, etc.), mental disorders (depression, anxiety disorders, bipolar disorders, attention deficit hyperactivity disorder, self Autism, autism spectrum disorder, drug dependence, etc.), neurodegenerative diseases (such as Alzheimer's disease), memory disorders (such as dementia) or eating disorders (such as bulimia), especially diseases involving the orexin 2 receptor Or as an agent for preventing and / or treating sleep disorders such as insomnia.
本発明の化合物は、オレキシン受容体拮抗作用を適宜選択した方法、例えば、後述の薬理実験例1(オレキシン受容体拮抗活性評価)で測定した場合、オレキシン受容体に対するIC50値が1μM以下である化合物が好ましい。より好ましくは、オレキシン受容体に対するIC50値が200nM以下、更に好ましくは40nM以下である化合物である。また、オレキシン2受容体拮抗作用を有する化合物として、オレキシン2受容体に対するIC50値が1μM以下である化合物が好ましく、より好ましくは200nM以下、更に好ましくは40nM以下である化合物である。このような活性を有する化合物は、オレキシン受容体拮抗作用、とりわけオレキシン2受容体拮抗作用を有する化合物であり、オレキシン受容体拮抗剤、とりわけオレキシン2受容体拮抗剤、または医薬組成物として、利用可能である。また、オレキシン受容体が関与する疾患、睡眠障害(不眠症、概日リズム睡眠障害、睡眠時随伴症等)、精神疾患(うつ病、不安障害、双極性障害、注意欠陥多動性障害、自閉症、自閉症スペクトラム障害、薬物依存症等)、神経変性疾患(アルツハイマー病等)、記憶障害(認知症等)または摂食障害(過食症等)、とりわけオレキシン2受容体が関与する疾患、または不眠症等の睡眠障害の予防及び/または治療剤として、利用可能である。 [14] In a fourteenth aspect of the present invention, the disease is insomnia, circadian rhythm sleep disorder, parasomnia, depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, autism A prophylactic and / or therapeutic agent according to aspect [9] or a method according to aspect [13], selected from the group of: autism spectrum disorder, drug dependence, Alzheimer's disease, dementia, bulimia.
The compound of the present invention has an IC 50 value of 1 μM or less for the orexin receptor when measured by a method in which orexin receptor antagonism is appropriately selected, for example, Pharmacological Experiment Example 1 (orexin receptor antagonism evaluation) described later. Compounds are preferred. More preferred is a compound having an IC 50 value for the orexin receptor of 200 nM or less, more preferably 40 nM or less. Further, as a compound having a orexin 2 receptor antagonism is preferably a compound an IC 50 value is less than 1μM for the orexin 2 receptor, more preferably 200nM or less, more preferably a compound or less 40 nM. The compound having such an activity is a compound having an orexin receptor antagonistic action, particularly an orexin 2 receptor antagonistic action, and can be used as an orexin receptor antagonist, particularly an orexin 2 receptor antagonist or a pharmaceutical composition It is. In addition, diseases involving orexin receptors, sleep disorders (insomnia, circadian rhythm sleep disorders, sleep-related complications, etc.), mental disorders (depression, anxiety disorders, bipolar disorders, attention deficit hyperactivity disorder, self Autism, autism spectrum disorder, drug dependence, etc.), neurodegenerative diseases (such as Alzheimer's disease), memory disorders (such as dementia) or eating disorders (such as bulimia), especially diseases involving the orexin 2 receptor Or as an agent for preventing and / or treating sleep disorders such as insomnia.
また、本発明の化合物は、オレキシン2受容体拮抗作用を有するが、オレキシン1受容体拮抗作用を有さないあるいは低い作用を有する化合物を包含しており、このような化合物は、オレキシン2受容体選択的な拮抗作用を有する化合物、またはオレキシン2受容体選択的拮抗剤として、利用可能である。例えば、オレキシン1受容体に対するIC50値が、オレキシン2受容体に対するIC50値の10倍以上、20倍以上、50倍以上または100倍以上である化合物が挙げられる。オレキシン2受容体選択的な拮抗作用を有する化合物は、オレキシン1受容体拮抗作用による副作用を有さない医薬組成物として有用である。また、オレキシン2受容体が関与する疾患、睡眠障害(不眠症、概日リズム睡眠障害、睡眠時随伴症等)、精神疾患(うつ病、不安障害、双極性障害、注意欠陥多動性障害、自閉症、自閉症スペクトラム障害、薬物依存症等)、神経変性疾患(アルツハイマー病等)、記憶障害(認知症等)または摂食障害(過食症等)、とりわけ不眠症等の睡眠障害の予防及び/または治療剤として、利用可能である。
本発明の化合物は、オレキシン2受容体拮抗作用と共に、オレキシン1受容体拮抗作用を同程度に有する化合物を包含しており、このような化合物は、オレキシン受容体dual拮抗作用を有する化合物であり、オレキシン受容体dual拮抗剤または医薬組成物として、利用可能である。また、上述したオレキシン受容体が関与する疾患の予防及び/または治療剤として、利用可能である。 The compounds of the present invention include compounds having orexin 2 receptor antagonistic activity but not having orexining orexin 1 receptor antagonistic activity. Such compounds include orexin 2 receptor. It can be used as a compound having a selective antagonism or an orexin 2 receptor selective antagonist. For example, a compound having an IC 50 value for orexin 1 receptor of 10 times or more, 20 times or more, 50 times or more, or 100 times or more of the IC 50 value for orexin 2 receptor can be mentioned. A compound having an orexin 2 receptor selective antagonism is useful as a pharmaceutical composition having no side effects due to orexin 1 receptor antagonism. In addition, diseases involving orexin 2 receptor, sleep disorders (insomnia, circadian rhythm sleep disorders, sleep-related complications, etc.), mental disorders (depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, Autism, autism spectrum disorder, drug addiction, etc.), neurodegenerative diseases (Alzheimer's disease, etc.), memory disorders (dementia, etc.) or eating disorders (eg, bulimia), especially sleep disorders such as insomnia It can be used as a preventive and / or therapeutic agent.
The compounds of the present invention include compounds having orexin 2 receptor antagonism as well as orexin 1 receptor antagonism, and such compounds are compounds having orexin receptor dual antagonism, It can be used as an orexin receptor dual antagonist or a pharmaceutical composition. Moreover, it can utilize as a preventive and / or therapeutic agent of the disease in which the above orexin receptor is involved.
本発明の化合物は、オレキシン2受容体拮抗作用と共に、オレキシン1受容体拮抗作用を同程度に有する化合物を包含しており、このような化合物は、オレキシン受容体dual拮抗作用を有する化合物であり、オレキシン受容体dual拮抗剤または医薬組成物として、利用可能である。また、上述したオレキシン受容体が関与する疾患の予防及び/または治療剤として、利用可能である。 The compounds of the present invention include compounds having orexin 2 receptor antagonistic activity but not having orexining orexin 1 receptor antagonistic activity. Such compounds include orexin 2 receptor. It can be used as a compound having a selective antagonism or an orexin 2 receptor selective antagonist. For example, a compound having an IC 50 value for orexin 1 receptor of 10 times or more, 20 times or more, 50 times or more, or 100 times or more of the IC 50 value for orexin 2 receptor can be mentioned. A compound having an orexin 2 receptor selective antagonism is useful as a pharmaceutical composition having no side effects due to orexin 1 receptor antagonism. In addition, diseases involving orexin 2 receptor, sleep disorders (insomnia, circadian rhythm sleep disorders, sleep-related complications, etc.), mental disorders (depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, Autism, autism spectrum disorder, drug addiction, etc.), neurodegenerative diseases (Alzheimer's disease, etc.), memory disorders (dementia, etc.) or eating disorders (eg, bulimia), especially sleep disorders such as insomnia It can be used as a preventive and / or therapeutic agent.
The compounds of the present invention include compounds having orexin 2 receptor antagonism as well as orexin 1 receptor antagonism, and such compounds are compounds having orexin receptor dual antagonism, It can be used as an orexin receptor dual antagonist or a pharmaceutical composition. Moreover, it can utilize as a preventive and / or therapeutic agent of the disease in which the above orexin receptor is involved.
以上の全ての態様において、「化合物」の文言を用いるとき、「その製薬学的に許容される塩」についても言及するものとする。
また、本明細書中、特に断りのない限り、「式(I)の化合物」、「式(I)で表される化合物」等と記載している場合、「式(I)-1の化合物」、「式(II)の化合物」等の、「式(I)の化合物」の下位概念にあたる化合物にも言及するものとする。 In all of the above embodiments, when the term “compound” is used, “a pharmaceutically acceptable salt thereof” is also referred to.
In addition, unless otherwise specified in this specification, “a compound of formula (I)”, “a compound represented by formula (I)”, etc. ”,“ Compounds of formula (II) ”and so on, which are subordinate concepts of“ compounds of formula (I) ”.
また、本明細書中、特に断りのない限り、「式(I)の化合物」、「式(I)で表される化合物」等と記載している場合、「式(I)-1の化合物」、「式(II)の化合物」等の、「式(I)の化合物」の下位概念にあたる化合物にも言及するものとする。 In all of the above embodiments, when the term “compound” is used, “a pharmaceutically acceptable salt thereof” is also referred to.
In addition, unless otherwise specified in this specification, “a compound of formula (I)”, “a compound represented by formula (I)”, etc. ”,“ Compounds of formula (II) ”and so on, which are subordinate concepts of“ compounds of formula (I) ”.
本発明の化合物は、置換基の種類によって、酸付加塩を形成する場合や塩基との塩を形成する場合がある。かかる塩としては、製薬学的に許容しうる塩であれば特に限定されないが、例えば、金属塩、アンモニウム塩、有機塩基との塩、無機酸との塩、有機酸との塩、塩基性、又は酸性アミノ酸との塩などが挙げられる。金属塩の好適な例としては、例えば、リチウム塩、ナトリウム塩、カリウム塩、セシウム塩などのアルカリ金属塩、カルシウム塩、マグネシウム塩、バリウム塩などのアルカリ土類金属塩、アルミニウム塩などが挙げられる(例えば、モノ塩の他、二ナトリウム塩、二カリウム塩も含む)。有機塩基との塩の好適な例としては、例えば、メチルアミン、エチルアミン、t-ブチルアミン、t-オクチルアミン、ジエチルアミン、トリメチルアミン、トリエチルアミン、シクロヘキシルアミン、ジシクロヘキシルアミン、ジベンジルアミン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、ピペリジン、モルホリン、ピリジン、ピコリン、リシン、アルギニン、オルニチン、エチレンジアミン、N-メチルグルカミン、グルコサミン、フェニルグリシンアルキルエステル、グアニジン、2,6-ルチジン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、N,N'-ジベンジルエチレンジアミン等との塩が挙げられる。無機酸との塩の好適な例としては、例えば、塩酸、臭化水素酸、よう化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。有機酸との塩の好適な例としては、例えば、ギ酸、酢酸、トリフルオロ酢酸、プロピオン酸、酪酸、吉草酸、エナント酸、カプリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、乳酸、ソルビン酸、マンデル酸等の脂肪族モノカルボン酸等との塩、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、リンゴ酸、酒石酸等の脂肪族ジカルボン酸との塩、クエン酸等の脂肪族トリカルボン酸との塩、安息香酸、サリチル酸等の芳香族モノカルボン酸との塩、フタル酸等の芳香族ジカルボン酸の塩、桂皮酸、グリコール酸、ピルビン酸、オキシル酸、サリチル酸、N-アセチルシステイン等の有機カルボン酸との塩、メタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸等の有機スルホン酸との塩、アスパラギン酸、グルタミン酸等の酸性アミノ酸類との酸付加塩が挙げられる。塩基性アミノ酸との塩の好適な例としては、例えば、アルギニン、リジン、オルニチンなどとの塩が挙げられ、酸性アミノ酸との塩の好適な例としては、例えば、アスパラギン酸、グルタミン酸などとの塩が挙げられる。このうち、薬学的に許容し得る塩が好ましい。例えば、化合物内に酸性官能基を有する場合にはアルカリ金属塩(例、ナトリウム塩、カリウム塩など)、アルカリ土類金属塩(例、カルシウム塩、マグネシウム塩、バリウム塩など)などの無機塩、アンモニウム塩など、また、化合物内に塩基性官能基を有する場合には、例えば、塩酸、臭化水素酸、硝酸、硫酸、リン酸など無機酸との塩、又は酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、メタンスルホン酸、p-トルエンスルホン酸などの有機酸との塩が挙げられる。
The compound of the present invention may form an acid addition salt or a salt with a base depending on the type of substituent. Such a salt is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basics, Or the salt with an acidic amino acid etc. are mentioned. Preferable examples of the metal salt include alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt, alkaline earth metal salts such as calcium salt, magnesium salt and barium salt, and aluminum salt. (For example, besides a mono salt, a disodium salt and a dipotassium salt are also included). Preferable examples of the salt with an organic base include, for example, methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine, diethanolamine, triamine. Ethanolamine, piperidine, morpholine, pyridine, picoline, lysine, arginine, ornithine, ethylenediamine, N-methylglucamine, glucosamine, phenylglycine alkyl ester, guanidine, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, N , N′-dibenzylethylenediamine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with an organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acids such as citric acid Salts with acids, salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid, salts of aromatic dicarboxylic acids such as phthalic acid, cinnamic acid, glycolic acid, pyruvic acid, oxylic acid, salicylic acid, N-acetylcysteine, etc. Salt with organic carboxylic acid, salt with organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, gluta Acid addition salts with acidic amino acids such as phosphate and the like. Preferable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, and preferable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt), In the case where the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, Examples thereof include salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
前記塩は、常法に従い、例えば、本発明の化合物と適量の酸もしくは塩基を含む溶液を混合することにより目的の塩を形成させた後に分別濾取するか、もしくは該混合溶媒を留去することにより得ることができる。また、本発明の化合物またはその塩は、水、エタノール、グリセロール等の溶媒と溶媒和物を形成しうる。
According to a conventional method, for example, the salt is formed by mixing the compound of the present invention with a solution containing an appropriate amount of acid or base to form the desired salt, and then separated by filtration, or the mixed solvent is distilled off. Can be obtained. In addition, the compound of the present invention or a salt thereof can form a solvate with a solvent such as water, ethanol or glycerol.
塩に関する総説として、Handbook of Pharmaceutical Salts:Properties,Selection,and Use、Stahl&Wermuth(Wiley-VCH、2002)が出版されており、本書に詳細な記載がなされている。
本発明の化合物は、非溶媒和形態もしくは溶媒和形態で存在することができる。本明細書において、「溶媒和物」は、本発明の化合物と1種または複数の薬学的に許容される溶媒分子(例えば、水、エタノール等)を含む分子複合体を意味する。前記溶媒分子が水であるとき、特に「水和物」と言う。
以下、本発明の化合物に関する記載においては、その塩、溶媒和物、ならびにその塩の溶媒和物に関する記載を包含する。 Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl & Wermuth (Wiley-VCH, 2002) are published as detailed reviews on salts, and are described in detail in this document.
The compounds of the invention can exist in unsolvated or solvated forms. As used herein, “solvate” means a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules (eg, water, ethanol, etc.). When the solvent molecule is water, it is specifically called “hydrate”.
Hereinafter, the description relating to the compound of the present invention includes the description relating to the salt, solvate, and solvate of the salt.
本発明の化合物は、非溶媒和形態もしくは溶媒和形態で存在することができる。本明細書において、「溶媒和物」は、本発明の化合物と1種または複数の薬学的に許容される溶媒分子(例えば、水、エタノール等)を含む分子複合体を意味する。前記溶媒分子が水であるとき、特に「水和物」と言う。
以下、本発明の化合物に関する記載においては、その塩、溶媒和物、ならびにその塩の溶媒和物に関する記載を包含する。 Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl & Wermuth (Wiley-VCH, 2002) are published as detailed reviews on salts, and are described in detail in this document.
The compounds of the invention can exist in unsolvated or solvated forms. As used herein, “solvate” means a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules (eg, water, ethanol, etc.). When the solvent molecule is water, it is specifically called “hydrate”.
Hereinafter, the description relating to the compound of the present invention includes the description relating to the salt, solvate, and solvate of the salt.
本発明の化合物の「プロドラッグ」も本発明の化合物に包含される。「プロドラッグ」とは、例えば、目的とする薬理活性を殆どもしくは全く示さない可能性のある、本発明の化合物のある種の誘導体を、身体内または身体上に投与した時、例えば、加水分解等により目的とする薬理活性を有する、本発明の化合物に変換される場合、投与前の化合物のことを「プロドラッグ」と呼ぶ。
本発明の化合物の「プロドラッグ」は、例えば、本発明の化合物に存在する適切な官能基を、文献公知の方法、例えば、Design of Prodrugs、H.Bundgaard(Elsevier、1985)に記載されている方法に準じることで製造することができる。
本発明の化合物の「プロドラッグ」としては、具体的には、以下の(1)~(3)に示すものがあり得るが、これに限定されるものではない。 “Prodrugs” of the compounds of the present invention are also encompassed by the compounds of the present invention. A “prodrug” is, for example, when a certain derivative of a compound of the invention, which may exhibit little or no desired pharmacological activity, is administered in or on the body, eg, hydrolysis. When converted to the compound of the present invention having the desired pharmacological activity by the like, the compound before administration is called “prodrug”.
“Prodrugs” of the compounds of the present invention may be prepared, for example, by combining suitable functional groups present in the compounds of the present invention with methods known in the literature, such as Design of Prodrugs, H. et al. It can be produced according to the method described in Bundgaard (Elsevier, 1985).
Specific examples of the “prodrug” of the compound of the present invention include the following (1) to (3), but are not limited thereto.
本発明の化合物の「プロドラッグ」は、例えば、本発明の化合物に存在する適切な官能基を、文献公知の方法、例えば、Design of Prodrugs、H.Bundgaard(Elsevier、1985)に記載されている方法に準じることで製造することができる。
本発明の化合物の「プロドラッグ」としては、具体的には、以下の(1)~(3)に示すものがあり得るが、これに限定されるものではない。 “Prodrugs” of the compounds of the present invention are also encompassed by the compounds of the present invention. A “prodrug” is, for example, when a certain derivative of a compound of the invention, which may exhibit little or no desired pharmacological activity, is administered in or on the body, eg, hydrolysis. When converted to the compound of the present invention having the desired pharmacological activity by the like, the compound before administration is called “prodrug”.
“Prodrugs” of the compounds of the present invention may be prepared, for example, by combining suitable functional groups present in the compounds of the present invention with methods known in the literature, such as Design of Prodrugs, H. et al. It can be produced according to the method described in Bundgaard (Elsevier, 1985).
Specific examples of the “prodrug” of the compound of the present invention include the following (1) to (3), but are not limited thereto.
(1)本発明の化合物にカルボキシ基が置換している場合:そのエステル、即ち、該カルボキシ基の水素原子が「C1~6アルキル基」で置換されている化合物。
(2)本発明の化合物に水酸基が置換している場合:そのアルカノイルオキシもしくはエーテル、即ち、該水酸基の水素原子が「C2~6アルカノイル基」もしくは「C2~6アルカノイルオキシメチル基」で置換されている化合物。
(3)本発明の化合物にアミノ基(-NH2もしくは-NHR’(式中、R’≠H))が置換している場合:そのアミド、即ち、該アミノ基の一方または両方の水素原子が「C2~6アルカノイル基」で置換されている化合物。 (1) When the compound of the present invention is substituted with a carboxy group: an ester thereof, that is, a compound in which a hydrogen atom of the carboxy group is substituted with a “C 1-6 alkyl group”.
(2) When the hydroxyl group in the compounds of the present invention is substituted: Part alkanoyloxy or ethers, i.e., hydrogen atoms of the hydroxyl groups in the "C 2 ~ 6 alkanoyl group" or "C 2 ~ 6 alkanoyloxymethyl group" Substituted compound.
(3) When the compound of the present invention is substituted with an amino group (—NH 2 or —NHR ′ (where R ′ ≠ H)): the amide, that is, one or both hydrogen atoms of the amino group There compounds substituted by "C 2 ~ 6 alkanoyl group".
(2)本発明の化合物に水酸基が置換している場合:そのアルカノイルオキシもしくはエーテル、即ち、該水酸基の水素原子が「C2~6アルカノイル基」もしくは「C2~6アルカノイルオキシメチル基」で置換されている化合物。
(3)本発明の化合物にアミノ基(-NH2もしくは-NHR’(式中、R’≠H))が置換している場合:そのアミド、即ち、該アミノ基の一方または両方の水素原子が「C2~6アルカノイル基」で置換されている化合物。 (1) When the compound of the present invention is substituted with a carboxy group: an ester thereof, that is, a compound in which a hydrogen atom of the carboxy group is substituted with a “C 1-6 alkyl group”.
(2) When the hydroxyl group in the compounds of the present invention is substituted: Part alkanoyloxy or ethers, i.e., hydrogen atoms of the hydroxyl groups in the "C 2 ~ 6 alkanoyl group" or "C 2 ~ 6 alkanoyloxymethyl group" Substituted compound.
(3) When the compound of the present invention is substituted with an amino group (—NH 2 or —NHR ′ (where R ′ ≠ H)): the amide, that is, one or both hydrogen atoms of the amino group There compounds substituted by "C 2 ~ 6 alkanoyl group".
本発明の化合物が、幾何異性体、配置異性体、互変異性体、光学異性体、立体異性体、位置異性体、回転異性体などの異性体を有する場合には、いずれか一方の異性体も混合物も本発明の化合物に包含される。さらに、本発明の化合物に光学異性体が存在する場合には、ラセミ体から分割された光学異性体も本発明の化合物に包含される。
本発明の化合物に、1つまたは複数の不斉炭素原子が有る場合には、2種以上の立体異性体が存在できる。また、本発明の化合物に、「C2~6アルケニル基」が含まれる場合、幾何異性体(シス/トランス、またはZ/E)が存在できる。また、構造異性体が低いエネルギー障壁により相互変換可能である場合には、互変異性が生じうる。互変異性としては、例えば、イミノ、ケト、もしくはオキシム基を有する化合物においてプロトン互変異性の形態が挙げられる。 When the compound of the present invention has isomers such as geometric isomers, configuration isomers, tautomers, optical isomers, stereoisomers, positional isomers, rotational isomers, etc., any one isomer And mixtures thereof are encompassed by the compounds of the present invention. Furthermore, when an optical isomer exists in the compound of the present invention, the optical isomer resolved from the racemate is also encompassed in the compound of the present invention.
When the compound of the present invention has one or more asymmetric carbon atoms, two or more stereoisomers can exist. Further, the compounds of the present invention, if it contains "C 2 ~ 6 alkenyl group", geometric isomers (cis / trans or Z / E,) can be present. Also, tautomerism can occur when structural isomers can be interconverted by a low energy barrier. Examples of tautomerism include proton tautomerism in compounds having an imino, keto, or oxime group.
本発明の化合物に、1つまたは複数の不斉炭素原子が有る場合には、2種以上の立体異性体が存在できる。また、本発明の化合物に、「C2~6アルケニル基」が含まれる場合、幾何異性体(シス/トランス、またはZ/E)が存在できる。また、構造異性体が低いエネルギー障壁により相互変換可能である場合には、互変異性が生じうる。互変異性としては、例えば、イミノ、ケト、もしくはオキシム基を有する化合物においてプロトン互変異性の形態が挙げられる。 When the compound of the present invention has isomers such as geometric isomers, configuration isomers, tautomers, optical isomers, stereoisomers, positional isomers, rotational isomers, etc., any one isomer And mixtures thereof are encompassed by the compounds of the present invention. Furthermore, when an optical isomer exists in the compound of the present invention, the optical isomer resolved from the racemate is also encompassed in the compound of the present invention.
When the compound of the present invention has one or more asymmetric carbon atoms, two or more stereoisomers can exist. Further, the compounds of the present invention, if it contains "C 2 ~ 6 alkenyl group", geometric isomers (cis / trans or Z / E,) can be present. Also, tautomerism can occur when structural isomers can be interconverted by a low energy barrier. Examples of tautomerism include proton tautomerism in compounds having an imino, keto, or oxime group.
本発明の化合物に、幾何異性体、配置異性体、立体異性体、配座異性体等が存在する場合には、公知の手段によりそれぞれを単離することができる。
また、本発明の化合物が光学活性体である場合には、ラセミ体を通常の光学分割手段により(+)体もしくは(-)体[(D)体もしくは(L)体]に分離することができる。
本発明の化合物が、光学異性体、立体異性体、位置異性体、回転異性体、互変異性体を含有する場合には、自体公知の合成手法、分離手法により各々の異性体を単一の化合物として得ることができる。例えば、光学分割法としては、自体公知の方法、例えば、(1)分別再結晶法、(2)ジアステレオマー法、(3)キラルカラム法等が挙げられる。 When there are geometrical isomers, configurational isomers, stereoisomers, conformational isomers and the like in the compound of the present invention, each can be isolated by known means.
In addition, when the compound of the present invention is an optically active substance, the racemate may be separated into a (+) form or a (−) form [(D) form or (L) form] by a conventional optical resolution means. it can.
When the compound of the present invention contains optical isomers, stereoisomers, positional isomers, rotational isomers, and tautomers, each isomer is converted to a single isomer by a known synthesis method or separation method. It can be obtained as a compound. For example, examples of the optical resolution method include methods known per se, such as (1) fractional recrystallization method, (2) diastereomer method, (3) chiral column method and the like.
また、本発明の化合物が光学活性体である場合には、ラセミ体を通常の光学分割手段により(+)体もしくは(-)体[(D)体もしくは(L)体]に分離することができる。
本発明の化合物が、光学異性体、立体異性体、位置異性体、回転異性体、互変異性体を含有する場合には、自体公知の合成手法、分離手法により各々の異性体を単一の化合物として得ることができる。例えば、光学分割法としては、自体公知の方法、例えば、(1)分別再結晶法、(2)ジアステレオマー法、(3)キラルカラム法等が挙げられる。 When there are geometrical isomers, configurational isomers, stereoisomers, conformational isomers and the like in the compound of the present invention, each can be isolated by known means.
In addition, when the compound of the present invention is an optically active substance, the racemate may be separated into a (+) form or a (−) form [(D) form or (L) form] by a conventional optical resolution means. it can.
When the compound of the present invention contains optical isomers, stereoisomers, positional isomers, rotational isomers, and tautomers, each isomer is converted to a single isomer by a known synthesis method or separation method. It can be obtained as a compound. For example, examples of the optical resolution method include methods known per se, such as (1) fractional recrystallization method, (2) diastereomer method, (3) chiral column method and the like.
(1)分別再結晶法:ラセミ体に対して光学分割剤をイオン結合させることにより結晶性のジアステレオマーを得た後、これを分別再結晶法によって分離し、所望により、中和工程を経てフリーの光学的に純粋な化合物を得る方法である。光学分割剤としては、例えば、(+)-マンデル酸、(-)-マンデル酸、(+)-酒石酸、(-)-酒石酸、(+)-1-フェネチルアミン、(-)-1-フェネチルアミン、シンコニン、(-)-シンコニジン、ブルシン等が挙げられる。
(2)ジアステレオマー法:ラセミ体の混合物に光学分割剤を共有結合(反応)させ、ジアステレオマーの混合物とした後、これを通常の分離手段(例、分別再結晶、シリカゲルカラムクロマトグラフィー、高速液体クロマトグラフィー(HPLC)等)等を経て光学的に純粋なジアステレオマーへ分離した後、加水分解反応等の化学的な処理により、光学分割剤を除去することにより、光学的に純粋な光学異性体を得る方法。例えば、本発明の化合物に分子内水酸基または1級、2級アミノ基を有する場合、該化合物と光学活性な有機酸(例、MTPA〔α-メトキシ-α-(トリフルオロメチル)フェニル酢酸〕、(-)-メントキシ酢酸等)等とを縮合反応に付すことにより、それぞれエステル体またはアミド体のジアステレオマーが得られる。一方、本発明の化合物にカルボキシル基が有る場合、該化合物と光学活性アミンまたはアルコール試薬とを縮合反応に付すことにより、それぞれアミド体またはエステル体のジアステレオマーが得られる。上記の分離された各ジアステレオマーは、酸加水分解または塩基性加水分解反応に付すことにより、元の化合物の光学異性体に変換される。 (1) Fractionation recrystallization method: After obtaining a crystalline diastereomer by ion-bonding an optical resolving agent to a racemate, it is separated by a fractional recrystallization method and, if desired, a neutralization step is performed. This is a method for obtaining a free optically pure compound. Examples of the optical resolution agent include (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaric acid, (+)-1-phenethylamine, (−)-1-phenethylamine, Examples include cinchonine, (−)-cinchonidine, brucine and the like.
(2) Diastereomer method: An optical resolution agent is covalently bonded (reacted) to a racemic mixture to obtain a mixture of diastereomers, which is then subjected to usual separation means (eg, fractional recrystallization, silica gel column chromatography). , High-performance liquid chromatography (HPLC), etc.) and then optically pure by removing the optical resolving agent by chemical treatment such as hydrolysis reaction. To obtain an optical isomer. For example, when the compound of the present invention has an intramolecular hydroxyl group or a primary or secondary amino group, the compound and an optically active organic acid (eg, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid], (-)-Menthoxyacetic acid and the like) are subjected to a condensation reaction to obtain ester or amide diastereomers, respectively. On the other hand, when the compound of the present invention has a carboxyl group, an amide or ester diastereomer can be obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. Each of the separated diastereomers is converted to an optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.
(2)ジアステレオマー法:ラセミ体の混合物に光学分割剤を共有結合(反応)させ、ジアステレオマーの混合物とした後、これを通常の分離手段(例、分別再結晶、シリカゲルカラムクロマトグラフィー、高速液体クロマトグラフィー(HPLC)等)等を経て光学的に純粋なジアステレオマーへ分離した後、加水分解反応等の化学的な処理により、光学分割剤を除去することにより、光学的に純粋な光学異性体を得る方法。例えば、本発明の化合物に分子内水酸基または1級、2級アミノ基を有する場合、該化合物と光学活性な有機酸(例、MTPA〔α-メトキシ-α-(トリフルオロメチル)フェニル酢酸〕、(-)-メントキシ酢酸等)等とを縮合反応に付すことにより、それぞれエステル体またはアミド体のジアステレオマーが得られる。一方、本発明の化合物にカルボキシル基が有る場合、該化合物と光学活性アミンまたはアルコール試薬とを縮合反応に付すことにより、それぞれアミド体またはエステル体のジアステレオマーが得られる。上記の分離された各ジアステレオマーは、酸加水分解または塩基性加水分解反応に付すことにより、元の化合物の光学異性体に変換される。 (1) Fractionation recrystallization method: After obtaining a crystalline diastereomer by ion-bonding an optical resolving agent to a racemate, it is separated by a fractional recrystallization method and, if desired, a neutralization step is performed. This is a method for obtaining a free optically pure compound. Examples of the optical resolution agent include (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaric acid, (+)-1-phenethylamine, (−)-1-phenethylamine, Examples include cinchonine, (−)-cinchonidine, brucine and the like.
(2) Diastereomer method: An optical resolution agent is covalently bonded (reacted) to a racemic mixture to obtain a mixture of diastereomers, which is then subjected to usual separation means (eg, fractional recrystallization, silica gel column chromatography). , High-performance liquid chromatography (HPLC), etc.) and then optically pure by removing the optical resolving agent by chemical treatment such as hydrolysis reaction. To obtain an optical isomer. For example, when the compound of the present invention has an intramolecular hydroxyl group or a primary or secondary amino group, the compound and an optically active organic acid (eg, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid], (-)-Menthoxyacetic acid and the like) are subjected to a condensation reaction to obtain ester or amide diastereomers, respectively. On the other hand, when the compound of the present invention has a carboxyl group, an amide or ester diastereomer can be obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. Each of the separated diastereomers is converted to an optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.
(3)キラルカラム法:ラセミ体またはその塩をキラルカラム(光学異性体分離用カラム)でのクロマトグラフィーに付すことで、直接光学分割する方法。例えば、高速液体クロマトグラフィーの場合、CHIRALシリーズ(ダイセル)等のキラルカラムに光学異性体の混合物を添加し、水、種々の緩衝液(例、リン酸緩衝液)、有機溶媒(例、エタノール、メタノール、イソプロパノール、アセトニトリル、トリフルオロ酢酸、ジエチルアミン)を単独で、または混合した溶液として用いて、展開させることにより、光学異性体を分離することができる。また、例えば、ガスクロマトグラフィーの場合、CP-Chirasil-DeX CB(ジーエルサイエンス)等のキラルカラムを使用して分離することができる。
本発明の化合物は、結晶であってもよく、結晶形が単一であっても結晶形混合物であっても本発明の化合物に包含される。
本発明の化合物は、薬学的に許容され得る共結晶または共結晶塩であってもよい。ここで、共結晶または共結晶塩とは、各々が異なる物理的特性(例えば、構造、融点、融解熱、吸湿性、溶解性および安定性等)を持つ、室温で二種またはそれ以上の独特な固体から構成される結晶性物質を意味する。共結晶または共結晶塩は、自体公知の共結晶化法に従い製造することができる。 (3) Chiral column method: A method in which a racemate or a salt thereof is subjected to direct optical resolution by subjecting it to chromatography on a chiral column (optical isomer separation column). For example, in the case of high performance liquid chromatography, a mixture of optical isomers is added to a chiral column such as CHIRAL series (Daicel), water, various buffers (eg, phosphate buffer), organic solvents (eg, ethanol, methanol) , Isopropanol, acetonitrile, trifluoroacetic acid, diethylamine) alone or as a mixed solution, the optical isomers can be separated by development. Further, for example, in the case of gas chromatography, separation can be performed using a chiral column such as CP-Chirasil-DeX CB (GL Science).
The compound of the present invention may be a crystal, and a single crystal form or a crystal form mixture is included in the compound of the present invention.
The compound of the present invention may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid. The cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
本発明の化合物は、結晶であってもよく、結晶形が単一であっても結晶形混合物であっても本発明の化合物に包含される。
本発明の化合物は、薬学的に許容され得る共結晶または共結晶塩であってもよい。ここで、共結晶または共結晶塩とは、各々が異なる物理的特性(例えば、構造、融点、融解熱、吸湿性、溶解性および安定性等)を持つ、室温で二種またはそれ以上の独特な固体から構成される結晶性物質を意味する。共結晶または共結晶塩は、自体公知の共結晶化法に従い製造することができる。 (3) Chiral column method: A method in which a racemate or a salt thereof is subjected to direct optical resolution by subjecting it to chromatography on a chiral column (optical isomer separation column). For example, in the case of high performance liquid chromatography, a mixture of optical isomers is added to a chiral column such as CHIRAL series (Daicel), water, various buffers (eg, phosphate buffer), organic solvents (eg, ethanol, methanol) , Isopropanol, acetonitrile, trifluoroacetic acid, diethylamine) alone or as a mixed solution, the optical isomers can be separated by development. Further, for example, in the case of gas chromatography, separation can be performed using a chiral column such as CP-Chirasil-DeX CB (GL Science).
The compound of the present invention may be a crystal, and a single crystal form or a crystal form mixture is included in the compound of the present invention.
The compound of the present invention may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid. The cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
本発明の化合物には、同位元素(例えば、水素の同位体、2Hおよび3Hなど、炭素の同位体、11C、13C、および14Cなど、塩素の同位体、36Clなど、フッ素の同位体、18Fなど、ヨウ素の同位体、123Iおよび125Iなど、窒素の同位体、13Nおよび15Nなど、酸素の同位体、15O、17O、および18Oなど、リンの同位体、32Pなど、ならびに硫黄の同位体、35Sなど)で標識、又は置換された化合物も包含される。
ある種の同位元素(例えば、11C、18F、15O、および13Nなどの陽電子放出同位元素)で標識または置換された本発明の化合物は、例えば、陽電子断層法(Positron Emission Tomography;PET)において使用するトレーサー(PETトレーサー)として用いることができ、医療診断などの分野において有用である。
ある種の同位体標識で標識または置換された本発明の化合物は、薬物および/または基質の組織分布研究において有用である。例えば、3Hおよび14Cは、それらの標識または置換が容易であり、かつ検出手段が容易である点から、該研究目的において有用である。 Compounds of the present invention include isotopes (eg, hydrogen isotopes, 2 H and 3 H, carbon isotopes, 11 C, 13 C, and 14 C, chlorine isotopes, 36 Cl, etc., fluorine Isotopes, 18 F, iodine isotopes, 123 I and 125 I, nitrogen isotopes, 13 N and 15 N, oxygen isotopes, 15 O, 17 O, and 18 O, phosphorus Also included are compounds labeled or substituted with isotopes, 32 P and the like, as well as sulfur isotopes, 35 S and the like.
Compounds of the invention labeled or substituted with certain isotopes (eg, positron emitting isotopes such as 11 C, 18 F, 15 O, and 13 N) can be synthesized, for example, by Positron Emission Tomography; PET ) Can be used as a tracer (PET tracer) for use in medical diagnosis and the like.
Compounds of the invention labeled or substituted with certain isotopic labels are useful in drug and / or substrate tissue distribution studies. For example, 3 H and 14 C are useful for this research purpose because they are easy to label or displace and easy to detect.
ある種の同位元素(例えば、11C、18F、15O、および13Nなどの陽電子放出同位元素)で標識または置換された本発明の化合物は、例えば、陽電子断層法(Positron Emission Tomography;PET)において使用するトレーサー(PETトレーサー)として用いることができ、医療診断などの分野において有用である。
ある種の同位体標識で標識または置換された本発明の化合物は、薬物および/または基質の組織分布研究において有用である。例えば、3Hおよび14Cは、それらの標識または置換が容易であり、かつ検出手段が容易である点から、該研究目的において有用である。 Compounds of the present invention include isotopes (eg, hydrogen isotopes, 2 H and 3 H, carbon isotopes, 11 C, 13 C, and 14 C, chlorine isotopes, 36 Cl, etc., fluorine Isotopes, 18 F, iodine isotopes, 123 I and 125 I, nitrogen isotopes, 13 N and 15 N, oxygen isotopes, 15 O, 17 O, and 18 O, phosphorus Also included are compounds labeled or substituted with isotopes, 32 P and the like, as well as sulfur isotopes, 35 S and the like.
Compounds of the invention labeled or substituted with certain isotopes (eg, positron emitting isotopes such as 11 C, 18 F, 15 O, and 13 N) can be synthesized, for example, by Positron Emission Tomography; PET ) Can be used as a tracer (PET tracer) for use in medical diagnosis and the like.
Compounds of the invention labeled or substituted with certain isotopic labels are useful in drug and / or substrate tissue distribution studies. For example, 3 H and 14 C are useful for this research purpose because they are easy to label or displace and easy to detect.
2H(あるいはDまたは重水素と表記する場合がある)で標識または置換された化合物(D化化合物、重水素化化合物)は、安定性が高くなることが期待され、活性化合物自体として有用である。例えば、代謝を受ける位置の水素原子を2Hに置換した化合物が挙げられ、化合物の性質にほとんど影響を与えずに、代謝反応速度を低下させることができる。また、代謝酵素と不可逆的に結合する位置を2Hに置換した化合物は、その代謝酵素の作用を阻害することを抑制し、併用時の薬物相互作用を軽減することができる。
同位体標識された本発明の化合物は、当業者に知られている通常の技法によって、または後述の実施例に記載する合成方法に類似する方法によって得る事ができる。また、非標識化合物の代わりに、得られた同位体標識化合物を薬理実験に用いる事ができる。 A compound labeled or substituted with 2 H (or sometimes referred to as D or deuterium) (D compound, deuterated compound) is expected to have high stability and is useful as an active compound itself. is there. For example, a compound in which a hydrogen atom at a position to undergo metabolism is substituted with 2 H can be mentioned, and the metabolic reaction rate can be reduced with little influence on the properties of the compound. In addition, a compound in which the position of irreversibly binding to a metabolic enzyme is substituted with 2 H can suppress the inhibition of the action of the metabolic enzyme, and can reduce the drug interaction at the time of combined use.
Isotopically-labeled compounds of the invention can be obtained by conventional techniques known to those skilled in the art or by methods analogous to the synthetic methods described in the examples below. In addition, the obtained isotope-labeled compound can be used for pharmacological experiments instead of the unlabeled compound.
同位体標識された本発明の化合物は、当業者に知られている通常の技法によって、または後述の実施例に記載する合成方法に類似する方法によって得る事ができる。また、非標識化合物の代わりに、得られた同位体標識化合物を薬理実験に用いる事ができる。 A compound labeled or substituted with 2 H (or sometimes referred to as D or deuterium) (D compound, deuterated compound) is expected to have high stability and is useful as an active compound itself. is there. For example, a compound in which a hydrogen atom at a position to undergo metabolism is substituted with 2 H can be mentioned, and the metabolic reaction rate can be reduced with little influence on the properties of the compound. In addition, a compound in which the position of irreversibly binding to a metabolic enzyme is substituted with 2 H can suppress the inhibition of the action of the metabolic enzyme, and can reduce the drug interaction at the time of combined use.
Isotopically-labeled compounds of the invention can be obtained by conventional techniques known to those skilled in the art or by methods analogous to the synthetic methods described in the examples below. In addition, the obtained isotope-labeled compound can be used for pharmacological experiments instead of the unlabeled compound.
[本発明化合物の製造方法]
以下に、本発明の式(I)で表される化合物の製造方法について説明する。本発明化合物である式(I)で表される化合物、その塩およびそれらの溶媒和物は、市販化合物または市販化合物から文献公知の製造方法により容易に得ることが出来る化合物を出発原料もしくは合成中間体として、既知の一般的化学的な製造方法を組み合わせることで容易に製造することが可能であり、以下に示す代表的な製造方法に従い製造することができる。また、本発明は以下に説明する製造方法に、何ら限定されるものではない。 [Method for producing compound of the present invention]
Below, the manufacturing method of the compound represented by Formula (I) of this invention is demonstrated. Compounds of the present invention represented by formula (I), salts thereof and solvates thereof are commercially available compounds or compounds that can be easily obtained from commercially available compounds by known production methods in the literature as starting materials or intermediates of synthesis. As a body, it can be easily produced by combining known general chemical production methods, and can be produced according to the following typical production methods. Further, the present invention is not limited to the manufacturing method described below.
以下に、本発明の式(I)で表される化合物の製造方法について説明する。本発明化合物である式(I)で表される化合物、その塩およびそれらの溶媒和物は、市販化合物または市販化合物から文献公知の製造方法により容易に得ることが出来る化合物を出発原料もしくは合成中間体として、既知の一般的化学的な製造方法を組み合わせることで容易に製造することが可能であり、以下に示す代表的な製造方法に従い製造することができる。また、本発明は以下に説明する製造方法に、何ら限定されるものではない。 [Method for producing compound of the present invention]
Below, the manufacturing method of the compound represented by Formula (I) of this invention is demonstrated. Compounds of the present invention represented by formula (I), salts thereof and solvates thereof are commercially available compounds or compounds that can be easily obtained from commercially available compounds by known production methods in the literature as starting materials or intermediates of synthesis. As a body, it can be easily produced by combining known general chemical production methods, and can be produced according to the following typical production methods. Further, the present invention is not limited to the manufacturing method described below.
以下の製造方法の各々の式中におけるL、環A、環B、Ra、Rb等の式(I)に現れる定義は、特に断らない限り、前記態様に記載された式(I)の各々の定義と同一である。なお、製造方法中におけるL'やL''の定義は、式(I)のLの定義に包含されるものであり、各製造方法にて各々定義する。製造方法中におけるMの定義は、特に断らない限り、リチウム、ナトリウム、カリウム等の金属である。製造方法中におけるXの定義は、特に断らない限り、ハロゲン原子、またはトリフルオロメタンスルホナート(OTf)である。製造方法中におけるBの定義は、特に断らない限り、ボロン酸エステル、ボロン酸、トリフルオロボレート塩、またはボロン酸N-メチルイミノ二酢酸エステルである。製造方法中におけるP1、およびP2の定義は、特に断らない限り、水素原子もしくはイミノ基の保護基である。製造方法中におけるRAの定義は、特に断らない限り、C1~6アルキル基、C6~14アリール基またはC7~20アラルキル基である。製造方法中におけるRBの定義は、特に断らない限り、C1~6アルキル基またはC3~8シクロアルキル基である。製造方法中におけるRCの定義は、特に断らない限り、C3~8シクロアルキル基、C1~6アルコキシル基、C1~6アルキルチオ基、非芳香族複素環基、または-NRaRb基である。
Definitions appearing in formula (I) such as L, ring A, ring B, R a , and R b in each formula of the following production methods are those of formula (I) described in the above embodiment unless otherwise specified. Each definition is the same. The definitions of L ′ and L ″ in the production method are included in the definition of L in formula (I) and are defined in each production method. The definition of M in the production method is a metal such as lithium, sodium and potassium unless otherwise specified. The definition of X in the production method is a halogen atom or trifluoromethanesulfonate (OTf) unless otherwise specified. The definition of B in the production method is boronic acid ester, boronic acid, trifluoroborate salt, or boronic acid N-methyliminodiacetic acid ester unless otherwise specified. Unless otherwise specified, the definitions of P 1 and P 2 in the production method are a protecting group for a hydrogen atom or an imino group. Definition of R A in the manufacturing method, unless otherwise specified, is a C 1 ~ 6 alkyl group, C 6 ~ 14 aryl group or a C 7 ~ 20 aralkyl group. Definition of R B in the production process, unless otherwise specified, is a C 1 ~ 6 alkyl group or a C 3 ~ 8 cycloalkyl group. The definition of R C during manufacturing process, unless otherwise specified, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 1 ~ 6 alkylthio group, non-aromatic heterocyclic group or -NR a R b, It is a group.
以下の各製造方法において、式(I)の製造に用いられる各原料化合物は、塩を形成していてもよく、このような塩としては、前述した式(I)の塩と同様のものが挙げられる。また、式(I)の製造に用いられる各原料化合物は、反応液のままか粗製物として次の反応に用いることもできるが、常法に従って反応混合物から単離することもでき、それ自体が公知の手段、例えば、抽出、濃縮、中和、濾過、蒸留、再結晶、クロマトグラフィーなどの分離手段により容易に精製することができる。
In each of the following production methods, each raw material compound used for the production of formula (I) may form a salt, and as such a salt, the same salts as those of the aforementioned formula (I) can be mentioned. Can be mentioned. Each raw material compound used in the production of formula (I) can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from a reaction mixture according to a conventional method. It can be easily purified by known means, for example, separation means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, chromatography and the like.
上記再結晶に用いられる溶媒としては、例えば、水;メタノール、エタノール、2-プロパノール、ブタノール等のアルコール類;ジエチルエーテル、テトラヒドロフラン、1,4-ジオキサン等のエーテル類;n-ヘキサン、シクロヘキサン、ヘプタン等の炭化水素類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類;N,N‐ジメチルホルムアミド、N,N‐ジメチルアセトアミド、1,3‐ジメチル‐2‐イミダゾリジノン等のアミド類;クロロホルム、塩化メチレン、1,2‐ジクロロエタン等のハロゲン化炭化水素類;アセトニトリル等のニトリル類;アセトン、ジフェニルケトン等のケトン類;酢酸メチル、酢酸エチル等のエステル類、ジメチルスルホキシド等のスルホキジド類;酢酸、トリフルオロ酢酸、メタンスルホン酸、p‐トルエンスルホン酸等の有機酸類;等が挙げられる。これらの溶媒は、単独で用いることもできるし、二種以上の溶媒を適当な割合、例えば、1:1~1:10の割合で混合して用いてもよい。また、式中の化合物が市販されている場合には市販品をそのまま用いることもでき、自体公知の方法、またはそれに準じた方法にて製造したものを用いることもできる。
Examples of the solvent used for the recrystallization include water; alcohols such as methanol, ethanol, 2-propanol and butanol; ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; n-hexane, cyclohexane and heptane. Hydrocarbons such as benzene, toluene, xylene, etc .; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone; chloroform , Halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane; nitriles such as acetonitrile; ketones such as acetone and diphenyl ketone; esters such as methyl acetate and ethyl acetate; sulfoxides such as dimethyl sulfoxide; , Trifluoroacetic acid, methanesulfur Phosphate, organic acids such as p- toluenesulfonic acid; and the like. These solvents can be used alone, or two or more kinds of solvents can be mixed at an appropriate ratio, for example, a ratio of 1: 1 to 1:10. Moreover, when the compound in a formula is marketed, a commercial item can also be used as it is, and what was manufactured by the method known per se or a method according to it can also be used.
式(I)が有する置換基において、変換可能な官能基(例えば、カルボキシ基、アミノ基、水酸基、カルボニル基、メルカプト基、C1~6アルコキシルカルボニル基、C6~14アリールオキシカルボニル基、C7~20アラルキルオキシカルボニル基、スルホ基(-SO2OH)、ハロゲン原子等)を含む場合、これらの官能基を自体公知の方法またはそれに準ずる方法によって変換することにより種々の化合物を製造することができる。
「カルボキシ基」の場合、例えば、エステル化、還元、アミド化、保護されていてもよいアミノ基への変換反応等の反応により変換可能である。
「アミノ基」の場合、例えば、アミド化、スルホニル化、ニトロソ化、アルキル化、アリール化、イミド化等の反応により変換可能である。 In substituent having the formula (I) is transformable functional group (e.g., carboxyl group, an amino group, a hydroxyl group, a carbonyl group, a mercapto groups, C 1 ~ 6 alkoxycarbonyl groups, C 6 ~ 14 aryloxycarbonyl groups, C In the case of containing 7-20 aralkyloxycarbonyl groups, sulfo groups (—SO 2 OH), halogen atoms, etc.), various compounds can be produced by converting these functional groups by a method known per se or a method analogous thereto. Can do.
In the case of a “carboxy group”, it can be converted by a reaction such as esterification, reduction, amidation, or a conversion reaction to an optionally protected amino group.
In the case of an “amino group”, it can be converted by a reaction such as amidation, sulfonylation, nitrosation, alkylation, arylation, imidation and the like.
「カルボキシ基」の場合、例えば、エステル化、還元、アミド化、保護されていてもよいアミノ基への変換反応等の反応により変換可能である。
「アミノ基」の場合、例えば、アミド化、スルホニル化、ニトロソ化、アルキル化、アリール化、イミド化等の反応により変換可能である。 In substituent having the formula (I) is transformable functional group (e.g., carboxyl group, an amino group, a hydroxyl group, a carbonyl group, a mercapto groups, C 1 ~ 6 alkoxycarbonyl groups, C 6 ~ 14 aryloxycarbonyl groups, C In the case of containing 7-20 aralkyloxycarbonyl groups, sulfo groups (—SO 2 OH), halogen atoms, etc.), various compounds can be produced by converting these functional groups by a method known per se or a method analogous thereto. Can do.
In the case of a “carboxy group”, it can be converted by a reaction such as esterification, reduction, amidation, or a conversion reaction to an optionally protected amino group.
In the case of an “amino group”, it can be converted by a reaction such as amidation, sulfonylation, nitrosation, alkylation, arylation, imidation and the like.
「水酸基」の場合、例えば、エステル化、カルバモイル化、スルホニル化、アルキル化、アリール化、酸化、ハロゲン化等の反応により変換可能である。
「カルボニル基」の場合、例えば、還元、酸化、イミノ化(オキシム化、ヒドラゾン化を含む)、(チオ)ケタール化、アルキリデン化、チオカルボニル化等の反応により変換可能である。
「メルカプト基」の場合、例えば、アルキル化、酸化等の反応により変換可能である。
「C1~6アルコキシルカルボニル基」、「C6~14アリールオキシカルボニル基」、または「C7~20アラルキルオキシカルボニル基」の場合、例えば、還元、加水分解等の反応により変換可能である。
「スルホ基」の場合、例えば、スルホンアミド化、還元等の反応により変換可能である。 In the case of “hydroxyl group”, it can be converted by a reaction such as esterification, carbamoylation, sulfonylation, alkylation, arylation, oxidation, halogenation and the like.
In the case of a “carbonyl group”, it can be converted by a reaction such as reduction, oxidation, imination (including oximation and hydrazone formation), (thio) ketalization, alkylidene formation, thiocarbonylation and the like.
In the case of a “mercapto group”, it can be converted by a reaction such as alkylation or oxidation.
If the "C 1 ~ 6 alkoxycarbonyl group", "C 6 ~ 14 aryloxycarbonyl group", or "C 7 ~ 20 aralkyloxycarbonyl group", for example, the reduction can be converted by reaction such as hydrolysis.
In the case of a “sulfo group”, it can be converted by a reaction such as sulfonamidation or reduction.
「カルボニル基」の場合、例えば、還元、酸化、イミノ化(オキシム化、ヒドラゾン化を含む)、(チオ)ケタール化、アルキリデン化、チオカルボニル化等の反応により変換可能である。
「メルカプト基」の場合、例えば、アルキル化、酸化等の反応により変換可能である。
「C1~6アルコキシルカルボニル基」、「C6~14アリールオキシカルボニル基」、または「C7~20アラルキルオキシカルボニル基」の場合、例えば、還元、加水分解等の反応により変換可能である。
「スルホ基」の場合、例えば、スルホンアミド化、還元等の反応により変換可能である。 In the case of “hydroxyl group”, it can be converted by a reaction such as esterification, carbamoylation, sulfonylation, alkylation, arylation, oxidation, halogenation and the like.
In the case of a “carbonyl group”, it can be converted by a reaction such as reduction, oxidation, imination (including oximation and hydrazone formation), (thio) ketalization, alkylidene formation, thiocarbonylation and the like.
In the case of a “mercapto group”, it can be converted by a reaction such as alkylation or oxidation.
If the "C 1 ~ 6 alkoxycarbonyl group", "C 6 ~ 14 aryloxycarbonyl group", or "C 7 ~ 20 aralkyloxycarbonyl group", for example, the reduction can be converted by reaction such as hydrolysis.
In the case of a “sulfo group”, it can be converted by a reaction such as sulfonamidation or reduction.
「ハロゲン原子」の場合、例えば、各種求核置換反応、各種カップリング反応等により変換可能である。
前記の各反応において、化合物が遊離の状態で得られる場合には、常法に従って塩に変換してもよく、また塩として得られる場合には、常法に従って遊離体またはその他の塩に変換することもできる。
これらの官能基の変換は、例えば、Larockらの、Comprehensive Organic Transformations、第2版、1999年10月刊、Wiley-VCH社、の成書に記載の方法等に準じて行う事ができる。
また、本発明の式(I)で表される化合物の製造方法の各反応および原料化合物合成の各反応において、置換基として水酸基(アルコール性水酸基、フェノール性水酸基、複素環水酸基等)、アミノ基、カルボキシ基、チオール基等の反応性基がある場合には、各反応工程においてこれらの基を適宜保護し、適当な段階で当該保護基を除去することもできる。 In the case of “halogen atom”, it can be converted by, for example, various nucleophilic substitution reactions, various coupling reactions and the like.
In each of the above reactions, when the compound is obtained in a free state, it may be converted into a salt according to a conventional method. When it is obtained as a salt, it is converted into a free form or other salt according to a conventional method. You can also
These functional groups can be converted in accordance with, for example, the method described in the book of Larock et al., Comprehensive Organic Transformations, 2nd edition, October 1999, Wiley-VCH.
Moreover, in each reaction of the manufacturing method of a compound represented by the formula (I) of this invention and each reaction of a raw material compound synthesis, a hydroxyl group (an alcoholic hydroxyl group, a phenolic hydroxyl group, a heterocyclic hydroxyl group, etc.), an amino group as a substituent When there are reactive groups such as carboxy group and thiol group, these groups can be appropriately protected in each reaction step, and the protecting group can be removed at an appropriate stage.
前記の各反応において、化合物が遊離の状態で得られる場合には、常法に従って塩に変換してもよく、また塩として得られる場合には、常法に従って遊離体またはその他の塩に変換することもできる。
これらの官能基の変換は、例えば、Larockらの、Comprehensive Organic Transformations、第2版、1999年10月刊、Wiley-VCH社、の成書に記載の方法等に準じて行う事ができる。
また、本発明の式(I)で表される化合物の製造方法の各反応および原料化合物合成の各反応において、置換基として水酸基(アルコール性水酸基、フェノール性水酸基、複素環水酸基等)、アミノ基、カルボキシ基、チオール基等の反応性基がある場合には、各反応工程においてこれらの基を適宜保護し、適当な段階で当該保護基を除去することもできる。 In the case of “halogen atom”, it can be converted by, for example, various nucleophilic substitution reactions, various coupling reactions and the like.
In each of the above reactions, when the compound is obtained in a free state, it may be converted into a salt according to a conventional method. When it is obtained as a salt, it is converted into a free form or other salt according to a conventional method. You can also
These functional groups can be converted in accordance with, for example, the method described in the book of Larock et al., Comprehensive Organic Transformations, 2nd edition, October 1999, Wiley-VCH.
Moreover, in each reaction of the manufacturing method of a compound represented by the formula (I) of this invention and each reaction of a raw material compound synthesis, a hydroxyl group (an alcoholic hydroxyl group, a phenolic hydroxyl group, a heterocyclic hydroxyl group, etc.), an amino group as a substituent When there are reactive groups such as carboxy group and thiol group, these groups can be appropriately protected in each reaction step, and the protecting group can be removed at an appropriate stage.
当該水酸基(アルコール性水酸基、フェノール性水酸基、複素環水酸基等)の保護基としては、例えば、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、tert-ブチル等に代表されるC1~6アルキル基;メトキシメチル、メトキシエトキシメチル等に代表されるアルコキシルアルキル基;テトラヒドロピラニル基;ベンジル、トリフェニルメチル等に代表されるアラルキル基;トリメチルシリル、トリエチルシリル、t‐ブチルジメチルシリル、t‐ブチルジフェニルシリル等に代表されるシリル基;アセチル、エチルカルボニル、ピバロイル等に代表されるアルカノイル基;ベンジルカルボニル等に代表されるアラルキルカルボニル基;ベンゾイル等に代表されるアロイル基;メトキシカルボニル、エトキシカルボニル、t‐ブトキシカルボニル等に代表されるアルコキシルカルボニル基;ベンジルオキシカルボニル等に代表されるアラルキルオキシカルボニル基等が用いられる。
Examples of the protective group for the hydroxyl group (alcoholic hydroxyl group, phenolic hydroxyl group, heterocyclic hydroxyl group, etc.) include C 1-6 represented by methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and the like. Alkyl group; alkoxylalkyl group represented by methoxymethyl, methoxyethoxymethyl, etc .; tetrahydropyranyl group; aralkyl group represented by benzyl, triphenylmethyl, etc .; trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyl A silyl group typified by diphenylsilyl and the like; an alkanoyl group typified by acetyl, ethylcarbonyl, pivaloyl and the like; an aralkylcarbonyl group typified by benzylcarbonyl and the like; an aroyl group typified by benzoyl and the like; methoxycarbonyl, ethoxycarbonyl, - alkoxycarbonyl groups typified butoxycarbonyl; aralkyloxycarbonyl group represented by benzyloxycarbonyl and the like are used.
当該アミノ基(-NH2基)もしくはイミノ基(-NH-基)の保護基としては、例えば、アセチル、エチルカルボニル、ピバロイル等に代表されるアルカノイル基;メトキシカルボニル、エトキシカルボニル、t‐ブトキシカルボニル等に代表されるアルコキシルカルボニル基;アリルオキシカルボニル基;フルオレニルメトキシカルボニル基;フェニルオキシカルボニル;ベンジルオキシカルボニル、パラメトキシベンジルオキシカルボニル、パラニトロベンジルオキシカルボニル等に代表されるアラルキルオキシカルボニル基;ベンジル、トリフェニルメチル等に代表されるアラルキル基;ベンゾイル等に代表されるアロイル基;ベンジルカルボニル等に代表されるアラルキルカルボニル基;メタンスルホニル、p-トルエンスルホニル、2,4-ジニトロベンゼンスルホニル、ベンゼンスルホニル等に代表されるスルホニル基;2-(トリメチルシリル)エトキシメチル基;フタロイル基;N,N-ジメチルアミノメチレン基等が用いられる。
Examples of the protecting group for the amino group (—NH 2 group) or imino group (—NH— group) include alkanoyl groups represented by acetyl, ethylcarbonyl, pivaloyl, etc .; methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl Allyloxycarbonyl group; fluorenylmethoxycarbonyl group; phenyloxycarbonyl; aralkyloxycarbonyl group represented by benzyloxycarbonyl, paramethoxybenzyloxycarbonyl, paranitrobenzyloxycarbonyl and the like; Aralkyl groups typified by benzyl, triphenylmethyl, etc .; aroyl groups typified by benzoyl, etc .; aralkylcarbonyl groups typified by benzylcarbonyl, etc .; methanesulfonyl, p-toluenesulfonate , 2,4-nitrobenzenesulfonyl, a sulfonyl group represented by benzenesulfonyl; 2- (trimethylsilyl) ethoxymethyl group; phthaloyl group; N, N-dimethylaminomethylene group, etc. are used.
当該カルボキシ基(-COOH基)の保護基としては、例えば、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、tert-ブチル等に代表されるアルキル基;アリル等に代表されるアルケニル基;フェニル等に代表されるアリール基;ベンジル、トリフェニルメチル等に代表されるアラルキル基;トリメチルシリル、トリエチルシリル、t‐ブチルジメチルシリル、t‐ブチルジフェニルシリル等に代表されるシリル基等が用いられる。
当該チオール基(-SH基)の保護基としては、例えば、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、tert-ブチル等に代表されるアルキル基;ベンジル、トリフェニルメチル等に代表されるアラルキル基;アセチル、エチルカルボニル、ピバロイル等に代表されるアルカノイル基;ベンゾイル等に代表されるアロイル基等が用いられる。
こうした保護基の導入・除去の方法は、保護される基あるいは保護基の種類により適宜行われるが、例えば、Greeneらの『Protective Groups in Organic Synthesis 第4版、2007年、John Wiley & Sons』の成書に記載の方法により行うことができる。 Examples of the protecting group for the carboxy group (—COOH group) include alkyl groups typified by methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc .; alkenyl groups typified by allyl; An aryl group typified by phenyl or the like; an aralkyl group typified by benzyl, triphenylmethyl or the like; a silyl group typified by trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl or the like is used.
Examples of the protecting group for the thiol group (—SH group) include alkyl groups typified by methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and the like; benzyl, triphenylmethyl and the like. Aralkyl groups represented by acetyl, ethylcarbonyl, pivaloyl and the like; aroyl groups represented by benzoyl and the like are used.
Such a method for introducing / removing a protecting group is appropriately performed depending on the group to be protected or the type of protecting group. For example, Greene et al., Protective Groups in Organic Synthesis 4th Edition, 2007, John Wiley & Sons. It can be performed by the method described in the book.
当該チオール基(-SH基)の保護基としては、例えば、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、tert-ブチル等に代表されるアルキル基;ベンジル、トリフェニルメチル等に代表されるアラルキル基;アセチル、エチルカルボニル、ピバロイル等に代表されるアルカノイル基;ベンゾイル等に代表されるアロイル基等が用いられる。
こうした保護基の導入・除去の方法は、保護される基あるいは保護基の種類により適宜行われるが、例えば、Greeneらの『Protective Groups in Organic Synthesis 第4版、2007年、John Wiley & Sons』の成書に記載の方法により行うことができる。 Examples of the protecting group for the carboxy group (—COOH group) include alkyl groups typified by methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc .; alkenyl groups typified by allyl; An aryl group typified by phenyl or the like; an aralkyl group typified by benzyl, triphenylmethyl or the like; a silyl group typified by trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl or the like is used.
Examples of the protecting group for the thiol group (—SH group) include alkyl groups typified by methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and the like; benzyl, triphenylmethyl and the like. Aralkyl groups represented by acetyl, ethylcarbonyl, pivaloyl and the like; aroyl groups represented by benzoyl and the like are used.
Such a method for introducing / removing a protecting group is appropriately performed depending on the group to be protected or the type of protecting group. For example, Greene et al., Protective Groups in Organic Synthesis 4th Edition, 2007, John Wiley & Sons. It can be performed by the method described in the book.
保護基の脱保護法としては、例えば、アセチル、エチルカルボニル、ピバロイル等に代表されるアルカノイル基;メトキシカルボニル、エトキシカルボニル、t‐ブトキシカルボニル等に代表されるアルコキシルカルボニル基;ベンゾイル等に代表されるアロイル基のようなアシル型保護基では、例えば、水酸化リチウム、水酸化ナトリウムもしくは水酸化カリウムのような水酸化アルカリ金属等の適当な塩基を用いることにより加水分解し脱保護できる。
メトキシメチル、メトキシエトキシメチル、テトラヒドロピラニル等に代表されるアルコキシルアルキル型保護基;t‐ブトキシカルボニル等に代表されるアルコキシルカルボニル型保護基;ベンジルオキシカルボニル、パラメトキシベンジルオキシカルボニル等に代表されるアラルキルオキシカルボニル型保護基;トリメチルシリル、トリエチルシリル、t‐ブチルジメチルシリル等に代表されるシリル型保護基は、例えば、酢酸、塩酸、臭化水素酸、硫酸、リン酸、トリフルオロ酢酸、トリフルオロメタンスルホン酸等の適当な酸、あるいはこれらを組み合わせた酸を用いることにより脱保護できる。 Examples of the deprotection method of the protecting group include alkanoyl groups represented by acetyl, ethylcarbonyl, pivaloyl, etc .; alkoxylcarbonyl groups represented by methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc .; benzoyl, etc. An acyl-type protecting group such as an aroyl group can be hydrolyzed and deprotected by using an appropriate base such as an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
Alkoxylalkyl-type protecting groups represented by methoxymethyl, methoxyethoxymethyl, tetrahydropyranyl, etc .; Alkoxylcarbonyl-type protecting groups represented by t-butoxycarbonyl, etc .; benzyloxycarbonyl, paramethoxybenzyloxycarbonyl, etc. Aralkyloxycarbonyl-type protecting groups; silyl-type protecting groups represented by trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and the like include, for example, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethane Deprotection can be achieved by using an appropriate acid such as sulfonic acid or a combination thereof.
メトキシメチル、メトキシエトキシメチル、テトラヒドロピラニル等に代表されるアルコキシルアルキル型保護基;t‐ブトキシカルボニル等に代表されるアルコキシルカルボニル型保護基;ベンジルオキシカルボニル、パラメトキシベンジルオキシカルボニル等に代表されるアラルキルオキシカルボニル型保護基;トリメチルシリル、トリエチルシリル、t‐ブチルジメチルシリル等に代表されるシリル型保護基は、例えば、酢酸、塩酸、臭化水素酸、硫酸、リン酸、トリフルオロ酢酸、トリフルオロメタンスルホン酸等の適当な酸、あるいはこれらを組み合わせた酸を用いることにより脱保護できる。 Examples of the deprotection method of the protecting group include alkanoyl groups represented by acetyl, ethylcarbonyl, pivaloyl, etc .; alkoxylcarbonyl groups represented by methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc .; benzoyl, etc. An acyl-type protecting group such as an aroyl group can be hydrolyzed and deprotected by using an appropriate base such as an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
Alkoxylalkyl-type protecting groups represented by methoxymethyl, methoxyethoxymethyl, tetrahydropyranyl, etc .; Alkoxylcarbonyl-type protecting groups represented by t-butoxycarbonyl, etc .; benzyloxycarbonyl, paramethoxybenzyloxycarbonyl, etc. Aralkyloxycarbonyl-type protecting groups; silyl-type protecting groups represented by trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and the like include, for example, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethane Deprotection can be achieved by using an appropriate acid such as sulfonic acid or a combination thereof.
また、前記シリル型保護基は、適当なフッ素イオン(F-)発生試薬、例えばフッ化テトラブチルアンモニウム、フッ化水素等の試薬を用いることでも脱保護できる。
ベンジルオキシカルボニル、パラメトキシベンジルオキシカルボニル、パラニトロベンジルオキシカルボニル等に代表されるアラルキルオキシカルボニル基ならびにベンジルに代表されるアラルキル基は、例えば、パラジウム-炭素(Pd-C)触媒を用いる加水素分解により脱保護できる。
また前記ベンジル基は、例えば、液体アンモニア中、金属ナトリウムを用いるバーチ還元によっても脱保護できる。
トリフェニルメチル基は、適当な酸、例えば、酢酸、塩酸、臭化水素酸、硫酸、リン酸、トリフルオロ酢酸、トリフルオロメタンスルホン酸等の酸あるいはこれらを組み合わせた酸を用いることにより脱保護できる。また、液体アンモニア中、金属ナトリウムもしくは金属リチウムを用いるバーチ還元や、パラジウム炭素触媒を用いる加水素分解によっても脱保護できる。 The silyl-type protecting group can also be deprotected by using a suitable fluorine ion (F − ) generating reagent such as a reagent such as tetrabutylammonium fluoride and hydrogen fluoride.
Aralkyloxycarbonyl groups typified by benzyloxycarbonyl, paramethoxybenzyloxycarbonyl, paranitrobenzyloxycarbonyl and the like and aralkyl groups typified by benzyl are, for example, hydrogenolysis using a palladium-carbon (Pd-C) catalyst. Can be deprotected.
The benzyl group can also be deprotected by, for example, Birch reduction using metallic sodium in liquid ammonia.
The triphenylmethyl group can be deprotected by using an appropriate acid, for example, an acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or a combination thereof. . It can also be deprotected by liquid Birch reduction using metallic sodium or metallic lithium or hydrogenolysis using a palladium carbon catalyst.
ベンジルオキシカルボニル、パラメトキシベンジルオキシカルボニル、パラニトロベンジルオキシカルボニル等に代表されるアラルキルオキシカルボニル基ならびにベンジルに代表されるアラルキル基は、例えば、パラジウム-炭素(Pd-C)触媒を用いる加水素分解により脱保護できる。
また前記ベンジル基は、例えば、液体アンモニア中、金属ナトリウムを用いるバーチ還元によっても脱保護できる。
トリフェニルメチル基は、適当な酸、例えば、酢酸、塩酸、臭化水素酸、硫酸、リン酸、トリフルオロ酢酸、トリフルオロメタンスルホン酸等の酸あるいはこれらを組み合わせた酸を用いることにより脱保護できる。また、液体アンモニア中、金属ナトリウムもしくは金属リチウムを用いるバーチ還元や、パラジウム炭素触媒を用いる加水素分解によっても脱保護できる。 The silyl-type protecting group can also be deprotected by using a suitable fluorine ion (F − ) generating reagent such as a reagent such as tetrabutylammonium fluoride and hydrogen fluoride.
Aralkyloxycarbonyl groups typified by benzyloxycarbonyl, paramethoxybenzyloxycarbonyl, paranitrobenzyloxycarbonyl and the like and aralkyl groups typified by benzyl are, for example, hydrogenolysis using a palladium-carbon (Pd-C) catalyst. Can be deprotected.
The benzyl group can also be deprotected by, for example, Birch reduction using metallic sodium in liquid ammonia.
The triphenylmethyl group can be deprotected by using an appropriate acid, for example, an acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or a combination thereof. . It can also be deprotected by liquid Birch reduction using metallic sodium or metallic lithium or hydrogenolysis using a palladium carbon catalyst.
スルホニル基は、例えば、低温下にてNa/アンスラセン、Na/ナフタレンを用いる一電子還元、もしくは、液体アンモニア中、金属ナトリウムもしくは金属リチウムを用いるバーチ還元等を用いることにより脱保護できる。
また、スルホニル基の中でも、2-ニトロベンゼンスルホニル基は、例えば、炭酸カリウムもしくはトリエチルアミン等の塩基性試薬存在下、チオールを反応させる、穏和な条件にて脱保護できる。
ここに示した、保護基の脱保護法は1例にしかなく、例えば、Greeneらの『Protective Groups in Organic Synthesis 第4版、2007年、John Wiley & Sons』の成書に記載の方法もしくは公知に発表されている各種論文を適用することで、脱保護が可能である。
下記に述べる製造方法中の反応条件については、特に断らない限り、以下の如きとする。反応温度は、-78℃から溶媒が還流する温度の範囲であり、特に温度が記載されていない場合は、室温(0~35℃)であり、反応時間は、反応が十分進行する時間である。 The sulfonyl group can be deprotected by, for example, one-electron reduction using Na / anthracene or Na / naphthalene at low temperature or Birch reduction using metallic sodium or metallic lithium in liquid ammonia.
Among the sulfonyl groups, the 2-nitrobenzenesulfonyl group can be deprotected under mild conditions in which a thiol is reacted in the presence of a basic reagent such as potassium carbonate or triethylamine.
The protecting group deprotection method shown here is only one example. For example, the method described in the book of Greene et al., "Protective Groups in Organic Synthesis 4th Edition, 2007, John Wiley &Sons" or publicly known Deprotection is possible by applying various papers published in.
The reaction conditions in the production method described below are as follows unless otherwise specified. The reaction temperature is in the range from −78 ° C. to the temperature at which the solvent is refluxed. When the temperature is not described, it is room temperature (0 to 35 ° C.), and the reaction time is the time for which the reaction proceeds sufficiently. .
また、スルホニル基の中でも、2-ニトロベンゼンスルホニル基は、例えば、炭酸カリウムもしくはトリエチルアミン等の塩基性試薬存在下、チオールを反応させる、穏和な条件にて脱保護できる。
ここに示した、保護基の脱保護法は1例にしかなく、例えば、Greeneらの『Protective Groups in Organic Synthesis 第4版、2007年、John Wiley & Sons』の成書に記載の方法もしくは公知に発表されている各種論文を適用することで、脱保護が可能である。
下記に述べる製造方法中の反応条件については、特に断らない限り、以下の如きとする。反応温度は、-78℃から溶媒が還流する温度の範囲であり、特に温度が記載されていない場合は、室温(0~35℃)であり、反応時間は、反応が十分進行する時間である。 The sulfonyl group can be deprotected by, for example, one-electron reduction using Na / anthracene or Na / naphthalene at low temperature or Birch reduction using metallic sodium or metallic lithium in liquid ammonia.
Among the sulfonyl groups, the 2-nitrobenzenesulfonyl group can be deprotected under mild conditions in which a thiol is reacted in the presence of a basic reagent such as potassium carbonate or triethylamine.
The protecting group deprotection method shown here is only one example. For example, the method described in the book of Greene et al., "Protective Groups in Organic Synthesis 4th Edition, 2007, John Wiley &Sons" or publicly known Deprotection is possible by applying various papers published in.
The reaction conditions in the production method described below are as follows unless otherwise specified. The reaction temperature is in the range from −78 ° C. to the temperature at which the solvent is refluxed. When the temperature is not described, it is room temperature (0 to 35 ° C.), and the reaction time is the time for which the reaction proceeds sufficiently. .
また、製造方法中の各工程は、無溶媒、あるいは反応前に原料化合物を適当な反応に関与しない溶媒に溶解又は懸濁して行うことができる。反応に関与しない溶媒としては、具体的には、水;シクロヘキサン、ヘキサン等の飽和炭化水素系溶媒;ベンゼン、クロロベンゼン、トルエン、キシレン等の芳香族炭化水素溶媒;メタノール、エタノール、1-プロパノール、2-プロパノール、tert-ブチルアルコール、2-メトキシエタノール等のアルコール系溶媒;N,N-ジメチルホルムアミド(DMF)、N,N-ジメチルアセトアミド、ヘキサメチルホスホリックトリアミド、1,3‐ジメチル‐2‐イミダゾリジノン等の極性アミド系溶媒:ジメチルスルホキシド(DMSO)等のスルホキシド系溶媒;アセトニトリル、プロピオニトリル等のニトリル系溶媒;ジエチルエーテル、ジイソプロピルエーテル、メチルtert-ブチルエーテル(MTBE)、ジフェニルエーテル、テトラヒドロフラン(THF)、1,4-ジオキサン、1,2-ジメトキシエタン等のエーテル系溶媒;酢酸メチル、酢酸エチル、酢酸ブチル等のエステル系溶媒;アセトン、メチルエチルケトン等のケトン系溶媒;ジクロロメタン、クロロホルム、四塩化炭素、1,2-ジクロロエタン等のハロゲン化炭化水素系溶媒;トリエチルアミン、N,N-ジイソプロピルエチルアミン、ピリジン、ルチジン等の塩基性溶媒;無水酢酸等の酸無水物;ギ酸、酢酸、プロピオン酸、トリフルオロ酢酸、メタンスルホン酸等の有機酸;塩酸、硫酸等の無機酸;であるが、一種の溶媒を単独で用いてもよく、または反応条件により適宜選択し二種以上の溶媒を適宜の割合で混合して用いてもよい。
In addition, each step in the production method can be performed without solvent or by dissolving or suspending the raw material compound in a solvent not involved in an appropriate reaction before the reaction. Specific examples of solvents that do not participate in the reaction include water; saturated hydrocarbon solvents such as cyclohexane and hexane; aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene, and xylene; methanol, ethanol, 1-propanol, 2 Alcohol solvents such as propanol, tert-butyl alcohol, 2-methoxyethanol; N, N-dimethylformamide (DMF), N, N-dimethylacetamide, hexamethylphosphoric triamide, 1,3-dimethyl-2- Polar amide solvents such as imidazolidinone: sulfoxide solvents such as dimethyl sulfoxide (DMSO); nitrile solvents such as acetonitrile and propionitrile; diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), diphenyl ether Ether solvents such as tellurium, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane; ester solvents such as methyl acetate, ethyl acetate and butyl acetate; ketone solvents such as acetone and methyl ethyl ketone; dichloromethane, Halogenated hydrocarbon solvents such as chloroform, carbon tetrachloride and 1,2-dichloroethane; basic solvents such as triethylamine, N, N-diisopropylethylamine, pyridine and lutidine; acid anhydrides such as acetic anhydride; formic acid, acetic acid, An organic acid such as propionic acid, trifluoroacetic acid, methanesulfonic acid, etc .; an inorganic acid such as hydrochloric acid, sulfuric acid, etc., but one kind of solvent may be used alone, or two or more kinds of solvents may be appropriately selected according to reaction conditions May be mixed and used at an appropriate ratio.
本発明化合物の製造方法中において用いられる塩基(又は脱酸剤)として、具体的には、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化マグネシウム、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸カルシウム、炭酸水素ナトリウム等の無機塩基;トリエチルアミン、N,N-ジイソプロピルエチルアミン(DIPEA)、トリブチルアミン、シクロヘキシルジメチルアミン、ピリジン、ルチジン、4-ジメチルアミノピリジン(DMAP)、N,N-ジメチルアニリン、N-メチルピペリジン、N-メチルピロリジン、N-メチルモルホリン、1,5-ジアザビシクロ[4.3.0]-5-ノネン、1,4-ジアザビシクロ[2.2.2]オクタン、1,8-ジアザビシクロ[5.4.0]-7-ウンデセン、イミダゾール等の有機塩基;ナトリウムメトキシド、ナトリウムエトキシド、カリウムtert-ブトキシド、ナトリウムtert-ブトキシド等金属アルコキシルド類;水素化ナトリウム、水素化カリウム等のアルカリ金属水素化物;ナトリウムアミド、リチウムジイソプロピルアミド(LDA)、リチウムヘキサメチルジシラジド等の金属アミド;メチルリチウム、n-ブチルリチウム(n-BuLi)、sec-ブチルリチウム、tert-ブチルリチウム等の有機リチウム試薬;が挙げられる。また、本発明化合物の製造方法において用いられる酸、又は酸触媒として、具体的には、塩酸、硫酸、硝酸、臭化水素酸、リン酸等の無機酸;酢酸、トリフルオロ酢酸、シュウ酸、フタル酸、フマル酸、酒石酸、マレイン酸、クエン酸、コハク酸、メタンスルホン酸、p-トルエンスルホン酸、10-カンファースルホン酸等の有機酸;三フッ化ホウ素エーテル錯体、ヨウ化亜鉛、無水塩化アルミニウム、無水塩化亜鉛、無水塩化鉄等のルイス酸;が挙げられる。ただし、上記に記載したものに必ずしも限定されるわけではない。
Specific examples of the base (or deoxidizer) used in the production method of the compound of the present invention include lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, and carbonate. Inorganic bases such as cesium, calcium carbonate, sodium bicarbonate; triethylamine, N, N-diisopropylethylamine (DIPEA), tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4-dimethylaminopyridine (DMAP), N, N-dimethyl Aniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,4-diazabicyclo [2.2.2] octane, 1, 8-Diazabicyclo [5.4.0] -7-undecene Organic bases such as imidazole; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide; alkali metal hydrides such as sodium hydride and potassium hydride; sodium amide, lithium diisopropylamide ( LDA), metal amides such as lithium hexamethyldisilazide; organolithium reagents such as methyllithium, n-butyllithium (n-BuLi), sec-butyllithium, and tert-butyllithium. Further, as the acid or acid catalyst used in the method for producing the compound of the present invention, specifically, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid; acetic acid, trifluoroacetic acid, oxalic acid, Organic acids such as phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid; boron trifluoride ether complex, zinc iodide, anhydrous chloride Lewis acids such as aluminum, anhydrous zinc chloride, and anhydrous iron chloride. However, it is not necessarily limited to those described above.
式(I)の塩は、それ自体公知の手段に従い、例えば、式(I)が塩基性化合物である場合には塩酸、臭化水素酸、硝酸、硫酸、リン酸等無機酸(鉱酸)またはギ酸、酢酸、トリフルオロ酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸等有機酸を加えることによって、または式(I)が酸性化合物である場合にはアンモニア、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、2,6-ルチジン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、シクロヘキシルアミン、ジシクロヘキシルアミン、N,N-ジイソプロピルエチルアミン、N,N'-ジベンジルエチレンジアミン、N,N‐ジアルキルアニリン等の有機塩基または炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、炭酸水素ナトリウム等無機塩基を加えることによって製造することができる。
The salt of the formula (I) is prepared according to a method known per se. For example, when the formula (I) is a basic compound, an inorganic acid (mineral acid) such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Or add organic acids such as formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid Or when formula (I) is an acidic compound, ammonia, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N -Diisopropylethylamine, N, N'-dibenzylethylenediamine, N, N-dialkyl It can be produced by adding an organic base such as ruaniline or an inorganic base such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate.
本発明の式(I)で表される化合物は、式(AM)で表されるアミン誘導体を出発原料として、製造方法A(P1=Hの場合:環A基の導入、続くP2基の脱保護、式(CA)で表されるカルボン酸誘導体の縮合反応)、もしくは製造方法B(P2=Hの場合:式(CA)で表されるカルボン酸誘導体の縮合反応、続くP1基の脱保護、環A基の導入)により得ることができる。
The compound represented by the formula (I) of the present invention is prepared by using the amine derivative represented by the formula (AM) as a starting material and the production method A (when P 1 = H: introduction of the ring A group, followed by the P 2 group Deprotection of carboxylic acid derivative represented by formula (CA), or production method B (when P 2 = H: condensation reaction of carboxylic acid derivative represented by formula (CA), followed by P 1 Group deprotection, introduction of ring A group).
以下に、式(I)、式(I-1)[式(I)でL=単環式非芳香族複素環、フェニルまたは単環式ヘテロアリールの場合]、式(I-2)[式(I)で環A=3-置換-4-シアノ-2-ピリジンの場合]、および式(CA)[式(CA-3)、式(CA-4)、式(CA-5-1)、式(CA-5-2)、および式(CA-5-3)]で表される化合物の製造方法を示す。
Formula (I), Formula (I-1) [in the formula (I) where L = monocyclic non-aromatic heterocycle, phenyl or monocyclic heteroaryl], formula (I-2) [formula In the case of (I) ring A = 3-substituted-4-cyano-2-pyridine], and formula (CA) [formula (CA-3), formula (CA-4), formula (CA-5-1) , Formula (CA-5-2), and formula (CA-5-3)].
<工程1>
[環A=5~14員ヘテロアリール基;X=ハロゲン原子の場合]
式(AM-1)(式(AM)でP1=H)で表される化合物、および式(AR-1)で表される化合物(式(AM-1)および式(AR-1)で表される化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)を用いて、文献公知の方法、例えば、『Tetrahedron、66(13)、2398-2403頁、2010年』等に記載された方法に準じて、無溶媒で反応温度120~150度にて反応を行い、式(AM-3)の化合物を製造することができる。 <Step 1>
[Ring A = 5 to 14-membered heteroaryl group; X = halogen atom]
A compound represented by formula (AM-1) (P 1 = H in formula (AM)), and a compound represented by formula (AR-1) (in formula (AM-1) and formula (AR-1) The compound represented is a commercially available compound or a compound that can be produced from a commercially available compound by a production method known in the literature). The compound of formula (AM-3) can be produced by carrying out the reaction at a reaction temperature of 120 to 150 ° C. without solvent in accordance with the method described in “Year” and the like.
