JP2023015414A - epoxy azepane derivative - Google Patents

Abstract

To provide a morphinan derivative having an opioidκ receptor agonist action.SOLUTION: Disclosed are an azepane derivative represented by formula (I) and a pharmaceutically accepted salt thereof (in the formula, R1, R2, R3, R4 and R5 are H, C1-6 alkyl and the like, respectively; R6 is H, C1-6 alkoxy; R7, R8, R9, R10, R11 are H, C1-6 alkyl and the like, respectively; A and B are methylene, carbonyl and the like respectively, different from each other; X is N or N-oxide; Y is methylene, carbonyl or thiocarbonyl; Z is NR15, O and the like; R15 is H, C1-6 alkyl and the like; m is integer of 0 to 1; and n is integer of 0 to 3).SELECTED DRAWING: None

Description

TECHNICAL FIELD The present invention relates to azepane derivatives having κ opioid receptor agonistic activity.

Since humans perceive some kind of abnormality or abnormality in the body by feeling "pain", "pain" can be regarded as a warning response in the body. However, long-term "pain", for example, "pain" associated with terminal cancer, rheumatoid arthritis, etc., is a factor that significantly lowers the patient's quality of life (QOL). Therefore, controlling pain is extremely important in improving the patient's QOL.
Pain control is achieved with drugs, such as morphine, fentanyl and oxycodone. Although these drugs have strong analgesic effects, they have serious side effects of drug dependence, so their use needs to be done with caution.
Morphine has mu opioid receptor agonist activity among the 3 opioid receptor subtypes (mu, delta, and kappa) and exhibits analgesic effects. Known to cause adverse events.
On the other hand, κ opioid receptor agonists have been reported to exhibit an analgesic effect without causing morphine-induced adverse events (Non-Patent Document 1).
Therefore, κ opioid receptor agonists are expected as safe and effective analgesics to replace morphine, but there are no κ opioid receptor selective agonists approved as analgesics.
Patent Document 1 describes the following formula (A):

It is disclosed that compounds represented by have κ opioid receptor agonist activity. However, its activity was not sufficient.
Further, in Patent Document 2, the following formula (B):

A compound represented by is reported. This compound is said to have kappa opioid receptor selective binding and analgesic activity. However, its analgesic activity was not satisfactory.
Further, in Patent Document 3 and Non-Patent Document 2, a compound (C) represented by the following formula:

has been disclosed to have extremely high activity, but this compound was not sufficiently stable in vivo.
Further, Patent Document 4 discloses a morphinan derivative (I) represented by the following formula:

has been disclosed to have extremely high analgesic and diuretic effects.

JP 2008-179554 A Japanese Patent No. 2525552 U.S. Pat. No. 963,460 WO 1993/15081 Pamphlet

Pharmaceutica Acta Helvetiae, Vol.74, No.2-3, pp.337-344 JNRC2016 The 36th Analgesics/Opioid Peptides Symposium Program/Abstracts, Page 37, Analgesics/Opioid Peptide Research Group

An object of the present invention is to provide a medicament that has a high κ opioid receptor agonist activity and is effective in treating, improving, or preventing various diseases and symptoms associated with κ opioid receptors.

（式中、Ｒ^１は水素原子、置換基を有していてもよいＣ_１－６アルキル基、置換基を有していてもよいＣ_３－６シクロアルキル基、置換基を有していてもよいＣ_３－６シクロアルキルＣ_１－６アルキル基、置換基を有していてもよいＣ_６－１０アリール基、置換基を有していてもよいヘテロアリール基、置換基を有していてもよいアラルキル基、置換基を有していてもよいヘテロアリールアルキル基、置換基を有していてもよいＣ_２－６アルケニル基、置換基を有していてもよいＣ_２－６アルキニル基、置換基を有していてもよいアシル基又はアミノ保護基を示し、
Ｒ^２及びＲ^３は同一又は異なって水素原子、置換基を有していてもよいＣ_１－６アルキル基、置換基を有していてもよいＣ_１－６アルコキシ基、ハロゲン原子、ヒドロキシ基又はＲ^２及びＲ^３が一緒になってカルボニル基又はチオカルボニル基を示すかＲ^２及びＲ^３が結合して置換基を有していてもよいＣ_３－６飽和炭化水素環又は置換基を有していてもよい環状ケタールを示し、
Ｒ^４及びＲ^５は同一又は異なって水素原子、置換基を有していてもよいＣ_１－６アルキル基、置換基を有していてもよいＣ_１－６アルコキシ基、置換基を有していてもよいアミノ基、保護されたアミノ基、ハロゲン原子又はヒドロキシ基を示し、
Ｒ^６は水素原子、置換基を有していてもよいＣ_１－６アルコキシ基、置換基を有していてもよいアミノ基、保護されたアミノ基、ハロゲン原子、ヒドロキシ基、シアノ基、カルボキシ基、カルボン酸エステル基又は置換基を有していてもよいカルバモイル基を示し、
Ｒ^７及びＲ^８は同一又は異なって水素原子、置換基を有していてもよいＣ_１－６アルキル基、置換基を有していてもよいＣ_１－６アルコキシ基、ハロゲン原子、ヒドロキシ基又はＲ^７及びＲ^８が一緒になってカルボニル基又はチオカルボニル基を示すかＲ^７及びＲ^８が結合して置換基を有していてもよいＣ_３－６飽和炭化水素環又は置換基を有していてもよい環状ケタールを示し、
Ｒ^９及びＲ^１０は同一又は異なって水素原子、置換基を有していてもよいＣ_１－６アルキル基、置換基を有していてもよいＣ_１－６アルコキシ基、ハロゲン原子、ヒドロキシ基又はＲ^９及びＲ^１０が一緒になってカルボニル基又はチオカルボニル基を示すかＲ^９及びＲ^１０が結合して置換基を有していてもよいＣ_３－６飽和炭化水素環又は置換基を有していてもよい環状ケタールを示し、
Ｒ^１１は水素原子、置換基を有していてもよいＣ_１－６アルキル基、置換基を有していてもよいＣ_１－６アルコキシ基、置換基を有していてもよいアラルキルオキシ基、置換基を有していてもよいアミノ基、保護されたアミノ基、ハロゲン原子、ヒドロキシ基又はシアノ基を示し、
Ａ及びＢは異なってメチレン基、カルボニル基又は下記一般式（ＩＩ）：