[環A=5~14員ヘテロアリール基;X=ハロゲン原子の場合]
式(AM-1)(式(AM)でP1=H)で表される化合物、および式(AR-1)で表される化合物(式(AM-1)および式(AR-1)で表される化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)を用いて、文献公知の方法、例えば、『Tetrahedron、66(13)、2398-2403頁、2010年』等に記載された方法に準じて、無溶媒で反応温度120~150度にて反応を行い、式(AM-3)の化合物を製造することができる。 <Step 1>
[Ring A = 5 to 14-membered heteroaryl group; X = halogen atom]
A compound represented by formula (AM-1) (P 1 = H in formula (AM)), and a compound represented by formula (AR-1) (in formula (AM-1) and formula (AR-1) The compound represented is a commercially available compound or a compound that can be produced from a commercially available compound by a production method known in the literature). The compound of formula (AM-3) can be produced by carrying out the reaction at a reaction temperature of 120 to 150 ° C. without solvent in accordance with the method described in “Year” and the like.
また、式(AM-1)(式(AM)でP1=H)で表される化合物、および式(AR-1)で表される化合物を用いて、文献公知の方法、例えば、『Journal of Organic Chemistry、70(13)、5164-5173頁、2005年』等に記載された方法に準じて、ヨウ化銅(CuI)等のCu触媒、および(S)-プロリン、および炭酸カリウム、炭酸ナトリウム、炭酸セシウム、トリエチルアミン、N,N-ジイソプロピルエチルアミン、リン酸カリウム等塩基存在下、ジメチルスルホキシド、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、ジメトキシエタン、1,4-ジオキサン、テトラヒドロフラン、トルエン、キシレン、アセトニトリル等の反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(AM-3)で表される化合物を製造することができる。
更に、式(AM-1)(式(AM)でP1=H)で表される化合物、および式(AR-1)で表される化合物を用いて、文献公知の方法、例えば、『WO2012/076430号パンフレット』などに記載された方法に準じて、トリス(ジベンジリデンアセトン)ジパラジウム(Pd2(dba)3)等のPd触媒、および4,5’-ビス(ジフェニルホスフィノ)-9,9’-ジメチルキサンテン(XANTPHOS)等のホスフィン系試薬、およびトリエチルアミン、N,N-ジイソプロピルエチルアミン、リン酸カリウム、炭酸カリウム、炭酸セシウム等の有機または無機塩基存在下、トルエン、キシレン、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、ジメトキシエタン、アセトニトリル(アセトニトリル/水)、ジオキサン(ジオキサン/水)、テトラヒドロフラン(テトラヒドロフラン/水)等の反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(AM-3)で表される化合物を製造することができる。 Further, using a compound represented by the formula (AM-1) (P 1 = H in the formula (AM)) and a compound represented by the formula (AR-1), methods known in the literature, for example, “Journal of Organic Chemistry, 70 (13), 5164-5173, 2005 ”and the like, a Cu catalyst such as copper iodide (CuI), and (S) -proline, and potassium carbonate, carbonate In the presence of a base such as sodium, cesium carbonate, triethylamine, N, N-diisopropylethylamine, potassium phosphate, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, dimethoxyethane, 1,4-dioxane, tetrahydrofuran, Solvents that do not participate in the reaction, such as toluene, xylene, and acetonitrile, or these Using a solvent mixture, the reaction was carried out in the temperature at which the solvent refluxes from 0 ° C., it is possible to produce a compound represented by the formula (AM-3).
Further, using a compound represented by the formula (AM-1) (P 1 = H in the formula (AM)) and a compound represented by the formula (AR-1), methods known in the literature, for example, “WO2012 / P76 catalyst such as tris (dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ) and 4,5′-bis (diphenylphosphino) -9 , 9'-dimethylxanthene (XANTPHOS) and the like, and toluene, xylene, N, N in the presence of organic or inorganic bases such as triethylamine, N, N-diisopropylethylamine, potassium phosphate, potassium carbonate, cesium carbonate -Dimethylformamide, N, N-dimethylacetamide, dimethoxyethane, acetonitrile (acetonitrile / water) Using a solvent that does not participate in the reaction such as dioxane (dioxane / water), tetrahydrofuran (tetrahydrofuran / water), or a mixed solvent thereof, the reaction is performed at a temperature at which the solvent is refluxed from 0 ° C. The compounds represented can be produced.
更に、式(AM-1)(式(AM)でP1=H)で表される化合物、および式(AR-1)で表される化合物を用いて、文献公知の方法、例えば、『WO2012/076430号パンフレット』などに記載された方法に準じて、トリス(ジベンジリデンアセトン)ジパラジウム(Pd2(dba)3)等のPd触媒、および4,5’-ビス(ジフェニルホスフィノ)-9,9’-ジメチルキサンテン(XANTPHOS)等のホスフィン系試薬、およびトリエチルアミン、N,N-ジイソプロピルエチルアミン、リン酸カリウム、炭酸カリウム、炭酸セシウム等の有機または無機塩基存在下、トルエン、キシレン、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、ジメトキシエタン、アセトニトリル(アセトニトリル/水)、ジオキサン(ジオキサン/水)、テトラヒドロフラン(テトラヒドロフラン/水)等の反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(AM-3)で表される化合物を製造することができる。 Further, using a compound represented by the formula (AM-1) (P 1 = H in the formula (AM)) and a compound represented by the formula (AR-1), methods known in the literature, for example, “Journal of Organic Chemistry, 70 (13), 5164-5173, 2005 ”and the like, a Cu catalyst such as copper iodide (CuI), and (S) -proline, and potassium carbonate, carbonate In the presence of a base such as sodium, cesium carbonate, triethylamine, N, N-diisopropylethylamine, potassium phosphate, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, dimethoxyethane, 1,4-dioxane, tetrahydrofuran, Solvents that do not participate in the reaction, such as toluene, xylene, and acetonitrile, or these Using a solvent mixture, the reaction was carried out in the temperature at which the solvent refluxes from 0 ° C., it is possible to produce a compound represented by the formula (AM-3).
Further, using a compound represented by the formula (AM-1) (P 1 = H in the formula (AM)) and a compound represented by the formula (AR-1), methods known in the literature, for example, “WO2012 / P76 catalyst such as tris (dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ) and 4,5′-bis (diphenylphosphino) -9 , 9'-dimethylxanthene (XANTPHOS) and the like, and toluene, xylene, N, N in the presence of organic or inorganic bases such as triethylamine, N, N-diisopropylethylamine, potassium phosphate, potassium carbonate, cesium carbonate -Dimethylformamide, N, N-dimethylacetamide, dimethoxyethane, acetonitrile (acetonitrile / water) Using a solvent that does not participate in the reaction such as dioxane (dioxane / water), tetrahydrofuran (tetrahydrofuran / water), or a mixed solvent thereof, the reaction is performed at a temperature at which the solvent is refluxed from 0 ° C. The compounds represented can be produced.
[環A=5~14員ヘテロアリール基;X=OTfの場合]
式(AM-1)(式(AM)でP1=H)で表される化合物、および式(AR-1)で表される化合物を用いて、文献公知の方法、例えば、『Synlett、(12)、1400-1402、1997年』等に記載された方法に準じて、ジクロロメタン、クロロホルム等のハロゲン系溶媒、ジエチルエーテル、テトラヒドロフラン、1,2-ジメトキシエタン、1,4-ジオキサン等のエーテル系溶媒、ベンゼン、トルエン等の芳香族炭化水素系溶媒、アセトニトリル、N,N-ジメチルホルムアミド、ジメチルスルホキシド等の極性溶媒など反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(AM-3)で表される化合物を製造することができる。 [Ring A = 5 to 14-membered heteroaryl group; when X = OTf]
Using a compound represented by formula (AM-1) (P 1 = H in formula (AM)) and a compound represented by formula (AR-1), methods known in the literature, for example, “Synlett, ( 12) 1400-1402, 1997 ”and the like, halogen solvents such as dichloromethane and chloroform, ether systems such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and the like. Solvent, solvent such as benzene, toluene, polar solvents such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, etc., or a mixed solvent of these solvents are used. The reaction can be performed at a refluxing temperature to produce a compound represented by the formula (AM-3).
式(AM-1)(式(AM)でP1=H)で表される化合物、および式(AR-1)で表される化合物を用いて、文献公知の方法、例えば、『Synlett、(12)、1400-1402、1997年』等に記載された方法に準じて、ジクロロメタン、クロロホルム等のハロゲン系溶媒、ジエチルエーテル、テトラヒドロフラン、1,2-ジメトキシエタン、1,4-ジオキサン等のエーテル系溶媒、ベンゼン、トルエン等の芳香族炭化水素系溶媒、アセトニトリル、N,N-ジメチルホルムアミド、ジメチルスルホキシド等の極性溶媒など反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(AM-3)で表される化合物を製造することができる。 [Ring A = 5 to 14-membered heteroaryl group; when X = OTf]
Using a compound represented by formula (AM-1) (P 1 = H in formula (AM)) and a compound represented by formula (AR-1), methods known in the literature, for example, “Synlett, ( 12) 1400-1402, 1997 ”and the like, halogen solvents such as dichloromethane and chloroform, ether systems such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and the like. Solvent, solvent such as benzene, toluene, polar solvents such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, etc., or a mixed solvent of these solvents are used. The reaction can be performed at a refluxing temperature to produce a compound represented by the formula (AM-3).
[環A=C6~14アリール基;X=ハロゲン原子の場合]
式(AM-1)(式(AM)でP1=H)で表される化合物、および式(AR-1)で表される化合物を用いて、文献公知の方法、例えば、『WO2009/059112号パンフレット』などに記載された方法に準じて、トリス(ジベンジリデンアセトン)ジパラジウム(Pd2(dba)3)、酢酸パラジウム(Pd(OAc)2)、クロロ(2-ジシクロヘキシルホスフィノ-2’,6’-ジイソプロポキシ-1,1’-ビフェニル)[2-(2’-アミノ-1,1’-ビフェニル)]パラジウム(II)(RuPhos Pd G2)等のPd触媒、および2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピルビフェニル(X-phos)、4,5’-ビス(ジフェニルホスフィノ)-9,9’-ジメチルキサンテン(XANTPHOS)、(Ph2P)2-ビナフチル、2’,2-ビス(ジフェニルホスフィノ)-1’,1-ビナフチル(BINAP)、 2-ジシクロヘキシルホスフィノ-2’,6’-ジイソプロポキシ-1,1’-ビフェニル(RuPhos)、[1’,1-ビフェニル]-2-イル ジ-tert-ブチルホスフィン(JohnPhos)等のホスフィン系試薬、および炭酸セシウム、炭酸カリウム、リン酸カリウム、tert-BuONa、トリエチルアミン、N,N-ジイソプロピルエチルアミン、等の有機または無機塩基存在下、トルエン、N,N-ジメチルホルムアミド、N-メチルピロリドン(NMP)、N,N-ジメチルアセトアミド、アセトニトリル、アセトニトリル/水、ジオキサン、ジオキサン/水、テトラヒドロフラン、テトラヒドロフラン/水、等の反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、室温から溶媒が還流する温度で反応を行い、式(AM-3)で表される化合物を製造することができる。 [; When X = halogen atom ring A = C 6 ~ 14 aryl group]
Using a compound represented by formula (AM-1) (P 1 = H in formula (AM)) and a compound represented by formula (AR-1), methods known in the literature, for example, “WO2009 / 059112” Tris (dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ), palladium acetate (Pd (OAc) 2 ), chloro (2-dicyclohexylphosphino-2 ′) , 6′-diisopropoxy-1,1′-biphenyl) [2- (2′-amino-1,1′-biphenyl)] palladium (II) (RuPhos Pd G2) and the like, and 2-dicyclohexyl Phosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (X-phos), 4,5′-bis (diphenylphosphino) -9,9′-dimethylxanthene (XANTP OS), (Ph 2 P) 2-binaphthyl, 2 ', 2-bis (diphenylphosphino) -1', 1 binaphthyl (BINAP), 2-dicyclohexyl phosphino-2 ', 6'-diisopropoxy - Phosphine reagents such as 1,1′-biphenyl (RuPhos), [1 ′, 1-biphenyl] -2-yl di-tert-butylphosphine (JohnPhos), and cesium carbonate, potassium carbonate, potassium phosphate, tert- In the presence of an organic or inorganic base such as BuONa, triethylamine, N, N-diisopropylethylamine, etc., toluene, N, N-dimethylformamide, N-methylpyrrolidone (NMP), N, N-dimethylacetamide, acetonitrile, acetonitrile / water, Dioxane, dioxane / water, tetrahydrofuran, tetrahydro A compound represented by the formula (AM-3) can be produced by performing a reaction at a temperature at which the solvent is refluxed from a room temperature using a solvent such as furan / water that does not participate in the reaction or a mixed solvent thereof. .
式(AM-1)(式(AM)でP1=H)で表される化合物、および式(AR-1)で表される化合物を用いて、文献公知の方法、例えば、『WO2009/059112号パンフレット』などに記載された方法に準じて、トリス(ジベンジリデンアセトン)ジパラジウム(Pd2(dba)3)、酢酸パラジウム(Pd(OAc)2)、クロロ(2-ジシクロヘキシルホスフィノ-2’,6’-ジイソプロポキシ-1,1’-ビフェニル)[2-(2’-アミノ-1,1’-ビフェニル)]パラジウム(II)(RuPhos Pd G2)等のPd触媒、および2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピルビフェニル(X-phos)、4,5’-ビス(ジフェニルホスフィノ)-9,9’-ジメチルキサンテン(XANTPHOS)、(Ph2P)2-ビナフチル、2’,2-ビス(ジフェニルホスフィノ)-1’,1-ビナフチル(BINAP)、 2-ジシクロヘキシルホスフィノ-2’,6’-ジイソプロポキシ-1,1’-ビフェニル(RuPhos)、[1’,1-ビフェニル]-2-イル ジ-tert-ブチルホスフィン(JohnPhos)等のホスフィン系試薬、および炭酸セシウム、炭酸カリウム、リン酸カリウム、tert-BuONa、トリエチルアミン、N,N-ジイソプロピルエチルアミン、等の有機または無機塩基存在下、トルエン、N,N-ジメチルホルムアミド、N-メチルピロリドン(NMP)、N,N-ジメチルアセトアミド、アセトニトリル、アセトニトリル/水、ジオキサン、ジオキサン/水、テトラヒドロフラン、テトラヒドロフラン/水、等の反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、室温から溶媒が還流する温度で反応を行い、式(AM-3)で表される化合物を製造することができる。 [; When X = halogen atom ring A = C 6 ~ 14 aryl group]
Using a compound represented by formula (AM-1) (P 1 = H in formula (AM)) and a compound represented by formula (AR-1), methods known in the literature, for example, “WO2009 / 059112” Tris (dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ), palladium acetate (Pd (OAc) 2 ), chloro (2-dicyclohexylphosphino-2 ′) , 6′-diisopropoxy-1,1′-biphenyl) [2- (2′-amino-1,1′-biphenyl)] palladium (II) (RuPhos Pd G2) and the like, and 2-dicyclohexyl Phosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (X-phos), 4,5′-bis (diphenylphosphino) -9,9′-dimethylxanthene (XANTP OS), (Ph 2 P) 2-binaphthyl, 2 ', 2-bis (diphenylphosphino) -1', 1 binaphthyl (BINAP), 2-dicyclohexyl phosphino-2 ', 6'-diisopropoxy - Phosphine reagents such as 1,1′-biphenyl (RuPhos), [1 ′, 1-biphenyl] -2-yl di-tert-butylphosphine (JohnPhos), and cesium carbonate, potassium carbonate, potassium phosphate, tert- In the presence of an organic or inorganic base such as BuONa, triethylamine, N, N-diisopropylethylamine, etc., toluene, N, N-dimethylformamide, N-methylpyrrolidone (NMP), N, N-dimethylacetamide, acetonitrile, acetonitrile / water, Dioxane, dioxane / water, tetrahydrofuran, tetrahydro A compound represented by the formula (AM-3) can be produced by performing a reaction at a temperature at which the solvent is refluxed from a room temperature using a solvent such as furan / water that does not participate in the reaction or a mixed solvent thereof. .
<工程2>
[製造方法A]<工程1>で得られる式(AM-3)で表される化合物を用い、文献公知の方法、例えば、『Protective Groups in Organic Synthesis 4th、2007年、John Wiley & Sons、Greeneら』の成書に記載された方法に準じて、保護基P2を保護基の種類に応じた方法で反応させることにより、P2基が脱保護された、式(AM-4)で表される化合物を製造することができる。 <Step 2>
[Production Method A] Using a compound represented by the formula (AM-3) obtained in <Step 1>, a method known in the literature, for example, “Protective Groups in Organic Synthesis 4th, 2007, John Wiley & Sons, Greene” In accordance with the method described in the book of the et al., The P 2 group is deprotected by reacting the protecting group P 2 with a method according to the type of the protecting group, and the formula (AM-4) Can be produced.
[製造方法A]<工程1>で得られる式(AM-3)で表される化合物を用い、文献公知の方法、例えば、『Protective Groups in Organic Synthesis 4th、2007年、John Wiley & Sons、Greeneら』の成書に記載された方法に準じて、保護基P2を保護基の種類に応じた方法で反応させることにより、P2基が脱保護された、式(AM-4)で表される化合物を製造することができる。 <Step 2>
[Production Method A] Using a compound represented by the formula (AM-3) obtained in <Step 1>, a method known in the literature, for example, “Protective Groups in Organic Synthesis 4th, 2007, John Wiley & Sons, Greene” In accordance with the method described in the book of the et al., The P 2 group is deprotected by reacting the protecting group P 2 with a method according to the type of the protecting group, and the formula (AM-4) Can be produced.
<工程3>
[製造方法A]<工程2>で得られる式(AM-4)のアミン、および式(CA)の化合物(式(CA)の化合物は、市販化合物、もしくは市販化合物から文献公知の製造方法により製造できる化合物、または後述する[製造方法E]、[製造方法F]、[製造方法G]、[製造方法H]もしくは[製造方法J]の方法で製造できる化合物である)を用いて、文献公知の方法、例えば、『実験化学講座 第4版 22 有機合成IV 酸・アミノ酸・ペプチド、191-309頁、1992年、丸善』等に記載された方法に準じて、1,3-ジシクロヘキシルカルボジイミド(DCC)、1-エチル-3-(3’-ジメチルアミノプロピル)カルボジイミド塩酸塩(EDCI)、1-ヒドロキシベンゾトリアゾール(HOBT)、ベンゾトリアゾール-1-イロキシトリス(ジメチルアミノ)ホスホニウムヘキサフルオロホスフェイト(BOP試薬)、ビス(2-オキソ-3-オキサゾリジニル)ホスフィニッククロリド(BOP-Cl)、2-クロロ-1,3-ジメチルイミダゾリニウムヘキサフルオロホスフェイト(CIP)、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(DMTMM)、ポリリン酸(PPA)、2-(1H-7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスフェート メタンアミニウム(HATU)、(1-シアノ-2-エトキシ-2-オキソエチリデンアミノオキシ)ジメチルアミノ-モルホリノ-カルベニウムヘキサフルオロリン酸塩(COMU)、プロピルホスホン酸無水物(T3P)等の縮合剤の存在下、ジクロロメタン、クロロホルム等のハロゲン系溶媒、ジエチルエーテル、テトラヒドロフラン等のエーテル系溶媒、トルエン、ベンゼン等の芳香族炭化水素系溶媒、N,N-ジメチルホルムアミド等の極性溶媒、メタノール、エタノール、2-プロパノール等のアルコール系溶媒等の反応に関与しない溶媒中、トリエチルアミン、N,N-ジイソプロピルエチルアミン、ピリジン等の塩基の存在下または非存在下、0℃から溶媒が還流する温度で反応させることにより、式(I)で表される化合物を製造することができる。 <Step 3>
[Production Method A] The amine of formula (AM-4) obtained in <Step 2> and the compound of formula (CA) (the compound of formula (CA) is a commercially available compound or a commercially available compound from a known method in the literature. A compound that can be produced, or a compound that can be produced by the method of [Production Method E], [Production Method F], [Production Method G], [Production Method H] or [Production Method J] described later), In accordance with a known method, for example, a method described in “Experimental Chemistry Course 4th edition 22 Organic Synthesis IV Acid / Amino Acid / Peptide, 191-309, 1992, Maruzen” and the like, 1,3-dicyclohexylcarbodiimide ( DCC), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBT), benzotriazol -1-Iroxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent), bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOP-Cl), 2-chloro-1,3-dimethylimidazolinium Hexafluorophosphate (CIP), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (DMTMM), polyphosphoric acid (PPA), 2- ( 1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy ) Dimethylamino-morpholino-carbenium hexafluorophosphate (COMU) In the presence of a condensing agent such as propylphosphonic anhydride (T3P), halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, aromatic hydrocarbon solvents such as toluene and benzene, N, In the presence or absence of a base such as triethylamine, N, N-diisopropylethylamine, or pyridine in a solvent that does not participate in the reaction, such as a polar solvent such as N-dimethylformamide, or an alcohol solvent such as methanol, ethanol, or 2-propanol. The compound represented by the formula (I) can be produced by reacting at a temperature at which the solvent is refluxed from 0 ° C.
[製造方法A]<工程2>で得られる式(AM-4)のアミン、および式(CA)の化合物(式(CA)の化合物は、市販化合物、もしくは市販化合物から文献公知の製造方法により製造できる化合物、または後述する[製造方法E]、[製造方法F]、[製造方法G]、[製造方法H]もしくは[製造方法J]の方法で製造できる化合物である)を用いて、文献公知の方法、例えば、『実験化学講座 第4版 22 有機合成IV 酸・アミノ酸・ペプチド、191-309頁、1992年、丸善』等に記載された方法に準じて、1,3-ジシクロヘキシルカルボジイミド(DCC)、1-エチル-3-(3’-ジメチルアミノプロピル)カルボジイミド塩酸塩(EDCI)、1-ヒドロキシベンゾトリアゾール(HOBT)、ベンゾトリアゾール-1-イロキシトリス(ジメチルアミノ)ホスホニウムヘキサフルオロホスフェイト(BOP試薬)、ビス(2-オキソ-3-オキサゾリジニル)ホスフィニッククロリド(BOP-Cl)、2-クロロ-1,3-ジメチルイミダゾリニウムヘキサフルオロホスフェイト(CIP)、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(DMTMM)、ポリリン酸(PPA)、2-(1H-7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスフェート メタンアミニウム(HATU)、(1-シアノ-2-エトキシ-2-オキソエチリデンアミノオキシ)ジメチルアミノ-モルホリノ-カルベニウムヘキサフルオロリン酸塩(COMU)、プロピルホスホン酸無水物(T3P)等の縮合剤の存在下、ジクロロメタン、クロロホルム等のハロゲン系溶媒、ジエチルエーテル、テトラヒドロフラン等のエーテル系溶媒、トルエン、ベンゼン等の芳香族炭化水素系溶媒、N,N-ジメチルホルムアミド等の極性溶媒、メタノール、エタノール、2-プロパノール等のアルコール系溶媒等の反応に関与しない溶媒中、トリエチルアミン、N,N-ジイソプロピルエチルアミン、ピリジン等の塩基の存在下または非存在下、0℃から溶媒が還流する温度で反応させることにより、式(I)で表される化合物を製造することができる。 <Step 3>
[Production Method A] The amine of formula (AM-4) obtained in <Step 2> and the compound of formula (CA) (the compound of formula (CA) is a commercially available compound or a commercially available compound from a known method in the literature. A compound that can be produced, or a compound that can be produced by the method of [Production Method E], [Production Method F], [Production Method G], [Production Method H] or [Production Method J] described later), In accordance with a known method, for example, a method described in “Experimental Chemistry Course 4th edition 22 Organic Synthesis IV Acid / Amino Acid / Peptide, 191-309, 1992, Maruzen” and the like, 1,3-dicyclohexylcarbodiimide ( DCC), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBT), benzotriazol -1-Iroxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent), bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOP-Cl), 2-chloro-1,3-dimethylimidazolinium Hexafluorophosphate (CIP), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (DMTMM), polyphosphoric acid (PPA), 2- ( 1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy ) Dimethylamino-morpholino-carbenium hexafluorophosphate (COMU) In the presence of a condensing agent such as propylphosphonic anhydride (T3P), halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, aromatic hydrocarbon solvents such as toluene and benzene, N, In the presence or absence of a base such as triethylamine, N, N-diisopropylethylamine, or pyridine in a solvent that does not participate in the reaction, such as a polar solvent such as N-dimethylformamide, or an alcohol solvent such as methanol, ethanol, or 2-propanol. The compound represented by the formula (I) can be produced by reacting at a temperature at which the solvent is refluxed from 0 ° C.
また、式(CA)の化合物を、文献公知の方法、例えば『Journal of the American Chemical Society、109(24)、p7488-7494、1987年』等に記載された方法に準じて、トリエチルアミン、N,N-ジイソプロピルエチルアミン、N,N-ジメチルアミノピリジン等の塩基の存在もしくは非存在下、塩化チオニル、塩化オキサリル、塩化ホスホリル、塩化スルフリル、三塩化リン、五塩化リン、三臭化リン等のハロゲン化剤と、ジオキサン、テトラヒドロフラン、ベンゼン、トルエン、ジクロロメタン、1,2-ジクロロエタン、クロロホルム等の反応に不活性な溶媒、もしくはこれらの混合溶媒を用いて、0℃から溶媒が還流する温度で反応を行い得られる酸ハライド、および[製造方法A]<工程2>で得られる式(AM-4)のアミンを用い、例えば『実験化学講座 第4版 22 有機合成IV酸・アミノ酸・ペプチド、144-146頁、1992年、丸善』等に記載された方法に準じて、トリエチルアミン、N,N-ジイソプロピルエチルアミン、ピリジン、4-ジメチルアミノピリジン等の塩基の存在下、ジクロロメタン、クロロホルム、1,2-ジクロロエタン等のハロゲン系溶媒、ジエチルエーテル、テトラドロフラン、1,4-ジオキサン等のエーテル系溶媒、トルエン、ベンゼン等の芳香族炭化水素系溶媒、N,N-ジメチルホルムアミド等の極性溶媒等の反応に関与しない溶媒中、0℃から溶媒が還流する温度で反応させることにより、式(I)の化合物を同様に製造することができる。
In addition, the compound of formula (CA) can be prepared according to methods known in the literature, for example, “Journal of the American Chemical Society, 109 (24), p7488-7494, 1987”. Halogenation of thionyl chloride, oxalyl chloride, phosphoryl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide in the presence or absence of bases such as N-diisopropylethylamine and N, N-dimethylaminopyridine The reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. using an agent and a solvent inert to the reaction such as dioxane, tetrahydrofuran, benzene, toluene, dichloromethane, 1,2-dichloroethane, chloroform, or a mixed solvent thereof. The resulting acid halide, And [Production Method A] using the amine of the formula (AM-4) obtained in <Step 2>, for example, “Experimental Chemistry Course, 4th Edition, 22. Organic Synthetic IV Acid / Amino Acid / Peptide, 144-146, 1992, In the presence of bases such as triethylamine, N, N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, In a solvent that does not participate in the reaction, such as an ether solvent such as diethyl ether, tetradrofuran, or 1,4-dioxane, an aromatic hydrocarbon solvent such as toluene or benzene, or a polar solvent such as N, N-dimethylformamide, 0 By reacting at a temperature at which the solvent refluxes from 0 ° C., the compound of formula (I) can be similarly produced.
<工程1>
式(AM-2)(式(AM)でP2=H)の化合物、および式(CA)の化合物(式(AM-2)および式(CA)の化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物であり、式(CA)の化合物は、後述する[製造方法E]、[製造方法F]、[製造方法G]、[製造方法H]もしくは[製造方法J]の方法で製造できる化合物でもよい)を用いて、[製造方法A]<工程3>に準じる反応を行い、式(AM-5)の化合物を製造することができる。 <Step 1>
Compounds of formula (AM-2) (P 2 = H in formula (AM)) and compounds of formula (CA) (formula (AM-2) and compounds of formula (CA) are commercially available compounds or commercially available compounds) A compound that can be produced by a production method known in the literature, and the compound of the formula (CA) is [Production Method E], [Production Method F], [Production Method G], [Production Method H], or [Production Method J] described later. The compound of formula (AM-5) can be produced by carrying out a reaction according to [Production Method A] <Step 3>.
式(AM-2)(式(AM)でP2=H)の化合物、および式(CA)の化合物(式(AM-2)および式(CA)の化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物であり、式(CA)の化合物は、後述する[製造方法E]、[製造方法F]、[製造方法G]、[製造方法H]もしくは[製造方法J]の方法で製造できる化合物でもよい)を用いて、[製造方法A]<工程3>に準じる反応を行い、式(AM-5)の化合物を製造することができる。 <Step 1>
Compounds of formula (AM-2) (P 2 = H in formula (AM)) and compounds of formula (CA) (formula (AM-2) and compounds of formula (CA) are commercially available compounds or commercially available compounds) A compound that can be produced by a production method known in the literature, and the compound of the formula (CA) is [Production Method E], [Production Method F], [Production Method G], [Production Method H], or [Production Method J] described later. The compound of formula (AM-5) can be produced by carrying out a reaction according to [Production Method A] <Step 3>.
<工程2>
[製造方法B]<工程1>で得られる式(AM-5)の化合物を用い、文献公知の方法、例えば、『Protective Groups in Organic Synthesis 4th、2007年、John Wiley & Sons、Greeneら』の成書に記載された方法に準じて、保護基P1を保護基の種類に応じた方法で反応させることにより、P1基が脱保護された、式(AM-6)で表される化合物を製造することができる。 <Step 2>
[Production Method B] Using a compound of formula (AM-5) obtained in <Step 1>, a method known in the literature, for example, “Protective Groups in Organic Synthesis 4th, 2007, John Wiley & Sons, Green et al.” A compound represented by the formula (AM-6), wherein the P 1 group is deprotected by reacting the protecting group P 1 according to the method according to the type of the protecting group in accordance with the method described in the document Can be manufactured.
[製造方法B]<工程1>で得られる式(AM-5)の化合物を用い、文献公知の方法、例えば、『Protective Groups in Organic Synthesis 4th、2007年、John Wiley & Sons、Greeneら』の成書に記載された方法に準じて、保護基P1を保護基の種類に応じた方法で反応させることにより、P1基が脱保護された、式(AM-6)で表される化合物を製造することができる。 <Step 2>
[Production Method B] Using a compound of formula (AM-5) obtained in <Step 1>, a method known in the literature, for example, “Protective Groups in Organic Synthesis 4th, 2007, John Wiley & Sons, Green et al.” A compound represented by the formula (AM-6), wherein the P 1 group is deprotected by reacting the protecting group P 1 according to the method according to the type of the protecting group in accordance with the method described in the document Can be manufactured.
<工程3>
[製造方法B]<工程2>で得られる式(AM-6)の化合物、および式(AR-1)の化合物(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)を用いて、[製造方法A]<工程1>に準じる反応を行い、式(I)の化合物を製造することができる。 <Step 3>
[Production Method B] The compound of formula (AM-6) obtained in <Step 2> and the compound of formula (AR-1) (this compound is a commercially available compound or can be produced from a commercially available compound by a method known in the literature) The compound of formula (I) can be produced by carrying out a reaction according to [Production Method A] <Step 1>.
[製造方法B]<工程2>で得られる式(AM-6)の化合物、および式(AR-1)の化合物(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)を用いて、[製造方法A]<工程1>に準じる反応を行い、式(I)の化合物を製造することができる。 <Step 3>
[Production Method B] The compound of formula (AM-6) obtained in <Step 2> and the compound of formula (AR-1) (this compound is a commercially available compound or can be produced from a commercially available compound by a method known in the literature) The compound of formula (I) can be produced by carrying out a reaction according to [Production Method A] <Step 1>.
[製造方法C]式(I-1)[式(I)で環B≠1-置換-1H-ピラゾール環;L=L’=単環式非芳香族複素環、フェニルまたは単環式ヘテロアリールの場合]の製造方法
[Production Method C] Formula (I-1) [In Formula (I), ring B ≠ 1-substituted-1H-pyrazole ring; L = L ′ = monocyclic non-aromatic heterocycle, phenyl or monocyclic heteroaryl In the case of
<工程1>
[製造方法A]<工程2>で得られる式(AM-4)の化合物、および式(CA-1)(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)の化合物を用いて、[製造方法A]<工程3>に準じる反応を行い、式(IM-1)の化合物を製造することができる。 <Step 1>
[Production Method A] Compound of formula (AM-4) obtained in <Step 2> and formula (CA-1) The compound of formula (IM-1) can be produced by carrying out a reaction according to [Production method A] <Step 3>.
[製造方法A]<工程2>で得られる式(AM-4)の化合物、および式(CA-1)(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)の化合物を用いて、[製造方法A]<工程3>に準じる反応を行い、式(IM-1)の化合物を製造することができる。 <Step 1>
[Production Method A] Compound of formula (AM-4) obtained in <Step 2> and formula (CA-1) The compound of formula (IM-1) can be produced by carrying out a reaction according to [Production method A] <Step 3>.
<工程2>
[製造方法C]<工程1>で得られる式(IM-1)の化合物、および式(RG-1)のハロゲン化化合物(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)を用い、文献公知の方法、例えば 『実験化学講座 第5版 18 有機化合物の合成 VI -金属を用いる有機合成-、327‐352頁、2004年、丸善』、および『Journal of Medicinal Chemistry、48(20)、p6326‐6339、2005年』に記載された方法に準じて、酢酸パラジウム(II)(Pd(OAc)2)、テトラキストリフェニルホスフィンパラジウム(Pd(PPh3)4)、トリス(ジベンジリデンアセトン)ジパラジウム(Pd2(dba)3)、ビス(ジベンジリデンアセトン)パラジウム(Pd(dba)2)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(PdCl2(dppf))等のパラジウム触媒、トリフェニルホスフィン、トリス(tert-ブチル)ホスフィン、トリス(o-トリル)ホスフィン、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル、2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピルビフェニル等のホスフィン系試薬、およびトリエチルアミン、N,N-ジイソプロピルエチルアミン、リン酸カリウム、炭酸カリウム、炭酸セシウム等の有機または無機塩基存在下、トルエン、キシレン、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、ジメトキシエタン、アセトニトリル(アセトニトリル/水)、ジオキサン(ジオキサン/水)、テトラヒドロフラン(テトラヒドロフラン/水)等の反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(I-1)で表される化合物を製造することができる。またはホスフィン系試薬の替わりにテトラメチルアンモニウムクロリド、テトラブチルアンモニウムクロリド等を用いて、同様の方法にて製造することができる。 <Step 2>
[Production Method C] The compound of formula (IM-1) obtained in <Step 1> and the halogenated compound of formula (RG-1) (this compound is a commercially available compound or a commercially available compound from a known method in the literature). And the methods known in the literature, such as “Experimental Chemistry Course 5th edition 18 Synthesis of organic compounds VI —Organic synthesis using metals—327-352, 2004, Maruzen” and “Journal” of Medicinal Chemistry, 48 (20), p 6326-6339, 2005 ”, palladium (II) acetate (Pd (OAc) 2 ), tetrakistriphenylphosphine palladium (Pd (PPh 3 ) 4 ), tris (dibenzylideneacetone) dipalladium (Pd 2 (dba) 3), bis (Jibenjiri N'aseton) palladium (Pd (dba) 2), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (PdCl 2 (dppf)) or the like of a palladium catalyst, triphenylphosphine, tris (tert- Phosphine reagents such as butyl) phosphine, tris (o-tolyl) phosphine, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl In the presence of an organic or inorganic base such as triethylamine, N, N-diisopropylethylamine, potassium phosphate, potassium carbonate, cesium carbonate, etc., toluene, xylene, N, N-dimethylformamide, N, N-dimethylacetamide, dimethoxyethane, Acetonitrile ( Using a solvent that does not participate in the reaction, such as cetonitrile / water), dioxane (dioxane / water), tetrahydrofuran (tetrahydrofuran / water), or a mixed solvent thereof, the reaction is performed at a temperature at which the solvent is refluxed from 0 ° C. The compound represented by I-1) can be produced. Or it can manufacture by the same method using tetramethylammonium chloride, tetrabutylammonium chloride, etc. instead of a phosphine-type reagent.
[製造方法C]<工程1>で得られる式(IM-1)の化合物、および式(RG-1)のハロゲン化化合物(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)を用い、文献公知の方法、例えば 『実験化学講座 第5版 18 有機化合物の合成 VI -金属を用いる有機合成-、327‐352頁、2004年、丸善』、および『Journal of Medicinal Chemistry、48(20)、p6326‐6339、2005年』に記載された方法に準じて、酢酸パラジウム(II)(Pd(OAc)2)、テトラキストリフェニルホスフィンパラジウム(Pd(PPh3)4)、トリス(ジベンジリデンアセトン)ジパラジウム(Pd2(dba)3)、ビス(ジベンジリデンアセトン)パラジウム(Pd(dba)2)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(PdCl2(dppf))等のパラジウム触媒、トリフェニルホスフィン、トリス(tert-ブチル)ホスフィン、トリス(o-トリル)ホスフィン、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル、2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピルビフェニル等のホスフィン系試薬、およびトリエチルアミン、N,N-ジイソプロピルエチルアミン、リン酸カリウム、炭酸カリウム、炭酸セシウム等の有機または無機塩基存在下、トルエン、キシレン、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、ジメトキシエタン、アセトニトリル(アセトニトリル/水)、ジオキサン(ジオキサン/水)、テトラヒドロフラン(テトラヒドロフラン/水)等の反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(I-1)で表される化合物を製造することができる。またはホスフィン系試薬の替わりにテトラメチルアンモニウムクロリド、テトラブチルアンモニウムクロリド等を用いて、同様の方法にて製造することができる。 <Step 2>
[Production Method C] The compound of formula (IM-1) obtained in <Step 1> and the halogenated compound of formula (RG-1) (this compound is a commercially available compound or a commercially available compound from a known method in the literature). And the methods known in the literature, such as “Experimental Chemistry Course 5th edition 18 Synthesis of organic compounds VI —Organic synthesis using metals—327-352, 2004, Maruzen” and “Journal” of Medicinal Chemistry, 48 (20), p 6326-6339, 2005 ”, palladium (II) acetate (Pd (OAc) 2 ), tetrakistriphenylphosphine palladium (Pd (PPh 3 ) 4 ), tris (dibenzylideneacetone) dipalladium (Pd 2 (dba) 3), bis (Jibenjiri N'aseton) palladium (Pd (dba) 2), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (PdCl 2 (dppf)) or the like of a palladium catalyst, triphenylphosphine, tris (tert- Phosphine reagents such as butyl) phosphine, tris (o-tolyl) phosphine, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl In the presence of an organic or inorganic base such as triethylamine, N, N-diisopropylethylamine, potassium phosphate, potassium carbonate, cesium carbonate, etc., toluene, xylene, N, N-dimethylformamide, N, N-dimethylacetamide, dimethoxyethane, Acetonitrile ( Using a solvent that does not participate in the reaction, such as cetonitrile / water), dioxane (dioxane / water), tetrahydrofuran (tetrahydrofuran / water), or a mixed solvent thereof, the reaction is performed at a temperature at which the solvent is refluxed from 0 ° C. The compound represented by I-1) can be produced. Or it can manufacture by the same method using tetramethylammonium chloride, tetrabutylammonium chloride, etc. instead of a phosphine-type reagent.
<工程3>
[製造方法A]<工程2>で得られる式(AM-4)の化合物、および式(CA-2)(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)の化合物を用いて、[製造方法A]<工程3>に準じる反応を行い、式(IM-2)の化合物を製造することができる。 <Step 3>
[Production Method A] Compound of formula (AM-4) obtained in <Step 2> and formula (CA-2) The compound of formula (IM-2) can be produced by carrying out a reaction according to [Production Method A] <Step 3>.
[製造方法A]<工程2>で得られる式(AM-4)の化合物、および式(CA-2)(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)の化合物を用いて、[製造方法A]<工程3>に準じる反応を行い、式(IM-2)の化合物を製造することができる。 <Step 3>
[Production Method A] Compound of formula (AM-4) obtained in <Step 2> and formula (CA-2) The compound of formula (IM-2) can be produced by carrying out a reaction according to [Production Method A] <Step 3>.
<工程4>
[式(RG-2)のボロン酸試薬を用いる場合]
[製造方法C]<工程3>で得られる式(IM-2)の化合物、および式(RG-2)(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)の化合物を用いて、[製造方法C]<工程2>に準じる反応を行い、式(I-1)の化合物を製造することができる。
[式(RG-3)のスズ試薬を用いる場合]
[製造方法C]<工程3>で得られる式(IM-2)の化合物、および式(RG-3)(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)の化合物を用いて、文献公知の方法、例えば、『Synlett、25(5)、653-656頁、2014年』、『Europian Journal of Organic Chemistry、2013(28)、6404-6419頁、2013年』、『Chemical Communication、48(71)、8907‐8909、2012年』、『Bioorganic & Medicinal Chemistry、21(8)、2370-2378頁、2013年』等に記載された方法に準じて、テトラキストリフェニルホスフィンパラジウム(Pd(PPh3)4)、ビス(トリフェニルホスフィン)パラジウム(II)ジクロライド(Pd2(PPh3)2)等のパラジウム触媒の存在下(テトラキストリフェニルホスフィンパラジウム(Pd(PPh3)4)を用いる場合、ヨウ化銅(CuI)等の銅試薬の存在下または非存在下)、フッ化セシウム、塩化リチウム等の塩の存在下または非存在下、トルエン、テトラヒドロフラン、N,N-ジメチルホルムアミド、1,4-ジオキサン等の反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(I-1)の化合物を製造することができる。 <Step 4>
[When using a boronic acid reagent of the formula (RG-2)]
[Production Method C] Compound of formula (IM-2) obtained in <Step 3> and formula (RG-2) (This compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature. The compound of formula (I-1) can be produced by carrying out a reaction according to [Production Method C] <Step 2> using the compound of (A).
[When using a tin reagent of the formula (RG-3)]
[Production Method C] Compound of formula (IM-2) obtained in <Step 3> and formula (RG-3) (This compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature. A compound known in the literature, for example, “Synlett, 25 (5), pages 653-656, 2014”, “European Journal of Organic Chemistry, 2013 (28), pages 6404-6419, 2013”. In accordance with the method described in "Chemical Communication, 48 (71), 8907-8909, 2012", "Bioorganic & Medicinal Chemistry, 21 (8), pages 2370-2378, 2013", etc. Triphenylphosphie Palladium (Pd (PPh 3) 4), bis (triphenylphosphine) palladium (II) dichloride (Pd 2 (PPh 3) 2) the presence of a palladium catalyst such as (tetrakis triphenylphosphine palladium (Pd (PPh 3) 4 In the presence or absence of a copper reagent such as copper iodide (CuI), in the presence or absence of a salt such as cesium fluoride and lithium chloride, toluene, tetrahydrofuran, N, N-dimethyl Using a solvent such as formamide, 1,4-dioxane, or a solvent not involved in the reaction, or a mixed solvent thereof, the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. to produce the compound of formula (I-1). it can.
[式(RG-2)のボロン酸試薬を用いる場合]
[製造方法C]<工程3>で得られる式(IM-2)の化合物、および式(RG-2)(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)の化合物を用いて、[製造方法C]<工程2>に準じる反応を行い、式(I-1)の化合物を製造することができる。
[式(RG-3)のスズ試薬を用いる場合]
[製造方法C]<工程3>で得られる式(IM-2)の化合物、および式(RG-3)(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)の化合物を用いて、文献公知の方法、例えば、『Synlett、25(5)、653-656頁、2014年』、『Europian Journal of Organic Chemistry、2013(28)、6404-6419頁、2013年』、『Chemical Communication、48(71)、8907‐8909、2012年』、『Bioorganic & Medicinal Chemistry、21(8)、2370-2378頁、2013年』等に記載された方法に準じて、テトラキストリフェニルホスフィンパラジウム(Pd(PPh3)4)、ビス(トリフェニルホスフィン)パラジウム(II)ジクロライド(Pd2(PPh3)2)等のパラジウム触媒の存在下(テトラキストリフェニルホスフィンパラジウム(Pd(PPh3)4)を用いる場合、ヨウ化銅(CuI)等の銅試薬の存在下または非存在下)、フッ化セシウム、塩化リチウム等の塩の存在下または非存在下、トルエン、テトラヒドロフラン、N,N-ジメチルホルムアミド、1,4-ジオキサン等の反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(I-1)の化合物を製造することができる。 <Step 4>
[When using a boronic acid reagent of the formula (RG-2)]
[Production Method C] Compound of formula (IM-2) obtained in <Step 3> and formula (RG-2) (This compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature. The compound of formula (I-1) can be produced by carrying out a reaction according to [Production Method C] <Step 2> using the compound of (A).
[When using a tin reagent of the formula (RG-3)]
[Production Method C] Compound of formula (IM-2) obtained in <Step 3> and formula (RG-3) (This compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature. A compound known in the literature, for example, “Synlett, 25 (5), pages 653-656, 2014”, “European Journal of Organic Chemistry, 2013 (28), pages 6404-6419, 2013”. In accordance with the method described in "Chemical Communication, 48 (71), 8907-8909, 2012", "Bioorganic & Medicinal Chemistry, 21 (8), pages 2370-2378, 2013", etc. Triphenylphosphie Palladium (Pd (PPh 3) 4), bis (triphenylphosphine) palladium (II) dichloride (Pd 2 (PPh 3) 2) the presence of a palladium catalyst such as (tetrakis triphenylphosphine palladium (Pd (PPh 3) 4 In the presence or absence of a copper reagent such as copper iodide (CuI), in the presence or absence of a salt such as cesium fluoride and lithium chloride, toluene, tetrahydrofuran, N, N-dimethyl Using a solvent such as formamide, 1,4-dioxane, or a solvent not involved in the reaction, or a mixed solvent thereof, the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. to produce the compound of formula (I-1). it can.
<工程5>
[式(IM-1)でB=ボロン酸エステルの場合]
[製造方法C]<工程3>で得られる式(IM-2)の化合物を用い、文献公知の方法、例えば、『The Journal of Organic Chemistry、60、7508‐2665、1995年』に記載された方法に準じて、ビス(ピナコラート)ジボロン、ビス(ネオペンチルグリコラート)ジボロン等のジボロンエステル存在下、酢酸パラジウム(II)、テトラキストリフェニルホスフィンパラジウム、トリス(ジベンジリデンアセトン)ジパラジウム、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)などのパラジウム触媒の存在下、トリフェニルホスフィン、トリス(tert-ブチル)ホスフィン、トリス(o-トリル)ホスフィン、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル等のホスフィン系試薬、およびトリエチルアミン、N,N-ジイソプロピルエチルアミン、酢酸カリウム等の有機または無機塩基存在下または非存在下、またはホスフィン系試薬の替わりにテトラメチルアンモニウムクロリド、テトラブチルアンモニウムクロリド等存在下または非存在下、トルエン、N,N-ジメチルホルムアミド、ジメチルスルホキシド、1,4-ジオキサン等の反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(IM-1)のボロン酸エステルを製造することができる。 <Step 5>
[In the formula (IM-1) where B = boronic acid ester]
[Production Method C] The compound of formula (IM-2) obtained in <Step 3> is used and described in a method known in the literature, for example, “The Journal of Organic Chemistry, 60, 7508-2665, 1995”. According to the method, palladium (II) acetate, tetrakistriphenylphosphine palladium, tris (dibenzylideneacetone) dipalladium, [1] in the presence of diboron esters such as bis (pinacolato) diboron and bis (neopentylglycolate) diboron , 1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) in the presence of a palladium catalyst such as triphenylphosphine, tris (tert-butyl) phosphine, tris (o-tolyl) phosphine, 2-dicyclohexylphosphino -2 ', 6' Phosphine reagents such as dimethoxybiphenyl, and in the presence or absence of organic or inorganic bases such as triethylamine, N, N-diisopropylethylamine, potassium acetate, or tetramethylammonium chloride, tetrabutylammonium chloride instead of phosphine reagents The temperature at which the solvent refluxs from 0 ° C. using a solvent that does not participate in the reaction, such as toluene, N, N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, or a mixed solvent thereof in the presence or absence of To give a boronic ester of formula (IM-1)
[式(IM-1)でB=ボロン酸エステルの場合]
[製造方法C]<工程3>で得られる式(IM-2)の化合物を用い、文献公知の方法、例えば、『The Journal of Organic Chemistry、60、7508‐2665、1995年』に記載された方法に準じて、ビス(ピナコラート)ジボロン、ビス(ネオペンチルグリコラート)ジボロン等のジボロンエステル存在下、酢酸パラジウム(II)、テトラキストリフェニルホスフィンパラジウム、トリス(ジベンジリデンアセトン)ジパラジウム、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)などのパラジウム触媒の存在下、トリフェニルホスフィン、トリス(tert-ブチル)ホスフィン、トリス(o-トリル)ホスフィン、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル等のホスフィン系試薬、およびトリエチルアミン、N,N-ジイソプロピルエチルアミン、酢酸カリウム等の有機または無機塩基存在下または非存在下、またはホスフィン系試薬の替わりにテトラメチルアンモニウムクロリド、テトラブチルアンモニウムクロリド等存在下または非存在下、トルエン、N,N-ジメチルホルムアミド、ジメチルスルホキシド、1,4-ジオキサン等の反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(IM-1)のボロン酸エステルを製造することができる。 <Step 5>
[In the formula (IM-1) where B = boronic acid ester]
[Production Method C] The compound of formula (IM-2) obtained in <Step 3> is used and described in a method known in the literature, for example, “The Journal of Organic Chemistry, 60, 7508-2665, 1995”. According to the method, palladium (II) acetate, tetrakistriphenylphosphine palladium, tris (dibenzylideneacetone) dipalladium, [1] in the presence of diboron esters such as bis (pinacolato) diboron and bis (neopentylglycolate) diboron , 1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) in the presence of a palladium catalyst such as triphenylphosphine, tris (tert-butyl) phosphine, tris (o-tolyl) phosphine, 2-dicyclohexylphosphino -2 ', 6' Phosphine reagents such as dimethoxybiphenyl, and in the presence or absence of organic or inorganic bases such as triethylamine, N, N-diisopropylethylamine, potassium acetate, or tetramethylammonium chloride, tetrabutylammonium chloride instead of phosphine reagents The temperature at which the solvent refluxs from 0 ° C. using a solvent that does not participate in the reaction, such as toluene, N, N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, or a mixed solvent thereof in the presence or absence of To give a boronic ester of formula (IM-1)
[式(IM-1)でB=ボロン酸の場合]
[製造方法C]<工程3>で得られる式(IM-2)の化合物を用い、文献公知の方法、例えば、『Chemische Berichte、42、3090、1909年』等に記載された方法に準じて、トルエン、テトラヒドロフラン、1,4-ジオキサン等の反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、n-ブチルリチウム、sec-ブチルリチウム等のアルキルリチウム、イソプロピルマグネシウムクロリド等のグリニャール(Grignard)試薬、または金属マグネシウムの存在下、トリメチルボレート、トリイソプロピルボレート等のトリアルキルボレートを加え、-78℃から室温で反応を行った後、塩酸、硫酸等の酸を加え、0℃から溶媒が還流する温度で反応を行い、式(IM-1)のボロン酸を製造することができる。 [In the formula (IM-1) where B = boronic acid]
[Production Method C] Using a compound of the formula (IM-2) obtained in <Step 3>, according to a method known in the literature, for example, a method described in “Chemische Berichte, 42, 3090, 1909”, etc. , Toluene, tetrahydrofuran, 1,4-dioxane and the like, or a mixed solvent thereof, alkyl lithium such as n-butyllithium and sec-butyllithium, Grignard such as isopropylmagnesium chloride, etc. Trialkylborate such as trimethylborate and triisopropylborate is added in the presence of a reagent or magnesium metal, and the reaction is carried out at −78 ° C. to room temperature, then an acid such as hydrochloric acid and sulfuric acid is added, and the solvent is refluxed from 0 ° C. Reaction at a temperature to produce a boronic acid of formula (IM-1) Can.
[製造方法C]<工程3>で得られる式(IM-2)の化合物を用い、文献公知の方法、例えば、『Chemische Berichte、42、3090、1909年』等に記載された方法に準じて、トルエン、テトラヒドロフラン、1,4-ジオキサン等の反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、n-ブチルリチウム、sec-ブチルリチウム等のアルキルリチウム、イソプロピルマグネシウムクロリド等のグリニャール(Grignard)試薬、または金属マグネシウムの存在下、トリメチルボレート、トリイソプロピルボレート等のトリアルキルボレートを加え、-78℃から室温で反応を行った後、塩酸、硫酸等の酸を加え、0℃から溶媒が還流する温度で反応を行い、式(IM-1)のボロン酸を製造することができる。 [In the formula (IM-1) where B = boronic acid]
[Production Method C] Using a compound of the formula (IM-2) obtained in <Step 3>, according to a method known in the literature, for example, a method described in “Chemische Berichte, 42, 3090, 1909”, etc. , Toluene, tetrahydrofuran, 1,4-dioxane and the like, or a mixed solvent thereof, alkyl lithium such as n-butyllithium and sec-butyllithium, Grignard such as isopropylmagnesium chloride, etc. Trialkylborate such as trimethylborate and triisopropylborate is added in the presence of a reagent or magnesium metal, and the reaction is carried out at −78 ° C. to room temperature, then an acid such as hydrochloric acid and sulfuric acid is added, and the solvent is refluxed from 0 ° C. Reaction at a temperature to produce a boronic acid of formula (IM-1) Can.
[式(IM-1)でB=トリフルオロボレート塩の場合]
前述の方法にて得られるボロン酸エステル、またはボロン酸を用い、文献公知の方法、例えば、『Chemical Reviews、108、288‐325、2008年』等に記載された方法に準じて、ジフッ化水素カリウム存在下、メタノール、エタノール、水等の反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(IM-1)のトリフルオロボレート塩を製造することができる。 [In the formula (IM-1) where B = trifluoroborate salt]
Using boronic acid ester obtained by the above-mentioned method or boronic acid, according to a method known in the literature, for example, a method described in “Chemical Reviews, 108, 288-325, 2008” or the like, In the presence of potassium, the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. using a solvent that does not participate in the reaction such as methanol, ethanol, water or the like, or a mixed solvent thereof, and the trifluoroborate salt of the formula (IM-1) Can be manufactured.
前述の方法にて得られるボロン酸エステル、またはボロン酸を用い、文献公知の方法、例えば、『Chemical Reviews、108、288‐325、2008年』等に記載された方法に準じて、ジフッ化水素カリウム存在下、メタノール、エタノール、水等の反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(IM-1)のトリフルオロボレート塩を製造することができる。 [In the formula (IM-1) where B = trifluoroborate salt]
Using boronic acid ester obtained by the above-mentioned method or boronic acid, according to a method known in the literature, for example, a method described in “Chemical Reviews, 108, 288-325, 2008” or the like, In the presence of potassium, the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. using a solvent that does not participate in the reaction such as methanol, ethanol, water or the like, or a mixed solvent thereof, and the trifluoroborate salt of the formula (IM-1) Can be manufactured.
[式(IM-1)でB=ボロン酸N-メチルイミノ二酢酸エステルの場合]
[製造方法C]<工程3>で得られる式(IM-2)で表される化合物を用い、文献公知の方法、例えば、『Journal of Organometallic Chemistry、307(1)、1‐6、1986年』等に記載された方法に準じて、N-メチルイミノ二酢酸の存在下、ベンゼン、トルエン、キシレンまたはジメチルスルホキシド等の反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(IM-1)のボロン酸N-メチルイミノ二酢酸エステルを製造することができる。 [In the formula (IM-1), B = boronic acid N-methyliminodiacetic acid ester]
[Production Method C] Using a compound represented by the formula (IM-2) obtained in <Step 3>, a method known in the literature, for example, “Journal of Organometallic Chemistry, 307 (1), 1-6, 1986” In the presence of N-methyliminodiacetic acid, a solvent not involved in the reaction such as benzene, toluene, xylene or dimethyl sulfoxide, or a mixed solvent thereof is used from 0 ° C. By reacting at the refluxing temperature, the boronic acid N-methyliminodiacetic acid ester of the formula (IM-1) can be produced.
[製造方法C]<工程3>で得られる式(IM-2)で表される化合物を用い、文献公知の方法、例えば、『Journal of Organometallic Chemistry、307(1)、1‐6、1986年』等に記載された方法に準じて、N-メチルイミノ二酢酸の存在下、ベンゼン、トルエン、キシレンまたはジメチルスルホキシド等の反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(IM-1)のボロン酸N-メチルイミノ二酢酸エステルを製造することができる。 [In the formula (IM-1), B = boronic acid N-methyliminodiacetic acid ester]
[Production Method C] Using a compound represented by the formula (IM-2) obtained in <Step 3>, a method known in the literature, for example, “Journal of Organometallic Chemistry, 307 (1), 1-6, 1986” In the presence of N-methyliminodiacetic acid, a solvent not involved in the reaction such as benzene, toluene, xylene or dimethyl sulfoxide, or a mixed solvent thereof is used from 0 ° C. By reacting at the refluxing temperature, the boronic acid N-methyliminodiacetic acid ester of the formula (IM-1) can be produced.
<工程6>
[製造方法A]<工程2>で得られる式(AM-4)の化合物、および式(CA-3)(後述の[製造方法E]を参照)の化合物を用いて、[製造方法A]<工程3>に準じる反応を行い、式(I-1)の化合物を製造することができる。 <Step 6>
[Production Method A] [Production Method A] using the compound of formula (AM-4) obtained in <Step 2> and the compound of formula (CA-3) (see [Production Method E] described later) A reaction according to <Step 3> can be carried out to produce a compound of formula (I-1).
[製造方法A]<工程2>で得られる式(AM-4)の化合物、および式(CA-3)(後述の[製造方法E]を参照)の化合物を用いて、[製造方法A]<工程3>に準じる反応を行い、式(I-1)の化合物を製造することができる。 <Step 6>
[Production Method A] [Production Method A] using the compound of formula (AM-4) obtained in <Step 2> and the compound of formula (CA-3) (see [Production Method E] described later) A reaction according to <Step 3> can be carried out to produce a compound of formula (I-1).
[製造方法D]式(I-2)[式(I)で環A=3-置換-4-シアノ-2-ピリジンの場合]の製造方法
[Production Method D] Production method of formula (I-2) [in the case of formula A, ring A = 3-substituted-4-cyano-2-pyridine]
<工程1>
[製造方法B]<工程2>で得られる式(AM-6)の化合物、および式(AR-2)(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)の化合物を用いて、[製造方法B]<工程3>に準じる反応を行い、式(IM-3)の化合物を製造することができる。
<工程2>
[RC=C3~8シクロアルキル基の場合]
[製造方法D]<工程1>で得られる式(IM-3)の化合物、および式(RG-4)(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)の亜鉛化合物を用いて、文献公知の方法、例えば、『WO2014/066196号パンフレット』等に記載された方法に準じて、テトラキストリフェニルホスフィンパラジウム(Pd(PPh3)4)、ビス[トリス(1,1-ジメチルエチル)ホスフィン]パラジウム等のPd触媒存在下、テトラヒドロフラン、2,2-ジメトキシエタン等の反応に関与しない溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(I-2)の化合物を製造することができる。 <Step 1>
[Production Method B] Compound of formula (AM-6) obtained in <Step 2> and formula (AR-2) (This compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature. A compound of formula (IM-3) can be produced by carrying out a reaction according to [Production method B] <Step 3>.
<Step 2>
[For R C = C 3 ~ 8 cycloalkyl radical
[Production Method D] Compound of formula (IM-3) obtained in <Step 1> and formula (RG-4) (This compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature. In accordance with a method known in the literature, for example, a method described in “WO2014 / 066196 pamphlet” or the like, tetrakistriphenylphosphine palladium (Pd (PPh 3 ) 4 ), bis [tris In the presence of a Pd catalyst such as (1,1-dimethylethyl) phosphine] palladium, the reaction is performed at a temperature at which the solvent is refluxed from 0 ° C. using a solvent that does not participate in the reaction, such as tetrahydrofuran and 2,2-dimethoxyethane, Compounds of formula (I-2) can be prepared.
[製造方法B]<工程2>で得られる式(AM-6)の化合物、および式(AR-2)(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)の化合物を用いて、[製造方法B]<工程3>に準じる反応を行い、式(IM-3)の化合物を製造することができる。
<工程2>
[RC=C3~8シクロアルキル基の場合]
[製造方法D]<工程1>で得られる式(IM-3)の化合物、および式(RG-4)(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)の亜鉛化合物を用いて、文献公知の方法、例えば、『WO2014/066196号パンフレット』等に記載された方法に準じて、テトラキストリフェニルホスフィンパラジウム(Pd(PPh3)4)、ビス[トリス(1,1-ジメチルエチル)ホスフィン]パラジウム等のPd触媒存在下、テトラヒドロフラン、2,2-ジメトキシエタン等の反応に関与しない溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(I-2)の化合物を製造することができる。 <Step 1>
[Production Method B] Compound of formula (AM-6) obtained in <Step 2> and formula (AR-2) (This compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature. A compound of formula (IM-3) can be produced by carrying out a reaction according to [Production method B] <Step 3>.
<Step 2>
[For R C = C 3 ~ 8 cycloalkyl radical
[Production Method D] Compound of formula (IM-3) obtained in <Step 1> and formula (RG-4) (This compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature. In accordance with a method known in the literature, for example, a method described in “WO2014 / 066196 pamphlet” or the like, tetrakistriphenylphosphine palladium (Pd (PPh 3 ) 4 ), bis [tris In the presence of a Pd catalyst such as (1,1-dimethylethyl) phosphine] palladium, the reaction is performed at a temperature at which the solvent is refluxed from 0 ° C. using a solvent that does not participate in the reaction, such as tetrahydrofuran and 2,2-dimethoxyethane, Compounds of formula (I-2) can be prepared.
[RC=-NRaRb基(RaおよびRbが単環式非芳香族複素環基を形成する場合を含む)の場合]
[製造方法D]<工程1>で得られる式(IM-3)の化合物、および式(RG-5)(式(RG-5)の化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)のアミンを用いて、文献公知の方法、例えば、『WO2005/111003号パンフレット』、『Journal of Medicinal Chemistry、48(23)、7374-7388頁、2005年』等に記載された方法に準じて、ジイソプロピルエチルアミン、トリエチルアミン等の塩基の存在下もしくは非存在下、水、N,N-ジメチルホルムアミド、N-メチルピロリドン、アセトニトリル、テトラヒドロフラン等の反応に関与しない溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(I-2)の化合物を製造することができる。
[RC=C1~6アルキルチオ基の場合]
[製造方法D]<工程1>で得られる式(IM-3)の化合物、および式(RG-6)(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)の化合物を用いて、文献公知の方法、例えば、『WO2011/049222号パンフレット』等に記載された方法に準じて、N,N-ジメチルホルムアミド、N-メチルピロリドン等の反応に関与しない溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(I-2)の化合物を製造することができる。 [In the case of R C = —NR a R b group (including the case where R a and R b form a monocyclic non-aromatic heterocyclic group)]
[Production Method D] The compound of the formula (IM-3) obtained in <Step 1> and the compound of the formula (RG-5) (the compound of the formula (RG-5) are commercially available compounds or known productions from the commercially available compounds. And a known method such as “WO2005 / 111003 pamphlet”, “Journal of Medicinal Chemistry, 48 (23), 7374-7388, 2005”, etc. According to the described method, using a solvent that does not participate in the reaction, such as water, N, N-dimethylformamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, in the presence or absence of a base such as diisopropylethylamine or triethylamine. The reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. It can be produced compound.
[When R C = C 1-6 alkylthio group]
[Production Method D] Compound of formula (IM-3) obtained in <Step 1> and formula (RG-6) (This compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature. And a solvent that does not participate in the reaction, such as N, N-dimethylformamide, N-methylpyrrolidone, etc., in accordance with a method known in the literature, for example, the method described in “WO2011 / 049222 pamphlet” or the like. The compound of formula (I-2) can be produced by performing the reaction at a temperature at which the solvent is refluxed from 0 ° C.
[製造方法D]<工程1>で得られる式(IM-3)の化合物、および式(RG-5)(式(RG-5)の化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)のアミンを用いて、文献公知の方法、例えば、『WO2005/111003号パンフレット』、『Journal of Medicinal Chemistry、48(23)、7374-7388頁、2005年』等に記載された方法に準じて、ジイソプロピルエチルアミン、トリエチルアミン等の塩基の存在下もしくは非存在下、水、N,N-ジメチルホルムアミド、N-メチルピロリドン、アセトニトリル、テトラヒドロフラン等の反応に関与しない溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(I-2)の化合物を製造することができる。
[RC=C1~6アルキルチオ基の場合]
[製造方法D]<工程1>で得られる式(IM-3)の化合物、および式(RG-6)(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)の化合物を用いて、文献公知の方法、例えば、『WO2011/049222号パンフレット』等に記載された方法に準じて、N,N-ジメチルホルムアミド、N-メチルピロリドン等の反応に関与しない溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(I-2)の化合物を製造することができる。 [In the case of R C = —NR a R b group (including the case where R a and R b form a monocyclic non-aromatic heterocyclic group)]
[Production Method D] The compound of the formula (IM-3) obtained in <Step 1> and the compound of the formula (RG-5) (the compound of the formula (RG-5) are commercially available compounds or known productions from the commercially available compounds. And a known method such as “WO2005 / 111003 pamphlet”, “Journal of Medicinal Chemistry, 48 (23), 7374-7388, 2005”, etc. According to the described method, using a solvent that does not participate in the reaction, such as water, N, N-dimethylformamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, in the presence or absence of a base such as diisopropylethylamine or triethylamine. The reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. It can be produced compound.
[When R C = C 1-6 alkylthio group]
[Production Method D] Compound of formula (IM-3) obtained in <Step 1> and formula (RG-6) (This compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature. And a solvent that does not participate in the reaction, such as N, N-dimethylformamide, N-methylpyrrolidone, etc., in accordance with a method known in the literature, for example, the method described in “WO2011 / 049222 pamphlet” or the like. The compound of formula (I-2) can be produced by performing the reaction at a temperature at which the solvent is refluxed from 0 ° C.
[RC=C1~6アルコキシル基の場合]
[製造方法D]<工程1>で得られる式(IM-3)の化合物、および式(RG-7)(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)の化合物を用いて、『Journal of Medicinal Chemistry、55(22)、10118-10129頁、2012年』等に記載された方法に準じて、N,N-ジメチルホルムアミド、N-メチルピロリドン等の反応に関与しない溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(I-2)の化合物を製造することができる。
なお、式(IM-3)でX=ClまたはFの場合の式(IM-3-1)(X’=ClまたはF)は、後述する[製造方法D]<工程3>から<工程7>の方法でも製造する事ができる。
<工程3>
式(AR-2-1)および式(AM-1)の化合物(式(AR-2-1)および式(AM-1)の化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)を用いて、[製造方法A]<工程1>に準じる反応を行い、式(AM-3-1)(X’=Cl)の化合物を製造することができる。
<工程4>
式(AR-2-2)の化合物、および式(AM-1)(式(AR-2-2)、および式(AM-1)の化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)の化合物を用いて、[製造方法A]<工程1>に準じる反応を行い、式(AM-3-2)の化合物を製造することができる。
<工程5>
[製造方法D]<工程4>で得られた式(AM-3-2)の化合物、およびトリフルオロ酢酸無水物(TFAA)を用いて、文献公知の方法、例えば、『WO2007/043677号パンフレット』等に記載された方法に準じて、トリエチルアミン等の塩基存在下、ジクロロメタン等の反応に関与しない溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(AM-3-1)(X’=F)の化合物を製造することができる。
<工程6>
[製造方法D]<工程3>または[製造方法D]<工程5>で得られた式(AM-3-1)(X’=ClまたはF)の化合物を用いて、[製造方法A]<工程2>に準じる反応を行い、式(AM-4-1)の化合物を製造することができる。
<工程7>
[製造方法D]<工程6>で得られた式(AM-4-1)の化合物、および式(CA)の化合物を用いて、[製造方法A]<工程3>に準じる反応を行い、式(IM-3-1)の化合物を製造することができる。 [In the case of R C = C 1-6 alkoxyl group]
[Production Method D] Compound of formula (IM-3) obtained in <Step 1> and formula (RG-7) (This compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature. In accordance with the method described in “Journal of Medicinal Chemistry, 55 (22), pages 10118-10129, 2012” and the like, N, N-dimethylformamide, N-methylpyrrolidone etc. A compound of formula (I-2) can be produced by carrying out the reaction at a temperature at which the solvent is refluxed from 0 ° C. using a solvent that does not participate in the reaction.
The formula (IM-3-1) (X ′ = Cl or F) when X = Cl or F in the formula (IM-3) is described in [Manufacturing Method D] <Step 3> to <Step 7 > Can also be produced.
<Step 3>
Compounds of formula (AR-2-1) and formula (AM-1) (formula (AR-2-1) and compound of formula (AM-1) are commercially available compounds, or commercially available compounds from the literature by known production methods) The compound of formula (AM-3-1) (X ′ = Cl) can be produced by carrying out a reaction according to [Production method A] <Step 1>.
<Step 4>
The compound of formula (AR-2-2), and the compound of formula (AM-1) (formula (AR-2-2) and compound of formula (AM-1) are commercially available compounds, or prepared from commercially available compounds in the literature The compound of formula (AM-3-2) can be produced by carrying out a reaction according to [Production Method A] <Step 1> using a compound of (a compound that can be produced by the method).
<Step 5>
[Production Method D] Using the compound of formula (AM-3-2) obtained in <Step 4> and trifluoroacetic anhydride (TFAA), a method known in the literature, for example, “WO2007 / 043677 pamphlet”. In the presence of a base such as triethylamine, the reaction is performed at a temperature at which the solvent refluxes from 0 ° C. in the presence of a base such as triethylamine. ) (X ′ = F) can be produced.
<Step 6>
[Production Method D] <Step 3> or [Production Method D] Using the compound of formula (AM-3-1) (X ′ = Cl or F) obtained in <Step 5>, [Production Method A] A compound of formula (AM-4-1) can be produced by performing a reaction according to <Step 2>.
<Step 7>
[Production Method D] Using the compound of formula (AM-4-1) obtained in <Step 6> and the compound of formula (CA), a reaction according to [Production Method A] <Step 3> is performed. A compound of formula (IM-3-1) can be prepared.
[製造方法D]<工程1>で得られる式(IM-3)の化合物、および式(RG-7)(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)の化合物を用いて、『Journal of Medicinal Chemistry、55(22)、10118-10129頁、2012年』等に記載された方法に準じて、N,N-ジメチルホルムアミド、N-メチルピロリドン等の反応に関与しない溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(I-2)の化合物を製造することができる。
なお、式(IM-3)でX=ClまたはFの場合の式(IM-3-1)(X’=ClまたはF)は、後述する[製造方法D]<工程3>から<工程7>の方法でも製造する事ができる。
<工程3>
式(AR-2-1)および式(AM-1)の化合物(式(AR-2-1)および式(AM-1)の化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)を用いて、[製造方法A]<工程1>に準じる反応を行い、式(AM-3-1)(X’=Cl)の化合物を製造することができる。
<工程4>
式(AR-2-2)の化合物、および式(AM-1)(式(AR-2-2)、および式(AM-1)の化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)の化合物を用いて、[製造方法A]<工程1>に準じる反応を行い、式(AM-3-2)の化合物を製造することができる。
<工程5>
[製造方法D]<工程4>で得られた式(AM-3-2)の化合物、およびトリフルオロ酢酸無水物(TFAA)を用いて、文献公知の方法、例えば、『WO2007/043677号パンフレット』等に記載された方法に準じて、トリエチルアミン等の塩基存在下、ジクロロメタン等の反応に関与しない溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(AM-3-1)(X’=F)の化合物を製造することができる。
<工程6>
[製造方法D]<工程3>または[製造方法D]<工程5>で得られた式(AM-3-1)(X’=ClまたはF)の化合物を用いて、[製造方法A]<工程2>に準じる反応を行い、式(AM-4-1)の化合物を製造することができる。
<工程7>
[製造方法D]<工程6>で得られた式(AM-4-1)の化合物、および式(CA)の化合物を用いて、[製造方法A]<工程3>に準じる反応を行い、式(IM-3-1)の化合物を製造することができる。 [In the case of R C = C 1-6 alkoxyl group]
[Production Method D] Compound of formula (IM-3) obtained in <Step 1> and formula (RG-7) (This compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature. In accordance with the method described in “Journal of Medicinal Chemistry, 55 (22), pages 10118-10129, 2012” and the like, N, N-dimethylformamide, N-methylpyrrolidone etc. A compound of formula (I-2) can be produced by carrying out the reaction at a temperature at which the solvent is refluxed from 0 ° C. using a solvent that does not participate in the reaction.
The formula (IM-3-1) (X ′ = Cl or F) when X = Cl or F in the formula (IM-3) is described in [Manufacturing Method D] <Step 3> to <Step 7 > Can also be produced.
<Step 3>
Compounds of formula (AR-2-1) and formula (AM-1) (formula (AR-2-1) and compound of formula (AM-1) are commercially available compounds, or commercially available compounds from the literature by known production methods) The compound of formula (AM-3-1) (X ′ = Cl) can be produced by carrying out a reaction according to [Production method A] <Step 1>.
<Step 4>
The compound of formula (AR-2-2), and the compound of formula (AM-1) (formula (AR-2-2) and compound of formula (AM-1) are commercially available compounds, or prepared from commercially available compounds in the literature The compound of formula (AM-3-2) can be produced by carrying out a reaction according to [Production Method A] <Step 1> using a compound of (a compound that can be produced by the method).
<Step 5>
[Production Method D] Using the compound of formula (AM-3-2) obtained in <Step 4> and trifluoroacetic anhydride (TFAA), a method known in the literature, for example, “WO2007 / 043677 pamphlet”. In the presence of a base such as triethylamine, the reaction is performed at a temperature at which the solvent refluxes from 0 ° C. in the presence of a base such as triethylamine. ) (X ′ = F) can be produced.
<Step 6>
[Production Method D] <Step 3> or [Production Method D] Using the compound of formula (AM-3-1) (X ′ = Cl or F) obtained in <Step 5>, [Production Method A] A compound of formula (AM-4-1) can be produced by performing a reaction according to <Step 2>.
<Step 7>
[Production Method D] Using the compound of formula (AM-4-1) obtained in <Step 6> and the compound of formula (CA), a reaction according to [Production Method A] <Step 3> is performed. A compound of formula (IM-3-1) can be prepared.
[製造方法E]式(CA-3)[式(CA)で環B≠1-置換-1H-ピラゾール環;L=L’=単環式非芳香族複素環、フェニルまたは単環式ヘテロアリールの場合]の製造方法
[Production Method E] Formula (CA-3) [In Formula (CA), ring B ≠ 1-substituted-1H-pyrazole ring; L = L ′ = monocyclic non-aromatic heterocycle, phenyl or monocyclic heteroaryl In the case of
<工程1>
式(E-1)の化合物(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)、および式(RG-2)もしくは式(RG-3)の化合物を用いて、[製造方法C]<工程4>に準じる反応を行い、式(E-2)の化合物を製造することができる。 <Step 1>
A compound of formula (E-1) (the compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature), and a compound of formula (RG-2) or formula (RG-3) The compound of formula (E-2) can be produced by carrying out a reaction according to [Production method C] <Step 4>.
式(E-1)の化合物(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)、および式(RG-2)もしくは式(RG-3)の化合物を用いて、[製造方法C]<工程4>に準じる反応を行い、式(E-2)の化合物を製造することができる。 <Step 1>
A compound of formula (E-1) (the compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature), and a compound of formula (RG-2) or formula (RG-3) The compound of formula (E-2) can be produced by carrying out a reaction according to [Production method C] <Step 4>.
<工程2>
[RA=C1~6アルキル基(例えば、メチル、エチル基など)の場合]
式(E-2)の化合物を用い、文献公知の方法、例えば、『実験化学講座 第4版 22 有機合成IV 酸・アミノ酸・ペプチド、1-43頁、1992年、丸善』などに記載された方法に準じて、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、炭酸リチウム、炭酸ナトリウム、炭酸カリウム等の塩基存在下、水およびメタノール、エタノール、2-プロパノール、N,N-ジメチルホルムアミド、1,4-ジオキサン、テトラヒドロフラン等の反応に不活性な溶媒、もしくはこれらの混合溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(CA-3)の化合物を製造することができる。 <Step 2>
[In the case of R A = C 1-6 alkyl group (for example, methyl, ethyl group, etc.)]
Using a compound of the formula (E-2), it is described in literature known methods such as “Experimental Chemistry Course 4th Edition 22 Organic Synthesis IV Acid / Amino Acid / Peptide, 1-43, 1992, Maruzen”. According to the method, in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, water and methanol, ethanol, 2-propanol, N, N-dimethylformamide, 1, The compound of the formula (CA-3) can be produced by performing the reaction at a temperature at which the solvent is refluxed from 0 ° C. using a solvent inert to the reaction such as 4-dioxane and tetrahydrofuran, or a mixed solvent thereof. .
[RA=C1~6アルキル基(例えば、メチル、エチル基など)の場合]
式(E-2)の化合物を用い、文献公知の方法、例えば、『実験化学講座 第4版 22 有機合成IV 酸・アミノ酸・ペプチド、1-43頁、1992年、丸善』などに記載された方法に準じて、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、炭酸リチウム、炭酸ナトリウム、炭酸カリウム等の塩基存在下、水およびメタノール、エタノール、2-プロパノール、N,N-ジメチルホルムアミド、1,4-ジオキサン、テトラヒドロフラン等の反応に不活性な溶媒、もしくはこれらの混合溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(CA-3)の化合物を製造することができる。 <Step 2>
[In the case of R A = C 1-6 alkyl group (for example, methyl, ethyl group, etc.)]
Using a compound of the formula (E-2), it is described in literature known methods such as “Experimental Chemistry Course 4th Edition 22 Organic Synthesis IV Acid / Amino Acid / Peptide, 1-43, 1992, Maruzen”. According to the method, in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, water and methanol, ethanol, 2-propanol, N, N-dimethylformamide, 1, The compound of the formula (CA-3) can be produced by performing the reaction at a temperature at which the solvent is refluxed from 0 ° C. using a solvent inert to the reaction such as 4-dioxane and tetrahydrofuran, or a mixed solvent thereof. .
[RA=tert-ブチル基の場合]
式(E-2)の化合物を用い、文献公知の方法、例えば、『Protective Groups in Organic Synthesis 4th、2007年、John Wiley & Sons、Greeneら』の成書に記載された脱保護の方法に準じて、塩酸、硫酸、酢酸、トリフルオロ酢酸等の酸を用いて、0℃から溶媒が還流する温度で反応を行い、式(CA-3)の化合物を製造することができる。 [In the case of R A = tert-butyl group]
According to a method known in the literature using a compound of the formula (E-2), for example, a method of deprotection described in the book of Protective Groups in Organic Synthesis 4th, 2007, John Wiley & Sons, Green et al. The compound of the formula (CA-3) can be produced by performing a reaction with an acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid and the like at a temperature at which the solvent is refluxed from 0 ° C.
式(E-2)の化合物を用い、文献公知の方法、例えば、『Protective Groups in Organic Synthesis 4th、2007年、John Wiley & Sons、Greeneら』の成書に記載された脱保護の方法に準じて、塩酸、硫酸、酢酸、トリフルオロ酢酸等の酸を用いて、0℃から溶媒が還流する温度で反応を行い、式(CA-3)の化合物を製造することができる。 [In the case of R A = tert-butyl group]
According to a method known in the literature using a compound of the formula (E-2), for example, a method of deprotection described in the book of Protective Groups in Organic Synthesis 4th, 2007, John Wiley & Sons, Green et al. The compound of the formula (CA-3) can be produced by performing a reaction with an acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid and the like at a temperature at which the solvent is refluxed from 0 ° C.
[RA=C7~20アラルキル基(例えば、ベンジル基など)の場合]
式(E-2)の化合物を用い、文献公知の方法、例えば、『実験化学講座 第4版 26 有機合成VIII 不斉合成・還元・糖・標識化合物、159-266頁、1992年、丸善』等に記載された方法に準じて、パラジウム-炭素(Pd-C)、ラネーニッケル(Raney-Ni)、酸化白金(PtO2)、ジクロロトリトリフェニルホスフィンルテニウム等の触媒存在下、水素ガス雰囲気下にて、メタノール、エタノール、2-プロパノール等のアルコール系溶媒、ジエチルエーテル、テトラヒドロフラン、1,2-ジメトキシエタン、1,4-ジオキサン等のエーテル系溶媒、酢酸エチル、酢酸メチル等の極性溶媒など反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(CA-3)の化合物を製造することができる。 [For R A = C 7 ~ 20 aralkyl group (e.g., benzyl group)]
A method known in the literature using a compound of formula (E-2), for example, “Experimental Chemistry Course 4th Edition 26 Organic Synthesis VIII Asymmetric Synthesis / Reduction / Sugar / Labeled Compound, 159-266, 1992, Maruzen” In the presence of a catalyst such as palladium-carbon (Pd—C), Raney nickel (Raney-Ni), platinum oxide (PtO 2 ), dichlorotritriphenylphosphine ruthenium, etc. in a hydrogen gas atmosphere. Alcohol solvents such as methanol, ethanol, 2-propanol, ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, polar solvents such as ethyl acetate, methyl acetate, etc. The reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. using a solvent that does not react or a mixture thereof. -3) can be produced.
式(E-2)の化合物を用い、文献公知の方法、例えば、『実験化学講座 第4版 26 有機合成VIII 不斉合成・還元・糖・標識化合物、159-266頁、1992年、丸善』等に記載された方法に準じて、パラジウム-炭素(Pd-C)、ラネーニッケル(Raney-Ni)、酸化白金(PtO2)、ジクロロトリトリフェニルホスフィンルテニウム等の触媒存在下、水素ガス雰囲気下にて、メタノール、エタノール、2-プロパノール等のアルコール系溶媒、ジエチルエーテル、テトラヒドロフラン、1,2-ジメトキシエタン、1,4-ジオキサン等のエーテル系溶媒、酢酸エチル、酢酸メチル等の極性溶媒など反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(CA-3)の化合物を製造することができる。 [For R A = C 7 ~ 20 aralkyl group (e.g., benzyl group)]
A method known in the literature using a compound of formula (E-2), for example, “Experimental Chemistry Course 4th Edition 26 Organic Synthesis VIII Asymmetric Synthesis / Reduction / Sugar / Labeled Compound, 159-266, 1992, Maruzen” In the presence of a catalyst such as palladium-carbon (Pd—C), Raney nickel (Raney-Ni), platinum oxide (PtO 2 ), dichlorotritriphenylphosphine ruthenium, etc. in a hydrogen gas atmosphere. Alcohol solvents such as methanol, ethanol, 2-propanol, ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, polar solvents such as ethyl acetate, methyl acetate, etc. The reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. using a solvent that does not react or a mixture thereof. -3) can be produced.
<工程3>
式(E-3)の化合物(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)、および式(RG-1)の化合物を用いて、[製造方法C]<工程2>に準じる反応を行い、式(E-2)の化合物を製造することができる。 <Step 3>
Using a compound of formula (E-3) (this compound is a commercially available compound or a compound that can be produced from a commercially available compound by a production method known in the literature) and a compound of formula (RG-1), [Production Method C The compound of formula (E-2) can be produced by carrying out a reaction according to <Step 2>.
式(E-3)の化合物(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)、および式(RG-1)の化合物を用いて、[製造方法C]<工程2>に準じる反応を行い、式(E-2)の化合物を製造することができる。 <Step 3>
Using a compound of formula (E-3) (this compound is a commercially available compound or a compound that can be produced from a commercially available compound by a production method known in the literature) and a compound of formula (RG-1), [Production Method C The compound of formula (E-2) can be produced by carrying out a reaction according to <Step 2>.
[製造方法F]式(CA-4)[式(CA)で環B≠1-置換-1H-ピラゾール環;L=L''=窒素原子を含む単環式複素環の場合]の製造方法
式(CA-2)の化合物、および式(F-1)の化合物(式(CA-2)および式(F-1)の化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)を用いて、文献公知の方法、例えば、『Angewandte Chemie,International Edition、50、48、11511-11515頁、2011年』等に記載された方法に準じて、ヨウ化銅(CuI)等の銅触媒、および炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の塩基存在下、アセトニトリル、テトラヒドロフラン、ジメチルホルムアミド等の反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(CA-4)の化合物を製造することができる。
[Production Method F] Production method of formula (CA-4) [in formula (CA), ring B ≠ 1-substituted-1H-pyrazole ring; L = L ″ = in the case of a monocyclic heterocycle containing a nitrogen atom]
The compound of formula (CA-2) and the compound of formula (F-1) (the compounds of formula (CA-2) and formula (F-1) are commercially available compounds or produced from commercially available compounds by methods known in the literature) In accordance with a method known in the literature, for example, “Angewandte Chemie, International Edition, 50, 48, 11511-11515, 2011”, etc., copper iodide (CuI In the presence of a copper catalyst such as sodium carbonate, potassium carbonate, cesium carbonate, etc., the solvent is refluxed from 0 ° C. using a solvent not involved in the reaction such as acetonitrile, tetrahydrofuran, dimethylformamide, or a mixed solvent thereof. The compound of formula (CA-4) can be produced by carrying out the reaction at a temperature at which
[製造方法G]式(CA-5-1)[式(CA)で環B=ピラゾール;L=2-ピリジンの場合(1)]の製造方法
[Production Method G] Production Method of Formula (CA-5-1) [In Formula (CA) Ring B = Pyrazole; L = 2-Pyridine (1)]
<工程1>
式(G-1)の化合物(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)、および2-ヒドラジノピリジンを用いて、文献公知の方法、例えば、『WO2007/043677号パンフレット』等に記載された方法に準じて、酢酸存在下、テトラヒドロフラン、2-メトキシエタノール等の反応に関与しない溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(G-2)の化合物を製造することができる。 <Step 1>
Using a compound of the formula (G-1) (the compound is a commercially available compound or a compound that can be produced from a commercially available compound by a method known in the literature) and 2-hydrazinopyridine, a method known in the literature, for example, In accordance with the method described in “WO2007 / 043677 pamphlet” and the like, the reaction is performed in the presence of acetic acid using a solvent that does not participate in the reaction, such as tetrahydrofuran and 2-methoxyethanol, at a temperature at which the solvent refluxes from 0 ° C. A compound of the formula (G-2) can be produced.
式(G-1)の化合物(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)、および2-ヒドラジノピリジンを用いて、文献公知の方法、例えば、『WO2007/043677号パンフレット』等に記載された方法に準じて、酢酸存在下、テトラヒドロフラン、2-メトキシエタノール等の反応に関与しない溶媒を用いて、0℃から溶媒が還流する温度で反応を行い、式(G-2)の化合物を製造することができる。 <Step 1>
Using a compound of the formula (G-1) (the compound is a commercially available compound or a compound that can be produced from a commercially available compound by a method known in the literature) and 2-hydrazinopyridine, a method known in the literature, for example, In accordance with the method described in “WO2007 / 043677 pamphlet” and the like, the reaction is performed in the presence of acetic acid using a solvent that does not participate in the reaction, such as tetrahydrofuran and 2-methoxyethanol, at a temperature at which the solvent refluxes from 0 ° C. A compound of the formula (G-2) can be produced.
<工程2>
[製造方法G]<工程1>で得られる式(G-2)の化合物を用いて、[製造方法E]<工程2>に準じる反応を行い、式(CA-5-1)の化合物を製造することができる。 <Step 2>
[Production Method G] Using the compound of formula (G-2) obtained in <Step 1>, a reaction according to [Production Method E] <Step 2> is carried out to give a compound of formula (CA-5-1). Can be manufactured.
[製造方法G]<工程1>で得られる式(G-2)の化合物を用いて、[製造方法E]<工程2>に準じる反応を行い、式(CA-5-1)の化合物を製造することができる。 <Step 2>
[Production Method G] Using the compound of formula (G-2) obtained in <Step 1>, a reaction according to [Production Method E] <Step 2> is carried out to give a compound of formula (CA-5-1). Can be manufactured.
[製造方法H]式(CA-5-2)[式(CA)で環B=ピラゾール;L=2-ピリジンの場合(2)]の製造方法
[Production Method H] Production Method of Formula (CA-5-2) [In Formula (CA), Ring B = Pyrazole; L = 2-Pyridine (2)]
<工程1>
式(H-1)の化合物(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)、および2-ヒドラジノピリジンを用いて、[製造方法G]<工程1>に準じる反応を行い、式(H-2)の化合物を製造することができる。 <Step 1>
Using the compound of formula (H-1) (the compound is a commercially available compound or a compound that can be produced from a commercially available compound by a production method known in the literature) and 2-hydrazinopyridine, [Production Method G] <Step The compound of the formula (H-2) can be produced by performing a reaction according to 1>.
式(H-1)の化合物(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)、および2-ヒドラジノピリジンを用いて、[製造方法G]<工程1>に準じる反応を行い、式(H-2)の化合物を製造することができる。 <Step 1>
Using the compound of formula (H-1) (the compound is a commercially available compound or a compound that can be produced from a commercially available compound by a production method known in the literature) and 2-hydrazinopyridine, [Production Method G] <Step The compound of the formula (H-2) can be produced by performing a reaction according to 1>.
<工程2>
[製造方法H]<工程1>で得られる式(H-2)の化合物を用いて、[製造方法E]<工程2>に準じる反応を行い、式(CA-5-2)の化合物を製造することができる。 <Step 2>
[Production Method H] Using the compound of formula (H-2) obtained in <Step 1>, a reaction according to [Production Method E] <Step 2> is carried out to give a compound of formula (CA-5-2). Can be manufactured.
[製造方法H]<工程1>で得られる式(H-2)の化合物を用いて、[製造方法E]<工程2>に準じる反応を行い、式(CA-5-2)の化合物を製造することができる。 <Step 2>
[Production Method H] Using the compound of formula (H-2) obtained in <Step 1>, a reaction according to [Production Method E] <Step 2> is carried out to give a compound of formula (CA-5-2). Can be manufactured.
[製造方法J]式(CA-5-3)[式(CA)で環B=ピラゾール;L=2-ピリジンの場合(3)]の製造方法
文献公知の方法、例えば、『Bioorganic & Medicinal Chemistry Letters、23、23、6341-6345頁、2013年』等に記載された方法に準じて、テトラヒドロフラン等の溶媒中、-78℃にて、ジイソプロピルアミン、およびn-ブチルリチウムを反応させ、リチウムジイソプロピルアミドを調整し、同温にて式(J-1)の化合物(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)を加え、更に同温にて反応溶液に過剰のドライアイス(固体片)もしくは過剰の炭酸ガスを加え反応を行い、後処理段階で塩酸等の酸で酸性化する事で、式(CA-5-3)の化合物を製造することができる。 [Production Method J] Production Method of Formula (CA-5-3) [In Formula (CA), Ring B = Pyrazole; L = 2-Pyridine (3)]
In accordance with a method known in the literature, for example, the method described in “Bioorganic & Medicinal Chemistry Letters, 23, 23, pages 6341-6345, 2013”, diisopropylamine in a solvent such as tetrahydrofuran at −78 ° C. , And n-butyllithium to prepare lithium diisopropylamide, and the compound of formula (J-1) at the same temperature (the compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature) The reaction solution is added with excess dry ice (solid piece) or excess carbon dioxide gas at the same temperature, and reacted, and acidified with an acid such as hydrochloric acid in the post-treatment stage, the formula ( A compound of CA-5-3) can be produced.
文献公知の方法、例えば、『Bioorganic & Medicinal Chemistry Letters、23、23、6341-6345頁、2013年』等に記載された方法に準じて、テトラヒドロフラン等の溶媒中、-78℃にて、ジイソプロピルアミン、およびn-ブチルリチウムを反応させ、リチウムジイソプロピルアミドを調整し、同温にて式(J-1)の化合物(該化合物は、市販化合物、または市販化合物から文献公知の製造方法により製造できる化合物である)を加え、更に同温にて反応溶液に過剰のドライアイス(固体片)もしくは過剰の炭酸ガスを加え反応を行い、後処理段階で塩酸等の酸で酸性化する事で、式(CA-5-3)の化合物を製造することができる。 [Production Method J] Production Method of Formula (CA-5-3) [In Formula (CA), Ring B = Pyrazole; L = 2-Pyridine (3)]
In accordance with a method known in the literature, for example, the method described in “Bioorganic & Medicinal Chemistry Letters, 23, 23, pages 6341-6345, 2013”, diisopropylamine in a solvent such as tetrahydrofuran at −78 ° C. , And n-butyllithium to prepare lithium diisopropylamide, and the compound of formula (J-1) at the same temperature (the compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature) The reaction solution is added with excess dry ice (solid piece) or excess carbon dioxide gas at the same temperature, and reacted, and acidified with an acid such as hydrochloric acid in the post-treatment stage, the formula ( A compound of CA-5-3) can be produced.
[本発明化合物を含有する併用剤]
本発明化合物や医薬組成物は、医療現場で行われている一般的な方法で、他の薬物もしくは薬剤と併用することも可能である。本発明の化合物と配合または併用しうる薬物としては、例えば、(A)睡眠障害関連薬、(B)睡眠障害を併発しやすい疾患の治療薬等が挙げられる。 [Combination agent containing the compound of the present invention]
The compound and pharmaceutical composition of the present invention can be used in combination with other drugs or drugs by a general method performed in the medical field. Examples of the drug that can be combined or used in combination with the compound of the present invention include (A) a sleep disorder-related drug, (B) a therapeutic drug for a disease that easily causes sleep disorder, and the like.
本発明化合物や医薬組成物は、医療現場で行われている一般的な方法で、他の薬物もしくは薬剤と併用することも可能である。本発明の化合物と配合または併用しうる薬物としては、例えば、(A)睡眠障害関連薬、(B)睡眠障害を併発しやすい疾患の治療薬等が挙げられる。 [Combination agent containing the compound of the present invention]
The compound and pharmaceutical composition of the present invention can be used in combination with other drugs or drugs by a general method performed in the medical field. Examples of the drug that can be combined or used in combination with the compound of the present invention include (A) a sleep disorder-related drug, (B) a therapeutic drug for a disease that easily causes sleep disorder, and the like.
前記(A)の薬物としては、例えば、(1)睡眠導入剤((i)ベンゾジアゼピン系睡眠導入剤[具体的には、ニトラゼパム、エスタゾラム、塩酸フルラゼパム、ニメタゼパム、フルラゼパム、ハロキサゾラム、フルニトラゼパム、塩酸リルマザポン、ロルメタゼパム、トリアゾラム等]、(ii)チエノジアゼピン系眠導入剤[具体的には、ブロチゾラム等]、(iii)非ベンゾジアゼピン系睡眠導入剤[具体的には、ゾルピデム等]、(iv)メラトニン受容体作動薬[具体的には、ラメルテオン等])、(v)シクロピロロン系眠導入剤[具体的には、ゾピクロン等]、(vi)オレキシン受容体拮抗薬[具体的には、スボレキサント等]、(2)睡眠時無呼吸症候群で処方される薬剤[具体的にはアセタゾラミド等]、(3)レストレスレッグス症候群で処方される薬剤((i)ベンゾジアゼピン系睡眠導入剤[具体的には、クロナゼパム等]、(ii)ドーパミン作動薬[具体的には、レボドパ、塩酸アマンタジン、メシル酸ブロモクリプチン、メシル酸ペルゴリド、カベルゴリン、塩酸タリペキソール、塩酸プラミペキソール水和物、塩酸セレギリン、塩酸ロピニロール等]、(iii)オピオイド製剤[具体的には、コデイン等])等が挙げられる。
Examples of the drug (A) include: (1) a sleep inducer ((i) a benzodiazepine sleep inducer [specifically, nitrazepam, estazolam, flurazepam hydrochloride, nimetazepam, flurazepam, haloxazolam, flunitrazepam, rilmazapine hydrochloride, Lormetazepam, triazolam, etc.], (ii) thienodiazepine sleep inducer [specifically, brotizolam, etc.], (iii) non-benzodiazepine sleep inducer [specifically, zolpidem, etc.], (iv) melatonin receptor operation Drugs (specifically, ramelteon, etc.), (v) cyclopyrrolone sleep inducers [specifically, zopiclone, etc.], (vi) orexin receptor antagonists [specifically, suvorexant, etc.], ( 2) Drugs prescribed for sleep apnea syndrome [specifically, acetazolamide, etc.], (3) Drugs prescribed for Treslegs syndrome ((i) benzodiazepine sleep inducers [specifically, clonazepam, etc.], (ii) dopamine agonists [specifically, levodopa, amantadine hydrochloride, bromocriptine mesylate, mesylate] Pergolide, cabergoline, talipexol hydrochloride, pramipexole hydrochloride hydrate, selegiline hydrochloride, ropinirole hydrochloride, etc.], (iii) opioid preparations [specifically, codeine etc.]) and the like.
前記(B)の薬物としては、例えば(4)非定型抗精神病薬[具体的には、オランザピン、クエチアピン、クロザピン、ジプラシドン、リスペリドン、パリペリドン、ペロスピロン、ブロナンセリン、ルラシドン、アリピプラゾール、セルチンドール、アミスルプリド、イロペリドン、ビフェプルノックス、アセナピン、メルペロン、ブレクスピプラゾール、ゾテピン等]、(5)定型抗精神病薬[具体的には、クロルプロマジン、プクロルペラジン、ペルフェナジン、レボメプロマジン、フルフェナジン、チオリダジン、プロペリシアジン、スピペロン、モペロン、ハロペリドール、チミペロン、ブロムペリドール、ピモジド、フロロピパミド、スルピリド、チアプリド、スルトプリド、ネモナプリド、オキシペルチン等]、(6)選択的セロトニン再取り込み阻害薬(SSRI)[具体的には、エスシタロプラム、シタロプラム、パロキセチン、セルトラリン、フルボキサミン、フルオキセチン等]、(7)選択的セロトニン・ノルアドレナリン再取り込み阻害薬(SNRI)[具体的には、ミルナシプラン、デュロキセチン、ベンラファキシン、ネファゾドン等]、(8)選択的ノルアドレナリン・ドーパミン再取り込み阻害薬(NDRI)[具体的には、ブブロピン等]、(9)ノルアドレナリン作動性・特異的セロトニン作動性抗うつ薬(NaSSA)[具体的には、ミルタザピン等]、(10)トリアゾロピリジン系抗うつ薬(SARI)[具体的には、トラゾドン等]、(11)四環系抗うつ薬[具体的には、セチプチリン、ミアンセリン、マプロチリン等]、(12)三環系抗うつ薬[具体的には、アミトリプチリン、トリミプラミン、イミプラミン、ノルトリプチリン、クロミプラミン、ロフェプラミン、アモキサピン、ドスレピン等]、(13)その他抗うつ薬[具体的には、NS-2359、Lu AA21004、DOV21947等]、(14)α7ニコチン受容体作動薬、(15)α7ニコチン受容体活性調節薬、(16)α7ニコチン受容体部分調節薬[具体的には、SSR-180711、PNU-120596等]、(17)PDE阻害薬[PDE1阻害薬、PDE2阻害薬、PDE4阻害薬、PDE5阻害薬、PDE7阻害薬、PDE9阻害薬、PDE10阻害薬等]、(18)NK2拮抗薬、(19)NK3拮抗薬、
Examples of the drug of (B) include (4) atypical antipsychotic drugs [specifically, olanzapine, quetiapine, clozapine, ziprasidone, risperidone, paliperidone, perospirone, blonanserin, lurasidone, aripiprazole, sertindole, amisulpride, Iloperidone, bifeprunox, asenapine, melperone, brexpiprazole, zotepine, etc.], (5) typical antipsychotics [specifically, chlorpromazine, pchlorperazine, perphenazine, levomepromazine, fluphenazine, thioridazine, propericazine, spiperone] , Moperon, haloperidol, timiperone, bromperidol, pimozide, fluropipamide, sulpiride, thioprid, sultopride, nemonapride, oxypertin, etc.], (6) selection Serotonin reuptake inhibitor (SSRI) [specifically, escitalopram, citalopram, paroxetine, sertraline, fluvoxamine, fluoxetine, etc.], (7) selective serotonin / noradrenaline reuptake inhibitor (SNRI) [specifically, MIL Nasiplan, duloxetine, venlafaxine, nefazodone, etc.], (8) selective noradrenaline / dopamine reuptake inhibitor (NDRI) [specifically, bubropine, etc.], (9) noradrenergic / specific serotonergic Antidepressant (NaSSA) [specifically, mirtazapine and the like], (10) Triazolopyridine antidepressant (SARI) [specifically, trazodone and the like], (11) Tetracyclic antidepressant [specifically In particular, cetiptiline, mianserin, maprotiline, etc.], ( 2) Tricyclic antidepressants [specifically, amitriptyline, trimipramine, imipramine, nortriptyline, clomipramine, lofepramine, amoxapine, dosrepin, etc.], (13) other antidepressants [specifically, NS-2359, Lu AA21004, DOV21947 etc.], (14) α7 nicotinic receptor agonist, (15) α7 nicotinic receptor activity modulator, (16) α7 nicotinic receptor partial modulator [specifically, SSR-180711, PNU-120596] Etc.], (17) PDE inhibitors [PDE1 inhibitors, PDE2 inhibitors, PDE4 inhibitors, PDE5 inhibitors, PDE7 inhibitors, PDE9 inhibitors, PDE10 inhibitors, etc.], (18) NK2 antagonists, (19) NK3 antagonist,
(20)ムスカリン型M1アセチルコリン受容体活性調節薬、(21)ムスカリン型M2アセチルコリン受容体活性調節薬、(22)アデノシン受容体調節薬、(23)ムスカリン型M4アセチルコリン受容体活性調節薬、(24)ムスカリン型M5アセチルコリン受容体活性調節薬、(25)アデノシン受容体調節薬、(26)グリシントランスポーター1(GlyT1)阻害薬[具体的には、ALX5407、SSR504734等]、(27)グルタミン酸増強薬[具体的には、アンパカイン]、(28)NMDA受容体阻害薬[具体的には、塩酸メマンチン等]、(29)代謝性グルタミン酸受容体調節薬(mGlu)[具体的には、CDPPB、MPEP等]、(30)抗不安薬((i)ベンゾジアゼピン系抗不安薬[具体的には、クロルジアゼポキシド、ジアゼパム、オキサゾラム、メダゼパム、クロキサゾラム、ロラゼパム、クロラゼプ酸二カリウム、プラゼパム、ブロマゼパム、フルジアゼパム、メキサゾラム、アルプラゾラム、フルトプラゼパム、フルタゾラム、ロフラゼプ酸エチル等]、(ii)チエノジアゼピン系抗不安薬[具体的には、エチゾラム、クロチアゼパム等]、(iii)セロトニン5-HT1A作動薬[具体的には、タンドスピロン等])、(31)βアミロイドワクチン、(32)βアミロイド分解酵素等、(33)脳機能賦活薬[具体的には、アニラセタム、ニセルゴリン等]、(34)カンナビノイド調節薬、(35)コリンエステラーゼ阻害薬[具体的には、塩酸ドネペジル、リバスチグミン、臭化水素酸ガランタミン等]、(36)MAO-B阻害剤[具体的には、ラサリジン等]、(37)パーキンソン病治療薬((i)ドーパミン受容体作動薬[具体的には、レボドパ、塩酸アマンタジン、メシル酸ブロモクリプチン、メシル酸ペルゴリド、カベルゴリン、塩酸タリペキソール、塩酸プラミペキソール水和物、塩酸セレギリン、塩酸ロピニロール等]、(ii)モノアミン酸化酵素阻害薬[具体的には、デプレニル、セルジリン(セレギリン)、レマセミド,リルゾール等]、(iii)抗コリン剤[具体的には、トリヘキシフェニジル、プロフェナミン、ビペリデン、塩酸ピロヘプチン、塩酸メチキセン、塩酸マザチコール等]、(iv)COMT阻害剤[具体的には、エンタカポン等]、(v)筋萎縮性側索硬化症治療薬[具体的には、リルゾール等、神経栄養因子等]、(vi)アポトーシス阻害薬[具体的には、CPI-1189、IDN-6556、CEP-1347等]、(vii)神経分化・再生促進剤[具体的には、レテプリニム(Leteprinim]、キサリプローデン(Xaliproden;SR-57746-A]、SB-216763等])、
(20) Muscarinic M1 acetylcholine receptor activity modulator, (21) Muscarinic M2 acetylcholine receptor activity modulator, (22) Adenosine receptor modulator, (23) Muscarinic M4 acetylcholine receptor activity regulator, (24 ) Muscarinic M5 acetylcholine receptor activity modulator, (25) adenosine receptor modulator, (26) glycine transporter 1 (GlyT1) inhibitor [specifically, ALX5407, SSR504734, etc.], (27) glutamate enhancer [Specifically, ampakine], (28) NMDA receptor inhibitor [specifically, memantine hydrochloride and the like], (29) metabolic glutamate receptor modulator (mGlu) [specifically, CDPPB, MPEP Etc.], (30) Anti-anxiety drugs ((i) benzodiazepine anxiolytic drugs [specifically Chlordiazepoxide, diazepam, oxazolam, medazepam, cloxazolam, lorazepam, dipotassium chlorazepate, prazepam, bromazepam, fludiazepam, mexazolam, alprazolam, fltoprazepam, flutazolam, ethyl loflazepate, etc. Ethiram, clothiazepam, etc.], (iii) serotonin 5-HT1A agonist [specifically, tandospirone, etc.)), (31) β-amyloid vaccine, (32) β-amyloid degrading enzyme, etc., (33) activation of brain function Drug [specifically, aniracetam, nicergoline, etc.], (34) cannabinoid modulator, (35) cholinesterase inhibitor [specifically, donepezil hydrochloride, rivastigmine, galantamine hydrobromide, etc.], (36) AO-B inhibitors [specifically, lasalidine, etc.], (37) Parkinson's disease therapeutic agent ((i) dopamine receptor agonists [specifically, levodopa, amantadine hydrochloride, bromocriptine mesylate, pergolide mesylate, Cabergoline, talipexol hydrochloride, pramipexole hydrochloride hydrate, selegiline hydrochloride, ropinirole hydrochloride, etc.], (ii) monoamine oxidase inhibitors [specifically, deprenyl, sergiline (selegiline), remasemide, riluzole, etc.], (iii) anti Choline agents [specifically, trihexyphenidyl, prophenamine, biperidene, pyroheptin hydrochloride, methixene hydrochloride, masaticol hydrochloride, etc.], (iv) COMT inhibitors [specifically, entacapone, etc.], (v) muscle atrophy Drugs for lateral sclerosis [specifically, riluzole and other neurotrophic factors Etc.], (vi) Apoptosis inhibitors [specifically CPI-1189, IDN-6556, CEP-1347, etc.], (vii) Neural differentiation / regeneration promoters [Specifically, leteprinim, xaliproden (Xaliproden; SR-57746-A], SB-216763 etc.),
(38)糖尿病治療薬((i)PPARγ作用薬(作動薬、阻害薬)[具体的には、ピオグリタゾン、ロシグリタゾン、トログリタゾン、シグリタゾン、ダルグリタゾン、エングリタゾン、ネトグリタゾン等]、(ii)インスリン分泌促進薬[(a)スルホニル尿素剤(具体的には、トルブタミド、アセトヘキサミド、クロルプロパミド、グリベンクラミド、グリクラジド、グリピジド、グリメピリド、グリペンチド、グリキドン、グリソラミド、トラザミド等)、(b)非スルホニル尿素剤等]、(iii)速効型インスリン分泌促進剤(具体的には、ナテグリニド、ミチグリニド、レパグリニド等)、(iv)αグルコシダーゼ阻害薬[具体的には、アカルボース、ボグリボース、ミグリトール、カミグリボース、アジポシン、エミグリテート、プラジミシン-Q、サルボスタチン等]、(v)インスリン抵抗性改善薬[具体的には、(a)PPAR-γ作用薬、(b)PTP-1B阻害薬、(c)DPP-4阻害薬[具体的には、シタグリプチン、ビルダグリプチン、アログリプチン、サクサグリプチン、NVP-DPP-728等]、(d)GLP-1及びGLP-1作動薬[具体的には、エキセナチド、リラグルチド等]、(e)11β-HSD阻害薬等、(f)GPR40作動薬、(g)GPR119作動薬、(h)GPR120作動薬]、(vi)肝糖新生抑制剤[具体的には、グルカゴン拮抗薬等]、(vii)ビグアナイド剤[具体的には、メトホルミン、ブホルミン、フェンホルミン等]、(viii)インスリンまたはインスリン誘導体[具体的には、インスリン亜鉛懸濁液、インスリンリスプロ、インスリンアスパルト、レギュラーインスリン、NPHインスリン、インスリングラルギン、インスリンデテミル、混合型インスリン等]、(ix)α2拮抗薬[具体的には、ミダグリゾール、イサグリドール、デリグリドール、イダゾキサン、エファロキサン等])、
(38) Antidiabetic agent ((i) PPARγ agonist (agonist, inhibitor) [specifically, pioglitazone, rosiglitazone, troglitazone, siglitazone, darglitazone, englitazone, netoglitazone, etc.], (ii) insulin Secretion enhancer [(a) sulfonylurea (specifically, tolbutamide, acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, glimepiride, glipentide, glyquidone, glisolamide, tolazamide, etc.), (b) non-sulfonylurea Agents, etc.], (iii) fast-acting insulin secretagogues (specifically, nateglinide, mitiglinide, repaglinide, etc.), (iv) α-glucosidase inhibitors [specifically, acarbose, voglibose, miglitol, camiglibose, adiposine, Emigli Tate, pradimicin-Q, sarvostatin, etc.], (v) insulin sensitizers [specifically, (a) PPAR-γ agonists, (b) PTP-1B inhibitors, (c) DPP-4 inhibition Drugs [specifically sitagliptin, vildagliptin, alogliptin, saxagliptin, NVP-DPP-728, etc.], (d) GLP-1 and GLP-1 agonists [specifically, exenatide, liraglutide, etc.], (e) 11β-HSD inhibitors, etc. (f) GPR40 agonists, (g) GPR119 agonists, (h) GPR120 agonists], (vi) hepatic gluconeogenesis inhibitors [specifically, glucagon antagonists, etc.], vii) biguanides [specifically, metformin, buformin, phenformin, etc.], (viii) insulin or insulin derivatives [specifically, insulin Phosphorus zinc suspension, insulin lispro, insulin aspart, regular insulin, NPH insulin, insulin glargine, insulin detemir, mixed insulin, etc.], (ix) α2 antagonist [specifically, midaglyzol, isagridol, deliglidol, idazoxan , Efaloxane, etc.]),
(39)抗肥満薬((i)アドレナリンβ3受容体作動薬[具体的には、KRP-204、TRK-380/TAC-301等]、(ii)CB-1受容体拮抗薬[具体的には、リモナバン、SR-147778、BAY-65-2520等]、(iii)ニューロペプチドY(NPY)受容体拮抗薬[具体的には、S-2367等]、(iv)摂食抑制薬[モノアミン再取り込み阻害剤[具体的には、シブトラミン、マジンドール等]]、(v)リパーゼ阻害薬[具体的には、オルリスタット、セチリスタット等]、(vi)ペプチドYY(PYY)受容体拮抗薬等)、(40)コレステロール低下薬等の高脂血症治療薬((i)ω3脂肪酸類[具体的には、イコサペント酸エチル(EPA-E製剤、例えば、製品名:エパデール(登録商標)等)、ドコサヘキサエン酸(DHA)、イコサペント酸エチルおよびドコサヘキサエン酸エチルの混合製剤(例えば、製品名:ロバザ(登録商標)、オマコール(登録商標)等)等]、(ii)HMG-CoA還元酵素阻害剤[具体的には、アトルバスタチン、シンバスタチン、ピタバスタチン、イタバスタチン、フルバスタチン、ロバスタチン、プラバスタチン、リバスタチン、ロスバスタチン等](iii)HMG-CoA合成酵素阻害剤、(iv)コレステロール吸収阻害剤[具体的には、エゼチミブ]、(v)アシル-CoA・コレステロールアシル転移酵素阻害剤、(vi)CETP阻害剤、(vii)スクアレン合成酵素阻害剤、(viii)抗酸化剤[具体的には、プロブコール等]、(ix)PPARα作動薬[具体的には、クロフィブラート、エトフィブラート、フェノフィブラート、ベザフィブラート、シプロフィブラート、ゲムフィブロジル、KRP-101等]、(x)PPARδ作動薬、(xi)LXR作動薬、(xii)FXR作動薬[具体的には、INT-747等]、(xiii)MTTP阻害剤、(xiv)スクアレンエポシダーゼ阻害剤等)、
(39) anti-obesity drugs ((i) adrenergic β3 receptor agonists [specifically, KRP-204, TRK-380 / TAC-301, etc.], (ii) CB-1 receptor antagonists [specifically Rimonabant, SR-147778, BAY-65-2520 etc.], (iii) Neuropeptide Y (NPY) receptor antagonist [specifically, S-2367 etc.], (iv) Antifeedant [monoamine] Reuptake inhibitors [specifically sibutramine, mazindol, etc.]], (v) lipase inhibitors [specifically, orlistat, cetiristat, etc.], (vi) peptide YY (PYY) receptor antagonists, etc.), (40) Antihyperlipidemic drugs such as cholesterol-lowering drugs ((i) ω3 fatty acids [specifically, ethyl icosapentate (EPA-E preparation, for example, product name: Epadale (registered trademark) ), Docosahexaenoic acid (DHA), ethyl icosapentate and ethyl docosahexaenoate (eg, product name: Lovaza (registered trademark), omacol (registered trademark), etc.), etc.], (ii) HMG-CoA reductase inhibitor [Specifically, atorvastatin, simvastatin, pitavastatin, itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, etc.] (iii) HMG-CoA synthase inhibitor, (iv) cholesterol absorption inhibitor [specifically , Ezetimibe], (v) acyl-CoA / cholesterol acyltransferase inhibitor, (vi) CETP inhibitor, (vii) squalene synthase inhibitor, (viii) antioxidant [specifically, probucol and the like], (Ix) PPARα agonist [specifically, black Ibrate, etofibrate, fenofibrate, bezafibrate, ciprofibrate, gemfibrozil, KRP-101, etc.], (x) PPARδ agonist, (xi) LXR agonist, (xii) FXR agonist [specifically, INT-747 Etc.], (xiii) MTTP inhibitor, (xiv) squalene eposidase inhibitor, etc.)
(41)降圧剤((i)利尿剤[具体的には、トリクロルメチアジド、ヒドロクロロチアジド、メフルシド、インダパミド、メチクラン、クロルタリドン、トリパミド、フロセミド、トラセミド、ブメタニド、エタクリン酸、スピロノラクトン、トリアムテレン、エプレレノン等]、(ii)カルシウム受容体拮抗薬[具体的には、アムロジピン、フェロジピン、ニカルジピン、ニフェジピン、ニモジピン、ニトレンジピン、ニルバジピン、アラニジピン、アゼルニジピン、マニジピン、バルニジピン、エホニジピン、シルニジピン、ベニジピン、ジルチアゼム等]、(iii)アンジオテンシン変換酵素阻害薬[具体的には、カプトプリル、リシノプリル、エナラプリル、デラプリル、ペリンドプリル、ベナゼプリル、トランドラプリル、キナプリル、アラセプリル、イミダプリル、テモカプリル、シラザプリル等]、(iv)アンジオテンシン受容体拮抗薬[具体的には、ロサルタン、オルメサルタン、テルミサルタン、バルサルタン、カンデサルタンシレキセチル、イルベサルタン等]、(v)直接的レニン阻害薬[具体的には、アリスキレン等]、(vi)α受容体遮断薬[具体的には、トラゾリン、フェントラミン、ドキサゾシン、プラゾシン、ブナゾシン、テラゾシン、ウラピジル等]、(vii)β受容体遮断薬[具体的には、ボピンドロール、ピンドロール、チモロール、ジクロロイソプレナリン、アルプレノロール、カルテオロール、インデノロール、ブニトロロール、ペンブトロール、プロプラノロール、ナドロール、ニプラジロール、チリソロール、アセブトロール、セリプロロール、メトプロロール、アテノロール、ビソプロロール、ベタキソロール、プラクトロール、ベバントロール、ブトキサミン、カルベジロール、アモスラロール、アロチノロール、ラベタロール等]、(viii)α1β遮断薬[具体的には、カルベジロール、ラベタロール、アロチノロール、ベバントロール等]、(ix)α2受容体刺激薬[具体的には、クロニジン、メチルドパ、グアンファシン等])、
(41) Antihypertensive agent ((i) diuretic [specifically, trichlormethiazide, hydrochlorothiazide, mefluside, indapamide, methiclan, chlorthalidone, tripamide, furosemide, torasemide, bumetanide, ethacrynic acid, spironolactone, triamterene, eplerenone, etc.] (Ii) Calcium receptor antagonists [specifically, amlodipine, felodipine, nicardipine, nifedipine, nimodipine, nitrendipine, nilvadipine, alanidipine, azelnidipine, manidipine, varnidipine, efonidipine, cilnidipine, benidipine, diltiazem etc.], (synten) Converting enzyme inhibitors [specifically, captopril, lisinopril, enalapril, delapril, perindopril, benazepril, trandolapril, Napril, alacepril, imidapril, temocapril, cilazapril, etc.], (iv) angiotensin receptor antagonist [specifically, losartan, olmesartan, telmisartan, valsartan, candesartan cilexetil, irbesartan, etc.], (v) direct renin inhibition Drugs [specifically, aliskiren, etc.], (vi) α receptor blockers [specifically, tolazoline, phentolamine, doxazosin, prazosin, bunazosin, terazosin, urapidil, etc.], (vii) β receptor blockers [ Specifically, bopindolol, pindolol, timolol, dichloroisoprenalin, alprenolol, carteolol, indenolol, bunitrolol, penbutolol, propranolol, nadolol, nipradilol, chilisolol, acebutol Lumpur, celiprolol, metoprolol, atenolol, bisoprolol, betaxolol, practolol, bevantolol, butoxamine, carvedilol, amosulalol, arotinolol, labetalol, etc.], the (viii) α 1 β-blockers [specifically, carvedilol, labetalol, Arotinolol, bevantolol, etc.], (ix) α 2 receptor stimulants [specifically, clonidine, methyldopa, guanfacine, etc.]),
(42)非ステロイド性抗炎症薬[具体的には、メロキシカム、テオキシカム、インドメタシン、イブプロフェン、セレコキシブ、ロフェコキシブ、アスピリン、インドメタシン等]、(43)疾患修飾性抗リウマチ薬、(44)抗サイトカイン薬[具体的には、TNF阻害薬、MAPキナーゼ阻害薬]、(45)ステロイド薬[具体的には、デキサメサゾン、ヘキセストロール、酢酸コルチゾン等]、(46)性ホルモンまたはその誘導体[具体的には、プロゲステロン、エストラジオール、安息香酸エストラジオール等]、(47)副甲状腺ホルモン、(48)オピオイド作動薬[具体的には、モルヒネ、ペンタゾシン、トラマドール]、(49)ピリン系解熱鎮痛薬[具体的には、スルピリン]、(50)非ピリン系解熱鎮痛薬[具体的には、アセトアミノフェン(パラセタモール)]、(51)非ステロイド性抗炎症薬(NSAIDs)[具体的には、アスピリン、メフェナム酸、ジクロフェナク、インドメタシン、イブプロフェン、ケトプロフェン、ナプロキセン、プラノプロフェン、ロキソプロフェン、ザルトプロフェン、ピロキシカム、ロルノキシカム、エピリゾール、チアラミド]、(52)COX-2選択的阻害薬[具体的には、セレコキシブ]、(53)末梢性神経障害性疼痛・線維筋痛症薬[具体的には、プレガバリン]が挙げられる。また、神経因性疼痛に転用し、処方されている以下の薬物、(54)抗てんかん薬[具体的には、ガバペンチン、フェニトイン、カルバマゼピン]等が挙げられる。
(42) Non-steroidal anti-inflammatory drugs [specifically, meloxicam, teoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin, etc.], (43) disease-modifying anti-rheumatic drugs, (44) anti-cytokine drugs [44] Specifically, TNF inhibitors, MAP kinase inhibitors], (45) steroid drugs [specifically, dexamethasone, hexestrol, cortisone acetate, etc.], (46) sex hormones or derivatives thereof [specifically, , Progesterone, estradiol, estradiol benzoate, etc.], (47) parathyroid hormone, (48) opioid agonist [specifically, morphine, pentazocine, tramadol], (49) pilin antipyretic analgesic [specifically, Sulpyrine], (50) non-pyrine antipyretic analgesics [specific Acetaminophen (paracetamol)], (51) non-steroidal anti-inflammatory drugs (NSAIDs) [specifically, aspirin, mefenamic acid, diclofenac, indomethacin, ibuprofen, ketoprofen, naproxen, pranoprofen, loxoprofen, Zaltoprofen, piroxicam, lornoxicam, epirisol, thiaramide], (52) COX-2 selective inhibitor [specifically, celecoxib], (53) peripheral neuropathic pain / fibromyalgia agent [specifically , Pregabalin]. In addition, the following drugs that have been diverted to neuropathic pain and are prescribed (54) antiepileptic drugs [specifically, gabapentin, phenytoin, carbamazepine] and the like can be mentioned.
前記疾患に対して既存薬と併用することにより、既存薬の投薬量を下げることが可能であり、既存薬の副作用を軽減することが可能となる。もちろん、当該薬物を用いた併用方法は、前記疾患に限定されるものではなく、且つ併用される薬物は前記に例示した化合物に限定されない。
本発明化合物と併用される薬物とを組み合わせて使用する場合は、別々の製剤であっても、合剤であってもよい。また、別々の製剤においては、両者を同時に服用することも、時間をずらして投与することも可能である。 By using in combination with existing drugs for the above diseases, the dosage of existing drugs can be reduced, and the side effects of existing drugs can be reduced. Of course, the combination method using the said drug is not limited to the said disease, and the drug used together is not limited to the compound illustrated above.
When the compound of the present invention is used in combination with a drug used in combination, it may be a separate preparation or a combination. Moreover, in separate preparations, both can be taken simultaneously or can be administered at different times.
本発明化合物と併用される薬物とを組み合わせて使用する場合は、別々の製剤であっても、合剤であってもよい。また、別々の製剤においては、両者を同時に服用することも、時間をずらして投与することも可能である。 By using in combination with existing drugs for the above diseases, the dosage of existing drugs can be reduced, and the side effects of existing drugs can be reduced. Of course, the combination method using the said drug is not limited to the said disease, and the drug used together is not limited to the compound illustrated above.
When the compound of the present invention is used in combination with a drug used in combination, it may be a separate preparation or a combination. Moreover, in separate preparations, both can be taken simultaneously or can be administered at different times.
本発明の化合物は、単回または多回投与のいずれかで、単独でまたは薬学的に許容できる担体と組み合わせて投与することができる。適切な医薬担体には、不活性固体希釈剤または充填剤、滅菌水溶液、および種々の有機溶媒が包含される。それにより形成される医薬組成物は次いで、錠剤、粉剤、ロゼンジ、液体調剤、シロップ剤、注射液などの様々な投与形態で容易に投与することができる。これらの医薬組成物は、香味剤、結合剤、賦形剤などの追加成分を場合により含有できる。したがって、本発明の化合物は、経口、口腔、鼻腔、非経口(例えば、静脈内、筋内、または皮下)、経皮(たとえば、パッチ)、もしくは直腸投与用に、または吸入もしくは注入(insufflation)による投与に適した形態で製剤化することができる。
The compounds of the present invention can be administered either alone or in combination with a pharmaceutically acceptable carrier, either single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution, and various organic solvents. The pharmaceutical composition thereby formed can then be easily administered in various dosage forms such as tablets, powders, lozenges, liquid preparations, syrups, injection solutions and the like. These pharmaceutical compositions can optionally contain additional ingredients such as flavoring agents, binders, excipients and the like. Accordingly, the compounds of the present invention may be used for oral, buccal, nasal, parenteral (eg, intravenous, intramuscular, or subcutaneous), transdermal (eg, patch), or rectal administration, or by inhalation or insufflation. Can be formulated in a form suitable for administration by.
[併用・配合剤/組み合わせ剤の投与形態]
本発明の化合物と併用薬物の投与形態は、特に限定されず、投与時に、本発明の化合物と併用薬物とが組み合わされていればよい。このような投与形態としては、例えば、
(1)本発明の化合物と併用薬物とを同時に製剤化して得られる単一の製剤の投与、
(2)本発明の化合物と併用薬物とを別々に製剤化して得られる2種の製剤の同一投与経路での同時投与、
(3)本発明の化合物と併用薬物とを別々に製剤化して得られる2種の製剤の同一投与経路での時間差をおいての投与、
(4)本発明の化合物と併用薬物とを別々に製剤化して得られる2種の製剤の異なる投与経路での同時投与、
(5)本発明の化合物と併用薬物とを別々に製剤化して得られる2種の製剤の異なる投与経路での時間差をおいての投与(例えば、本発明の化合物→併用薬物の順序での投与、または逆の順序での投与)などが用いられる。以下、これらの投与形態をまとめて、本発明の併用剤と略記する。 [Combination / Combination / Combination dosage form]
The administration mode of the compound of the present invention and the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Such dosage forms include, for example,
(1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug,
(2) Simultaneous administration by the same route of administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug,
(3) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at the same administration route with a time difference,
(4) Simultaneous administration of two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes,
(5) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at different time intervals in different administration routes (for example, administration in the order of the compound of the present invention → the concomitant drug) Or administration in the reverse order). Hereinafter, these administration forms are collectively abbreviated as the combination agent of the present invention.
本発明の化合物と併用薬物の投与形態は、特に限定されず、投与時に、本発明の化合物と併用薬物とが組み合わされていればよい。このような投与形態としては、例えば、
(1)本発明の化合物と併用薬物とを同時に製剤化して得られる単一の製剤の投与、
(2)本発明の化合物と併用薬物とを別々に製剤化して得られる2種の製剤の同一投与経路での同時投与、
(3)本発明の化合物と併用薬物とを別々に製剤化して得られる2種の製剤の同一投与経路での時間差をおいての投与、
(4)本発明の化合物と併用薬物とを別々に製剤化して得られる2種の製剤の異なる投与経路での同時投与、
(5)本発明の化合物と併用薬物とを別々に製剤化して得られる2種の製剤の異なる投与経路での時間差をおいての投与(例えば、本発明の化合物→併用薬物の順序での投与、または逆の順序での投与)などが用いられる。以下、これらの投与形態をまとめて、本発明の併用剤と略記する。 [Combination / Combination / Combination dosage form]
The administration mode of the compound of the present invention and the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Such dosage forms include, for example,
(1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug,
(2) Simultaneous administration by the same route of administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug,
(3) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at the same administration route with a time difference,
(4) Simultaneous administration of two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes,
(5) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at different time intervals in different administration routes (for example, administration in the order of the compound of the present invention → the concomitant drug) Or administration in the reverse order). Hereinafter, these administration forms are collectively abbreviated as the combination agent of the present invention.
本発明の併用剤を投与するに際しては、併用薬物と本発明の化合物とを同時期に投与してもよいが、併用薬物の投与の後、本発明の化合物を投与してもよいし、本発明の化合物の投与後、併用薬物を投与してもよい。時間差をおいて投与する場合、時間差は投与する有効成分、剤形、および投与方法により異なるが、例えば、併用薬物を先に投与する場合、併用薬物を投与した後1分~3日以内、好ましくは10分~1日以内、より好ましくは15分~1時間以内に本発明の化合物を投与する方法が挙げられる。本発明の化合物を先に投与する場合、本発明の化合物を投与した後、1分~1日以内、好ましくは10分~6時間以内、より好ましくは15分~1時間以内に併用薬物を投与する方法が挙げられる。
When administering the concomitant drug of the present invention, the concomitant drug and the compound of the present invention may be administered at the same time, but after administering the concomitant drug, the compound of the present invention may be administered. A concomitant drug may be administered after administration of the compound of the invention. When administered at a time difference, the time difference varies depending on the active ingredient to be administered, dosage form, and administration method. For example, when administering the concomitant drug first, preferably within 1 minute to 3 days after administering the concomitant drug. Includes a method of administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When the compound of the present invention is administered first, the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after the administration of the compound of the present invention. The method of doing is mentioned.
併用薬物は、副作用が問題とならなければ、どのような量を設定することも可能である。併用薬物としての一日投与量は、投与量は、投与対象、投与ルート、対象疾患、症状等によっても異なるが、例えば、統合失調症の患者(成人、体重約60kg)に経口投与する場合、通常1回量として約0.1~約20mg/kg体重、好ましくは約0.2~約10mg/kg体重、さらに好ましくは約0.5~約10mg/kg体重であり、この量を1日1回~数回(例、2回、3回、4回又は8回)投与するのが望ましい。
本発明の化合物が併用薬物と組み合せて使用される場合には、お互いの剤の量は、それらの剤の反対効果を考えて安全な範囲内で低減できる。
本発明の併用剤は、毒性が低く、例えば、本発明の化合物、または(および)上記併用薬物を公知の方法に従って、薬理学的に許容される担体と混合して医薬組成物、例えば、錠剤(糖衣錠、フィルムコーティング錠を含む)、散剤、顆粒剤、カプセル剤(ソフトカプセルを含む)、液剤、注射剤、坐剤、徐放剤などとすることができ、それらは、経口的、または非経口的(例、局所、直腸、静脈など)に安全に投与することができる。 Any amount of the concomitant drug can be set as long as side effects are not a problem. The daily dose as a concomitant drug varies depending on the administration subject, administration route, target disease, symptom, etc., for example, when orally administered to a patient with schizophrenia (adult, body weight about 60 kg), Usually, the dose is about 0.1 to about 20 mg / kg body weight, preferably about 0.2 to about 10 mg / kg body weight, more preferably about 0.5 to about 10 mg / kg body weight. It is desirable to administer once to several times (eg, 2, 3, 4 or 8 times).
When the compound of the present invention is used in combination with a concomitant drug, the amount of each agent can be reduced within a safe range in consideration of the opposite effect of those agents.
The concomitant drug of the present invention has low toxicity. For example, the compound of the present invention, or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a known method, for example, a pharmaceutical composition such as a tablet. (Including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release agents, and the like, which can be oral or parenteral (Eg, topical, rectal, intravenous, etc.).
本発明の化合物が併用薬物と組み合せて使用される場合には、お互いの剤の量は、それらの剤の反対効果を考えて安全な範囲内で低減できる。
本発明の併用剤は、毒性が低く、例えば、本発明の化合物、または(および)上記併用薬物を公知の方法に従って、薬理学的に許容される担体と混合して医薬組成物、例えば、錠剤(糖衣錠、フィルムコーティング錠を含む)、散剤、顆粒剤、カプセル剤(ソフトカプセルを含む)、液剤、注射剤、坐剤、徐放剤などとすることができ、それらは、経口的、または非経口的(例、局所、直腸、静脈など)に安全に投与することができる。 Any amount of the concomitant drug can be set as long as side effects are not a problem. The daily dose as a concomitant drug varies depending on the administration subject, administration route, target disease, symptom, etc., for example, when orally administered to a patient with schizophrenia (adult, body weight about 60 kg), Usually, the dose is about 0.1 to about 20 mg / kg body weight, preferably about 0.2 to about 10 mg / kg body weight, more preferably about 0.5 to about 10 mg / kg body weight. It is desirable to administer once to several times (eg, 2, 3, 4 or 8 times).
When the compound of the present invention is used in combination with a concomitant drug, the amount of each agent can be reduced within a safe range in consideration of the opposite effect of those agents.
The concomitant drug of the present invention has low toxicity. For example, the compound of the present invention, or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a known method, for example, a pharmaceutical composition such as a tablet. (Including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release agents, and the like, which can be oral or parenteral (Eg, topical, rectal, intravenous, etc.).
本発明の併用剤の製造に用いられてもよい薬理学的に許容される担体としては、上記した本発明の医薬組成物に使用されるものと同様のものを使用することができる。
本発明の併用剤における本発明の化合物と併用薬物との配合比は、投与対象、投与ルート、疾患などにより適宜選択することができる。
上記併用薬物は、2種以上を適宜の割合で組み合せて用いてもよい。
併用薬物の投与量は、臨床上用いられている用量を基準として適宜選択することができる。また、本発明の化合物と併用薬物の配合比は、投与対象、投与ルート、対象疾患、症状、組み合わせ等により適宜選択することができる。例えば、投与対象がヒトである場合、本発明の化合物1質量部に対し、併用薬物を0.01~100質量部用いればよい。
例えば、本発明の併用剤における本発明の化合物の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約0.01~99.9質量%の範囲であり、好ましくは約0.1~50質量%の範囲であり、さらに好ましくは約0.5~20質量%程度の範囲である。
本発明の併用剤における併用薬物の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約0.01~99.9質量%の範囲であり、好ましくは約0.1~約50質量%の範囲であり、さらに好ましくは約0.5~約20質量%の範囲である。
本発明の併用剤における担体などの添加剤の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約1~99.99質量%の範囲であり、好ましくは約10~約90質量%の範囲である。
本発明の化合物、および併用薬物をそれぞれ別々に製剤化する場合も同様の含有量でよい。
上記したように投与量は種々の条件で変動するので、上記投与量より少ない量で十分な場合もあり、また範囲を超えて投与する必要がある場合もある。 As the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention, the same carriers as those used for the pharmaceutical composition of the present invention described above can be used.
The compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
The dose of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by mass of the concomitant drug may be used per 1 part by mass of the compound of the present invention.
For example, the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by mass, preferably about 0, based on the whole preparation. The range is from 1 to 50% by mass, and more preferably from about 0.5 to 20% by mass.
The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by mass, preferably about 0.1 to about It is in the range of 50% by weight, more preferably in the range of about 0.5 to about 20% by weight.
The content of an additive such as a carrier in the combination agent of the present invention varies depending on the form of the preparation, but is usually in the range of about 1 to 99.99% by mass, preferably about 10 to about 90% with respect to the whole preparation. It is the range of mass%.
The same content may be used when the compound of the present invention and the concomitant drug are formulated separately.
As described above, since the dosage varies depending on various conditions, an amount smaller than the above dosage may be sufficient, and it may be necessary to administer beyond the range.
本発明の併用剤における本発明の化合物と併用薬物との配合比は、投与対象、投与ルート、疾患などにより適宜選択することができる。
上記併用薬物は、2種以上を適宜の割合で組み合せて用いてもよい。
併用薬物の投与量は、臨床上用いられている用量を基準として適宜選択することができる。また、本発明の化合物と併用薬物の配合比は、投与対象、投与ルート、対象疾患、症状、組み合わせ等により適宜選択することができる。例えば、投与対象がヒトである場合、本発明の化合物1質量部に対し、併用薬物を0.01~100質量部用いればよい。
例えば、本発明の併用剤における本発明の化合物の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約0.01~99.9質量%の範囲であり、好ましくは約0.1~50質量%の範囲であり、さらに好ましくは約0.5~20質量%程度の範囲である。
本発明の併用剤における併用薬物の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約0.01~99.9質量%の範囲であり、好ましくは約0.1~約50質量%の範囲であり、さらに好ましくは約0.5~約20質量%の範囲である。
本発明の併用剤における担体などの添加剤の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約1~99.99質量%の範囲であり、好ましくは約10~約90質量%の範囲である。
本発明の化合物、および併用薬物をそれぞれ別々に製剤化する場合も同様の含有量でよい。
上記したように投与量は種々の条件で変動するので、上記投与量より少ない量で十分な場合もあり、また範囲を超えて投与する必要がある場合もある。 As the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention, the same carriers as those used for the pharmaceutical composition of the present invention described above can be used.
The compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
The dose of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by mass of the concomitant drug may be used per 1 part by mass of the compound of the present invention.
For example, the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by mass, preferably about 0, based on the whole preparation. The range is from 1 to 50% by mass, and more preferably from about 0.5 to 20% by mass.
The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by mass, preferably about 0.1 to about It is in the range of 50% by weight, more preferably in the range of about 0.5 to about 20% by weight.
The content of an additive such as a carrier in the combination agent of the present invention varies depending on the form of the preparation, but is usually in the range of about 1 to 99.99% by mass, preferably about 10 to about 90% with respect to the whole preparation. It is the range of mass%.
The same content may be used when the compound of the present invention and the concomitant drug are formulated separately.
As described above, since the dosage varies depending on various conditions, an amount smaller than the above dosage may be sufficient, and it may be necessary to administer beyond the range.
[本発明の予防・治療剤の製剤化]
本発明の医薬は、医薬組成物の形態で投与される。
本発明の医薬組成物は、本発明の式(I)で表される化合物の少なくとも一つ以上を含んでいればよく、任意に医薬上許容される添加剤と組み合わせてつくられる。より詳細には、賦形剤(例;乳糖、白糖、マンニット、結晶セルロース、ケイ酸、トウモロコシデンプン、バレイショデンプン)、結合剤(例;セルロース類(ヒドロキシプロピルセルロース(HPC)、ヒドロキシプロピルメチルセルロース(HPMC))、結晶セルロース、糖類(乳糖、マンニット、白糖、ソルビトール、エリスリトール、キシリトール、)、デンプン類(トウモロコシデンプン、バレイショデンプン)、α化デンプン、デキストリン、ポリビニルピロリドン(PVP)、マクロゴール、ポリビニルアルコール(PVA))、滑沢剤(例;ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、カルボキシメチルセルロース)、崩壊剤(例;デンプン類(トウモロコシデンプン、バレイショデンプン)、カルボキシメチルスターチナトリウム、カルメロース、カルメロースカルシウム、クロスカルメロースナトリウム、クロスポピドン)、被膜剤(例;セルロース類(ヒドロキシプロピルセルロース(HPC)、ヒドロキシプロピルメチルセルロース(HPMC)、アミノアルキルメタクリレートコポリマーE、メタクリル酸コポリマーLD)、可塑剤(例;クエン酸トリエチル、マクロゴール)、隠蔽剤(例;酸化チタン)、着色剤、香味剤、防腐剤(例;塩化ベンザルコニウム、パラオキシ安息香酸エステル)、等張化剤(例;グリセリン、塩化ナトリウム、塩化カルシウム、マンニトール、ブドウ糖)、pH調節剤(例;水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、塩酸、硫酸、リン酸緩衝液などの緩衝液)、安定化剤(例;糖、糖アルコール、キサンタンガム)、分散剤、酸化防止剤(例;アスコルビン酸、ブチルヒドロキシアニソール(BHA)、没食子酸プロピル、dl-α-トコフェロール)、緩衝剤、保存剤(例;パラベン、ベンジルアルコール、塩化ベンザルコニウム)、芳香剤(例;バニリン、l-メントール、ローズ油)、溶解補助剤(例;ポリオキシエチレン硬化ヒマシ油、ポリソルベート80、ポリエチレングリコール、リン脂質コレステロール、トリエタノールアミン)、吸収促進剤(例;グリコール酸ナトリウム、エデト酸ナトリウム、カプリン酸ナトリウム、アシルカルニチン類、リモネン)、ゲル化剤、懸濁化剤、または乳化剤、一般的に用いられる適当な添加剤または溶媒の類を、本発明の化合物と適宜組み合わせて種々の剤形とすることが出来る。 [Formulation of the preventive / therapeutic agent of the present invention]
The medicament of the present invention is administered in the form of a pharmaceutical composition.
The pharmaceutical composition of the present invention only needs to contain at least one of the compounds represented by the formula (I) of the present invention, and is optionally combined with a pharmaceutically acceptable additive. More particularly, excipients (eg; lactose, sucrose, mannitol, crystalline cellulose, silicic acid, corn starch, potato starch), binders (eg; celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose ( HPMC)), crystalline cellulose, saccharides (lactose, mannitol, sucrose, sorbitol, erythritol, xylitol), starches (corn starch, potato starch), pregelatinized starch, dextrin, polyvinylpyrrolidone (PVP), macrogol, polyvinyl Alcohol (PVA)), lubricants (eg; magnesium stearate, calcium stearate, talc, carboxymethylcellulose), disintegrants (eg; starches (corn starch, potato starch), carboxymethyl starch sodium, potassium Lumellose, carmellose calcium, croscarmellose sodium, crospovidone), coating agent (eg, celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), aminoalkyl methacrylate copolymer E, methacrylic acid copolymer LD), plastic) Agents (e.g. triethyl citrate, macrogol), masking agents (e.g. titanium oxide), colorants, flavoring agents, preservatives (e.g. benzalkonium chloride, paraoxybenzoate), isotonic agents (e.g .; Glycerin, sodium chloride, calcium chloride, mannitol, glucose), pH adjuster (eg; buffer solution such as sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid, sulfuric acid, phosphate buffer), stabilizer (eg; Sugar, sugar alcohol, xanthan gum), dispersant, antioxidant (eg Asco Binic acid, butylhydroxyanisole (BHA), propyl gallate, dl-α-tocopherol), buffer, preservative (eg, paraben, benzyl alcohol, benzalkonium chloride), fragrance (eg, vanillin, l-menthol) , Rose oil), solubilizers (eg, polyoxyethylene hydrogenated castor oil, polysorbate 80, polyethylene glycol, phospholipid cholesterol, triethanolamine), absorption enhancers (eg, sodium glycolate, sodium edetate, sodium caprate) , Acylcarnitines, limonene), gelling agents, suspending agents, or emulsifiers, commonly used suitable additives or solvents, and various combinations of the compounds of the present invention. I can do it.
本発明の医薬は、医薬組成物の形態で投与される。
本発明の医薬組成物は、本発明の式(I)で表される化合物の少なくとも一つ以上を含んでいればよく、任意に医薬上許容される添加剤と組み合わせてつくられる。より詳細には、賦形剤(例;乳糖、白糖、マンニット、結晶セルロース、ケイ酸、トウモロコシデンプン、バレイショデンプン)、結合剤(例;セルロース類(ヒドロキシプロピルセルロース(HPC)、ヒドロキシプロピルメチルセルロース(HPMC))、結晶セルロース、糖類(乳糖、マンニット、白糖、ソルビトール、エリスリトール、キシリトール、)、デンプン類(トウモロコシデンプン、バレイショデンプン)、α化デンプン、デキストリン、ポリビニルピロリドン(PVP)、マクロゴール、ポリビニルアルコール(PVA))、滑沢剤(例;ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、カルボキシメチルセルロース)、崩壊剤(例;デンプン類(トウモロコシデンプン、バレイショデンプン)、カルボキシメチルスターチナトリウム、カルメロース、カルメロースカルシウム、クロスカルメロースナトリウム、クロスポピドン)、被膜剤(例;セルロース類(ヒドロキシプロピルセルロース(HPC)、ヒドロキシプロピルメチルセルロース(HPMC)、アミノアルキルメタクリレートコポリマーE、メタクリル酸コポリマーLD)、可塑剤(例;クエン酸トリエチル、マクロゴール)、隠蔽剤(例;酸化チタン)、着色剤、香味剤、防腐剤(例;塩化ベンザルコニウム、パラオキシ安息香酸エステル)、等張化剤(例;グリセリン、塩化ナトリウム、塩化カルシウム、マンニトール、ブドウ糖)、pH調節剤(例;水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、塩酸、硫酸、リン酸緩衝液などの緩衝液)、安定化剤(例;糖、糖アルコール、キサンタンガム)、分散剤、酸化防止剤(例;アスコルビン酸、ブチルヒドロキシアニソール(BHA)、没食子酸プロピル、dl-α-トコフェロール)、緩衝剤、保存剤(例;パラベン、ベンジルアルコール、塩化ベンザルコニウム)、芳香剤(例;バニリン、l-メントール、ローズ油)、溶解補助剤(例;ポリオキシエチレン硬化ヒマシ油、ポリソルベート80、ポリエチレングリコール、リン脂質コレステロール、トリエタノールアミン)、吸収促進剤(例;グリコール酸ナトリウム、エデト酸ナトリウム、カプリン酸ナトリウム、アシルカルニチン類、リモネン)、ゲル化剤、懸濁化剤、または乳化剤、一般的に用いられる適当な添加剤または溶媒の類を、本発明の化合物と適宜組み合わせて種々の剤形とすることが出来る。 [Formulation of the preventive / therapeutic agent of the present invention]
The medicament of the present invention is administered in the form of a pharmaceutical composition.
The pharmaceutical composition of the present invention only needs to contain at least one of the compounds represented by the formula (I) of the present invention, and is optionally combined with a pharmaceutically acceptable additive. More particularly, excipients (eg; lactose, sucrose, mannitol, crystalline cellulose, silicic acid, corn starch, potato starch), binders (eg; celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose ( HPMC)), crystalline cellulose, saccharides (lactose, mannitol, sucrose, sorbitol, erythritol, xylitol), starches (corn starch, potato starch), pregelatinized starch, dextrin, polyvinylpyrrolidone (PVP), macrogol, polyvinyl Alcohol (PVA)), lubricants (eg; magnesium stearate, calcium stearate, talc, carboxymethylcellulose), disintegrants (eg; starches (corn starch, potato starch), carboxymethyl starch sodium, potassium Lumellose, carmellose calcium, croscarmellose sodium, crospovidone), coating agent (eg, celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), aminoalkyl methacrylate copolymer E, methacrylic acid copolymer LD), plastic) Agents (e.g. triethyl citrate, macrogol), masking agents (e.g. titanium oxide), colorants, flavoring agents, preservatives (e.g. benzalkonium chloride, paraoxybenzoate), isotonic agents (e.g .; Glycerin, sodium chloride, calcium chloride, mannitol, glucose), pH adjuster (eg; buffer solution such as sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid, sulfuric acid, phosphate buffer), stabilizer (eg; Sugar, sugar alcohol, xanthan gum), dispersant, antioxidant (eg Asco Binic acid, butylhydroxyanisole (BHA), propyl gallate, dl-α-tocopherol), buffer, preservative (eg, paraben, benzyl alcohol, benzalkonium chloride), fragrance (eg, vanillin, l-menthol) , Rose oil), solubilizers (eg, polyoxyethylene hydrogenated castor oil, polysorbate 80, polyethylene glycol, phospholipid cholesterol, triethanolamine), absorption enhancers (eg, sodium glycolate, sodium edetate, sodium caprate) , Acylcarnitines, limonene), gelling agents, suspending agents, or emulsifiers, commonly used suitable additives or solvents, and various combinations of the compounds of the present invention. I can do it.
種々の剤形としては、例えば、錠剤、カプセル剤、顆粒剤、散剤、丸剤、エアゾール剤、吸入剤、軟膏剤、貼付剤、坐剤、注射剤、トローチ剤、液剤、酒精剤、懸濁剤、エキス剤、エリキシル剤等があげられる。また、本発明の医薬は、例えば、経口、皮下投与、筋肉内投与、鼻腔内投与、経皮投与、静脈内投与、動脈内投与、神経周囲投与、硬膜外投与、硬膜下腔内投与、脳室内投与、直腸内投与、吸入等により患者に投与し得る。
Various dosage forms include, for example, tablets, capsules, granules, powders, pills, aerosols, inhalants, ointments, patches, suppositories, injections, troches, liquids, spirits, suspensions Agents, extracts, elixirs and the like. The medicament of the present invention is, for example, oral, subcutaneous administration, intramuscular administration, intranasal administration, transdermal administration, intravenous administration, intraarterial administration, perineural administration, epidural administration, intradural administration. It can be administered to patients by intraventricular administration, rectal administration, inhalation and the like.
本発明の化合物は、通常のカテーテル技法または注入(infusion)を用いることを含む、注射による非経口投与用に製剤化することができる。注射用製剤は、保存剤を添加して、たとえばアンプルまたは多回投与容器で、単位投与形態として提供することができる。これらの製剤は、油性または水性ビヒクル中の懸濁剤、液剤、またはエマルションなどの形態をとることができ、懸濁化剤、安定化剤、および/または分散剤などの製剤化剤を含有することができる。あるいは活性成分は、使用前に、適切なビヒクル、たとえば滅菌発熱物質除去水で再構成するための粉末形態であることもできる。
The compounds of the present invention can be formulated for parenteral administration by injection, including using conventional catheter techniques or infusion. Injectable formulations may be presented as unit dosage forms, for example, in ampoules or multi-dose containers, with the addition of preservatives. These formulations can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and contain formulation agents such as suspending, stabilizing, and / or dispersing agents. be able to. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.
製品溶液が必要とされる場合、製品溶液は患者への経口または非経口投与に必要とされる強度の溶液を生じるのに充分な量で、水(または他の水性媒質)に単離包接複合体を溶解することによって製造できる。これらの化合物は、口腔内で活性成分が放出されるように設計されている、迅速分散投与形態(fddf)に製剤化することができる。これらの製剤は多くの場合、急速溶解性ゼラチンをベースとしたマトリクスを用いて製剤化されている。これらの投与形態はよく知られており、広範な薬物を送達するために用いることができる。ほとんどの迅速分散投与形態は、担体または構造形成剤としてゼラチンを利用する。典型的に、ゼラチンは、包装から取り出すときに破損を防ぐ充分な強度を投与形態に付与するために用いられるが、ひとたび口に入れると、ゼラチンはその投与形態が即時分解することを可能にする。あるいは、同じ効果を得るために、種々のデンプンが用いられる。
If a product solution is required, the product solution is isolated and included in water (or other aqueous medium) in an amount sufficient to produce a solution of the strength required for oral or parenteral administration to the patient. It can be produced by dissolving the complex. These compounds can be formulated into rapidly dispersed dosage forms (fddf) that are designed to release the active ingredient in the oral cavity. These formulations are often formulated using a matrix based on fast dissolving gelatin. These dosage forms are well known and can be used to deliver a wide range of drugs. Most rapid dispersion dosage forms utilize gelatin as a carrier or structure-forming agent. Gelatin is typically used to give a dosage form sufficient strength to prevent breakage when removed from the package, but once in the mouth, gelatin allows the dosage form to break down immediately. . Alternatively, various starches are used to achieve the same effect.
本発明の化合物はまた、たとえば通常の坐剤基剤、たとえばカカオバターまたは他のグリセリドなどを含有する、坐剤または停留浣腸などの直腸組成物に製剤化することもできる。
The compounds of the invention can also be formulated in rectal compositions such as suppositories or retention enemas, eg containing conventional suppository bases such as cocoa butter or other glycerides.
鼻腔内投与または吸入による投与の場合、本発明の化合物は、患者によって圧搾されるか、もしくはポンプで送り出されるポンプスプレー容器から溶液または懸濁液の形態で、または適切な噴射剤、たとえば、ジクロロジフルオロメタン、トリクロロフルオロメタン、ジクロロテトラフルオロエタン、二酸化炭素、もしくは他の適切なガスを用いて、加圧式容器もしくはネブライザからエアロゾルスプレー形(aerosol spray presentation)として、好都合に送達される。加圧式エアロゾルの場合、投与単位は、計量された量を送達する弁を提供することによって決定することができる。加圧式容器またはネブライザは、活性化合物の溶液または懸濁液を含有することができる。吸入器または注入器で用いるカプセル剤およびカートリッジ剤(たとえば、ゼラチンから製造される)は、本発明の化合物とラクトースまたはデンプンなどの適切な粉末基剤との混合粉末を含有させて製剤化することができる。
For intranasal administration or administration by inhalation, the compounds of the invention may be administered in the form of a solution or suspension from a pump spray container which is squeezed or pumped by the patient, or a suitable propellant such as dichloromethane. Conveniently delivered as an aerosol spray presentation from a pressurized container or nebulizer using difluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve that delivers a metered amount. A pressurized container or nebulizer can contain a solution or suspension of the active compound. Capsules and cartridges (eg, made from gelatin) for use in an inhaler or insufflator should be formulated containing a mixed powder of a compound of the invention and a suitable powder base such as lactose or starch. Can do.
平均的成人において上述の状態(たとえば、片頭痛)を治療するためのエアロゾル製剤は、好ましくはエアロゾルの各計量用量または「1吹き(puff)」が本発明の化合物約20mgから約1000mgを含有するように設定される。エアロゾルによる総日用量は、約100mgから約10mgの範囲内となる。投与は1日数回、たとえば2、3、4、または8回、たとえば各回1、2、または3用量の投与であることができる。
Aerosol formulations for treating the above-described conditions (eg, migraine) in the average adult preferably each metered dose or “puff” of the aerosol contains from about 20 mg to about 1000 mg of the compound of the invention. Is set as follows. The total daily dose with an aerosol will be within the range of about 100 mg to about 10 mg. Administration can be several times daily, for example 2, 3, 4 or 8 times, for example 1, 2 or 3 doses each time.
上述の状態を治療するために、平均的成人に経口、非経口、直腸、または口腔投与される本発明の化合物の提案される日用量は、たとえば1日1から4回投与することのできる単位用量当たり、式(I)の活性成分約0.01mgから約2000mg、好ましくは約0.1mgから約200mgである。
Proposed daily doses of the compounds of the invention administered orally, parenterally, rectally, or buccally to the average adult to treat the above conditions are, for example, units that can be administered 1 to 4 times daily From about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg, of the active ingredient of formula (I) per dose.
[薬理実験例]
以下に実験例を挙げて、本発明を具体的に説明するが、本発明はこれらによって何ら限定されるものではない。
以下の薬理実施例1ないし11は、本発明の化合物の有効性を試験する方法を提供する。 [Pharmacological experiment example]
Hereinafter, the present invention will be specifically described with reference to experimental examples, but the present invention is not limited to these examples.
The following Pharmacological Examples 1 to 11 provide methods for testing the effectiveness of the compounds of the present invention.
以下に実験例を挙げて、本発明を具体的に説明するが、本発明はこれらによって何ら限定されるものではない。
以下の薬理実施例1ないし11は、本発明の化合物の有効性を試験する方法を提供する。 [Pharmacological experiment example]
Hereinafter, the present invention will be specifically described with reference to experimental examples, but the present invention is not limited to these examples.
The following Pharmacological Examples 1 to 11 provide methods for testing the effectiveness of the compounds of the present invention.
薬理実験例1:オレキシン受容体拮抗活性評価
ヒトオレキシン1受容体(hOX1R)、ヒトオレキシン2受容体(hOX2R)に対する拮抗活性の評価は、以下の方法で行った。hOX1R、hOX2Rを安定発現させたCHO-DXB11細胞を、96ウェル黒色ボトムプレート(Greiner)に40,000細胞/ウェルにて播種し、100units/mLペニシリン-0.1mg/mLストレプトマイシン溶液(Invitrogen)、0.4mg/mL G418(Invitrogen)、10% 非動化ウシ胎児血清(Cell Culture BioscienceもしくはSIGMA)を含むHam‘s F-12培地(SIGMA)中で37℃、5%CO2の条件下で一晩培養した。細胞外液を除去後、1.25mmol/Lプロべネシド(SIGMA)およびFLIPR Calcium 5 assay kit(Molecular Devices)を含むバッファー(20mmol/L HEPES(SIGMA)、Hank’s balanced salt solution(HBSS)(Invitrogen))を200μL添加し、60分間インキュベートした。被験化合物は、10mMとなるようにジメチルスルホキシド(和光純薬)溶液を調製し、終濃度10-10000nM(hOX1R)または終濃度3-3000nM(hOX2R)となるようにアッセイ用バッファー(0.1%ウシ血清アルブミン(BSA),20mmol/L HEPES(SIGMA),HBSS(Invitrogen))で希釈後、25μL添加し5分間インキュベートした。アゴニストであるオレキシン-A(Tocris bioscience)は、終濃度が同日に予め測定したEC80と同じ濃度になるようアッセイ用バッファーで調製し、各ウェルへ25μL添加することで反応を開始させた。反応開始から3分間、Functional Drug Screening System(FDSS:浜松ホトニクス)を用いて、細胞内Ca2+濃度の指標である蛍光値(Ex.480nm/Em.540nm)を経時的に測定した。
被検化合物のオレキシン受容体拮抗活性はIC50値で表し、IC50値が40nmol/L以下の化合物を+++、IC50値が40nmol/Lより大きく200nmol/L以下の本発明の化合物を++、IC50値が200nmol/Lより大きく1000nmol/L以下の化合物を+、IC50値が1000nmol/Lより大きい化合物を-として表1に示した。 Pharmacological Experiment Example 1: Evaluation of orexin receptor antagonistic activity Evaluation of antagonistic activity against human orexin 1 receptor (hOX1R) and human orexin 2 receptor (hOX2R) was performed by the following method. CHO-DXB11 cells stably expressing hOX1R and hOX2R were seeded at 40,000 cells / well in a 96-well black bottom plate (Greiner), 100 units / mL penicillin-0.1 mg / mL streptomycin solution (Invitrogen), In Ham's F-12 medium (SIGMA) containing 0.4 mg / mL G418 (Invitrogen), 10% non-immobilized fetal calf serum (Cell Culture Bioscience or SIGMA) under conditions of 37 ° C. and 5% CO 2 Incubated overnight. After removing the extracellular fluid, a buffer containing 1.25 mmol / L probenecid (SIGMA) and FLIPR Calcium 5 assay kit (Molecular Devices) (20 mmol / L HEPES (SIGMA), Hank's balanced salt solution (HBSS) ( 200 μL of Invitrogen)) was added and incubated for 60 minutes. Prepare a dimethyl sulfoxide (Wako Pure Chemicals) solution so that the test compound is 10 mM, and assay buffer (0.1%) to a final concentration of 10-10000 nM (hOX1R) or a final concentration of 3-3000 nM (hOX2R). After dilution with bovine serum albumin (BSA), 20 mmol / L HEPES (SIGMA), HBSS (Invitrogen)), 25 μL was added and incubated for 5 minutes. The agonist orexin-A (Tocris bioscience) was prepared in assay buffer so that the final concentration was the same as EC80 measured in advance on the same day, and the reaction was started by adding 25 μL to each well. Using a Functional Drug Screening System (FDSS: Hamamatsu Photonics) for 3 minutes from the start of the reaction, the fluorescence value (Ex. 480 nm / Em. 540 nm), which is an index of intracellular Ca 2+ concentration, was measured over time.
Orexin receptor antagonistic activity of the test compounds are expressed as an IC 50 value, an IC 50 value is +++ The following compounds 40 nmol / L, an IC 50 value greater than 40nmol / L 200nmol / L following compounds of the present invention ++, the IC 50 values are 200 nmol / L a greater than 1000 nmol / L or less of compound +, an IC 50 value is the 1000 nmol / L is greater than compounds - shown as in Table 1.
ヒトオレキシン1受容体(hOX1R)、ヒトオレキシン2受容体(hOX2R)に対する拮抗活性の評価は、以下の方法で行った。hOX1R、hOX2Rを安定発現させたCHO-DXB11細胞を、96ウェル黒色ボトムプレート(Greiner)に40,000細胞/ウェルにて播種し、100units/mLペニシリン-0.1mg/mLストレプトマイシン溶液(Invitrogen)、0.4mg/mL G418(Invitrogen)、10% 非動化ウシ胎児血清(Cell Culture BioscienceもしくはSIGMA)を含むHam‘s F-12培地(SIGMA)中で37℃、5%CO2の条件下で一晩培養した。細胞外液を除去後、1.25mmol/Lプロべネシド(SIGMA)およびFLIPR Calcium 5 assay kit(Molecular Devices)を含むバッファー(20mmol/L HEPES(SIGMA)、Hank’s balanced salt solution(HBSS)(Invitrogen))を200μL添加し、60分間インキュベートした。被験化合物は、10mMとなるようにジメチルスルホキシド(和光純薬)溶液を調製し、終濃度10-10000nM(hOX1R)または終濃度3-3000nM(hOX2R)となるようにアッセイ用バッファー(0.1%ウシ血清アルブミン(BSA),20mmol/L HEPES(SIGMA),HBSS(Invitrogen))で希釈後、25μL添加し5分間インキュベートした。アゴニストであるオレキシン-A(Tocris bioscience)は、終濃度が同日に予め測定したEC80と同じ濃度になるようアッセイ用バッファーで調製し、各ウェルへ25μL添加することで反応を開始させた。反応開始から3分間、Functional Drug Screening System(FDSS:浜松ホトニクス)を用いて、細胞内Ca2+濃度の指標である蛍光値(Ex.480nm/Em.540nm)を経時的に測定した。
被検化合物のオレキシン受容体拮抗活性はIC50値で表し、IC50値が40nmol/L以下の化合物を+++、IC50値が40nmol/Lより大きく200nmol/L以下の本発明の化合物を++、IC50値が200nmol/Lより大きく1000nmol/L以下の化合物を+、IC50値が1000nmol/Lより大きい化合物を-として表1に示した。 Pharmacological Experiment Example 1: Evaluation of orexin receptor antagonistic activity Evaluation of antagonistic activity against human orexin 1 receptor (hOX1R) and human orexin 2 receptor (hOX2R) was performed by the following method. CHO-DXB11 cells stably expressing hOX1R and hOX2R were seeded at 40,000 cells / well in a 96-well black bottom plate (Greiner), 100 units / mL penicillin-0.1 mg / mL streptomycin solution (Invitrogen), In Ham's F-12 medium (SIGMA) containing 0.4 mg / mL G418 (Invitrogen), 10% non-immobilized fetal calf serum (Cell Culture Bioscience or SIGMA) under conditions of 37 ° C. and 5% CO 2 Incubated overnight. After removing the extracellular fluid, a buffer containing 1.25 mmol / L probenecid (SIGMA) and FLIPR Calcium 5 assay kit (Molecular Devices) (20 mmol / L HEPES (SIGMA), Hank's balanced salt solution (HBSS) ( 200 μL of Invitrogen)) was added and incubated for 60 minutes. Prepare a dimethyl sulfoxide (Wako Pure Chemicals) solution so that the test compound is 10 mM, and assay buffer (0.1%) to a final concentration of 10-10000 nM (hOX1R) or a final concentration of 3-3000 nM (hOX2R). After dilution with bovine serum albumin (BSA), 20 mmol / L HEPES (SIGMA), HBSS (Invitrogen)), 25 μL was added and incubated for 5 minutes. The agonist orexin-A (Tocris bioscience) was prepared in assay buffer so that the final concentration was the same as EC80 measured in advance on the same day, and the reaction was started by adding 25 μL to each well. Using a Functional Drug Screening System (FDSS: Hamamatsu Photonics) for 3 minutes from the start of the reaction, the fluorescence value (Ex. 480 nm / Em. 540 nm), which is an index of intracellular Ca 2+ concentration, was measured over time.
Orexin receptor antagonistic activity of the test compounds are expressed as an IC 50 value, an IC 50 value is +++ The following compounds 40 nmol / L, an IC 50 value greater than 40nmol / L 200nmol / L following compounds of the present invention ++, the IC 50 values are 200 nmol / L a greater than 1000 nmol / L or less of compound +, an IC 50 value is the 1000 nmol / L is greater than compounds - shown as in Table 1.
薬理実験例2:[Ala11,D-Leu15]-オレキシンB誘発ロコモーター活性評価
雄性Sprague-Dawleyラットを購入し、飼育施設に到着後、動物を少なくとも一週間の馴化期間をおいて実験に使用する。動物は、温度と湿度をコントロールした実験室で、12時間明暗サイクル下で飼育し、食餌と水を自由摂取させる。
脳内オレキシンとオレキシン2受容体の相互作用に対する被験化合物の拮抗作用を確認するために、ラットを使用して[Ala11,D-Leu15]-オレキシンB(ADL-OXB)(Tocris bioscience)誘発自発運動量試験を行う。ADL-OXBはヒトオレキシンBの2アミノ酸を置換したペプチドであり、OX1Rと比較してOX2Rに400倍ほど高い親和性を持つ。ADL-OXBを脳室内投与するため、ラットにカニューレ埋め込み手術を行い、回復期間として1週間以上飼育する。回復期間を経て、正しい位置にカニューレが埋め込まれているかを確認するため、予備試験として100ng/5μLのアンジオテンシン2(ペプチド研究所)を脳室内投与し、投与後30分間の飲水量を測定する。飲水量が5gに達したラットのみ本試験に使用する。本試験まで、ラットを測定ケージ内で120分以上馴化させる。馴化後、溶媒又は被験化合物のいずれかを投与し、すぐに測定ケージに戻す。被験化合物の投与30~120分後に、再びラットを飼育ケージより取り出し、溶媒(生理食塩水)またはADL-OXB(3nmol/5μL/ラット)を脳室内投与し、すぐに測定ケージへ戻す。自発運動量測定は赤外線センサーの付いた自発運動量測定チャンバー(室町機械)に入れて行う。自発運動量は、10分ごとにカウントし、ADL-OXB投与後30、60、120分間の累積カウントを各処置群について計算する。全てのデータは平均値と平均値の標準誤差として表す。統計解析は、コントロール群とADL-OXB単独投与群の比較はStudent’s t-test(p<0.05で有意差あり)を使用し、ADL-OXB単独投与群と被験化合物投与群の比較はDunnett’s test(p<0.05で有意差あり)を使用する。 Pharmacological Experiment Example 2: Evaluation of [Ala 11 , D-Leu 15 ] -Orexin B-Induced Locomotor Activity After purchasing male Sprague-Dawley rats and arriving at the breeding facility, the animals were subjected to an experiment with an acclimatization period of at least one week. use. Animals are housed in a laboratory with controlled temperature and humidity under a 12 hour light / dark cycle, with free access to food and water.
[Ala 11 , D-Leu 15 ] -Orexin B (ADL-OXB) (Tocris bioscience) induction using rats to confirm the antagonism of test compounds against the interaction of orexin and orexin 2 receptor in the brain Perform spontaneous exercise test. ADL-OXB is a peptide in which two amino acids of human orexin B are substituted, and has a 400 times higher affinity for OX2R than OX1R. In order to administer ADL-OXB intracerebroventricularly, rats are cannulated and kept for at least 1 week as a recovery period. In order to confirm whether the cannula is implanted at the correct position after the recovery period, 100 ng / 5 μL of angiotensin 2 (Peptide Institute) is administered intraventricularly as a preliminary test, and the amount of water consumed for 30 minutes after the administration is measured. Only rats that have reached 5 g of drinking water are used in this study. Rats are acclimated for at least 120 minutes in the measurement cage until this test. After acclimatization, either vehicle or test compound is administered and immediately returned to the measurement cage. 30 to 120 minutes after administration of the test compound, the rat is again taken out from the housing cage, and the solvent (saline) or ADL-OXB (3 nmol / 5 μL / rat) is administered into the ventricle and immediately returned to the measurement cage. Spontaneous momentum is measured in a spontaneous momentum measurement chamber (Muromachi Kikai) equipped with an infrared sensor. Spontaneous exercise is counted every 10 minutes, and cumulative counts for 30, 60, 120 minutes after ADL-OXB administration are calculated for each treatment group. All data are expressed as mean and standard error of the mean. For statistical analysis, comparison between the control group and ADL-OXB single administration group was performed using Student's t-test (significant difference at p <0.05), and comparison between ADL-OXB single administration group and test compound administration group Uses Dunnett's test (significantly different at p <0.05).
雄性Sprague-Dawleyラットを購入し、飼育施設に到着後、動物を少なくとも一週間の馴化期間をおいて実験に使用する。動物は、温度と湿度をコントロールした実験室で、12時間明暗サイクル下で飼育し、食餌と水を自由摂取させる。
脳内オレキシンとオレキシン2受容体の相互作用に対する被験化合物の拮抗作用を確認するために、ラットを使用して[Ala11,D-Leu15]-オレキシンB(ADL-OXB)(Tocris bioscience)誘発自発運動量試験を行う。ADL-OXBはヒトオレキシンBの2アミノ酸を置換したペプチドであり、OX1Rと比較してOX2Rに400倍ほど高い親和性を持つ。ADL-OXBを脳室内投与するため、ラットにカニューレ埋め込み手術を行い、回復期間として1週間以上飼育する。回復期間を経て、正しい位置にカニューレが埋め込まれているかを確認するため、予備試験として100ng/5μLのアンジオテンシン2(ペプチド研究所)を脳室内投与し、投与後30分間の飲水量を測定する。飲水量が5gに達したラットのみ本試験に使用する。本試験まで、ラットを測定ケージ内で120分以上馴化させる。馴化後、溶媒又は被験化合物のいずれかを投与し、すぐに測定ケージに戻す。被験化合物の投与30~120分後に、再びラットを飼育ケージより取り出し、溶媒(生理食塩水)またはADL-OXB(3nmol/5μL/ラット)を脳室内投与し、すぐに測定ケージへ戻す。自発運動量測定は赤外線センサーの付いた自発運動量測定チャンバー(室町機械)に入れて行う。自発運動量は、10分ごとにカウントし、ADL-OXB投与後30、60、120分間の累積カウントを各処置群について計算する。全てのデータは平均値と平均値の標準誤差として表す。統計解析は、コントロール群とADL-OXB単独投与群の比較はStudent’s t-test(p<0.05で有意差あり)を使用し、ADL-OXB単独投与群と被験化合物投与群の比較はDunnett’s test(p<0.05で有意差あり)を使用する。 Pharmacological Experiment Example 2: Evaluation of [Ala 11 , D-Leu 15 ] -Orexin B-Induced Locomotor Activity After purchasing male Sprague-Dawley rats and arriving at the breeding facility, the animals were subjected to an experiment with an acclimatization period of at least one week. use. Animals are housed in a laboratory with controlled temperature and humidity under a 12 hour light / dark cycle, with free access to food and water.