（Ｒ^１２及びＲ^１３は同一又は異なって水素原子、Ｒ^１２及びＲ^１３が一緒になってカルボニル基又はチオカルボニル基を示すか、置換基を有していてもよいＣ_１－６アルキル基を示すか、同一炭素上のＲ^１２とＲ^１３が結合して置換基を有していてもよいＣ_３－６飽和炭化水素環、置換基を有していてもよい飽和複素環を示すか、ｎが２～３の場合において隣接する一組のＲ^１２同士が結合して置換基を有していてもよいＣ_３－６飽和炭化水素環又は置換基を有していてもよい飽和複素環を形成することができ、
Ｒ^１４は水素原子、置換基を有していてもよいＣ_１－６アルキル基、置換基を有していてもよいＣ_３－６シクロアルキル基、置換基を有していてもよいＣ_２－４アルケニル基、置換基を有していてもよいＣ_２－６アルキニル基、置換基を有していてもよいＣ_１－６アルコキシ基、置換基を有していてもよいアミノ基、保護されたアミノ基、ハロゲン原子、ヒドロキシ基、置換基を有していてもよいＣ_６－１０アリール基、置換基を有していてもよいヘテロアリール基、置換基を有していてもよい環状アミノ基を示す。）で表される基を示し（ただし、Ａ、Ｂのいずれか一方は式（ＩＩ）を示す）、
Ｘは窒素原子又はＮ－オキシドを示し、
Ｙは置換基を有していてもよいメチレン基、カルボニル基又はチオカルボニル基示し、
ＺはＮＲ^１５、酸素原子、結合手、置換基を有しても良いエテニレン基又はエチニレン基を示し（ただし、ｍが０の時はｎは０及びＺはＮＲ^１５を示さない。）、
Ｒ^１５は水素原子、置換基を有していてもよいＣ_１－６アルキル基を示すか、Ｒ^１５とＲ^１４が結合して置換基を有していてもよい含窒素飽和複素環を示し、
ｍは０～１の整数を示し、
ｎは０～３の整数を示す。
（ただし、Ｚが結合手の場合、ｍとｎは同時に０を示さない。））
で表されるアゼパン誘導体及びその薬学的に許容される塩に関する。
［２］また本発明は、Ｒ^６がヒドロキシ基又は置換基を有していてもよいＣ_１－６アルコキシ基である前記［１］記載のエポキシアゼパン誘導体及びその薬学的に許容される塩に関する。
［３］また本発明は、Ｒ^６がヒドロキシ基である前記［１］又は［２］記載のエポキシアゼパン誘導体及びその薬学的に許容される塩に関する。
［４］また本発明は、Ｒ^１が置換基を有していてもよいＣ_１－６アルキル基又は置換基を有していてもよいＣ_３－６シクロアルキルＣ_１－６アルキル基である前記［１］～［３］記載のエポキシアゼパン誘導体及びその薬学的に許容される塩に関する。
［５］また本発明は、Ｚが結合手である前記［１］～［４］記載のエポキシアゼパン誘導体及びその薬学的に許容される塩に関する。
［６］また本発明は、ｎが１～３である前記［１］～［５］記載のエポキシアゼパン誘導体及びその薬学的に許容される塩に関する。
［７］また本発明は、Ｒ^１４が置換基を有していてもよいヘテロアリール基である前記［１］～［６］記載のエポキシアゼパン誘導体及びその薬学的に許容される塩に関する。
［８］また本発明は、Ｙがカルボニル基である前記［１］～［７］記載のエポキシアゼパン誘導体及びその薬学的に許容される塩に関する。
［９］また本発明は、Ａが[１]記載の一般式（ＩＩ）で表される基を示し、Ｂがメチレン基を示す前記［１］～［８］記載のエポキシアゼパン誘導体及びその薬学的に許容される塩に関する。
[１０]また本発明は、Ｒ^１１がヒドロキシ基である前記［１］～［９］記載のエポキシアゼパン誘導体及びその薬学的に許容される塩に関する。
［１１］また本発明は、前記［１］～［１０］いずれか１項記載のエポキシアゼパン誘導体及びその薬学的に許容される塩を有効成分として含有する医薬組成物に関する。
［１２］また本発明は、 κオピオイド受容体に関連する疾患の治療又は改善、予防剤である前記［１１］記載の医薬に関する。
［１３］また本発明は、鎮痛薬である前記［１１］又は［１２］記載の医薬に関する。
［１４］また本発明は、止痒薬である前記［１１］又は［１２］記載の医薬に関する。 Under such circumstances, the present inventors conducted intensive studies and found that a specific epoxyazepane derivative exhibits a strong agonistic activity to κ opioid receptors and high stability in vivo. Furthermore, this epoxyazepane derivative showed a strong analgesic effect. As described above, the inventors have found that epoxyazepane derivatives exhibit high in vivo stability and strong analgesic action, and have completed the present invention.
[1] That is, the present invention provides the following general formula (I),

(In the formula, R ¹ is a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, a substituted optionally substituted C _3-6 cycloalkyl C _1-6 alkyl group, optionally substituted C _6-10 aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group optionally having substituent(s), heteroarylalkyl group optionally having substituent(s), C _2-6 alkenyl group optionally having substituent(s), C _2-6 alkynyl optionally having substituent(s) a group, an optionally substituted acyl group or an amino-protecting group,
R ² and R ³ are the same or different, hydrogen atom, optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, halogen atom, hydroxy group or R ² and R ³ together represent a carbonyl group or a thiocarbonyl group, or R ² and R ³ combine to represent an optionally substituted C _3-6 saturated hydrocarbon ring or substituent indicates a cyclic ketal that may have
R ⁴ and R ⁵ are the same or different and have a hydrogen atom, optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, substituted represents an optional amino group, a protected amino group, a halogen atom or a hydroxy group,
R ⁶ is a hydrogen atom, an optionally substituted C _1-6 alkoxy group, an optionally substituted amino group, a protected amino group, a halogen atom, a hydroxy group, a cyano group, a carboxy represents a carbamoyl group which may have a group, a carboxylic acid ester group or a substituent,
R ⁷ and R ⁸ are the same or different, hydrogen atom, optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, halogen atom, hydroxy group or R ⁷ and R ⁸ together represent a carbonyl group or a thiocarbonyl group, or R ⁷ and R ⁸ combine to represent an optionally substituted C _3-6 saturated hydrocarbon ring or substituent indicates a cyclic ketal that may have
R ⁹ and R ¹⁰ are the same or different, hydrogen atom, optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, halogen atom, hydroxy group or R ⁹ and R ¹⁰ together represent a carbonyl group or a thiocarbonyl group, or R ⁹ and R ¹⁰ combine to represent an optionally substituted C _3-6 saturated hydrocarbon ring or substituent indicates a cyclic ketal that may have
R ¹¹ is a hydrogen atom, optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, optionally substituted aralkyloxy group , an optionally substituted amino group, a protected amino group, a halogen atom, a hydroxy group or a cyano group,
A and B are different methylene groups, carbonyl groups or the following general formula (II):

(R ¹² and R ¹³ are the same or different and are a hydrogen atom, R ¹² and R ¹³ together represent a carbonyl group or a thiocarbonyl group, or a C _1-6 alkyl group optionally having a substituent or R ¹² and R ¹³ on the same carbon are bonded to represent an optionally substituted C _3-6 saturated hydrocarbon ring, an optionally substituted saturated heterocyclic ring, optionally substituted C _3-6 saturated hydrocarbon ring or optionally substituted saturated heterocyclic ring in which a pair of adjacent R ¹² are bonded together when n is 2 to 3 can form
R ¹⁴ is a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _{2 -4} alkenyl group, optionally substituted C _2-6 alkynyl group, optionally substituted C _1-6 alkoxy group, optionally substituted amino group, protected amino group, halogen atom, hydroxy group, optionally substituted _C6-10 aryl group, optionally substituted heteroaryl group, optionally substituted cyclic Indicates an amino group. ) represents a group represented by (provided that either A or B represents formula (II)),
X represents a nitrogen atom or N-oxide,
Y represents an optionally substituted methylene group, a carbonyl group or a thiocarbonyl group,
Z represents NR ¹⁵ , an oxygen atom, a bond, an optionally substituted ethenylene group or an ethynylene group (however, when m is 0, n is 0 and Z does not represent NR ¹⁵ ),
R ¹⁵ represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, or R ¹⁵ and R ¹⁴ combine to represent an optionally substituted nitrogen-containing saturated heterocyclic ring ,
m represents an integer of 0 to 1,
n represents an integer of 0-3.
(However, when Z is a bond, m and n do not indicate 0 at the same time.))
Represented by azepane derivatives and pharmaceutically acceptable salts thereof.
[2] The present invention also provides the epoxyazepane derivative according to [1] above, wherein R ⁶ is a hydroxy group or a C _1-6 alkoxy group optionally having a substituent, and a pharmaceutically acceptable salt thereof. Regarding.
[3] The present invention also relates to the epoxyazepane derivative according to the above [1] or [ ² ], wherein R6 is a hydroxy group, and a pharmaceutically acceptable salt thereof.
[4] In the present invention, R ¹ is an optionally substituted C _1-6 alkyl group or an optionally substituted C _3-6 cycloalkylC _1-6 alkyl group It relates to epoxyazepane derivatives and pharmaceutically acceptable salts thereof according to the above [1] to [3].
[5] The present invention also relates to the epoxyazepane derivatives and pharmaceutically acceptable salts thereof according to the above [1] to [4], wherein Z is a bond.
[6] The present invention also relates to the epoxyazepane derivative according to the above [1] to [5], wherein n is 1 to 3, and a pharmaceutically acceptable salt thereof.
[7] The present invention also relates to the epoxyazepane derivatives and pharmaceutically acceptable salts thereof according to the above [1] to [6], wherein R ¹⁴ is an optionally substituted heteroaryl group.
[8] The present invention also relates to the epoxyazepane derivatives and pharmaceutically acceptable salts thereof according to the above [1] to [7], wherein Y is a carbonyl group.
[9] The present invention also provides the epoxyazepane derivative according to the above [1] to [8], wherein A represents a group represented by the general formula (II) according to [1], and B represents a methylene group, and its It relates to pharmaceutically acceptable salts.
[10] The present invention also relates to epoxyazepane derivatives and pharmaceutically acceptable salts thereof according to the above [1] to [9], wherein R ¹¹ is a hydroxy group.
[11] The present invention also relates to a pharmaceutical composition containing, as an active ingredient, the epoxyazepane derivative according to any one of [1] to [10] and a pharmaceutically acceptable salt thereof.
[12] The present invention also relates to the medicament according to the above [11], which is a therapeutic, ameliorating, or prophylactic agent for diseases associated with κ opioid receptors.
[13] The present invention also relates to the medicament according to the above [11] or [12], which is an analgesic.
[14] The present invention also relates to the medicament according to the above [11] or [12], which is an antipruritic.