[Ala 11 , D-Leu 15 ] -Orexin B (ADL-OXB) (Tocris bioscience) induction using rats to confirm the antagonism of test compounds against the interaction of orexin and orexin 2 receptor in the brain Perform spontaneous exercise test. ADL-OXB is a peptide in which two amino acids of human orexin B are substituted, and has a 400 times higher affinity for OX2R than OX1R. In order to administer ADL-OXB intracerebroventricularly, rats are cannulated and kept for at least 1 week as a recovery period. In order to confirm whether the cannula is implanted at the correct position after the recovery period, 100 ng / 5 μL of angiotensin 2 (Peptide Institute) is administered intraventricularly as a preliminary test, and the amount of water consumed for 30 minutes after the administration is measured. Only rats that have reached 5 g of drinking water are used in this study. Rats are acclimated for at least 120 minutes in the measurement cage until this test. After acclimatization, either vehicle or test compound is administered and immediately returned to the measurement cage. 30 to 120 minutes after administration of the test compound, the rat is again taken out from the housing cage, and the solvent (saline) or ADL-OXB (3 nmol / 5 μL / rat) is administered into the ventricle and immediately returned to the measurement cage. Spontaneous momentum is measured in a spontaneous momentum measurement chamber (Muromachi Kikai) equipped with an infrared sensor. Spontaneous exercise is counted every 10 minutes, and cumulative counts for 30, 60, 120 minutes after ADL-OXB administration are calculated for each treatment group. All data are expressed as mean and standard error of the mean. For statistical analysis, comparison between the control group and ADL-OXB single administration group was performed using Student's t-test (significant difference at p <0.05), and comparison between ADL-OXB single administration group and test compound administration group Uses Dunnett's test (significantly different at p <0.05).
薬理実験例3:睡眠脳波測定試験
雄性Sprague-Dawleyラットを購入し、飼育施設に到着後、動物を少なくとも一週間の馴化期間をおいて実験に使用する。動物は、温度と湿度をコントロールした実験室で、12時間明暗サイクル下で飼育し、食餌と水を自由摂取させる。
睡眠への効果を確認するためにラットにおける睡眠脳波試験を実施する。脳波(Electroencephalogram:EEG)および筋電図(Electromyogram:EMG)測定のためにラットにEEGおよびEMG電極埋め込み手術を行ない、回復期間として1週間以上飼育する。溶媒または被験化合物を投与した後、EEGおよびEMG信号を6時間ないし12時間記録する。
解析は自動解析ソフトであるSleepSign(登録商標)(キッセイコムテック)を用いて、脳波周波数と筋電図の活動信号を分析し、覚醒、REM睡眠、NREM睡眠の3ステージの何れかを分類させる。各ステージの累積時間を計算し、覚醒時間の減少、総睡眠時間の上昇(REM睡眠+NREM睡眠)から被験化合物の睡眠作用を確認する。また総睡眠時間に対するREM睡眠のパーセンテージを算出し、コントロール群の結果と比較することにより生理的な睡眠パターンを示しているか検討する。 Pharmacological experiment example 3: Sleep EEG measurement test
After purchasing male Sprague-Dawley rats and arriving at the breeding facility, the animals are used for experiments with an acclimatization period of at least one week. Animals are housed in a laboratory with controlled temperature and humidity under a 12 hour light / dark cycle, with free access to food and water.
In order to confirm the effect on sleep, a sleep electroencephalogram test in rats is performed. Rats are subjected to EEG and EMG electrode implantation surgery for electroencephalogram (EEG) and electromyogram (EMG) measurement, and are kept for at least 1 week as a recovery period. After administration of vehicle or test compound, EEG and EMG signals are recorded for 6-12 hours.
The analysis is performed by using an automatic analysis software SleepSign (registered trademark) (Kissei Comtech) to analyze an electroencephalogram frequency and an electromyogram activity signal to classify one of three stages of arousal, REM sleep, and NREM sleep. The cumulative time of each stage is calculated, and the sleep action of the test compound is confirmed from the decrease in the awakening time and the increase in the total sleep time (REM sleep + NREM sleep). Moreover, the percentage of REM sleep with respect to the total sleep time is calculated, and it is examined whether a physiological sleep pattern is shown by comparing with the result of the control group.
雄性Sprague-Dawleyラットを購入し、飼育施設に到着後、動物を少なくとも一週間の馴化期間をおいて実験に使用する。動物は、温度と湿度をコントロールした実験室で、12時間明暗サイクル下で飼育し、食餌と水を自由摂取させる。
睡眠への効果を確認するためにラットにおける睡眠脳波試験を実施する。脳波(Electroencephalogram:EEG)および筋電図(Electromyogram:EMG)測定のためにラットにEEGおよびEMG電極埋め込み手術を行ない、回復期間として1週間以上飼育する。溶媒または被験化合物を投与した後、EEGおよびEMG信号を6時間ないし12時間記録する。
解析は自動解析ソフトであるSleepSign(登録商標)(キッセイコムテック)を用いて、脳波周波数と筋電図の活動信号を分析し、覚醒、REM睡眠、NREM睡眠の3ステージの何れかを分類させる。各ステージの累積時間を計算し、覚醒時間の減少、総睡眠時間の上昇(REM睡眠+NREM睡眠)から被験化合物の睡眠作用を確認する。また総睡眠時間に対するREM睡眠のパーセンテージを算出し、コントロール群の結果と比較することにより生理的な睡眠パターンを示しているか検討する。 Pharmacological experiment example 3: Sleep EEG measurement test
After purchasing male Sprague-Dawley rats and arriving at the breeding facility, the animals are used for experiments with an acclimatization period of at least one week. Animals are housed in a laboratory with controlled temperature and humidity under a 12 hour light / dark cycle, with free access to food and water.
In order to confirm the effect on sleep, a sleep electroencephalogram test in rats is performed. Rats are subjected to EEG and EMG electrode implantation surgery for electroencephalogram (EEG) and electromyogram (EMG) measurement, and are kept for at least 1 week as a recovery period. After administration of vehicle or test compound, EEG and EMG signals are recorded for 6-12 hours.
The analysis is performed by using an automatic analysis software SleepSign (registered trademark) (Kissei Comtech) to analyze an electroencephalogram frequency and an electromyogram activity signal to classify one of three stages of arousal, REM sleep, and NREM sleep. The cumulative time of each stage is calculated, and the sleep action of the test compound is confirmed from the decrease in the awakening time and the increase in the total sleep time (REM sleep + NREM sleep). Moreover, the percentage of REM sleep with respect to the total sleep time is calculated, and it is examined whether a physiological sleep pattern is shown by comparing with the result of the control group.
薬理実験例4:溶解性試験
(1)DMSO析出溶解性(Kinetic Solubility)
本発明化合物の10mMのDMSO溶液を最終濃度100μMとなるように50mMリン酸緩衝液(pH7.4)に添加する。その溶液を室温で1.5時間、600rpmにて撹拌しながらインキュベーションした後、フィルタープレート(MultiScreenHTS-PCFフィルタープレート(MerckMillipore))でろ過し、プレートリーダー(Powerscan HT(大日本製薬))を用いて、ろ液の吸光度を最大吸収波長で測定する。同時に、試験化合物の既知濃度(1、3、10、30、100μM)を添加したDMSO溶液を検量線標準溶液として各々の標準溶液吸光度を測定し、検量線を作成する。ろ液および標準溶液の吸光度値より化合物の溶解度(μM)を算出する。
(2)結晶溶解性(Thermodynamic Solubility)
本発明化合物を1mg/mLとなるように溶媒(例えば、水、緩衝液)に添加する。その溶液を25℃または37℃で24時間1000rpmにて撹拌しながらインキュベーションした後、フィルタープレートでろ過する。ろ液をHPLCにて分析し、最大吸収波長にてピークを検出し、ピーク面積を測定する。同様に試験化合物の既知濃度(例えば、0.01、0.03、0.1、0.3、1、3、10μg/mL)を添加した溶液(例えば、DMSO溶液、1,4-ジオキサン溶液、メタノール溶液)を検量線標準溶液として各々のピーク面積を測定し、検量線のピーク面積より化合物の溶解度(μg/mL)を算出する。 Pharmacological Experiment Example 4: Solubility Test (1) DMSO Precipitation Solubility (Kinetic Solubility)
A 10 mM DMSO solution of the compound of the present invention is added to a 50 mM phosphate buffer (pH 7.4) to a final concentration of 100 μM. The solution was incubated at 600 rpm with stirring at room temperature for 1.5 hours, then filtered through a filter plate (MultiScreen HTS- PCF filter plate (Merck Millipore)), and using a plate reader (Powerscan HT (Dainippon Pharmaceutical)). Then, the absorbance of the filtrate is measured at the maximum absorption wavelength. At the same time, the absorbance of each standard solution is measured using a DMSO solution to which a known concentration (1, 3, 10, 30, 100 μM) of the test compound is added as a calibration curve standard solution, and a calibration curve is created. The solubility (μM) of the compound is calculated from the absorbance values of the filtrate and standard solution.
(2) Crystal solubility (Thermodynamic Solubility)
The compound of the present invention is added to a solvent (for example, water, buffer) so as to be 1 mg / mL. The solution is incubated with stirring at 1000 rpm for 24 hours at 25 ° C. or 37 ° C. and then filtered through a filter plate. The filtrate is analyzed by HPLC, the peak is detected at the maximum absorption wavelength, and the peak area is measured. Similarly, a solution (eg, DMSO solution, 1,4-dioxane solution) to which a known concentration of the test compound (eg, 0.01, 0.03, 0.1, 0.3, 1, 3, 10 μg / mL) is added. , Methanol solution) is used as a standard curve standard solution to measure each peak area, and the solubility (μg / mL) of the compound is calculated from the peak area of the standard curve.
(1)DMSO析出溶解性(Kinetic Solubility)
本発明化合物の10mMのDMSO溶液を最終濃度100μMとなるように50mMリン酸緩衝液(pH7.4)に添加する。その溶液を室温で1.5時間、600rpmにて撹拌しながらインキュベーションした後、フィルタープレート(MultiScreenHTS-PCFフィルタープレート(MerckMillipore))でろ過し、プレートリーダー(Powerscan HT(大日本製薬))を用いて、ろ液の吸光度を最大吸収波長で測定する。同時に、試験化合物の既知濃度(1、3、10、30、100μM)を添加したDMSO溶液を検量線標準溶液として各々の標準溶液吸光度を測定し、検量線を作成する。ろ液および標準溶液の吸光度値より化合物の溶解度(μM)を算出する。
(2)結晶溶解性(Thermodynamic Solubility)
本発明化合物を1mg/mLとなるように溶媒(例えば、水、緩衝液)に添加する。その溶液を25℃または37℃で24時間1000rpmにて撹拌しながらインキュベーションした後、フィルタープレートでろ過する。ろ液をHPLCにて分析し、最大吸収波長にてピークを検出し、ピーク面積を測定する。同様に試験化合物の既知濃度(例えば、0.01、0.03、0.1、0.3、1、3、10μg/mL)を添加した溶液(例えば、DMSO溶液、1,4-ジオキサン溶液、メタノール溶液)を検量線標準溶液として各々のピーク面積を測定し、検量線のピーク面積より化合物の溶解度(μg/mL)を算出する。 Pharmacological Experiment Example 4: Solubility Test (1) DMSO Precipitation Solubility (Kinetic Solubility)
A 10 mM DMSO solution of the compound of the present invention is added to a 50 mM phosphate buffer (pH 7.4) to a final concentration of 100 μM. The solution was incubated at 600 rpm with stirring at room temperature for 1.5 hours, then filtered through a filter plate (MultiScreen HTS- PCF filter plate (Merck Millipore)), and using a plate reader (Powerscan HT (Dainippon Pharmaceutical)). Then, the absorbance of the filtrate is measured at the maximum absorption wavelength. At the same time, the absorbance of each standard solution is measured using a DMSO solution to which a known concentration (1, 3, 10, 30, 100 μM) of the test compound is added as a calibration curve standard solution, and a calibration curve is created. The solubility (μM) of the compound is calculated from the absorbance values of the filtrate and standard solution.
(2) Crystal solubility (Thermodynamic Solubility)
The compound of the present invention is added to a solvent (for example, water, buffer) so as to be 1 mg / mL. The solution is incubated with stirring at 1000 rpm for 24 hours at 25 ° C. or 37 ° C. and then filtered through a filter plate. The filtrate is analyzed by HPLC, the peak is detected at the maximum absorption wavelength, and the peak area is measured. Similarly, a solution (eg, DMSO solution, 1,4-dioxane solution) to which a known concentration of the test compound (eg, 0.01, 0.03, 0.1, 0.3, 1, 3, 10 μg / mL) is added. , Methanol solution) is used as a standard curve standard solution to measure each peak area, and the solubility (μg / mL) of the compound is calculated from the peak area of the standard curve.
薬理実験例5:代謝安定性試験
(1)代謝安定性試験1
本発明化合物の10mMのDMSO溶液を最終濃度1μMとなるように肝ミクロソーム溶液(ヒト、ラット、マウス、イヌまたはサル;XenoTech)、NADPH生成溶液(β-NADP、Glucose-6-Phosphate、G-6-PDH(Y)、MgCl2を含む水)に添加する。その溶液を37℃で5、10、20または30分間インキュベートした後、アセトニトリルで反応停止する。反応液をフィルタープレート(MultiScreenHTS-HVプレート(MerckMillipore))で遠心ろ過し、高速液体クロマトグラム/マススペクトロメトリーを用いて、ろ液中の試験化合物を測定する。同様に反応時間0分のサンプルをコントロールとして測定し、各時点における残存率(%)を算出する。反応時間を横軸、残存率を縦軸としてプロットし、その傾きからクリアランス(μL/min/mg protein)を算出する。
(2)代謝安定性試験2
本発明化合物の10mMのDMSO溶液を最終濃度1μMとなるように肝細胞懸濁液(ヒト;GIBCO、ラット、イヌ、サル;XenoTech)に添加する。その溶液を37℃で5、15、30、45、60、120分間インキュベートした後、アセトニトリルで反応停止する。反応液をフィルタープレート(MultiScreenHTS-HVプレート(MerckMillipore))で遠心ろ過し、高速液体クロマトグラム/マススペクトロメトリーを用いて、ろ液中の試験化合物を測定する。同様に反応時間0分のサンプルをコントロールとして測定し、肝細胞反応サンプルとコントロールの比より、各時点における残存率(%)を算出する。反応時間を横軸、残存率を縦軸としてプロットし、その傾きからクリアランス(μL/min/mg protein)を算出する。 Pharmacological experiment example 5: Metabolic stability test (1) Metabolic stability test 1
Liver microsome solution (human, rat, mouse, dog or monkey; XenoTech), NADPH generating solution (β-NADP, Glucose-6-phosphate, G-6) -PDH (Y), water containing MgCl 2 ). The solution is incubated at 37 ° C. for 5, 10, 20 or 30 minutes and then quenched with acetonitrile. The reaction solution is centrifuged through a filter plate (MultiScreen HTS- HV plate (Merck Millipore)), and the test compound in the filtrate is measured using high performance liquid chromatogram / mass spectrometry. Similarly, a sample with a reaction time of 0 minutes is measured as a control, and the residual rate (%) at each time point is calculated. The reaction time is plotted on the horizontal axis and the residual ratio is plotted on the vertical axis, and the clearance (μL / min / mg protein) is calculated from the slope.
(2) Metabolic stability test 2
A 10 mM DMSO solution of the compound of the present invention is added to a hepatocyte suspension (human; GIBCO, rat, dog, monkey; XenoTech) to a final concentration of 1 μM. The solution is incubated at 37 ° C. for 5, 15, 30, 45, 60, 120 minutes and then quenched with acetonitrile. The reaction solution is centrifuged through a filter plate (MultiScreenHTS-HV plate (Merck Millipore)), and the test compound in the filtrate is measured using high performance liquid chromatogram / mass spectrometry. Similarly, a sample with a reaction time of 0 minutes is measured as a control, and the residual rate (%) at each time point is calculated from the ratio of the hepatocyte reaction sample and the control. The reaction time is plotted on the horizontal axis and the residual ratio is plotted on the vertical axis, and the clearance (μL / min / mg protein) is calculated from the slope.
(1)代謝安定性試験1
本発明化合物の10mMのDMSO溶液を最終濃度1μMとなるように肝ミクロソーム溶液(ヒト、ラット、マウス、イヌまたはサル;XenoTech)、NADPH生成溶液(β-NADP、Glucose-6-Phosphate、G-6-PDH(Y)、MgCl2を含む水)に添加する。その溶液を37℃で5、10、20または30分間インキュベートした後、アセトニトリルで反応停止する。反応液をフィルタープレート(MultiScreenHTS-HVプレート(MerckMillipore))で遠心ろ過し、高速液体クロマトグラム/マススペクトロメトリーを用いて、ろ液中の試験化合物を測定する。同様に反応時間0分のサンプルをコントロールとして測定し、各時点における残存率(%)を算出する。反応時間を横軸、残存率を縦軸としてプロットし、その傾きからクリアランス(μL/min/mg protein)を算出する。
(2)代謝安定性試験2
本発明化合物の10mMのDMSO溶液を最終濃度1μMとなるように肝細胞懸濁液(ヒト;GIBCO、ラット、イヌ、サル;XenoTech)に添加する。その溶液を37℃で5、15、30、45、60、120分間インキュベートした後、アセトニトリルで反応停止する。反応液をフィルタープレート(MultiScreenHTS-HVプレート(MerckMillipore))で遠心ろ過し、高速液体クロマトグラム/マススペクトロメトリーを用いて、ろ液中の試験化合物を測定する。同様に反応時間0分のサンプルをコントロールとして測定し、肝細胞反応サンプルとコントロールの比より、各時点における残存率(%)を算出する。反応時間を横軸、残存率を縦軸としてプロットし、その傾きからクリアランス(μL/min/mg protein)を算出する。 Pharmacological experiment example 5: Metabolic stability test (1) Metabolic stability test 1
Liver microsome solution (human, rat, mouse, dog or monkey; XenoTech), NADPH generating solution (β-NADP, Glucose-6-phosphate, G-6) -PDH (Y), water containing MgCl 2 ). The solution is incubated at 37 ° C. for 5, 10, 20 or 30 minutes and then quenched with acetonitrile. The reaction solution is centrifuged through a filter plate (MultiScreen HTS- HV plate (Merck Millipore)), and the test compound in the filtrate is measured using high performance liquid chromatogram / mass spectrometry. Similarly, a sample with a reaction time of 0 minutes is measured as a control, and the residual rate (%) at each time point is calculated. The reaction time is plotted on the horizontal axis and the residual ratio is plotted on the vertical axis, and the clearance (μL / min / mg protein) is calculated from the slope.
(2) Metabolic stability test 2
A 10 mM DMSO solution of the compound of the present invention is added to a hepatocyte suspension (human; GIBCO, rat, dog, monkey; XenoTech) to a final concentration of 1 μM. The solution is incubated at 37 ° C. for 5, 15, 30, 45, 60, 120 minutes and then quenched with acetonitrile. The reaction solution is centrifuged through a filter plate (MultiScreenHTS-HV plate (Merck Millipore)), and the test compound in the filtrate is measured using high performance liquid chromatogram / mass spectrometry. Similarly, a sample with a reaction time of 0 minutes is measured as a control, and the residual rate (%) at each time point is calculated from the ratio of the hepatocyte reaction sample and the control. The reaction time is plotted on the horizontal axis and the residual ratio is plotted on the vertical axis, and the clearance (μL / min / mg protein) is calculated from the slope.
薬理実験例6:パッチクランプ法によるhERG阻害試験
hERG(human ether-a-go-go related gene)チャネルに対する作用を全自動パッチクランプシステム(QPatch HT(Sophion Bioscience))を用いて測定する。細胞(CHO hERG DUO(B’SYS))のhERG IKr電流を確認するため、膜電位を-80mVに保持し、-50mV、0.02秒間および20mV、4.8秒間の脱分極パルスに続く-50mV、5秒間の再分極パルスを15秒に1回の頻度で与える。試験化合物のhERGチャネルに対する作用は、再分極パルスによって誘導されるテール電流の変化によって確認する。測定は室温で行う。hERGチャネル阻害率は、試験化合物添加前のテール電流ピーク値に対する添加後4分のテール電流の減少率(抑制率)として算出する。
この抑制率を算出することにより、薬物によるQT延長とそれに続く致死的な副作用(心室頻拍や突然死など)を誘発する可能性が示される。 Pharmacological Experiment Example 6 hERG Inhibition Test by Patch Clamp Method The effect on hERG (human ether-a-go related gene) channels is measured using a fully automatic patch clamp system (QPatch HT (Sophion Bioscience)). To confirm the hERG I Kr current of the cells (CHO hERG DUO (B'SYS)), the membrane potential is held at −80 mV, followed by a depolarization pulse of −50 mV, 0.02 seconds and 20 mV, 4.8 seconds. -50 mV, 5 seconds of repolarization pulse given once every 15 seconds. The effect of the test compound on the hERG channel is confirmed by the tail current change induced by the repolarization pulse. The measurement is performed at room temperature. The hERG channel inhibition rate is calculated as the reduction rate (suppression rate) of the tail current 4 minutes after the addition relative to the tail current peak value before the addition of the test compound.
By calculating this suppression rate, the possibility of inducing QT prolongation by drugs and subsequent fatal side effects (such as ventricular tachycardia and sudden death) is shown.
hERG(human ether-a-go-go related gene)チャネルに対する作用を全自動パッチクランプシステム(QPatch HT(Sophion Bioscience))を用いて測定する。細胞(CHO hERG DUO(B’SYS))のhERG IKr電流を確認するため、膜電位を-80mVに保持し、-50mV、0.02秒間および20mV、4.8秒間の脱分極パルスに続く-50mV、5秒間の再分極パルスを15秒に1回の頻度で与える。試験化合物のhERGチャネルに対する作用は、再分極パルスによって誘導されるテール電流の変化によって確認する。測定は室温で行う。hERGチャネル阻害率は、試験化合物添加前のテール電流ピーク値に対する添加後4分のテール電流の減少率(抑制率)として算出する。
この抑制率を算出することにより、薬物によるQT延長とそれに続く致死的な副作用(心室頻拍や突然死など)を誘発する可能性が示される。 Pharmacological Experiment Example 6 hERG Inhibition Test by Patch Clamp Method The effect on hERG (human ether-a-go related gene) channels is measured using a fully automatic patch clamp system (QPatch HT (Sophion Bioscience)). To confirm the hERG I Kr current of the cells (CHO hERG DUO (B'SYS)), the membrane potential is held at −80 mV, followed by a depolarization pulse of −50 mV, 0.02 seconds and 20 mV, 4.8 seconds. -50 mV, 5 seconds of repolarization pulse given once every 15 seconds. The effect of the test compound on the hERG channel is confirmed by the tail current change induced by the repolarization pulse. The measurement is performed at room temperature. The hERG channel inhibition rate is calculated as the reduction rate (suppression rate) of the tail current 4 minutes after the addition relative to the tail current peak value before the addition of the test compound.
By calculating this suppression rate, the possibility of inducing QT prolongation by drugs and subsequent fatal side effects (such as ventricular tachycardia and sudden death) is shown.
薬理実験例7:ファーマコキネティクス(PK)試験
(1)ラットカセットPK試験
本発明化合物を7あるいは8週齢の雄性CD(SD)IGS Jclに1mg/kg(投与溶媒は、DMSO:Tween80:超純水=1:1:8、10mL/kg)で経口単回投与した後、0.5、1、2、4時間後に腹大静脈より採血する。血液を遠心分離(3000rpm、15分間、4℃)して得られた血漿を用いて、高速液体クロマトグラム/マススペクトロメトリーにて、血漿中の試験化合物を測定する。同様に試験化合物の既知濃度(0.01、0.02、0.05、0.1、0.2、0.5、1μg/mL)を添加した標準溶液を測定し、作成した検量線より血漿中濃度(μg/mL)を算出し、最高血漿中濃度をCmax(μg/mL)とする。
(2)PK試験
本発明化合物を動物(約7から8週齢の雄性Crl:CD(SD)ラット、もしくは、約4カ年齢の雄性ビーグル犬、もしくは、約6カ年齢の雄性カニクイザル)に1mg/kg(投与溶媒は、Dimethylacetamide:Tween80:超純水=4:4:2、1mL/kg)で静脈内投与あるいは10mg/kg(投与溶媒は、0.5% Methylcellulose、5mL/kg)で経口投与した後、0.083、0.25、0.5、1、2,4、8、24時間後に頚静脈より採血する。血液を遠心分離(3000rpm、15分間、4℃)して得られた血漿を用いて、高速液体クロマトグラム/マススペクトロメトリーにて、血漿中の試験化合物を測定する。同様に試験化合物の既知濃度(0.001、0.002、0.005、0.01、0.02、0.05、0.1、0.2、0.5、1、2、10μg/mL)を添加した標準溶液を測定し、作成した検量線より血漿中濃度(μg/mL)を算出し、最高血漿中濃度をCmax(μg/mL)とする。 Pharmacological Experiment Example 7: Pharmacokinetics (PK) test (1) Rat cassette PK test 1 mg / kg of the present compound in 7 or 8 weeks old male CD (SD) IGS Jcl (administration solvent is DMSO: Tween 80: over (Pure water = 1: 1: 8, 10 mL / kg), and the blood is collected from the abdominal vena cava 0.5, 1, 2, and 4 hours later. Using plasma obtained by centrifuging blood (3000 rpm, 15 minutes, 4 ° C.), the test compound in plasma is measured by high performance liquid chromatogram / mass spectrometry. Similarly, a standard solution to which a known concentration of a test compound (0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1 μg / mL) was added was measured, and a calibration curve was prepared. The plasma concentration (μg / mL) is calculated, and the maximum plasma concentration is defined as Cmax (μg / mL).
(2) PK test 1 mg of the compound of the present invention in an animal (male Crl: CD (SD) rat, about 7 to 8 weeks old, male beagle dog about 4 years old, or male cynomolgus monkey about 6 years old) / Kg (administration solvent is dimethylacetamide: Tween 80: ultrapure water = 4: 4: 2, 1 mL / kg) or intravenous administration or 10 mg / kg (administration solvent is 0.5% methylcellulose, 5 mL / kg) After administration, blood is collected from the jugular vein 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours later. Using plasma obtained by centrifuging blood (3000 rpm, 15 minutes, 4 ° C.), the test compound in plasma is measured by high performance liquid chromatogram / mass spectrometry. Similarly, known concentrations of test compounds (0.001, 0.002, 0.005, 0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1, 2, 10 μg / (mL) is measured, the plasma concentration (μg / mL) is calculated from the prepared calibration curve, and the maximum plasma concentration is defined as Cmax (μg / mL).
(1)ラットカセットPK試験
本発明化合物を7あるいは8週齢の雄性CD(SD)IGS Jclに1mg/kg(投与溶媒は、DMSO:Tween80:超純水=1:1:8、10mL/kg)で経口単回投与した後、0.5、1、2、4時間後に腹大静脈より採血する。血液を遠心分離(3000rpm、15分間、4℃)して得られた血漿を用いて、高速液体クロマトグラム/マススペクトロメトリーにて、血漿中の試験化合物を測定する。同様に試験化合物の既知濃度(0.01、0.02、0.05、0.1、0.2、0.5、1μg/mL)を添加した標準溶液を測定し、作成した検量線より血漿中濃度(μg/mL)を算出し、最高血漿中濃度をCmax(μg/mL)とする。
(2)PK試験
本発明化合物を動物(約7から8週齢の雄性Crl:CD(SD)ラット、もしくは、約4カ年齢の雄性ビーグル犬、もしくは、約6カ年齢の雄性カニクイザル)に1mg/kg(投与溶媒は、Dimethylacetamide:Tween80:超純水=4:4:2、1mL/kg)で静脈内投与あるいは10mg/kg(投与溶媒は、0.5% Methylcellulose、5mL/kg)で経口投与した後、0.083、0.25、0.5、1、2,4、8、24時間後に頚静脈より採血する。血液を遠心分離(3000rpm、15分間、4℃)して得られた血漿を用いて、高速液体クロマトグラム/マススペクトロメトリーにて、血漿中の試験化合物を測定する。同様に試験化合物の既知濃度(0.001、0.002、0.005、0.01、0.02、0.05、0.1、0.2、0.5、1、2、10μg/mL)を添加した標準溶液を測定し、作成した検量線より血漿中濃度(μg/mL)を算出し、最高血漿中濃度をCmax(μg/mL)とする。 Pharmacological Experiment Example 7: Pharmacokinetics (PK) test (1) Rat cassette PK test 1 mg / kg of the present compound in 7 or 8 weeks old male CD (SD) IGS Jcl (administration solvent is DMSO: Tween 80: over (Pure water = 1: 1: 8, 10 mL / kg), and the blood is collected from the abdominal vena cava 0.5, 1, 2, and 4 hours later. Using plasma obtained by centrifuging blood (3000 rpm, 15 minutes, 4 ° C.), the test compound in plasma is measured by high performance liquid chromatogram / mass spectrometry. Similarly, a standard solution to which a known concentration of a test compound (0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1 μg / mL) was added was measured, and a calibration curve was prepared. The plasma concentration (μg / mL) is calculated, and the maximum plasma concentration is defined as Cmax (μg / mL).
(2) PK test 1 mg of the compound of the present invention in an animal (male Crl: CD (SD) rat, about 7 to 8 weeks old, male beagle dog about 4 years old, or male cynomolgus monkey about 6 years old) / Kg (administration solvent is dimethylacetamide: Tween 80: ultrapure water = 4: 4: 2, 1 mL / kg) or intravenous administration or 10 mg / kg (administration solvent is 0.5% methylcellulose, 5 mL / kg) After administration, blood is collected from the jugular vein 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours later. Using plasma obtained by centrifuging blood (3000 rpm, 15 minutes, 4 ° C.), the test compound in plasma is measured by high performance liquid chromatogram / mass spectrometry. Similarly, known concentrations of test compounds (0.001, 0.002, 0.005, 0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1, 2, 10 μg / (mL) is measured, the plasma concentration (μg / mL) is calculated from the prepared calibration curve, and the maximum plasma concentration is defined as Cmax (μg / mL).
薬理実験例8:タンパク結合試験
本発明化合物の10mMのDMSO溶液を最終濃度10μMとなるように正常血漿(ヒト、ラット、イヌ、サル)に添加する。簡易平衡透析装置(HTD96b Complete Unit(HTDialysis))にて37℃で4時間透析した後、透析膜の内側(血漿側)溶液および外側(PBS側)溶液中の試験化合物濃度を、高速液体クロマトグラム/マススペクトロメトリーを用いて測定する。PBS側と血漿側の比から非結合分率(%)を算出し、100-非結合分率(%)より蛋白結合率(%)を算出する。
薬理実験例9:ファーマコキネティクス試験における各種パラメータの算出
ラット、イヌ、サルの各動物種におけるPK試験(前記薬理実験例7)によって得られた血漿中濃度の時間推移についてモデル非依存的解析を行い、全身クリアランスCLtot(L/kg/hr)、定常状態における分布容積Vdss(L/kg)、血漿中濃度―時間曲線下面積AUC(μg・hr/mL)、半減期T1/2(hr)を算出する。また、静脈内投与時のAUCと経口投与時のAUCを比較してバイオアベイラビリティを算出する。 Pharmacological Experiment Example 8: Protein Binding Test A 10 mM DMSO solution of the compound of the present invention is added to normal plasma (human, rat, dog, monkey) to a final concentration of 10 μM. After dialyzing for 4 hours at 37 ° C. with a simple equilibrium dialysis machine (HTD96b Complete Unit (HTDialissis)), the test compound concentrations in the inner (plasma side) solution and outer (PBS side) solution of the dialysis membrane were measured using a high-performance liquid chromatogram. / Measure using mass spectrometry. The non-binding fraction (%) is calculated from the ratio between the PBS side and the plasma side, and the protein binding rate (%) is calculated from 100−non-binding fraction (%).
Pharmacological experiment example 9: Calculation of various parameters in pharmacokinetics test Model-independent analysis of time course of plasma concentration obtained by PK test in rat, dog and monkey animal species (pharmacological experiment example 7) Systemic clearance CLtot (L / kg / hr), distribution volume Vdss in steady state (L / kg), plasma concentration-time curve area AUC (μg · hr / mL), half-life T1 / 2 (hr) Is calculated. In addition, the bioavailability is calculated by comparing the AUC at the time of intravenous administration with the AUC at the time of oral administration.
本発明化合物の10mMのDMSO溶液を最終濃度10μMとなるように正常血漿(ヒト、ラット、イヌ、サル)に添加する。簡易平衡透析装置(HTD96b Complete Unit(HTDialysis))にて37℃で4時間透析した後、透析膜の内側(血漿側)溶液および外側(PBS側)溶液中の試験化合物濃度を、高速液体クロマトグラム/マススペクトロメトリーを用いて測定する。PBS側と血漿側の比から非結合分率(%)を算出し、100-非結合分率(%)より蛋白結合率(%)を算出する。
薬理実験例9:ファーマコキネティクス試験における各種パラメータの算出
ラット、イヌ、サルの各動物種におけるPK試験(前記薬理実験例7)によって得られた血漿中濃度の時間推移についてモデル非依存的解析を行い、全身クリアランスCLtot(L/kg/hr)、定常状態における分布容積Vdss(L/kg)、血漿中濃度―時間曲線下面積AUC(μg・hr/mL)、半減期T1/2(hr)を算出する。また、静脈内投与時のAUCと経口投与時のAUCを比較してバイオアベイラビリティを算出する。 Pharmacological Experiment Example 8: Protein Binding Test A 10 mM DMSO solution of the compound of the present invention is added to normal plasma (human, rat, dog, monkey) to a final concentration of 10 μM. After dialyzing for 4 hours at 37 ° C. with a simple equilibrium dialysis machine (HTD96b Complete Unit (HTDialissis)), the test compound concentrations in the inner (plasma side) solution and outer (PBS side) solution of the dialysis membrane were measured using a high-performance liquid chromatogram. / Measure using mass spectrometry. The non-binding fraction (%) is calculated from the ratio between the PBS side and the plasma side, and the protein binding rate (%) is calculated from 100−non-binding fraction (%).
Pharmacological experiment example 9: Calculation of various parameters in pharmacokinetics test Model-independent analysis of time course of plasma concentration obtained by PK test in rat, dog and monkey animal species (pharmacological experiment example 7) Systemic clearance CLtot (L / kg / hr), distribution volume Vdss in steady state (L / kg), plasma concentration-time curve area AUC (μg · hr / mL), half-life T1 / 2 (hr) Is calculated. In addition, the bioavailability is calculated by comparing the AUC at the time of intravenous administration with the AUC at the time of oral administration.
薬理実験例10:ヒトにおける薬物動態パラメータの予測
前記薬理実験例5、7または8等に記載の方法にて得られた、動物のファーマコキネティクス試験における各種パラメータ、インビトロ試験における代謝安定性、タンパク結合率などのパラメータを用い、アロメトリックスケーリングによる方法またはIVIVE(in vitro/in vivo extrapolation)法などの当業者に知られた方法により、ヒトにおける薬物動態パラメータを予測する。 Pharmacological experiment example 10: Prediction of pharmacokinetic parameters in humans Various parameters in animal pharmacokinetic tests, metabolic stability in in vitro tests, proteins obtained by the method described in pharmacological experiment examples 5, 7 or 8 Using parameters such as binding rate, pharmacokinetic parameters in humans are predicted by methods known to those skilled in the art such as allometric scaling or IVIVE (in vitro / in vivo extrapolation).
前記薬理実験例5、7または8等に記載の方法にて得られた、動物のファーマコキネティクス試験における各種パラメータ、インビトロ試験における代謝安定性、タンパク結合率などのパラメータを用い、アロメトリックスケーリングによる方法またはIVIVE(in vitro/in vivo extrapolation)法などの当業者に知られた方法により、ヒトにおける薬物動態パラメータを予測する。 Pharmacological experiment example 10: Prediction of pharmacokinetic parameters in humans Various parameters in animal pharmacokinetic tests, metabolic stability in in vitro tests, proteins obtained by the method described in pharmacological experiment examples 5, 7 or 8 Using parameters such as binding rate, pharmacokinetic parameters in humans are predicted by methods known to those skilled in the art such as allometric scaling or IVIVE (in vitro / in vivo extrapolation).
薬理実験例11:安全性試験
本発明化合物をマウスまたはラットに単回で経口投与し、死亡例は認められず、目立った行動異常も観察されないことにより、本発明化合物の安全性が示される。 Pharmacological Experiment Example 11: Safety test The compound of the present invention is orally administered to a mouse or rat once, and no deaths are observed, and no remarkable behavioral abnormality is observed, indicating the safety of the compound of the present invention.
本発明化合物をマウスまたはラットに単回で経口投与し、死亡例は認められず、目立った行動異常も観察されないことにより、本発明化合物の安全性が示される。 Pharmacological Experiment Example 11: Safety test The compound of the present invention is orally administered to a mouse or rat once, and no deaths are observed, and no remarkable behavioral abnormality is observed, indicating the safety of the compound of the present invention.
以上の結果より、本発明化合物は、優れたオレキシン受容体拮抗作用を有することが示された。更に、ラットを用いた[Ala11,D-Leu15]-オレキシンB誘発自発運動量亢進に対する拮抗作用試験によって、オレキシン拮抗作用が示され、睡眠脳波測定試験によって、睡眠作用が示される。また、安全性試験において何ら異常が認められず、本発明の低い毒性が示される。更に、本発明化合物は、上記の試験を行うことにより、溶解性、代謝安定性、薬物動態、hERGチャネル阻害作用の回避等の1つの点において良好であることが確認される。
From the above results, it was shown that the compound of the present invention has an excellent orexin receptor antagonistic action. Furthermore, orexin antagonism is shown by an antagonism test against [Ala 11 , D-Leu 15 ] -orexin B-induced locomotor activity enhancement using rats, and sleep action is shown by a sleep electroencephalogram measurement test. In addition, no abnormality is observed in the safety test, indicating the low toxicity of the present invention. Furthermore, it is confirmed that the compound of the present invention is good in one point such as solubility, metabolic stability, pharmacokinetics, and avoidance of hERG channel inhibitory effect by conducting the above test.
従って、本発明化合物は、オレキシン受容体拮抗剤として、睡眠障害(不眠症、概日リズム睡眠障害、睡眠時随伴症等)、精神疾患(うつ病、不安障害、双極性障害、注意欠陥多動性障害、自閉症、自閉症スペクトラム障害、薬物依存症等)、神経変性疾患(アルツハイマー病等)、記憶障害(認知症等)および摂食障害(過食症等)等の疾患の予防及び/または治療剤に用いることが期待される。
本発明化合物は、以下に示す各種疾患に対して有望な予防、あるいは治療効果を示すことが期待される。具体的には、不眠症、概日リズム睡眠障害、睡眠時随伴症、うつ病、不安障害、双極性障害、注意欠陥多動性障害、自閉症、自閉症スペクトラム障害、薬物依存症、アルツハイマー病、認知症、過食症等に対して有望な治療効果が期待できる。 Therefore, the compounds of the present invention are orexin receptor antagonists, such as sleep disorders (insomnia, circadian rhythm sleep disorders, sleep-related complications, etc.), mental disorders (depression, anxiety disorders, bipolar disorders, attention deficit hyperactivity) Prevention of diseases such as sexual disorders, autism, autism spectrum disorder, drug dependence), neurodegenerative diseases (Alzheimer's disease, etc.), memory disorders (dementia, etc.) and eating disorders (eg, bulimia) It is expected to be used as a therapeutic agent.
The compound of the present invention is expected to show promising preventive or therapeutic effects for various diseases shown below. Specifically, insomnia, circadian rhythm sleep disorder, sleep-related comorbidities, depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, autism, autism spectrum disorder, drug addiction, Promising therapeutic effects can be expected for Alzheimer's disease, dementia, bulimia and the like.
本発明化合物は、以下に示す各種疾患に対して有望な予防、あるいは治療効果を示すことが期待される。具体的には、不眠症、概日リズム睡眠障害、睡眠時随伴症、うつ病、不安障害、双極性障害、注意欠陥多動性障害、自閉症、自閉症スペクトラム障害、薬物依存症、アルツハイマー病、認知症、過食症等に対して有望な治療効果が期待できる。 Therefore, the compounds of the present invention are orexin receptor antagonists, such as sleep disorders (insomnia, circadian rhythm sleep disorders, sleep-related complications, etc.), mental disorders (depression, anxiety disorders, bipolar disorders, attention deficit hyperactivity) Prevention of diseases such as sexual disorders, autism, autism spectrum disorder, drug dependence), neurodegenerative diseases (Alzheimer's disease, etc.), memory disorders (dementia, etc.) and eating disorders (eg, bulimia) It is expected to be used as a therapeutic agent.
The compound of the present invention is expected to show promising preventive or therapeutic effects for various diseases shown below. Specifically, insomnia, circadian rhythm sleep disorder, sleep-related comorbidities, depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, autism, autism spectrum disorder, drug addiction, Promising therapeutic effects can be expected for Alzheimer's disease, dementia, bulimia and the like.
次に、本発明をさらに詳細に説明するために実施例、製造例をあげるが、これらの例は単なる実施であって、本発明を限定するものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。
Next, in order to describe the present invention in more detail, examples and production examples will be given. However, these examples are merely implementations, and do not limit the present invention, and do not depart from the scope of the present invention. It may be changed with.
核磁気共鳴スペクトル(NMR)の測定には、JEOL JNM-ECX400 FT-NMR(日本電子)またはJEOL JNM-ECX300 FT-NMR(日本電子)を用いた。
液体クロマトグラフィー-質量分析スペクトル(LC -Mass)は以下のいずれかの方法で測定した。[UPLC]Waters UPLC-ZQ MSシステム(Waters)とMGIII-Hカラム(2.1mm×5cm、3μm)(資生堂)を用い、移動相は、メタノール:0.05%トリフルオロ酢酸水溶液=5:95(0分)~100:0(1分)~100:0(2分)のグラジエント条件を用いた。[LCMS]Waters FractionLynx MSシステム(Waters)とSunFireカラム(4.6mm×5cm、5μm)(Waters)を用い、移動相は、[メソッドA]メタノール:0.05%トリフルオロ酢酸水溶液=10:90(0分)~100:0(5分)~100:0(7分)、または[メソッドB]メタノール:0.05%酢酸水溶液=10:90(0分)~100:0(5分)~100:0(7分)のグラジエント条件を用いた。分取系には化合物により適宜変更したグラジエント条件を用いた。
マイクロウェーブを用いた合成は、マイクロウェーブ合成装置Initiator(登録商標)Sixty(バイオタージ)を用いた。 For the measurement of nuclear magnetic resonance spectrum (NMR), JEOL JNM-ECX400 FT-NMR (JEOL) or JEOL JNM-ECX300 FT-NMR (JEOL) was used.
Liquid chromatography-mass spectrometry spectrum (LC-Mass) was measured by one of the following methods. [UPLC] Waters UPLC-ZQ MS system (Waters) and MGIII-H column (2.1 mm × 5 cm, 3 μm) (Shiseido) were used, and the mobile phase was methanol: 0.05% trifluoroacetic acid aqueous solution = 5: 95. Gradient conditions from (0 minutes) to 100: 0 (1 minute) to 100: 0 (2 minutes) were used. [LCMS] Waters FractionLynx MS system (Waters) and SunFire column (4.6 mm × 5 cm, 5 μm) (Waters) were used, and the mobile phase was [Method A] methanol: 0.05% aqueous trifluoroacetic acid = 10: 90 (0 min) to 100: 0 (5 min) to 100: 0 (7 min), or [Method B] methanol: 0.05% aqueous acetic acid solution = 10: 90 (0 min) to 100: 0 (5 min) Gradient conditions of ˜100: 0 (7 minutes) were used. For the preparative system, gradient conditions appropriately changed depending on the compound were used.
For the synthesis using the microwave, a microwave synthesizer Initiator (registered trademark) Sixty (Biotage) was used.
液体クロマトグラフィー-質量分析スペクトル(LC -Mass)は以下のいずれかの方法で測定した。[UPLC]Waters UPLC-ZQ MSシステム(Waters)とMGIII-Hカラム(2.1mm×5cm、3μm)(資生堂)を用い、移動相は、メタノール:0.05%トリフルオロ酢酸水溶液=5:95(0分)~100:0(1分)~100:0(2分)のグラジエント条件を用いた。[LCMS]Waters FractionLynx MSシステム(Waters)とSunFireカラム(4.6mm×5cm、5μm)(Waters)を用い、移動相は、[メソッドA]メタノール:0.05%トリフルオロ酢酸水溶液=10:90(0分)~100:0(5分)~100:0(7分)、または[メソッドB]メタノール:0.05%酢酸水溶液=10:90(0分)~100:0(5分)~100:0(7分)のグラジエント条件を用いた。分取系には化合物により適宜変更したグラジエント条件を用いた。
マイクロウェーブを用いた合成は、マイクロウェーブ合成装置Initiator(登録商標)Sixty(バイオタージ)を用いた。 For the measurement of nuclear magnetic resonance spectrum (NMR), JEOL JNM-ECX400 FT-NMR (JEOL) or JEOL JNM-ECX300 FT-NMR (JEOL) was used.
Liquid chromatography-mass spectrometry spectrum (LC-Mass) was measured by one of the following methods. [UPLC] Waters UPLC-ZQ MS system (Waters) and MGIII-H column (2.1 mm × 5 cm, 3 μm) (Shiseido) were used, and the mobile phase was methanol: 0.05% trifluoroacetic acid aqueous solution = 5: 95. Gradient conditions from (0 minutes) to 100: 0 (1 minute) to 100: 0 (2 minutes) were used. [LCMS] Waters FractionLynx MS system (Waters) and SunFire column (4.6 mm × 5 cm, 5 μm) (Waters) were used, and the mobile phase was [Method A] methanol: 0.05% aqueous trifluoroacetic acid = 10: 90 (0 min) to 100: 0 (5 min) to 100: 0 (7 min), or [Method B] methanol: 0.05% aqueous acetic acid solution = 10: 90 (0 min) to 100: 0 (5 min) Gradient conditions of ˜100: 0 (7 minutes) were used. For the preparative system, gradient conditions appropriately changed depending on the compound were used.
For the synthesis using the microwave, a microwave synthesizer Initiator (registered trademark) Sixty (Biotage) was used.
1H-NMRデータ中、NMRシグナルのパターンで、sはシングレット、dはダブレット、tはトリプレット、qはカルテット、mはマルチプレット、brはブロード、Jはカップリング定数、Hzはヘルツ、CDCl3は重クロロホルム、DMSO-d6は重ジメチルスルホキシド、CD3ODは重メタノールを意味する。1H-NMRデータ中、水酸基、アミノ基、カルボキシル基のプロトン等、ブロードバンドであるため確認ができないシグナルについては、データに記載していない。
LC-Massデータは、各実施例において「UPLC」、「LCMS[メソッドA]」または「LCMS[メソッドB]」として示した。LC-Massデータ中、[M+H]+、[M+Na]+、[M-CO2]+は分子イオンピークを意味する。
実施例及び製造例中の「室温」は、実験室内の温度、通常は20±15℃の温度を示すものとする。 1 H-NMR data, NMR signal pattern, s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, br is broad, J is coupling constant, Hz is Hertz, CDCl 3 Represents deuterated chloroform, DMSO-d 6 represents deuterated dimethyl sulfoxide, and CD3OD represents deuterated methanol. In the 1 H-NMR data, signals that cannot be confirmed due to broadband, such as protons of hydroxyl groups, amino groups, and carboxyl groups, are not described in the data.
The LC-Mass data was indicated as “UPLC”, “LCMS [Method A]” or “LCMS [Method B]” in each example. In the LC-Mass data, [M + H] + , [M + Na] + and [M-CO 2 ] + mean molecular ion peaks.
“Room temperature” in the examples and production examples represents the temperature in the laboratory, usually 20 ± 15 ° C.
LC-Massデータは、各実施例において「UPLC」、「LCMS[メソッドA]」または「LCMS[メソッドB]」として示した。LC-Massデータ中、[M+H]+、[M+Na]+、[M-CO2]+は分子イオンピークを意味する。
実施例及び製造例中の「室温」は、実験室内の温度、通常は20±15℃の温度を示すものとする。 1 H-NMR data, NMR signal pattern, s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, br is broad, J is coupling constant, Hz is Hertz, CDCl 3 Represents deuterated chloroform, DMSO-d 6 represents deuterated dimethyl sulfoxide, and CD3OD represents deuterated methanol. In the 1 H-NMR data, signals that cannot be confirmed due to broadband, such as protons of hydroxyl groups, amino groups, and carboxyl groups, are not described in the data.
The LC-Mass data was indicated as “UPLC”, “LCMS [Method A]” or “LCMS [Method B]” in each example. In the LC-Mass data, [M + H] + , [M + Na] + and [M-CO 2 ] + mean molecular ion peaks.
“Room temperature” in the examples and production examples represents the temperature in the laboratory, usually 20 ± 15 ° C.
(製造例1)8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体1)の合成
<工程1>tert-ブチル 8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体1-1)の合成
tert-ブチル 3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(1.1g)と炭酸カリウム(1.7g)のNMP(5.0mL)混合液に2-クロロ-4,6-ジメチルピリミジン(0.86g)を加え、窒素雰囲気下、100℃にて16時間撹拌した。反応溶液を室温へ冷却し、酢酸エチルを加えた後、有機層を水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=100:0~70:30)にて精製し、標記化合物(1.6g)を無色液体として得た。
UPLC:319[M+H]+(保持時間1.00分) Production Example 1 Synthesis of 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 1) <Step 1> tert-Butyl 8- ( Synthesis of 4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 1-1) tert-butyl 3,8-diazabicyclo [3. 2.1] Add 2-chloro-4,6-dimethylpyrimidine (0.86 g) to a mixture of NMP (5.0 mL) of octane-3-carboxylate (1.1 g) and potassium carbonate (1.7 g). The mixture was stirred at 100 ° C. for 16 hours in a nitrogen atmosphere. The reaction solution was cooled to room temperature, ethyl acetate was added, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 70:30) to obtain the title compound (1.6 g) as a colorless liquid. .
UPLC: 319 [M + H] + (retention time 1.00 min)
<工程1>tert-ブチル 8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体1-1)の合成
tert-ブチル 3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(1.1g)と炭酸カリウム(1.7g)のNMP(5.0mL)混合液に2-クロロ-4,6-ジメチルピリミジン(0.86g)を加え、窒素雰囲気下、100℃にて16時間撹拌した。反応溶液を室温へ冷却し、酢酸エチルを加えた後、有機層を水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=100:0~70:30)にて精製し、標記化合物(1.6g)を無色液体として得た。
UPLC:319[M+H]+(保持時間1.00分) Production Example 1 Synthesis of 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 1) <Step 1> tert-Butyl 8- ( Synthesis of 4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 1-1) tert-butyl 3,8-diazabicyclo [3. 2.1] Add 2-chloro-4,6-dimethylpyrimidine (0.86 g) to a mixture of NMP (5.0 mL) of octane-3-carboxylate (1.1 g) and potassium carbonate (1.7 g). The mixture was stirred at 100 ° C. for 16 hours in a nitrogen atmosphere. The reaction solution was cooled to room temperature, ethyl acetate was added, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 70:30) to obtain the title compound (1.6 g) as a colorless liquid. .
UPLC: 319 [M + H] + (retention time 1.00 min)
<工程2>8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体1)の合成
tert-ブチル 8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体1-1)(1.6g)のジクロロメタン(5.0mL)溶液にトリフルオロ酢酸(5.0mL)を加え、窒素雰囲気下、室温にて1時間撹拌した。反応溶液を減圧下留去して得られた残渣を1規定塩酸(20mL)に溶解し、酢酸エチル-ヘプタン混合溶媒(1:1)で洗浄した。得られた水層に1規定水酸化ナトリウム水溶液(30mL)と塩化ナトリウムを加えた後に、酢酸エチルで5回抽出し、抽出液を無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去して標記化合物(1.0g)を白色固体として得た。
UPLC:219[M+H]+(保持時間0.59分)
1H-NMR (CDCl3, 400MHz) δ: 6.26 (1H, s), 4.75-4.70 (2H, m), 3.13-3.07 (2H, m), 2.73-2.67 (2H, m), 2.28 (6H, s), 2.05-1.87 (4H, m). <Step 2> Synthesis of 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 1) tert-butyl 8- (4,6-dimethyl Pyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 1-1) (1.6 g) in dichloromethane (5.0 mL) in trifluoroacetic acid ( 5.0 mL) was added and stirred at room temperature for 1 hour under a nitrogen atmosphere. The residue obtained by evaporating the reaction solution under reduced pressure was dissolved in 1N hydrochloric acid (20 mL) and washed with an ethyl acetate-heptane mixed solvent (1: 1). A 1N aqueous sodium hydroxide solution (30 mL) and sodium chloride were added to the obtained aqueous layer, followed by extraction five times with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.0 g) as a white solid.
UPLC: 219 [M + H] + (retention time 0.59 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 6.26 (1H, s), 4.75-4.70 (2H, m), 3.13-3.07 (2H, m), 2.73-2.67 (2H, m), 2.28 (6H, s), 2.05-1.87 (4H, m).
tert-ブチル 8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体1-1)(1.6g)のジクロロメタン(5.0mL)溶液にトリフルオロ酢酸(5.0mL)を加え、窒素雰囲気下、室温にて1時間撹拌した。反応溶液を減圧下留去して得られた残渣を1規定塩酸(20mL)に溶解し、酢酸エチル-ヘプタン混合溶媒(1:1)で洗浄した。得られた水層に1規定水酸化ナトリウム水溶液(30mL)と塩化ナトリウムを加えた後に、酢酸エチルで5回抽出し、抽出液を無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去して標記化合物(1.0g)を白色固体として得た。
UPLC:219[M+H]+(保持時間0.59分)
1H-NMR (CDCl3, 400MHz) δ: 6.26 (1H, s), 4.75-4.70 (2H, m), 3.13-3.07 (2H, m), 2.73-2.67 (2H, m), 2.28 (6H, s), 2.05-1.87 (4H, m). <Step 2> Synthesis of 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 1) tert-butyl 8- (4,6-dimethyl Pyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 1-1) (1.6 g) in dichloromethane (5.0 mL) in trifluoroacetic acid ( 5.0 mL) was added and stirred at room temperature for 1 hour under a nitrogen atmosphere. The residue obtained by evaporating the reaction solution under reduced pressure was dissolved in 1N hydrochloric acid (20 mL) and washed with an ethyl acetate-heptane mixed solvent (1: 1). A 1N aqueous sodium hydroxide solution (30 mL) and sodium chloride were added to the obtained aqueous layer, followed by extraction five times with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.0 g) as a white solid.
UPLC: 219 [M + H] + (retention time 0.59 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 6.26 (1H, s), 4.75-4.70 (2H, m), 3.13-3.07 (2H, m), 2.73-2.67 (2H, m), 2.28 (6H, s), 2.05-1.87 (4H, m).
(製造例2)8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体2)の合成
<工程1>2-クロロ-4-ヨード-3-メトキシピリジン(中間体2-1)の合成
2-クロロ-3-メトキシピリジン(4.0g)のTHF(80mL)溶液を-78℃に冷却した後、1.6Mのn-BuLiヘキサン溶液(19mL)を徐々に加え、1時間撹拌した。その後、反応溶液にヨウ素(7.8g)を加え、さらに30分攪拌した。反応溶液を室温に戻し、飽和塩化アンモニウム水溶液を加えた後に、酢酸エチルで抽出した。有機層をチオ硫酸ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=100:0~90:10)にて精製し、標記化合物(6.0g)を無色固体として得た。
UPLC:270[M+H]+(保持時間0.99分)
1H-NMR (CDCl3, 300MHz) δ: 7.78 (1H, d, J = 5 Hz), 7.66 (1H, d, J = 5 Hz), 3.92 (3H, s). Production Example 2 Synthesis of 8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 2) <Step 1> Synthesis of 2-chloro-4-iodo-3-methoxypyridine (intermediate 2-1) A solution of 2-chloro-3-methoxypyridine (4.0 g) in THF (80 mL) was cooled to −78 ° C., then 1 .6M n-BuLi hexane solution (19 mL) was gradually added and stirred for 1 hour. Thereafter, iodine (7.8 g) was added to the reaction solution, and the mixture was further stirred for 30 minutes. The reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 90:10) to obtain the title compound (6.0 g) as a colorless solid. .
UPLC: 270 [M + H] + (retention time 0.99 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 7.78 (1H, d, J = 5 Hz), 7.66 (1H, d, J = 5 Hz), 3.92 (3H, s).
<工程1>2-クロロ-4-ヨード-3-メトキシピリジン(中間体2-1)の合成
2-クロロ-3-メトキシピリジン(4.0g)のTHF(80mL)溶液を-78℃に冷却した後、1.6Mのn-BuLiヘキサン溶液(19mL)を徐々に加え、1時間撹拌した。その後、反応溶液にヨウ素(7.8g)を加え、さらに30分攪拌した。反応溶液を室温に戻し、飽和塩化アンモニウム水溶液を加えた後に、酢酸エチルで抽出した。有機層をチオ硫酸ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=100:0~90:10)にて精製し、標記化合物(6.0g)を無色固体として得た。
UPLC:270[M+H]+(保持時間0.99分)
1H-NMR (CDCl3, 300MHz) δ: 7.78 (1H, d, J = 5 Hz), 7.66 (1H, d, J = 5 Hz), 3.92 (3H, s). Production Example 2 Synthesis of 8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 2) <Step 1> Synthesis of 2-chloro-4-iodo-3-methoxypyridine (intermediate 2-1) A solution of 2-chloro-3-methoxypyridine (4.0 g) in THF (80 mL) was cooled to −78 ° C., then 1 .6M n-BuLi hexane solution (19 mL) was gradually added and stirred for 1 hour. Thereafter, iodine (7.8 g) was added to the reaction solution, and the mixture was further stirred for 30 minutes. The reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 90:10) to obtain the title compound (6.0 g) as a colorless solid. .
UPLC: 270 [M + H] + (retention time 0.99 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 7.78 (1H, d, J = 5 Hz), 7.66 (1H, d, J = 5 Hz), 3.92 (3H, s).
<工程2>2-クロロ-3-メトキシ-4-(トリフルオロメチル)ピリジン(中間体2-2)の合成
2-クロロ-4-ヨード-3-メトキシピリジン(中間体2-1)(3.0g)、フッ化カリウム(2.1g)、ヨウ化銅(I)(3.4g)のDMF(20mL)混合液に(トリフルオロメチル)トリメチルシラン(8.3mL)を加え、窒素雰囲気下、85℃の油浴にて4時間加熱還流した。反応溶液を室温まで冷却し10%アンモニア水を加え、ジエチルエーテルで抽出した後、水ならびに飽和食塩水で洗浄した。抽出液を無水硫酸ナトリウムで乾燥した後、溶媒を減圧下留去し、得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=100:0~92:8)にて精製し、標記化合物(1.2g)を淡黄色液体として得た。
UPLC:212[M+H]+(保持時間1.01分)
1H-NMR (CDCl3, 300MHz) δ: 8.31 (1H, d, J = 5 Hz), 7.44 (1H, d, J = 5 Hz), 4.01 (3H, s). <Step 2> Synthesis of 2-chloro-3-methoxy-4- (trifluoromethyl) pyridine (intermediate 2-2) 2-chloro-4-iodo-3-methoxypyridine (intermediate 2-1) (3) (Trifluoromethyl) trimethylsilane (8.3 mL) was added to a DMF (20 mL) mixture of potassium fluoride (2.1 g) and copper (I) iodide (3.4 g) under a nitrogen atmosphere. The mixture was heated to reflux in an oil bath at 85 ° C. for 4 hours. The reaction solution was cooled to room temperature, added with 10% aqueous ammonia, extracted with diethyl ether, and then washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 92: 8) to give the title compound (1.2 g) was obtained as a pale yellow liquid.
UPLC: 212 [M + H] + (retention time 1.01 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.31 (1H, d, J = 5 Hz), 7.44 (1H, d, J = 5 Hz), 4.01 (3H, s).
2-クロロ-4-ヨード-3-メトキシピリジン(中間体2-1)(3.0g)、フッ化カリウム(2.1g)、ヨウ化銅(I)(3.4g)のDMF(20mL)混合液に(トリフルオロメチル)トリメチルシラン(8.3mL)を加え、窒素雰囲気下、85℃の油浴にて4時間加熱還流した。反応溶液を室温まで冷却し10%アンモニア水を加え、ジエチルエーテルで抽出した後、水ならびに飽和食塩水で洗浄した。抽出液を無水硫酸ナトリウムで乾燥した後、溶媒を減圧下留去し、得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=100:0~92:8)にて精製し、標記化合物(1.2g)を淡黄色液体として得た。
UPLC:212[M+H]+(保持時間1.01分)
1H-NMR (CDCl3, 300MHz) δ: 8.31 (1H, d, J = 5 Hz), 7.44 (1H, d, J = 5 Hz), 4.01 (3H, s). <Step 2> Synthesis of 2-chloro-3-methoxy-4- (trifluoromethyl) pyridine (intermediate 2-2) 2-chloro-4-iodo-3-methoxypyridine (intermediate 2-1) (3) (Trifluoromethyl) trimethylsilane (8.3 mL) was added to a DMF (20 mL) mixture of potassium fluoride (2.1 g) and copper (I) iodide (3.4 g) under a nitrogen atmosphere. The mixture was heated to reflux in an oil bath at 85 ° C. for 4 hours. The reaction solution was cooled to room temperature, added with 10% aqueous ammonia, extracted with diethyl ether, and then washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 92: 8) to give the title compound (1.2 g) was obtained as a pale yellow liquid.
UPLC: 212 [M + H] + (retention time 1.01 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.31 (1H, d, J = 5 Hz), 7.44 (1H, d, J = 5 Hz), 4.01 (3H, s).
<工程3>tert-ブチル 8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体2-3)の合成
tert-ブチル 3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(0.89g)、2-クロロ-3-メトキシ-4-(トリフルオロメチル)ピリジン(中間体2-2)(0.88g)、ナトリウム tert-ブトキシド(0.48g)、RuPhos(60mg)のTHF(10mL)混合液にRuPhos Pd G2(0.10g)を加え、窒素雰囲気下、90℃で3.5時間攪拌した。反応溶液を室温へ冷却し、水を加え、酢酸エチルで抽出した後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=100:0~85:15)にて精製し、標記化合物(0.85g)を黄色液体として得た。
UPLC:410[M+Na]+(保持時間1.24分) <Step 3> tert-Butyl 8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (Intermediate 2) -3) Synthesis of tert-butyl 3,8-diazabicyclo [3.2.1] octane-3-carboxylate (0.89 g), 2-chloro-3-methoxy-4- (trifluoromethyl) pyridine (intermediate) Body 2-2) (0.88 g), sodium tert-butoxide (0.48 g), RuPhos (60 mg) in THF (10 mL) was added RuPhos Pd G2 (0.10 g), and the mixture was heated at 90 ° C. under a nitrogen atmosphere. For 3.5 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 85:15) to obtain the title compound (0.85 g) as a yellow liquid. .
UPLC: 410 [M + Na] + (retention time 1.24 minutes)
tert-ブチル 3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(0.89g)、2-クロロ-3-メトキシ-4-(トリフルオロメチル)ピリジン(中間体2-2)(0.88g)、ナトリウム tert-ブトキシド(0.48g)、RuPhos(60mg)のTHF(10mL)混合液にRuPhos Pd G2(0.10g)を加え、窒素雰囲気下、90℃で3.5時間攪拌した。反応溶液を室温へ冷却し、水を加え、酢酸エチルで抽出した後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=100:0~85:15)にて精製し、標記化合物(0.85g)を黄色液体として得た。
UPLC:410[M+Na]+(保持時間1.24分) <Step 3> tert-Butyl 8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (Intermediate 2) -3) Synthesis of tert-butyl 3,8-diazabicyclo [3.2.1] octane-3-carboxylate (0.89 g), 2-chloro-3-methoxy-4- (trifluoromethyl) pyridine (intermediate) Body 2-2) (0.88 g), sodium tert-butoxide (0.48 g), RuPhos (60 mg) in THF (10 mL) was added RuPhos Pd G2 (0.10 g), and the mixture was heated at 90 ° C. under a nitrogen atmosphere. For 3.5 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 85:15) to obtain the title compound (0.85 g) as a yellow liquid. .
UPLC: 410 [M + Na] + (retention time 1.24 minutes)
<工程4>8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体2)の合成
tert-ブチル 8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体2-3)(0.85g)にトリフルオロ酢酸(4.0mL)を加え、窒素雰囲気下、室温にて1時間撹拌した。反応溶液を減圧下留去して得られた残渣に酢酸エチル-ヘプタン混合溶媒(1:1)を加え、1規定塩酸で3回抽出した。得られた水層に1規定水酸化ナトリウム水溶液と塩化ナトリウムを加えた後に、酢酸エチルで5回抽出し、抽出液を無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去して標記化合物(0.56g)を淡紫色液体として得た。
UPLC:288[M+H]+(保持時間0.83分)
1H-NMR (CDCl3, 400MHz) δ: 8.03 (1H, d, J = 5 Hz), 6.86 (1H, d, J = 5 Hz), 4.59-4.52 (2H, m), 3.78 (3H, s), 3.21-3.15 (2H, m), 2.74-2.68 (2H, m), 2.00-1.87 (4H, m). <Step 4> Synthesis of 8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 2) tert-butyl 8- To (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 2-3) (0.85 g) Trifluoroacetic acid (4.0 mL) was added, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction solution was evaporated under reduced pressure, an ethyl acetate-heptane mixed solvent (1: 1) was added to the resulting residue, and the mixture was extracted 3 times with 1N hydrochloric acid. A 1N aqueous sodium hydroxide solution and sodium chloride were added to the resulting aqueous layer, followed by extraction five times with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.56 g) as a pale purple liquid.
UPLC: 288 [M + H] + (retention time 0.83 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.03 (1H, d, J = 5 Hz), 6.86 (1H, d, J = 5 Hz), 4.59-4.52 (2H, m), 3.78 (3H, s ), 3.21-3.15 (2H, m), 2.74-2.68 (2H, m), 2.00-1.87 (4H, m).
tert-ブチル 8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体2-3)(0.85g)にトリフルオロ酢酸(4.0mL)を加え、窒素雰囲気下、室温にて1時間撹拌した。反応溶液を減圧下留去して得られた残渣に酢酸エチル-ヘプタン混合溶媒(1:1)を加え、1規定塩酸で3回抽出した。得られた水層に1規定水酸化ナトリウム水溶液と塩化ナトリウムを加えた後に、酢酸エチルで5回抽出し、抽出液を無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去して標記化合物(0.56g)を淡紫色液体として得た。
UPLC:288[M+H]+(保持時間0.83分)
1H-NMR (CDCl3, 400MHz) δ: 8.03 (1H, d, J = 5 Hz), 6.86 (1H, d, J = 5 Hz), 4.59-4.52 (2H, m), 3.78 (3H, s), 3.21-3.15 (2H, m), 2.74-2.68 (2H, m), 2.00-1.87 (4H, m). <Step 4> Synthesis of 8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 2) tert-butyl 8- To (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 2-3) (0.85 g) Trifluoroacetic acid (4.0 mL) was added, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction solution was evaporated under reduced pressure, an ethyl acetate-heptane mixed solvent (1: 1) was added to the resulting residue, and the mixture was extracted 3 times with 1N hydrochloric acid. A 1N aqueous sodium hydroxide solution and sodium chloride were added to the resulting aqueous layer, followed by extraction five times with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.56 g) as a pale purple liquid.
UPLC: 288 [M + H] + (retention time 0.83 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.03 (1H, d, J = 5 Hz), 6.86 (1H, d, J = 5 Hz), 4.59-4.52 (2H, m), 3.78 (3H, s ), 3.21-3.15 (2H, m), 2.74-2.68 (2H, m), 2.00-1.87 (4H, m).
(製造例3)2-(3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(中間体3)の合成
<工程1>2-クロロ-3-メトキシイソニコチン酸(中間体3-1)の合成
2-クロロ-3-メトキシピリジン(5.2g)のTHF(100mL)溶液を-78℃に冷却した後、1.6Mのn-BuLiヘキサン溶液(25mL)を徐々に加え、1時間撹拌した。その後、反応溶液にドライアイスを加え、徐々に室温まで昇温した。飽和塩化アンモニウム水溶液を加えてpH=6とした後に、酢酸エチルで逆抽出を行った。水層に1規定塩酸を加えてpH=2とし、析出した固体を濾取した後、減圧下乾燥を行い、標記化合物(6.3g)を無色固体として得た。
UPLC:188[M+H]+(保持時間0.71分)
1H-NMR (DMSO-d6, 300MHz) δ: 8.26 (1H, d, J = 5 Hz), 7.62 (1H, d, J = 5 Hz), 3.87 (3H, s). Production Example 3 Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (Intermediate 3) <Step 1> 2-Chloro-3 Synthesis of -methoxyisonicotinic acid (intermediate 3-1) A solution of 2-chloro-3-methoxypyridine (5.2 g) in THF (100 mL) was cooled to -78 ° C, and then 1.6 M n-BuLi hexane The solution (25 mL) was added slowly and stirred for 1 hour. Thereafter, dry ice was added to the reaction solution, and the temperature was gradually raised to room temperature. A saturated aqueous ammonium chloride solution was added to adjust to pH = 6, and then back extraction was performed with ethyl acetate. 1N Hydrochloric acid was added to the aqueous layer to adjust to pH = 2, and the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (6.3 g) as a colorless solid.
UPLC: 188 [M + H] + (retention time 0.71 minutes)
1 H-NMR (DMSO-d 6 , 300 MHz) δ: 8.26 (1H, d, J = 5 Hz), 7.62 (1H, d, J = 5 Hz), 3.87 (3H, s).
<工程1>2-クロロ-3-メトキシイソニコチン酸(中間体3-1)の合成
2-クロロ-3-メトキシピリジン(5.2g)のTHF(100mL)溶液を-78℃に冷却した後、1.6Mのn-BuLiヘキサン溶液(25mL)を徐々に加え、1時間撹拌した。その後、反応溶液にドライアイスを加え、徐々に室温まで昇温した。飽和塩化アンモニウム水溶液を加えてpH=6とした後に、酢酸エチルで逆抽出を行った。水層に1規定塩酸を加えてpH=2とし、析出した固体を濾取した後、減圧下乾燥を行い、標記化合物(6.3g)を無色固体として得た。
UPLC:188[M+H]+(保持時間0.71分)
1H-NMR (DMSO-d6, 300MHz) δ: 8.26 (1H, d, J = 5 Hz), 7.62 (1H, d, J = 5 Hz), 3.87 (3H, s). Production Example 3 Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (Intermediate 3) <Step 1> 2-Chloro-3 Synthesis of -methoxyisonicotinic acid (intermediate 3-1) A solution of 2-chloro-3-methoxypyridine (5.2 g) in THF (100 mL) was cooled to -78 ° C, and then 1.6 M n-BuLi hexane The solution (25 mL) was added slowly and stirred for 1 hour. Thereafter, dry ice was added to the reaction solution, and the temperature was gradually raised to room temperature. A saturated aqueous ammonium chloride solution was added to adjust to pH = 6, and then back extraction was performed with ethyl acetate. 1N Hydrochloric acid was added to the aqueous layer to adjust to pH = 2, and the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (6.3 g) as a colorless solid.
UPLC: 188 [M + H] + (retention time 0.71 minutes)
1 H-NMR (DMSO-d 6 , 300 MHz) δ: 8.26 (1H, d, J = 5 Hz), 7.62 (1H, d, J = 5 Hz), 3.87 (3H, s).
<工程2>2-クロロ-3-メトキシイソニコチンアミド(中間体3-2)の合成
2-クロロ-3-メトキシイソニコチン酸(中間体3-1)(6.8g)、ピリジン(15mL)、炭酸水素アンモニウム(14g)の1,4-ジオキサン(100mL)混合溶液に二炭酸ジ-tert-ブチル(13mL)を加え、室温で1時間攪拌した。反応溶液に0.1規定塩酸水溶液を加えて中和した後、酢酸エチルで2回、抽出を行った。有機層を無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去して、標記化合物の粗生成物(7.5g)を、無色固体として得た。
UPLC:187[M+H]+(保持時間0.61分) <Step 2> Synthesis of 2-chloro-3-methoxyisonicotinamide (Intermediate 3-2) 2-Chloro-3-methoxyisonicotinic acid (Intermediate 3-1) (6.8 g), pyridine (15 mL) To a mixed solution of ammonium hydrogen carbonate (14 g) in 1,4-dioxane (100 mL) was added di-tert-butyl dicarbonate (13 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with 0.1N aqueous hydrochloric acid solution, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product (7.5 g) of the title compound as a colorless solid.
UPLC: 187 [M + H] + (retention time 0.61 minutes)
2-クロロ-3-メトキシイソニコチン酸(中間体3-1)(6.8g)、ピリジン(15mL)、炭酸水素アンモニウム(14g)の1,4-ジオキサン(100mL)混合溶液に二炭酸ジ-tert-ブチル(13mL)を加え、室温で1時間攪拌した。反応溶液に0.1規定塩酸水溶液を加えて中和した後、酢酸エチルで2回、抽出を行った。有機層を無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去して、標記化合物の粗生成物(7.5g)を、無色固体として得た。
UPLC:187[M+H]+(保持時間0.61分) <Step 2> Synthesis of 2-chloro-3-methoxyisonicotinamide (Intermediate 3-2) 2-Chloro-3-methoxyisonicotinic acid (Intermediate 3-1) (6.8 g), pyridine (15 mL) To a mixed solution of ammonium hydrogen carbonate (14 g) in 1,4-dioxane (100 mL) was added di-tert-butyl dicarbonate (13 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with 0.1N aqueous hydrochloric acid solution, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product (7.5 g) of the title compound as a colorless solid.
UPLC: 187 [M + H] + (retention time 0.61 minutes)
<工程3>2-クロロ-3-メトキシイソニコチノニトリル(中間体3-3)の合成
製造例3の工程2で得た2-クロロ-3-メトキシイソニコチンアミド(中間体3-2)の粗生成物(7.4g)、トリエチルアミン(15mL)のジクロロメタン(66mL)混合溶液を0℃に冷却した後、無水トリフルオロ酢酸(7.5mL)を徐々に加え、反応溶液を0℃で30分間撹拌した。反応溶液を室温に戻した後に飽和炭酸水素ナトリウム水溶液を加え、ジエチルエーテルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去して得られた残渣を、カラムクロマトグラフィー(NHシリカゲル、ヘプタン:酢酸エチル=100:0~90:10)にて精製し、標記化合物(4.8g)を無色固体として得た。
UPLC:169[M+H]+(保持時間0.83分)
1H-NMR (CDCl3, 300MHz) δ: 8.24 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz), 4.17 (3H, s). <Step 3> Synthesis of 2-chloro-3-methoxyisonicotinonitrile (Intermediate 3-3) 2-Chloro-3-methoxyisonicotinamide (Intermediate 3-2) obtained in Step 2 of Production Example 3 After cooling a mixed solution of crude product (7.4 g) and triethylamine (15 mL) in dichloromethane (66 mL) to 0 ° C., trifluoroacetic anhydride (7.5 mL) was gradually added, and the reaction solution was stirred at 0 ° C. for 30 minutes. Stir for minutes. After returning the reaction solution to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with diethyl ether. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (NH silica gel, heptane: ethyl acetate = 100: 0 to 90:10), The title compound (4.8 g) was obtained as a colorless solid.
UPLC: 169 [M + H] + (retention time 0.83 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.24 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz), 4.17 (3H, s).
製造例3の工程2で得た2-クロロ-3-メトキシイソニコチンアミド(中間体3-2)の粗生成物(7.4g)、トリエチルアミン(15mL)のジクロロメタン(66mL)混合溶液を0℃に冷却した後、無水トリフルオロ酢酸(7.5mL)を徐々に加え、反応溶液を0℃で30分間撹拌した。反応溶液を室温に戻した後に飽和炭酸水素ナトリウム水溶液を加え、ジエチルエーテルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去して得られた残渣を、カラムクロマトグラフィー(NHシリカゲル、ヘプタン:酢酸エチル=100:0~90:10)にて精製し、標記化合物(4.8g)を無色固体として得た。
UPLC:169[M+H]+(保持時間0.83分)
1H-NMR (CDCl3, 300MHz) δ: 8.24 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz), 4.17 (3H, s). <Step 3> Synthesis of 2-chloro-3-methoxyisonicotinonitrile (Intermediate 3-3) 2-Chloro-3-methoxyisonicotinamide (Intermediate 3-2) obtained in Step 2 of Production Example 3 After cooling a mixed solution of crude product (7.4 g) and triethylamine (15 mL) in dichloromethane (66 mL) to 0 ° C., trifluoroacetic anhydride (7.5 mL) was gradually added, and the reaction solution was stirred at 0 ° C. for 30 minutes. Stir for minutes. After returning the reaction solution to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with diethyl ether. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (NH silica gel, heptane: ethyl acetate = 100: 0 to 90:10), The title compound (4.8 g) was obtained as a colorless solid.
UPLC: 169 [M + H] + (retention time 0.83 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.24 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz), 4.17 (3H, s).
<工程4>tert-ブチル 8-(4-シアノ-3-メトキシピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体3-4)の合成
2-クロロ-3-メトキシイソニコチノニトリル(中間体3-3)(0.87g)、tert-ブチル 3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(1.0g)、RuPhos(0.22g)、炭酸セシウム(2.3g)のテトラヒドロフラン(10mL)混合溶液に、RuPhos Pd G2(0.37g)を加え、窒素雰囲気下、90℃にて15時間撹拌した。反応溶液を室温に戻した後に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去して得られた残渣を、カラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=90:10~84:16)にて精製し、標記化合物(1.1g)を黄色液体として得た。
UPLC:367[M+Na]+(保持時間1.15分)
1H-NMR (CDCl3, 300MHz) δ: 7.99 (1H, d, J = 5 Hz), 6.83 (1H, d, J = 5 Hz), 4.73-4.61 (2H, m), 3.92 (3H, s), 3.91-3.66 (2H, m), 3.27-3.08 (2H, m), 1.99-1.76 (4H, m), 1.46 (9H, s). <Step 4> of tert-butyl 8- (4-cyano-3-methoxypyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 3-4) Synthesis 2-chloro-3-methoxyisonicotinonitrile (intermediate 3-3) (0.87 g), tert-butyl 3,8-diazabicyclo [3.2.1] octane-3-carboxylate (1.0 g ), RuPhos (0.22 g) and cesium carbonate (2.3 g) in a tetrahydrofuran (10 mL) mixed solution were added RuPhos Pd G2 (0.37 g), and the mixture was stirred at 90 ° C. for 15 hours in a nitrogen atmosphere. The reaction solution was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 90: 10 to 84:16) Compound (1.1 g) was obtained as a yellow liquid.
UPLC: 367 [M + Na] + (retention time 1.15 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 7.99 (1H, d, J = 5 Hz), 6.83 (1H, d, J = 5 Hz), 4.73-4.61 (2H, m), 3.92 (3H, s ), 3.91-3.66 (2H, m), 3.27-3.08 (2H, m), 1.99-1.76 (4H, m), 1.46 (9H, s).
2-クロロ-3-メトキシイソニコチノニトリル(中間体3-3)(0.87g)、tert-ブチル 3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(1.0g)、RuPhos(0.22g)、炭酸セシウム(2.3g)のテトラヒドロフラン(10mL)混合溶液に、RuPhos Pd G2(0.37g)を加え、窒素雰囲気下、90℃にて15時間撹拌した。反応溶液を室温に戻した後に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去して得られた残渣を、カラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=90:10~84:16)にて精製し、標記化合物(1.1g)を黄色液体として得た。
UPLC:367[M+Na]+(保持時間1.15分)
1H-NMR (CDCl3, 300MHz) δ: 7.99 (1H, d, J = 5 Hz), 6.83 (1H, d, J = 5 Hz), 4.73-4.61 (2H, m), 3.92 (3H, s), 3.91-3.66 (2H, m), 3.27-3.08 (2H, m), 1.99-1.76 (4H, m), 1.46 (9H, s). <Step 4> of tert-butyl 8- (4-cyano-3-methoxypyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 3-4) Synthesis 2-chloro-3-methoxyisonicotinonitrile (intermediate 3-3) (0.87 g), tert-butyl 3,8-diazabicyclo [3.2.1] octane-3-carboxylate (1.0 g ), RuPhos (0.22 g) and cesium carbonate (2.3 g) in a tetrahydrofuran (10 mL) mixed solution were added RuPhos Pd G2 (0.37 g), and the mixture was stirred at 90 ° C. for 15 hours in a nitrogen atmosphere. The reaction solution was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 90: 10 to 84:16) Compound (1.1 g) was obtained as a yellow liquid.
UPLC: 367 [M + Na] + (retention time 1.15 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 7.99 (1H, d, J = 5 Hz), 6.83 (1H, d, J = 5 Hz), 4.73-4.61 (2H, m), 3.92 (3H, s ), 3.91-3.66 (2H, m), 3.27-3.08 (2H, m), 1.99-1.76 (4H, m), 1.46 (9H, s).
<工程5>2-(3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(中間体3)の合成
製造例2の工程4と同様の方法もしくは、これに準ずる方法でtert-ブチル 8-(4-シアノ-3-メトキシピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体3-4)(1.1g)を用いて標記化合物(0.75g)を黄色液体として得た。
UPLC:245[M+H]+(保持時間0.66分)
1H-NMR (CDCl3, 300MHz) δ: 8.00 (1H, d, J = 5 Hz), 6.85 (1H, d, J = 5 Hz), 4.70-4.64 (2H, m), 3.92 (3H, s), 3.28-3.18 (2H, m), 2.93-2.81 (2H, m), 2.13-2.00 (4H, m). <Step 5> Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (Intermediate 3) The same method as in Step 4 of Production Example 2 Alternatively, tert-butyl 8- (4-cyano-3-methoxypyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 3- 4) The title compound (0.75 g) was obtained as a yellow liquid using (1.1 g).
UPLC: 245 [M + H] + (retention time 0.66 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.00 (1H, d, J = 5 Hz), 6.85 (1H, d, J = 5 Hz), 4.70-4.64 (2H, m), 3.92 (3H, s ), 3.28-3.18 (2H, m), 2.93-2.81 (2H, m), 2.13-2.00 (4H, m).
製造例2の工程4と同様の方法もしくは、これに準ずる方法でtert-ブチル 8-(4-シアノ-3-メトキシピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体3-4)(1.1g)を用いて標記化合物(0.75g)を黄色液体として得た。
UPLC:245[M+H]+(保持時間0.66分)
1H-NMR (CDCl3, 300MHz) δ: 8.00 (1H, d, J = 5 Hz), 6.85 (1H, d, J = 5 Hz), 4.70-4.64 (2H, m), 3.92 (3H, s), 3.28-3.18 (2H, m), 2.93-2.81 (2H, m), 2.13-2.00 (4H, m). <Step 5> Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (Intermediate 3) The same method as in Step 4 of Production Example 2 Alternatively, tert-butyl 8- (4-cyano-3-methoxypyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 3- 4) The title compound (0.75 g) was obtained as a yellow liquid using (1.1 g).
UPLC: 245 [M + H] + (retention time 0.66 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.00 (1H, d, J = 5 Hz), 6.85 (1H, d, J = 5 Hz), 4.70-4.64 (2H, m), 3.92 (3H, s ), 3.28-3.18 (2H, m), 2.93-2.81 (2H, m), 2.13-2.00 (4H, m).
(製造例4)2-(3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(中間体4)の合成
<工程1>tert-ブチル 8-(4-シアノピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体4-1)の合成
2-フルオロイソニコチノニトリル(1.0g)、tert-ブチル 3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(2.1g)、DIPEA(4.3mL)の1-プロパノール(8.2mL)混合溶液を窒素雰囲気下、100℃にて23時間撹拌した。反応溶液を室温へ冷却し、減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=94:6~50:50)にて精製し、標記化合物(1.6g)を淡黄色液体として得た。
UPLC:337[M+Na]+(保持時間1.08分) Production Example 4 Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Intermediate 4) <Step 1> tert-Butyl 8- (4-cyano Synthesis of Pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (Intermediate 4-1) 2-fluoroisonicotinonitrile (1.0 g), tert-butyl A mixed solution of 3,8-diazabicyclo [3.2.1] octane-3-carboxylate (2.1 g) and DIPEA (4.3 mL) in 1-propanol (8.2 mL) at 100 ° C. under a nitrogen atmosphere. Stir for 23 hours. The reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 94: 6 to 50:50) to give the title compound (1. 6 g) was obtained as a pale yellow liquid.
UPLC: 337 [M + Na] + (retention time 1.08 minutes)
<工程1>tert-ブチル 8-(4-シアノピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体4-1)の合成
2-フルオロイソニコチノニトリル(1.0g)、tert-ブチル 3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(2.1g)、DIPEA(4.3mL)の1-プロパノール(8.2mL)混合溶液を窒素雰囲気下、100℃にて23時間撹拌した。反応溶液を室温へ冷却し、減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=94:6~50:50)にて精製し、標記化合物(1.6g)を淡黄色液体として得た。
UPLC:337[M+Na]+(保持時間1.08分) Production Example 4 Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Intermediate 4) <Step 1> tert-Butyl 8- (4-cyano Synthesis of Pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (Intermediate 4-1) 2-fluoroisonicotinonitrile (1.0 g), tert-butyl A mixed solution of 3,8-diazabicyclo [3.2.1] octane-3-carboxylate (2.1 g) and DIPEA (4.3 mL) in 1-propanol (8.2 mL) at 100 ° C. under a nitrogen atmosphere. Stir for 23 hours. The reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 94: 6 to 50:50) to give the title compound (1. 6 g) was obtained as a pale yellow liquid.