The present invention will now be described in more detail.
The epoxyazepane derivatives represented by the general formula (I) and pharmaceutically acceptable salts thereof include tautomers, stereoisomers and solvates thereof.
The C _1-6 alkyl group in the optionally substituted C _1-6 alkyl group represented by R ¹ to R ⁵ and R ⁷ to R ¹⁵ includes a methyl group, an ethyl group, a propyl group and an isopropyl group. , butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group and the like straight or branched alkyl groups, preferably methyl group, ethyl group, propyl group, more preferably methyl group mentioned.
Substituents in the C _1-6 alkyl group which may have a substituent include a halogen atom such as a fluorine atom and a chlorine atom; a hydroxy group; a C _1-6 alkylamino group and a di-C _1-6 alkylamino group , an amino group optionally having a substituent such as an acylamino group; a protected amino group; a formyl group, an acetyl group, a cyclopropanecarbonyl group, an acyl group such as a benzoyl group; an azetidinyl group, a pyrrolidinyl group, a piperazinyl group, cyclic amino groups such as morpholinyl group; cyclic lactam groups such as β-lactam, γ-lactam and δ-lactam;

Examples of the C _3-6 cycloalkyl group in the optionally substituted C _3-6 cycloalkyl group represented by R ¹ and R ¹⁴ include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group. and preferably a cyclopropyl group.
Substituents in the optionally substituted C _3-6 cycloalkyl group represented by R ¹ and R ¹⁴ include C _1-6 alkyl groups such as methyl group, ethyl group and propyl group; fluoromethyl group , difluoromethyl group, halogenated methyl group such as trifluoromethyl group; fluorine atom, halogen atom such as chlorine atom; hydroxy group; C _1-6 alkylamino group, di-C _1-6 alkylamino group, acylamino group and the like optionally substituted amino group; protected amino group; acyl group such as formyl group, acetyl group, cyclopropanecarbonyl group, benzoyl group; cyclic group such as azetidinyl group, pyrrolidinyl group, piperazinyl group, morpholinyl group amino group; cyclic lactam groups such as β-lactam, γ-lactam and δ-lactam;

The C _1-6 alkoxy group in the optionally substituted C _1-6 alkoxy group represented by R ² to R ¹¹ and R ¹⁴ includes methoxy, ethoxy, propoxy, isopropoxy, butoxy linear or branched alkoxy groups such as isobutoxy group, preferably methoxy group.
Examples of substituents in the optionally substituted C _1-6 alkoxy group include C _1-6 alkoxy groups such as methoxy group and ethoxy group; phenoxy group; and halogen atoms such as fluorine atom and chlorine atom. , preferably a fluorine atom, and examples thereof include a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a 2,2,2-trifluoroethoxy group and the like.

Examples of the C _6-10 aryl group in the optionally substituted C _6-10 aryl group represented by R ¹ and R ¹⁴ include a phenyl group and a naphthyl group.

The heteroaryl group in the optionally substituted heteroaryl group represented by R ¹ and R ¹⁴ includes, for example, furanyl group, thienyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl 5-membered ring heteroaryl groups such as groups, isothiazolyl groups, triazolyl groups, and tetrazolyl groups; 6-membered ring heteroaryl groups such as pyridyl groups, pyridazinyl groups, pyrazinyl groups, and pyrimidyl groups; , indolyl group, indazolyl group, benzimidazolyl group, benzofuranyl group, benzothienyl group, benzoxazolyl group, benzothiazolyl group, imidazopyridinyl group, pyrazolopyridinyl group, bicyclic heteroaryl group such as indazolyl group, etc. monocyclic or bicyclic heteroaryl groups containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms as ring-constituting atoms.
In addition, depending on the substituents on these heteroaryl groups, tautomers may exist. For example, when a hydroxy group is substituted on a pyridyl group, a 6-hydroxypyridin-2-yl group and its tautomer 6-oxo-1,6-dihydropyridin-2-yl group, 4-hydroxypyridin-2-yl group, and 4-oxo-1,4-dihydropyridin-2-yl group as its tautomer. be done.
Preferred examples of R ¹ include 6-membered heteroaryl groups such as pyridyl group, pyridazinyl group, pyrazinyl group and pyrimidyl group.
Preferable R ¹⁴ includes furanyl group, thienyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, thiazolyl group, triazole group, pyridyl group, pyridazinyl group, pyrazinyl group, pyrimidyl group, quinolyl group, isoquinolyl group, indolyl group and indazolyl group. , benzoxazolyl group, benzothiazolyl group, imidazopyridinyl group, pyrazolopyridinyl group, indazole group, more preferably furan-2-yl group, thiazol-2-yl group, thiazol-4- yl group, 1H-imidazol-4-yl group, 1H-pyrazol-3-yl group, 1H-pyrazol-1-yl group, 2H-1,2,3-triazol-2-yl group, pyridin-2-yl group, pyrimidin-2-yl group, pyrazin-2-yl group, 1H-indazol-3-yl group, imidazo[1,2-a]pyridin-2-yl group, pyrazolo[1,5-a]1H- Indazol-1-yl group, quinolin-2-yl group, isoquinolin-3-yl group, indolin-1-yl group, benzo[d]thiazol-2-yl group.