UPLC: 337 [M + Na] + (retention time 1.08 minutes)
<工程2>2-(3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(中間体4)の合成
tert-ブチル 8-(4-シアノピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体4-1)(1.6g)と4M塩化水素-酢酸エチル(25mL)の混合溶液を窒素雰囲気下、室温にて10分撹拌した。溶媒を減圧下留去して得られた残渣を2規定水酸化ナトリウム水溶液でpH=10~12にした後、ジクロロメタン-イソプロパノール混合溶媒(3:1)で5回抽出した。集めた抽出液を無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去して標記化合物(0.38g)を黄色固体として得た。
UPLC:215[M+H]+(保持時間0.61分)
1H-NMR (CDCl3, 400MHz) δ: 8.24 (1H, dd, J = 5, 1 Hz), 6.69-6.68 (1H, m), 6.67 (1H, dd, J = 5, 1 Hz), 4.45-4.40 (2H, m), 3.08 (2H, dd, J = 12, 1 Hz), 2.71-2.64 (2H, m), 2.08-1.95 (4H, m). <Step 2> Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (intermediate 4) tert-butyl 8- (4-cyanopyridin-2-yl ) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 4-1) (1.6 g) and 4M hydrogen chloride-ethyl acetate (25 mL) in a nitrogen atmosphere. Stir at room temperature for 10 minutes. The residue obtained by evaporating the solvent under reduced pressure was adjusted to pH = 10-12 with 2N aqueous sodium hydroxide solution, and then extracted five times with a dichloromethane-isopropanol mixed solvent (3: 1). The collected extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.38 g) as a yellow solid.
UPLC: 215 [M + H] + (retention time 0.61 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.24 (1H, dd, J = 5, 1 Hz), 6.69-6.68 (1H, m), 6.67 (1H, dd, J = 5, 1 Hz), 4.45 -4.40 (2H, m), 3.08 (2H, dd, J = 12, 1 Hz), 2.71-2.64 (2H, m), 2.08-1.95 (4H, m).
tert-ブチル 8-(4-シアノピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体4-1)(1.6g)と4M塩化水素-酢酸エチル(25mL)の混合溶液を窒素雰囲気下、室温にて10分撹拌した。溶媒を減圧下留去して得られた残渣を2規定水酸化ナトリウム水溶液でpH=10~12にした後、ジクロロメタン-イソプロパノール混合溶媒(3:1)で5回抽出した。集めた抽出液を無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去して標記化合物(0.38g)を黄色固体として得た。
UPLC:215[M+H]+(保持時間0.61分)
1H-NMR (CDCl3, 400MHz) δ: 8.24 (1H, dd, J = 5, 1 Hz), 6.69-6.68 (1H, m), 6.67 (1H, dd, J = 5, 1 Hz), 4.45-4.40 (2H, m), 3.08 (2H, dd, J = 12, 1 Hz), 2.71-2.64 (2H, m), 2.08-1.95 (4H, m). <Step 2> Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (intermediate 4) tert-butyl 8- (4-cyanopyridin-2-yl ) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 4-1) (1.6 g) and 4M hydrogen chloride-ethyl acetate (25 mL) in a nitrogen atmosphere. Stir at room temperature for 10 minutes. The residue obtained by evaporating the solvent under reduced pressure was adjusted to pH = 10-12 with 2N aqueous sodium hydroxide solution, and then extracted five times with a dichloromethane-isopropanol mixed solvent (3: 1). The collected extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.38 g) as a yellow solid.
UPLC: 215 [M + H] + (retention time 0.61 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.24 (1H, dd, J = 5, 1 Hz), 6.69-6.68 (1H, m), 6.67 (1H, dd, J = 5, 1 Hz), 4.45 -4.40 (2H, m), 3.08 (2H, dd, J = 12, 1 Hz), 2.71-2.64 (2H, m), 2.08-1.95 (4H, m).
(製造例5)8-(4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体5)の合成
<工程1>tert-ブチル 8-(4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体5-1)の合成
tert-ブチル 3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(2.1g)、2-ブロモ-4-(トリフルオロメチル)ピリジン(2.3g)、ナトリウム tert-ブトキシド(1.9g)、Pd2(dba)3(0.46g)、BINAP(0.62g)のトルエン(30mL)混合液を脱気後、窒素雰囲気下90℃で2時間攪拌した。反応液をセライトでろ過してろ液を減圧下濃縮後、残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=95:5~85:15)にて精製し、標記化合物(2.9g)を黄色液体として得た。
UPLC:380[M+Na]+(保持時間1.18分) Production Example 5 Synthesis of 8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 5) <Step 1> tert-Butyl 8 Synthesis of — (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 5-1) tert-butyl 3,8- Diazabicyclo [3.2.1] octane-3-carboxylate (2.1 g), 2-bromo-4- (trifluoromethyl) pyridine (2.3 g), sodium tert-butoxide (1.9 g), Pd 2 A toluene (30 mL) mixed solution of (dba) 3 (0.46 g) and BINAP (0.62 g) was deaerated and then stirred at 90 ° C. for 2 hours in a nitrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 95: 5 to 85:15) to give the title compound (2.9 g) as yellow. Obtained as a liquid.
UPLC: 380 [M + Na] + (retention time 1.18 minutes)
<工程1>tert-ブチル 8-(4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体5-1)の合成
tert-ブチル 3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(2.1g)、2-ブロモ-4-(トリフルオロメチル)ピリジン(2.3g)、ナトリウム tert-ブトキシド(1.9g)、Pd2(dba)3(0.46g)、BINAP(0.62g)のトルエン(30mL)混合液を脱気後、窒素雰囲気下90℃で2時間攪拌した。反応液をセライトでろ過してろ液を減圧下濃縮後、残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=95:5~85:15)にて精製し、標記化合物(2.9g)を黄色液体として得た。
UPLC:380[M+Na]+(保持時間1.18分) Production Example 5 Synthesis of 8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 5) <Step 1> tert-Butyl 8 Synthesis of — (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 5-1) tert-butyl 3,8- Diazabicyclo [3.2.1] octane-3-carboxylate (2.1 g), 2-bromo-4- (trifluoromethyl) pyridine (2.3 g), sodium tert-butoxide (1.9 g), Pd 2 A toluene (30 mL) mixed solution of (dba) 3 (0.46 g) and BINAP (0.62 g) was deaerated and then stirred at 90 ° C. for 2 hours in a nitrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 95: 5 to 85:15) to give the title compound (2.9 g) as yellow. Obtained as a liquid.
UPLC: 380 [M + Na] + (retention time 1.18 minutes)
<工程2>8-(4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体5)の合成
製造例1の工程2と同様の方法もしくは、これに準ずる方法でtert-ブチル 8-(4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体5-1)(2.9g)を用いて標記化合物(2.0g)を黄色固体として得た。
UPLC:258[M+H]+(保持時間0.74分)
1H-NMR (CDCl3, 400MHz) δ: 8.26 (1H, d, J = 5 Hz), 6.69 (1H, d, J = 5 Hz), 6.67 (1H, s), 4.53-4.42 (2H, m), 3.15-3.07 (2H, m), 2.72-2.64 (2H, m), 2.11-1.94 (4H, m). <Step 2> Synthesis of 8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 5) Similar to step 2 of Production Example 1 Tert-Butyl 8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (Intermediate 5) -1) The title compound (2.0 g) was obtained as a yellow solid using (2.9 g).
UPLC: 258 [M + H] + (retention time 0.74 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.26 (1H, d, J = 5 Hz), 6.69 (1H, d, J = 5 Hz), 6.67 (1H, s), 4.53-4.42 (2H, m ), 3.15-3.07 (2H, m), 2.72-2.64 (2H, m), 2.11-1.94 (4H, m).
製造例1の工程2と同様の方法もしくは、これに準ずる方法でtert-ブチル 8-(4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体5-1)(2.9g)を用いて標記化合物(2.0g)を黄色固体として得た。
UPLC:258[M+H]+(保持時間0.74分)
1H-NMR (CDCl3, 400MHz) δ: 8.26 (1H, d, J = 5 Hz), 6.69 (1H, d, J = 5 Hz), 6.67 (1H, s), 4.53-4.42 (2H, m), 3.15-3.07 (2H, m), 2.72-2.64 (2H, m), 2.11-1.94 (4H, m). <Step 2> Synthesis of 8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 5) Similar to step 2 of Production Example 1 Tert-Butyl 8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (Intermediate 5) -1) The title compound (2.0 g) was obtained as a yellow solid using (2.9 g).
UPLC: 258 [M + H] + (retention time 0.74 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.26 (1H, d, J = 5 Hz), 6.69 (1H, d, J = 5 Hz), 6.67 (1H, s), 4.53-4.42 (2H, m ), 3.15-3.07 (2H, m), 2.72-2.64 (2H, m), 2.11-1.94 (4H, m).
(製造例6)2-(3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-クロロイソニコチノニトリル(中間体6)の合成
<工程1>tert-ブチル 8-(3-クロロ-4-シアノピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体6-1)の合成
2,3-ジクロロイソニコチン酸(0.41g)、tert-ブチル 3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(0.42g)のDMSO(10mL)混合溶液に、炭酸カリウム(1.1g)を加え、150℃にて3時間撹拌した。反応溶液を室温に戻した後に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去して標記化合物の粗生成物(1.0g)を茶色固体として得た。
1H-NMR (CDCl3, 300MHz) δ: 8.18 (1H, d, J = 5 Hz), 7.00 (1H, d, J = 5 Hz), 4.66-4.33 (2H, m), 3.97-3.63 (2H, m), 3.53-2.85 (2H, m), 1.98-1.62 (4H, m), 1.51-1.42 (9H, m). Production Example 6 Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-chloroisonicotinonitrile (Intermediate 6) <Step 1> tert-Butyl 8- Synthesis of (3-chloro-4-cyanopyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 6-1) 2,3-dichloroisonicotinic acid (0.41 g), tert-butyl 3,8-diazabicyclo [3.2.1] octane-3-carboxylate (0.42 g) in DMSO (10 mL) mixed solution was added potassium carbonate (1.1 g). , And stirred at 150 ° C. for 3 hours. The reaction solution was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (1.0 g) of the title compound as a brown solid.
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.18 (1H, d, J = 5 Hz), 7.00 (1H, d, J = 5 Hz), 4.66-4.33 (2H, m), 3.97-3.63 (2H , m), 3.53-2.85 (2H, m), 1.98-1.62 (4H, m), 1.51-1.42 (9H, m).
<工程1>tert-ブチル 8-(3-クロロ-4-シアノピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体6-1)の合成
2,3-ジクロロイソニコチン酸(0.41g)、tert-ブチル 3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(0.42g)のDMSO(10mL)混合溶液に、炭酸カリウム(1.1g)を加え、150℃にて3時間撹拌した。反応溶液を室温に戻した後に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去して標記化合物の粗生成物(1.0g)を茶色固体として得た。
1H-NMR (CDCl3, 300MHz) δ: 8.18 (1H, d, J = 5 Hz), 7.00 (1H, d, J = 5 Hz), 4.66-4.33 (2H, m), 3.97-3.63 (2H, m), 3.53-2.85 (2H, m), 1.98-1.62 (4H, m), 1.51-1.42 (9H, m). Production Example 6 Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-chloroisonicotinonitrile (Intermediate 6) <Step 1> tert-Butyl 8- Synthesis of (3-chloro-4-cyanopyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 6-1) 2,3-dichloroisonicotinic acid (0.41 g), tert-butyl 3,8-diazabicyclo [3.2.1] octane-3-carboxylate (0.42 g) in DMSO (10 mL) mixed solution was added potassium carbonate (1.1 g). , And stirred at 150 ° C. for 3 hours. The reaction solution was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (1.0 g) of the title compound as a brown solid.
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.18 (1H, d, J = 5 Hz), 7.00 (1H, d, J = 5 Hz), 4.66-4.33 (2H, m), 3.97-3.63 (2H , m), 3.53-2.85 (2H, m), 1.98-1.62 (4H, m), 1.51-1.42 (9H, m).
<工程2>2-(3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-クロロイソニコチノニトリル(中間体6)の合成
製造例6の工程1で得たtert-ブチル 8-(3-クロロ-4-シアノピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体6-1)の粗生成物(1.0g)を用いて、製造例2の工程4と同様の方法もしくは、これに準ずる方法で、標記化合物(0.16g)の粗生成物を茶色液体として得た。
UPLC:249[M+H]+(保持時間0.69分)
1H-NMR (CDCl3, 300MHz) δ: 8.17 (1H, d, J = 5 Hz), 6.95 (1H, d, J = 5 Hz), 4.55-4.49 (2H, m), 3.24-3.16 (2H, m), 2.80-2.72 (2H, m), 2.02-1.86 (4H, m). <Step 2> Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-chloroisonicotinonitrile (intermediate 6) tert obtained in Step 1 of Production Example 6 -Butyl 8- (3-chloro-4-cyanopyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 6-1) crude product (1 The crude product of the title compound (0.16 g) was obtained as a brown liquid in the same manner as in Step 4 of Production Example 2 or a method analogous thereto.
UPLC: 249 [M + H] + (retention time 0.69 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.17 (1H, d, J = 5 Hz), 6.95 (1H, d, J = 5 Hz), 4.55-4.49 (2H, m), 3.24-3.16 (2H , m), 2.80-2.72 (2H, m), 2.02-1.86 (4H, m).
製造例6の工程1で得たtert-ブチル 8-(3-クロロ-4-シアノピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体6-1)の粗生成物(1.0g)を用いて、製造例2の工程4と同様の方法もしくは、これに準ずる方法で、標記化合物(0.16g)の粗生成物を茶色液体として得た。
UPLC:249[M+H]+(保持時間0.69分)
1H-NMR (CDCl3, 300MHz) δ: 8.17 (1H, d, J = 5 Hz), 6.95 (1H, d, J = 5 Hz), 4.55-4.49 (2H, m), 3.24-3.16 (2H, m), 2.80-2.72 (2H, m), 2.02-1.86 (4H, m). <Step 2> Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-chloroisonicotinonitrile (intermediate 6) tert obtained in Step 1 of Production Example 6 -Butyl 8- (3-chloro-4-cyanopyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 6-1) crude product (1 The crude product of the title compound (0.16 g) was obtained as a brown liquid in the same manner as in Step 4 of Production Example 2 or a method analogous thereto.
UPLC: 249 [M + H] + (retention time 0.69 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.17 (1H, d, J = 5 Hz), 6.95 (1H, d, J = 5 Hz), 4.55-4.49 (2H, m), 3.24-3.16 (2H , m), 2.80-2.72 (2H, m), 2.02-1.86 (4H, m).
(製造例7)2-(3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-フルオロイソニコチノニトリル(中間体7)の合成
<工程1>2,3-ジフルオロイソニコチンアミド(中間体7-1)の合成
2,3-ジフルオロイソニコチン酸(1.3g)の1,4-ジオキサン(15mL)溶液に二炭酸ジ-tert-ブチル(2.8g)、炭酸水素アンモニウム(3.3g)、ピリジン(3.4mL)を加え、窒素雰囲気下、室温にて終夜攪拌した。0.1Mの塩酸水溶液を加え反応を停止させた後、酢酸エチルで抽出し飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して標記化合物(1.2g)を白色固体として得た。
UPLC:159[M+H]+(保持時間0.51分)
1H-NMR (CD3OD, 400MHz) δ: 8.07-8.03 (1H, m), 7.54-7.49 (1H, m). Production Example 7 Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-fluoroisonicotinonitrile (Intermediate 7) <Step 1> 2,3-Difluoro Synthesis of isonicotinamide (intermediate 7-1) To a solution of 2,3-difluoroisonicotinic acid (1.3 g) in 1,4-dioxane (15 mL), di-tert-butyl dicarbonate (2.8 g), carbonic acid Ammonium hydrogen (3.3 g) and pyridine (3.4 mL) were added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was stopped by adding a 0.1 M aqueous hydrochloric acid solution, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.2 g) as a white solid.
UPLC: 159 [M + H] + (retention time 0.51 minutes)
1 H-NMR (CD 3 OD, 400 MHz) δ: 8.07-8.03 (1H, m), 7.54-7.49 (1H, m).
<工程1>2,3-ジフルオロイソニコチンアミド(中間体7-1)の合成
2,3-ジフルオロイソニコチン酸(1.3g)の1,4-ジオキサン(15mL)溶液に二炭酸ジ-tert-ブチル(2.8g)、炭酸水素アンモニウム(3.3g)、ピリジン(3.4mL)を加え、窒素雰囲気下、室温にて終夜攪拌した。0.1Mの塩酸水溶液を加え反応を停止させた後、酢酸エチルで抽出し飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して標記化合物(1.2g)を白色固体として得た。
UPLC:159[M+H]+(保持時間0.51分)
1H-NMR (CD3OD, 400MHz) δ: 8.07-8.03 (1H, m), 7.54-7.49 (1H, m). Production Example 7 Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-fluoroisonicotinonitrile (Intermediate 7) <Step 1> 2,3-Difluoro Synthesis of isonicotinamide (intermediate 7-1) To a solution of 2,3-difluoroisonicotinic acid (1.3 g) in 1,4-dioxane (15 mL), di-tert-butyl dicarbonate (2.8 g), carbonic acid Ammonium hydrogen (3.3 g) and pyridine (3.4 mL) were added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was stopped by adding a 0.1 M aqueous hydrochloric acid solution, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.2 g) as a white solid.
UPLC: 159 [M + H] + (retention time 0.51 minutes)
1 H-NMR (CD 3 OD, 400 MHz) δ: 8.07-8.03 (1H, m), 7.54-7.49 (1H, m).
<工程2>tert-ブチル 8-(4-カルバモイル-3-フルオロピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体7-2)の合成
製造例6の工程1と同様の方法もしくは、これに準ずる方法で2,3-ジフルオロイソニコチンアミド(中間体7-1)(0.27g)を用いて、120℃にて15時間撹拌し、標記化合物(0.15g)を黄色液体として得た。
UPLC:373[M+Na]+(保持時間1.01分) <Step 2> of tert-butyl 8- (4-carbamoyl-3-fluoropyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 7-2) Synthesis The mixture was stirred at 120 ° C. for 15 hours using 2,3-difluoroisonicotinamide (intermediate 7-1) (0.27 g) in the same manner as in Step 1 of Production Example 6 or a method analogous thereto. The title compound (0.15 g) was obtained as a yellow liquid.
UPLC: 373 [M + Na] + (retention time 1.01 minutes)
製造例6の工程1と同様の方法もしくは、これに準ずる方法で2,3-ジフルオロイソニコチンアミド(中間体7-1)(0.27g)を用いて、120℃にて15時間撹拌し、標記化合物(0.15g)を黄色液体として得た。
UPLC:373[M+Na]+(保持時間1.01分) <Step 2> of tert-butyl 8- (4-carbamoyl-3-fluoropyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 7-2) Synthesis The mixture was stirred at 120 ° C. for 15 hours using 2,3-difluoroisonicotinamide (intermediate 7-1) (0.27 g) in the same manner as in Step 1 of Production Example 6 or a method analogous thereto. The title compound (0.15 g) was obtained as a yellow liquid.
UPLC: 373 [M + Na] + (retention time 1.01 minutes)
<工程3>tert-ブチル 8-(4-シアノ-3-フルオロピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体7-3)の合成
製造例3の工程3と同様の方法もしくは、これに準ずる方法でtert-ブチル 8-(4-カルバモイル-3-フルオロピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体7-2)(0.15g)を用いて、標記化合物(0.15g)を黄色液体として得た。
UPLC:355[M+Na]+(保持時間1.16分) <Step 3> of tert-butyl 8- (4-cyano-3-fluoropyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 7-3) Synthesis In the same manner as in Step 3 of Production Example 3 or a method analogous thereto, tert-butyl 8- (4-carbamoyl-3-fluoropyridin-2-yl) -3,8-diazabicyclo [3.2.1] Octane-3-carboxylate (Intermediate 7-2) (0.15 g) was used to give the title compound (0.15 g) as a yellow liquid.
UPLC: 355 [M + Na] + (retention time 1.16 minutes)
製造例3の工程3と同様の方法もしくは、これに準ずる方法でtert-ブチル 8-(4-カルバモイル-3-フルオロピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体7-2)(0.15g)を用いて、標記化合物(0.15g)を黄色液体として得た。
UPLC:355[M+Na]+(保持時間1.16分) <Step 3> of tert-butyl 8- (4-cyano-3-fluoropyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 7-3) Synthesis In the same manner as in Step 3 of Production Example 3 or a method analogous thereto, tert-butyl 8- (4-carbamoyl-3-fluoropyridin-2-yl) -3,8-diazabicyclo [3.2.1] Octane-3-carboxylate (Intermediate 7-2) (0.15 g) was used to give the title compound (0.15 g) as a yellow liquid.
UPLC: 355 [M + Na] + (retention time 1.16 minutes)
<工程4>2-(3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-フルオロイソニコチノニトリル(中間体7)の合成
製造例2の工程4と同様の方法もしくは、これに準ずる方法でtert-ブチル 8-(4-シアノ-3-フルオロピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体7-3)(0.15g)を用いて、標記化合物(0.10g)を黄色液体として得た。
UPLC:233[M+H]+(保持時間0.67分) <Step 4> Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-fluoroisonicotinonitrile (Intermediate 7) The same method as in Step 4 of Production Example 2 Alternatively, tert-butyl 8- (4-cyano-3-fluoropyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 7- 3) The title compound (0.10 g) was obtained as a yellow liquid using (0.15 g).
UPLC: 233 [M + H] + (retention time 0.67 minutes)
製造例2の工程4と同様の方法もしくは、これに準ずる方法でtert-ブチル 8-(4-シアノ-3-フルオロピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体7-3)(0.15g)を用いて、標記化合物(0.10g)を黄色液体として得た。
UPLC:233[M+H]+(保持時間0.67分) <Step 4> Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-fluoroisonicotinonitrile (Intermediate 7) The same method as in Step 4 of Production Example 2 Alternatively, tert-butyl 8- (4-cyano-3-fluoropyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 7- 3) The title compound (0.10 g) was obtained as a yellow liquid using (0.15 g).
UPLC: 233 [M + H] + (retention time 0.67 minutes)
(製造例8)8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-2,2,4,4-d4(中間体8)の合成
<工程1>3-ベンジル-3,8-ジアザビシクロ[3.2.1]オクタン-2,2,4,4-d4(中間体8-1)の合成
3-ベンジル-3,8-ジアザビシクロ[3.2.1]オクタン-2,4-ジオン(0.20g)のジエチルエーテル(2.0mL)溶液に1.0MのLiAlD4-ジエチルエーテル溶液(2.6mL)をゆっくり滴下して加え、窒素雰囲気下、室温にて3時間攪拌した。水を加え反応を停止させた後、生じた沈殿物をろ過して除去した。ろ液を減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ジクロロメタン:メタノール=90:10)にて精製し、標記化合物(92mg)を黄色液体として得た。
UPLC:207[M+H]+(保持時間0.56分)
1H-NMR (CD3OD, 300MHz) δ: 7.32-7.16 (5H, m), 3.45 (2H, s), 3.38-3.33 (2H, m), 1.95-1.85 (2H, m), 1.76-1.68 (2H, m). (Production Example 8) 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-2,2,4,4-d 4 (Intermediate 8) Synthesis <Step 1> Synthesis of 3-benzyl-3,8-diazabicyclo [3.2.1] octane-2,2,4,4-d 4 (intermediate 8-1) 3-benzyl-3,8- To a solution of diazabicyclo [3.2.1] octane-2,4-dione (0.20 g) in diethyl ether (2.0 mL) was slowly added dropwise a 1.0 M LiAlD 4 -diethyl ether solution (2.6 mL). In addition, the mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. Water was added to stop the reaction, and the resulting precipitate was removed by filtration. The residue obtained by evaporating the solvent from the filtrate under reduced pressure was purified by column chromatography (silica gel, dichloromethane: methanol = 90: 10) to obtain the title compound (92 mg) as a yellow liquid.
UPLC: 207 [M + H] + (retention time 0.56 minutes)
1 H-NMR (CD 3 OD, 300 MHz) δ: 7.32-7.16 (5H, m), 3.45 (2H, s), 3.38-3.33 (2H, m), 1.95-1.85 (2H, m), 1.76-1.68 (2H, m).
<工程1>3-ベンジル-3,8-ジアザビシクロ[3.2.1]オクタン-2,2,4,4-d4(中間体8-1)の合成
3-ベンジル-3,8-ジアザビシクロ[3.2.1]オクタン-2,4-ジオン(0.20g)のジエチルエーテル(2.0mL)溶液に1.0MのLiAlD4-ジエチルエーテル溶液(2.6mL)をゆっくり滴下して加え、窒素雰囲気下、室温にて3時間攪拌した。水を加え反応を停止させた後、生じた沈殿物をろ過して除去した。ろ液を減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ジクロロメタン:メタノール=90:10)にて精製し、標記化合物(92mg)を黄色液体として得た。
UPLC:207[M+H]+(保持時間0.56分)
1H-NMR (CD3OD, 300MHz) δ: 7.32-7.16 (5H, m), 3.45 (2H, s), 3.38-3.33 (2H, m), 1.95-1.85 (2H, m), 1.76-1.68 (2H, m). (Production Example 8) 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-2,2,4,4-d 4 (Intermediate 8) Synthesis <Step 1> Synthesis of 3-benzyl-3,8-diazabicyclo [3.2.1] octane-2,2,4,4-d 4 (intermediate 8-1) 3-benzyl-3,8- To a solution of diazabicyclo [3.2.1] octane-2,4-dione (0.20 g) in diethyl ether (2.0 mL) was slowly added dropwise a 1.0 M LiAlD 4 -diethyl ether solution (2.6 mL). In addition, the mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. Water was added to stop the reaction, and the resulting precipitate was removed by filtration. The residue obtained by evaporating the solvent from the filtrate under reduced pressure was purified by column chromatography (silica gel, dichloromethane: methanol = 90: 10) to obtain the title compound (92 mg) as a yellow liquid.
UPLC: 207 [M + H] + (retention time 0.56 minutes)
1 H-NMR (CD 3 OD, 300 MHz) δ: 7.32-7.16 (5H, m), 3.45 (2H, s), 3.38-3.33 (2H, m), 1.95-1.85 (2H, m), 1.76-1.68 (2H, m).
<工程2>3-ベンジル-8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-2,2,4,4-d4(中間体8-2)の合成
3-ベンジル-3,8-ジアザビシクロ[3.2.1]オクタン-2,2,4,4-d4(中間体8-1)(92mg)、2-クロロ-4,6-ジメチルピリミジン(64mg)のエタノール(1.0mL)溶液に、DMAP(5.5mg)、DIPEA(0.23mL)を加え、マイクロウェーブ反応装置にて160℃で1時間加熱した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=100:0~90:10)にて精製し、標記化合物(0.12g)を白色固体として得た。
UPLC:313[M+H]+(保持時間0.77分)
1H-NMR (CDCl3, 300MHz) δ: 7.34-7.19 (5H, m), 6.24 (1H, s), 4.77-4.72 (2H, m), 3.44 (2H, s), 2.27 (6H, s), 2.07-1.80 (4H, m). <Step 2> 3-Benzyl-8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-2,2,4,4-d 4 (intermediate) 8-2) Synthesis 3-Benzyl-3,8-diazabicyclo [3.2.1] octane-2,2,4,4-d 4 (Intermediate 8-1) (92 mg), 2-chloro-4 DMAP (5.5 mg) and DIPEA (0.23 mL) were added to a solution of 1,6-dimethylpyrimidine (64 mg) in ethanol (1.0 mL), and the mixture was heated at 160 ° C. for 1 hour in a microwave reactor. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 90:10) to obtain the title compound (0.12 g) as a white solid. .
UPLC: 313 [M + H] + (retention time 0.77 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 7.34-7.19 (5H, m), 6.24 (1H, s), 4.77-4.72 (2H, m), 3.44 (2H, s), 2.27 (6H, s) , 2.07-1.80 (4H, m).
3-ベンジル-3,8-ジアザビシクロ[3.2.1]オクタン-2,2,4,4-d4(中間体8-1)(92mg)、2-クロロ-4,6-ジメチルピリミジン(64mg)のエタノール(1.0mL)溶液に、DMAP(5.5mg)、DIPEA(0.23mL)を加え、マイクロウェーブ反応装置にて160℃で1時間加熱した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=100:0~90:10)にて精製し、標記化合物(0.12g)を白色固体として得た。
UPLC:313[M+H]+(保持時間0.77分)
1H-NMR (CDCl3, 300MHz) δ: 7.34-7.19 (5H, m), 6.24 (1H, s), 4.77-4.72 (2H, m), 3.44 (2H, s), 2.27 (6H, s), 2.07-1.80 (4H, m). <Step 2> 3-Benzyl-8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-2,2,4,4-d 4 (intermediate) 8-2) Synthesis 3-Benzyl-3,8-diazabicyclo [3.2.1] octane-2,2,4,4-d 4 (Intermediate 8-1) (92 mg), 2-chloro-4 DMAP (5.5 mg) and DIPEA (0.23 mL) were added to a solution of 1,6-dimethylpyrimidine (64 mg) in ethanol (1.0 mL), and the mixture was heated at 160 ° C. for 1 hour in a microwave reactor. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 90:10) to obtain the title compound (0.12 g) as a white solid. .
UPLC: 313 [M + H] + (retention time 0.77 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 7.34-7.19 (5H, m), 6.24 (1H, s), 4.77-4.72 (2H, m), 3.44 (2H, s), 2.27 (6H, s) , 2.07-1.80 (4H, m).
<工程3>8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-2,2,4,4-d4(中間体8)
3-ベンジル-8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-2,2,4,4-d4(中間体8-2)(0.12g)のメタノール溶液に10%Pd-C(40mg)を加え、水素雰囲気下、室温にて終夜攪拌した。反応溶液をろ過後、減圧下溶媒を留去して標記化合物(78mg)を白色固体として得た。
UPLC:223[M+H]+(保持時間0.59分)
1H-NMR (CDCl3, 300MHz) δ: 6.25 (1H, s), 4.72-4.68 (2H, m), 2.27 (6H, s), 2.03-1.84 (4H, m). <Step 3> 8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-2,2,4,4-d 4 (Intermediate 8)
3-Benzyl-8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-2,2,4,4-d 4 (Intermediate 8-2) 10% Pd—C (40 mg) was added to a methanol solution of (0.12 g) and stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered, and the solvent was evaporated under reduced pressure to obtain the title compound (78 mg) as a white solid.
UPLC: 223 [M + H] + (retention time 0.59 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 6.25 (1H, s), 4.72-4.68 (2H, m), 2.27 (6H, s), 2.03-1.84 (4H, m).
3-ベンジル-8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-2,2,4,4-d4(中間体8-2)(0.12g)のメタノール溶液に10%Pd-C(40mg)を加え、水素雰囲気下、室温にて終夜攪拌した。反応溶液をろ過後、減圧下溶媒を留去して標記化合物(78mg)を白色固体として得た。
UPLC:223[M+H]+(保持時間0.59分)
1H-NMR (CDCl3, 300MHz) δ: 6.25 (1H, s), 4.72-4.68 (2H, m), 2.27 (6H, s), 2.03-1.84 (4H, m). <Step 3> 8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-2,2,4,4-d 4 (Intermediate 8)
3-Benzyl-8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-2,2,4,4-d 4 (Intermediate 8-2) 10% Pd—C (40 mg) was added to a methanol solution of (0.12 g) and stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered, and the solvent was evaporated under reduced pressure to obtain the title compound (78 mg) as a white solid.
UPLC: 223 [M + H] + (retention time 0.59 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 6.25 (1H, s), 4.72-4.68 (2H, m), 2.27 (6H, s), 2.03-1.84 (4H, m).
(製造例9)8-(6-メチル-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体9)の合成
<工程1>tert-ブチル 8-(6-クロロ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体9-1)の合成
2,6-ジクロロ-4-(トリフルオロメチル)ピリジン(0.56g)、tert-ブチル 3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(0.50g)のDMSO(2.0mL)混合溶液に、トリエチルアミン(1.6mL)を加え、マイクロウェーブ条件下、120℃にて1時間撹拌した。反応溶液を室温に戻した後に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去して標記化合物の粗生成物(0.96g)を橙色固体として得た。
UPLC:414[M+Na]+(保持時間1.29分) Production Example 9 Synthesis of 8- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 9) <Step 1> of tert-butyl 8- (6-chloro-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 9-1) Synthesis 2,6-dichloro-4- (trifluoromethyl) pyridine (0.56 g), tert-butyl 3,8-diazabicyclo [3.2.1] octane-3-carboxylate (0.50 g) in DMSO ( (2.0 mL) To the mixed solution, triethylamine (1.6 mL) was added and stirred at 120 ° C. for 1 hour under microwave conditions. The reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (0.96 g) of the title compound as an orange solid.
UPLC: 414 [M + Na] + (retention time 1.29 minutes)
<工程1>tert-ブチル 8-(6-クロロ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体9-1)の合成
2,6-ジクロロ-4-(トリフルオロメチル)ピリジン(0.56g)、tert-ブチル 3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(0.50g)のDMSO(2.0mL)混合溶液に、トリエチルアミン(1.6mL)を加え、マイクロウェーブ条件下、120℃にて1時間撹拌した。反応溶液を室温に戻した後に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去して標記化合物の粗生成物(0.96g)を橙色固体として得た。
UPLC:414[M+Na]+(保持時間1.29分) Production Example 9 Synthesis of 8- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 9) <Step 1> of tert-butyl 8- (6-chloro-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 9-1) Synthesis 2,6-dichloro-4- (trifluoromethyl) pyridine (0.56 g), tert-butyl 3,8-diazabicyclo [3.2.1] octane-3-carboxylate (0.50 g) in DMSO ( (2.0 mL) To the mixed solution, triethylamine (1.6 mL) was added and stirred at 120 ° C. for 1 hour under microwave conditions. The reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (0.96 g) of the title compound as an orange solid.
UPLC: 414 [M + Na] + (retention time 1.29 minutes)
<工程2>tert-ブチル 8-(6-メチル-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体9-2)の合成
製造例9の工程1で得たtert-ブチル 8-(6-クロロ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体9-1)の粗生成物(0.95g)、テトラキス(トリフェニルホスフィン)パラジウム(0.56g)のTHF(16mL)混合溶液に、トリメチルアルミニウム(1.8Mトルエン溶液、2.6mL)を加え、100℃にて15時間撹拌した。反応溶液を室温に戻した後に水、1規定水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去して標記化合物の粗生成物(2.3g)を赤色液体として得た。
UPLC:394[M+Na]+(保持時間1.23分) <Step 2> tert-Butyl 8- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (Intermediate 9) -2) Synthesis of tert-butyl 8- (6-chloro-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] obtained in Step 1 of Production Example 9 To a mixed solution of crude product (0.95 g) of octane-3-carboxylate (intermediate 9-1) and tetrakis (triphenylphosphine) palladium (0.56 g) in THF (16 mL) was added trimethylaluminum (1.8 M (Toluene solution, 2.6 mL) was added, and the mixture was stirred at 100 ° C. for 15 hours. After returning the reaction solution to room temperature, water and 1N aqueous sodium hydroxide solution were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of the title compound (2.3 g) as a red liquid.
UPLC: 394 [M + Na] + (retention time 1.23 minutes)
製造例9の工程1で得たtert-ブチル 8-(6-クロロ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体9-1)の粗生成物(0.95g)、テトラキス(トリフェニルホスフィン)パラジウム(0.56g)のTHF(16mL)混合溶液に、トリメチルアルミニウム(1.8Mトルエン溶液、2.6mL)を加え、100℃にて15時間撹拌した。反応溶液を室温に戻した後に水、1規定水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去して標記化合物の粗生成物(2.3g)を赤色液体として得た。
UPLC:394[M+Na]+(保持時間1.23分) <Step 2> tert-Butyl 8- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (Intermediate 9) -2) Synthesis of tert-butyl 8- (6-chloro-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] obtained in Step 1 of Production Example 9 To a mixed solution of crude product (0.95 g) of octane-3-carboxylate (intermediate 9-1) and tetrakis (triphenylphosphine) palladium (0.56 g) in THF (16 mL) was added trimethylaluminum (1.8 M (Toluene solution, 2.6 mL) was added, and the mixture was stirred at 100 ° C. for 15 hours. After returning the reaction solution to room temperature, water and 1N aqueous sodium hydroxide solution were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of the title compound (2.3 g) as a red liquid.
UPLC: 394 [M + Na] + (retention time 1.23 minutes)
<工程3>8-(6-メチル-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体9)の合成
製造例9の工程2で得たtert-ブチル 8-(6-メチル-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体9-2)の粗生成物(2.3g)を用いて、製造例2の工程4と同様の方法もしくは、これに準ずる方法で、標記化合物(0.68g)を黄色液体として得た。
UPLC:272[M+H]+(保持時間0.83分)
1H-NMR (CDCl3, 300MHz) δ: 6.67 (1H, s), 6.51 (1H, s), 4.62-4.56 (2H, m), 3.25-3.18 (2H, m), 2.96-2.88 (2H, m), 2.44 (3H, s), 2.17-2.11 (4H, m). <Step 3> Synthesis of 8- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 9) Tert-butyl 8- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 9) -2) Using the crude product (2.3 g), the title compound (0.68 g) was obtained as a yellow liquid in the same manner as in Step 4 of Production Example 2 or a method analogous thereto.
UPLC: 272 [M + H] + (retention time 0.83 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 6.67 (1H, s), 6.51 (1H, s), 4.62-4.56 (2H, m), 3.25-3.18 (2H, m), 2.96-2.88 (2H, m), 2.44 (3H, s), 2.17-2.11 (4H, m).
製造例9の工程2で得たtert-ブチル 8-(6-メチル-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体9-2)の粗生成物(2.3g)を用いて、製造例2の工程4と同様の方法もしくは、これに準ずる方法で、標記化合物(0.68g)を黄色液体として得た。
UPLC:272[M+H]+(保持時間0.83分)
1H-NMR (CDCl3, 300MHz) δ: 6.67 (1H, s), 6.51 (1H, s), 4.62-4.56 (2H, m), 3.25-3.18 (2H, m), 2.96-2.88 (2H, m), 2.44 (3H, s), 2.17-2.11 (4H, m). <Step 3> Synthesis of 8- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 9) Tert-butyl 8- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 9) -2) Using the crude product (2.3 g), the title compound (0.68 g) was obtained as a yellow liquid in the same manner as in Step 4 of Production Example 2 or a method analogous thereto.
UPLC: 272 [M + H] + (retention time 0.83 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 6.67 (1H, s), 6.51 (1H, s), 4.62-4.56 (2H, m), 3.25-3.18 (2H, m), 2.96-2.88 (2H, m), 2.44 (3H, s), 2.17-2.11 (4H, m).
(製造例10)8-(3-メトキシ-6-メチルピラジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体10)の合成
<工程1>3-ベンジル-8-(6-ブロモ-3-メトキシピラジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体10-1)の合成
3,5-ジブロモ-2-メトキシピラジン(0.50g)、3-ベンジル-3,8-ジアザビシクロ[3.2.1]オクタン(0.45g)、炭酸カリウム(0.77g)、フッ化セシウム(0.28g)のDMSO(1.9mL)混合液を窒素雰囲気下、130℃で17時間攪拌した。反応液を室温に冷却し、水(50mL)を加えてヘプタン-酢酸エチル(2:1)混合液(150mL)で抽出した。抽出液を水(40mL×2)、飽和食塩水(20mL)で順次洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去し、残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=97:3~60:40)にて精製し、標記化合物(0.41g)を淡黄色液体として得た。
UPLC:389、391[M+H]+(保持時間0.89分) Production Example 10 Synthesis of 8- (3-methoxy-6-methylpyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 10) <Step 1> 3-Benzyl- Synthesis of 8- (6-bromo-3-methoxypyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 10-1) 3,5-dibromo-2-methoxypyrazine ( 0.50 g), 3-benzyl-3,8-diazabicyclo [3.2.1] octane (0.45 g), potassium carbonate (0.77 g), cesium fluoride (0.28 g) in DMSO (1.9 mL) ) The mixture was stirred at 130 ° C. for 17 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with a heptane-ethyl acetate (2: 1) mixture (150 mL). The extract was washed successively with water (40 mL × 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 97 : 3 to 60:40) to obtain the title compound (0.41 g) as a pale yellow liquid.
UPLC: 389, 391 [M + H] + (retention time 0.89 minutes)
<工程1>3-ベンジル-8-(6-ブロモ-3-メトキシピラジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体10-1)の合成
3,5-ジブロモ-2-メトキシピラジン(0.50g)、3-ベンジル-3,8-ジアザビシクロ[3.2.1]オクタン(0.45g)、炭酸カリウム(0.77g)、フッ化セシウム(0.28g)のDMSO(1.9mL)混合液を窒素雰囲気下、130℃で17時間攪拌した。反応液を室温に冷却し、水(50mL)を加えてヘプタン-酢酸エチル(2:1)混合液(150mL)で抽出した。抽出液を水(40mL×2)、飽和食塩水(20mL)で順次洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去し、残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=97:3~60:40)にて精製し、標記化合物(0.41g)を淡黄色液体として得た。
UPLC:389、391[M+H]+(保持時間0.89分) Production Example 10 Synthesis of 8- (3-methoxy-6-methylpyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 10) <Step 1> 3-Benzyl- Synthesis of 8- (6-bromo-3-methoxypyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 10-1) 3,5-dibromo-2-methoxypyrazine ( 0.50 g), 3-benzyl-3,8-diazabicyclo [3.2.1] octane (0.45 g), potassium carbonate (0.77 g), cesium fluoride (0.28 g) in DMSO (1.9 mL) ) The mixture was stirred at 130 ° C. for 17 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with a heptane-ethyl acetate (2: 1) mixture (150 mL). The extract was washed successively with water (40 mL × 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 97 : 3 to 60:40) to obtain the title compound (0.41 g) as a pale yellow liquid.
UPLC: 389, 391 [M + H] + (retention time 0.89 minutes)
<工程2>3-ベンジル-8-(3-メトキシ-6-メチルピラジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体10-2)
3-ベンジル-8-(6-ブロモ-3-メトキシピラジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体10-1)(0.40g)、トリメチルボロキシン(0.26g)、PdCl2(dppf)(38mg)、炭酸カリウム(0.43g)のDME(5.1mL)混合液を窒素雰囲気下、90℃で14時間攪拌した。反応液を室温へ冷却後、セライトでろ過し、ろ液に水(20mL)を加え、酢酸エチル(20mL)で抽出した。抽出液を飽和食塩水(10mL)で洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去し、残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=97:3~60:40)にて精製し、標記化合物(0.31g)を淡黄色液体として得た。
UPLC:325[M+H]+(保持時間0.84分) <Step 2> 3-Benzyl-8- (3-methoxy-6-methylpyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 10-2)
3-benzyl-8- (6-bromo-3-methoxypyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 10-1) (0.40 g), trimethylboroxine (0.26 g), PdCl 2 (dppf) (38 mg), potassium carbonate (0.43 g) in DME (5.1 mL) was stirred at 90 ° C. for 14 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered through celite, water (20 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (20 mL). The extract was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 97: 3 to 60:40). The title compound (0.31 g) was obtained as a pale yellow liquid.
UPLC: 325 [M + H] + (retention time 0.84 minutes)
3-ベンジル-8-(6-ブロモ-3-メトキシピラジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体10-1)(0.40g)、トリメチルボロキシン(0.26g)、PdCl2(dppf)(38mg)、炭酸カリウム(0.43g)のDME(5.1mL)混合液を窒素雰囲気下、90℃で14時間攪拌した。反応液を室温へ冷却後、セライトでろ過し、ろ液に水(20mL)を加え、酢酸エチル(20mL)で抽出した。抽出液を飽和食塩水(10mL)で洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去し、残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=97:3~60:40)にて精製し、標記化合物(0.31g)を淡黄色液体として得た。
UPLC:325[M+H]+(保持時間0.84分) <Step 2> 3-Benzyl-8- (3-methoxy-6-methylpyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 10-2)
3-benzyl-8- (6-bromo-3-methoxypyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 10-1) (0.40 g), trimethylboroxine (0.26 g), PdCl 2 (dppf) (38 mg), potassium carbonate (0.43 g) in DME (5.1 mL) was stirred at 90 ° C. for 14 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered through celite, water (20 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (20 mL). The extract was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 97: 3 to 60:40). The title compound (0.31 g) was obtained as a pale yellow liquid.
UPLC: 325 [M + H] + (retention time 0.84 minutes)
<工程3>8-(3-メトキシ-6-メチルピラジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体10)の合成
3-ベンジル-8-(3-メトキシ-6-メチルピラジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体10-2)(0.30g)と10%Pd-C(18mg)のメタノール(9.2mL)混合液を水素雰囲気下、室温で17時間攪拌した。反応液をセライトでろ過し、ろ液を減圧下濃縮して、標記化合物(0.24g)を茶色液体として得た。
UPLC:235[M+H]+(保持時間0.74分)
1H-NMR (CDCl3, 300MHz) δ: 7.27-7.24 (1H, m), 4.73-4.67 (2H, m), 3.91 (3H, s), 3.21-3.11 (2H, m), 2.70-2.60 (2H, m), 2.27 (3H, s), 2.06-1.83 (4H, m). <Step 3> Synthesis of 8- (3-methoxy-6-methylpyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 10) 3-Benzyl-8- (3- Methoxy-6-methylpyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 10-2) (0.30 g) and 10% Pd—C (18 mg) in methanol (9 .2 mL) The mixture was stirred under a hydrogen atmosphere at room temperature for 17 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (0.24 g) as a brown liquid.
UPLC: 235 [M + H] + (retention time 0.74 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 7.27-7.24 (1H, m), 4.73-4.67 (2H, m), 3.91 (3H, s), 3.21-3.11 (2H, m), 2.70-2.60 ( 2H, m), 2.27 (3H, s), 2.06-1.83 (4H, m).
3-ベンジル-8-(3-メトキシ-6-メチルピラジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体10-2)(0.30g)と10%Pd-C(18mg)のメタノール(9.2mL)混合液を水素雰囲気下、室温で17時間攪拌した。反応液をセライトでろ過し、ろ液を減圧下濃縮して、標記化合物(0.24g)を茶色液体として得た。
UPLC:235[M+H]+(保持時間0.74分)
1H-NMR (CDCl3, 300MHz) δ: 7.27-7.24 (1H, m), 4.73-4.67 (2H, m), 3.91 (3H, s), 3.21-3.11 (2H, m), 2.70-2.60 (2H, m), 2.27 (3H, s), 2.06-1.83 (4H, m). <Step 3> Synthesis of 8- (3-methoxy-6-methylpyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 10) 3-Benzyl-8- (3- Methoxy-6-methylpyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 10-2) (0.30 g) and 10% Pd—C (18 mg) in methanol (9 .2 mL) The mixture was stirred under a hydrogen atmosphere at room temperature for 17 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (0.24 g) as a brown liquid.
UPLC: 235 [M + H] + (retention time 0.74 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 7.27-7.24 (1H, m), 4.73-4.67 (2H, m), 3.91 (3H, s), 3.21-3.11 (2H, m), 2.70-2.60 ( 2H, m), 2.27 (3H, s), 2.06-1.83 (4H, m).
(製造例11)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)メタノン(中間体11)の合成
2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)安息香酸(1.2g)とDIPEA(2.6mL)のDMF(10mL)混合溶液にHATU(2.3g)を加え、窒素雰囲気下、室温で1時間攪拌した後、8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体1)(1.1g)を加え、さらに17時間攪拌した。反応液に水(50mL)を加え、酢酸エチル(100mL)で抽出し、抽出液を水(30mL×2)と飽和食塩水(20mL)で順次洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去し、残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=70:30~50:50)にて精製し、標記化合物(1.5g)を淡黄色アモルファスとして得た。
UPLC:449[M+H]+(保持時間1.13分)
1H-NMR (CDCl3, 300MHz) δ: 7.82-7.76 (1H, m), 7.48-7.39 (1H, m), 7.38-7.30 (1H, m), 7.27-7.20 (1H, m), 6.31 (1H, s), 4.94-4.86 (1H, m), 4.68-4.61 (1H, m), 4.49-4.39 (1H, m), 3.42-3.33 (1H, m), 3.20-3.04 (2H, m), 2.27 (6H, s), 2.09-1.77 (4H, m), 1.33-1.10 (12H, m). Production Example 11 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (4,4,5,5 Synthesis of -tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methanone (intermediate 11) 2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) HATU (2.3 g) was added to a mixed solution of benzoic acid (1.2 g) and DIPEA (2.6 mL) in DMF (10 mL), and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. 6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 1) (1.1 g) was added, and the mixture was further stirred for 17 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The extract was washed successively with water (30 mL × 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was reduced in pressure. The residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 70: 30-50: 50) to obtain the title compound (1.5 g) as a pale yellow amorphous.
UPLC: 449 [M + H] + (retention time 1.13 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 7.82-7.76 (1H, m), 7.48-7.39 (1H, m), 7.38-7.30 (1H, m), 7.27-7.20 (1H, m), 6.31 ( 1H, s), 4.94-4.86 (1H, m), 4.68-4.61 (1H, m), 4.49-4.39 (1H, m), 3.42-3.33 (1H, m), 3.20-3.04 (2H, m), 2.27 (6H, s), 2.09-1.77 (4H, m), 1.33-1.10 (12H, m).
2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)安息香酸(1.2g)とDIPEA(2.6mL)のDMF(10mL)混合溶液にHATU(2.3g)を加え、窒素雰囲気下、室温で1時間攪拌した後、8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体1)(1.1g)を加え、さらに17時間攪拌した。反応液に水(50mL)を加え、酢酸エチル(100mL)で抽出し、抽出液を水(30mL×2)と飽和食塩水(20mL)で順次洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去し、残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=70:30~50:50)にて精製し、標記化合物(1.5g)を淡黄色アモルファスとして得た。
UPLC:449[M+H]+(保持時間1.13分)
1H-NMR (CDCl3, 300MHz) δ: 7.82-7.76 (1H, m), 7.48-7.39 (1H, m), 7.38-7.30 (1H, m), 7.27-7.20 (1H, m), 6.31 (1H, s), 4.94-4.86 (1H, m), 4.68-4.61 (1H, m), 4.49-4.39 (1H, m), 3.42-3.33 (1H, m), 3.20-3.04 (2H, m), 2.27 (6H, s), 2.09-1.77 (4H, m), 1.33-1.10 (12H, m). Production Example 11 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (4,4,5,5 Synthesis of -tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methanone (intermediate 11) 2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) HATU (2.3 g) was added to a mixed solution of benzoic acid (1.2 g) and DIPEA (2.6 mL) in DMF (10 mL), and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. 6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 1) (1.1 g) was added, and the mixture was further stirred for 17 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The extract was washed successively with water (30 mL × 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was reduced in pressure. The residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 70: 30-50: 50) to obtain the title compound (1.5 g) as a pale yellow amorphous.
UPLC: 449 [M + H] + (retention time 1.13 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 7.82-7.76 (1H, m), 7.48-7.39 (1H, m), 7.38-7.30 (1H, m), 7.27-7.20 (1H, m), 6.31 ( 1H, s), 4.94-4.86 (1H, m), 4.68-4.61 (1H, m), 4.49-4.39 (1H, m), 3.42-3.33 (1H, m), 3.20-3.04 (2H, m), 2.27 (6H, s), 2.09-1.77 (4H, m), 1.33-1.10 (12H, m).
(製造例12)2-(ピリミジン-2-イル)安息香酸(中間体12)の合成
<工程1>2-(ピリミジン-2-イル)安息香酸メチル(中間体12-1)の合成
2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)安息香酸メチル(3.0g)、2-クロロピリミジン(2.0g)、PdCl2(dppf)ジクロロメタン錯体(0.47g)、炭酸ナトリウム(3.6g)の2-メチルテトラヒドロフラン(57mL)-水(11mL)混合液を窒素雰囲気下、80℃で4時間攪拌した。反応液を室温へ冷却し、酢酸エチル(100mL)を用いてセライトでろ過した後、ろ液に水(100mL)を加え、酢酸エチル(50mL×2)で抽出した。集めた抽出液を飽和食塩水(50mL)で洗浄し、有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去し、残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=88:12~0:100)にて精製し、標記化合物(1.9g)を茶色液体として得た。
UPLC:237[M+Na]+(保持時間0.79分) Production Example 12 Synthesis of 2- (pyrimidin-2-yl) benzoic acid (intermediate 12) <Step 1> Synthesis of methyl 2- (pyrimidin-2-yl) benzoate (intermediate 12-1) 2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) methyl benzoate (3.0 g), 2-chloropyrimidine (2.0 g), PdCl 2 (dppf) dichloromethane complex (0.47 g) and sodium carbonate (3.6 g) in 2-methyltetrahydrofuran (57 mL) -water (11 mL) were stirred at 80 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through celite with ethyl acetate (100 mL), water (100 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (50 mL × 2). The collected extract was washed with saturated brine (50 mL), the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 88: 12 to 0: 100) to obtain the title compound (1.9 g) as a brown liquid.
UPLC: 237 [M + Na] + (retention time 0.79 minutes)
<工程1>2-(ピリミジン-2-イル)安息香酸メチル(中間体12-1)の合成
2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)安息香酸メチル(3.0g)、2-クロロピリミジン(2.0g)、PdCl2(dppf)ジクロロメタン錯体(0.47g)、炭酸ナトリウム(3.6g)の2-メチルテトラヒドロフラン(57mL)-水(11mL)混合液を窒素雰囲気下、80℃で4時間攪拌した。反応液を室温へ冷却し、酢酸エチル(100mL)を用いてセライトでろ過した後、ろ液に水(100mL)を加え、酢酸エチル(50mL×2)で抽出した。集めた抽出液を飽和食塩水(50mL)で洗浄し、有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去し、残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=88:12~0:100)にて精製し、標記化合物(1.9g)を茶色液体として得た。
UPLC:237[M+Na]+(保持時間0.79分) Production Example 12 Synthesis of 2- (pyrimidin-2-yl) benzoic acid (intermediate 12) <Step 1> Synthesis of methyl 2- (pyrimidin-2-yl) benzoate (intermediate 12-1) 2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) methyl benzoate (3.0 g), 2-chloropyrimidine (2.0 g), PdCl 2 (dppf) dichloromethane complex (0.47 g) and sodium carbonate (3.6 g) in 2-methyltetrahydrofuran (57 mL) -water (11 mL) were stirred at 80 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through celite with ethyl acetate (100 mL), water (100 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (50 mL × 2). The collected extract was washed with saturated brine (50 mL), the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 88: 12 to 0: 100) to obtain the title compound (1.9 g) as a brown liquid.
UPLC: 237 [M + Na] + (retention time 0.79 minutes)
<工程2>2-(ピリミジン-2-イル)安息香酸(中間体12)の合成
2-(ピリミジン-2-イル)安息香酸メチル(中間体12-1)(1.9g)と水酸化リチウム(0.63g)のTHF(22mL)-水(22mL)混合溶液を室温で62時間攪拌した。反応液を濃塩酸で酸性(pH=1~2)にした後、酢酸エチル(100mL×6)で抽出した。集めた抽出液を飽和食塩水(50mL)で洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去し、標記化合物(1.3g)を淡橙色固体として得た。
UPLC:223[M+Na]+(保持時間0.68分)
1H-NMR (DMSO-d6, 400MHz) δ: 8.85 (2H, d, J = 5 Hz), 7.84 (1H, dd, J = 8, 1 Hz), 7.69-7.52 (3H, m), 7.45 (1H, t, J = 5 Hz). <Step 2> Synthesis of 2- (pyrimidin-2-yl) benzoic acid (intermediate 12) Methyl 2- (pyrimidin-2-yl) benzoate (intermediate 12-1) (1.9 g) and lithium hydroxide A mixed solution of (0.63 g) in THF (22 mL) -water (22 mL) was stirred at room temperature for 62 hours. The reaction solution was acidified with concentrated hydrochloric acid (pH = 1 to 2) and extracted with ethyl acetate (100 mL × 6). The collected extract was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (1.3 g) as a pale orange solid.
UPLC: 223 [M + Na] + (retention time 0.68 minutes)
1 H-NMR (DMSO-d 6 , 400 MHz) δ: 8.85 (2H, d, J = 5 Hz), 7.84 (1H, dd, J = 8, 1 Hz), 7.69-7.52 (3H, m), 7.45 (1H, t, J = 5 Hz).
2-(ピリミジン-2-イル)安息香酸メチル(中間体12-1)(1.9g)と水酸化リチウム(0.63g)のTHF(22mL)-水(22mL)混合溶液を室温で62時間攪拌した。反応液を濃塩酸で酸性(pH=1~2)にした後、酢酸エチル(100mL×6)で抽出した。集めた抽出液を飽和食塩水(50mL)で洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去し、標記化合物(1.3g)を淡橙色固体として得た。
UPLC:223[M+Na]+(保持時間0.68分)
1H-NMR (DMSO-d6, 400MHz) δ: 8.85 (2H, d, J = 5 Hz), 7.84 (1H, dd, J = 8, 1 Hz), 7.69-7.52 (3H, m), 7.45 (1H, t, J = 5 Hz). <Step 2> Synthesis of 2- (pyrimidin-2-yl) benzoic acid (intermediate 12) Methyl 2- (pyrimidin-2-yl) benzoate (intermediate 12-1) (1.9 g) and lithium hydroxide A mixed solution of (0.63 g) in THF (22 mL) -water (22 mL) was stirred at room temperature for 62 hours. The reaction solution was acidified with concentrated hydrochloric acid (pH = 1 to 2) and extracted with ethyl acetate (100 mL × 6). The collected extract was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (1.3 g) as a pale orange solid.
UPLC: 223 [M + Na] + (retention time 0.68 minutes)
1 H-NMR (DMSO-d 6 , 400 MHz) δ: 8.85 (2H, d, J = 5 Hz), 7.84 (1H, dd, J = 8, 1 Hz), 7.69-7.52 (3H, m), 7.45 (1H, t, J = 5 Hz).
(製造例13)6-メトキシ-2-(1H-ピラゾール-1-イル)ニコチン酸(中間体13)の合成
<工程1>6-メトキシ-2-(1H-ピラゾール-1-イル)ニコチン酸メチル(中間体13-1)の合成
2-クロロ-6-メトキシニコチン酸メチル(0.50g)、1H-ピラゾール(0.51g)のDMF(5.0mL)混合液に炭酸カリウム(2.1g)を加え、100℃にて69時間攪拌した。反応溶液を室温へ冷却し、水を加え、酢酸エチルで抽出した後、有機層を水ならびに飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=100:0~80:20)にて精製し、標記化合物(0.12g)を無色液体として得た。
UPLC:256[M+Na]+(保持時間0.93分) (Production Example 13) Synthesis of 6-methoxy-2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 13) <Step 1> 6-Methoxy-2- (1H-pyrazol-1-yl) nicotinic acid Synthesis of methyl (intermediate 13-1) To a mixed solution of methyl 2-chloro-6-methoxynicotinate (0.50 g) and 1H-pyrazole (0.51 g) in DMF (5.0 mL) was added potassium carbonate (2.1 g). ) And stirred at 100 ° C. for 69 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 80:20) to obtain the title compound (0.12 g) as a colorless liquid. .
UPLC: 256 [M + Na] + (retention time 0.93 minutes)
<工程1>6-メトキシ-2-(1H-ピラゾール-1-イル)ニコチン酸メチル(中間体13-1)の合成
2-クロロ-6-メトキシニコチン酸メチル(0.50g)、1H-ピラゾール(0.51g)のDMF(5.0mL)混合液に炭酸カリウム(2.1g)を加え、100℃にて69時間攪拌した。反応溶液を室温へ冷却し、水を加え、酢酸エチルで抽出した後、有機層を水ならびに飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=100:0~80:20)にて精製し、標記化合物(0.12g)を無色液体として得た。
UPLC:256[M+Na]+(保持時間0.93分) (Production Example 13) Synthesis of 6-methoxy-2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 13) <Step 1> 6-Methoxy-2- (1H-pyrazol-1-yl) nicotinic acid Synthesis of methyl (intermediate 13-1) To a mixed solution of methyl 2-chloro-6-methoxynicotinate (0.50 g) and 1H-pyrazole (0.51 g) in DMF (5.0 mL) was added potassium carbonate (2.1 g). ) And stirred at 100 ° C. for 69 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 80:20) to obtain the title compound (0.12 g) as a colorless liquid. .
UPLC: 256 [M + Na] + (retention time 0.93 minutes)
<工程2>6-メトキシ-2-(1H-ピラゾール-1-イル)ニコチン酸(中間体13)の合成
6-メトキシ-2-(1H-ピラゾール-1-イル)ニコチン酸メチル(中間体13-1)(0.12g)のメタノール-水(1.0mL,1:1)混合溶液に水酸化ナトリウム(62mg)を加え、50℃にて1時間攪拌した。反応液を室温まで冷却した後、溶媒を減圧下留去して得られた残渣に酢酸エチルを加え、1規定水酸化ナトリウム水溶液で3回抽出した。得られた水層に1規定塩酸を加え、酢酸エチルで5回抽出した後、抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去して標記化合物(88mg)を白色固体として得た。
UPLC:242[M+Na]+(保持時間0.83分)
1H-NMR (CDCl3, 400MHz) δ: 8.77-8.73 (1H, m), 7.92-7.80 (2H, m), 6.83-6.77 (1H, m), 6.61-6.57 (1H, m), 4.04 (3H, s). <Step 2> Synthesis of 6-methoxy-2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 13) 6-methoxy-2- (1H-pyrazol-1-yl) methyl nicotinate (intermediate 13) -1) Sodium hydroxide (62 mg) was added to a methanol-water (1.0 mL, 1: 1) mixed solution of (0.12 g), and the mixture was stirred at 50 ° C. for 1 hour. After cooling the reaction solution to room temperature, the solvent was evaporated under reduced pressure, ethyl acetate was added to the resulting residue, and the mixture was extracted 3 times with 1N aqueous sodium hydroxide solution. 1N Hydrochloric acid was added to the obtained aqueous layer, and the mixture was extracted 5 times with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (88 mg) as a white solid.
UPLC: 242 [M + Na] + (retention time 0.83 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.77-8.73 (1H, m), 7.92-7.80 (2H, m), 6.83-6.77 (1H, m), 6.61-6.57 (1H, m), 4.04 ( 3H, s).
6-メトキシ-2-(1H-ピラゾール-1-イル)ニコチン酸メチル(中間体13-1)(0.12g)のメタノール-水(1.0mL,1:1)混合溶液に水酸化ナトリウム(62mg)を加え、50℃にて1時間攪拌した。反応液を室温まで冷却した後、溶媒を減圧下留去して得られた残渣に酢酸エチルを加え、1規定水酸化ナトリウム水溶液で3回抽出した。得られた水層に1規定塩酸を加え、酢酸エチルで5回抽出した後、抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去して標記化合物(88mg)を白色固体として得た。
UPLC:242[M+Na]+(保持時間0.83分)
1H-NMR (CDCl3, 400MHz) δ: 8.77-8.73 (1H, m), 7.92-7.80 (2H, m), 6.83-6.77 (1H, m), 6.61-6.57 (1H, m), 4.04 (3H, s). <Step 2> Synthesis of 6-methoxy-2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 13) 6-methoxy-2- (1H-pyrazol-1-yl) methyl nicotinate (intermediate 13) -1) Sodium hydroxide (62 mg) was added to a methanol-water (1.0 mL, 1: 1) mixed solution of (0.12 g), and the mixture was stirred at 50 ° C. for 1 hour. After cooling the reaction solution to room temperature, the solvent was evaporated under reduced pressure, ethyl acetate was added to the resulting residue, and the mixture was extracted 3 times with 1N aqueous sodium hydroxide solution. 1N Hydrochloric acid was added to the obtained aqueous layer, and the mixture was extracted 5 times with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (88 mg) as a white solid.
UPLC: 242 [M + Na] + (retention time 0.83 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.77-8.73 (1H, m), 7.92-7.80 (2H, m), 6.83-6.77 (1H, m), 6.61-6.57 (1H, m), 4.04 ( 3H, s).
(製造例14)3-(2H-1,2,3-トリアゾール-2-イル)イソニコチン酸(中間体14)の合成
3-ブロモイソニコチン酸(0.50g)、炭酸セシウム(1.6g)、1H-1,2,3-トリアゾール(0.29mL)、ヨウ化銅(I)(24mg)、トランス-N,N’-ジメチルシクロヘキサン-1,2-ジアミン(70mg)のDME(3.0mL)混合溶液に水(45μL)を加え、100℃にて4時間攪拌した。反応溶液に水を加え、酢酸エチルで3回抽出した後、得られた有機層を1規定水酸化ナトリウム水溶液で3回抽出した。得られた水層に1規定塩酸を加え、酢酸エチルで5回抽出した後、抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去して標記化合物(0.18g)を白色固体として得た。
UPLC:191[M+H]+(保持時間0.41分)
1H-NMR (DMSO-d6, 400MHz) δ: 9.07 (1H, s), 8.79 (1H, d, J = 5 Hz), 8.19 (2H, s), 7.72 (1H, d, J = 5 Hz). Production Example 14 Synthesis of 3- (2H-1,2,3-triazol-2-yl) isonicotinic acid (Intermediate 14) 3-Bromoisonicotinic acid (0.50 g), cesium carbonate (1.6 g) ) 1H-1,2,3-triazole (0.29 mL), copper (I) iodide (24 mg), trans-N, N′-dimethylcyclohexane-1,2-diamine (70 mg) in DME (3. Water (45 μL) was added to the mixed solution and stirred at 100 ° C. for 4 hours. Water was added to the reaction solution, followed by extraction three times with ethyl acetate, and then the resulting organic layer was extracted three times with a 1N aqueous sodium hydroxide solution. 1N Hydrochloric acid was added to the obtained aqueous layer, and the mixture was extracted 5 times with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.18 g) as a white solid.
UPLC: 191 [M + H] + (retention time 0.41 minutes)
1 H-NMR (DMSO-d 6 , 400 MHz) δ: 9.07 (1H, s), 8.79 (1H, d, J = 5 Hz), 8.19 (2H, s), 7.72 (1H, d, J = 5 Hz ).
3-ブロモイソニコチン酸(0.50g)、炭酸セシウム(1.6g)、1H-1,2,3-トリアゾール(0.29mL)、ヨウ化銅(I)(24mg)、トランス-N,N’-ジメチルシクロヘキサン-1,2-ジアミン(70mg)のDME(3.0mL)混合溶液に水(45μL)を加え、100℃にて4時間攪拌した。反応溶液に水を加え、酢酸エチルで3回抽出した後、得られた有機層を1規定水酸化ナトリウム水溶液で3回抽出した。得られた水層に1規定塩酸を加え、酢酸エチルで5回抽出した後、抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去して標記化合物(0.18g)を白色固体として得た。
UPLC:191[M+H]+(保持時間0.41分)
1H-NMR (DMSO-d6, 400MHz) δ: 9.07 (1H, s), 8.79 (1H, d, J = 5 Hz), 8.19 (2H, s), 7.72 (1H, d, J = 5 Hz). Production Example 14 Synthesis of 3- (2H-1,2,3-triazol-2-yl) isonicotinic acid (Intermediate 14) 3-Bromoisonicotinic acid (0.50 g), cesium carbonate (1.6 g) ) 1H-1,2,3-triazole (0.29 mL), copper (I) iodide (24 mg), trans-N, N′-dimethylcyclohexane-1,2-diamine (70 mg) in DME (3. Water (45 μL) was added to the mixed solution and stirred at 100 ° C. for 4 hours. Water was added to the reaction solution, followed by extraction three times with ethyl acetate, and then the resulting organic layer was extracted three times with a 1N aqueous sodium hydroxide solution. 1N Hydrochloric acid was added to the obtained aqueous layer, and the mixture was extracted 5 times with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.18 g) as a white solid.
UPLC: 191 [M + H] + (retention time 0.41 minutes)
1 H-NMR (DMSO-d 6 , 400 MHz) δ: 9.07 (1H, s), 8.79 (1H, d, J = 5 Hz), 8.19 (2H, s), 7.72 (1H, d, J = 5 Hz ).
(製造例15)4-メチル-2-(ピリミジン-2-イル)安息香酸(中間体15)の合成
製造例12と同様の方法もしくは、これに準ずる方法で、4-メチル-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)安息香酸メチル(3.6g)から標記化合物(0.98g)を淡茶色固体として得た。
UPLC:237[M+Na]+(保持時間0.77分)
1H-NMR (CDCl3, 400MHz) δ: 8.87 (2H, d, J = 5 Hz), 8.05 (1H, d, J = 8 Hz), 7.94 (1H, s), 7.41-7.33 (2H, m), 2.48 (3H, s). (Production Example 15) Synthesis of 4-methyl-2- (pyrimidin-2-yl) benzoic acid (Intermediate 15) 4-Methyl-2- (4 , 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) methyl benzoate (3.6 g) gave the title compound (0.98 g) as a light brown solid.
UPLC: 237 [M + Na] + (retention time 0.77 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.87 (2H, d, J = 5 Hz), 8.05 (1H, d, J = 8 Hz), 7.94 (1H, s), 7.41-7.33 (2H, m ), 2.48 (3H, s).
製造例12と同様の方法もしくは、これに準ずる方法で、4-メチル-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)安息香酸メチル(3.6g)から標記化合物(0.98g)を淡茶色固体として得た。
UPLC:237[M+Na]+(保持時間0.77分)
1H-NMR (CDCl3, 400MHz) δ: 8.87 (2H, d, J = 5 Hz), 8.05 (1H, d, J = 8 Hz), 7.94 (1H, s), 7.41-7.33 (2H, m), 2.48 (3H, s). (Production Example 15) Synthesis of 4-methyl-2- (pyrimidin-2-yl) benzoic acid (Intermediate 15) 4-Methyl-2- (4 , 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) methyl benzoate (3.6 g) gave the title compound (0.98 g) as a light brown solid.
UPLC: 237 [M + Na] + (retention time 0.77 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.87 (2H, d, J = 5 Hz), 8.05 (1H, d, J = 8 Hz), 7.94 (1H, s), 7.41-7.33 (2H, m ), 2.48 (3H, s).
(製造例16)4-クロロ-2-(ピリミジン-2-イル)安息香酸(中間体16)の合成
製造例12と同様の方法もしくは、これに準ずる方法で、4-クロロ-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)安息香酸エチル(3.5g)から標記化合物(1.6g)を無色固体として得た。
UPLC:257[M+Na]+(保持時間0.88分)
1H-NMR (DMSO-d6, 400MHz) δ: 8.81 (2H, d, J = 5 Hz), 7.79 (1H, d, J = 2 Hz), 7.69 (1H, d, J = 8 Hz), 7.61 (1H, dd, J = 8, 2 Hz), 7.45 (1H, t, J = 5 Hz). (Production Example 16) Synthesis of 4-chloro-2- (pyrimidin-2-yl) benzoic acid (Intermediate 16) 4-Chloro-2- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid ethyl ester (3.5 g) to give the title compound (1.6 g) as a colorless solid.
UPLC: 257 [M + Na] + (retention time 0.88 minutes)
1 H-NMR (DMSO-d 6 , 400 MHz) δ: 8.81 (2H, d, J = 5 Hz), 7.79 (1H, d, J = 2 Hz), 7.69 (1H, d, J = 8 Hz), 7.61 (1H, dd, J = 8, 2 Hz), 7.45 (1H, t, J = 5 Hz).
製造例12と同様の方法もしくは、これに準ずる方法で、4-クロロ-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)安息香酸エチル(3.5g)から標記化合物(1.6g)を無色固体として得た。
UPLC:257[M+Na]+(保持時間0.88分)
1H-NMR (DMSO-d6, 400MHz) δ: 8.81 (2H, d, J = 5 Hz), 7.79 (1H, d, J = 2 Hz), 7.69 (1H, d, J = 8 Hz), 7.61 (1H, dd, J = 8, 2 Hz), 7.45 (1H, t, J = 5 Hz). (Production Example 16) Synthesis of 4-chloro-2- (pyrimidin-2-yl) benzoic acid (Intermediate 16) 4-Chloro-2- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid ethyl ester (3.5 g) to give the title compound (1.6 g) as a colorless solid.
UPLC: 257 [M + Na] + (retention time 0.88 minutes)
1 H-NMR (DMSO-d 6 , 400 MHz) δ: 8.81 (2H, d, J = 5 Hz), 7.79 (1H, d, J = 2 Hz), 7.69 (1H, d, J = 8 Hz), 7.61 (1H, dd, J = 8, 2 Hz), 7.45 (1H, t, J = 5 Hz).
(製造例17)5-フルオロ-3-(ピリミジン-2-イル)ピコリン酸(中間体17)の合成
<工程1>5-フルオロ-3-(ピリミジン-2-イル)ピコリン酸メチル(中間体17-1)の合成
3-ブロモ-5-フルオロピコリン酸メチル(0.30g)、2-(トリブチルスズ)ピリミジン(0.47g)、テトラキス(トリフェニルホスフィン)パラジウム(0.15g)、ヨウ化銅(I)(24mg)、フッ化セシウム(0.39g)のDMF(1.3mL)混合液を窒素雰囲気下、100℃で18時間攪拌した。反応液を室温へ冷却後、水(10mL)と酢酸エチル(30mL)を加えセライトでろ過し、ろ液を酢酸エチル(30mL×2)で抽出した。集めた抽出液を飽和食塩水(20mL)で洗浄し、有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去し、残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=90:10~0:100)にて精製し、標記化合物(0.17g)を橙色固体として得た。
UPLC:256[M+Na]+(保持時間0.76分) (Production Example 17) Synthesis of 5-fluoro-3- (pyrimidin-2-yl) picolinic acid (intermediate 17) <Step 1> Methyl 5-fluoro-3- (pyrimidin-2-yl) picolinate (intermediate) 17-1) Synthesis of methyl 3-bromo-5-fluoropicolinate (0.30 g), 2- (tributyltin) pyrimidine (0.47 g), tetrakis (triphenylphosphine) palladium (0.15 g), copper iodide A mixed solution of (I) (24 mg) and cesium fluoride (0.39 g) in DMF (1.3 mL) was stirred at 100 ° C. for 18 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (10 mL) and ethyl acetate (30 mL) were added, and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate (30 mL × 2). The collected extract was washed with saturated brine (20 mL), the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 90: 10 to 0: 100) to give the title compound (0.17 g) as an orange solid.
UPLC: 256 [M + Na] + (retention time 0.76 minutes)
<工程1>5-フルオロ-3-(ピリミジン-2-イル)ピコリン酸メチル(中間体17-1)の合成
3-ブロモ-5-フルオロピコリン酸メチル(0.30g)、2-(トリブチルスズ)ピリミジン(0.47g)、テトラキス(トリフェニルホスフィン)パラジウム(0.15g)、ヨウ化銅(I)(24mg)、フッ化セシウム(0.39g)のDMF(1.3mL)混合液を窒素雰囲気下、100℃で18時間攪拌した。反応液を室温へ冷却後、水(10mL)と酢酸エチル(30mL)を加えセライトでろ過し、ろ液を酢酸エチル(30mL×2)で抽出した。集めた抽出液を飽和食塩水(20mL)で洗浄し、有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去し、残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=90:10~0:100)にて精製し、標記化合物(0.17g)を橙色固体として得た。
UPLC:256[M+Na]+(保持時間0.76分) (Production Example 17) Synthesis of 5-fluoro-3- (pyrimidin-2-yl) picolinic acid (intermediate 17) <Step 1> Methyl 5-fluoro-3- (pyrimidin-2-yl) picolinate (intermediate) 17-1) Synthesis of methyl 3-bromo-5-fluoropicolinate (0.30 g), 2- (tributyltin) pyrimidine (0.47 g), tetrakis (triphenylphosphine) palladium (0.15 g), copper iodide A mixed solution of (I) (24 mg) and cesium fluoride (0.39 g) in DMF (1.3 mL) was stirred at 100 ° C. for 18 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (10 mL) and ethyl acetate (30 mL) were added, and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate (30 mL × 2). The collected extract was washed with saturated brine (20 mL), the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 90: 10 to 0: 100) to give the title compound (0.17 g) as an orange solid.
UPLC: 256 [M + Na] + (retention time 0.76 minutes)
<工程2>5-フルオロ-3-(ピリミジン-2-イル)ピコリン酸(中間体17)の合成
製造例12の工程2と同様の方法もしくは、これに準ずる方法で、5-フルオロ-3-(ピリミジン-2-イル)ピコリン酸メチル(中間体17-1)(0.17g)を用いて、標記化合物(0.17g)を淡黄色アモルファスとして得た。
UPLC:176[M-CO2]+(保持時間0.63分)
1H-NMR (DMSO-d6, 300MHz) δ: 8.95 (2H, d, J = 5 Hz), 8.74 (1H, d, J = 3 Hz), 8.30 (1H, dd, J = 10, 3 Hz), 7.57 (1H, t, J = 5 Hz). <Step 2> Synthesis of 5-fluoro-3- (pyrimidin-2-yl) picolinic acid (intermediate 17) 5-Fluoro-3-yl by the same method as in Step 2 of Production Example 12 or a method analogous thereto. Using (pyrimidin-2-yl) methyl picolinate (intermediate 17-1) (0.17 g), the title compound (0.17 g) was obtained as a pale yellow amorphous product.
UPLC: 176 [M-CO 2 ] + (retention time 0.63 minutes)
1 H-NMR (DMSO-d 6 , 300 MHz) δ: 8.95 (2H, d, J = 5 Hz), 8.74 (1H, d, J = 3 Hz), 8.30 (1H, dd, J = 10, 3 Hz ), 7.57 (1H, t, J = 5 Hz).
製造例12の工程2と同様の方法もしくは、これに準ずる方法で、5-フルオロ-3-(ピリミジン-2-イル)ピコリン酸メチル(中間体17-1)(0.17g)を用いて、標記化合物(0.17g)を淡黄色アモルファスとして得た。
UPLC:176[M-CO2]+(保持時間0.63分)
1H-NMR (DMSO-d6, 300MHz) δ: 8.95 (2H, d, J = 5 Hz), 8.74 (1H, d, J = 3 Hz), 8.30 (1H, dd, J = 10, 3 Hz), 7.57 (1H, t, J = 5 Hz). <Step 2> Synthesis of 5-fluoro-3- (pyrimidin-2-yl) picolinic acid (intermediate 17) 5-Fluoro-3-yl by the same method as in Step 2 of Production Example 12 or a method analogous thereto. Using (pyrimidin-2-yl) methyl picolinate (intermediate 17-1) (0.17 g), the title compound (0.17 g) was obtained as a pale yellow amorphous product.
UPLC: 176 [M-CO 2 ] + (retention time 0.63 minutes)
1 H-NMR (DMSO-d 6 , 300 MHz) δ: 8.95 (2H, d, J = 5 Hz), 8.74 (1H, d, J = 3 Hz), 8.30 (1H, dd, J = 10, 3 Hz ), 7.57 (1H, t, J = 5 Hz).
(製造例18)1-(チアゾール-2-イル)-1H-ピラゾール-5-カルボン酸メチル(中間体18)の合成
文献(J.Med.Chem.2001,44,566-578.)の方法に従い、2-ヒドラジニルチアゾール塩酸塩(1.0g)を用いて、標記化合物(43mg)を黄色液体として得た。
UPLC:210[M+H]+(保持時間0.77分)
1H-NMR (CDCl3, 400MHz) δ: 7.73 (1H, d, J = 2 Hz), 7.68 (1H, d, J = 4 Hz), 7.33 (1H, d, J = 3 Hz), 6.94 (1H, d, J = 2 Hz), 3.88 (3H, s). (Production Example 18) Synthesis of methyl 1- (thiazol-2-yl) -1H-pyrazole-5-carboxylate (intermediate 18) Method of literature (J. Med. Chem. 2001, 44, 566-578.) The title compound (43 mg) was obtained as a yellow liquid using 2-hydrazinylthiazole hydrochloride (1.0 g).
UPLC: 210 [M + H] + (retention time 0.77 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 7.73 (1H, d, J = 2 Hz), 7.68 (1H, d, J = 4 Hz), 7.33 (1H, d, J = 3 Hz), 6.94 ( 1H, d, J = 2 Hz), 3.88 (3H, s).
文献(J.Med.Chem.2001,44,566-578.)の方法に従い、2-ヒドラジニルチアゾール塩酸塩(1.0g)を用いて、標記化合物(43mg)を黄色液体として得た。
UPLC:210[M+H]+(保持時間0.77分)
1H-NMR (CDCl3, 400MHz) δ: 7.73 (1H, d, J = 2 Hz), 7.68 (1H, d, J = 4 Hz), 7.33 (1H, d, J = 3 Hz), 6.94 (1H, d, J = 2 Hz), 3.88 (3H, s). (Production Example 18) Synthesis of methyl 1- (thiazol-2-yl) -1H-pyrazole-5-carboxylate (intermediate 18) Method of literature (J. Med. Chem. 2001, 44, 566-578.) The title compound (43 mg) was obtained as a yellow liquid using 2-hydrazinylthiazole hydrochloride (1.0 g).
UPLC: 210 [M + H] + (retention time 0.77 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 7.73 (1H, d, J = 2 Hz), 7.68 (1H, d, J = 4 Hz), 7.33 (1H, d, J = 3 Hz), 6.94 ( 1H, d, J = 2 Hz), 3.88 (3H, s).
(製造例19)(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン塩酸塩(中間体19)の合成
<工程1>tert-ブチル 3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-カルボキシレート(中間体19-1)の合成
2-(2H-1,2,3-トリアゾール-2-イル)安息香酸(2.1g)のジクロロメタン(25mL)溶液に塩化オキサリル(1.9mL)と触媒量のDMFを加え、窒素雰囲気下、室温にて30分撹拌後、減圧下溶媒を留去した。この残渣をジクロロメタン(10mL)に溶解し、tert-ブチル 3,8-ジアザビシクロ[3.2.1]オクタン-8-カルボキシレート(2.3g)とトリエチルアミン(6.0mL)のジクロロメタン(25mL)混合溶液へ水浴で反応容器を冷やしながら滴下した。反応液を窒素雰囲気下、室温にて30分撹拌後、ろ過、減圧下濃縮後、残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=70:30~40:60)にて精製し、標記化合物(3.9g)を白色アモルファスとして得た。
UPLC:384[M+H]+(保持時間1.05分) Production Example 19 (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3-yl) methanone hydrochloride (intermediate) 19) Synthesis <Step 1> tert-Butyl 3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8- Synthesis of carboxylate (intermediate 19-1) To a solution of 2- (2H-1,2,3-triazol-2-yl) benzoic acid (2.1 g) in dichloromethane (25 mL) was added oxalyl chloride (1.9 mL). A catalytic amount of DMF was added, and the mixture was stirred at room temperature for 30 minutes in a nitrogen atmosphere, and then the solvent was distilled off under reduced pressure. This residue was dissolved in dichloromethane (10 mL), and tert-butyl 3,8-diazabicyclo [3.2.1] octane-8-carboxylate (2.3 g) and triethylamine (6.0 mL) were mixed in dichloromethane (25 mL). The reaction vessel was added dropwise to the solution while cooling the reaction vessel with a water bath. The reaction mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 70: 30 to 40:60) to give the title compound. (3.9 g) was obtained as a white amorphous.
UPLC: 384 [M + H] + (retention time 1.05 minutes)
<工程1>tert-ブチル 3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-カルボキシレート(中間体19-1)の合成
2-(2H-1,2,3-トリアゾール-2-イル)安息香酸(2.1g)のジクロロメタン(25mL)溶液に塩化オキサリル(1.9mL)と触媒量のDMFを加え、窒素雰囲気下、室温にて30分撹拌後、減圧下溶媒を留去した。この残渣をジクロロメタン(10mL)に溶解し、tert-ブチル 3,8-ジアザビシクロ[3.2.1]オクタン-8-カルボキシレート(2.3g)とトリエチルアミン(6.0mL)のジクロロメタン(25mL)混合溶液へ水浴で反応容器を冷やしながら滴下した。反応液を窒素雰囲気下、室温にて30分撹拌後、ろ過、減圧下濃縮後、残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=70:30~40:60)にて精製し、標記化合物(3.9g)を白色アモルファスとして得た。
UPLC:384[M+H]+(保持時間1.05分) Production Example 19 (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3-yl) methanone hydrochloride (intermediate) 19) Synthesis <Step 1> tert-Butyl 3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8- Synthesis of carboxylate (intermediate 19-1) To a solution of 2- (2H-1,2,3-triazol-2-yl) benzoic acid (2.1 g) in dichloromethane (25 mL) was added oxalyl chloride (1.9 mL). A catalytic amount of DMF was added, and the mixture was stirred at room temperature for 30 minutes in a nitrogen atmosphere, and then the solvent was distilled off under reduced pressure. This residue was dissolved in dichloromethane (10 mL), and tert-butyl 3,8-diazabicyclo [3.2.1] octane-8-carboxylate (2.3 g) and triethylamine (6.0 mL) were mixed in dichloromethane (25 mL). The reaction vessel was added dropwise to the solution while cooling the reaction vessel with a water bath. The reaction mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 70: 30 to 40:60) to give the title compound. (3.9 g) was obtained as a white amorphous.