The optionally substituted C _6-10 aryl group and optionally substituted heteroaryl group represented by R ¹ and R ¹⁴ have 1 to 3 substituents on the ring. Such substituents include linear or branched C _1-6 alkyl groups such as methyl group, ethyl group, propyl group; fluoromethyl group, chloromethyl group, difluoromethyl group, dichloromethyl group, Linear or branched halogenated alkyl groups such as trifluoromethyl group; hydroxymethyl group; hydroxyalkyl groups such as hydroxyethyl group and 1-hydroxypropyl group; C _3-6 groups such as cyclopropyl group, cyclobutyl group and cyclopentyl group Cycloalkyl group; linear or branched C _1-6 alkoxy group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group; trifluoromethoxy group, 2,2,2-trifluoroethoxy group and the like Linear or branched halogenated C _1-6 alkoxy group; fluorine atom, halogen atom such as chlorine atom; hydroxy group; nitro group; cyano group; C _1-6 alkylamino group, di-C _1-6 alkylamino group , an amino group optionally having a substituent such as an acylamino group; a protected amino group; a formyl group, an acetyl group, a cyclopropylcarbonyl group, an acyl group such as a benzoyl group; an azetidinyl group, a pyrrolidinyl group, a piperazinyl group, cyclic amino groups such as morpholinyl group; cyclic lactam groups such as β-lactam, γ-lactam and δ-lactam;

The C _3-6 cycloalkylC _1-6 alkyl group in the optionally substituted C _3-6 cycloalkylC _1-6 alkyl group represented by R ¹ includes a cyclopropylmethyl group, cyclopropylethyl group, cyclopropylpropyl group, cyclobutylmethyl group, cyclobutylethyl group, cyclopentylmethyl group, cyclopentylethyl group, cyclopentylpropyl group, cyclohexylmethyl group, cyclohexylethyl group, cyclohexylpropyl group and the like, preferably cyclopropylmethyl cyclopropylethyl group, cyclobutylmethyl group, cyclobutylethyl group, cyclopentylmethyl group, cyclopentylethyl group, more preferably cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, most preferably cyclopropyl A methyl group is mentioned.
Examples of substituents in the optionally substituted C _3-6 cycloalkyl C _1-6 alkyl group include fluorine atoms, halogen atoms such as chlorine atoms, and hydroxy groups.

The aralkyl in the optionally substituted aralkyl group represented by R ¹ and the optionally substituted aralkyloxy group represented by R ¹¹ is an aryl moiety having C _6-10 carbon atoms. and the alkylene moiety having C _1-5 carbon atoms, such as a benzyl group, a phenylethyl group, a 1-naphthylmethyl group and the like, preferably a benzyl group.

The heteroaryl moiety in the optionally substituted heteroarylalkyl group represented by R ¹ contains 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms as ring-constituting atoms. heteroaryl, and alkyl moieties include C _1-6 alkyl groups such as methyl group, ethyl group, propyl group, for example, (pyridin-2-yl)methyl group, (pyridin-3-yl) methyl group, (pyridin-4-yl) methyl group, 2-(pyridin-2-yl) ethyl group, (furan-2-yl) methyl group, (furan-3-yl) methyl group, (imidazole-2- yl) methyl group, (imidazol-4-yl) methyl group, (imidazol-5-yl) methyl group, (thiazol-2-yl) methyl group, (thiazol-4-yl) methyl group, (thiazol-5- monocyclic heteroarylalkyl groups such as yl)methyl group, (thiophen-2-yl)methyl group or 2-(thiophen-2-yl)ethyl group, (quinolin-3-yl)methyl group, (indole-3- and bicyclic heteroarylalkyl groups such as yl)methyl groups.

Aryl in an optionally substituted aralkyloxy group represented by R ¹¹ , an optionally substituted aralkyl group represented by R ¹ and an optionally substituted heteroarylalkyl group may have a substituent on the aryl and heteroaryl in Paragraph [ ₀₀₂₀ ]. things are mentioned.

The C _2-6 alkenyl group in the optionally substituted C _2-6 alkenyl group represented by R ¹ and R ¹⁴ includes a C _2-6 linear or branched alkenyl group, allyl group, vinyl group, 1-propenyl group, 2-butenyl group, 3-butenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group , 5-hexenyl group and the like.

The C _2-6 alkynyl group in the optionally substituted C _2-6 alkynyl group represented by R ¹ and R ¹⁴ is a C _2-6 linear or branched alkynyl group. , for example, an ethynyl group, a propynyl group, a butynyl group, and the like.

Examples of groups that can be substituted for such alkenyl groups and alkynyl groups include C _1-6 alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group and propoxycarbonyl group, benzyl group, 2-phenylethyl group and 3-phenylpropyl group. , aralkyl groups such as 4-phenylbutyl group; C _1-6 alkoxy groups such as methoxy group, ethoxy group, propoxy group and butoxy group; aralkyloxy groups such as benzyloxy group and 2-phenylethyloxy group; C _1- an amino group which may be substituted with a linear or branched alkyl group of ₆ ; a halogen atom such as a fluorine atom and a chlorine atom; a carboxy group and a hydroxy group;

Examples of the optionally substituted acyl group represented by R ¹ include C _1-6 alkanoyl groups such as formyl group, acetyl group, propionyl group, butanoyl group, pentanoyl group and hexanoyl group; cyclopropanecarbonyl group; _C4-7 cycloalkanoyl groups such as cyclobutanecarbonyl group and cyclopentanecarbonyl group; aroyl groups such as benzoyl group and naphthoyl group; 5- to 6-membered heteroaroyl groups such as furoyl group, thiophenecarbonyl group, nicotinyl group and isonicotinoyl group etc.
Further, the substituents in the C _1-6 alkanoyl group include those described in paragraph [0015], and the substituents in the C _4-7 cycloalkanoyl group include those described in paragraph [0016]. Examples of substituents in are the same as the substituents described in paragraph [0020].

Substituents for the optionally substituted carbamoyl group represented by R ⁶ and substituents for the optionally substituted amino group represented by R ⁴ to R ⁶ and R ¹⁴ include a methyl group. C 1-6 alkyl groups optionally having substituents such as , ethyl group, propyl group, and isopropyl group, and substituents in the C _1-6 alkyl groups _optionally having such substituents Examples include those described in paragraph [0015], and may have one or two of these substituents.

Examples of protective groups for the amino-protecting group represented by R ¹ and the protected amino groups represented by R ⁴ to R ⁶ , R ¹¹ and R ¹⁴ include methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert- amyloxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, p-chlorobenzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, 3,5-dimethoxy carbamate protective groups such as benzyloxycarbonyl group, 3,4,5-trimethoxybenzyloxycarbonyl group, 2-(trimethylsilyl)ethoxycarbonyl group, 9-fluorenylmethyloxycarbonyl group; p-toluenesulfonyl group, 2 - sulfonamide protecting groups such as nitrobenzenesulfonyl group; imide protecting groups such as phthaloyl group; and _C7-19 aralkyl groups such as benzyl group, trityl group and naphthylmethyl group.

Halogen atoms represented by R ² to R ¹¹ and R ¹⁴ include fluorine atom, chlorine atom, bromine atom and iodine atom, preferably fluorine atom and chlorine atom, more preferably fluorine atom. .

Ester-forming groups in the carboxylic acid ester group represented by R6 include methyl group, ethyl group, propyl group, ² -propyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, and the like. Linear or branched C _1-6 alkyl group; C _2-6 alkenyl group such as vinyl group, allyl group, 1-propenyl group, butenyl group, pentenyl group, hexenyl group; aralkyl group such as benzyl group; aryl groups such as naphthyl group; C _1-6 alkanoyloxy C _1-4 lower alkyl groups such as acetoxymethyl group and pivaloyloxymethyl group;

The cyclic amino group in the optionally substituted cyclic amino group represented by R ¹⁴ includes an azetidinyl group, a pyrrolidinyl group, an azepanyl group, a piperidinyl group, a piperazinyl group, a morphonyl group, a thiomorpholinyl group and an oxaazabicyclooctyl group. , azasilinyl group, indolinyl group, isoindolyl group and the like, preferably 1-pyrrolidinyl group, 1-piperidinyl group, 2-oxa-5-azabicyclo[2.2.2]octan-5-yl group, 3- oxa-8-azabicyclo[3.2.1]octan-8-yl group, azasilynan-1-yl group, 1-indolinyl group, more preferably 1-pyrrolidinyl group, 1-piperidinyl group, azasilynan-1 -yl group and 1-indolinyl group.
Examples of substituents include C _1-6 alkyl groups optionally having a substituent such as a methyl group and an ethyl group; C 1-6 optionally having a substituent such as a methoxy group, an ethoxy group and a _propoxy group; _hexaalkoxy group; halogen atom such as fluorine atom and chlorine atom; hydroxy group and the like.
Substituents for the optionally substituted C _1-6 alkyl group include those described in paragraph [0015], and substituents for the optionally substituted C _1-6 alkoxy group Examples include the substituents described in paragraph [0017].