UPLC: 384 [M + H] + (retention time 1.05 minutes)
<工程2>(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン塩酸塩(中間体19)の合成
tert-ブチル 3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-カルボキシレート(中間体19-1)(3.9g)をジクロロメタン(40mL)に溶解させ、4M塩化水素-1,4-ジオキサン溶液(38mL)を加え、室温で2時間攪拌した。反応液を減圧下濃縮し、標記化合物(3.3g)を白色固体として得た。
UPLC:284[M+H]+(保持時間0.58分)
1H-NMR (DMSO-d6, 300MHz) δ: 9.33 (2H, brs), 8.11 (2H, s), 7.99-7.90 (1H, m), 7.70-7.62 (1H, m), 7.59-7.43 (2H, m), 4.38-4.20 (1H, m), 4.15-4.08 (1H, m), 3.93-3.80 (1H, m), 3.70-2.94 (3H, m), 2.05-1.66 (4H, m). <Step 2> (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3-yl) methanone hydrochloride (Intermediate 19 ) Tert-butyl 3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (intermediate) 19-1) (3.9 g) was dissolved in dichloromethane (40 mL), 4M hydrogen chloride-1,4-dioxane solution (38 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure to obtain the title compound (3.3 g) as a white solid.
UPLC: 284 [M + H] + (retention time 0.58 minutes)
1 H-NMR (DMSO-d 6 , 300 MHz) δ: 9.33 (2H, brs), 8.11 (2H, s), 7.99-7.90 (1H, m), 7.70-7.62 (1H, m), 7.59-7.43 ( 2H, m), 4.38-4.20 (1H, m), 4.15-4.08 (1H, m), 3.93-3.80 (1H, m), 3.70-2.94 (3H, m), 2.05-1.66 (4H, m).
tert-ブチル 3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-カルボキシレート(中間体19-1)(3.9g)をジクロロメタン(40mL)に溶解させ、4M塩化水素-1,4-ジオキサン溶液(38mL)を加え、室温で2時間攪拌した。反応液を減圧下濃縮し、標記化合物(3.3g)を白色固体として得た。
UPLC:284[M+H]+(保持時間0.58分)
1H-NMR (DMSO-d6, 300MHz) δ: 9.33 (2H, brs), 8.11 (2H, s), 7.99-7.90 (1H, m), 7.70-7.62 (1H, m), 7.59-7.43 (2H, m), 4.38-4.20 (1H, m), 4.15-4.08 (1H, m), 3.93-3.80 (1H, m), 3.70-2.94 (3H, m), 2.05-1.66 (4H, m). <Step 2> (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3-yl) methanone hydrochloride (Intermediate 19 ) Tert-butyl 3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (intermediate) 19-1) (3.9 g) was dissolved in dichloromethane (40 mL), 4M hydrogen chloride-1,4-dioxane solution (38 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure to obtain the title compound (3.3 g) as a white solid.
UPLC: 284 [M + H] + (retention time 0.58 minutes)
1 H-NMR (DMSO-d 6 , 300 MHz) δ: 9.33 (2H, brs), 8.11 (2H, s), 7.99-7.90 (1H, m), 7.70-7.62 (1H, m), 7.59-7.43 ( 2H, m), 4.38-4.20 (1H, m), 4.15-4.08 (1H, m), 3.93-3.80 (1H, m), 3.70-2.94 (3H, m), 2.05-1.66 (4H, m).
(製造例20)(3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン塩酸塩(中間体20)の合成
製造例19と同様の方法もしくは、これに準ずる方法で2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)安息香酸(1.0g)を用いて標記化合物(1.4g)を無色固体として得た。
UPLC:302[M+H]+(保持時間0.59、0.61分、回転異性体)
1H-NMR (DMSO-d6, 400MHz) δ: 9.35 (2H, brs), 8.18-8.15 (2H, m), 7.90-7.84 (1H, m), 7.74-7.67 (1H, m), 7.50-7.43 (1H, m), 4.34-4.11 (2H, m), 3.94-3.86 (1H, m), 3.70-3.50 (1H, m), 3.39-3.13 (2H, m), 2.06-1.70 (4H, m). (Production Example 20) (3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-6- (2H-1,2,3-triazol-2-yl) phenyl) methanone hydrochloride Synthesis of salt (intermediate 20) 2-Fluoro-6- (2H-1,2,3-triazol-2-yl) benzoic acid (1.0 g) by the same method as in Production Example 19 or a method analogous thereto To give the title compound (1.4 g) as a colorless solid.
UPLC: 302 [M + H] + (retention time 0.59, 0.61 min, rotamer)
1 H-NMR (DMSO-d 6 , 400 MHz) δ: 9.35 (2H, brs), 8.18-8.15 (2H, m), 7.90-7.84 (1H, m), 7.74-7.67 (1H, m), 7.50- 7.43 (1H, m), 4.34-4.11 (2H, m), 3.94-3.86 (1H, m), 3.70-3.50 (1H, m), 3.39-3.13 (2H, m), 2.06-1.70 (4H, m ).
製造例19と同様の方法もしくは、これに準ずる方法で2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)安息香酸(1.0g)を用いて標記化合物(1.4g)を無色固体として得た。
UPLC:302[M+H]+(保持時間0.59、0.61分、回転異性体)
1H-NMR (DMSO-d6, 400MHz) δ: 9.35 (2H, brs), 8.18-8.15 (2H, m), 7.90-7.84 (1H, m), 7.74-7.67 (1H, m), 7.50-7.43 (1H, m), 4.34-4.11 (2H, m), 3.94-3.86 (1H, m), 3.70-3.50 (1H, m), 3.39-3.13 (2H, m), 2.06-1.70 (4H, m). (Production Example 20) (3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-6- (2H-1,2,3-triazol-2-yl) phenyl) methanone hydrochloride Synthesis of salt (intermediate 20) 2-Fluoro-6- (2H-1,2,3-triazol-2-yl) benzoic acid (1.0 g) by the same method as in Production Example 19 or a method analogous thereto To give the title compound (1.4 g) as a colorless solid.
UPLC: 302 [M + H] + (retention time 0.59, 0.61 min, rotamer)
1 H-NMR (DMSO-d 6 , 400 MHz) δ: 9.35 (2H, brs), 8.18-8.15 (2H, m), 7.90-7.84 (1H, m), 7.74-7.67 (1H, m), 7.50- 7.43 (1H, m), 4.34-4.11 (2H, m), 3.94-3.86 (1H, m), 3.70-3.50 (1H, m), 3.39-3.13 (2H, m), 2.06-1.70 (4H, m ).
(製造例21)(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン塩酸塩(中間体21)の合成
製造例19と同様の方法もしくは、これに準ずる方法で2-(1H-ピラゾール-1-イル)ニコチン酸(中間体28)(2.2g)を用いて標記化合物(3.0g)を無色固体として得た。
UPLC:284[M+H]+(保持時間0.53分)
1H-NMR (DMSO-d6, 400MHz) δ: 9.50-9.12 (2H, brm), 8.58-8.52 (2H, m), 8.02-7.87 (1H, m), 7.76 (1H, dd, J = 6, 1 Hz), 7.51-7.44 (1H, m), 6.60-6.56 (1H, m), 4.40-4.09 (2H, m), 3.88-3.79 (1H, m), 3.64-3.04 (3H, m), 2.06-1.67 (4H, m). Production Example 21 (2- (1H-pyrazol-1-yl) pyridin-3-yl) (3,8-diazabicyclo [3.2.1] octane-3-yl) methanone hydrochloride (Intermediate 21) The title compound (3.0 g) was prepared using 2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 28) (2.2 g) in the same manner as in Production Example 19 or a method analogous thereto. Obtained as a colorless solid.
UPLC: 284 [M + H] + (retention time 0.53 minutes)
1 H-NMR (DMSO-d 6 , 400 MHz) δ: 9.50-9.12 (2H, brm), 8.58-8.52 (2H, m), 8.02-7.87 (1H, m), 7.76 (1H, dd, J = 6 , 1 Hz), 7.51-7.44 (1H, m), 6.60-6.56 (1H, m), 4.40-4.09 (2H, m), 3.88-3.79 (1H, m), 3.64-3.04 (3H, m), 2.06-1.67 (4H, m).
製造例19と同様の方法もしくは、これに準ずる方法で2-(1H-ピラゾール-1-イル)ニコチン酸(中間体28)(2.2g)を用いて標記化合物(3.0g)を無色固体として得た。
UPLC:284[M+H]+(保持時間0.53分)
1H-NMR (DMSO-d6, 400MHz) δ: 9.50-9.12 (2H, brm), 8.58-8.52 (2H, m), 8.02-7.87 (1H, m), 7.76 (1H, dd, J = 6, 1 Hz), 7.51-7.44 (1H, m), 6.60-6.56 (1H, m), 4.40-4.09 (2H, m), 3.88-3.79 (1H, m), 3.64-3.04 (3H, m), 2.06-1.67 (4H, m). Production Example 21 (2- (1H-pyrazol-1-yl) pyridin-3-yl) (3,8-diazabicyclo [3.2.1] octane-3-yl) methanone hydrochloride (Intermediate 21) The title compound (3.0 g) was prepared using 2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 28) (2.2 g) in the same manner as in Production Example 19 or a method analogous thereto. Obtained as a colorless solid.
UPLC: 284 [M + H] + (retention time 0.53 minutes)
1 H-NMR (DMSO-d 6 , 400 MHz) δ: 9.50-9.12 (2H, brm), 8.58-8.52 (2H, m), 8.02-7.87 (1H, m), 7.76 (1H, dd, J = 6 , 1 Hz), 7.51-7.44 (1H, m), 6.60-6.56 (1H, m), 4.40-4.09 (2H, m), 3.88-3.79 (1H, m), 3.64-3.04 (3H, m), 2.06-1.67 (4H, m).
(製造例22)1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボン酸(中間体22)の合成
<工程1>メチル 1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボキシレート(中間体22-1)の合成
2-ヒドラジニルピリジン(1.0g)、(E)-メチル 4-(ジメチルアミノ)-2-オキソブト-3-エノエート(2.9g)の酢酸(10mL)混合液を、110℃にて終夜攪拌した。減圧下溶媒を留去し、得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=100:0~70:30)にて精製し、標記化合物(0.72g)を橙色液体として得た。
UPLC:204[M+H]+(保持時間0.75分) Production Example 22 Synthesis of 1- (pyridin-2-yl) -1H-pyrazole-5-carboxylic acid (Intermediate 22) <Step 1> Methyl 1- (pyridin-2-yl) -1H-pyrazole-5 Synthesis of carboxylate (Intermediate 22-1) Acetic acid of 2-hydrazinylpyridine (1.0 g), (E) -methyl 4- (dimethylamino) -2-oxobut-3-enoate (2.9 g) (10 mL) The mixture was stirred at 110 ° C. overnight. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 70:30) to obtain the title compound (0.72 g) as an orange liquid. .
UPLC: 204 [M + H] + (retention time 0.75 minutes)
<工程1>メチル 1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボキシレート(中間体22-1)の合成
2-ヒドラジニルピリジン(1.0g)、(E)-メチル 4-(ジメチルアミノ)-2-オキソブト-3-エノエート(2.9g)の酢酸(10mL)混合液を、110℃にて終夜攪拌した。減圧下溶媒を留去し、得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=100:0~70:30)にて精製し、標記化合物(0.72g)を橙色液体として得た。
UPLC:204[M+H]+(保持時間0.75分) Production Example 22 Synthesis of 1- (pyridin-2-yl) -1H-pyrazole-5-carboxylic acid (Intermediate 22) <Step 1> Methyl 1- (pyridin-2-yl) -1H-pyrazole-5 Synthesis of carboxylate (Intermediate 22-1) Acetic acid of 2-hydrazinylpyridine (1.0 g), (E) -methyl 4- (dimethylamino) -2-oxobut-3-enoate (2.9 g) (10 mL) The mixture was stirred at 110 ° C. overnight. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 70:30) to obtain the title compound (0.72 g) as an orange liquid. .
UPLC: 204 [M + H] + (retention time 0.75 minutes)
<工程2>1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボン酸(中間体22)の合成
メチル 1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボキシレート(中間体22-1)(0.35g)のTHF(2.0mL)-水(0.50mL)混合溶液に水酸化リチウム1水和物(0.11g)を加え、窒素雰囲気下、60℃にて2時間攪拌した。1規定塩酸水溶液を加え反応を停止させた後に、酢酸エチルで抽出し飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して標記化合物(0.33g)を白色固体として得た。
UPLC:212[M+Na]+(保持時間0.67分)
1H-NMR (CDCl3, 300MHz) δ: 8.41-8.37 (1H, m), 8.36-8.32 (1H, m), 8.10-8.03 (1H, m), 7.76 (1H, d, J = 2 Hz), 7.45-7.39 (2H, m). <Step 2> Synthesis of 1- (pyridin-2-yl) -1H-pyrazole-5-carboxylic acid (intermediate 22) Methyl 1- (pyridin-2-yl) -1H-pyrazole-5-carboxylate (intermediate) Lithium hydroxide monohydrate (0.11 g) was added to a THF (2.0 mL) -water (0.50 mL) mixed solution of compound 22-1) (0.35 g), and the mixture was added at 60 ° C. under a nitrogen atmosphere. Stir for 2 hours. 1N Hydrochloric acid aqueous solution was added to stop the reaction, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.33 g) as a white solid.
UPLC: 212 [M + Na] + (retention time 0.67 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.41-8.37 (1H, m), 8.36-8.32 (1H, m), 8.10-8.03 (1H, m), 7.76 (1H, d, J = 2 Hz) , 7.45-7.39 (2H, m).
メチル 1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボキシレート(中間体22-1)(0.35g)のTHF(2.0mL)-水(0.50mL)混合溶液に水酸化リチウム1水和物(0.11g)を加え、窒素雰囲気下、60℃にて2時間攪拌した。1規定塩酸水溶液を加え反応を停止させた後に、酢酸エチルで抽出し飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して標記化合物(0.33g)を白色固体として得た。
UPLC:212[M+Na]+(保持時間0.67分)
1H-NMR (CDCl3, 300MHz) δ: 8.41-8.37 (1H, m), 8.36-8.32 (1H, m), 8.10-8.03 (1H, m), 7.76 (1H, d, J = 2 Hz), 7.45-7.39 (2H, m). <Step 2> Synthesis of 1- (pyridin-2-yl) -1H-pyrazole-5-carboxylic acid (intermediate 22) Methyl 1- (pyridin-2-yl) -1H-pyrazole-5-carboxylate (intermediate) Lithium hydroxide monohydrate (0.11 g) was added to a THF (2.0 mL) -water (0.50 mL) mixed solution of compound 22-1) (0.35 g), and the mixture was added at 60 ° C. under a nitrogen atmosphere. Stir for 2 hours. 1N Hydrochloric acid aqueous solution was added to stop the reaction, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.33 g) as a white solid.
UPLC: 212 [M + Na] + (retention time 0.67 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.41-8.37 (1H, m), 8.36-8.32 (1H, m), 8.10-8.03 (1H, m), 7.76 (1H, d, J = 2 Hz) , 7.45-7.39 (2H, m).
(製造例23)3-シアノ-1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボン酸(中間体23)の合成
ジイソプロピルアミン(0.67mL)のTHF(5mL)溶液、1.6Mのn-BuLi-ヘキサン溶液(2.5mL)から調整したLDA溶液に1-(ピリミジン-2-イル)-1H-ピラゾール-3-カルボニトリル(0.23g)のTHF(5.0mL)溶液を、-78℃にて加え、0℃まで自然昇温させながら1時間攪拌した。反応溶液にドライアイスを加え反応を停止させた後、1規定塩酸水溶液を加え、酢酸エチルで抽出し飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して標記化合物(0.22g)を黄色固体として得た。
UPLC:215[M+H]+(保持時間0.72分) Production Example 23 Synthesis of 3-cyano-1- (pyridin-2-yl) -1H-pyrazole-5-carboxylic acid (Intermediate 23) Diisopropylamine (0.67 mL) in THF (5 mL) A solution of 1- (pyrimidin-2-yl) -1H-pyrazole-3-carbonitrile (0.23 g) in THF (5.0 mL) was added to an LDA solution prepared from a 6M n-BuLi-hexane solution (2.5 mL). Was added at −78 ° C. and stirred for 1 hour while allowing the temperature to rise naturally to 0 ° C. Dry ice was added to the reaction solution to stop the reaction, 1N aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.22 g) as a yellow solid.
UPLC: 215 [M + H] + (retention time 0.72 minutes)
ジイソプロピルアミン(0.67mL)のTHF(5mL)溶液、1.6Mのn-BuLi-ヘキサン溶液(2.5mL)から調整したLDA溶液に1-(ピリミジン-2-イル)-1H-ピラゾール-3-カルボニトリル(0.23g)のTHF(5.0mL)溶液を、-78℃にて加え、0℃まで自然昇温させながら1時間攪拌した。反応溶液にドライアイスを加え反応を停止させた後、1規定塩酸水溶液を加え、酢酸エチルで抽出し飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して標記化合物(0.22g)を黄色固体として得た。
UPLC:215[M+H]+(保持時間0.72分) Production Example 23 Synthesis of 3-cyano-1- (pyridin-2-yl) -1H-pyrazole-5-carboxylic acid (Intermediate 23) Diisopropylamine (0.67 mL) in THF (5 mL) A solution of 1- (pyrimidin-2-yl) -1H-pyrazole-3-carbonitrile (0.23 g) in THF (5.0 mL) was added to an LDA solution prepared from a 6M n-BuLi-hexane solution (2.5 mL). Was added at −78 ° C. and stirred for 1 hour while allowing the temperature to rise naturally to 0 ° C. Dry ice was added to the reaction solution to stop the reaction, 1N aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.22 g) as a yellow solid.
UPLC: 215 [M + H] + (retention time 0.72 minutes)
(製造例24)5-フルオロ-2-(1H-ピラゾール-1-イル)ニコチン酸(中間体24)の合成
2,5-ジフルオロニコチン酸(0.30g)、1H-ピラゾール(0.13g)のDMSO(3.0mL)溶液に、炭酸カリウム(1.0g)を加え、120℃で30分、さらに160℃で2時間攪拌した。反応溶液に水を加え、ろ過した後、ろ液に濃塩酸を加えてpH=2とし、酢酸エチルで抽出した。減圧下溶媒を留去して標記化合物(0.12g)を黄色液体として得た。
UPLC:208[M+H]+(保持時間0.70分) (Production Example 24) Synthesis of 5-fluoro-2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 24) 2,5-difluoronicotinic acid (0.30 g), 1H-pyrazole (0.13 g) Was added to a DMSO (3.0 mL) solution, and the mixture was stirred at 120 ° C. for 30 minutes and further at 160 ° C. for 2 hours. Water was added to the reaction solution and filtered, and then concentrated hydrochloric acid was added to the filtrate to pH = 2, followed by extraction with ethyl acetate. The solvent was distilled off under reduced pressure to obtain the title compound (0.12 g) as a yellow liquid.
UPLC: 208 [M + H] + (Retention time 0.70 minutes)
2,5-ジフルオロニコチン酸(0.30g)、1H-ピラゾール(0.13g)のDMSO(3.0mL)溶液に、炭酸カリウム(1.0g)を加え、120℃で30分、さらに160℃で2時間攪拌した。反応溶液に水を加え、ろ過した後、ろ液に濃塩酸を加えてpH=2とし、酢酸エチルで抽出した。減圧下溶媒を留去して標記化合物(0.12g)を黄色液体として得た。
UPLC:208[M+H]+(保持時間0.70分) (Production Example 24) Synthesis of 5-fluoro-2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 24) 2,5-difluoronicotinic acid (0.30 g), 1H-pyrazole (0.13 g) Was added to a DMSO (3.0 mL) solution, and the mixture was stirred at 120 ° C. for 30 minutes and further at 160 ° C. for 2 hours. Water was added to the reaction solution and filtered, and then concentrated hydrochloric acid was added to the filtrate to pH = 2, followed by extraction with ethyl acetate. The solvent was distilled off under reduced pressure to obtain the title compound (0.12 g) as a yellow liquid.
UPLC: 208 [M + H] + (Retention time 0.70 minutes)
(製造例25)2-(1-メチル-1H-ピラゾール-3-イル)ニコチン酸リチウム(中間体25)の合成
<工程1>2-(1-メチル-1H-ピラゾール-3-イル)ニコチン酸メチル(中間体25-1)の合成
3-ブロモ-1-メチル-1H-ピラゾール(0.70g)、ビス(ピナコラト)ジボロン(1.2g)、PdCl2(dppf)ジクロロメタン付加体(0.18g)、酢酸カリウム(1.3g)の1,4-ジオキサン(8.7mL)混合液を脱気後、窒素雰囲気下110℃で6時間攪拌した。反応液を綿栓ろ過した後、ろ液に2-ブロモニコチン酸メチル(0.94g)、リン酸三カリウム(2.8g)、PdCl2(dppf)ジクロロメタン付加体(0.18g)を加え、窒素雰囲気下110℃で1時間、室温で16時間攪拌した。反応液を酢酸エチルで希釈後、水で洗浄し、有機層を無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=80:20~0:100)にて精製し、標記化合物(0.29g)を茶色液体として得た。
UPLC:218[M+H]+(保持時間0.69分) Production Example 25 Synthesis of Lithium 2- (1-Methyl-1H-pyrazol-3-yl) nicotinate (Intermediate 25) <Step 1> 2- (1-Methyl-1H-pyrazol-3-yl) nicotine Synthesis of methyl acid (intermediate 25-1) 3-Bromo-1-methyl-1H-pyrazole (0.70 g), bis (pinacolato) diboron (1.2 g), PdCl 2 (dppf) dichloromethane adduct (0. 18 g) and potassium acetate (1.3 g) in 1,4-dioxane (8.7 mL) were degassed and then stirred at 110 ° C. for 6 hours under a nitrogen atmosphere. After filtering the reaction solution with a cotton plug, methyl 2-bromonicotinate (0.94 g), tripotassium phosphate (2.8 g) and PdCl 2 (dppf) dichloromethane adduct (0.18 g) were added to the filtrate, and nitrogen was added. The mixture was stirred at 110 ° C. for 1 hour and at room temperature for 16 hours. The reaction solution is diluted with ethyl acetate, washed with water, the organic layer is dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, and the resulting residue is subjected to column chromatography (silica gel, heptane: ethyl acetate = 80: 20 to 0: 100) to give the title compound (0.29 g) as a brown liquid.
UPLC: 218 [M + H] + (retention time 0.69 minutes)
<工程1>2-(1-メチル-1H-ピラゾール-3-イル)ニコチン酸メチル(中間体25-1)の合成
3-ブロモ-1-メチル-1H-ピラゾール(0.70g)、ビス(ピナコラト)ジボロン(1.2g)、PdCl2(dppf)ジクロロメタン付加体(0.18g)、酢酸カリウム(1.3g)の1,4-ジオキサン(8.7mL)混合液を脱気後、窒素雰囲気下110℃で6時間攪拌した。反応液を綿栓ろ過した後、ろ液に2-ブロモニコチン酸メチル(0.94g)、リン酸三カリウム(2.8g)、PdCl2(dppf)ジクロロメタン付加体(0.18g)を加え、窒素雰囲気下110℃で1時間、室温で16時間攪拌した。反応液を酢酸エチルで希釈後、水で洗浄し、有機層を無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=80:20~0:100)にて精製し、標記化合物(0.29g)を茶色液体として得た。
UPLC:218[M+H]+(保持時間0.69分) Production Example 25 Synthesis of Lithium 2- (1-Methyl-1H-pyrazol-3-yl) nicotinate (Intermediate 25) <Step 1> 2- (1-Methyl-1H-pyrazol-3-yl) nicotine Synthesis of methyl acid (intermediate 25-1) 3-Bromo-1-methyl-1H-pyrazole (0.70 g), bis (pinacolato) diboron (1.2 g), PdCl 2 (dppf) dichloromethane adduct (0. 18 g) and potassium acetate (1.3 g) in 1,4-dioxane (8.7 mL) were degassed and then stirred at 110 ° C. for 6 hours under a nitrogen atmosphere. After filtering the reaction solution with a cotton plug, methyl 2-bromonicotinate (0.94 g), tripotassium phosphate (2.8 g) and PdCl 2 (dppf) dichloromethane adduct (0.18 g) were added to the filtrate, and nitrogen was added. The mixture was stirred at 110 ° C. for 1 hour and at room temperature for 16 hours. The reaction solution is diluted with ethyl acetate, washed with water, the organic layer is dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, and the resulting residue is subjected to column chromatography (silica gel, heptane: ethyl acetate = 80: 20 to 0: 100) to give the title compound (0.29 g) as a brown liquid.
UPLC: 218 [M + H] + (retention time 0.69 minutes)
<工程2>2-(1-メチル-1H-ピラゾール-3-イル)ニコチン酸リチウム(中間体25)の合成
2-(1-メチル-1H-ピラゾール-3-イル)ニコチン酸メチル(中間体25-1)(0.28g)のメタノール(1.0mL)-THF(1.0mL)溶液に水酸化リチウム1水和物(60mg)の水溶液(0.50mL)を加え、50℃で6時間加熱した。溶媒の一部を留去した後、0℃に冷やしてろ取し、得られた固体を冷えたTHF-メタノール(3:1)で洗浄し、標記化合物(0.11g)を白色固体として得た。
UPLC:204[M+H]+(保持時間0.36分)
1H-NMR (DMSO-d6, 400MHz) δ: 8.32 (1H, dd, J = 5, 2 Hz), 7.59 (1H, d, J = 2 Hz), 7.45 (1H, dd, J = 7, 2 Hz), 7.13 (1H, dd, J = 7, 5 Hz), 6.71 (1H, d, J = 2 Hz), 3.84 (3H, s). <Step 2> Synthesis of lithium 2- (1-methyl-1H-pyrazol-3-yl) nicotinate (intermediate 25) 2- (1-methyl-1H-pyrazol-3-yl) methyl nicotinate (intermediate) 25-1) (0.28 g) in methanol (1.0 mL) -THF (1.0 mL) was added an aqueous solution (0.50 mL) of lithium hydroxide monohydrate (60 mg) and stirred at 50 ° C. for 6 hours. Heated. A part of the solvent was distilled off, and the mixture was cooled to 0 ° C. and collected by filtration. The obtained solid was washed with cold THF-methanol (3: 1) to obtain the title compound (0.11 g) as a white solid. .
UPLC: 204 [M + H] + (retention time 0.36 minutes)
1 H-NMR (DMSO-d 6 , 400 MHz) δ: 8.32 (1H, dd, J = 5, 2 Hz), 7.59 (1H, d, J = 2 Hz), 7.45 (1H, dd, J = 7, 2 Hz), 7.13 (1H, dd, J = 7, 5 Hz), 6.71 (1H, d, J = 2 Hz), 3.84 (3H, s).
2-(1-メチル-1H-ピラゾール-3-イル)ニコチン酸メチル(中間体25-1)(0.28g)のメタノール(1.0mL)-THF(1.0mL)溶液に水酸化リチウム1水和物(60mg)の水溶液(0.50mL)を加え、50℃で6時間加熱した。溶媒の一部を留去した後、0℃に冷やしてろ取し、得られた固体を冷えたTHF-メタノール(3:1)で洗浄し、標記化合物(0.11g)を白色固体として得た。
UPLC:204[M+H]+(保持時間0.36分)
1H-NMR (DMSO-d6, 400MHz) δ: 8.32 (1H, dd, J = 5, 2 Hz), 7.59 (1H, d, J = 2 Hz), 7.45 (1H, dd, J = 7, 2 Hz), 7.13 (1H, dd, J = 7, 5 Hz), 6.71 (1H, d, J = 2 Hz), 3.84 (3H, s). <Step 2> Synthesis of lithium 2- (1-methyl-1H-pyrazol-3-yl) nicotinate (intermediate 25) 2- (1-methyl-1H-pyrazol-3-yl) methyl nicotinate (intermediate) 25-1) (0.28 g) in methanol (1.0 mL) -THF (1.0 mL) was added an aqueous solution (0.50 mL) of lithium hydroxide monohydrate (60 mg) and stirred at 50 ° C. for 6 hours. Heated. A part of the solvent was distilled off, and the mixture was cooled to 0 ° C. and collected by filtration. The obtained solid was washed with cold THF-methanol (3: 1) to obtain the title compound (0.11 g) as a white solid. .
UPLC: 204 [M + H] + (retention time 0.36 minutes)
1 H-NMR (DMSO-d 6 , 400 MHz) δ: 8.32 (1H, dd, J = 5, 2 Hz), 7.59 (1H, d, J = 2 Hz), 7.45 (1H, dd, J = 7, 2 Hz), 7.13 (1H, dd, J = 7, 5 Hz), 6.71 (1H, d, J = 2 Hz), 3.84 (3H, s).
(製造例26)3-メチル-1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボン酸(中間体26)の合成
<工程1>3-メチル-1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボン酸エチル(中間体26-1)の合成
2-メトキシイミノ-4-オキソペンタン酸エチル(0.40g)と2-ヒドラジニルピリジン(0.35g)の酢酸(3.0mL)溶液を窒素雰囲気下、110℃にて2時間攪拌した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=100:0~90:10)にて精製し、標記化合物(0.15g)を無色液体として得た。
UPLC:232[M+H]+(保持時間0.90分)
1H-NMR (CDCl3, 300MHz) δ: 8.48-8.44 (1H, m), 7.87-7.80 (1H, m), 7.64-7.59 (1H, m), 7.31-7.26 (1H, m), 6.70 (1H, s), 4.28 (2H, q, J = 7 Hz), 2.37 (3H, s), 1.25 (3H, t, J = 7 Hz). Production Example 26 Synthesis of 3-methyl-1- (pyridin-2-yl) -1H-pyrazole-5-carboxylic acid (Intermediate 26) <Step 1> 3-Methyl-1- (pyridin-2-yl) ) Synthesis of ethyl 1H-pyrazole-5-carboxylate (intermediate 26-1) Acetic acid of ethyl 2-methoxyimino-4-oxopentanoate (0.40 g) and 2-hydrazinylpyridine (0.35 g) The (3.0 mL) solution was stirred at 110 ° C. for 2 hours under a nitrogen atmosphere. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 90:10) to obtain the title compound (0.15 g) as a colorless liquid. .
UPLC: 232 [M + H] + (retention time 0.90 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.48-8.44 (1H, m), 7.87-7.80 (1H, m), 7.64-7.59 (1H, m), 7.31-7.26 (1H, m), 6.70 ( 1H, s), 4.28 (2H, q, J = 7 Hz), 2.37 (3H, s), 1.25 (3H, t, J = 7 Hz).
<工程1>3-メチル-1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボン酸エチル(中間体26-1)の合成
2-メトキシイミノ-4-オキソペンタン酸エチル(0.40g)と2-ヒドラジニルピリジン(0.35g)の酢酸(3.0mL)溶液を窒素雰囲気下、110℃にて2時間攪拌した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=100:0~90:10)にて精製し、標記化合物(0.15g)を無色液体として得た。
UPLC:232[M+H]+(保持時間0.90分)
1H-NMR (CDCl3, 300MHz) δ: 8.48-8.44 (1H, m), 7.87-7.80 (1H, m), 7.64-7.59 (1H, m), 7.31-7.26 (1H, m), 6.70 (1H, s), 4.28 (2H, q, J = 7 Hz), 2.37 (3H, s), 1.25 (3H, t, J = 7 Hz). Production Example 26 Synthesis of 3-methyl-1- (pyridin-2-yl) -1H-pyrazole-5-carboxylic acid (Intermediate 26) <Step 1> 3-Methyl-1- (pyridin-2-yl) ) Synthesis of ethyl 1H-pyrazole-5-carboxylate (intermediate 26-1) Acetic acid of ethyl 2-methoxyimino-4-oxopentanoate (0.40 g) and 2-hydrazinylpyridine (0.35 g) The (3.0 mL) solution was stirred at 110 ° C. for 2 hours under a nitrogen atmosphere. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 90:10) to obtain the title compound (0.15 g) as a colorless liquid. .
UPLC: 232 [M + H] + (retention time 0.90 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.48-8.44 (1H, m), 7.87-7.80 (1H, m), 7.64-7.59 (1H, m), 7.31-7.26 (1H, m), 6.70 ( 1H, s), 4.28 (2H, q, J = 7 Hz), 2.37 (3H, s), 1.25 (3H, t, J = 7 Hz).
<工程2>3-メチル-1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボン酸(中間体26)の合成
3-メチル-1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボン酸エチル(中間体26-1)(0.11g)のTHF(1.5mL)-水(0.5mL)混合溶液に水酸化リチウム1水和物(25mg)を加え、窒素雰囲気下、室温にて終夜攪拌した。反応液を酢酸エチルで逆抽出した後、得られた水層に1.0Mの塩酸水溶液を加えて酢酸エチルで抽出し飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して標記化合物(73mg)を得た。
UPLC:226[M+Na]+(保持時間0.78分)
1H-NMR (CDCl3, 300MHz) δ: 8.36-8.32 (1H, m), 8.30-8.26 (1H, m), 8.06-7.99 (1H, m), 7.39-7.33 (1H, m), 7.21 (1H, s), 2.37 (3H, s). <Step 2> Synthesis of 3-methyl-1- (pyridin-2-yl) -1H-pyrazole-5-carboxylic acid (intermediate 26) 3-methyl-1- (pyridin-2-yl) -1H-pyrazole Lithium hydroxide monohydrate (25 mg) was added to a mixed solution of ethyl 5-carboxylate (intermediate 26-1) (0.11 g) in THF (1.5 mL) -water (0.5 mL), and a nitrogen atmosphere was added. The mixture was stirred overnight at room temperature. The reaction solution was back-extracted with ethyl acetate, 1.0 M hydrochloric acid aqueous solution was added to the obtained aqueous layer, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (73 mg).
UPLC: 226 [M + Na] + (retention time 0.78 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.36-8.32 (1H, m), 8.30-8.26 (1H, m), 8.06-7.99 (1H, m), 7.39-7.33 (1H, m), 7.21 ( 1H, s), 2.37 (3H, s).
3-メチル-1-(ピリジン-2-イル)-1H-ピラゾール-5-カルボン酸エチル(中間体26-1)(0.11g)のTHF(1.5mL)-水(0.5mL)混合溶液に水酸化リチウム1水和物(25mg)を加え、窒素雰囲気下、室温にて終夜攪拌した。反応液を酢酸エチルで逆抽出した後、得られた水層に1.0Mの塩酸水溶液を加えて酢酸エチルで抽出し飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して標記化合物(73mg)を得た。
UPLC:226[M+Na]+(保持時間0.78分)
1H-NMR (CDCl3, 300MHz) δ: 8.36-8.32 (1H, m), 8.30-8.26 (1H, m), 8.06-7.99 (1H, m), 7.39-7.33 (1H, m), 7.21 (1H, s), 2.37 (3H, s). <Step 2> Synthesis of 3-methyl-1- (pyridin-2-yl) -1H-pyrazole-5-carboxylic acid (intermediate 26) 3-methyl-1- (pyridin-2-yl) -1H-pyrazole Lithium hydroxide monohydrate (25 mg) was added to a mixed solution of ethyl 5-carboxylate (intermediate 26-1) (0.11 g) in THF (1.5 mL) -water (0.5 mL), and a nitrogen atmosphere was added. The mixture was stirred overnight at room temperature. The reaction solution was back-extracted with ethyl acetate, 1.0 M hydrochloric acid aqueous solution was added to the obtained aqueous layer, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (73 mg).
UPLC: 226 [M + Na] + (retention time 0.78 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.36-8.32 (1H, m), 8.30-8.26 (1H, m), 8.06-7.99 (1H, m), 7.39-7.33 (1H, m), 7.21 ( 1H, s), 2.37 (3H, s).
(製造例27)1-(ピラジン-3-イル)-1H-ピラゾール-5-カルボン酸(中間体27)の合成
製造例22と同様の方法もしくは、これに準ずる方法で、3-ヒドラジニルピリダジン塩酸塩(1.0g)を用いて、標記化合物(0.48g)を黄色固体として得た。
UPLC:191[M+H]+(保持時間0.52分) (Production Example 27) Synthesis of 1- (pyrazin-3-yl) -1H-pyrazole-5-carboxylic acid (intermediate 27) Pyridazine hydrochloride (1.0 g) was used to give the title compound (0.48 g) as a yellow solid.
UPLC: 191 [M + H] + (retention time 0.52 minutes)
製造例22と同様の方法もしくは、これに準ずる方法で、3-ヒドラジニルピリダジン塩酸塩(1.0g)を用いて、標記化合物(0.48g)を黄色固体として得た。
UPLC:191[M+H]+(保持時間0.52分) (Production Example 27) Synthesis of 1- (pyrazin-3-yl) -1H-pyrazole-5-carboxylic acid (intermediate 27) Pyridazine hydrochloride (1.0 g) was used to give the title compound (0.48 g) as a yellow solid.
UPLC: 191 [M + H] + (retention time 0.52 minutes)
(製造例28)2-(1H-ピラゾール-1-イル)ニコチン酸(中間体28)の合成
<工程1>2-(1H-ピラゾール-1-イル)ニコチン酸エチル(中間体28-1)の合成
2-クロロニコチン酸エチル(25g)、1H-ピラゾール(18g)、炭酸カリウム(56g)、フッ化セシウム(20g)のDMSO(140mL)混合液を窒素雰囲気下、120℃(内温)で3時間加熱した。反応液を室温へ冷却後、水(300mL)を加え、ヘプタン-酢酸エチル(2:1)混合溶媒(600mL)で抽出した。抽出液を水(300mL×2)と飽和食塩水(200mL)で順次洗浄後、有機層を無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して標記化合物(20g)を得た。
UPLC:218[M+H]+(保持時間0.86分) (Production Example 28) Synthesis of 2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 28) <Step 1> Ethyl 2- (1H-pyrazol-1-yl) nicotinate (intermediate 28-1) Synthesis of DMSO (140 mL) mixture of ethyl 2-chloronicotinate (25 g), 1H-pyrazole (18 g), potassium carbonate (56 g), cesium fluoride (20 g) at 120 ° C. (internal temperature) under nitrogen atmosphere Heated for 3 hours. The reaction mixture was cooled to room temperature, water (300 mL) was added, and the mixture was extracted with a mixed solvent (600 mL) of heptane-ethyl acetate (2: 1). The extract was washed successively with water (300 mL × 2) and saturated brine (200 mL), then the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (20 g).
UPLC: 218 [M + H] + (retention time 0.86 minutes)
<工程1>2-(1H-ピラゾール-1-イル)ニコチン酸エチル(中間体28-1)の合成
2-クロロニコチン酸エチル(25g)、1H-ピラゾール(18g)、炭酸カリウム(56g)、フッ化セシウム(20g)のDMSO(140mL)混合液を窒素雰囲気下、120℃(内温)で3時間加熱した。反応液を室温へ冷却後、水(300mL)を加え、ヘプタン-酢酸エチル(2:1)混合溶媒(600mL)で抽出した。抽出液を水(300mL×2)と飽和食塩水(200mL)で順次洗浄後、有機層を無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して標記化合物(20g)を得た。
UPLC:218[M+H]+(保持時間0.86分) (Production Example 28) Synthesis of 2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 28) <Step 1> Ethyl 2- (1H-pyrazol-1-yl) nicotinate (intermediate 28-1) Synthesis of DMSO (140 mL) mixture of ethyl 2-chloronicotinate (25 g), 1H-pyrazole (18 g), potassium carbonate (56 g), cesium fluoride (20 g) at 120 ° C. (internal temperature) under nitrogen atmosphere Heated for 3 hours. The reaction mixture was cooled to room temperature, water (300 mL) was added, and the mixture was extracted with a mixed solvent (600 mL) of heptane-ethyl acetate (2: 1). The extract was washed successively with water (300 mL × 2) and saturated brine (200 mL), then the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (20 g).
UPLC: 218 [M + H] + (retention time 0.86 minutes)
<工程2>2-(1H-ピラゾール-1-イル)ニコチン酸(中間体28)の合成
2-(1H-ピラゾール-1-イル)ニコチン酸エチル(中間体28-1)(20g)と水酸化ナトリウム(7.3g)のTHF(150mL)-水(150mL)混合溶液を室温で3日間攪拌した。反応液を減圧下濃縮してTHFを留去した後、MTBE(100mL)で水層を洗浄した。水層を濃塩酸でpH=1にした後、酢酸エチル(450mL×2)で抽出した。集めた抽出液を飽和食塩水(90mL)で洗浄し、無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して標記化合物(17g)を得た。
UPLC:190[M+H]+(保持時間0.64分)
1H-NMR (DMSO-d6, 400MHz) δ: 13.18 (1H, brs), 8.57 (1H, dd, J = 5, 2 Hz), 8.48-8.46 (1H, m), 8.07 (1H, dd, J = 8, 2 Hz), 7.77-7.75 (1H, m), 7.48 (1H, dd, J = 8, 5 Hz), 6.56 (1H, dd, J = 3, 2 Hz). <Step 2> Synthesis of 2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 28) Ethyl 2- (1H-pyrazol-1-yl) nicotinate (intermediate 28-1) (20 g) and water A mixed solution of sodium oxide (7.3 g) in THF (150 mL) -water (150 mL) was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure to remove THF, and the aqueous layer was washed with MTBE (100 mL). The aqueous layer was adjusted to pH = 1 with concentrated hydrochloric acid, and extracted with ethyl acetate (450 mL × 2). The collected extract was washed with saturated brine (90 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (17 g).
UPLC: 190 [M + H] + (retention time 0.64 minutes)
1 H-NMR (DMSO-d 6 , 400 MHz) δ: 13.18 (1H, brs), 8.57 (1H, dd, J = 5, 2 Hz), 8.48-8.46 (1H, m), 8.07 (1H, dd, J = 8, 2 Hz), 7.77-7.75 (1H, m), 7.48 (1H, dd, J = 8, 5 Hz), 6.56 (1H, dd, J = 3, 2 Hz).
2-(1H-ピラゾール-1-イル)ニコチン酸エチル(中間体28-1)(20g)と水酸化ナトリウム(7.3g)のTHF(150mL)-水(150mL)混合溶液を室温で3日間攪拌した。反応液を減圧下濃縮してTHFを留去した後、MTBE(100mL)で水層を洗浄した。水層を濃塩酸でpH=1にした後、酢酸エチル(450mL×2)で抽出した。集めた抽出液を飽和食塩水(90mL)で洗浄し、無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して標記化合物(17g)を得た。
UPLC:190[M+H]+(保持時間0.64分)
1H-NMR (DMSO-d6, 400MHz) δ: 13.18 (1H, brs), 8.57 (1H, dd, J = 5, 2 Hz), 8.48-8.46 (1H, m), 8.07 (1H, dd, J = 8, 2 Hz), 7.77-7.75 (1H, m), 7.48 (1H, dd, J = 8, 5 Hz), 6.56 (1H, dd, J = 3, 2 Hz). <Step 2> Synthesis of 2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 28) Ethyl 2- (1H-pyrazol-1-yl) nicotinate (intermediate 28-1) (20 g) and water A mixed solution of sodium oxide (7.3 g) in THF (150 mL) -water (150 mL) was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure to remove THF, and the aqueous layer was washed with MTBE (100 mL). The aqueous layer was adjusted to pH = 1 with concentrated hydrochloric acid, and extracted with ethyl acetate (450 mL × 2). The collected extract was washed with saturated brine (90 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (17 g).
UPLC: 190 [M + H] + (retention time 0.64 minutes)
1 H-NMR (DMSO-d 6 , 400 MHz) δ: 13.18 (1H, brs), 8.57 (1H, dd, J = 5, 2 Hz), 8.48-8.46 (1H, m), 8.07 (1H, dd, J = 8, 2 Hz), 7.77-7.75 (1H, m), 7.48 (1H, dd, J = 8, 5 Hz), 6.56 (1H, dd, J = 3, 2 Hz).
(製造例29)2-(1H-1,2,3-トリアゾール-1-イル)ニコチン酸(中間体29-1)及び2-(2H-1,2,3-トリアゾール-2-イル)ニコチン酸(中間体29-2)の合成
2-クロロニコチン酸(5.0g)、ヨウ化銅(I)(0.30g)、炭酸セシウム(21g)、1H-1,2,3-トリアゾール(4.4g)、トランス-N,N’-ジメチルシクロヘキサン-1,2-ジアミン(0.90g)の1,4-ジオキサン(40mL)-水(0.50mL)混合液を窒素雰囲気下、100℃で4時間攪拌した。反応液を室温へ冷却し、2規定塩酸(10mL)で酸性にした後、酢酸エチル(50mL×3)で抽出した。集めた抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して得られた粗生成物を酢酸エチル-石油エーテル(1:2)の混合溶媒でトリチュレートして、中間体29-1(0.90g)を白色固体として得た。その後、ろ液から酢酸エチル-石油エーテルの混合溶媒で再結晶により中間体29-2(0.44g)を白色固体として得た。
(中間体29-1)UPLC:191[M+H]+(保持時間0.53分)
1H-NMR (DMSO-d6, 400MHz): δ: 8.77-8.68 (2H, m), 8.37-8.30 (1H, m), 7.95 (1H, s), 7.75-7.68 (1H, m).
(中間体29-2)UPLC:191[M+H]+(保持時間0.51分)
1H-NMR (DMSO-d6, 400MHz): δ: 8.76-8.69 (1H, m), 8.31-8.25 (1H, m), 8.13 (2H, s), 7.74-7.67 (1H, m).
(製造例30)2-クロロ-6-(2H-1,2,3-トリアゾール-2-イル)安息香酸(中間体30)
製造例14と同様の方法もしくは、これに準ずる方法で2-ブロモ-6-クロロ安息香酸(2.0g)から標記化合物(0.80g)を橙色アモルファスとして得た。
UPLC:179[M-CO2]+(保持時間0.80分)
1H-NMR (DMSO-d6, 300MHz) δ: 13.68 (1H, brs), 8.16 (2H, s), 7.96-7.91 (1H, m), 7.66-7.62 (2H, m). Production Example 29 2- (1H-1,2,3-triazol-1-yl) nicotinic acid (intermediate 29-1) and 2- (2H-1,2,3-triazol-2-yl) nicotine Synthesis of acid (intermediate 29-2) 2-chloronicotinic acid (5.0 g), copper (I) iodide (0.30 g), cesium carbonate (21 g), 1H-1,2,3-triazole (4 .4 g), a mixture of trans-N, N′-dimethylcyclohexane-1,2-diamine (0.90 g) in 1,4-dioxane (40 mL) -water (0.50 mL) at 100 ° C. under a nitrogen atmosphere. Stir for 4 hours. The reaction mixture was cooled to room temperature, acidified with 2N hydrochloric acid (10 mL), and extracted with ethyl acetate (50 mL × 3). The collected extract was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was triturated with a mixed solvent of ethyl acetate-petroleum ether (1: 2). Intermediate 29-1 (0.90 g) was obtained as a white solid. Thereafter, intermediate 29-2 (0.44 g) was obtained as a white solid by recrystallization from the filtrate with a mixed solvent of ethyl acetate-petroleum ether.
(Intermediate 29-1) UPLC: 191 [M + H] + (retention time 0.53 minutes)
1 H-NMR (DMSO-d 6 , 400 MHz): δ: 8.77-8.68 (2H, m), 8.37-8.30 (1H, m), 7.95 (1H, s), 7.75-7.68 (1H, m).
(Intermediate 29-2) UPLC: 191 [M + H] + (retention time 0.51 min)
1 H-NMR (DMSO-d 6 , 400 MHz): δ: 8.76-8.69 (1H, m), 8.31-8.25 (1H, m), 8.13 (2H, s), 7.74-7.67 (1H, m).
Production Example 30 2-Chloro-6- (2H-1,2,3-triazol-2-yl) benzoic acid (Intermediate 30)
The title compound (0.80 g) was obtained as an orange amorphous form from 2-bromo-6-chlorobenzoic acid (2.0 g) by the same method as in Production Example 14 or a method analogous thereto.
UPLC: 179 [M-CO 2 ] + (retention time 0.80 minutes)
1 H-NMR (DMSO-d 6 , 300 MHz) δ: 13.68 (1H, brs), 8.16 (2H, s), 7.96-7.91 (1H, m), 7.66-7.62 (2H, m).
2-クロロニコチン酸(5.0g)、ヨウ化銅(I)(0.30g)、炭酸セシウム(21g)、1H-1,2,3-トリアゾール(4.4g)、トランス-N,N’-ジメチルシクロヘキサン-1,2-ジアミン(0.90g)の1,4-ジオキサン(40mL)-水(0.50mL)混合液を窒素雰囲気下、100℃で4時間攪拌した。反応液を室温へ冷却し、2規定塩酸(10mL)で酸性にした後、酢酸エチル(50mL×3)で抽出した。集めた抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して得られた粗生成物を酢酸エチル-石油エーテル(1:2)の混合溶媒でトリチュレートして、中間体29-1(0.90g)を白色固体として得た。その後、ろ液から酢酸エチル-石油エーテルの混合溶媒で再結晶により中間体29-2(0.44g)を白色固体として得た。
(中間体29-1)UPLC:191[M+H]+(保持時間0.53分)
1H-NMR (DMSO-d6, 400MHz): δ: 8.77-8.68 (2H, m), 8.37-8.30 (1H, m), 7.95 (1H, s), 7.75-7.68 (1H, m).
(中間体29-2)UPLC:191[M+H]+(保持時間0.51分)
1H-NMR (DMSO-d6, 400MHz): δ: 8.76-8.69 (1H, m), 8.31-8.25 (1H, m), 8.13 (2H, s), 7.74-7.67 (1H, m).
(製造例30)2-クロロ-6-(2H-1,2,3-トリアゾール-2-イル)安息香酸(中間体30)
製造例14と同様の方法もしくは、これに準ずる方法で2-ブロモ-6-クロロ安息香酸(2.0g)から標記化合物(0.80g)を橙色アモルファスとして得た。
UPLC:179[M-CO2]+(保持時間0.80分)
1H-NMR (DMSO-d6, 300MHz) δ: 13.68 (1H, brs), 8.16 (2H, s), 7.96-7.91 (1H, m), 7.66-7.62 (2H, m). Production Example 29 2- (1H-1,2,3-triazol-1-yl) nicotinic acid (intermediate 29-1) and 2- (2H-1,2,3-triazol-2-yl) nicotine Synthesis of acid (intermediate 29-2) 2-chloronicotinic acid (5.0 g), copper (I) iodide (0.30 g), cesium carbonate (21 g), 1H-1,2,3-triazole (4 .4 g), a mixture of trans-N, N′-dimethylcyclohexane-1,2-diamine (0.90 g) in 1,4-dioxane (40 mL) -water (0.50 mL) at 100 ° C. under a nitrogen atmosphere. Stir for 4 hours. The reaction mixture was cooled to room temperature, acidified with 2N hydrochloric acid (10 mL), and extracted with ethyl acetate (50 mL × 3). The collected extract was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was triturated with a mixed solvent of ethyl acetate-petroleum ether (1: 2). Intermediate 29-1 (0.90 g) was obtained as a white solid. Thereafter, intermediate 29-2 (0.44 g) was obtained as a white solid by recrystallization from the filtrate with a mixed solvent of ethyl acetate-petroleum ether.
(Intermediate 29-1) UPLC: 191 [M + H] + (retention time 0.53 minutes)
1 H-NMR (DMSO-d 6 , 400 MHz): δ: 8.77-8.68 (2H, m), 8.37-8.30 (1H, m), 7.95 (1H, s), 7.75-7.68 (1H, m).
(Intermediate 29-2) UPLC: 191 [M + H] + (retention time 0.51 min)
1 H-NMR (DMSO-d 6 , 400 MHz): δ: 8.76-8.69 (1H, m), 8.31-8.25 (1H, m), 8.13 (2H, s), 7.74-7.67 (1H, m).
Production Example 30 2-Chloro-6- (2H-1,2,3-triazol-2-yl) benzoic acid (Intermediate 30)
The title compound (0.80 g) was obtained as an orange amorphous form from 2-bromo-6-chlorobenzoic acid (2.0 g) by the same method as in Production Example 14 or a method analogous thereto.
UPLC: 179 [M-CO 2 ] + (retention time 0.80 minutes)
1 H-NMR (DMSO-d 6 , 300 MHz) δ: 13.68 (1H, brs), 8.16 (2H, s), 7.96-7.91 (1H, m), 7.66-7.62 (2H, m).
(製造例31)2-(チアゾール-2-イル)ニコチン酸(中間体31)の合成
製造例17と同様の方法もしくは、これに準ずる方法で2-ブロモニコチン酸メチル(0.25g)と2-(トリブチルスズ)チアゾール(0.43g)から標記化合物(57mg)を淡黄色固体として得た。
UPLC:229[M+Na]+(保持時間0.72分)
1H-NMR (DMSO-d6, 400MHz) δ: 8.70 (1H, dd, J = 5, 2 Hz), 8.01-7.89 (3H, m), 7.55 (1H, dd, J = 8, 5 Hz). Production Example 31 Synthesis of 2- (thiazol-2-yl) nicotinic acid (Intermediate 31) In the same manner as in Production Example 17 or a method analogous thereto, The title compound (57 mg) was obtained as a pale yellow solid from-(tributyltin) thiazole (0.43 g).
UPLC: 229 [M + Na] + (retention time 0.72 minutes)
1 H-NMR (DMSO-d 6 , 400 MHz) δ: 8.70 (1H, dd, J = 5, 2 Hz), 8.01-7.89 (3H, m), 7.55 (1H, dd, J = 8, 5 Hz) .
製造例17と同様の方法もしくは、これに準ずる方法で2-ブロモニコチン酸メチル(0.25g)と2-(トリブチルスズ)チアゾール(0.43g)から標記化合物(57mg)を淡黄色固体として得た。
UPLC:229[M+Na]+(保持時間0.72分)
1H-NMR (DMSO-d6, 400MHz) δ: 8.70 (1H, dd, J = 5, 2 Hz), 8.01-7.89 (3H, m), 7.55 (1H, dd, J = 8, 5 Hz). Production Example 31 Synthesis of 2- (thiazol-2-yl) nicotinic acid (Intermediate 31) In the same manner as in Production Example 17 or a method analogous thereto, The title compound (57 mg) was obtained as a pale yellow solid from-(tributyltin) thiazole (0.43 g).
UPLC: 229 [M + Na] + (retention time 0.72 minutes)
1 H-NMR (DMSO-d 6 , 400 MHz) δ: 8.70 (1H, dd, J = 5, 2 Hz), 8.01-7.89 (3H, m), 7.55 (1H, dd, J = 8, 5 Hz) .
(製造例32)4-エトキシ-2-(1H-ピラゾール-1-イル)ニコチン酸(中間体32)の合成
<工程1>2-クロロ-4-エトキシニコチン酸エチル(中間体32-1)の合成
2,4-ジクロロニコチン酸エチル(1.0g)のエタノール(15mL)溶液に20%ナトリウムエトキシド-エタノール溶液(1.4mL)を加えて、窒素雰囲気下、40℃で13時間攪拌した。反応液に飽和塩化アンモニウム水溶液(30mL)を加えて酢酸エチル(150mL)で抽出した。抽出液を水(30mL)と飽和食塩水(30mL)で順次洗浄し、無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=92:8~30:70)にて精製し、標記化合物(0.75g)を橙色液体として得た。
UPLC:230、232[M+H]+(保持時間0.93分)
1H-NMR (CDCl3, 400MHz) δ: 8.26 (1H, d, J = 6 Hz), 6.79 (1H, d, J = 6 Hz), 4.43 (2H, q, J = 7 Hz), 4.14 (2H, q, J = 7 Hz), 1.46-1.37 (6H, m). Production Example 32 Synthesis of 4-ethoxy-2- (1H-pyrazol-1-yl) nicotinic acid (Intermediate 32) <Step 1> Ethyl 2-chloro-4-ethoxynicotinate (Intermediate 32-1) A 20% sodium ethoxide-ethanol solution (1.4 mL) was added to a solution of ethyl 2,4-dichloronicotinate (1.0 g) in ethanol (15 mL), and the mixture was stirred at 40 ° C. for 13 hours under a nitrogen atmosphere. . A saturated aqueous ammonium chloride solution (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL). The extract was washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 92: 8-30: 70) to give the title compound (0.75 g) as an orange liquid.
UPLC: 230, 232 [M + H] + (retention time 0.93 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.26 (1H, d, J = 6 Hz), 6.79 (1H, d, J = 6 Hz), 4.43 (2H, q, J = 7 Hz), 4.14 ( 2H, q, J = 7 Hz), 1.46-1.37 (6H, m).
<工程1>2-クロロ-4-エトキシニコチン酸エチル(中間体32-1)の合成
2,4-ジクロロニコチン酸エチル(1.0g)のエタノール(15mL)溶液に20%ナトリウムエトキシド-エタノール溶液(1.4mL)を加えて、窒素雰囲気下、40℃で13時間攪拌した。反応液に飽和塩化アンモニウム水溶液(30mL)を加えて酢酸エチル(150mL)で抽出した。抽出液を水(30mL)と飽和食塩水(30mL)で順次洗浄し、無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=92:8~30:70)にて精製し、標記化合物(0.75g)を橙色液体として得た。
UPLC:230、232[M+H]+(保持時間0.93分)
1H-NMR (CDCl3, 400MHz) δ: 8.26 (1H, d, J = 6 Hz), 6.79 (1H, d, J = 6 Hz), 4.43 (2H, q, J = 7 Hz), 4.14 (2H, q, J = 7 Hz), 1.46-1.37 (6H, m). Production Example 32 Synthesis of 4-ethoxy-2- (1H-pyrazol-1-yl) nicotinic acid (Intermediate 32) <Step 1> Ethyl 2-chloro-4-ethoxynicotinate (Intermediate 32-1) A 20% sodium ethoxide-ethanol solution (1.4 mL) was added to a solution of ethyl 2,4-dichloronicotinate (1.0 g) in ethanol (15 mL), and the mixture was stirred at 40 ° C. for 13 hours under a nitrogen atmosphere. . A saturated aqueous ammonium chloride solution (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL). The extract was washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 92: 8-30: 70) to give the title compound (0.75 g) as an orange liquid.
UPLC: 230, 232 [M + H] + (retention time 0.93 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.26 (1H, d, J = 6 Hz), 6.79 (1H, d, J = 6 Hz), 4.43 (2H, q, J = 7 Hz), 4.14 ( 2H, q, J = 7 Hz), 1.46-1.37 (6H, m).
<工程2>4-エトキシ-2-(1H-ピラゾール-1-イル)ニコチン酸エチル(中間体32-2)
2-クロロ-4-エトキシニコチン酸エチル(中間体32-1)(0.75g)、1H-ピラゾール(0.44g)、炭酸カリウム(1.4g)、フッ化セシウム(0.50g)のDMSO(3.3mL)混合液を窒素雰囲気下、130℃で17時間攪拌した。反応液を室温へ冷却後、水(50mL)を加えてヘプタン-酢酸エチル(2:1)混合溶液(100mL)で抽出した。抽出液を水(30mL)と飽和食塩水(30mL)で順次洗浄し、無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=92:8~30:70)にて精製し、標記化合物(0.31g)を淡黄色液体として得た。
UPLC:284[M+Na]+(保持時間0.94分) <Step 2> Ethyl 4-ethoxy-2- (1H-pyrazol-1-yl) nicotinate (Intermediate 32-2)
DMSO of ethyl 2-chloro-4-ethoxynicotinate (intermediate 32-1) (0.75 g), 1H-pyrazole (0.44 g), potassium carbonate (1.4 g), cesium fluoride (0.50 g) The (3.3 mL) mixture was stirred at 130 ° C. for 17 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with a mixed solution of heptane-ethyl acetate (2: 1) (100 mL). The extract was washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 92: 8 to 30:70) to obtain the title compound (0.31 g) as a pale yellow liquid.
UPLC: 284 [M + Na] + (retention time 0.94 minutes)
2-クロロ-4-エトキシニコチン酸エチル(中間体32-1)(0.75g)、1H-ピラゾール(0.44g)、炭酸カリウム(1.4g)、フッ化セシウム(0.50g)のDMSO(3.3mL)混合液を窒素雰囲気下、130℃で17時間攪拌した。反応液を室温へ冷却後、水(50mL)を加えてヘプタン-酢酸エチル(2:1)混合溶液(100mL)で抽出した。抽出液を水(30mL)と飽和食塩水(30mL)で順次洗浄し、無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=92:8~30:70)にて精製し、標記化合物(0.31g)を淡黄色液体として得た。
UPLC:284[M+Na]+(保持時間0.94分) <Step 2> Ethyl 4-ethoxy-2- (1H-pyrazol-1-yl) nicotinate (Intermediate 32-2)
DMSO of ethyl 2-chloro-4-ethoxynicotinate (intermediate 32-1) (0.75 g), 1H-pyrazole (0.44 g), potassium carbonate (1.4 g), cesium fluoride (0.50 g) The (3.3 mL) mixture was stirred at 130 ° C. for 17 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with a mixed solution of heptane-ethyl acetate (2: 1) (100 mL). The extract was washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 92: 8 to 30:70) to obtain the title compound (0.31 g) as a pale yellow liquid.
UPLC: 284 [M + Na] + (retention time 0.94 minutes)
<工程3>4-エトキシ-2-(1H-ピラゾール-1-イル)ニコチン酸(中間体32)の合成
4-エトキシ-2-(1H-ピラゾール-1-イル)ニコチン酸エチル(中間体32-2)(0.30g)と水酸化リチウム(0.14g)のTHF(2.9mL)-水(2.9mL)混合溶液を窒素雰囲気下、50℃で3日間攪拌した。反応液を室温へ冷却後、減圧下濃縮してTHFを留去し、水層をMTBE(30mL)で洗浄した。水層を2規定塩酸でpH=1にした後、酢酸エチル(30mL×2)で抽出した。集めた抽出液を飽和食塩水(10mL)で洗浄し、無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して標記化合物(0.25g)を淡黄色固体として得た。
UPLC:256[M+Na]+(保持時間0.69分)
1H-NMR (DMSO-d6, 400MHz) δ: 12.97 (1H, brs), 8.53-8.49 (1H, m), 8.36 (1H, d, J = 6 Hz), 7.74-7.70 (1H, m), 7.14 (1H, d, J = 6 Hz), 6.54-6.52 (1H, m), 4.23 (2H, q, J = 7 Hz), 1.33 (3H, t, J = 7 Hz). <Step 3> Synthesis of 4-ethoxy-2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 32) Ethyl 4-ethoxy-2- (1H-pyrazol-1-yl) nicotinate (intermediate 32) -2) A mixed solution of (0.30 g) and lithium hydroxide (0.14 g) in THF (2.9 mL) -water (2.9 mL) was stirred at 50 ° C. for 3 days in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove THF, and the aqueous layer was washed with MTBE (30 mL). The aqueous layer was adjusted to pH = 1 with 2N hydrochloric acid, and extracted with ethyl acetate (30 mL × 2). The collected extract was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.25 g) as a pale yellow solid.
UPLC: 256 [M + Na] + (retention time 0.69 minutes)
1 H-NMR (DMSO-d 6 , 400 MHz) δ: 12.97 (1H, brs), 8.53-8.49 (1H, m), 8.36 (1H, d, J = 6 Hz), 7.74-7.70 (1H, m) , 7.14 (1H, d, J = 6 Hz), 6.54-6.52 (1H, m), 4.23 (2H, q, J = 7 Hz), 1.33 (3H, t, J = 7 Hz).
4-エトキシ-2-(1H-ピラゾール-1-イル)ニコチン酸エチル(中間体32-2)(0.30g)と水酸化リチウム(0.14g)のTHF(2.9mL)-水(2.9mL)混合溶液を窒素雰囲気下、50℃で3日間攪拌した。反応液を室温へ冷却後、減圧下濃縮してTHFを留去し、水層をMTBE(30mL)で洗浄した。水層を2規定塩酸でpH=1にした後、酢酸エチル(30mL×2)で抽出した。集めた抽出液を飽和食塩水(10mL)で洗浄し、無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して標記化合物(0.25g)を淡黄色固体として得た。
UPLC:256[M+Na]+(保持時間0.69分)
1H-NMR (DMSO-d6, 400MHz) δ: 12.97 (1H, brs), 8.53-8.49 (1H, m), 8.36 (1H, d, J = 6 Hz), 7.74-7.70 (1H, m), 7.14 (1H, d, J = 6 Hz), 6.54-6.52 (1H, m), 4.23 (2H, q, J = 7 Hz), 1.33 (3H, t, J = 7 Hz). <Step 3> Synthesis of 4-ethoxy-2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 32) Ethyl 4-ethoxy-2- (1H-pyrazol-1-yl) nicotinate (intermediate 32) -2) A mixed solution of (0.30 g) and lithium hydroxide (0.14 g) in THF (2.9 mL) -water (2.9 mL) was stirred at 50 ° C. for 3 days in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove THF, and the aqueous layer was washed with MTBE (30 mL). The aqueous layer was adjusted to pH = 1 with 2N hydrochloric acid, and extracted with ethyl acetate (30 mL × 2). The collected extract was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.25 g) as a pale yellow solid.
UPLC: 256 [M + Na] + (retention time 0.69 minutes)
1 H-NMR (DMSO-d 6 , 400 MHz) δ: 12.97 (1H, brs), 8.53-8.49 (1H, m), 8.36 (1H, d, J = 6 Hz), 7.74-7.70 (1H, m) , 7.14 (1H, d, J = 6 Hz), 6.54-6.52 (1H, m), 4.23 (2H, q, J = 7 Hz), 1.33 (3H, t, J = 7 Hz).
(製造例33)4-メトキシ-2-(1H-ピラゾール-1-イル)ニコチン酸リチウム(中間体33)の合成
<工程1>2-クロロ-4-メトキシニコチン酸エチル(中間体33-1)の合成
2,4-ジクロロニコチン酸エチル(1.0g)のメタノール溶液(15mL)にナトリウム tert-ブトキシド(0.87g)を加え、窒素雰囲気下、50℃で13時間攪拌した。反応液を室温へ冷却した後、飽和塩化アンモニウム水溶液(30mL)を加え、酢酸エチル(150mL)で抽出した。集めた抽出液を水(30mL)と飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=92:8~30:70)にて精製し、標記化合物(0.84g)を無色液体として得た。
UPLC:216、218[M+H]+(保持時間0.87分) Production Example 33 Synthesis of Lithium 4-methoxy-2- (1H-pyrazol-1-yl) nicotinate (Intermediate 33) <Step 1> Ethyl 2-chloro-4-methoxynicotinate (Intermediate 33-1) ) To a methanol solution (15 mL) of ethyl 2,4-dichloronicotinate (1.0 g) was added sodium tert-butoxide (0.87 g), and the mixture was stirred at 50 ° C. for 13 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution (30 mL) was added, and the mixture was extracted with ethyl acetate (150 mL). The collected extract was washed successively with water (30 mL) and saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 92 : 8 to 30:70) to obtain the title compound (0.84 g) as a colorless liquid.
UPLC: 216, 218 [M + H] + (retention time 0.87 minutes)
<工程1>2-クロロ-4-メトキシニコチン酸エチル(中間体33-1)の合成
2,4-ジクロロニコチン酸エチル(1.0g)のメタノール溶液(15mL)にナトリウム tert-ブトキシド(0.87g)を加え、窒素雰囲気下、50℃で13時間攪拌した。反応液を室温へ冷却した後、飽和塩化アンモニウム水溶液(30mL)を加え、酢酸エチル(150mL)で抽出した。集めた抽出液を水(30mL)と飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=92:8~30:70)にて精製し、標記化合物(0.84g)を無色液体として得た。
UPLC:216、218[M+H]+(保持時間0.87分) Production Example 33 Synthesis of Lithium 4-methoxy-2- (1H-pyrazol-1-yl) nicotinate (Intermediate 33) <Step 1> Ethyl 2-chloro-4-methoxynicotinate (Intermediate 33-1) ) To a methanol solution (15 mL) of ethyl 2,4-dichloronicotinate (1.0 g) was added sodium tert-butoxide (0.87 g), and the mixture was stirred at 50 ° C. for 13 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution (30 mL) was added, and the mixture was extracted with ethyl acetate (150 mL). The collected extract was washed successively with water (30 mL) and saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 92 : 8 to 30:70) to obtain the title compound (0.84 g) as a colorless liquid.
UPLC: 216, 218 [M + H] + (retention time 0.87 minutes)
<工程2>4-メトキシ-2-(1H-ピラゾール-1-イル)ニコチン酸エチル(中間体33-2)の合成
製造例32の工程2と同様の方法もしくは、これに準ずる方法で、2-クロロ-4-メトキシニコチン酸エチル(中間体33-1)(0.84g)から標記化合物(30mg)を淡黄色液体として得た。
UPLC:270[M+Na]+(保持時間0.89分) <Step 2> Synthesis of ethyl 4-methoxy-2- (1H-pyrazol-1-yl) nicotinate (Intermediate 33-2) The title compound (30 mg) was obtained as a pale yellow liquid from ethyl chloro-4-methoxynicotinate (intermediate 33-1) (0.84 g).
UPLC: 270 [M + Na] + (retention time 0.89 minutes)
製造例32の工程2と同様の方法もしくは、これに準ずる方法で、2-クロロ-4-メトキシニコチン酸エチル(中間体33-1)(0.84g)から標記化合物(30mg)を淡黄色液体として得た。
UPLC:270[M+Na]+(保持時間0.89分) <Step 2> Synthesis of ethyl 4-methoxy-2- (1H-pyrazol-1-yl) nicotinate (Intermediate 33-2) The title compound (30 mg) was obtained as a pale yellow liquid from ethyl chloro-4-methoxynicotinate (intermediate 33-1) (0.84 g).
UPLC: 270 [M + Na] + (retention time 0.89 minutes)
<工程3>4-メトキシ-2-(1H-ピラゾール-1-イル)ニコチン酸リチウム(中間体33)の合成
製造例25の工程2と同様の方法もしくは、これに準ずる方法で、4-メトキシ-2-(1H-ピラゾール-1-イル)ニコチン酸エチル(中間体33-2)(30mg)から標記化合物(27mg)を淡黄色固体として得た。
UPLC:242[M+Na]+(保持時間0.62分) <Step 3> Synthesis of lithium 4-methoxy-2- (1H-pyrazol-1-yl) nicotinate (Intermediate 33) 4-methoxy-2- The title compound (27 mg) was obtained as a pale yellow solid from ethyl -2- (1H-pyrazol-1-yl) nicotinate (Intermediate 33-2) (30 mg).
UPLC: 242 [M + Na] + (retention time 0.62 minutes)
製造例25の工程2と同様の方法もしくは、これに準ずる方法で、4-メトキシ-2-(1H-ピラゾール-1-イル)ニコチン酸エチル(中間体33-2)(30mg)から標記化合物(27mg)を淡黄色固体として得た。
UPLC:242[M+Na]+(保持時間0.62分) <Step 3> Synthesis of lithium 4-methoxy-2- (1H-pyrazol-1-yl) nicotinate (Intermediate 33) 4-methoxy-2- The title compound (27 mg) was obtained as a pale yellow solid from ethyl -2- (1H-pyrazol-1-yl) nicotinate (Intermediate 33-2) (30 mg).
UPLC: 242 [M + Na] + (retention time 0.62 minutes)
(製造例34)3-ブロモ-1-メチル-1H-ピラゾロ[4,3-b]ピリジン(中間体34)の合成
3-ブロモ-1H-ピラゾロ[4,3-b]ピリジン(0.50g)、炭酸セシウム(1.7g)のDMF(5.0mL)混合液にヨードメタン(0.24mL)を加え、反応容器を水浴で冷却しながら2時間攪拌した。反応液に水(30mL)を加え、酢酸エチル(30mL)で抽出した。抽出液を水(10mL×2)と飽和食塩水(5.0mL)で順次洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して標記化合物(0.34g)を茶色固体として得た。
UPLC:212[M+H]+(保持時間0.76分)
1H-NMR (CDCl3, 300MHz) δ: 8.66-8.63 (1H, m), 7.78-7.74 (1H, m), 7.40-7.35 (1H, m), 4.09 (3H, s). Production Example 34 Synthesis of 3-bromo-1-methyl-1H-pyrazolo [4,3-b] pyridine (intermediate 34) 3-bromo-1H-pyrazolo [4,3-b] pyridine (0.50 g ), Iodomethane (0.24 mL) was added to a DMF (5.0 mL) mixture of cesium carbonate (1.7 g), and the reaction vessel was stirred for 2 hours while cooling in a water bath. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The extract was washed successively with water (10 mL × 2) and saturated brine (5.0 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.34 g) as a brown solid. It was.
UPLC: 212 [M + H] + (retention time 0.76 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.66-8.63 (1H, m), 7.78-7.74 (1H, m), 7.40-7.35 (1H, m), 4.09 (3H, s).
3-ブロモ-1H-ピラゾロ[4,3-b]ピリジン(0.50g)、炭酸セシウム(1.7g)のDMF(5.0mL)混合液にヨードメタン(0.24mL)を加え、反応容器を水浴で冷却しながら2時間攪拌した。反応液に水(30mL)を加え、酢酸エチル(30mL)で抽出した。抽出液を水(10mL×2)と飽和食塩水(5.0mL)で順次洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下溶媒を留去して標記化合物(0.34g)を茶色固体として得た。
UPLC:212[M+H]+(保持時間0.76分)
1H-NMR (CDCl3, 300MHz) δ: 8.66-8.63 (1H, m), 7.78-7.74 (1H, m), 7.40-7.35 (1H, m), 4.09 (3H, s). Production Example 34 Synthesis of 3-bromo-1-methyl-1H-pyrazolo [4,3-b] pyridine (intermediate 34) 3-bromo-1H-pyrazolo [4,3-b] pyridine (0.50 g ), Iodomethane (0.24 mL) was added to a DMF (5.0 mL) mixture of cesium carbonate (1.7 g), and the reaction vessel was stirred for 2 hours while cooling in a water bath. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The extract was washed successively with water (10 mL × 2) and saturated brine (5.0 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.34 g) as a brown solid. It was.
UPLC: 212 [M + H] + (retention time 0.76 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.66-8.63 (1H, m), 7.78-7.74 (1H, m), 7.40-7.35 (1H, m), 4.09 (3H, s).
(製造例35)3-ブロモ-1-メチル-1H-ピラゾロ[4,3-c]ピリジン(中間体35)
製造例34と同様の方法もしくは、これに準ずる方法で、3-ブロモ-1H-ピラゾロ[4,3-c]ピリジン(0.25g)を用いて標記化合物(39mg)を淡黄色固体として得た。
UPLC:212、214[M+H]+(保持時間0.47分)
1H-NMR (CDCl3, 400MHz) δ: 8.97 (1H, d, J = 1 Hz), 8.49 (1H, d, J = 6 Hz), 7.28 (1H, dd, J = 6, 1 Hz), 4.06 (3H, s). Production Example 35 3-Bromo-1-methyl-1H-pyrazolo [4,3-c] pyridine (Intermediate 35)
The title compound (39 mg) was obtained as a pale yellow solid using 3-bromo-1H-pyrazolo [4,3-c] pyridine (0.25 g) in the same manner as in Production Example 34 or a method analogous thereto. .
UPLC: 212, 214 [M + H] + (retention time 0.47 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.97 (1H, d, J = 1 Hz), 8.49 (1H, d, J = 6 Hz), 7.28 (1H, dd, J = 6, 1 Hz), 4.06 (3H, s).
製造例34と同様の方法もしくは、これに準ずる方法で、3-ブロモ-1H-ピラゾロ[4,3-c]ピリジン(0.25g)を用いて標記化合物(39mg)を淡黄色固体として得た。
UPLC:212、214[M+H]+(保持時間0.47分)
1H-NMR (CDCl3, 400MHz) δ: 8.97 (1H, d, J = 1 Hz), 8.49 (1H, d, J = 6 Hz), 7.28 (1H, dd, J = 6, 1 Hz), 4.06 (3H, s). Production Example 35 3-Bromo-1-methyl-1H-pyrazolo [4,3-c] pyridine (Intermediate 35)
The title compound (39 mg) was obtained as a pale yellow solid using 3-bromo-1H-pyrazolo [4,3-c] pyridine (0.25 g) in the same manner as in Production Example 34 or a method analogous thereto. .
UPLC: 212, 214 [M + H] + (retention time 0.47 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.97 (1H, d, J = 1 Hz), 8.49 (1H, d, J = 6 Hz), 7.28 (1H, dd, J = 6, 1 Hz), 4.06 (3H, s).
(製造例36)3-ブロモ-1-メチル-1H-ピラゾロ[3,4-c]ピリジン(中間体36)
製造例34と同様の方法もしくは、これに準ずる方法で、3-ブロモ-1H-ピラゾロ[3,4-c]ピリジン(0.50g)を用いて標記化合物(0.11g)を淡黄色固体として得た。
UPLC:212、214[M+H]+(保持時間0.60分)
1H-NMR (CDCl3, 400MHz) δ: 8.96 (1H, d, J = 1 Hz), 8.38 (1H, d, J = 6 Hz), 7.51 (1H, dd, J = 6, 1 Hz), 4.18 (3H, s). Production Example 36 3-Bromo-1-methyl-1H-pyrazolo [3,4-c] pyridine (Intermediate 36)
The title compound (0.11 g) was prepared as a pale yellow solid using 3-bromo-1H-pyrazolo [3,4-c] pyridine (0.50 g) in the same manner as in Production Example 34 or a method analogous thereto. Obtained.
UPLC: 212, 214 [M + H] + (retention time 0.60 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.96 (1H, d, J = 1 Hz), 8.38 (1H, d, J = 6 Hz), 7.51 (1H, dd, J = 6, 1 Hz), 4.18 (3H, s).
製造例34と同様の方法もしくは、これに準ずる方法で、3-ブロモ-1H-ピラゾロ[3,4-c]ピリジン(0.50g)を用いて標記化合物(0.11g)を淡黄色固体として得た。
UPLC:212、214[M+H]+(保持時間0.60分)
1H-NMR (CDCl3, 400MHz) δ: 8.96 (1H, d, J = 1 Hz), 8.38 (1H, d, J = 6 Hz), 7.51 (1H, dd, J = 6, 1 Hz), 4.18 (3H, s). Production Example 36 3-Bromo-1-methyl-1H-pyrazolo [3,4-c] pyridine (Intermediate 36)
The title compound (0.11 g) was prepared as a pale yellow solid using 3-bromo-1H-pyrazolo [3,4-c] pyridine (0.50 g) in the same manner as in Production Example 34 or a method analogous thereto. Obtained.
UPLC: 212, 214 [M + H] + (retention time 0.60 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.96 (1H, d, J = 1 Hz), 8.38 (1H, d, J = 6 Hz), 7.51 (1H, dd, J = 6, 1 Hz), 4.18 (3H, s).
(製造例37)2-クロロ-3-エトキシイソニコチノニトリル(中間体37)の合成
製造例3と同様の方法もしくは、これに準ずる方法で2-クロロ-3-エトキシピリジン(5.1g)を用いて標記化合物(2.9g)を無色固体として得た。
1H-NMR (CDCl3, 300MHz) δ: 8.24 (1H, d, J = 5 Hz), 7.41 (1H, d, J = 5 Hz), 4.39 (2H, q, J = 7 Hz), 1.53 (3H, t, J = 7 Hz). (Production Example 37) Synthesis of 2-chloro-3-ethoxyisonicotinonitrile (Intermediate 37) 2-Chloro-3-ethoxypyridine (5.1 g) by the same method as in Production Example 3 or a method analogous thereto To give the title compound (2.9 g) as a colorless solid.
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.24 (1H, d, J = 5 Hz), 7.41 (1H, d, J = 5 Hz), 4.39 (2H, q, J = 7 Hz), 1.53 ( (3H, t, J = 7 Hz).
製造例3と同様の方法もしくは、これに準ずる方法で2-クロロ-3-エトキシピリジン(5.1g)を用いて標記化合物(2.9g)を無色固体として得た。
1H-NMR (CDCl3, 300MHz) δ: 8.24 (1H, d, J = 5 Hz), 7.41 (1H, d, J = 5 Hz), 4.39 (2H, q, J = 7 Hz), 1.53 (3H, t, J = 7 Hz). (Production Example 37) Synthesis of 2-chloro-3-ethoxyisonicotinonitrile (Intermediate 37) 2-Chloro-3-ethoxypyridine (5.1 g) by the same method as in Production Example 3 or a method analogous thereto To give the title compound (2.9 g) as a colorless solid.
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.24 (1H, d, J = 5 Hz), 7.41 (1H, d, J = 5 Hz), 4.39 (2H, q, J = 7 Hz), 1.53 ( (3H, t, J = 7 Hz).
(製造例38)2-クロロ-3-(メトキシ-d3)イソニコチノニトリル(中間体38)の合成
<工程1>2-クロロ-3-(メトキシ-d3)ピリジン(中間体38-1)の合成
2-クロロピリジン-3-オール(10g)、炭酸カリウム(32g)のDMSO(100mL)混合溶液に、ヨードメタン-d3(5.0mL)を加え、50℃にて3日間撹拌した。反応溶液を室温に戻した後に水を加え、ジエチルエーテルで抽出した。有機層を食塩水で洗った後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去して標記化合物(10g)の粗生成物を無色液体として得た。
UPLC:147[M+H]+(保持時間0.76分) Production Example 38 Synthesis of 2-chloro-3- (methoxy-d 3 ) isonicotinonitrile (Intermediate 38) <Step 1> 2-Chloro-3- (methoxy-d 3 ) pyridine (Intermediate 38- Synthesis of 1) To a mixed solution of 2-chloropyridin-3-ol (10 g) and potassium carbonate (32 g) in DMSO (100 mL) was added iodomethane-d 3 (5.0 mL), and the mixture was stirred at 50 ° C. for 3 days. . The reaction solution was returned to room temperature, water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product of the title compound (10 g) as a colorless liquid.
UPLC: 147 [M + H] + (retention time 0.76 minutes)
<工程1>2-クロロ-3-(メトキシ-d3)ピリジン(中間体38-1)の合成
2-クロロピリジン-3-オール(10g)、炭酸カリウム(32g)のDMSO(100mL)混合溶液に、ヨードメタン-d3(5.0mL)を加え、50℃にて3日間撹拌した。反応溶液を室温に戻した後に水を加え、ジエチルエーテルで抽出した。有機層を食塩水で洗った後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去して標記化合物(10g)の粗生成物を無色液体として得た。
UPLC:147[M+H]+(保持時間0.76分) Production Example 38 Synthesis of 2-chloro-3- (methoxy-d 3 ) isonicotinonitrile (Intermediate 38) <Step 1> 2-Chloro-3- (methoxy-d 3 ) pyridine (Intermediate 38- Synthesis of 1) To a mixed solution of 2-chloropyridin-3-ol (10 g) and potassium carbonate (32 g) in DMSO (100 mL) was added iodomethane-d 3 (5.0 mL), and the mixture was stirred at 50 ° C. for 3 days. . The reaction solution was returned to room temperature, water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product of the title compound (10 g) as a colorless liquid.
UPLC: 147 [M + H] + (retention time 0.76 minutes)
<工程2>2-クロロ-3-(メトキシ-d3)イソニコチノニトリル(中間体38)の合成
製造例38の工程1で得た2-クロロ-3-(メトキシ-d3)ピリジン(中間体38-1)の粗生成物(5.0g)を用いて、製造例3と同様の方法もしくは、これに準ずる方法で、標記化合物(2.3g)を無色固体として得た。
UPLC:172[M+H]+(保持時間0.83分)
1H-NMR (CDCl3, 400MHz) δ: 8.24 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz). <Step 2> Synthesis of 2-chloro-3- (methoxy-d 3 ) isonicotinonitrile (Intermediate 38) 2-Chloro-3- (methoxy-d 3 ) pyridine obtained in Step 1 of Production Example 38 ( Using the crude product of Intermediate 38-1) (5.0 g), the title compound (2.3 g) was obtained as a colorless solid in the same manner as in Production Example 3 or a method analogous thereto.
UPLC: 172 [M + H] + (retention time 0.83 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.24 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz).
製造例38の工程1で得た2-クロロ-3-(メトキシ-d3)ピリジン(中間体38-1)の粗生成物(5.0g)を用いて、製造例3と同様の方法もしくは、これに準ずる方法で、標記化合物(2.3g)を無色固体として得た。
UPLC:172[M+H]+(保持時間0.83分)
1H-NMR (CDCl3, 400MHz) δ: 8.24 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz). <Step 2> Synthesis of 2-chloro-3- (methoxy-d 3 ) isonicotinonitrile (Intermediate 38) 2-Chloro-3- (methoxy-d 3 ) pyridine obtained in Step 1 of Production Example 38 ( Using the crude product of Intermediate 38-1) (5.0 g), the title compound (2.3 g) was obtained as a colorless solid in the same manner as in Production Example 3 or a method analogous thereto.