C _3-6 saturated hydrocarbon ring optionally having a substituent formed by combining R ² and R ³ , optionally having a substituent formed by combining R ⁷ and R ⁸ C _3-6 saturated hydrocarbon ring, optionally substituted C _3-6 saturated hydrocarbon ring formed by combining R ⁹ and R ¹⁰ , R ¹² and R ¹³ on the same carbon A C _{3-6 saturated hydrocarbon in a C 3-6 saturated} hydrocarbon ring optionally having a bond or a substituent formed by bonding a pair of adjacent R ^12s when n is 2 to 3 Examples of rings include cyclopropane ring, cyclobutane ring, cyclopentane ring, and cyclohexane ring.

When R ¹² and R ¹³ on the same carbon are bonded, or when n is 2 to 3, a pair of adjacent R ¹² are bonded or when n is 2 to 3, a pair of adjacent R ¹² are bonded The saturated heterocyclic ring which may have a substituent formed by binding includes a 3- to 6-membered saturated heterocyclic ring, such as aziridine, azetidine, pyrrolidine, piperidine, piperazine, morpholine, thio Cyclic amines such as morpholine, cyclic ethers such as epoxides, oxetanes, tetrahydrofuran, tetrahydropyran and dioxane, and cyclic thioethers such as thietane, thiolane and thiane.
Of these saturated heterocyclic rings, when they have a nitrogen atom as a ring-constituting atom, they further have a substituent such as a linear or branched C _1-6 alkyl group, an acyl group, or an amino protecting group on the nitrogen. may be These substituents are those described in paragraphs [0015], [0028] and [0030] respectively.

The optionally substituted nitrogen-containing saturated heterocyclic ring formed by combining R ¹⁴ and R ¹⁵ includes a 3- to 6-membered nitrogen-containing saturated heterocyclic ring, such as aziridine, azetidine, pyrrolidine. , piperidine, piperazine, morpholine and thiomorpholine.
These nitrogen-containing saturated heterocycles may further be condensed with a saturated hydrocarbon, saturated heterocycle, unsaturated hydrocarbon or unsaturated heterocycle, such as decahydroquinoline, decahydroisoquinoline, indoline, isoindoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, benzomorpholine, benzothiomorpholine and the like.
When these nitrogen-containing heterocycles have a nitrogen atom as a ring-constituting atom other than the nitrogen atom to which R ¹⁵ is bonded, further substituents such as linear or branched C _1-6 alkyl groups and acyl groups Alternatively, it may have an amino protecting group on the nitrogen atom. These substituents are those described in paragraphs [0015], [0028] and [0030] respectively.

Optionally substituted C _3-6 saturated hydrocarbon ring formed by combining R ¹² and R ¹³ on the same carbon, formed by combining R ¹² and R ¹³ on the same carbon optionally substituted saturated heterocyclic ring, optionally substituted C _3-6 saturated heterocyclic ring formed by bonding a pair of adjacent R ^12s when n is 2 to 3 The substituents in the hydrocarbon ring or the optionally substituted saturated heterocyclic ring and the optionally substituted nitrogen-containing saturated heterocyclic ring formed by combining R ¹⁴ and R ¹⁵ are those described in paragraph [ [0033] and the same substituents as those for the cyclic amino group described in [0033].

The optionally substituted cyclic ketals formed by combining R ² and R ³ , R ⁷ and R ⁸ , and R ⁹ and R ¹⁰ include dioxolane and dioxane. Such substituents include C _1-6 alkyl groups such as methyl, ethyl and propyl groups.

X represents a nitrogen atom or an N-oxide, preferably a nitrogen atom.

Y represents an optionally substituted methylene group, carbonyl group or thiocarbonyl group, preferably an optionally substituted methylene group or carbonyl group.
Examples of substituents on the optionally substituted methylene group include C _1-6 alkyl groups and hydroxy groups.

Z represents NR ¹⁵ , an oxygen atom, a bond, an ethenylene group or an ethynylene group, preferably NR ¹⁵ , an oxygen atom, a bond or an optionally substituted ethenylene group.
Substituents in the ethenylene group which may have a substituent include those described in paragraph [0027].

m represents an integer of 0 to 1, preferably 1; However, when n is 2, m is preferably 0.

n represents an integer of 0 to 3, preferably 1 or 2;

In preferred embodiments of the compound (I) used in the present invention, R ¹ is a C _1-6 alkyl group optionally having substituent(s), a C _3-6 cycloalkyl group optionally having substituent(s) a C _1-6 alkyl group, wherein R ² and R ³ are the same or different and are a hydrogen atom or an optionally substituted C _1-6 alkyl group, an optionally substituted C _{1- 6} alkoxy group, halogen atom and hydroxy group, and R ⁴ and R ⁵ are the same or different and are hydrogen atoms, optionally substituted C _1-6 alkyl groups, optionally substituted a C _1-6 alkoxy group, an optionally substituted amino group, a halogen atom or a hydroxy group, and R ⁶ is an optionally substituted C _1-6 alkoxy group or a hydroxy group; , R ⁷ and R ⁸ are the same or different and are hydrogen atoms, optionally substituted C _1-6 alkyl groups, optionally substituted C _1-6 alkoxy groups, halogen atoms or hydroxy group, and R ⁹ and R ¹⁰ are the same or different, hydrogen atom, optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, halogen an atom, a hydroxy group, R ¹¹ is a hydrogen atom or a hydroxy group, R ¹² and R ¹³ are the same or different hydrogen atoms or optionally substituted C _1-6 alkyl groups, and R ¹⁴ is a C _6-10 aryl group optionally having substituents, a heteroaryl group optionally having substituents or a cyclic amino group optionally having substituents, X is a nitrogen atom or N-oxide, Y is an optionally substituted methylene group or carbonyl group, Z is NR ¹⁵ , an oxygen atom, a bond, an optionally substituted ethenylene group or an ethynylene group and R ¹⁵ is a hydrogen atom or a C _1-6 alkyl group optionally having a substituent, m is an integer of 0 or 1, and n is an integer of 0 to 3.

In a more preferred embodiment of compound (I) used in the present invention, R ¹ is a C _1-6 alkyl group optionally having substituent(s) or a C _3-6 cycloalkyl group optionally having substituent(s) a C _1-6 alkyl group, R ² and R ³ being the same or different and being a hydrogen atom or optionally substituted C _1-6 alkyl group, R ⁴ and R ⁵ being the same or different a hydrogen atom or an optionally substituted C _1-6 alkyl group, R ⁶ is an optionally substituted C _1-6 alkoxy group or a hydroxy group, R ⁷ and R ⁸ are the same or different and are a hydrogen atom, an optionally substituted C _1-6 alkyl group or an optionally substituted C _1-6 alkoxy group, and R ⁹ and R ¹⁰ are the same or a C _1-6 alkyl group which may have different hydrogen atoms or substituents, R ¹¹ is a hydrogen atom or a hydroxy group, R ¹² and R ¹³ are the same or different and each have a hydrogen atom or a substituent; is a C _1-6 alkyl group optionally having substituents, and R ¹⁴ is a C _6-10 aryl group optionally having substituents, a heteroaryl group optionally having substituents or a substituent a cyclic amino group which may be substituted, X is a nitrogen atom or N-oxide, Y is a methylene group or a carbonyl group which may have a substituent, Z is NR ¹⁵ , an oxygen atom, a bond or an optionally substituted ethenylene group, R ¹⁵ is a hydrogen atom, an optionally substituted C _1-6 alkyl group, m is an integer of 0 or 1, n is an integer of 0-3.

Furthermore, as a preferred embodiment of the compound (I) used in the present invention, R ¹ is a C _1-6 alkyl group optionally having substituent(s), a C _3-6 cycloalkyl group optionally having substituent(s) a C _1-6 alkyl group, R ² and R ³ being the same or different and being hydrogen atoms or optionally substituted C _1-6 alkyl groups, R ⁴ and R ⁵ being hydrogen atoms , R ⁶ is a hydroxy group, R ⁷ and R ⁸ are the same or different hydrogen atoms or optionally substituted C _1-6 alkyl groups, R ⁹ and R ¹⁰ are the same or different a hydrogen atom or an optionally substituted C _1-6 alkyl group, R ¹¹ is a hydrogen atom or a hydroxy group, R ¹² and R ¹³ are the same or different and have a hydrogen atom or a substituent is a C _1-6 alkyl group which may be substituted, ^R is a heteroaryl group which may be substituted, X is a nitrogen atom, and Y is a methylene group which may be substituted or a carbonyl group, Z is a bond, m is 0, and n is 1-2.

In the epoxyazepane derivative represented by the above general formula (I) and a pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt is preferably an acid addition salt, and the acid addition salt is For example, (a) salts with mineral acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and (b) salts with organic carboxylic acids such as formic acid, acetic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid, maleic acid, and tartaric acid. and (c) salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.

The epoxyazepane derivatives represented by the general formula (I) and pharmaceutically acceptable salts thereof include tautomers and stereoisomers such as cis, trans isomers, racemates and optically active isomers. be

The epoxyazepane derivative represented by the general formula (I) and its pharmaceutically acceptable salt can also exist as a hydrate or solvate. Accordingly, the compounds of the present invention include all crystalline forms and hydrates or solvates thereof.

Next, a method for producing the epoxyazepane derivative represented by the general formula (I) and a pharmaceutically acceptable salt thereof will be described below.

(i) In the above general formula (I), a production method in which X is a nitrogen atom, either A or B is NH, and the other is a methylene group or a carbonyl group

(Method A) Using compound (a) as a starting material, invention compounds (d) to (g) can be obtained by the methods described below.

（式中、Ｌはメタンスルホニル基、ｐ－トルエンスルホニル基、トリフルオロメタンスルホニル基又は２－ニトロベンゼンスルホニル基等を示し、Ｒ^１～Ｒ^１１は前記と同じものを示す。）
（第一工程）
原料（ａ）を、ベンゼン、トルエン、キシレン等の芳香族炭化水素類；ジエチルエーテル、テトラヒドロフラン、ジオキサン、モノグライム、ジグライム等のエーテル類；メタノール、エタノール等のアルコール類；ジクロロメタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類；ペンタン、ヘキサン、ヘプタン、リグロイン等の脂肪族炭化水素類；水、酢酸等の溶媒；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非プロトン性極性溶媒中又はこれらの混合溶媒中、カリウムビス（トリメチルシリル）アミド（ＫＨＭＤＳ）、リチウムジイソプロピルアミド（ＬＤＡ）、水素化リチウム、水素化ナトリウム、水素化カリウム、ナトリウムメトキシド、ナトリウムエトキシド、ナトリウムｔｅｒｔ－ブトキシド、カリウムｔｅｒｔ－ブトキシド、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウム、酢酸ナトリウム等の無機塩基；トリメチルアミン、トリエチルアミン、トリブチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジメチルアミノピリジン、Ｎ－メチルピペリジン、Ｎ－メチルモルホリン、ジエチルアミン、シクロヘキシルアミン、プロカイン等の有機塩基等の存在下又は非存在下、ヒドロキシルアミン塩酸塩又はヒドロキシルアミン硫酸塩等と、室温～加熱還流下で１～２４時間反応させることで化合物（ｂ）を合成することができる。
（第二工程）
化合物（ｂ）を、ベンゼン、トルエン、キシレン等の芳香族炭化水素類；ジエチルエーテル、テトラヒドロフラン、ジオキサン、モノグライム、ジグライム等のエーテル類；ジクロロメタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類；ペンタン、ヘキサン、ヘプタン、リグロイン等の脂肪族炭化水素類；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非プロトン性極性溶媒中、カリウムビス（トリメチルシリル）アミド（ＫＨＭＤＳ）、リチウムジイソプロピルアミド（ＬＤＡ）、水素化リチウム、水素化ナトリウム、水素化カリウム、ナトリウムメトキシド、ナトリウムエトキシド、ナトリウムｔｅｒｔ－ブトキシド、カリウムｔｅｒｔ－ブトキシド、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウム、酢酸ナトリウム等の無機塩基；トリメチルアミン、トリエチルアミン、トリブチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジメチルアミノピリジン、Ｎ－メチルピペリジン、Ｎ－メチルモルホリン、ジエチルアミン、シクロヘキシルアミン、プロカイン等の有機塩基等の存在下、上記Ｌ－Ｃｌ又はＬ_２Ｏで表される試薬と、－７８℃～加熱還流下で１～２４時間反応させることで化合物（ｃ）を合成することができる。
（第三工程）
化合物（ｃ）を、ベンゼン、トルエン、キシレン等の芳香族炭化水素類；ジエチルエーテル、テトラヒドロフラン、ジオキサン、モノグライム、ジグライム等のエーテル類；メタノール、エタノール等のアルコール類；ジクロロメタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類；ペンタン、ヘキサン、ヘプタン、リグロイン等の脂肪族炭化水素類；水、酢酸等の溶媒；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非プロトン性極性溶媒中又はこれらの混合溶媒中又は無溶媒中、塩酸、硫酸、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ブレンステッド酸；三フッ化ホウ素－ジエチルエーテル錯体、塩化アルミニウム、塩化鉄（ＩＩＩ）、塩化亜鉛、塩化チタン（ＩＶ）等のルイス酸と、室温～加熱還流下で１～７２時間反応させることで発明化合物（ｄ）及び（e）をそれぞれ合成することができる。
（第四工程）
発明化合物（ｄ）及び（e）それぞれに対し、ジエチルエーテル、テトラヒドロフラン、ジオキサン、モノグライム、ジグライム等のエーテル類中、水素化アルミニウムリチウム、ボラン－テトラヒドロフラン錯体、ボラン－ジメチルスルフィド錯体等の還元剤を、０℃～加熱還流下で１～２４時間反応させることにより、発明化合物（ｆ）及び（ｇ）をそれぞれ合成することができる。

(In the formula, L represents a methanesulfonyl group, p-toluenesulfonyl group, trifluoromethanesulfonyl group, 2-nitrobenzenesulfonyl group or the like, and R ¹ to R ¹¹ are the same as above.)
(First step)
Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; alcohols such as methanol and ethanol; Halogenated hydrocarbons; Pentane, hexane, heptane, aliphatic hydrocarbons such as ligroin; Solvents such as water and acetic acid; potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), lithium hydride, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert- Inorganic bases such as butoxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate; trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N , N-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, in the presence or absence of an organic base such as procaine, with hydroxylamine hydrochloride or hydroxylamine sulfate, etc., at room temperature to The compound (b) can be synthesized by reacting for 1 to 24 hours while heating under reflux.
(Second step)
Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; , hexane, heptane, ligroin and other aliphatic hydrocarbons; acetonitrile, N,N-dimethylformamide, in aprotic polar solvents such as dimethylsulfoxide, potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA) , lithium hydride, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate inorganic bases such as trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N,N-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine , and the reagent represented by L—Cl or L ₂ O in the presence of an organic base such as procaine and the like at −78° C. to under reflux with heating for 1 to 24 hours to synthesize compound (c). can be done.
(Third step)
Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; alcohols such as methanol and ethanol; dichloromethane, chloroform, carbon tetrachloride and the like. Halogenated hydrocarbons; Pentane, hexane, heptane, aliphatic hydrocarbons such as ligroin; Solvents such as water and acetic acid; Bronsted acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid in a mixed solvent or in the absence of a solvent; boron trifluoride-diethyl ether complex, aluminum chloride, iron chloride (III ), zinc chloride, titanium (IV) chloride, and other Lewis acids at room temperature to heating under reflux for 1 to 72 hours to synthesize invention compounds (d) and (e), respectively.
(Fourth step)
For each of the invention compounds (d) and (e), a reducing agent such as lithium aluminum hydride, borane-tetrahydrofuran complex, borane-dimethylsulfide complex, etc. Inventive compounds (f) and (g) can be synthesized by reacting at 0° C. to under reflux with heating for 1 to 24 hours.