UPLC: 172 [M + H] + (retention time 0.83 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.24 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz).
(製造例39)(2-クロロピリジン-3-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(中間体39)の合成
製造例11と同様の方法もしくは、これに準ずる方法で2-クロロニコチン酸(0.24g)を用いて標記化合物(0.49g)を茶色液体として得た。
UPLC:358[M+H]+(保持時間0.82分)
1H-NMR (CDCl3, 300MHz) δ: 8.46-8.40 (1H, m), 7.77-7.43 (1H, m), 7.37-7.22 (1H, m), 6.36-6.31 (1H, m), 4.99-4.90 (1H, m), 4.80-4.69 (1H, m), 4.54-4.42 (1H, m), 3.67-3.38 (1H, m), 3.27-3.02 (2H, m), 2.82-2.78 (6H, m), 2.12-1.86 (2H, m), 1.53-1.40 (2H, m). Production Example 39 (2-Chloropyridin-3-yl) (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone Synthesis of (Intermediate 39) The title compound (0.49 g) was obtained as a brown liquid using 2-chloronicotinic acid (0.24 g) in the same manner as in Production Example 11 or a method analogous thereto.
UPLC: 358 [M + H] + (retention time 0.82 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.46-8.40 (1H, m), 7.77-7.43 (1H, m), 7.37-7.22 (1H, m), 6.36-6.31 (1H, m), 4.99- 4.90 (1H, m), 4.80-4.69 (1H, m), 4.54-4.42 (1H, m), 3.67-3.38 (1H, m), 3.27-3.02 (2H, m), 2.82-2.78 (6H, m ), 2.12-1.86 (2H, m), 1.53-1.40 (2H, m).
製造例11と同様の方法もしくは、これに準ずる方法で2-クロロニコチン酸(0.24g)を用いて標記化合物(0.49g)を茶色液体として得た。
UPLC:358[M+H]+(保持時間0.82分)
1H-NMR (CDCl3, 300MHz) δ: 8.46-8.40 (1H, m), 7.77-7.43 (1H, m), 7.37-7.22 (1H, m), 6.36-6.31 (1H, m), 4.99-4.90 (1H, m), 4.80-4.69 (1H, m), 4.54-4.42 (1H, m), 3.67-3.38 (1H, m), 3.27-3.02 (2H, m), 2.82-2.78 (6H, m), 2.12-1.86 (2H, m), 1.53-1.40 (2H, m). Production Example 39 (2-Chloropyridin-3-yl) (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone Synthesis of (Intermediate 39) The title compound (0.49 g) was obtained as a brown liquid using 2-chloronicotinic acid (0.24 g) in the same manner as in Production Example 11 or a method analogous thereto.
UPLC: 358 [M + H] + (retention time 0.82 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.46-8.40 (1H, m), 7.77-7.43 (1H, m), 7.37-7.22 (1H, m), 6.36-6.31 (1H, m), 4.99- 4.90 (1H, m), 4.80-4.69 (1H, m), 4.54-4.42 (1H, m), 3.67-3.38 (1H, m), 3.27-3.02 (2H, m), 2.82-2.78 (6H, m ), 2.12-1.86 (2H, m), 1.53-1.40 (2H, m).
(製造例40)(2-クロロ-5-フルオロピリジン-3-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(中間体40)の合成
製造例11と同様の方法もしくは、これに準ずる方法で2-クロロ-5-フルオロニコチン酸(88mg)を用いて標記化合物(0.17g)を黄色固体として得た。
UPLC:376、378[M+H]+(保持時間0.86分)
1H-NMR (DMSO-d6, 300MHz) δ: 8.56-8.51 (1H, m), 8.22-7.90 (1H, m), 6.50-6.47 (1H, m), 4.84-4.74 (1H, m), 4.64-4.55 (1H, m), 4.33-4.19 (1H, m), 3.45-2.94 (3H, m), 2.24 (6H, s), 2.06-1.67 (4H, m). Production Example 40 (2-Chloro-5-fluoropyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3 Synthesis of —yl) methanone (intermediate 40) The title compound (0.17 g) was obtained as a yellow solid using 2-chloro-5-fluoronicotinic acid (88 mg) in the same manner as in Production Example 11 or a method analogous thereto. Got as.
UPLC: 376, 378 [M + H] + (retention time 0.86 minutes)
1 H-NMR (DMSO-d 6 , 300 MHz) δ: 8.56-8.51 (1H, m), 8.22-7.90 (1H, m), 6.50-6.47 (1H, m), 4.84-4.74 (1H, m), 4.64-4.55 (1H, m), 4.33-4.19 (1H, m), 3.45-2.94 (3H, m), 2.24 (6H, s), 2.06-1.67 (4H, m).
製造例11と同様の方法もしくは、これに準ずる方法で2-クロロ-5-フルオロニコチン酸(88mg)を用いて標記化合物(0.17g)を黄色固体として得た。
UPLC:376、378[M+H]+(保持時間0.86分)
1H-NMR (DMSO-d6, 300MHz) δ: 8.56-8.51 (1H, m), 8.22-7.90 (1H, m), 6.50-6.47 (1H, m), 4.84-4.74 (1H, m), 4.64-4.55 (1H, m), 4.33-4.19 (1H, m), 3.45-2.94 (3H, m), 2.24 (6H, s), 2.06-1.67 (4H, m). Production Example 40 (2-Chloro-5-fluoropyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3 Synthesis of —yl) methanone (intermediate 40) The title compound (0.17 g) was obtained as a yellow solid using 2-chloro-5-fluoronicotinic acid (88 mg) in the same manner as in Production Example 11 or a method analogous thereto. Got as.
UPLC: 376, 378 [M + H] + (retention time 0.86 minutes)
1 H-NMR (DMSO-d 6 , 300 MHz) δ: 8.56-8.51 (1H, m), 8.22-7.90 (1H, m), 6.50-6.47 (1H, m), 4.84-4.74 (1H, m), 4.64-4.55 (1H, m), 4.33-4.19 (1H, m), 3.45-2.94 (3H, m), 2.24 (6H, s), 2.06-1.67 (4H, m).
(製造例41)3-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-5-ブロモ-1-メチルピラジン-2(1H)-オン(中間体41)の合成
製造例1の工程1と同様の方法もしくは、これに準ずる方法で、(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン塩酸塩(中間体19)(0.10g)と3,5-ジブロモ-1-メチルピラジン-2(1H)-オン(0.16g)を用いて標記化合物(0.12g)を白色アモルファスとして得た。
UPLC:470、472[M+H]+(保持時間1.06分)
1H-NMR (CDCl3, 400MHz) δ: 8.04-7.98 (1H, m), 7.85-7.74 (2H, m), 7.57-7.19 (3H, m), 6.73-6.67 (1H, m), 4.54-4.40 (1H, m), 3.45-2.34 (8H, m), 2.09-1.67 (4H, m). Production Example 41 3- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl)- Synthesis of 5-bromo-1-methylpyrazin-2 (1H) -one (Intermediate 41) In the same manner as in Step 1 of Production Example 1 or a method analogous thereto, (2- (2H-1,2, 3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3-yl) methanone hydrochloride (intermediate 19) (0.10 g) and 3,5-dibromo-1 Using -methylpyrazin-2 (1H) -one (0.16 g), the title compound (0.12 g) was obtained as a white amorphous.
UPLC: 470, 472 [M + H] + (retention time 1.06 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.04-7.98 (1H, m), 7.85-7.74 (2H, m), 7.57-7.19 (3H, m), 6.73-6.67 (1H, m), 4.54- 4.40 (1H, m), 3.45-2.34 (8H, m), 2.09-1.67 (4H, m).
製造例1の工程1と同様の方法もしくは、これに準ずる方法で、(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン塩酸塩(中間体19)(0.10g)と3,5-ジブロモ-1-メチルピラジン-2(1H)-オン(0.16g)を用いて標記化合物(0.12g)を白色アモルファスとして得た。
UPLC:470、472[M+H]+(保持時間1.06分)
1H-NMR (CDCl3, 400MHz) δ: 8.04-7.98 (1H, m), 7.85-7.74 (2H, m), 7.57-7.19 (3H, m), 6.73-6.67 (1H, m), 4.54-4.40 (1H, m), 3.45-2.34 (8H, m), 2.09-1.67 (4H, m). Production Example 41 3- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl)- Synthesis of 5-bromo-1-methylpyrazin-2 (1H) -one (Intermediate 41) In the same manner as in Step 1 of Production Example 1 or a method analogous thereto, (2- (2H-1,2, 3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3-yl) methanone hydrochloride (intermediate 19) (0.10 g) and 3,5-dibromo-1 Using -methylpyrazin-2 (1H) -one (0.16 g), the title compound (0.12 g) was obtained as a white amorphous.
UPLC: 470, 472 [M + H] + (retention time 1.06 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.04-7.98 (1H, m), 7.85-7.74 (2H, m), 7.57-7.19 (3H, m), 6.73-6.67 (1H, m), 4.54- 4.40 (1H, m), 3.45-2.34 (8H, m), 2.09-1.67 (4H, m).
(製造例42)tert-ブチル 3-(2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-6-カルボキシレート(中間体42)の合成
tert-ブチル 3,6-ジアザビシクロ[3.1.1]ヘプタン-6-カルボキシレート(99mg)、2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)安息香酸(0.11g)、トリエチルアミン(0.21mL)のジクロロメタン(0.50mL)溶液にEDCI(0.12g)を加え、窒素雰囲気下、室温で16時間攪拌した。反応液をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=90:10~0:100)にて精製し、標記化合物(39mg)を白色アモルファスとして得た。
UPLC:388[M+H]+(保持時間1.01分)
1H-NMR (CDCl3, 400MHz) δ: 7.93-7.85 (1H, m), 7.80-7.72 (2H, m), 7.53-7.45 (1H, m), 7.19-7.10 (1H, m), 4.34-3.79 (4H, m), 3.44-3.24 (1H, m), 2.66-2.56 (1H, m), 1.66-1.58 (2H, m), 1.49 (9H, s). (Production Example 42) tert-butyl 3- (2-fluoro-6- (2H-1,2,3-triazol-2-yl) benzoyl) -3,6-diazabicyclo [3.1.1] heptane-6 Synthesis of carboxylate (intermediate 42) tert-butyl 3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (99 mg), 2-fluoro-6- (2H-1,2,3- EDCI (0.12 g) was added to a solution of triazol-2-yl) benzoic acid (0.11 g) and triethylamine (0.21 mL) in dichloromethane (0.50 mL), and the mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction solution was purified by column chromatography (silica gel, heptane: ethyl acetate = 90: 10-0: 100) to obtain the title compound (39 mg) as a white amorphous.
UPLC: 388 [M + H] + (retention time 1.01 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 7.93-7.85 (1H, m), 7.80-7.72 (2H, m), 7.53-7.45 (1H, m), 7.19-7.10 (1H, m), 4.34- 3.79 (4H, m), 3.44-3.24 (1H, m), 2.66-2.56 (1H, m), 1.66-1.58 (2H, m), 1.49 (9H, s).
tert-ブチル 3,6-ジアザビシクロ[3.1.1]ヘプタン-6-カルボキシレート(99mg)、2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)安息香酸(0.11g)、トリエチルアミン(0.21mL)のジクロロメタン(0.50mL)溶液にEDCI(0.12g)を加え、窒素雰囲気下、室温で16時間攪拌した。反応液をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=90:10~0:100)にて精製し、標記化合物(39mg)を白色アモルファスとして得た。
UPLC:388[M+H]+(保持時間1.01分)
1H-NMR (CDCl3, 400MHz) δ: 7.93-7.85 (1H, m), 7.80-7.72 (2H, m), 7.53-7.45 (1H, m), 7.19-7.10 (1H, m), 4.34-3.79 (4H, m), 3.44-3.24 (1H, m), 2.66-2.56 (1H, m), 1.66-1.58 (2H, m), 1.49 (9H, s). (Production Example 42) tert-butyl 3- (2-fluoro-6- (2H-1,2,3-triazol-2-yl) benzoyl) -3,6-diazabicyclo [3.1.1] heptane-6 Synthesis of carboxylate (intermediate 42) tert-butyl 3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (99 mg), 2-fluoro-6- (2H-1,2,3- EDCI (0.12 g) was added to a solution of triazol-2-yl) benzoic acid (0.11 g) and triethylamine (0.21 mL) in dichloromethane (0.50 mL), and the mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction solution was purified by column chromatography (silica gel, heptane: ethyl acetate = 90: 10-0: 100) to obtain the title compound (39 mg) as a white amorphous.
UPLC: 388 [M + H] + (retention time 1.01 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 7.93-7.85 (1H, m), 7.80-7.72 (2H, m), 7.53-7.45 (1H, m), 7.19-7.10 (1H, m), 4.34- 3.79 (4H, m), 3.44-3.24 (1H, m), 2.66-2.56 (1H, m), 1.66-1.58 (2H, m), 1.49 (9H, s).
(製造例43)(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)メタノン(中間体43)の合成
<工程1>tert-ブチル 3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-6-カルボキシレート(中間体43-1)の合成
製造例11と同様の方法もしくは、これに準ずる方法でtert-ブチル 3,6-ジアザビシクロ[3.1.1]ヘプタン-6-カルボキシレート(0.10g)及び2-(1H-ピラゾール-1-イル)ニコチン酸(0.11g)を用いて標記化合物(0.19g)を黄色液体として得た。
UPLC:392[M+Na]+(保持時間0.96分) Production Example 43 Synthesis of (2- (1H-pyrazol-1-yl) pyridin-3-yl) (3,6-diazabicyclo [3.1.1] heptan-3-yl) methanone (Intermediate 43) <Step 1> of tert-butyl 3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate 43-1) Synthesis In the same manner as in Production Example 11 or a method analogous thereto, tert-butyl 3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (0.10 g) and 2- (1H-pyrazole-1 -Ill) The title compound (0.19 g) was obtained as a yellow liquid using nicotinic acid (0.11 g).
UPLC: 392 [M + Na] + (retention time 0.96 minutes)
<工程1>tert-ブチル 3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-6-カルボキシレート(中間体43-1)の合成
製造例11と同様の方法もしくは、これに準ずる方法でtert-ブチル 3,6-ジアザビシクロ[3.1.1]ヘプタン-6-カルボキシレート(0.10g)及び2-(1H-ピラゾール-1-イル)ニコチン酸(0.11g)を用いて標記化合物(0.19g)を黄色液体として得た。
UPLC:392[M+Na]+(保持時間0.96分) Production Example 43 Synthesis of (2- (1H-pyrazol-1-yl) pyridin-3-yl) (3,6-diazabicyclo [3.1.1] heptan-3-yl) methanone (Intermediate 43) <Step 1> of tert-butyl 3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate 43-1) Synthesis In the same manner as in Production Example 11 or a method analogous thereto, tert-butyl 3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (0.10 g) and 2- (1H-pyrazole-1 -Ill) The title compound (0.19 g) was obtained as a yellow liquid using nicotinic acid (0.11 g).
UPLC: 392 [M + Na] + (retention time 0.96 minutes)
<工程2>(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)メタノン(中間体43)の合成
tert-ブチル 3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-6-カルボキシレート(中間体43-1)(0.19g)に2規定塩酸-酢酸エチル溶液(4.0mL)を加え、50℃にて1時間撹拌した。減圧下溶媒を留去した後、水を加えて酢酸エチルで逆抽出を行った。飽和炭酸水素ナトリウム溶液で中和した後、ジクロロメタン-イソプロパノール(9:1)混合溶媒で抽出した後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去して標記化合物(0.14g)を橙色アモルファスとして得た。
UPLC:270[M+H]+(保持時間0.50分) <Step 2> Synthesis of (2- (1H-pyrazol-1-yl) pyridin-3-yl) (3,6-diazabicyclo [3.1.1] heptan-3-yl) methanone (intermediate 43) tert -Butyl 3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate 43-1) (0.19 g) 2N Hydrochloric acid-ethyl acetate solution (4.0 mL) was added, and the mixture was stirred at 50 ° C. for 1 hr. After evaporating the solvent under reduced pressure, water was added and back extraction was performed with ethyl acetate. After neutralization with a saturated sodium bicarbonate solution, extraction with a mixed solvent of dichloromethane-isopropanol (9: 1) was followed by drying over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (0.14 g) in orange Obtained as amorphous.
UPLC: 270 [M + H] + (retention time 0.50 minutes)
tert-ブチル 3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-6-カルボキシレート(中間体43-1)(0.19g)に2規定塩酸-酢酸エチル溶液(4.0mL)を加え、50℃にて1時間撹拌した。減圧下溶媒を留去した後、水を加えて酢酸エチルで逆抽出を行った。飽和炭酸水素ナトリウム溶液で中和した後、ジクロロメタン-イソプロパノール(9:1)混合溶媒で抽出した後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去して標記化合物(0.14g)を橙色アモルファスとして得た。
UPLC:270[M+H]+(保持時間0.50分) <Step 2> Synthesis of (2- (1H-pyrazol-1-yl) pyridin-3-yl) (3,6-diazabicyclo [3.1.1] heptan-3-yl) methanone (intermediate 43) tert -Butyl 3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate 43-1) (0.19 g) 2N Hydrochloric acid-ethyl acetate solution (4.0 mL) was added, and the mixture was stirred at 50 ° C. for 1 hr. After evaporating the solvent under reduced pressure, water was added and back extraction was performed with ethyl acetate. After neutralization with a saturated sodium bicarbonate solution, extraction with a mixed solvent of dichloromethane-isopropanol (9: 1) was followed by drying over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (0.14 g) in orange Obtained as amorphous.
UPLC: 270 [M + H] + (retention time 0.50 minutes)
(製造例44)2-(3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-シクロプロピルイソニコチノニトリル(中間体44)の合成
<工程1>tert-ブチル 8-(4-シアノ-3-シクロプロピルピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体44-1)の合成
tert-ブチル 8-(3-クロロ-4-シアノピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体6-1)(76mg)、シクロプロピル亜鉛ブロミド(0.5規定 THF溶液)(2.6mL)のTHF(0.73mL)混合溶液にテトラキス(トリフェニルホスフィン)パラジウム(0.10g)を加え、窒素雰囲気下、100℃にて3日間撹拌した。反応溶液を室温に戻した後に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去して標記化合物の粗生成物(77mg)を橙色液体として得た。 Production Example 44 Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-cyclopropylisonicotinonitrile (Intermediate 44) <Step 1> tert-Butyl 8 Synthesis of — (4-cyano-3-cyclopropylpyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 44-1) tert-butyl 8- ( 3-chloro-4-cyanopyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 6-1) (76 mg), cyclopropylzinc bromide (0. Tetrakis (triphenylphosphine) palladium (0.10 g) was added to a mixed solution of 5N THF solution) (2.6 mL) in THF (0.73 mL), and a nitrogen atmosphere at 100 ° C. Stir for 3 days. The reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (77 mg) of the title compound as an orange liquid.
<工程1>tert-ブチル 8-(4-シアノ-3-シクロプロピルピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体44-1)の合成
tert-ブチル 8-(3-クロロ-4-シアノピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体6-1)(76mg)、シクロプロピル亜鉛ブロミド(0.5規定 THF溶液)(2.6mL)のTHF(0.73mL)混合溶液にテトラキス(トリフェニルホスフィン)パラジウム(0.10g)を加え、窒素雰囲気下、100℃にて3日間撹拌した。反応溶液を室温に戻した後に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去して標記化合物の粗生成物(77mg)を橙色液体として得た。 Production Example 44 Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-cyclopropylisonicotinonitrile (Intermediate 44) <Step 1> tert-Butyl 8 Synthesis of — (4-cyano-3-cyclopropylpyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 44-1) tert-butyl 8- ( 3-chloro-4-cyanopyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 6-1) (76 mg), cyclopropylzinc bromide (0. Tetrakis (triphenylphosphine) palladium (0.10 g) was added to a mixed solution of 5N THF solution) (2.6 mL) in THF (0.73 mL), and a nitrogen atmosphere at 100 ° C. Stir for 3 days. The reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (77 mg) of the title compound as an orange liquid.
<工程2>2-(3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-シクロプロピルイソニコチノニトリル(中間体44)の合成
製造例44の工程1で得たtert-ブチル 8-(4-シアノ-3-シクロプロピルピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体44-1)の粗生成物(77mg)にトリフルオロ酢酸を加え、室温で30分攪拌した。減圧下溶媒を留去した後、1規定塩酸水溶液を加えて酢酸エチルで逆抽出を行った。1規定水酸化ナトリウム水溶液で中和した後、ジクロロメタン-イソプロパノール(9:1)混合溶媒で抽出した後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去して標記化合物(50mg)を黄色液体として得た。
UPLC:255[M+H]+(保持時間0.75分) <Step 2> Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-cyclopropylisonicotinonitrile (Intermediate 44) Obtained in Step 1 of Preparation Example 44 Crude product of tert-butyl 8- (4-cyano-3-cyclopropylpyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 44-1) (77 mg) was added with trifluoroacetic acid and stirred at room temperature for 30 minutes. After evaporating the solvent under reduced pressure, 1N aqueous hydrochloric acid solution was added, and back extraction was performed with ethyl acetate. The mixture was neutralized with 1N aqueous sodium hydroxide solution, extracted with a mixed solvent of dichloromethane-isopropanol (9: 1), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (50 mg) as a yellow liquid. Got as.
UPLC: 255 [M + H] + (retention time 0.75 minutes)
製造例44の工程1で得たtert-ブチル 8-(4-シアノ-3-シクロプロピルピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-カルボキシレート(中間体44-1)の粗生成物(77mg)にトリフルオロ酢酸を加え、室温で30分攪拌した。減圧下溶媒を留去した後、1規定塩酸水溶液を加えて酢酸エチルで逆抽出を行った。1規定水酸化ナトリウム水溶液で中和した後、ジクロロメタン-イソプロパノール(9:1)混合溶媒で抽出した後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去して標記化合物(50mg)を黄色液体として得た。
UPLC:255[M+H]+(保持時間0.75分) <Step 2> Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-cyclopropylisonicotinonitrile (Intermediate 44) Obtained in Step 1 of Preparation Example 44 Crude product of tert-butyl 8- (4-cyano-3-cyclopropylpyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 44-1) (77 mg) was added with trifluoroacetic acid and stirred at room temperature for 30 minutes. After evaporating the solvent under reduced pressure, 1N aqueous hydrochloric acid solution was added, and back extraction was performed with ethyl acetate. The mixture was neutralized with 1N aqueous sodium hydroxide solution, extracted with a mixed solvent of dichloromethane-isopropanol (9: 1), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (50 mg) as a yellow liquid. Got as.
UPLC: 255 [M + H] + (retention time 0.75 minutes)
(実施例1)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(5-メチル-2-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノンの合成
8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体1)(22mg)、5-メチル-2-(2H-1,2,3-トリアゾール-2-イル)安息香酸(20mg)、トリエチルアミン(42μL)のDMF(0.50mL)混合溶液に、HATU(46mg)を加え、窒素雰囲気下、室温にて2時間撹拌した。反応液をHPLCにて分取精製を行い、標記化合物(29mg)を得た。
UPLC:404[M+H]+(保持時間0.99分)
1H-NMR (CDCl3, 300MHz) δ: 7.89-7.66 (3H, m), 7.35-6.99 (2H, m), 6.33-6.29 (1H, m), 4.98-4.39 (3H, m), 3.49-2.66 (3H, m), 2.47-2.24 (9H, m), 2.06-1.60 (4H, m). Example 1 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (5-methyl-2- (2H-1 , 2,3-Triazol-2-yl) phenyl) methanone 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 1) 22 mg), 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (20 mg), triethylamine (42 μL) in DMF (0.50 mL) mixed with HATU (46 mg). In addition, the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction solution was subjected to preparative purification by HPLC to obtain the title compound (29 mg).
UPLC: 404 [M + H] + (retention time 0.99 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 7.89-7.66 (3H, m), 7.35-6.99 (2H, m), 6.33-6.29 (1H, m), 4.98-4.39 (3H, m), 3.49- 2.66 (3H, m), 2.47-2.24 (9H, m), 2.06-1.60 (4H, m).
8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体1)(22mg)、5-メチル-2-(2H-1,2,3-トリアゾール-2-イル)安息香酸(20mg)、トリエチルアミン(42μL)のDMF(0.50mL)混合溶液に、HATU(46mg)を加え、窒素雰囲気下、室温にて2時間撹拌した。反応液をHPLCにて分取精製を行い、標記化合物(29mg)を得た。
UPLC:404[M+H]+(保持時間0.99分)
1H-NMR (CDCl3, 300MHz) δ: 7.89-7.66 (3H, m), 7.35-6.99 (2H, m), 6.33-6.29 (1H, m), 4.98-4.39 (3H, m), 3.49-2.66 (3H, m), 2.47-2.24 (9H, m), 2.06-1.60 (4H, m). Example 1 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (5-methyl-2- (2H-1 , 2,3-Triazol-2-yl) phenyl) methanone 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 1) 22 mg), 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (20 mg), triethylamine (42 μL) in DMF (0.50 mL) mixed with HATU (46 mg). In addition, the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction solution was subjected to preparative purification by HPLC to obtain the title compound (29 mg).
UPLC: 404 [M + H] + (retention time 0.99 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 7.89-7.66 (3H, m), 7.35-6.99 (2H, m), 6.33-6.29 (1H, m), 4.98-4.39 (3H, m), 3.49- 2.66 (3H, m), 2.47-2.24 (9H, m), 2.06-1.60 (4H, m).
*実施例2~実施例15は、中間体1~中間体3の何れか及び中間体12~中間体14の何れかまたは市販化合物もしくは公知化合物を用いて、実施例1と同様の方法、もしくはこれに準ずる方法により合成した。
* Examples 2 to 15 are the same as in Example 1 using any one of Intermediates 1 to 3 and any of Intermediates 12 to 14 or commercially available or known compounds, or It was synthesized by a method according to this.
(実施例16)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(4-メトキシ-2-(1H-1,2,3-トリアゾール-1-イル)フェニル)メタノンの合成
8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体1)(22mg)、4-メトキシ-2-(1H-1,2,3-トリアゾール-1-イル)安息香酸(22mg)、DIPEA(52μL)のDMF(0.20mL)混合溶液に、HATU(46mg)を加え、窒素雰囲気下、室温にて2時間撹拌した。反応液に酢酸エチルを加え、水で洗浄し、有機層を減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=90:10~0:100)にて精製し、標記化合物(36mg)を白色アモルファスとして得た。
UPLC:420[M+H]+(保持時間0.85分)
1H-NMR (CDCl3, 400MHz) δ: 8.23-6.98 (5H, m), 6.30 (1H, s), 4.86-4.76 (1H, m), 4.63-4.57 (1H, m), 4.40-4.26 (1H, m), 3.91-3.87 (3H, m), 3.40-2.60 (7H, m), 2.02-0.97 (6H, m). Example 16 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-methoxy-2- (1H-1 , 2,3-Triazol-1-yl) phenyl) methanone 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 1) 22 mg), 4-methoxy-2- (1H-1,2,3-triazol-1-yl) benzoic acid (22 mg), DIPEA (52 μL) in DMF (0.20 mL) mixed with HATU (46 mg). In addition, the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. Ethyl acetate was added to the reaction mixture, washed with water, the organic layer was evaporated under reduced pressure to remove the solvent, and the resulting residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 90: 10 to 0: 100). Purification gave the title compound (36 mg) as a white amorphous.
UPLC: 420 [M + H] + (retention time 0.85 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.23-6.98 (5H, m), 6.30 (1H, s), 4.86-4.76 (1H, m), 4.63-4.57 (1H, m), 4.40-4.26 ( 1H, m), 3.91-3.87 (3H, m), 3.40-2.60 (7H, m), 2.02-0.97 (6H, m).
8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体1)(22mg)、4-メトキシ-2-(1H-1,2,3-トリアゾール-1-イル)安息香酸(22mg)、DIPEA(52μL)のDMF(0.20mL)混合溶液に、HATU(46mg)を加え、窒素雰囲気下、室温にて2時間撹拌した。反応液に酢酸エチルを加え、水で洗浄し、有機層を減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=90:10~0:100)にて精製し、標記化合物(36mg)を白色アモルファスとして得た。
UPLC:420[M+H]+(保持時間0.85分)
1H-NMR (CDCl3, 400MHz) δ: 8.23-6.98 (5H, m), 6.30 (1H, s), 4.86-4.76 (1H, m), 4.63-4.57 (1H, m), 4.40-4.26 (1H, m), 3.91-3.87 (3H, m), 3.40-2.60 (7H, m), 2.02-0.97 (6H, m). Example 16 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-methoxy-2- (1H-1 , 2,3-Triazol-1-yl) phenyl) methanone 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 1) 22 mg), 4-methoxy-2- (1H-1,2,3-triazol-1-yl) benzoic acid (22 mg), DIPEA (52 μL) in DMF (0.20 mL) mixed with HATU (46 mg). In addition, the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. Ethyl acetate was added to the reaction mixture, washed with water, the organic layer was evaporated under reduced pressure to remove the solvent, and the resulting residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 90: 10 to 0: 100). Purification gave the title compound (36 mg) as a white amorphous.
UPLC: 420 [M + H] + (retention time 0.85 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.23-6.98 (5H, m), 6.30 (1H, s), 4.86-4.76 (1H, m), 4.63-4.57 (1H, m), 4.40-4.26 ( 1H, m), 3.91-3.87 (3H, m), 3.40-2.60 (7H, m), 2.02-0.97 (6H, m).
*実施例17~実施例55は、中間体1~中間体8の何れか及び中間体15、中間体22~中間体28、中間体29-1の何れかまたは市販化合物もしくは公知化合物を用いて、実施例16と同様の方法、もしくはこれに準ずる方法により合成した。
* Example 17 to Example 55 were prepared using any of Intermediate 1 to Intermediate 8 and any of Intermediate 15, Intermediate 22 to Intermediate 28, Intermediate 29-1, or commercially available compounds or known compounds. This was synthesized by the same method as in Example 16 or a method analogous thereto.
(実施例56)(3-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノンの合成
3-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)安息香酸(40mg)のジクロロメタン(0.97mL)溶液に塩化オキサリル(51μL)と触媒量のDMFを加え、窒素雰囲気下、室温にて30分撹拌後、減圧下溶媒を留去した。この残渣をジクロロメタン(0.60mL)に溶解し、8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体2)(55mg)とトリエチルアミン(0.11mL)のジクロロメタン(0.97mL)混合溶液へ0℃で滴下した。反応液を窒素雰囲気下、0℃にて1時間撹拌後、カラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=88:12~0:100)にて精製し、標記化合物(42mg)を無色固体として得た。
UPLC:477[M+H]+(保持時間1.13分)
1H-NMR (CDCl3, 400MHz) δ: 8.10-7.75 (3H, m), 7.57-7.04 (3H, m), 6.96-6.92 (1H, m), 4.77-4.27 (3H, m), 3.80-3.70 (3H, m), 3.67-2.80 (3H, m), 2.18-1.62 (4H, m). Example 56 (3-Fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) Synthesis of 3,8-diazabicyclo [3.2.1] octane-3-yl) methanone 3-Fluoro-2- (2H-1,2,3-triazol-2-yl) benzoic acid (40 mg) in dichloromethane (0.97 mL) To the solution were added oxalyl chloride (51 μL) and a catalytic amount of DMF, and the mixture was stirred at room temperature for 30 minutes in a nitrogen atmosphere, and the solvent was distilled off under reduced pressure. This residue was dissolved in dichloromethane (0.60 mL) and 8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate) 2) To a mixed solution of 55 mg) and triethylamine (0.11 mL) in dichloromethane (0.97 mL) was added dropwise at 0 ° C. The reaction solution was stirred at 0 ° C. for 1 hour under a nitrogen atmosphere and then purified by column chromatography (silica gel, heptane: ethyl acetate = 88: 12 to 0: 100) to obtain the title compound (42 mg) as a colorless solid. It was.
UPLC: 477 [M + H] + (retention time 1.13 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.10-7.75 (3H, m), 7.57-7.04 (3H, m), 6.96-6.92 (1H, m), 4.77-4.27 (3H, m), 3.80- 3.70 (3H, m), 3.67-2.80 (3H, m), 2.18-1.62 (4H, m).
3-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)安息香酸(40mg)のジクロロメタン(0.97mL)溶液に塩化オキサリル(51μL)と触媒量のDMFを加え、窒素雰囲気下、室温にて30分撹拌後、減圧下溶媒を留去した。この残渣をジクロロメタン(0.60mL)に溶解し、8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体2)(55mg)とトリエチルアミン(0.11mL)のジクロロメタン(0.97mL)混合溶液へ0℃で滴下した。反応液を窒素雰囲気下、0℃にて1時間撹拌後、カラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=88:12~0:100)にて精製し、標記化合物(42mg)を無色固体として得た。
UPLC:477[M+H]+(保持時間1.13分)
1H-NMR (CDCl3, 400MHz) δ: 8.10-7.75 (3H, m), 7.57-7.04 (3H, m), 6.96-6.92 (1H, m), 4.77-4.27 (3H, m), 3.80-3.70 (3H, m), 3.67-2.80 (3H, m), 2.18-1.62 (4H, m). Example 56 (3-Fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) Synthesis of 3,8-diazabicyclo [3.2.1] octane-3-yl) methanone 3-Fluoro-2- (2H-1,2,3-triazol-2-yl) benzoic acid (40 mg) in dichloromethane (0.97 mL) To the solution were added oxalyl chloride (51 μL) and a catalytic amount of DMF, and the mixture was stirred at room temperature for 30 minutes in a nitrogen atmosphere, and the solvent was distilled off under reduced pressure. This residue was dissolved in dichloromethane (0.60 mL) and 8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate) 2) To a mixed solution of 55 mg) and triethylamine (0.11 mL) in dichloromethane (0.97 mL) was added dropwise at 0 ° C. The reaction solution was stirred at 0 ° C. for 1 hour under a nitrogen atmosphere and then purified by column chromatography (silica gel, heptane: ethyl acetate = 88: 12 to 0: 100) to obtain the title compound (42 mg) as a colorless solid. It was.
UPLC: 477 [M + H] + (retention time 1.13 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.10-7.75 (3H, m), 7.57-7.04 (3H, m), 6.96-6.92 (1H, m), 4.77-4.27 (3H, m), 3.80- 3.70 (3H, m), 3.67-2.80 (3H, m), 2.18-1.62 (4H, m).
*実施例57~実施例76は、中間体1、中間体3~中間体5の何れか及び中間体29-1、中間体29-2、中間体30、中間体31の何れかまたは市販化合物もしくは公知化合物を用いて、実施例56と同様の方法、もしくはこれに準ずる方法により合成した。
* Example 57 to Example 76 are any of Intermediate 1, Intermediate 3 to Intermediate 5, Intermediate 29-1, Intermediate 29-2, Intermediate 30, and Intermediate 31 or commercially available compounds. Alternatively, synthesis was performed using a known compound by the same method as in Example 56 or a method analogous thereto.
(実施例77)(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノンの合成
2-(2H-1,2,3-トリアゾール-2-イル)安息香酸(45mg)のDME(0.50mL)溶液に塩化オキサリル(42μL)と触媒量のDMFを加え、窒素雰囲気下、室温にて30分撹拌後、減圧下溶媒を留去した。この残渣をDME(0.10mL)に溶解し、8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体1)(44mg)とトリエチルアミン(56μL)のDME(0.50mL)混合溶液へ室温で滴下した。反応液を窒素雰囲気下、室温にて30分間撹拌した後、ろ過し、得られたろ液をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=60:40~40:60)にて精製し、標記化合物(53mg)を無色アモルファスとして得た。
UPLC:390[M+H]+(保持時間0.94分)
1H-NMR (CDCl3, 400MHz) δ: 8.02-7.99 (1H, m), 7.84 (1H, s), 7.70 (1H, s), 7.56-7.42 (2H, m), 7.40-7.18 (1H, m), 6.33-6.30 (1H, m), 4.98-4.89 (1H, m), 4.69-4.64 (1H, m), 4.48-4.41 (1H, m), 3.49-2.75 (3H, m), 2.29-2.25 (6H, m), 2.04-1.62 (4H, m). Example 77 (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2 .1] Synthesis of octan-3-yl) methanone 2- (2H-1,2,3-triazol-2-yl) benzoic acid (45 mg) in DME (0.50 mL) solution with oxalyl chloride (42 μL) and catalyst An amount of DMF was added, and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. This residue was dissolved in DME (0.10 mL) and 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 1) (44 mg) was combined with The mixture was added dropwise to a mixed solution of triethylamine (56 μL) in DME (0.50 mL) at room temperature. The reaction solution was stirred at room temperature for 30 minutes under a nitrogen atmosphere and then filtered. The obtained filtrate was purified by column chromatography (silica gel, heptane: ethyl acetate = 60: 40 to 40:60) to give the title compound. (53 mg) was obtained as a colorless amorphous.
UPLC: 390 [M + H] + (retention time 0.94 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.02-7.99 (1H, m), 7.84 (1H, s), 7.70 (1H, s), 7.56-7.42 (2H, m), 7.40-7.18 (1H, m), 6.33-6.30 (1H, m), 4.98-4.89 (1H, m), 4.69-4.64 (1H, m), 4.48-4.41 (1H, m), 3.49-2.75 (3H, m), 2.29- 2.25 (6H, m), 2.04-1.62 (4H, m).
2-(2H-1,2,3-トリアゾール-2-イル)安息香酸(45mg)のDME(0.50mL)溶液に塩化オキサリル(42μL)と触媒量のDMFを加え、窒素雰囲気下、室温にて30分撹拌後、減圧下溶媒を留去した。この残渣をDME(0.10mL)に溶解し、8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体1)(44mg)とトリエチルアミン(56μL)のDME(0.50mL)混合溶液へ室温で滴下した。反応液を窒素雰囲気下、室温にて30分間撹拌した後、ろ過し、得られたろ液をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=60:40~40:60)にて精製し、標記化合物(53mg)を無色アモルファスとして得た。
UPLC:390[M+H]+(保持時間0.94分)
1H-NMR (CDCl3, 400MHz) δ: 8.02-7.99 (1H, m), 7.84 (1H, s), 7.70 (1H, s), 7.56-7.42 (2H, m), 7.40-7.18 (1H, m), 6.33-6.30 (1H, m), 4.98-4.89 (1H, m), 4.69-4.64 (1H, m), 4.48-4.41 (1H, m), 3.49-2.75 (3H, m), 2.29-2.25 (6H, m), 2.04-1.62 (4H, m). Example 77 (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2 .1] Synthesis of octan-3-yl) methanone 2- (2H-1,2,3-triazol-2-yl) benzoic acid (45 mg) in DME (0.50 mL) solution with oxalyl chloride (42 μL) and catalyst An amount of DMF was added, and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. This residue was dissolved in DME (0.10 mL) and 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 1) (44 mg) was combined with The mixture was added dropwise to a mixed solution of triethylamine (56 μL) in DME (0.50 mL) at room temperature. The reaction solution was stirred at room temperature for 30 minutes under a nitrogen atmosphere and then filtered. The obtained filtrate was purified by column chromatography (silica gel, heptane: ethyl acetate = 60: 40 to 40:60) to give the title compound. (53 mg) was obtained as a colorless amorphous.
UPLC: 390 [M + H] + (retention time 0.94 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.02-7.99 (1H, m), 7.84 (1H, s), 7.70 (1H, s), 7.56-7.42 (2H, m), 7.40-7.18 (1H, m), 6.33-6.30 (1H, m), 4.98-4.89 (1H, m), 4.69-4.64 (1H, m), 4.48-4.41 (1H, m), 3.49-2.75 (3H, m), 2.29- 2.25 (6H, m), 2.04-1.62 (4H, m).
*実施例78~実施例87は、中間体1~中間体5、中間体9の何れか及び中間体28または市販化合物もしくは公知化合物を用いて、実施例77と同様の方法、もしくはこれに準ずる方法により合成した。
* Example 78 to Example 87 are the same as or similar to Example 77, using any of Intermediate 1 to Intermediate 5, Intermediate 9 and Intermediate 28, or a commercially available or known compound. It was synthesized by the method.
(実施例88)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(1,1,2,2-テトラフルオロエトキシ)フェニル)メタノンの合成
2-(1,1,2,2-テトラフルオロエトキシ)安息香酸(28mg)のジクロロメタン(0.20mL)溶液に1-クロロ-N,N,2-トリメチル-1-プロペニルアミン(17μL)を窒素雰囲気下、室温で加えた。反応液を室温にて30分撹拌後、8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体1)(22mg)とトリエチルアミン(28μL)を加え、反応液を室温にて30分撹拌した。反応液をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=100:0~60:40)にて精製し、標記化合物(35mg)を無色ガム状物質として得た。
UPLC:439[M+H]+(保持時間1.01分)
1H-NMR (CDCl3, 400MHz) δ: 7.53-7.14 (4H, m), 6.34 (1H, s), 6.14-5.64 (1H, m), 4.98-4.89 (1H, m), 4.78-4.68 (1H, m), 4.58-4.45 (1H, m), 3.52-3.37 (1H, m), 3.23-3.08 (2H, m), 2.30 (6H, s), 2.10-1.80 (4H, m). Example 88 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (1,1,2,2 Synthesis of -tetrafluoroethoxy) phenyl) methanone 2- (1,1,2,2-tetrafluoroethoxy) benzoic acid (28 mg) in dichloromethane (0.20 mL) in 1-chloro-N, N, 2-trimethyl -1-Propenylamine (17 μL) was added at room temperature under a nitrogen atmosphere. After stirring the reaction solution at room temperature for 30 minutes, 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 1) (22 mg) and triethylamine ( 28 μL) was added and the reaction was stirred at room temperature for 30 minutes. The reaction solution was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 60:40) to obtain the title compound (35 mg) as a colorless gum.
UPLC: 439 [M + H] + (retention time 1.01 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 7.53-7.14 (4H, m), 6.34 (1H, s), 6.14-5.64 (1H, m), 4.98-4.89 (1H, m), 4.78-4.68 ( 1H, m), 4.58-4.45 (1H, m), 3.52-3.37 (1H, m), 3.23-3.08 (2H, m), 2.30 (6H, s), 2.10-1.80 (4H, m).
2-(1,1,2,2-テトラフルオロエトキシ)安息香酸(28mg)のジクロロメタン(0.20mL)溶液に1-クロロ-N,N,2-トリメチル-1-プロペニルアミン(17μL)を窒素雰囲気下、室温で加えた。反応液を室温にて30分撹拌後、8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体1)(22mg)とトリエチルアミン(28μL)を加え、反応液を室温にて30分撹拌した。反応液をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=100:0~60:40)にて精製し、標記化合物(35mg)を無色ガム状物質として得た。
UPLC:439[M+H]+(保持時間1.01分)
1H-NMR (CDCl3, 400MHz) δ: 7.53-7.14 (4H, m), 6.34 (1H, s), 6.14-5.64 (1H, m), 4.98-4.89 (1H, m), 4.78-4.68 (1H, m), 4.58-4.45 (1H, m), 3.52-3.37 (1H, m), 3.23-3.08 (2H, m), 2.30 (6H, s), 2.10-1.80 (4H, m). Example 88 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (1,1,2,2 Synthesis of -tetrafluoroethoxy) phenyl) methanone 2- (1,1,2,2-tetrafluoroethoxy) benzoic acid (28 mg) in dichloromethane (0.20 mL) in 1-chloro-N, N, 2-trimethyl -1-Propenylamine (17 μL) was added at room temperature under a nitrogen atmosphere. After stirring the reaction solution at room temperature for 30 minutes, 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 1) (22 mg) and triethylamine ( 28 μL) was added and the reaction was stirred at room temperature for 30 minutes. The reaction solution was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 60:40) to obtain the title compound (35 mg) as a colorless gum.
UPLC: 439 [M + H] + (retention time 1.01 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 7.53-7.14 (4H, m), 6.34 (1H, s), 6.14-5.64 (1H, m), 4.98-4.89 (1H, m), 4.78-4.68 ( 1H, m), 4.58-4.45 (1H, m), 3.52-3.37 (1H, m), 3.23-3.08 (2H, m), 2.30 (6H, s), 2.10-1.80 (4H, m).
(実施例89)2-(3-(2-(1,1,2,2-テトラフルオロエトキシ)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリルの合成
2-(3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(中間体4)(22mg)を用いて、実施例88と同様の方法もしくは、これに準ずる方法で標記化合物(24mg)を無色ガム状物質として得た。
UPLC:435[M+H]+(保持時間1.04分) Example 89 2- (3- (2- (1,1,2,2-tetrafluoroethoxy) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotino Synthesis of nitrile 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (intermediate 4) (22 mg) was used in the same manner as in Example 88 or To give the title compound (24 mg) as a colorless gum.
UPLC: 435 [M + H] + (retention time 1.04 minutes)
2-(3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(中間体4)(22mg)を用いて、実施例88と同様の方法もしくは、これに準ずる方法で標記化合物(24mg)を無色ガム状物質として得た。
UPLC:435[M+H]+(保持時間1.04分) Example 89 2- (3- (2- (1,1,2,2-tetrafluoroethoxy) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotino Synthesis of nitrile 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (intermediate 4) (22 mg) was used in the same manner as in Example 88 or To give the title compound (24 mg) as a colorless gum.
UPLC: 435 [M + H] + (retention time 1.04 minutes)
(実施例90)3-メトキシ-2-(3-(4-メトキシ-2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリルの合成
リチウム 4-メトキシ-2-(1H-ピラゾール-1-イル)ニコチナート(中間体33)(27mg)と2-(3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(中間体3)(29mg)とHOBT(28mg)のDMF(0.60mL)混合溶液にEDCI(34mg)を加え、反応液を50℃にて3日間撹拌した。反応液に水(10mL)を加え、酢酸エチル(20mL)で抽出した。有機層を飽和炭酸水素ナトリウム水溶液(10mL×2)と飽和塩化アンモニウム水溶液(10mL)で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=88:12~0:100)にて精製し、標記化合物(8.7mg)を淡黄色固体として得た。
UPLC:446[M+H]+(保持時間1.01、1.04分、回転異性体)
1H-NMR (CDCl3, 400MHz) δ: 8.47-8.32 (2H, m), 8.01-7.96 (1H, m), 7.72-7.50 (1H, m), 6.86-6.75 (2H, m), 6.45-6.34 (1H, m), 4.88-4.36 (3H, m), 3.99-3.85 (6H, m), 3.50-3.04 (3H, m), 2.20-1.70 (4H, m). Example 90 3-Methoxy-2- (3- (4-methoxy-2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl ) Synthesis of isonicotionitrile Lithium 4-methoxy-2- (1H-pyrazol-1-yl) nicotinate (intermediate 33) (27 mg) and 2- (3,8-diazabicyclo [3.2.1] octane- EDCI (34 mg) was added to a mixed solution of 8-yl) -3-methoxyisonicotinonitrile (intermediate 3) (29 mg) and HOBT (28 mg) in DMF (0.60 mL), and the reaction solution was added at 50 ° C. Stir for days. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution (10 mL × 2) and a saturated aqueous ammonium chloride solution (10 mL), and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 88: 12 to 0: 100) to obtain the title compound (8.7 mg) as a pale yellow solid. It was.
UPLC: 446 [M + H] + (retention time 1.01, 1.04 min, rotamer)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.47-8.32 (2H, m), 8.01-7.96 (1H, m), 7.72-7.50 (1H, m), 6.86-6.75 (2H, m), 6.45- 6.34 (1H, m), 4.88-4.36 (3H, m), 3.99-3.85 (6H, m), 3.50-3.04 (3H, m), 2.20-1.70 (4H, m).
リチウム 4-メトキシ-2-(1H-ピラゾール-1-イル)ニコチナート(中間体33)(27mg)と2-(3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(中間体3)(29mg)とHOBT(28mg)のDMF(0.60mL)混合溶液にEDCI(34mg)を加え、反応液を50℃にて3日間撹拌した。反応液に水(10mL)を加え、酢酸エチル(20mL)で抽出した。有機層を飽和炭酸水素ナトリウム水溶液(10mL×2)と飽和塩化アンモニウム水溶液(10mL)で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=88:12~0:100)にて精製し、標記化合物(8.7mg)を淡黄色固体として得た。
UPLC:446[M+H]+(保持時間1.01、1.04分、回転異性体)
1H-NMR (CDCl3, 400MHz) δ: 8.47-8.32 (2H, m), 8.01-7.96 (1H, m), 7.72-7.50 (1H, m), 6.86-6.75 (2H, m), 6.45-6.34 (1H, m), 4.88-4.36 (3H, m), 3.99-3.85 (6H, m), 3.50-3.04 (3H, m), 2.20-1.70 (4H, m). Example 90 3-Methoxy-2- (3- (4-methoxy-2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl ) Synthesis of isonicotionitrile Lithium 4-methoxy-2- (1H-pyrazol-1-yl) nicotinate (intermediate 33) (27 mg) and 2- (3,8-diazabicyclo [3.2.1] octane- EDCI (34 mg) was added to a mixed solution of 8-yl) -3-methoxyisonicotinonitrile (intermediate 3) (29 mg) and HOBT (28 mg) in DMF (0.60 mL), and the reaction solution was added at 50 ° C. Stir for days. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution (10 mL × 2) and a saturated aqueous ammonium chloride solution (10 mL), and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 88: 12 to 0: 100) to obtain the title compound (8.7 mg) as a pale yellow solid. It was.
UPLC: 446 [M + H] + (retention time 1.01, 1.04 min, rotamer)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.47-8.32 (2H, m), 8.01-7.96 (1H, m), 7.72-7.50 (1H, m), 6.86-6.75 (2H, m), 6.45- 6.34 (1H, m), 4.88-4.36 (3H, m), 3.99-3.85 (6H, m), 3.50-3.04 (3H, m), 2.20-1.70 (4H, m).
(実施例91)2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリルの合成
2-(1H-ピラゾール-1-イル)ニコチン酸(中間体28)(0.55g)と2-(3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(中間体3)(0.64g)とHOBT(80mg)のジクロロメタン(7.0mL)混合溶液にEDCI(0.60g)を加え、反応液を室温にて2時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(20mL)を加え、酢酸エチル(30mL)で抽出を行い、有機層を水(20mL)、飽和食塩水(10mL)で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(NHシリカゲル、ヘプタン:酢酸エチル=45:55)にて精製し、標記化合物(0.54g)を白色アモルファスとして得た。
UPLC:416[M+H]+(保持時間1.03分)
1H-NMR (CDCl3, 400MHz) δ: 8.49-8.45 (2H, m), 8.02-7.95 (1H, m), 7.80-7.72 (1H, m), 7.55-7.51 (1H, m), 7.31-7.20 (1H, m), 6.87-6.85 (1H, m), 6.49-6.36 (1H, m), 4.86-4.81 (1H, m), 4.58-4.34 (2H, m), 3.92-3.89 (3H, m), 3.55-2.96 (3H, m), 2.20-1.64 (4H, m). Example 91 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotino Synthesis of nitrile 2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 28) (0.55 g) and 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3 EDCI (0.60 g) was added to a mixed solution of methoxyisonicotinonitrile (intermediate 3) (0.64 g) and HOBT (80 mg) in dichloromethane (7.0 mL), and the reaction solution was stirred at room temperature for 2 hours. . A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction solution, extraction was performed with ethyl acetate (30 mL), the organic layer was washed successively with water (20 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (NH silica gel, heptane: ethyl acetate = 45: 55) to obtain the title compound (0.54 g) as a white amorphous.
UPLC: 416 [M + H] + (retention time 1.03 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.49-8.45 (2H, m), 8.02-7.95 (1H, m), 7.80-7.72 (1H, m), 7.55-7.51 (1H, m), 7.31- 7.20 (1H, m), 6.87-6.85 (1H, m), 6.49-6.36 (1H, m), 4.86-4.81 (1H, m), 4.58-4.34 (2H, m), 3.92-3.89 (3H, m ), 3.55-2.96 (3H, m), 2.20-1.64 (4H, m).
2-(1H-ピラゾール-1-イル)ニコチン酸(中間体28)(0.55g)と2-(3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(中間体3)(0.64g)とHOBT(80mg)のジクロロメタン(7.0mL)混合溶液にEDCI(0.60g)を加え、反応液を室温にて2時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(20mL)を加え、酢酸エチル(30mL)で抽出を行い、有機層を水(20mL)、飽和食塩水(10mL)で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(NHシリカゲル、ヘプタン:酢酸エチル=45:55)にて精製し、標記化合物(0.54g)を白色アモルファスとして得た。
UPLC:416[M+H]+(保持時間1.03分)
1H-NMR (CDCl3, 400MHz) δ: 8.49-8.45 (2H, m), 8.02-7.95 (1H, m), 7.80-7.72 (1H, m), 7.55-7.51 (1H, m), 7.31-7.20 (1H, m), 6.87-6.85 (1H, m), 6.49-6.36 (1H, m), 4.86-4.81 (1H, m), 4.58-4.34 (2H, m), 3.92-3.89 (3H, m), 3.55-2.96 (3H, m), 2.20-1.64 (4H, m). Example 91 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotino Synthesis of nitrile 2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 28) (0.55 g) and 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3 EDCI (0.60 g) was added to a mixed solution of methoxyisonicotinonitrile (intermediate 3) (0.64 g) and HOBT (80 mg) in dichloromethane (7.0 mL), and the reaction solution was stirred at room temperature for 2 hours. . A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction solution, extraction was performed with ethyl acetate (30 mL), the organic layer was washed successively with water (20 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (NH silica gel, heptane: ethyl acetate = 45: 55) to obtain the title compound (0.54 g) as a white amorphous.
UPLC: 416 [M + H] + (retention time 1.03 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.49-8.45 (2H, m), 8.02-7.95 (1H, m), 7.80-7.72 (1H, m), 7.55-7.51 (1H, m), 7.31- 7.20 (1H, m), 6.87-6.85 (1H, m), 6.49-6.36 (1H, m), 4.86-4.81 (1H, m), 4.58-4.34 (2H, m), 3.92-3.89 (3H, m ), 3.55-2.96 (3H, m), 2.20-1.64 (4H, m).
*実施例92~実施例100は、中間体1~中間体3、中間体5、中間体10の何れか及び中間体28、中間体31、中間体32の何れかまたは市販化合物もしくは公知化合物を用いて、実施例91と同様の方法、もしくはこれに準ずる方法により合成した。
* Example 92 to Example 100 are any of Intermediate 1 to Intermediate 3, Intermediate 5, and Intermediate 10, and any of Intermediate 28, Intermediate 31, and Intermediate 32, or commercially available compounds or known compounds. And synthesized by the same method as in Example 91 or a method analogous thereto.
(実施例101)(4-クロロ-2-(ピリミジン-2-イル)フェニル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノンの合成
8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体1)(28mg)、4-クロロ-2-(ピリミジン-2-イル)安息香酸(中間体16)(30mg)、COMU(82mg)、2,6-ルチジン(30μL)のジクロロメタン(0.64mL)混合溶液を窒素雰囲気下、室温にて16時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液(20mL)を加え、酢酸エチル(20mL×2)で抽出を行い、集めた有機層を飽和食塩水(10mL)で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=88:12~0:100)にて精製し、標記化合物(20mg)を無色アモルファスとして得た。
UPLC:435[M+H]+(保持時間1.06分)
1H-NMR (CDCl3, 400MHz) δ: 8.85-8.62 (2H, m), 8.44-8.29 (1H, m), 7.54-7.08 (3H, m), 6.35-6.29 (1H, m), 5.04-4.38 (3H, m), 3.55-2.92 (3H, m), 2.31-2.23 (6H, m), 2.12-1.66 (4H, m). Example 101 (4-Chloro-2- (pyrimidin-2-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane Synthesis of 3-yl) methanone 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 1) (28 mg), 4-chloro-2 A mixed solution of-(pyrimidin-2-yl) benzoic acid (intermediate 16) (30 mg), COMU (82 mg) and 2,6-lutidine (30 μL) in dichloromethane (0.64 mL) at room temperature under a nitrogen atmosphere Stir for hours. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction solution, extraction was performed with ethyl acetate (20 mL × 2), and the collected organic layer was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 88: 12 to 0: 100) to obtain the title compound (20 mg) as a colorless amorphous.
UPLC: 435 [M + H] + (retention time 1.06 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.85-8.62 (2H, m), 8.44-8.29 (1H, m), 7.54-7.08 (3H, m), 6.35-6.29 (1H, m), 5.04- 4.38 (3H, m), 3.55-2.92 (3H, m), 2.31-2.23 (6H, m), 2.12-1.66 (4H, m).
8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体1)(28mg)、4-クロロ-2-(ピリミジン-2-イル)安息香酸(中間体16)(30mg)、COMU(82mg)、2,6-ルチジン(30μL)のジクロロメタン(0.64mL)混合溶液を窒素雰囲気下、室温にて16時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液(20mL)を加え、酢酸エチル(20mL×2)で抽出を行い、集めた有機層を飽和食塩水(10mL)で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=88:12~0:100)にて精製し、標記化合物(20mg)を無色アモルファスとして得た。
UPLC:435[M+H]+(保持時間1.06分)
1H-NMR (CDCl3, 400MHz) δ: 8.85-8.62 (2H, m), 8.44-8.29 (1H, m), 7.54-7.08 (3H, m), 6.35-6.29 (1H, m), 5.04-4.38 (3H, m), 3.55-2.92 (3H, m), 2.31-2.23 (6H, m), 2.12-1.66 (4H, m). Example 101 (4-Chloro-2- (pyrimidin-2-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane Synthesis of 3-yl) methanone 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 1) (28 mg), 4-chloro-2 A mixed solution of-(pyrimidin-2-yl) benzoic acid (intermediate 16) (30 mg), COMU (82 mg) and 2,6-lutidine (30 μL) in dichloromethane (0.64 mL) at room temperature under a nitrogen atmosphere Stir for hours. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction solution, extraction was performed with ethyl acetate (20 mL × 2), and the collected organic layer was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 88: 12 to 0: 100) to obtain the title compound (20 mg) as a colorless amorphous.
UPLC: 435 [M + H] + (retention time 1.06 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.85-8.62 (2H, m), 8.44-8.29 (1H, m), 7.54-7.08 (3H, m), 6.35-6.29 (1H, m), 5.04- 4.38 (3H, m), 3.55-2.92 (3H, m), 2.31-2.23 (6H, m), 2.12-1.66 (4H, m).
*実施例102~実施例104は、中間体1~中間体3の何れか及び中間体17を用いて、実施例101と同様の方法、もしくはこれに準ずる方法により合成した。
* Example 102 to Example 104 were synthesized using any one of Intermediate 1 to Intermediate 3 and Intermediate 17 by the same method as in Example 101 or a method analogous thereto.
(実施例105)(4-フルオロ-2-(ピリミジン-2-イル)フェニル)(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノンの合成
4-フルオロ-2-(ピリミジン-2-イル)安息香酸(40mg)、8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体2)(53mg)、T3P(0.11mL)、DIPEA(80μL)のDMF(0.92mL)混合溶液を窒素雰囲気下、室温にて19時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液(30mL)を加え、酢酸エチル(20mL×2)で抽出を行い、集めた有機層を飽和食塩水(10mL)で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=88:12~0:100)にて精製し、標記化合物(16mg)を茶色固体として得た。
UPLC:488[M+H]+(保持時間1.19分)
1H-NMR (CDCl3, 400MHz) δ: 8.85-8.62 (2H, m), 8.16-7.96 (2H, m), 7.44-7.09 (3H, m), 7.00-6.88 (1H, m), 4.83-4.34 (3H, m), 3.83-3.70 (3H, m), 3.66-3.00 (3H, m), 2.10-1.70 (4H, m). Example 105 (4-Fluoro-2- (pyrimidin-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3 2.1] Synthesis of Octan-3-yl) methanone 4-Fluoro-2- (pyrimidin-2-yl) benzoic acid (40 mg), 8- (3-methoxy-4- (trifluoromethyl) pyridine-2 -Il) -3,8-diazabicyclo [3.2.1] octane (intermediate 2) (53 mg), T3P (0.11 mL), DIPEA (80 μL) in DMF (0.92 mL) mixed solution under nitrogen atmosphere And stirred at room temperature for 19 hours. A saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the reaction solution, extraction was performed with ethyl acetate (20 mL × 2), and the collected organic layer was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 88: 12 to 0: 100) to obtain the title compound (16 mg) as a brown solid.
UPLC: 488 [M + H] + (retention time 1.19 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.85-8.62 (2H, m), 8.16-7.96 (2H, m), 7.44-7.09 (3H, m), 7.00-6.88 (1H, m), 4.83- 4.34 (3H, m), 3.83-3.70 (3H, m), 3.66-3.00 (3H, m), 2.10-1.70 (4H, m).
4-フルオロ-2-(ピリミジン-2-イル)安息香酸(40mg)、8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体2)(53mg)、T3P(0.11mL)、DIPEA(80μL)のDMF(0.92mL)混合溶液を窒素雰囲気下、室温にて19時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液(30mL)を加え、酢酸エチル(20mL×2)で抽出を行い、集めた有機層を飽和食塩水(10mL)で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=88:12~0:100)にて精製し、標記化合物(16mg)を茶色固体として得た。
UPLC:488[M+H]+(保持時間1.19分)
1H-NMR (CDCl3, 400MHz) δ: 8.85-8.62 (2H, m), 8.16-7.96 (2H, m), 7.44-7.09 (3H, m), 7.00-6.88 (1H, m), 4.83-4.34 (3H, m), 3.83-3.70 (3H, m), 3.66-3.00 (3H, m), 2.10-1.70 (4H, m). Example 105 (4-Fluoro-2- (pyrimidin-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3 2.1] Synthesis of Octan-3-yl) methanone 4-Fluoro-2- (pyrimidin-2-yl) benzoic acid (40 mg), 8- (3-methoxy-4- (trifluoromethyl) pyridine-2 -Il) -3,8-diazabicyclo [3.2.1] octane (intermediate 2) (53 mg), T3P (0.11 mL), DIPEA (80 μL) in DMF (0.92 mL) mixed solution under nitrogen atmosphere And stirred at room temperature for 19 hours. A saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the reaction solution, extraction was performed with ethyl acetate (20 mL × 2), and the collected organic layer was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 88: 12 to 0: 100) to obtain the title compound (16 mg) as a brown solid.
UPLC: 488 [M + H] + (retention time 1.19 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.85-8.62 (2H, m), 8.16-7.96 (2H, m), 7.44-7.09 (3H, m), 7.00-6.88 (1H, m), 4.83- 4.34 (3H, m), 3.83-3.70 (3H, m), 3.66-3.00 (3H, m), 2.10-1.70 (4H, m).
(実施例106)2-(3-(4-フルオロ-2-(ピリミジン-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリルの合成
実施例105と同様の方法もしくは、これに準ずる方法で、2-(3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(中間体3)(45mg)を用いて標記化合物(13mg)を橙色固体として得た。
UPLC:445[M+H]+(保持時間1.10分) Example 106 2- (3- (4-Fluoro-2- (pyrimidin-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyiso Synthesis of nicotinonitrile 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (in the same manner as in Example 105 or a method analogous thereto) Intermediate 3) (45 mg) was used to give the title compound (13 mg) as an orange solid.
UPLC: 445 [M + H] + (retention time 1.10 minutes)
実施例105と同様の方法もしくは、これに準ずる方法で、2-(3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリル(中間体3)(45mg)を用いて標記化合物(13mg)を橙色固体として得た。
UPLC:445[M+H]+(保持時間1.10分) Example 106 2- (3- (4-Fluoro-2- (pyrimidin-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyiso Synthesis of nicotinonitrile 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (in the same manner as in Example 105 or a method analogous thereto) Intermediate 3) (45 mg) was used to give the title compound (13 mg) as an orange solid.
UPLC: 445 [M + H] + (retention time 1.10 minutes)
(実施例107)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(1-(チアゾール-2-イル)-1H-ピラゾール-5-イル)メタノンの合成
1-(チアゾール-2-イル)-1H-ピラゾール-5-カルボン酸メチル(中間体18)(14mg)のメタノール(0.10mL)-THF(0.10mL)混合溶液に8規定水酸化ナトリウム水溶液(13μL)を加え、50℃で1時間攪拌した。減圧下溶媒を留去して得られた残渣をDMF(0.15mL)に溶解し、8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体1)(15mg)、DIPEA(35μL)、HATU(28mg)を加え、反応液を窒素雰囲気下、室温で2時間攪拌した。反応液に水(1mL)を加え、酢酸エチル(1mL)で抽出し、有機層を水(0.5mL×2)と飽和食塩水(0.5mL)で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣を分取TLC(シリカゲル、ヘプタン:酢酸エチル=50:50)にて精製し、標記化合物(4.8mg)を無色アモルファスとして得た。
UPLC:396[M+H]+(保持時間0.88分)
1H-NMR (CDCl3, 400MHz) δ: 7.68 (1H, d, J = 2 Hz), 7.46 (1H, d, J = 4 Hz), 7.10 (1H, d, J = 4 Hz), 6.43 (1H, d, J = 2 Hz), 6.33 (1H, s), 4.99-4.91 (1H, m), 4.78-4.71 (1H, m), 4.51-4.45 (1H, m), 3.45-3.38 (1H, m), 3.27-3.20 (2H, m), 2.28 (6H, s), 2.06-1.72 (4H, m). Example 107 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1- (thiazol-2-yl)- Synthesis of 1H-pyrazol-5-yl) methanone Methyl 1- (thiazol-2-yl) -1H-pyrazole-5-carboxylate (Intermediate 18) (14 mg) in methanol (0.10 mL) -THF (0. 10 mL) To the mixed solution was added 8N aqueous sodium hydroxide solution (13 μL), and the mixture was stirred at 50 ° C. for 1 hour. The residue obtained by distilling off the solvent under reduced pressure was dissolved in DMF (0.15 mL) to give 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1]. Octane (Intermediate 1) (15 mg), DIPEA (35 μL) and HATU (28 mg) were added, and the reaction solution was stirred at room temperature for 2 hours under a nitrogen atmosphere. Water (1 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (1 mL). The organic layer was washed successively with water (0.5 mL × 2) and saturated brine (0.5 mL), and dried over anhydrous sodium sulfate. . The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative TLC (silica gel, heptane: ethyl acetate = 50: 50) to obtain the title compound (4.8 mg) as a colorless amorphous.
UPLC: 396 [M + H] + (retention time 0.88 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 7.68 (1H, d, J = 2 Hz), 7.46 (1H, d, J = 4 Hz), 7.10 (1H, d, J = 4 Hz), 6.43 ( 1H, d, J = 2 Hz), 6.33 (1H, s), 4.99-4.91 (1H, m), 4.78-4.71 (1H, m), 4.51-4.45 (1H, m), 3.45-3.38 (1H, m), 3.27-3.20 (2H, m), 2.28 (6H, s), 2.06-1.72 (4H, m).
1-(チアゾール-2-イル)-1H-ピラゾール-5-カルボン酸メチル(中間体18)(14mg)のメタノール(0.10mL)-THF(0.10mL)混合溶液に8規定水酸化ナトリウム水溶液(13μL)を加え、50℃で1時間攪拌した。減圧下溶媒を留去して得られた残渣をDMF(0.15mL)に溶解し、8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体1)(15mg)、DIPEA(35μL)、HATU(28mg)を加え、反応液を窒素雰囲気下、室温で2時間攪拌した。反応液に水(1mL)を加え、酢酸エチル(1mL)で抽出し、有機層を水(0.5mL×2)と飽和食塩水(0.5mL)で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣を分取TLC(シリカゲル、ヘプタン:酢酸エチル=50:50)にて精製し、標記化合物(4.8mg)を無色アモルファスとして得た。
UPLC:396[M+H]+(保持時間0.88分)
1H-NMR (CDCl3, 400MHz) δ: 7.68 (1H, d, J = 2 Hz), 7.46 (1H, d, J = 4 Hz), 7.10 (1H, d, J = 4 Hz), 6.43 (1H, d, J = 2 Hz), 6.33 (1H, s), 4.99-4.91 (1H, m), 4.78-4.71 (1H, m), 4.51-4.45 (1H, m), 3.45-3.38 (1H, m), 3.27-3.20 (2H, m), 2.28 (6H, s), 2.06-1.72 (4H, m). Example 107 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1- (thiazol-2-yl)- Synthesis of 1H-pyrazol-5-yl) methanone Methyl 1- (thiazol-2-yl) -1H-pyrazole-5-carboxylate (Intermediate 18) (14 mg) in methanol (0.10 mL) -THF (0. 10 mL) To the mixed solution was added 8N aqueous sodium hydroxide solution (13 μL), and the mixture was stirred at 50 ° C. for 1 hour. The residue obtained by distilling off the solvent under reduced pressure was dissolved in DMF (0.15 mL) to give 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1]. Octane (Intermediate 1) (15 mg), DIPEA (35 μL) and HATU (28 mg) were added, and the reaction solution was stirred at room temperature for 2 hours under a nitrogen atmosphere. Water (1 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (1 mL). The organic layer was washed successively with water (0.5 mL × 2) and saturated brine (0.5 mL), and dried over anhydrous sodium sulfate. . The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative TLC (silica gel, heptane: ethyl acetate = 50: 50) to obtain the title compound (4.8 mg) as a colorless amorphous.
UPLC: 396 [M + H] + (retention time 0.88 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 7.68 (1H, d, J = 2 Hz), 7.46 (1H, d, J = 4 Hz), 7.10 (1H, d, J = 4 Hz), 6.43 ( 1H, d, J = 2 Hz), 6.33 (1H, s), 4.99-4.91 (1H, m), 4.78-4.71 (1H, m), 4.51-4.45 (1H, m), 3.45-3.38 (1H, m), 3.27-3.20 (2H, m), 2.28 (6H, s), 2.06-1.72 (4H, m).
(実施例108)3-メトキシ-2-(3-(1-(チアゾール-2-イル)-1H-ピラゾール-5-カルボニル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリルの合成
実施例107と同様の方法もしくは、これに準ずる方法で、3-メトキシ-2-(3-(1-(チアゾール-2-イル)-1H-ピラゾール-5-カルボニル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(中間体3)(16mg)を用いて標記化合物(7.0mg)を無色アモルファスとして得た。
UPLC:422[M+H]+(保持時間1.01分) Example 108 3-Methoxy-2- (3- (1- (thiazol-2-yl) -1H-pyrazole-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8- Yl) Synthesis of isonicotinonitrile 3-methoxy-2- (3- (1- (thiazol-2-yl) -1H-pyrazole-5-carbonyl) in the same manner as in Example 107 or a method analogous thereto ) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Intermediate 3) (16 mg) was used to obtain the title compound (7.0 mg) as a colorless amorphous.
UPLC: 422 [M + H] + (retention time 1.01 minutes)
実施例107と同様の方法もしくは、これに準ずる方法で、3-メトキシ-2-(3-(1-(チアゾール-2-イル)-1H-ピラゾール-5-カルボニル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)イソニコチノニトリル(中間体3)(16mg)を用いて標記化合物(7.0mg)を無色アモルファスとして得た。
UPLC:422[M+H]+(保持時間1.01分) Example 108 3-Methoxy-2- (3- (1- (thiazol-2-yl) -1H-pyrazole-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8- Yl) Synthesis of isonicotinonitrile 3-methoxy-2- (3- (1- (thiazol-2-yl) -1H-pyrazole-5-carbonyl) in the same manner as in Example 107 or a method analogous thereto ) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Intermediate 3) (16 mg) was used to obtain the title compound (7.0 mg) as a colorless amorphous.
UPLC: 422 [M + H] + (retention time 1.01 minutes)
(実施例109)(8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(1-(チアゾール-2-イル)-1H-ピラゾール-5-イル)メタノンの合成
実施例107と同様の方法もしくは、これに準ずる方法で、8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体2)(19mg)を用いて標記化合物(10mg)を無色アモルファスとして得た。
UPLC:465[M+H]+(保持時間1.13分) Example 109 (8- (3-Methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1- (thiazole Synthesis of -2-yl) -1H-pyrazol-5-yl) methanone By a method similar to that in Example 107 or a method analogous thereto, 8- (3-methoxy-4- (trifluoromethyl) pyridine-2- Yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 2) (19 mg) to give the title compound (10 mg) as a colorless amorphous.
UPLC: 465 [M + H] + (retention time 1.13 minutes)
実施例107と同様の方法もしくは、これに準ずる方法で、8-(3-メトキシ-4-(トリフルオロメチル)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体2)(19mg)を用いて標記化合物(10mg)を無色アモルファスとして得た。
UPLC:465[M+H]+(保持時間1.13分) Example 109 (8- (3-Methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1- (thiazole Synthesis of -2-yl) -1H-pyrazol-5-yl) methanone By a method similar to that in Example 107 or a method analogous thereto, 8- (3-methoxy-4- (trifluoromethyl) pyridine-2- Yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 2) (19 mg) to give the title compound (10 mg) as a colorless amorphous.
UPLC: 465 [M + H] + (retention time 1.13 minutes)
(実施例110)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-ヨードフェニル)メタノンの合成
8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体1)(0.20g)とトリエチルアミン(0.19mL)のDME(2.0mL)混合溶液に2-ヨードベンゾイルクロリド(0.24g)を室温で複数回に分けて加え、室温にて1時間攪拌した。反応液をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=65:35~50:50)にて精製し、標記化合物(0.31g)を白色固体として得た。
UPLC:449[M+H]+(保持時間1.01分)
1H-NMR (CDCl3, 400MHz) δ: 7.90-7.77 (1H, m), 7.45-6.98 (3H, m), 6.33 (1H, s), 4.97-4.91 (1H, m), 4.76-4.68 (1H, m), 4.53-4.46 (1H, m), 3.57-3.35 (1H, m), 3.24-3.05 (2H, m), 2.29 (6H, s), 2.17-1.90 (4H, m). Example 110 Synthesis of (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-iodophenyl) methanone 8- DME (2.0 mL) of (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 1) (0.20 g) and triethylamine (0.19 mL) 2-Iodobenzoyl chloride (0.24 g) was added to the mixed solution in several portions at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by column chromatography (silica gel, heptane: ethyl acetate = 65: 35-50: 50) to obtain the title compound (0.31 g) as a white solid.
UPLC: 449 [M + H] + (retention time 1.01 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 7.90-7.77 (1H, m), 7.45-6.98 (3H, m), 6.33 (1H, s), 4.97-4.91 (1H, m), 4.76-4.68 ( 1H, m), 4.53-4.46 (1H, m), 3.57-3.35 (1H, m), 3.24-3.05 (2H, m), 2.29 (6H, s), 2.17-1.90 (4H, m).
8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン(中間体1)(0.20g)とトリエチルアミン(0.19mL)のDME(2.0mL)混合溶液に2-ヨードベンゾイルクロリド(0.24g)を室温で複数回に分けて加え、室温にて1時間攪拌した。反応液をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=65:35~50:50)にて精製し、標記化合物(0.31g)を白色固体として得た。
UPLC:449[M+H]+(保持時間1.01分)
1H-NMR (CDCl3, 400MHz) δ: 7.90-7.77 (1H, m), 7.45-6.98 (3H, m), 6.33 (1H, s), 4.97-4.91 (1H, m), 4.76-4.68 (1H, m), 4.53-4.46 (1H, m), 3.57-3.35 (1H, m), 3.24-3.05 (2H, m), 2.29 (6H, s), 2.17-1.90 (4H, m). Example 110 Synthesis of (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-iodophenyl) methanone 8- DME (2.0 mL) of (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 1) (0.20 g) and triethylamine (0.19 mL) 2-Iodobenzoyl chloride (0.24 g) was added to the mixed solution in several portions at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by column chromatography (silica gel, heptane: ethyl acetate = 65: 35-50: 50) to obtain the title compound (0.31 g) as a white solid.
UPLC: 449 [M + H] + (retention time 1.01 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 7.90-7.77 (1H, m), 7.45-6.98 (3H, m), 6.33 (1H, s), 4.97-4.91 (1H, m), 4.76-4.68 ( 1H, m), 4.53-4.46 (1H, m), 3.57-3.35 (1H, m), 3.24-3.05 (2H, m), 2.29 (6H, s), 2.17-1.90 (4H, m).
(実施例111)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(オキサゾール-2-イル)フェニル)メタノンの合成
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-ヨードフェニル)メタノン(実施例110)(42mg)、2-(トリブチルスズ)オキサゾール(34mg)、フッ化セシウム(28mg)のDMF(0.50mL)混合液にテトラキス(トリフェニルホスフィン)パラジウム(11mg)とヨウ化銅(I)(1.8mg)を加え、窒素雰囲気下、110℃で18時間攪拌した。反応液を室温まで冷却した後、水を加えて酢酸エチルで抽出し、抽出液を無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=50:50~25:75)と分取TLC(NH-シリカゲル、ヘプタン:酢酸エチル)にて精製し、標記化合物(3.8mg)を無色アモルファスとして得た。
UPLC:390[M+H]+(保持時間0.89分)
1H-NMR (CDCl3, 400MHz) δ: 8.13-8.03 (1H, m), 7.76-7.26 (4H, m), 7.20-7.10 (1H, m), 6.31 (1H, s), 5.02-4.90 (1H, m), 4.72-4.60 (1H, m), 4.56-4.47 (1H, m), 3.42-3.05 (3H, m), 2.29-2.24 (6H, m), 2.06-1.65 (4H, m). Example 111 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (oxazol-2-yl) phenyl ) Synthesis of Methanone (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-iodophenyl) methanone (Example 110) (42 mg), 2- (tributyltin) oxazole (34 mg) and cesium fluoride (28 mg) in a mixed solution of DMF (0.50 mL) with tetrakis (triphenylphosphine) palladium (11 mg) and copper (I) iodide (1. 8 mg), and the mixture was stirred at 110 ° C. for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 50: 50 to 25:75) and preparative TLC (NH-silica gel, heptane: ethyl acetate). The title compound (3.8 mg) was obtained as a colorless amorphous.
UPLC: 390 [M + H] + (retention time 0.89 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.13-8.03 (1H, m), 7.76-7.26 (4H, m), 7.20-7.10 (1H, m), 6.31 (1H, s), 5.02-4.90 ( 1H, m), 4.72-4.60 (1H, m), 4.56-4.47 (1H, m), 3.42-3.05 (3H, m), 2.29-2.24 (6H, m), 2.06-1.65 (4H, m).
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-ヨードフェニル)メタノン(実施例110)(42mg)、2-(トリブチルスズ)オキサゾール(34mg)、フッ化セシウム(28mg)のDMF(0.50mL)混合液にテトラキス(トリフェニルホスフィン)パラジウム(11mg)とヨウ化銅(I)(1.8mg)を加え、窒素雰囲気下、110℃で18時間攪拌した。反応液を室温まで冷却した後、水を加えて酢酸エチルで抽出し、抽出液を無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=50:50~25:75)と分取TLC(NH-シリカゲル、ヘプタン:酢酸エチル)にて精製し、標記化合物(3.8mg)を無色アモルファスとして得た。
UPLC:390[M+H]+(保持時間0.89分)
1H-NMR (CDCl3, 400MHz) δ: 8.13-8.03 (1H, m), 7.76-7.26 (4H, m), 7.20-7.10 (1H, m), 6.31 (1H, s), 5.02-4.90 (1H, m), 4.72-4.60 (1H, m), 4.56-4.47 (1H, m), 3.42-3.05 (3H, m), 2.29-2.24 (6H, m), 2.06-1.65 (4H, m). Example 111 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (oxazol-2-yl) phenyl ) Synthesis of Methanone (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-iodophenyl) methanone (Example 110) (42 mg), 2- (tributyltin) oxazole (34 mg) and cesium fluoride (28 mg) in a mixed solution of DMF (0.50 mL) with tetrakis (triphenylphosphine) palladium (11 mg) and copper (I) iodide (1. 8 mg), and the mixture was stirred at 110 ° C. for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 50: 50 to 25:75) and preparative TLC (NH-silica gel, heptane: ethyl acetate). The title compound (3.8 mg) was obtained as a colorless amorphous.
UPLC: 390 [M + H] + (retention time 0.89 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.13-8.03 (1H, m), 7.76-7.26 (4H, m), 7.20-7.10 (1H, m), 6.31 (1H, s), 5.02-4.90 ( 1H, m), 4.72-4.60 (1H, m), 4.56-4.47 (1H, m), 3.42-3.05 (3H, m), 2.29-2.24 (6H, m), 2.06-1.65 (4H, m).
(実施例112)(2-(1H-ピラゾール-3-イル)フェニル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノンの合成
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-ヨードフェニル)メタノン(実施例110)(45mg)、(1H-ピラゾール-3-イル)ボロン酸(17mg)、PdCl2(dppf)(15mg)、炭酸カリウム(41mg)のDME(0.50mL)-水(0.20mL)混合液を窒素雰囲気下、85℃で6時間攪拌した。反応液をろ過後、ろ液をHPLCにて精製し、標記化合物(5.7mg)を無色アモルファスとして得た。
UPLC:389[M+H]+(保持時間0.86分)
1H-NMR (DMSO-d6, 400MHz) δ: 7.77-7.62 (2H, m), 7.50-7.14 (3H, m), 6.59-6.30 (2H, m), 4.83-4.72 (1H, m), 4.54-4.42 (1H, m), 4.33-4.18 (1H, m), 3.20-2.65 (3H, m), 2.24-2.20 (6H, m), 1.94-1.42 (4H, m). Example 112 (2- (1H-pyrazol-3-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3 Synthesis of (-yl) methanone (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-iodophenyl) methanone (Examples) 110) (45 mg), (1H-pyrazol-3-yl) boronic acid (17 mg), PdCl 2 (dppf) (15 mg), potassium carbonate (41 mg) in DME (0.50 mL) -water (0.20 mL) The solution was stirred at 85 ° C. for 6 hours under a nitrogen atmosphere. After the reaction solution was filtered, the filtrate was purified by HPLC to obtain the title compound (5.7 mg) as a colorless amorphous.
UPLC: 389 [M + H] + (retention time 0.86 minutes)
1 H-NMR (DMSO-d 6 , 400 MHz) δ: 7.77-7.62 (2H, m), 7.50-7.14 (3H, m), 6.59-6.30 (2H, m), 4.83-4.72 (1H, m), 4.54-4.42 (1H, m), 4.33-4.18 (1H, m), 3.20-2.65 (3H, m), 2.24-2.20 (6H, m), 1.94-1.42 (4H, m).
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-ヨードフェニル)メタノン(実施例110)(45mg)、(1H-ピラゾール-3-イル)ボロン酸(17mg)、PdCl2(dppf)(15mg)、炭酸カリウム(41mg)のDME(0.50mL)-水(0.20mL)混合液を窒素雰囲気下、85℃で6時間攪拌した。反応液をろ過後、ろ液をHPLCにて精製し、標記化合物(5.7mg)を無色アモルファスとして得た。
UPLC:389[M+H]+(保持時間0.86分)
1H-NMR (DMSO-d6, 400MHz) δ: 7.77-7.62 (2H, m), 7.50-7.14 (3H, m), 6.59-6.30 (2H, m), 4.83-4.72 (1H, m), 4.54-4.42 (1H, m), 4.33-4.18 (1H, m), 3.20-2.65 (3H, m), 2.24-2.20 (6H, m), 1.94-1.42 (4H, m). Example 112 (2- (1H-pyrazol-3-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3 Synthesis of (-yl) methanone (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-iodophenyl) methanone (Examples) 110) (45 mg), (1H-pyrazol-3-yl) boronic acid (17 mg), PdCl 2 (dppf) (15 mg), potassium carbonate (41 mg) in DME (0.50 mL) -water (0.20 mL) The solution was stirred at 85 ° C. for 6 hours under a nitrogen atmosphere. After the reaction solution was filtered, the filtrate was purified by HPLC to obtain the title compound (5.7 mg) as a colorless amorphous.
UPLC: 389 [M + H] + (retention time 0.86 minutes)
1 H-NMR (DMSO-d 6 , 400 MHz) δ: 7.77-7.62 (2H, m), 7.50-7.14 (3H, m), 6.59-6.30 (2H, m), 4.83-4.72 (1H, m), 4.54-4.42 (1H, m), 4.33-4.18 (1H, m), 3.20-2.65 (3H, m), 2.24-2.20 (6H, m), 1.94-1.42 (4H, m).
(実施例113)(2-(1H-ピラゾール-4-イル)フェニル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノンの合成
実施例112と同様の方法もしくは、これに準ずる方法で、(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-ヨードフェニル)メタノン(実施例110)(45mg)と4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール(29mg)を用いて、標記化合物(3.4mg)を無色アモルファスとして得た。
UPLC:389[M+H]+(保持時間0.87分) Example 113 (2- (1H-pyrazol-4-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3 Synthesis of -yl) methanone (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane) was carried out in the same manner as in Example 112 or a method analogous thereto. -3-yl) (2-iodophenyl) methanone (Example 110) (45 mg) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H- The title compound (3.4 mg) was obtained as a colorless amorphous using pyrazole (29 mg).