(Method B) Compounds (d) and (e) can also be synthesized from compound (b) in one step.

（式中、Ｒ^１～Ｒ^１１は前記と同じものを示す。）
化合物（ｂ）を、ベンゼン、トルエン、キシレン等の芳香族炭化水素類；ジエチルエーテル、テトラヒドロフラン、ジオキサン、モノグライム、ジグライム等のエーテル類；メタノール、エタノール等のアルコール類；ジクロロメタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類；ペンタン、ヘキサン、ヘプタン、リグロイン等の脂肪族炭化水素類；水、酢酸等の溶媒；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非プロトン性極性溶媒中又はこれらの混合溶媒中又は無溶媒中、塩酸、硫酸、酢酸、トリフルオロ酢酸等のブレンステッド酸；三フッ化ホウ素－ジエチルエーテル錯体、塩化アルミニウム、塩化鉄、塩化亜鉛等のルイス酸等の酸の存在下もしくは非存在下、室温～加熱還流下で１～７２時間反応させることで発明化合物（ｄ）及び（e）をそれぞれ合成することができる。

(In the formula, R ¹ to R ¹¹ are the same as above.)
Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; alcohols such as methanol and ethanol; dichloromethane, chloroform, carbon tetrachloride and the like. Halogenated hydrocarbons; pentane, hexane, heptane, aliphatic hydrocarbons such as ligroin; solvents such as water and acetic acid; in a mixed solvent or in the absence of a solvent, the presence of acids such as Bronsted acids such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid; boron trifluoride-diethyl ether complex, Lewis acids such as aluminum chloride, iron chloride, zinc chloride, etc. Compounds (d) and (e) of the present invention can be synthesized by reacting for 1 to 72 hours at room temperature to under reflux with heating or in the absence of the above.

(Method C) Invention compounds (d) and (e) described in Method A can be synthesized in one step from compound (a) by using sodium azide or trimethylsilyl azide, as described below. can.

（式中、Ｒ^１～Ｒ^１１は前記と同じものを示す。）
原料（ａ）を、ベンゼン、トルエン、キシレン等の芳香族炭化水素類；ジエチルエーテル、テトラヒドロフラン、ジオキサン、モノグライム、ジグライム等のエーテル類；メタノール、エタノール等のアルコール類；ジクロロメタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類；ペンタン、ヘキサン、ヘプタン、リグロイン等の脂肪族炭化水素類；水等の溶媒；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非プロトン性極性溶媒中又はこれらの混合溶媒中又は無溶媒中、塩酸、硫酸、酢酸、トリフルオロ酢酸、トリクロロ酢酸、ポリリン酸、Ｅａｔｏｎ試薬、メタンスルホン酸、ｐ－トルエンスルホン酸等のブレンステッド酸；三フッ化ホウ素－ジエチルエーテル錯体、塩化アルミニウム、塩化鉄、塩化亜鉛、塩化チタン（ＩＶ）等のルイス酸の存在下又は非存在下、アジ化ナトリウム（ＮａＮ_３）又はトリメチルシリルアジド（ＴＭＳＮ_３）と、０℃～加熱還流下で１～２４時間反応させることで発明化合物（ｄ）及び（ｅ）をそれぞれ合成することができる。

(In the formula, R ¹ to R ¹¹ are the same as above.)
Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; alcohols such as methanol and ethanol; Halogenated hydrocarbons; Pentane, hexane, heptane, aliphatic hydrocarbons such as ligroin; Solvents such as water; Bronsted acids such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, polyphosphoric acid, Eaton's reagent, methanesulfonic acid, p-toluenesulfonic acid, in a solvent or in the absence of solvent; boron trifluoride-diethyl ether complex, sodium azide (NaN ₃ ) or trimethylsilyl azide (TMSN ₃ ) in the presence or absence of a Lewis acid such as aluminum chloride, iron chloride, zinc chloride, titanium (IV) chloride, etc., at 0° C. to 1 under reflux with heating. Invention compounds (d) and (e) can be synthesized by reacting for up to 24 hours.

(ii) In the above general formula (I), X is a nitrogen atom, and either A or B is NR ¹⁶ (R ¹⁶ is a C _1-10 alkyl group optionally having a substituent, a substituent A production method in which an aralkyl group which may have an optionally substituted heteroarylalkyl group or a heteroarylalkyl group which may have a substituent and the other represents a carbonyl group

(Method D) Invention compounds (d-1) and (e-1) can be synthesized using compound (a) as a starting material.

（式中、Ｒ^１６は置換基を有しても良いＣ_１－１０アルキル基、置換基を有しても良いアラルキル基又は置換基を有しても良いヘテロアリールアルキル基を示し、Ｒ^１～Ｒ^１１は前記と同じものを示す。）
原料（ａ）を、ベンゼン、トルエン、キシレン等の芳香族炭化水素類；ジエチルエーテル、テトラヒドロフラン、ジオキサン、モノグライム、ジグライム等のエーテル類；メタノール、エタノール等のアルコール類；ジクロロメタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類；ペンタン、ヘキサン、ヘプタン、リグロイン等の脂肪族炭化水素類；水等の溶媒；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非プロトン性極性溶媒中又はこれらの混合溶媒中又は無溶媒中、塩酸、硫酸、酢酸、トリフルオロ酢酸、トリクロロ酢酸、ポリリン酸、Ｅａｔｏｎ試薬、メタンスルホン酸、ｐ－トルエンスルホン酸等のブレンステッド酸；三フッ化ホウ素－ジエチルエーテル錯体、塩化アルミニウム、塩化鉄、塩化亜鉛、塩化チタン（ＩＶ）等のルイス酸の存在下又は非存在下、Ｒ^１６－Ｎ_３で表されるアジ化物と、０℃～加熱還流下で１～２４時間反応させることで発明化合物（ｄ－１）及び（ｅ－１）をそれぞれ合成することができる。

(wherein R ¹⁶ represents an optionally substituted C _1-10 alkyl group, an optionally substituted aralkyl group or an optionally substituted heteroarylalkyl group, and R ¹ ~R ¹¹ are the same as above.)
Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; alcohols such as methanol and ethanol; Halogenated hydrocarbons; Pentane, hexane, heptane, aliphatic hydrocarbons such as ligroin; Solvents such as water; Bronsted acids such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, polyphosphoric acid, Eaton's reagent, methanesulfonic acid, p-toluenesulfonic acid, in a solvent or in the absence of solvent; boron trifluoride-diethyl ether complex, with an azide represented by R ¹⁶ —N ₃ in the presence or absence of a Lewis acid such as aluminum chloride, iron chloride, zinc chloride, titanium (IV) chloride, etc., at 0° C. to 1 to 24 hours while heating to reflux. Invention compounds (d-1) and (e-1) can be synthesized by reacting them.

(iii) In the above general formula (I), when X is a nitrogen atom, either A or B is a carbonyl group, and the other is general formula (II) (where m is 0 and Z is a bond) manufacturing method

(Method E) Invention compound (h) can be synthesized by subjecting invention compound (d) or (e) obtained in (i) above (both collectively represented as (de)) to an alkylation reaction. can.