UPLC: 389 [M + H] + (retention time 0.87 minutes)
実施例112と同様の方法もしくは、これに準ずる方法で、(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-ヨードフェニル)メタノン(実施例110)(45mg)と4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール(29mg)を用いて、標記化合物(3.4mg)を無色アモルファスとして得た。
UPLC:389[M+H]+(保持時間0.87分) Example 113 (2- (1H-pyrazol-4-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3 Synthesis of -yl) methanone (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane) was carried out in the same manner as in Example 112 or a method analogous thereto. -3-yl) (2-iodophenyl) methanone (Example 110) (45 mg) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H- The title compound (3.4 mg) was obtained as a colorless amorphous using pyrazole (29 mg).
UPLC: 389 [M + H] + (retention time 0.87 minutes)
(実施例114)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(4’-フルオロ-[1,1’-ビフェニル]-2-イル)メタノンの合成
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)メタノン(中間体11)(22mg)、1-ブロモ-4-フルオロベンゼン(9.0mg)、PdCl2(dppf)(7.3mg)、炭酸カリウム(21mg)のDME(0.50mL)-水(0.15mL)混合液を窒素雰囲気下、80℃で1時間攪拌した。反応液をろ過後、ろ液をHPLCにて精製し、標記化合物(7.6mg)を得た。
UPLC:417[M+H]+(保持時間1.10分) Example 114 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4′-fluoro- [1,1 ′ Synthesis of -biphenyl] -2-yl) methanone (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octan-3-yl) (2- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methanone (intermediate 11) (22 mg), 1-bromo-4-fluorobenzene (9.0 mg), PdCl 2 A mixture of (dppf) (7.3 mg) and potassium carbonate (21 mg) in DME (0.50 mL) -water (0.15 mL) was stirred at 80 ° C. for 1 hour under a nitrogen atmosphere. After the reaction solution was filtered, the filtrate was purified by HPLC to obtain the title compound (7.6 mg).
UPLC: 417 [M + H] + (retention time 1.10 minutes)
(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)メタノン(中間体11)(22mg)、1-ブロモ-4-フルオロベンゼン(9.0mg)、PdCl2(dppf)(7.3mg)、炭酸カリウム(21mg)のDME(0.50mL)-水(0.15mL)混合液を窒素雰囲気下、80℃で1時間攪拌した。反応液をろ過後、ろ液をHPLCにて精製し、標記化合物(7.6mg)を得た。
UPLC:417[M+H]+(保持時間1.10分) Example 114 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4′-fluoro- [1,1 ′ Synthesis of -biphenyl] -2-yl) methanone (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octan-3-yl) (2- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methanone (intermediate 11) (22 mg), 1-bromo-4-fluorobenzene (9.0 mg), PdCl 2 A mixture of (dppf) (7.3 mg) and potassium carbonate (21 mg) in DME (0.50 mL) -water (0.15 mL) was stirred at 80 ° C. for 1 hour under a nitrogen atmosphere. After the reaction solution was filtered, the filtrate was purified by HPLC to obtain the title compound (7.6 mg).
UPLC: 417 [M + H] + (retention time 1.10 minutes)
*実施例115~実施例126は、中間体11及び市販化合物を用いて、実施例114と同様の方法、もしくはこれに準ずる方法により合成した。
* Example 115 to Example 126 were synthesized by the same method as in Example 114 or a method analogous thereto, using Intermediate 11 and a commercially available compound.
(実施例127)(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4,6-ジメチルピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノンの合成
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン塩酸塩(中間体19)(38mg)、2-ブロモ-4,6-ジメチルピリジン(22mg)、ナトリウム tert-ブトキシド(29mg)、(±)-BINAP(7.5mg)のトルエン(1.0mL)混合液にPd2(dba)3(5.5mg)を加え、窒素雰囲気下、85℃で1.5時間攪拌した。反応液を室温まで冷却した後、水を加えて酢酸エチルで抽出し、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=70:30~50:50)にて精製し、標記化合物(39mg)を白色固体として得た。
UPLC:389[M+H]+(保持時間0.73分)
1H-NMR (CDCl3, 400MHz) δ: 8.03-7.97 (1H, m), 7.88-7.64 (2H, m), 7.57-7.17 (3H, m), 6.37-6.31 (1H, m), 6.24-6.14 (1H, m), 4.64-4.33 (3H, m), 3.54-2.76 (3H, m), 2.36-2.17 (6H, m), 2.07-1.59 (4H, m). Example 127 (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,6-dimethylpyridin-2-yl) -3,8-diazabicyclo [3.2 .1] Synthesis of octan-3-yl) methanone (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3-yl ) Methanone hydrochloride (intermediate 19) (38 mg), 2-bromo-4,6-dimethylpyridine (22 mg), sodium tert-butoxide (29 mg), (±) -BINAP (7.5 mg) in toluene (1. 0 mL) Pd 2 (dba) 3 (5.5 mg) was added to the mixture, and the mixture was stirred at 85 ° C. for 1.5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 70: 30-50: 50) to give the title compound ( 39 mg) as a white solid.
UPLC: 389 [M + H] + (retention time 0.73 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.03-7.97 (1H, m), 7.88-7.64 (2H, m), 7.57-7.17 (3H, m), 6.37-6.31 (1H, m), 6.24- 6.14 (1H, m), 4.64-4.33 (3H, m), 3.54-2.76 (3H, m), 2.36-2.17 (6H, m), 2.07-1.59 (4H, m).
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン塩酸塩(中間体19)(38mg)、2-ブロモ-4,6-ジメチルピリジン(22mg)、ナトリウム tert-ブトキシド(29mg)、(±)-BINAP(7.5mg)のトルエン(1.0mL)混合液にPd2(dba)3(5.5mg)を加え、窒素雰囲気下、85℃で1.5時間攪拌した。反応液を室温まで冷却した後、水を加えて酢酸エチルで抽出し、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=70:30~50:50)にて精製し、標記化合物(39mg)を白色固体として得た。
UPLC:389[M+H]+(保持時間0.73分)
1H-NMR (CDCl3, 400MHz) δ: 8.03-7.97 (1H, m), 7.88-7.64 (2H, m), 7.57-7.17 (3H, m), 6.37-6.31 (1H, m), 6.24-6.14 (1H, m), 4.64-4.33 (3H, m), 3.54-2.76 (3H, m), 2.36-2.17 (6H, m), 2.07-1.59 (4H, m). Example 127 (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,6-dimethylpyridin-2-yl) -3,8-diazabicyclo [3.2 .1] Synthesis of octan-3-yl) methanone (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3-yl ) Methanone hydrochloride (intermediate 19) (38 mg), 2-bromo-4,6-dimethylpyridine (22 mg), sodium tert-butoxide (29 mg), (±) -BINAP (7.5 mg) in toluene (1. 0 mL) Pd 2 (dba) 3 (5.5 mg) was added to the mixture, and the mixture was stirred at 85 ° C. for 1.5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 70: 30-50: 50) to give the title compound ( 39 mg) as a white solid.
UPLC: 389 [M + H] + (retention time 0.73 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.03-7.97 (1H, m), 7.88-7.64 (2H, m), 7.57-7.17 (3H, m), 6.37-6.31 (1H, m), 6.24- 6.14 (1H, m), 4.64-4.33 (3H, m), 3.54-2.76 (3H, m), 2.36-2.17 (6H, m), 2.07-1.59 (4H, m).
*実施例128~実施例129は、中間体19~中間体20の何れか及び市販化合物を用いて、実施例127と同様の方法、もしくはこれに準ずる方法により合成した。
* Example 128 to Example 129 were synthesized in the same manner as in Example 127 or a method analogous thereto, using any of Intermediate 19 to Intermediate 20 and commercially available compounds.
(実施例130)2-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-6-メチルイソニコチノニトリルの合成
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン塩酸塩(中間体19)(42mg)、2-クロロ-6-メチルイソニコチノニトリル(20mg)、ナトリウム tert-ブトキシド(31mg)、XPhos(6.8mg)のトルエン(1.0mL)混合液にPd2(dba)3(6.0mg)を加え、窒素雰囲気下、100℃で4時間攪拌した。反応液を室温まで冷却した後、水を加えて酢酸エチルで抽出し、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=75:25~50:50)にて精製し、標記化合物(3.7mg)を無色アモルファスとして得た。
UPLC:400[M+H]+(保持時間1.07分)
1H-NMR (CDCl3, 400MHz) δ: 8.04-7.99 (1H, m), 7.86-7.68 (2H, m), 7.57-7.19 (3H, m), 6.65-6.47 (2H, m), 4.70-4.34 (3H, m), 3.51-2.72 (3H, m), 2.43-2.35 (3H, m), 2.09-1.70 (4H, m). Example 130 2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl)- Synthesis of 6-methylisonicotinonitrile (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3-yl) methanone hydrochloride Salt (intermediate 19) (42 mg), 2-chloro-6-methylisonicotinonitrile (20 mg), sodium tert-butoxide (31 mg), XPhos (6.8 mg) in toluene (1.0 mL) mixed with Pd 2 (dba) 3 (6.0 mg) was added, and the mixture was stirred at 100 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 75: 25-50: 50) to give the title compound ( 3.7 mg) was obtained as a colorless amorphous.
UPLC: 400 [M + H] + (retention time 1.07 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.04-7.99 (1H, m), 7.86-7.68 (2H, m), 7.57-7.19 (3H, m), 6.65-6.47 (2H, m), 4.70- 4.34 (3H, m), 3.51-2.72 (3H, m), 2.43-2.35 (3H, m), 2.09-1.70 (4H, m).
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン塩酸塩(中間体19)(42mg)、2-クロロ-6-メチルイソニコチノニトリル(20mg)、ナトリウム tert-ブトキシド(31mg)、XPhos(6.8mg)のトルエン(1.0mL)混合液にPd2(dba)3(6.0mg)を加え、窒素雰囲気下、100℃で4時間攪拌した。反応液を室温まで冷却した後、水を加えて酢酸エチルで抽出し、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去して得られた残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=75:25~50:50)にて精製し、標記化合物(3.7mg)を無色アモルファスとして得た。
UPLC:400[M+H]+(保持時間1.07分)
1H-NMR (CDCl3, 400MHz) δ: 8.04-7.99 (1H, m), 7.86-7.68 (2H, m), 7.57-7.19 (3H, m), 6.65-6.47 (2H, m), 4.70-4.34 (3H, m), 3.51-2.72 (3H, m), 2.43-2.35 (3H, m), 2.09-1.70 (4H, m). Example 130 2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl)- Synthesis of 6-methylisonicotinonitrile (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3-yl) methanone hydrochloride Salt (intermediate 19) (42 mg), 2-chloro-6-methylisonicotinonitrile (20 mg), sodium tert-butoxide (31 mg), XPhos (6.8 mg) in toluene (1.0 mL) mixed with Pd 2 (dba) 3 (6.0 mg) was added, and the mixture was stirred at 100 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 75: 25-50: 50) to give the title compound ( 3.7 mg) was obtained as a colorless amorphous.
UPLC: 400 [M + H] + (retention time 1.07 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.04-7.99 (1H, m), 7.86-7.68 (2H, m), 7.57-7.19 (3H, m), 6.65-6.47 (2H, m), 4.70- 4.34 (3H, m), 3.51-2.72 (3H, m), 2.43-2.35 (3H, m), 2.09-1.70 (4H, m).
(実施例131)(8-(3,5-ジメチルフェニル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノンの合成
実施例130と同様の方法もしくは、これに準ずる方法により(3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン塩酸塩(中間体20)(34mg)と1-ブロモ-3,5-ジメチルベンゼン(19mg)を用いて標記化合物(8.1mg)を無色アモルファスして得た。
UPLC:406[M+H]+(保持時間1.16、1.18分、回転異性体) Example 131 (8- (3,5-dimethylphenyl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-6- (2H-1,2,3 Synthesis of -triazol-2-yl) phenyl) methanone (3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-) by the same method as in Example 130 or a method analogous thereto Using 6- (2H-1,2,3-triazol-2-yl) phenyl) methanone hydrochloride (intermediate 20) (34 mg) and 1-bromo-3,5-dimethylbenzene (19 mg), the title compound ( 8.1 mg) was obtained as a colorless amorphous.
UPLC: 406 [M + H] + (retention times 1.16, 1.18 min, rotamer)
実施例130と同様の方法もしくは、これに準ずる方法により(3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノン塩酸塩(中間体20)(34mg)と1-ブロモ-3,5-ジメチルベンゼン(19mg)を用いて標記化合物(8.1mg)を無色アモルファスして得た。
UPLC:406[M+H]+(保持時間1.16、1.18分、回転異性体) Example 131 (8- (3,5-dimethylphenyl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-6- (2H-1,2,3 Synthesis of -triazol-2-yl) phenyl) methanone (3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-) by the same method as in Example 130 or a method analogous thereto Using 6- (2H-1,2,3-triazol-2-yl) phenyl) methanone hydrochloride (intermediate 20) (34 mg) and 1-bromo-3,5-dimethylbenzene (19 mg), the title compound ( 8.1 mg) was obtained as a colorless amorphous.
UPLC: 406 [M + H] + (retention times 1.16, 1.18 min, rotamer)
(実施例132)(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4-(ジフルオロメトキシ)ピリジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノンの合成
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン塩酸塩(中間体19)(64mg)、2-クロロ-(4-ジフルオロメトキシ)ピリジン(36mg)、ナトリウム tert-ブトキシド(48mg)のTHF(1.5mL)混合液にRuPhos Pd G2(7.8mg)を加え、窒素雰囲気下、85℃で1.5時間攪拌した。反応液を室温まで冷却した後、ろ過し、減圧下溶媒を留去して粗生成物を得た。得られた粗生成物をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=80:20~40:60)にて精製し、標記化合物(56mg)を無色アモルファスとして得た。
UPLC:427[M+H]+(保持時間0.81分)
1H-NMR (CDCl3, 400MHz) δ: 8.14-7.98 (2H, m), 7.87-7.65 (2H, m), 7.58-7.18 (3H, m), 6.79-6.15 (3H, m), 4.62-4.31 (3H, m), 3.53-2.75 (3H, m), 2.10-1.69 (4H, m). Example 132 (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4- (difluoromethoxy) pyridin-2-yl) -3,8-diazabicyclo [3. 2.1] Synthesis of octan-3-yl) methanone (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3- Yl) methanone hydrochloride (intermediate 19) (64 mg), 2-chloro- (4-difluoromethoxy) pyridine (36 mg), sodium tert-butoxide (48 mg) in THF (1.5 mL) mixed with RuPhos Pd G2 ( 7.8 mg) was added, and the mixture was stirred at 85 ° C. for 1.5 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The resulting crude product was purified by column chromatography (silica gel, heptane: ethyl acetate = 80: 20 to 40:60) to obtain the title compound (56 mg) as a colorless amorphous.
UPLC: 427 [M + H] + (retention time 0.81 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.14-7.98 (2H, m), 7.87-7.65 (2H, m), 7.58-7.18 (3H, m), 6.79-6.15 (3H, m), 4.62- 4.31 (3H, m), 3.53-2.75 (3H, m), 2.10-1.69 (4H, m).
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン塩酸塩(中間体19)(64mg)、2-クロロ-(4-ジフルオロメトキシ)ピリジン(36mg)、ナトリウム tert-ブトキシド(48mg)のTHF(1.5mL)混合液にRuPhos Pd G2(7.8mg)を加え、窒素雰囲気下、85℃で1.5時間攪拌した。反応液を室温まで冷却した後、ろ過し、減圧下溶媒を留去して粗生成物を得た。得られた粗生成物をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=80:20~40:60)にて精製し、標記化合物(56mg)を無色アモルファスとして得た。
UPLC:427[M+H]+(保持時間0.81分)
1H-NMR (CDCl3, 400MHz) δ: 8.14-7.98 (2H, m), 7.87-7.65 (2H, m), 7.58-7.18 (3H, m), 6.79-6.15 (3H, m), 4.62-4.31 (3H, m), 3.53-2.75 (3H, m), 2.10-1.69 (4H, m). Example 132 (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4- (difluoromethoxy) pyridin-2-yl) -3,8-diazabicyclo [3. 2.1] Synthesis of octan-3-yl) methanone (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3- Yl) methanone hydrochloride (intermediate 19) (64 mg), 2-chloro- (4-difluoromethoxy) pyridine (36 mg), sodium tert-butoxide (48 mg) in THF (1.5 mL) mixed with RuPhos Pd G2 ( 7.8 mg) was added, and the mixture was stirred at 85 ° C. for 1.5 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The resulting crude product was purified by column chromatography (silica gel, heptane: ethyl acetate = 80: 20 to 40:60) to obtain the title compound (56 mg) as a colorless amorphous.
UPLC: 427 [M + H] + (retention time 0.81 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.14-7.98 (2H, m), 7.87-7.65 (2H, m), 7.58-7.18 (3H, m), 6.79-6.15 (3H, m), 4.62- 4.31 (3H, m), 3.53-2.75 (3H, m), 2.10-1.69 (4H, m).
*実施例133~実施例146は、中間体2-2、中間体34~中間体36の何れかまたは市販化合物もしくは公知化合物及び中間体19または中間体21を用いて、実施例132と同様の方法、もしくはこれに準ずる方法により合成した。
* Example 133 to Example 146 are the same as Example 132 using any of Intermediate 2-2, Intermediate 34 to Intermediate 36, or a commercially available compound or a known compound and Intermediate 19 or Intermediate 21. It was synthesized by the method or a method analogous thereto.
(実施例147)2-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-メトキシイソニコチノニトリルの合成
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン塩酸塩(中間体19)(32mg)、2-クロロ-3-メトキシイソニコチノニトリル(中間体3-3)(17mg)、炭酸セシウム(81mg)のTHF(1.0mL)混合液にRuPhos Pd G2(3.9mg)を加え、窒素雰囲気下、85℃で6時間攪拌した。反応液を室温まで冷却した後、ろ過し、減圧下溶媒を留去して粗生成物を得た。得られた粗生成物をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=70:30~50:50)にて精製し、標記化合物(7.4mg)を無色アモルファスとして得た。
UPLC:416[M+H]+(保持時間1.06分)
1H-NMR (CDCl3, 300MHz) δ: 8.05-7.93 (2H, m), 7.87-7.70 (2H, m), 7.59-7.20 (3H, m), 6.88-6.82 (1H, m), 4.86-4.35 (3H, m), 3.94-3.86 (3H, m), 3.58-2.79 (3H, m), 2.07-1.58 (4H, m). Example 147 2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl)- Synthesis of 3-methoxyisonicotinonitrile (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3-yl) methanone hydrochloride RuPhos Pd G2 was added to a THF (1.0 mL) mixture of a salt (intermediate 19) (32 mg), 2-chloro-3-methoxyisonicotinonitrile (intermediate 3-3) (17 mg), and cesium carbonate (81 mg). (3.9 mg) was added, and the mixture was stirred at 85 ° C. for 6 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The resulting crude product was purified by column chromatography (silica gel, heptane: ethyl acetate = 70: 30-50: 50) to obtain the title compound (7.4 mg) as a colorless amorphous.
UPLC: 416 [M + H] + (retention time 1.06 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.05-7.93 (2H, m), 7.87-7.70 (2H, m), 7.59-7.20 (3H, m), 6.88-6.82 (1H, m), 4.86- 4.35 (3H, m), 3.94-3.86 (3H, m), 3.58-2.79 (3H, m), 2.07-1.58 (4H, m).
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン塩酸塩(中間体19)(32mg)、2-クロロ-3-メトキシイソニコチノニトリル(中間体3-3)(17mg)、炭酸セシウム(81mg)のTHF(1.0mL)混合液にRuPhos Pd G2(3.9mg)を加え、窒素雰囲気下、85℃で6時間攪拌した。反応液を室温まで冷却した後、ろ過し、減圧下溶媒を留去して粗生成物を得た。得られた粗生成物をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=70:30~50:50)にて精製し、標記化合物(7.4mg)を無色アモルファスとして得た。
UPLC:416[M+H]+(保持時間1.06分)
1H-NMR (CDCl3, 300MHz) δ: 8.05-7.93 (2H, m), 7.87-7.70 (2H, m), 7.59-7.20 (3H, m), 6.88-6.82 (1H, m), 4.86-4.35 (3H, m), 3.94-3.86 (3H, m), 3.58-2.79 (3H, m), 2.07-1.58 (4H, m). Example 147 2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl)- Synthesis of 3-methoxyisonicotinonitrile (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3-yl) methanone hydrochloride RuPhos Pd G2 was added to a THF (1.0 mL) mixture of a salt (intermediate 19) (32 mg), 2-chloro-3-methoxyisonicotinonitrile (intermediate 3-3) (17 mg), and cesium carbonate (81 mg). (3.9 mg) was added, and the mixture was stirred at 85 ° C. for 6 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The resulting crude product was purified by column chromatography (silica gel, heptane: ethyl acetate = 70: 30-50: 50) to obtain the title compound (7.4 mg) as a colorless amorphous.
UPLC: 416 [M + H] + (retention time 1.06 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.05-7.93 (2H, m), 7.87-7.70 (2H, m), 7.59-7.20 (3H, m), 6.88-6.82 (1H, m), 4.86- 4.35 (3H, m), 3.94-3.86 (3H, m), 3.58-2.79 (3H, m), 2.07-1.58 (4H, m).
*実施例148~実施例154は、中間体37~中間体38の何れかまたは市販化合物もしくは公知化合物及び中間体19または中間体21を用いて、実施例147と同様の方法、もしくはこれに準ずる方法により合成した。
* Example 148 to Example 154 are the same as or similar to Example 147, using any of Intermediate 37 to Intermediate 38, commercially available compounds or known compounds, and Intermediate 19 or Intermediate 21. It was synthesized by the method.
(実施例155)(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(4-エチル-6-メチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノンの合成
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン塩酸塩(中間体19)(40mg)、DIPEA(0.11mL)、DMAP(1.5mg)のエタノール(1.0mL)混合溶液に2-クロロ-4-エチル-6-メチルピリミジン(20mg)を加え、マイクロウェーブ条件下、170℃にて1時間撹拌した。反応液を室温まで冷却した後、減圧下溶媒を留去して得られた残渣をHPLCにて分取精製を行い、標記化合物(19mg)を得た。
LCMS[メソッドB]:404[M+H]+(保持時間5.75分)
1H-NMR (CDCl3, 400MHz) δ: 8.04-7.97 (1H, m), 7.86-7.67 (2H, m), 7.57-7.19 (3H, m), 6.38-6.26 (1H, m), 5.07-4.37 (3H, m), 3.52-2.72 (3H, m), 2.63-2.47 (2H, m), 2.38-2.21 (3H, m), 2.08-1.64 (4H, m), 1.29-1.14 (3H, m). Example 155 (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4-ethyl-6-methylpyrimidin-2-yl) -3,8-diazabicyclo [3 Of 2.2.1] octan-3-yl) methanone (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3 2-yl-4-ethyl-6-methylpyrimidine in a mixed solution of -yl) methanone hydrochloride (intermediate 19) (40 mg), DIPEA (0.11 mL), DMAP (1.5 mg) in ethanol (1.0 mL) (20 mg) was added, and the mixture was stirred at 170 ° C. for 1 hour under microwave conditions. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to preparative purification by HPLC to obtain the title compound (19 mg).
LCMS [Method B]: 404 [M + H] + (Retention time 5.75 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.04-7.97 (1H, m), 7.86-7.67 (2H, m), 7.57-7.19 (3H, m), 6.38-6.26 (1H, m), 5.07- 4.37 (3H, m), 3.52-2.72 (3H, m), 2.63-2.47 (2H, m), 2.38-2.21 (3H, m), 2.08-1.64 (4H, m), 1.29-1.14 (3H, m ).
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン塩酸塩(中間体19)(40mg)、DIPEA(0.11mL)、DMAP(1.5mg)のエタノール(1.0mL)混合溶液に2-クロロ-4-エチル-6-メチルピリミジン(20mg)を加え、マイクロウェーブ条件下、170℃にて1時間撹拌した。反応液を室温まで冷却した後、減圧下溶媒を留去して得られた残渣をHPLCにて分取精製を行い、標記化合物(19mg)を得た。
LCMS[メソッドB]:404[M+H]+(保持時間5.75分)
1H-NMR (CDCl3, 400MHz) δ: 8.04-7.97 (1H, m), 7.86-7.67 (2H, m), 7.57-7.19 (3H, m), 6.38-6.26 (1H, m), 5.07-4.37 (3H, m), 3.52-2.72 (3H, m), 2.63-2.47 (2H, m), 2.38-2.21 (3H, m), 2.08-1.64 (4H, m), 1.29-1.14 (3H, m). Example 155 (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4-ethyl-6-methylpyrimidin-2-yl) -3,8-diazabicyclo [3 Of 2.2.1] octan-3-yl) methanone (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3 2-yl-4-ethyl-6-methylpyrimidine in a mixed solution of -yl) methanone hydrochloride (intermediate 19) (40 mg), DIPEA (0.11 mL), DMAP (1.5 mg) in ethanol (1.0 mL) (20 mg) was added, and the mixture was stirred at 170 ° C. for 1 hour under microwave conditions. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to preparative purification by HPLC to obtain the title compound (19 mg).
LCMS [Method B]: 404 [M + H] + (Retention time 5.75 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.04-7.97 (1H, m), 7.86-7.67 (2H, m), 7.57-7.19 (3H, m), 6.38-6.26 (1H, m), 5.07- 4.37 (3H, m), 3.52-2.72 (3H, m), 2.63-2.47 (2H, m), 2.38-2.21 (3H, m), 2.08-1.64 (4H, m), 1.29-1.14 (3H, m ).
*実施例156~実施例161は、中間体19または中間体20及び市販化合物または公知化合物を用いて、実施例155と同様の方法、もしくはこれに準ずる方法により合成した。
* Examples 156 to 161 were synthesized by the same method as in Example 155 or a method analogous thereto, using Intermediate 19 or Intermediate 20, and commercially available compounds or known compounds.
(実施例162)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)(2-(3-メチル-1H-ピラゾール-1-イル)ピリジン-3-イル)メタノンの合成
(2-クロロピリジン-3-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(中間体39)(50mg)、3-メチル-1H-ピラゾール(34mg)のDMSO(1.0mL)混合溶液に炭酸カリウム(77mg)を加え、200℃にて30分撹拌した。反応溶液を室温に戻した後に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去して得られた残渣を、カラムクロマトグラフィー(NHシリカゲル、ヘプタン:酢酸エチル=83:17~50:50)にて精製し、標記化合物(19mg)を無色ガム状物質として得た。
UPLC:404[M+H]+(保持時間0.96分)
1H-NMR (CDCl3, 300MHz) δ: 8.44-8.27 (2H, m), 7.78-7.11 (2H, m), 6.37-6.05 (2H, m), 5.00-4.90 (1H, m), 4.73-4.63 (1H, m), 4.54-4.28 (1H, m), 3.49-2.90 (3H, m), 2.37-2.25 (9H, m), 2.14-1.60 (4H, m). Example 162 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (3-methyl-1H-pyrazole Synthesis of (1-yl) pyridin-3-yl) methanone (2-chloropyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2. 1] Potassium carbonate (77 mg) was added to a mixed solution of octan-3-yl) methanone (intermediate 39) (50 mg) and 3-methyl-1H-pyrazole (34 mg) in DMSO (1.0 mL) at 200 ° C. Stir for 30 minutes. The reaction solution was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (NH silica gel, heptane: ethyl acetate = 83: 17 to 50:50), The title compound (19 mg) was obtained as a colorless gum.
UPLC: 404 [M + H] + (retention time 0.96 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.44-8.27 (2H, m), 7.78-7.11 (2H, m), 6.37-6.05 (2H, m), 5.00-4.90 (1H, m), 4.73- 4.63 (1H, m), 4.54-4.28 (1H, m), 3.49-2.90 (3H, m), 2.37-2.25 (9H, m), 2.14-1.60 (4H, m).
(2-クロロピリジン-3-イル)(8-(4,6-ジメチルピリミジン-2-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(中間体39)(50mg)、3-メチル-1H-ピラゾール(34mg)のDMSO(1.0mL)混合溶液に炭酸カリウム(77mg)を加え、200℃にて30分撹拌した。反応溶液を室温に戻した後に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去して得られた残渣を、カラムクロマトグラフィー(NHシリカゲル、ヘプタン:酢酸エチル=83:17~50:50)にて精製し、標記化合物(19mg)を無色ガム状物質として得た。
UPLC:404[M+H]+(保持時間0.96分)
1H-NMR (CDCl3, 300MHz) δ: 8.44-8.27 (2H, m), 7.78-7.11 (2H, m), 6.37-6.05 (2H, m), 5.00-4.90 (1H, m), 4.73-4.63 (1H, m), 4.54-4.28 (1H, m), 3.49-2.90 (3H, m), 2.37-2.25 (9H, m), 2.14-1.60 (4H, m). Example 162 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (3-methyl-1H-pyrazole Synthesis of (1-yl) pyridin-3-yl) methanone (2-chloropyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2. 1] Potassium carbonate (77 mg) was added to a mixed solution of octan-3-yl) methanone (intermediate 39) (50 mg) and 3-methyl-1H-pyrazole (34 mg) in DMSO (1.0 mL) at 200 ° C. Stir for 30 minutes. The reaction solution was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (NH silica gel, heptane: ethyl acetate = 83: 17 to 50:50), The title compound (19 mg) was obtained as a colorless gum.
UPLC: 404 [M + H] + (retention time 0.96 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.44-8.27 (2H, m), 7.78-7.11 (2H, m), 6.37-6.05 (2H, m), 5.00-4.90 (1H, m), 4.73- 4.63 (1H, m), 4.54-4.28 (1H, m), 3.49-2.90 (3H, m), 2.37-2.25 (9H, m), 2.14-1.60 (4H, m).
*実施例163~実施例166は、中間体39または中間体40及び市販化合物を用いて、実施例162同様の方法、もしくはこれに準ずる方法により合成した。
* Examples 163 to 166 were synthesized in the same manner as in Example 162, or a method analogous thereto, using Intermediate 39 or Intermediate 40 and commercially available compounds.
(実施例167)(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(2,3-ジヒドロフロ[3,2-c]ピリジン-4-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノンの合成
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(フロ[3,2-c]ピリジン-4-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例135)(30mg)のエタノール(4.0mL)溶液をフロー式水素化反応装置[H-Cube(登録商標)、ThalesNano社製]を用いて10% Pd-C CatCart(登録商標)を通過させる操作[水素圧;3.0bar,流速;1.0 mL/min,温度;50℃]を2回繰り返した。得られた反応液を減圧下で溶媒留去した後、残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=80:20~40:60)にて精製し、標記化合物(12mg)を無色アモルファスとして得た。
UPLC:403[M+H]+(保持時間0.69分)
1H-NMR (CDCl3, 400MHz) δ: 8.04-7.67 (4H, m), 7.57-7.19 (3H, m), 6.34-6.27 (1H, m), 4.64-4.33 (5H, m), 3.60-2.81 (5H, m), 2.11-1.63 (4H, m). Example 167 (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (2,3-dihydrofuro [3,2-c] pyridin-4-yl) -3, Synthesis of 8-diazabicyclo [3.2.1] octane-3-yl) methanone (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (fur [3,2-c ] Pyridin-4-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 135) (30 mg) in ethanol (4.0 mL) was added to a flow hydrogenation reactor. Operation of passing 10% Pd-C CatCart (registered trademark) using [H-Cube (registered trademark), manufactured by Theles Nano Co., Ltd.] [hydrogen pressure; 3.0 bar, flow rate; 1.0 mL / min, temperature; 50 ° C] was repeated twice. The obtained reaction solution was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 80: 20 to 40:60) to give the title compound (12 mg) as a colorless amorphous product. Obtained.
UPLC: 403 [M + H] + (retention time 0.69 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.04-7.67 (4H, m), 7.57-7.19 (3H, m), 6.34-6.27 (1H, m), 4.64-4.33 (5H, m), 3.60- 2.81 (5H, m), 2.11-1.63 (4H, m).
(2-(2H-1,2,3-トリアゾール-2-イル)フェニル)(8-(フロ[3,2-c]ピリジン-4-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例135)(30mg)のエタノール(4.0mL)溶液をフロー式水素化反応装置[H-Cube(登録商標)、ThalesNano社製]を用いて10% Pd-C CatCart(登録商標)を通過させる操作[水素圧;3.0bar,流速;1.0 mL/min,温度;50℃]を2回繰り返した。得られた反応液を減圧下で溶媒留去した後、残渣をカラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=80:20~40:60)にて精製し、標記化合物(12mg)を無色アモルファスとして得た。
UPLC:403[M+H]+(保持時間0.69分)
1H-NMR (CDCl3, 400MHz) δ: 8.04-7.67 (4H, m), 7.57-7.19 (3H, m), 6.34-6.27 (1H, m), 4.64-4.33 (5H, m), 3.60-2.81 (5H, m), 2.11-1.63 (4H, m). Example 167 (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (2,3-dihydrofuro [3,2-c] pyridin-4-yl) -3, Synthesis of 8-diazabicyclo [3.2.1] octane-3-yl) methanone (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (fur [3,2-c ] Pyridin-4-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 135) (30 mg) in ethanol (4.0 mL) was added to a flow hydrogenation reactor. Operation of passing 10% Pd-C CatCart (registered trademark) using [H-Cube (registered trademark), manufactured by Theles Nano Co., Ltd.] [hydrogen pressure; 3.0 bar, flow rate; 1.0 mL / min, temperature; 50 ° C] was repeated twice. The obtained reaction solution was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 80: 20 to 40:60) to give the title compound (12 mg) as a colorless amorphous product. Obtained.
UPLC: 403 [M + H] + (retention time 0.69 minutes)
1 H-NMR (CDCl 3 , 400 MHz) δ: 8.04-7.67 (4H, m), 7.57-7.19 (3H, m), 6.34-6.27 (1H, m), 4.64-4.33 (5H, m), 3.60- 2.81 (5H, m), 2.11-1.63 (4H, m).
(実施例168)(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(2,3-ジヒドロフロ[3,2-c]ピリジン-4-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノンの合成
実施例167と同様の方法もしくは、これに準ずる方法で、(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(フロ[3,2-c]ピリジン-4-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例137)(30mg)を用いて標記化合物(11mg)を無色アモルファスとして得た。
UPLC:403[M+H]+(保持時間0.67分) Example 168 (2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (2,3-dihydrofuro [3,2-c] pyridin-4-yl) -3,8- Synthesis of diazabicyclo [3.2.1] octane-3-yl) methanone In the same manner as in Example 167 or a method analogous thereto, (2- (1H-pyrazol-1-yl) pyridin-3-yl) Using (8- (furo [3,2-c] pyridin-4-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 137) (30 mg) Compound (11 mg) was obtained as colorless amorphous.
UPLC: 403 [M + H] + (retention time 0.67 minutes)
実施例167と同様の方法もしくは、これに準ずる方法で、(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(8-(フロ[3,2-c]ピリジン-4-イル)-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)メタノン(実施例137)(30mg)を用いて標記化合物(11mg)を無色アモルファスとして得た。
UPLC:403[M+H]+(保持時間0.67分) Example 168 (2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (2,3-dihydrofuro [3,2-c] pyridin-4-yl) -3,8- Synthesis of diazabicyclo [3.2.1] octane-3-yl) methanone In the same manner as in Example 167 or a method analogous thereto, (2- (1H-pyrazol-1-yl) pyridin-3-yl) Using (8- (furo [3,2-c] pyridin-4-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 137) (30 mg) Compound (11 mg) was obtained as colorless amorphous.
UPLC: 403 [M + H] + (retention time 0.67 minutes)
(実施例169)3-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-1,5-ジメチルピラジン-2(1H)-オンの合成
3-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-5-ブロモ-1-メチルピラジン-2(1H)-オン(中間体41)、テトラキス(トリフェニルホスフィン)パラジウム(23mg)、トリメチルボロキシン(63mg)、炭酸セシウム(0.16g)の1,4-ジオキサン(1.0mL)-水(0.10mL)混合液を減圧下脱気処理後、窒素雰囲気下、100℃で8時間攪拌した。反応液を室温まで冷却後、酢酸エチルで希釈し、水で洗浄した。有機層を濃縮後、カラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=80:20~0:100)にて精製し、標記化合物(24mg)を淡黄色ガム状物質として得た。
UPLC:406[M+H]+(保持時間0.95分)
1H-NMR (CDCl3, 300MHz) δ: 8.04-7.98 (1H, m), 7.85-7.72 (2H, m), 7.57-7.18 (3H, m), 6.42-6.38 (1H, m), 5.48-5.00 (2H, m), 4.49-4.37 (1H, m), 3.58-2.85 (6H, m), 2.20-1.64 (7H, m). Example 169 3- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl)- Synthesis of 1,5-dimethylpyrazin-2 (1H) -one 3- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2 .1] Octane-8-yl) -5-bromo-1-methylpyrazin-2 (1H) -one (intermediate 41), tetrakis (triphenylphosphine) palladium (23 mg), trimethylboroxine (63 mg), carbonic acid A mixture of cesium (0.16 g) in 1,4-dioxane (1.0 mL) -water (0.10 mL) was degassed under reduced pressure, and then stirred at 100 ° C. for 8 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer was concentrated and purified by column chromatography (silica gel, heptane: ethyl acetate = 80: 20 to 0: 100) to obtain the title compound (24 mg) as a pale yellow gum.
UPLC: 406 [M + H] + (retention time 0.95 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.04-7.98 (1H, m), 7.85-7.72 (2H, m), 7.57-7.18 (3H, m), 6.42-6.38 (1H, m), 5.48- 5.00 (2H, m), 4.49-4.37 (1H, m), 3.58-2.85 (6H, m), 2.20-1.64 (7H, m).
3-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-5-ブロモ-1-メチルピラジン-2(1H)-オン(中間体41)、テトラキス(トリフェニルホスフィン)パラジウム(23mg)、トリメチルボロキシン(63mg)、炭酸セシウム(0.16g)の1,4-ジオキサン(1.0mL)-水(0.10mL)混合液を減圧下脱気処理後、窒素雰囲気下、100℃で8時間攪拌した。反応液を室温まで冷却後、酢酸エチルで希釈し、水で洗浄した。有機層を濃縮後、カラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=80:20~0:100)にて精製し、標記化合物(24mg)を淡黄色ガム状物質として得た。
UPLC:406[M+H]+(保持時間0.95分)
1H-NMR (CDCl3, 300MHz) δ: 8.04-7.98 (1H, m), 7.85-7.72 (2H, m), 7.57-7.18 (3H, m), 6.42-6.38 (1H, m), 5.48-5.00 (2H, m), 4.49-4.37 (1H, m), 3.58-2.85 (6H, m), 2.20-1.64 (7H, m). Example 169 3- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl)- Synthesis of 1,5-dimethylpyrazin-2 (1H) -one 3- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2 .1] Octane-8-yl) -5-bromo-1-methylpyrazin-2 (1H) -one (intermediate 41), tetrakis (triphenylphosphine) palladium (23 mg), trimethylboroxine (63 mg), carbonic acid A mixture of cesium (0.16 g) in 1,4-dioxane (1.0 mL) -water (0.10 mL) was degassed under reduced pressure, and then stirred at 100 ° C. for 8 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer was concentrated and purified by column chromatography (silica gel, heptane: ethyl acetate = 80: 20 to 0: 100) to obtain the title compound (24 mg) as a pale yellow gum.
UPLC: 406 [M + H] + (retention time 0.95 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.04-7.98 (1H, m), 7.85-7.72 (2H, m), 7.57-7.18 (3H, m), 6.42-6.38 (1H, m), 5.48- 5.00 (2H, m), 4.49-4.37 (1H, m), 3.58-2.85 (6H, m), 2.20-1.64 (7H, m).
(実施例170)2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-シクロプロピルイソニコチノニトリルの合成
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-クロロイソニコチノニトリル(実施例48)(30mg)、シクロプロピル亜鉛ブロミド(0.5規定 THF溶液)(0.84mL)のTHF(0.4mL)混合溶液にテトラキス(トリフェニルホスフィン)パラジウム(33mg)を加え、窒素雰囲気下、100℃にて30分撹拌した。反応溶液を室温まで冷却した後に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去して得られた残渣を、カラムクロマトグラフィー(NHシリカゲル、ヘプタン:酢酸エチル=75:25~33:67)にて精製し、標記化合物(19mg)を無色固体として得た。
UPLC:426[M+H]+(保持時間1.09分)
1H-NMR (CDCl3, 300MHz) δ: 8.50-8.44 (2H, m), 8.15-8.08 (1H, m), 7.82-7.20 (3H, m), 6.97-6.93 (1H, m), 6.50-6.39 (1H, m), 4.76-4.33 (3H, m), 3.64-2.95 (3H, m), 2.21-1.58 (5H, m), 1.34-0.71 (4H, m). Example 170 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-cyclopropylisonicoti Synthesis of nononitrile 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-chloroisonicotinonitrile Example 48 Tetrakis (triphenylphosphine) palladium (33 mg) was added to a mixed solution of (30 mg), cyclopropylzinc bromide (0.5N THF solution) (0.84 mL) in THF (0.4 mL), and nitrogen was added. It stirred for 30 minutes at 100 degreeC under atmosphere. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (NH silica gel, heptane: ethyl acetate = 75: 25 to 33:67), The title compound (19 mg) was obtained as a colorless solid.
UPLC: 426 [M + H] + (retention time 1.09 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.50-8.44 (2H, m), 8.15-8.08 (1H, m), 7.82-7.20 (3H, m), 6.97-6.93 (1H, m), 6.50- 6.39 (1H, m), 4.76-4.33 (3H, m), 3.64-2.95 (3H, m), 2.21-1.58 (5H, m), 1.34-0.71 (4H, m).
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-クロロイソニコチノニトリル(実施例48)(30mg)、シクロプロピル亜鉛ブロミド(0.5規定 THF溶液)(0.84mL)のTHF(0.4mL)混合溶液にテトラキス(トリフェニルホスフィン)パラジウム(33mg)を加え、窒素雰囲気下、100℃にて30分撹拌した。反応溶液を室温まで冷却した後に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去して得られた残渣を、カラムクロマトグラフィー(NHシリカゲル、ヘプタン:酢酸エチル=75:25~33:67)にて精製し、標記化合物(19mg)を無色固体として得た。
UPLC:426[M+H]+(保持時間1.09分)
1H-NMR (CDCl3, 300MHz) δ: 8.50-8.44 (2H, m), 8.15-8.08 (1H, m), 7.82-7.20 (3H, m), 6.97-6.93 (1H, m), 6.50-6.39 (1H, m), 4.76-4.33 (3H, m), 3.64-2.95 (3H, m), 2.21-1.58 (5H, m), 1.34-0.71 (4H, m). Example 170 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-cyclopropylisonicoti Synthesis of nononitrile 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-chloroisonicotinonitrile Example 48 Tetrakis (triphenylphosphine) palladium (33 mg) was added to a mixed solution of (30 mg), cyclopropylzinc bromide (0.5N THF solution) (0.84 mL) in THF (0.4 mL), and nitrogen was added. It stirred for 30 minutes at 100 degreeC under atmosphere. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (NH silica gel, heptane: ethyl acetate = 75: 25 to 33:67), The title compound (19 mg) was obtained as a colorless solid.
UPLC: 426 [M + H] + (retention time 1.09 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.50-8.44 (2H, m), 8.15-8.08 (1H, m), 7.82-7.20 (3H, m), 6.97-6.93 (1H, m), 6.50- 6.39 (1H, m), 4.76-4.33 (3H, m), 3.64-2.95 (3H, m), 2.21-1.58 (5H, m), 1.34-0.71 (4H, m).
(実施例171)2-(3-(2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-シクロプロピルイソニコチノニトリルの合成
実施例16と同様の方法もしくは、これに準ずる方法で2-(3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-シクロプロピルイソニコチノニトリル(中間体44)(12mg)を用いて標記化合物(12mg)を無色固体として得た。
UPLC:426[M+H]+(保持時間1.09分) Example 171 2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl)- Synthesis of 3-cyclopropylisonicotinonitrile 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-cyclopropyl by a method similar to that of Example 16 or a method analogous thereto. Isonicotinonitrile (intermediate 44) (12 mg) was used to give the title compound (12 mg) as a colorless solid.
UPLC: 426 [M + H] + (retention time 1.09 minutes)
実施例16と同様の方法もしくは、これに準ずる方法で2-(3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-シクロプロピルイソニコチノニトリル(中間体44)(12mg)を用いて標記化合物(12mg)を無色固体として得た。
UPLC:426[M+H]+(保持時間1.09分) Example 171 2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl)- Synthesis of 3-cyclopropylisonicotinonitrile 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-cyclopropyl by a method similar to that of Example 16 or a method analogous thereto. Isonicotinonitrile (intermediate 44) (12 mg) was used to give the title compound (12 mg) as a colorless solid.
UPLC: 426 [M + H] + (retention time 1.09 minutes)
(実施例172)2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-(ピロリジン-1-イル)イソニコチノニトリルの合成
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-クロロイソニコチノニトリル(実施例48)(30mg)、DIPEA(20μL)のNMP(0.5mL)混合溶液にピロリジン(8.9μL)を加え、マイクロウェーブ条件下、150℃にて30分撹拌した。反応溶液を室温に戻した後に、ピロリジン(0.5mL)を加え、90℃で15時間攪拌した。反応溶液を減圧下で留去して得られた残渣をHPLCにて分取精製を行い、標記化合物(2.4mg)を無色個体として得た。
LCMS[メソッドB]:455[M+H]+(保持時間5.83分) Example 172 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (pyrrolidine-1 Synthesis of -yl) isonicotinonitrile 2- (3- (2- (1 (H) -pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- Pyrrolidine (8.9 μL) was added to a mixed solution of chloroisonicotinonitrile (Example 48) (30 mg) and DIPEA (20 μL) in NMP (0.5 mL), and the mixture was stirred at 150 ° C. for 30 minutes under microwave conditions. . After returning the reaction solution to room temperature, pyrrolidine (0.5 mL) was added, and the mixture was stirred at 90 ° C. for 15 hours. The residue obtained by evaporating the reaction solution under reduced pressure was subjected to preparative purification by HPLC to obtain the title compound (2.4 mg) as a colorless solid.
LCMS [Method B]: 455 [M + H] + (retention time 5.83 minutes)
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-クロロイソニコチノニトリル(実施例48)(30mg)、DIPEA(20μL)のNMP(0.5mL)混合溶液にピロリジン(8.9μL)を加え、マイクロウェーブ条件下、150℃にて30分撹拌した。反応溶液を室温に戻した後に、ピロリジン(0.5mL)を加え、90℃で15時間攪拌した。反応溶液を減圧下で留去して得られた残渣をHPLCにて分取精製を行い、標記化合物(2.4mg)を無色個体として得た。
LCMS[メソッドB]:455[M+H]+(保持時間5.83分) Example 172 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (pyrrolidine-1 Synthesis of -yl) isonicotinonitrile 2- (3- (2- (1 (H) -pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- Pyrrolidine (8.9 μL) was added to a mixed solution of chloroisonicotinonitrile (Example 48) (30 mg) and DIPEA (20 μL) in NMP (0.5 mL), and the mixture was stirred at 150 ° C. for 30 minutes under microwave conditions. . After returning the reaction solution to room temperature, pyrrolidine (0.5 mL) was added, and the mixture was stirred at 90 ° C. for 15 hours. The residue obtained by evaporating the reaction solution under reduced pressure was subjected to preparative purification by HPLC to obtain the title compound (2.4 mg) as a colorless solid.
LCMS [Method B]: 455 [M + H] + (retention time 5.83 minutes)
(実施例173)2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-(メチルチオ)イソニコチノニトリルの合成
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-クロロイソニコチノニトリル(実施例48)(27mg)のDMF(2.0mL)溶液にナトリウムチオメトキシド(6.7mg)を加え、室温にて1時間撹拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、析出した固体を桐山ロートを用いてろ取した後、固体を減圧下で乾燥し、標記化合物(12mg)を黄色固体として得た。
UPLC:432[M+H]+(保持時間1.07分)
1H-NMR (CDCl3, 300MHz) δ: 8.49-8.45 (2H, m), 8.21-8.14 (1H, m), 7.81-7.71 (1H, m), 7.61-7.56 (1H, m), 7.31-7.21 (1H, m), 7.03-6.99 (1H, m), 6.49-6.39 (1H, m), 4.95-4.83 (1H, m), 4.61-4.36 (2H, m), 3.64-3.00 (3H, m), 2.49-2.43 (3H, m), 2.15-1.50 (4H, m). Example 173 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (methylthio) iso Synthesis of nicotinonitrile 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-chloroisonicotino Sodium thiomethoxide (6.7 mg) was added to a solution of nitrile (Example 48) (27 mg) in DMF (2.0 mL), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the precipitated solid was collected by filtration using a Kiriyama funnel, and then the solid was dried under reduced pressure to obtain the title compound (12 mg) as a yellow solid.
UPLC: 432 [M + H] + (retention time 1.07 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.49-8.45 (2H, m), 8.21-8.14 (1H, m), 7.81-7.71 (1H, m), 7.61-7.56 (1H, m), 7.31- 7.21 (1H, m), 7.03-6.99 (1H, m), 6.49-6.39 (1H, m), 4.95-4.83 (1H, m), 4.61-4.36 (2H, m), 3.64-3.00 (3H, m ), 2.49-2.43 (3H, m), 2.15-1.50 (4H, m).
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-クロロイソニコチノニトリル(実施例48)(27mg)のDMF(2.0mL)溶液にナトリウムチオメトキシド(6.7mg)を加え、室温にて1時間撹拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、析出した固体を桐山ロートを用いてろ取した後、固体を減圧下で乾燥し、標記化合物(12mg)を黄色固体として得た。
UPLC:432[M+H]+(保持時間1.07分)
1H-NMR (CDCl3, 300MHz) δ: 8.49-8.45 (2H, m), 8.21-8.14 (1H, m), 7.81-7.71 (1H, m), 7.61-7.56 (1H, m), 7.31-7.21 (1H, m), 7.03-6.99 (1H, m), 6.49-6.39 (1H, m), 4.95-4.83 (1H, m), 4.61-4.36 (2H, m), 3.64-3.00 (3H, m), 2.49-2.43 (3H, m), 2.15-1.50 (4H, m). Example 173 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (methylthio) iso Synthesis of nicotinonitrile 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-chloroisonicotino Sodium thiomethoxide (6.7 mg) was added to a solution of nitrile (Example 48) (27 mg) in DMF (2.0 mL), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the precipitated solid was collected by filtration using a Kiriyama funnel, and then the solid was dried under reduced pressure to obtain the title compound (12 mg) as a yellow solid.
UPLC: 432 [M + H] + (retention time 1.07 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.49-8.45 (2H, m), 8.21-8.14 (1H, m), 7.81-7.71 (1H, m), 7.61-7.56 (1H, m), 7.31- 7.21 (1H, m), 7.03-6.99 (1H, m), 6.49-6.39 (1H, m), 4.95-4.83 (1H, m), 4.61-4.36 (2H, m), 3.64-3.00 (3H, m ), 2.49-2.43 (3H, m), 2.15-1.50 (4H, m).
(実施例174)2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-(ジメチルアミノ)イソニコチノニトリルの合成
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-フルオロイソニコチノニトリル(実施例49)(15mg)に9.5Mジメチルアミン水溶液(1.0mL)を加え、室温にて1日撹拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去して得られた残渣を、カラムクロマトグラフィー(NHシリカゲル、ヘプタン:酢酸エチル=75:25~33:67)にて精製し、標記化合物(5.4mg)を橙色固体として得た。
UPLC:429[M+H]+(保持時間1.08分)
1H-NMR (CDCl3, 300MHz) δ: 8.49-8.44 (2H, m), 7.94-7.71 (2H, m), 7.61-7.51 (1H, m), 7.31-7.19 (1H, m), 6.86-6.81 (1H, m), 6.50-6.36 (1H, m), 4.83-4.74 (1H, m), 4.55-4.28 (2H, m), 3.60-2.95 (3H, m), 2.96-2.91 (6H, m), 1.88-1.62 (4H, m). Example 174 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (dimethylamino) Synthesis of isonicotinonitrile 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-fluoroisonicoti 9.5 M dimethylamine aqueous solution (1.0 mL) was added to nononitrile (Example 49) (15 mg), and the mixture was stirred at room temperature for 1 day. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (NH silica gel, heptane: ethyl acetate = 75: 25 to 33:67), The title compound (5.4 mg) was obtained as an orange solid.
UPLC: 429 [M + H] + (retention time 1.08 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.49-8.44 (2H, m), 7.94-7.71 (2H, m), 7.61-7.51 (1H, m), 7.31-7.19 (1H, m), 6.86- 6.81 (1H, m), 6.50-6.36 (1H, m), 4.83-4.74 (1H, m), 4.55-4.28 (2H, m), 3.60-2.95 (3H, m), 2.96-2.91 (6H, m ), 1.88-1.62 (4H, m).
2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-3-フルオロイソニコチノニトリル(実施例49)(15mg)に9.5Mジメチルアミン水溶液(1.0mL)を加え、室温にて1日撹拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去して得られた残渣を、カラムクロマトグラフィー(NHシリカゲル、ヘプタン:酢酸エチル=75:25~33:67)にて精製し、標記化合物(5.4mg)を橙色固体として得た。
UPLC:429[M+H]+(保持時間1.08分)
1H-NMR (CDCl3, 300MHz) δ: 8.49-8.44 (2H, m), 7.94-7.71 (2H, m), 7.61-7.51 (1H, m), 7.31-7.19 (1H, m), 6.86-6.81 (1H, m), 6.50-6.36 (1H, m), 4.83-4.74 (1H, m), 4.55-4.28 (2H, m), 3.60-2.95 (3H, m), 2.96-2.91 (6H, m), 1.88-1.62 (4H, m). Example 174 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (dimethylamino) Synthesis of isonicotinonitrile 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-fluoroisonicoti 9.5 M dimethylamine aqueous solution (1.0 mL) was added to nononitrile (Example 49) (15 mg), and the mixture was stirred at room temperature for 1 day. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (NH silica gel, heptane: ethyl acetate = 75: 25 to 33:67), The title compound (5.4 mg) was obtained as an orange solid.
UPLC: 429 [M + H] + (retention time 1.08 minutes)
1 H-NMR (CDCl 3 , 300 MHz) δ: 8.49-8.44 (2H, m), 7.94-7.71 (2H, m), 7.61-7.51 (1H, m), 7.31-7.19 (1H, m), 6.86- 6.81 (1H, m), 6.50-6.36 (1H, m), 4.83-4.74 (1H, m), 4.55-4.28 (2H, m), 3.60-2.95 (3H, m), 2.96-2.91 (6H, m ), 1.88-1.62 (4H, m).
(実施例175)(6-(4,6-ジメチルピリミジン-2-イル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)(2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル)メタノンの合成
tert-ブチル 3-(2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-6-カルボキシレート(中間体42)(39mg)のジクロロメタン(0.40mL)溶液に室温でトリフルオロ酢酸(0.20mL)を加えた。反応液を30分攪拌した後、減圧下溶媒を留去した。残渣をNMP(0.20mL)に溶かし、炭酸カリウム(42mg)、2-クロロ-4,6-ジメチルピリミジン(15mg)を加え、100℃で16時間攪拌した。反応液を室温に冷却後、酢酸エチルで希釈し、水で洗浄した後、有機層を減圧下濃縮して得られた残渣を、カラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=70:30~0:100)2回で精製し、標記化合物(13mg)を白色アモルファスとして得た。
UPLC:394[M+H]+(保持時間0.86、0.89分、回転異性体)
1H-NMR (CDCl3, 400MHz) δ: 7.87-7.83 (1H, m), 7.80 (1H, s), 7.50-7.42 (1H, m), 7.29 (1H, s), 7.16-7.03 (1H, m), 6.45 (1H, s), 4.64-4.14 (3H, m), 3.97-3.60 (2H, m), 3.31-3.23 (1H, m), 2.82-2.72 (1H, m), 2.44-2.04 (6H, m), 1.74-1.63 (1H, m). Example 175 (6- (4,6-Dimethylpyrimidin-2-yl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) (2-fluoro-6- (2H-1 , 2,3-Triazol-2-yl) phenyl) methanone tert-butyl 3- (2-fluoro-6- (2H-1,2,3-triazol-2-yl) benzoyl) -3,6- To a solution of diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate 42) (39 mg) in dichloromethane (0.40 mL) was added trifluoroacetic acid (0.20 mL) at room temperature. After stirring the reaction solution for 30 minutes, the solvent was distilled off under reduced pressure. The residue was dissolved in NMP (0.20 mL), potassium carbonate (42 mg) and 2-chloro-4,6-dimethylpyrimidine (15 mg) were added, and the mixture was stirred at 100 ° C. for 16 hr. The reaction mixture is cooled to room temperature, diluted with ethyl acetate, washed with water, and the residue obtained by concentrating the organic layer under reduced pressure is subjected to column chromatography (silica gel, heptane: ethyl acetate = 70: 30-0). : 100) The product was purified twice, and the title compound (13 mg) was obtained as a white amorphous.
UPLC: 394 [M + H] + (retention time 0.86, 0.89 min, rotamer)
1 H-NMR (CDCl 3 , 400 MHz) δ: 7.87-7.83 (1H, m), 7.80 (1H, s), 7.50-7.42 (1H, m), 7.29 (1H, s), 7.16-7.03 (1H, m), 6.45 (1H, s), 4.64-4.14 (3H, m), 3.97-3.60 (2H, m), 3.31-3.23 (1H, m), 2.82-2.72 (1H, m), 2.44-2.04 ( 6H, m), 1.74-1.63 (1H, m).
tert-ブチル 3-(2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-6-カルボキシレート(中間体42)(39mg)のジクロロメタン(0.40mL)溶液に室温でトリフルオロ酢酸(0.20mL)を加えた。反応液を30分攪拌した後、減圧下溶媒を留去した。残渣をNMP(0.20mL)に溶かし、炭酸カリウム(42mg)、2-クロロ-4,6-ジメチルピリミジン(15mg)を加え、100℃で16時間攪拌した。反応液を室温に冷却後、酢酸エチルで希釈し、水で洗浄した後、有機層を減圧下濃縮して得られた残渣を、カラムクロマトグラフィー(シリカゲル、ヘプタン:酢酸エチル=70:30~0:100)2回で精製し、標記化合物(13mg)を白色アモルファスとして得た。
UPLC:394[M+H]+(保持時間0.86、0.89分、回転異性体)
1H-NMR (CDCl3, 400MHz) δ: 7.87-7.83 (1H, m), 7.80 (1H, s), 7.50-7.42 (1H, m), 7.29 (1H, s), 7.16-7.03 (1H, m), 6.45 (1H, s), 4.64-4.14 (3H, m), 3.97-3.60 (2H, m), 3.31-3.23 (1H, m), 2.82-2.72 (1H, m), 2.44-2.04 (6H, m), 1.74-1.63 (1H, m). Example 175 (6- (4,6-Dimethylpyrimidin-2-yl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) (2-fluoro-6- (2H-1 , 2,3-Triazol-2-yl) phenyl) methanone tert-butyl 3- (2-fluoro-6- (2H-1,2,3-triazol-2-yl) benzoyl) -3,6- To a solution of diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate 42) (39 mg) in dichloromethane (0.40 mL) was added trifluoroacetic acid (0.20 mL) at room temperature. After stirring the reaction solution for 30 minutes, the solvent was distilled off under reduced pressure. The residue was dissolved in NMP (0.20 mL), potassium carbonate (42 mg) and 2-chloro-4,6-dimethylpyrimidine (15 mg) were added, and the mixture was stirred at 100 ° C. for 16 hr. The reaction mixture is cooled to room temperature, diluted with ethyl acetate, washed with water, and the residue obtained by concentrating the organic layer under reduced pressure is subjected to column chromatography (silica gel, heptane: ethyl acetate = 70: 30-0). : 100) The product was purified twice, and the title compound (13 mg) was obtained as a white amorphous.
UPLC: 394 [M + H] + (retention time 0.86, 0.89 min, rotamer)
1 H-NMR (CDCl 3 , 400 MHz) δ: 7.87-7.83 (1H, m), 7.80 (1H, s), 7.50-7.42 (1H, m), 7.29 (1H, s), 7.16-7.03 (1H, m), 6.45 (1H, s), 4.64-4.14 (3H, m), 3.97-3.60 (2H, m), 3.31-3.23 (1H, m), 2.82-2.72 (1H, m), 2.44-2.04 ( 6H, m), 1.74-1.63 (1H, m).
(実施例176)2-(3-(2-(1H-ピラゾール-1-イル)ニコチノイル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-6-イル)-3-メトキシイソニコチノニトリルの合成
実施例147と同様の方法もしくは、これに準ずる方法で、(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)メタノン(中間体43)(72mg)を用いて標記化合物(7.6mg)を無色固体して得た。
UPLC:402[M+H]+(保持時間0.90分)
1H-NMR (DMSO-d6, 300MHz) δ: 8.56-8.42 (2H, m), 8.07-8.01 (1H, m), 7.94-7.76 (1H, m), 7.48-7.34 (1H, m), 7.18-7.11 (1H, m), 6.67-6.33 (2H, m), 4.60-4.49 (1H, m), 4.36-4.28 (1H, m), 4.05-3.62 (5H, m), 3.43-3.04 (2H, m), 2.79-2.68 (1H, m), 1.80-1.60 (1H, m). Example 176 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,6-diazabicyclo [3.1.1] heptane-6-yl) -3-methoxyisonicotino Synthesis of Nitrile (2- (1H-pyrazol-1-yl) pyridin-3-yl) (3,6-diazabicyclo [3.1.1] heptane) was prepared in the same manner as in Example 147 or a method analogous thereto. The title compound (7.6 mg) was obtained as a colorless solid using -3-yl) methanone (intermediate 43) (72 mg).
UPLC: 402 [M + H] + (retention time 0.90 minutes)
1 H-NMR (DMSO-d 6 , 300 MHz) δ: 8.56-8.42 (2H, m), 8.07-8.01 (1H, m), 7.94-7.76 (1H, m), 7.48-7.34 (1H, m), 7.18-7.11 (1H, m), 6.67-6.33 (2H, m), 4.60-4.49 (1H, m), 4.36-4.28 (1H, m), 4.05-3.62 (5H, m), 3.43-3.04 (2H , m), 2.79-2.68 (1H, m), 1.80-1.60 (1H, m).
実施例147と同様の方法もしくは、これに準ずる方法で、(2-(1H-ピラゾール-1-イル)ピリジン-3-イル)(3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)メタノン(中間体43)(72mg)を用いて標記化合物(7.6mg)を無色固体して得た。
UPLC:402[M+H]+(保持時間0.90分)
1H-NMR (DMSO-d6, 300MHz) δ: 8.56-8.42 (2H, m), 8.07-8.01 (1H, m), 7.94-7.76 (1H, m), 7.48-7.34 (1H, m), 7.18-7.11 (1H, m), 6.67-6.33 (2H, m), 4.60-4.49 (1H, m), 4.36-4.28 (1H, m), 4.05-3.62 (5H, m), 3.43-3.04 (2H, m), 2.79-2.68 (1H, m), 1.80-1.60 (1H, m). Example 176 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,6-diazabicyclo [3.1.1] heptane-6-yl) -3-methoxyisonicotino Synthesis of Nitrile (2- (1H-pyrazol-1-yl) pyridin-3-yl) (3,6-diazabicyclo [3.1.1] heptane) was prepared in the same manner as in Example 147 or a method analogous thereto. The title compound (7.6 mg) was obtained as a colorless solid using -3-yl) methanone (intermediate 43) (72 mg).
UPLC: 402 [M + H] + (retention time 0.90 minutes)
1 H-NMR (DMSO-d 6 , 300 MHz) δ: 8.56-8.42 (2H, m), 8.07-8.01 (1H, m), 7.94-7.76 (1H, m), 7.48-7.34 (1H, m), 7.18-7.11 (1H, m), 6.67-6.33 (2H, m), 4.60-4.49 (1H, m), 4.36-4.28 (1H, m), 4.05-3.62 (5H, m), 3.43-3.04 (2H , m), 2.79-2.68 (1H, m), 1.80-1.60 (1H, m).
上記の(実施例1)から(実施例176)で合成した最終化合物の構造を以下の図(化13ないし22)に示す。また、(製造例1)から(製造例44)で合成した中間体化合物の構造を以下の図(化23ないし25)に示す。なお中間体化合物については、例えば、(製造例1)で得られた化合物を(中間体1)、(製造例1)<工程1>で得られた化合物を(中間体1-1)のように表記した。
The structure of the final compound synthesized in the above (Example 1) to (Example 176) is shown in the following figures (Chemical Formulas 13 to 22). The structure of the intermediate compound synthesized in (Production Example 1) to (Production Example 44) is shown in the following figures (Chemical Formulas 23 to 25). As for the intermediate compound, for example, the compound obtained in (Preparation Example 1) is designated as (Intermediate 1), the compound obtained in (Preparation Example 1) <Step 1> as (Intermediate 1-1) Indicated.
Claims (10)
- 下記式(I):
(式中、
nは、1または2を表し;
環Aは、C6~14アリール基または5~14員ヘテロアリール基を表し、環Aにおける、前記C6~14アリール基または5~14員ヘテロアリール基は、それぞれ、1~5個のR1で置換されていてもよく;
環Bは、フェニル基または単環式ヘテロアリール基を表し、環Bにおける前記フェニル基または単環式ヘテロアリール基は、それぞれ、1~4個のR2で置換されていてもよく;
Lは、ハロゲン原子、C3~8シクロアルキル基、C1~6アルコキシル基、ハロゲン化C1~6アルコキシル基、フェノキシ基、単環式非芳香族複素環基、フェニル基または単環式ヘテロアリール基を表し、Lにおける前記フェノキシ基、単環式非芳香族複素環基、フェニル基または単環式ヘテロアリール基は、それぞれ、1~5個のR3で置換されていてもよく、または、Lは、R2と結合し、環Bの一部とともに縮合環基を形成してもよく、前記縮合環基は、ハロゲン原子で置換されていてもよい5~7員複素環基であり;
環B上においてLは環A-ビシクロ環-CO-の結合位置に隣接する置換基であり;
R1は、各々独立に、ハロゲン原子、C1~6アルキル基、C2~6アルケニル基、C2~6アルキニル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~6アルケニルオキシ基、C2~6アルキニルオキシ基、C2~7アルカノイル基、C1~6アルコキシルカルボニル基、C1~6アルキルチオ基、-NRaRb基、シアノ基及びオキソ基から任意に選ばれる基を表し、R1における前記C1~6アルキル基、C2~6アルケニル基、C2~6アルキニル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~6アルケニルオキシ基、C2~6アルキニルオキシ基、C2~7アルカノイル基、C1~6アルコキシルカルボニル基またはC1~6アルキルチオ基は、それぞれ、1~5個の置換基RIで置換されていてもよく;
R2は、各々独立に、ハロゲン原子、C1~6アルキル基、C2~6アルケニル基、C2~6アルキニル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~6アルケニルオキシ基、C2~6アルキニルオキシ基、シアノ基及び単環式ヘテロアリール基から任意に選ばれる基を表し、R2における前記C1~6アルキル基、C2~6アルケニル基、C2~6アルキニル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~6アルケニルオキシ基、C2~6アルキニルオキシ基または単環式ヘテロアリール基は、それぞれ、1~5個の置換基RIで置換されていてもよく;
R3は、各々独立に、ハロゲン原子、C1~6アルキル基、C2~6アルケニル基、C2~6アルキニル基、C1~6アルコキシル基、C2~6アルケニルオキシ基、C2~6アルキニルオキシ基及びシアノ基から任意に選ばれる基を表し、R3における前記C1~6アルキル基、C2~6アルケニル基、C2~6アルキニル基、C1~6アルコキシル基、C2~6アルケニルオキシ基またはC2~6アルキニルオキシ基は、それぞれ、1~5個の置換基RIで置換されていてもよく;
Ra及びRbは、各々独立に、C1~6アルキル基、ハロゲン化C1~6アルキル基、C2~6アルケニル基及びC2~6アルキニル基から任意に選ばれる基を表し、RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよく、RaおよびRbにおける前記単環式非芳香族複素環基は、その環内の炭素原子の少なくとも1個が、酸素原子、硫黄原子及びC1~6アルキル基で置換されていてもよい窒素原子から任意に選ばれる原子またはカルボニル基で置き換えられていてもよく;
置換基RIは、各々独立に、ハロゲン原子または水酸基を表す)
で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物。 The following formula (I):
(Where
n represents 1 or 2;
Ring A represents a C 6 ~ 14 aryl group or a 5-14 membered heteroaryl group, in the ring A, the C 6 ~ 14 aryl group or a 5-14 membered heteroaryl group, respectively, 1-5 R Optionally substituted by 1 ;
Ring B represents a phenyl group or a monocyclic heteroaryl group, and the phenyl group or the monocyclic heteroaryl group in Ring B may each be substituted with 1 to 4 R 2 ;
L is a halogen atom, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxyl group, a halogenated C 1 ~ 6 alkoxy group, a phenoxy group, a monocyclic non-aromatic heterocyclic group, a phenyl group or a monocyclic heteroaryl Represents an aryl group, and the phenoxy group, monocyclic non-aromatic heterocyclic group, phenyl group or monocyclic heteroaryl group in L may each be substituted with 1 to 5 R 3 , or , L may be bonded to R 2 to form a condensed ring group together with a part of ring B, and the condensed ring group is a 5- to 7-membered heterocyclic group which may be substituted with a halogen atom. ;
L on ring B is a substituent adjacent to the bond position of ring A-bicycloring-CO—;
R 1 is, each independently, a halogen atom, C 1 ~ 6 alkyl group, C 2 ~ 6 alkenyl group, C 2 ~ 6 alkynyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 2 ~ 6 alkenyloxy group, C 2 ~ 6 alkynyloxy group, C 2 ~ 7 alkanoyl group, C 1 ~ 6 alkoxycarbonyl group, C 1 ~ 6 alkylthio group, -NR a R b group, optionally cyano group and oxo group represents a group selected, the C 1 ~ 6 alkyl group in R 1, C 2 ~ 6 alkenyl group, C 2 ~ 6 alkynyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 2 ~ 6 alkenyloxy group, C 2 ~ 6 alkynyloxy group, C 2 ~ 7 alkanoyl group, C 1 ~ 6 alkoxycarbonyl group, or a C 1 ~ 6 alkylthio group, respectively, substituted with 1 to 5 substituents RI Well;
R 2 are each independently a halogen atom, C 1 ~ 6 alkyl group, C 2 ~ 6 alkenyl group, C 2 ~ 6 alkynyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 2 ~ 6 alkenyloxy groups, C 2 ~ 6 alkynyloxy group, a chosen group optionally cyano group and a monocyclic heteroaryl group, wherein the R 2 C 1 ~ 6 alkyl groups, C 2 ~ 6 alkenyl groups, C 2-6 alkynyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 2-6 alkenyloxy group, C 2-6 alkynyloxy group or a monocyclic heteroaryl group, respectively, 1-5 Optionally substituted by one substituent RI;
R 3 are each independently a halogen atom, C 1 ~ 6 alkyl group, C 2 ~ 6 alkenyl group, C 2 ~ 6 alkynyl group, C 1 ~ 6 alkoxy group, C 2 ~ 6 alkenyloxy group, C 2 ~ It represents 6 alkynyloxy group and chosen group optionally cyano group, wherein in R 3 C 1 ~ 6 alkyl group, C 2 ~ 6 alkenyl group, C 2 ~ 6 alkynyl group, C 1 ~ 6 alkoxy group, C 2 1-6 alkenyloxy group or a C 2 - 6 alkynyloxy groups may each be substituted with 1 to 5 substituents RI;
R a and R b represent each independently, C 1 ~ 6 alkyl group, a halogenated C 1 ~ 6 alkyl group, a chosen group optionally from C 2 ~ 6 alkenyl group and C 2 ~ 6 alkynyl radical, R a and R b together with the nitrogen atom to which they are attached may form a monocyclic non-aromatic heterocyclic group, and the monocyclic non-aromatic heterocyclic group in R a and R b At least one of the carbon atoms may be replaced with an atom or carbonyl group arbitrarily selected from an oxygen atom, a sulfur atom and a nitrogen atom optionally substituted with a C 1-6 alkyl group;
Each of the substituents RI independently represents a halogen atom or a hydroxyl group)
Or a pharmaceutically acceptable salt or solvate thereof. - 式(I)中、環Aは、フェニル基または5~10員ヘテロアリール基を表し、環Aにおける前記フェニル基またはヘテロアリール基は、それぞれ、1~5個のR1で置換されていてもよく;
環Bは、フェニル基または5~6員の単環式ヘテロアリール基を表し、環Bにおける前記フェニル基またはヘテロアリール基は、それぞれ、1~4個のR2で置換されていてもよく;
Lは、C3~8シクロアルキル基、C1~6アルコキシル基、ハロゲン化C1~6アルコキシル基、フェニル基または5~6員の単環式ヘテロアリール基を表し、Lにおける前記フェニル基またはヘテロアリール基は、それぞれ、1~5個のR3で置換されていてもよく、または、LとR2が環B上で互いに隣接する置換基である場合、Lは、R2と結合し、環Bの一部とともに縮合環基を形成してもよく、前記縮合環基は、ハロゲン原子で置換されていてもよい5~7員の単環式非芳香族複素環基である、
請求項1に記載の化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物。 In formula (I), ring A represents a phenyl group or a 5- to 10-membered heteroaryl group, and the phenyl group or heteroaryl group in ring A may be substituted with 1 to 5 R 1 s , respectively. Often;
Ring B represents a phenyl group or a 5- to 6-membered monocyclic heteroaryl group, and the phenyl group or heteroaryl group in Ring B may each be substituted with 1 to 4 R 2 ;
L is, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxyl group, a halogenated C 1 ~ 6 alkoxy group, a monocyclic heteroaryl group phenyl group or a 5-6-membered, or the phenyl group in L Each heteroaryl group may be substituted with 1 to 5 R 3 , or when L and R 2 are substituents adjacent to each other on ring B, L is bonded to R 2. A condensed ring group may be formed together with a part of ring B, and the condensed ring group is a 5- to 7-membered monocyclic non-aromatic heterocyclic group which may be substituted with a halogen atom.
The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof. - 式(I)中、環Aは、下記部分構造式(a1)、(a2)、(a3)または(a4):
(式(a1)、(a2)、(a3)または(a4)中、
環A1は、隣接するピリジン環とともに9~10員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成し、前記環A1は1~2個のハロゲン原子で置換されていてもよく、
環A2は、隣接するピラゾール環とともに8~9員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成し、前記環A2は1~2個のハロゲン原子で置換されていてもよく、
環A3は、隣接するイミダゾール環とともに8~9員の縮環式ヘテロアリール基または部分的に水素化された縮環式ヘテロアリール基を形成し、前記環A3は1~2個のハロゲン原子で置換されていてもよく、
X1は、窒素原子、C-HまたはC-R1aを表し、
X2は、窒素原子、C-HまたはC-R1dを表し、但し、X1が窒素原子の場合は、X2はC-HまたはC-R1dであり、
R1aは、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C2~7アルカノイル基またはシアノ基を表し、
R1b及びR1cは、各々独立に、水素原子またはC1~6アルキル基を表し、
R1dは、ハロゲン原子、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C1~6アルキルチオ基、-NRaRb基またはオキソ基を表し、但し、R1dがオキソ基の場合は、X1はC1~6アルキル基で置換されていてもよい窒素原子であり、
R1e及びR1fは、各々独立に、水素原子またはC1~6アルキル基を表し、
R1a、R1b、R1c、R1d、R1e及びR1fにおける前記アルキル基、シクロアルキル基、アルコキシル基、アルカノイル基またはアルキルチオ基は、それぞれ、1~5個の置換基RIで置換されていてもよい)を表し、
環Bは、フェニル基または5~6員ヘテロアリール基を表し、環Bにおける前記フェニル基またはヘテロアリール基は、それぞれ、1個のR2で置換されていてもよく、
Lは、フェニル基または5~6員ヘテロアリール基を表し、Lにおける前記フェニル基またはヘテロアリール基は、それぞれ、1個のR3で置換されていてもよい、
請求項1に記載の化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物。 In formula (I), ring A is the following partial structural formula (a1), (a2), (a3) or (a4):
(In the formula (a1), (a2), (a3) or (a4),
Ring A1 together with the adjacent pyridine ring forms a 9-10 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A1 is composed of 1 to 2 halogen atoms May be replaced,
Ring A2 together with the adjacent pyrazole ring forms an 8-9 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A2 is composed of 1 to 2 halogen atoms May be replaced,
Ring A3 together with the adjacent imidazole ring forms an 8-9 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A3 is composed of 1 to 2 halogen atoms May be replaced,
X 1 represents a nitrogen atom, C—H or C—R 1a ,
X 2 represents a nitrogen atom, C—H or C—R 1d , provided that when X 1 is a nitrogen atom, X 2 is C—H or C—R 1d ,
R 1a represents C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, a C 2 ~ 7 alkanoyl group or a cyano group,
R 1b and R 1c each independently represents a hydrogen atom or a C 1-6 alkyl group,
R 1d represents a halogen atom, C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, C 1 ~ 6 alkylthio group, a -NR a R b group or an oxo group, provided that, When R 1d is an oxo group, X 1 is a nitrogen atom which may be substituted with a C 1-6 alkyl group,
R 1e and R 1f each independently represents a hydrogen atom or a C 1-6 alkyl group,
The alkyl group, cycloalkyl group, alkoxyl group, alkanoyl group or alkylthio group in R 1a , R 1b , R 1c , R 1d , R 1e and R 1f is each substituted with 1 to 5 substituents RI. May represent)
Ring B represents a phenyl group or a 5- to 6-membered heteroaryl group, and each of the phenyl group or heteroaryl group in Ring B may be substituted with one R 2 ,
L represents a phenyl group or a 5- to 6-membered heteroaryl group, and each of the phenyl group or heteroaryl group in L may be substituted with one R 3 .
The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof. - 式(I)中、環Aは、前記部分構造式(a1)であり、ここでX1はC-R1aであり、X2は窒素原子、C-HまたはC-R1dであり、R1dは、ハロゲン原子、C1~6アルキル基、C3~8シクロアルキル基、C1~6アルコキシル基、C1~6アルキルチオ基または-NRaRb基を表し、;
環Bは、下記部分構造式(b1)または(b2):
(式(b1)または(b2)中、
Yは、窒素原子、C-HまたはC-R2bを表し、
R2aは、水素原子、ハロゲン原子、C1~6アルキル基、C1~6アルコキシル基または単環式ヘテロアリール基を表し、但し、YがC-R2bの場合は、R2aは水素原子であり、
R2bは、ハロゲン原子を表し、
R2cは、水素原子、C1~6アルキル基またはシアノ基を表し、
R2a及びR2cにおける前記アルキル基、アルコキシル基は、それぞれ、1~5個の置換基RIで置換されていてもよい)を表し;
R3は、C1~6アルキル基、C1~6アルコキシル基またはシアノ基を表し、ここでR3における前記アルキル基またはアルコキシル基は、それぞれ、1~5個の置換基RIで置換されていてもよく;
Ra及びRbは、各々独立に、C1~6アルキル基を表し、RaおよびRbは、それらが結合する窒素原子とともに単環式非芳香族複素環基を形成してもよく、RaおよびRbにおける前記単環式非芳香族複素環基は、その環内の炭素原子の少なくとも1個が、酸素原子、硫黄原子及びC1~6アルキル基で置換されていてもよい窒素原子から任意に選ばれる原子で置き換えられていてもよい、
請求項3に記載の化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物。 In formula (I), ring A is the partial structural formula (a1), wherein X 1 is C—R 1a , X 2 is a nitrogen atom, C—H or C—R 1d , R 1d represents a halogen atom, C 1 ~ 6 alkyl group, C 3 ~ 8 cycloalkyl group, C 1 ~ 6 alkoxy group, a C 1 ~ 6 alkylthio group or -NR a R b group;
Ring B has the following partial structural formula (b1) or (b2):
(In the formula (b1) or (b2),
Y represents a nitrogen atom, C—H or C—R 2b ,
R 2a represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxyl group or a monocyclic heteroaryl group, provided that when Y is C—R 2b , R 2a is a hydrogen atom And
R 2b represents a halogen atom,
R 2c represents a hydrogen atom, a C 1-6 alkyl group or a cyano group,
Each of the alkyl group and alkoxyl group in R 2a and R 2c may be substituted with 1 to 5 substituents RI;
R 3 represents a C 1-6 alkyl group, a C 1-6 alkoxyl group or a cyano group, wherein the alkyl group or alkoxyl group in R 3 is each substituted with 1 to 5 substituents RI. May be;
R a and R b each independently represent a C 1-6 alkyl group, R a and R b together with the nitrogen atom to which they are attached may form a monocyclic non-aromatic heterocyclic group; The monocyclic non-aromatic heterocyclic group for R a and R b is a nitrogen in which at least one of carbon atoms in the ring may be substituted with an oxygen atom, a sulfur atom and a C 1-6 alkyl group. It may be replaced with an atom arbitrarily selected from atoms,
The compound according to claim 3, or a pharmaceutically acceptable salt or solvate thereof. - 式(I)中、R1aは、C1~6アルキル基またはシアノ基を表し、R1bは、水素原子を表し、R1cは、水素原子またはC1~6アルキル基を表し、R1dは、C1~6アルコキシル基を表し、R1a、R1b、R1c及びR1dにおける前記アルキル基またはアルコキシル基は、それぞれ、1~5個のハロゲン原子で置換されていてもよく、
R2aは、水素原子またはハロゲン原子を表し、但し、YがC-R2bの場合は、R2aは水素原子であり、
R2cは、水素原子、C1~6アルキル基、ハロゲン化C1~6アルキル基またはシアノ基を表し、
Lは、下記部分構造式(c1)、(c2)または(c3):
(式(c1)、(c2)または(c3)中、
Z1、Z2、Z3は、各々独立に、窒素原子またはC-Hを表し、但し、Z2がC-Hの場合は、Z1はC-Hであり、
Z4は、酸素原子または硫黄原子を表し、
R3a、R3b及びR3cは、各々独立に、水素原子、C1~6アルキル基またはシアノ基を表す)を表す、
請求項4に記載の化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物。 In formula (I), R 1a represents a C 1-6 alkyl group or a cyano group, R 1b represents a hydrogen atom, R 1c represents a hydrogen atom or a C 1-6 alkyl group, and R 1d represents Represents a C 1-6 alkoxyl group, and the alkyl group or alkoxyl group in R 1a , R 1b , R 1c and R 1d may be substituted with 1 to 5 halogen atoms,
R 2a represents a hydrogen atom or a halogen atom, provided that when Y is C—R 2b , R 2a is a hydrogen atom;
R 2c represents a hydrogen atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group or a cyano group,
L is the following partial structural formula (c1), (c2) or (c3):
(In the formula (c1), (c2) or (c3),
Z 1 , Z 2 , and Z 3 each independently represent a nitrogen atom or C—H, provided that when Z 2 is C—H, Z 1 is C—H;
Z 4 represents an oxygen atom or a sulfur atom,
R 3a , R 3b and R 3c each independently represents a hydrogen atom, a C 1-6 alkyl group or a cyano group)
The compound according to claim 4, or a pharmaceutically acceptable salt or solvate thereof. - 請求項1ないし5の何れか1項に記載の化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも1つを有効成分として含有することを特徴とする、医薬組成物。 A pharmaceutical composition comprising as an active ingredient at least one of the compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof or a solvate thereof. .
- 請求項1ないし5の何れか1項に記載の化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも1つを有効成分として含有することを特徴とする、オレキシン受容体が関与する疾患の予防及び/または治療剤。 6. An orexin receptor comprising as an active ingredient at least one of the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof. Preventive and / or therapeutic agent for diseases involving
- 請求項1ないし5の何れか1項に記載の化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも1つを有効成分として含有することを特徴とする、睡眠障害の予防及び/または治療剤。 A compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, comprising as an active ingredient, the sleep disorder characterized by Prophylactic and / or therapeutic agent.
- 請求項1ないし5の何れか1項に記載の化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の1つ以上を含む、オレキシン受容体拮抗剤。 An orexin receptor antagonist comprising one or more of the compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof.
- 請求項1ないし5の何れか1項に記載の化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の1つ以上、並びに、睡眠障害関連薬または睡眠障害を併発しやすい疾患の治療薬の1種以上を含有することを特徴とする医薬組成物。 The compound according to any one of claims 1 to 5, or one or more of a pharmaceutically acceptable salt thereof or a solvate thereof, and a disorder easily associated with a sleep disorder-related drug or sleep disorder. A pharmaceutical composition comprising at least one therapeutic agent.
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