（式中、Ｌ´はメタンスルホニルオキシ基、ｐ－トルエンスルホニルオキシ基、ハロゲン等の脱離基を示し、Ｒ^１～Ｒ^１４、ｎは前記と同じものを示す。）
上記（ｉ）で得られた化合物（ｄ）又は（ｅ）（両者を合わせて（ｄ－ｅ）と表す）に、ベンゼン、トルエン、キシレン等の芳香族炭化水素類；ジエチルエーテル、テトラヒドロフラン、ジオキサン、モノグライム、ジグライム等のエーテル類；メタノール、エタノール等のアルコール類；ジクロロメタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類；ペンタン、ヘキサン、ヘプタン、リグロイン等の脂肪族炭化水素類；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非プロトン性極性溶媒中、カリウムビス（トリメチルシリル）アミド（ＫＨＭＤＳ）、リチウムジイソプロピルアミド（ＬＤＡ）、水素化リチウム、水素化ナトリウム、水素化カリウム、ナトリウムメトキシド、ナトリウムエトキシド、ナトリウムｔｅｒｔ－ブトキシド、カリウムｔｅｒｔ－ブトキシド、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウム、酢酸ナトリウム等の無機塩基；トリメチルアミン、トリエチルアミン、トリブチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジメチルアミノピリジン、Ｎ－メチルピペリジン、Ｎ－メチルモルホリン、ジエチルアミン、シクロヘキシルアミン、プロカイン等の有機塩基等の存在下、ヨウ化カリウム又はヨウ化ナトリウム存在下又は非存在下、（ｒ－１）で表されるアルキル化剤と、室温～加熱還流下で１～２４時間反応させることで発明化合物（ｈ）を合成することができる。

(In the formula, L' represents a leaving group such as methanesulfonyloxy group, p-toluenesulfonyloxy group, halogen, etc., and R ¹ to R ¹⁴ and n are the same as above.)
Aromatic hydrocarbons such as benzene, toluene, and xylene; , monoglyme, ethers such as diglyme; alcohols such as methanol and ethanol; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; aliphatic hydrocarbons such as pentane, hexane, heptane and ligroin; Potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), lithium hydride, sodium hydride, potassium hydride, sodium methoxide, in an aprotic polar solvent such as , N-dimethylformamide, dimethylsulfoxide, Inorganic bases such as sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate; trimethylamine, triethylamine, tributylamine, N,N-diisopropyl In the presence of an organic base such as ethylamine, pyridine, N,N-dimethylaniline, N,N-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, potassium iodide or iodide In the presence or absence of sodium, the compound (h) of the present invention can be synthesized by reacting it with an alkylating agent represented by (r-1) at room temperature to under reflux with heating for 1 to 24 hours.

(iv) In the above general formula (I), X is a nitrogen atom, either A or B is a methylene group, and the other is a general formula (II) (Y is a carbonyl group or a thiocarbonyl group, Z is a bond or a substituent Ethenylene group or ethynylene group, m represents 1)

(Method F) Reaction of invention compound (f) or (g) obtained in (i) above (both collectively represented as (fg)) with (r-2) or (r-3) (Second (step 1), compound (i) of the present invention, and (second step) (j) can be obtained by reaction with a sulfurizing agent.

（式中、Ａｈ又はＢｈのいずれかはＮＨ、他方はメチレン基、ｈａｌはハロゲン原子、Ｚは結合手及び置換基を有しても良いエテニレン基又はエチニレン基を示し、ｎ、Ｒ^１～Ｒ^１４は前記と同じものを示す。）
（第一工程）
上記（ｉ）で得られた発明化合物（ｆ）又は（ｇ）（両者を合わせて（ｆ－ｇ）と表す）にベンゼン、トルエン、キシレン等の芳香族炭化水素類；ジエチルエーテル、テトラヒドロフラン、ジオキサン、モノグライム、ジグライム等のエーテル類；ジクロロメタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類；メタノール、エタノール等のアルコール類；ペンタン、ヘキサン、ヘプタン、リグロイン等の脂肪族炭化水素類；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非プロトン性極性溶媒中、Ｎ，Ｎ－ジメチルアミノピリジン，トリメチルアミン、トリエチルアミン、トリブチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、Ｎ，Ｎ－ジメチルアニリン、Ｎ－メチルピペリジン、Ｎ－メチルモルホリン、ジエチルアミン、シクロヘキシルアミン、プロカイン等の有機塩基；炭酸カリウム、炭酸リチウム等の無機塩基の存在下、（ｒ－３）で表される酸ハロゲン化物と０℃～加熱還流下で１～１２時間反応させるか、又は（ｒ－２）で表されるカルボン酸を、前記溶媒中、Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムヘキサフルオロホスファート（ＨＡＴＵ）、Ｏ－（ベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムヘキサフルオロホスファート（ＨＢＴＵ）、Ｎ，Ｎ’－ジシクロへ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（ＷＳＣ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルフォリニウムクロライドｎ水和物（ＤＭＴ－ＭＭ）等の縮合剤存在下又は非存在下、０℃～加熱還流下で１～１２時間反応させることにより、発明化合物（ｉ）を合成することができる。
（第二工程）
発明化合物（ｉ）はベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、モノグライム、ジグライム等のエーテル類；ジクロロメタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類；ペンタン、ヘキサン、ヘプタン、リグロイン等の脂肪族炭化水素類中、五硫化二リン、ローソン試薬、デービー試薬、ジャパニーズ試薬及びベレオー試薬等の市販の硫化剤を用い、０℃～加熱還流下で１～１２時間反応させることにより、発明化合物（ｊ）に変換することができる。

(Wherein, either Ah or Bh is NH, the other is a methylene group, hal is a halogen atom, Z is an ethenylene group or an ethynylene group which may have a bond and a substituent, n, R ¹ to R ¹⁴ indicates the same as above.)
(First step)
Aromatic hydrocarbons such as benzene, toluene, xylene, etc.; , monoglyme, ethers such as diglyme; dichloromethane, chloroform, carbon tetrachloride and other halogenated hydrocarbons; methanol, ethanol and other alcohols; pentane, hexane, heptane, ligroin and other aliphatic hydrocarbons; , N-dimethylformamide, in an aprotic polar solvent such as dimethylsulfoxide, N,N-dimethylaminopyridine, trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N- Organic bases such as methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, and procaine; and an acid halide represented by (r-3) in the presence of an inorganic base such as potassium carbonate and lithium carbonate from 0°C to reflux with heating. for 1 to 12 hours at room temperature, or the carboxylic acid represented by (r-2) is treated with O-(7-azabenzotriazol-1-yl)-N,N,N',N '-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), N,N '-Dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl )-4-Methylmorpholinium chloride n-hydrate (DMT-MM) or the like in the presence or absence of a condensing agent at 0° C. or under reflux with heating for 1 to 12 hours to give the invention compound (i). can be synthesized.
(Second step)
Invention compound (i) includes aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; , in aliphatic hydrocarbons such as hexane, heptane, and ligroin, using a commercially available sulfurizing agent such as diphosphorus pentasulfide, Lawesson's reagent, Davy's reagent, Japanese reagent, and Belleo's reagent, from 0 ° C. to 1 to 12 under reflux. It can be converted to the invention compound (j) by reacting for time.

(v) Production when X is a nitrogen atom, either A or B is a methylene group, and the other is general formula (II) (m is 0, Z is a bond) in the above general formula (I) Method

(Method G) A reductive amination reaction of the invention compound (f) or (g) obtained in (i) above (both collectively represented as (fg)) and the aldehyde (r-4) yields Invention compound (k) can be obtained.

（式中、式中Ｒ^１～Ｒ^１４、Ａｈ、Ｂｈ及びｎは前記と同じものを示す。）
上記（ｉ）で得られた発明化合物（ｆ）又は（ｇ）（両者を合わせて（ｆ－ｇ）と表す）に、ベンゼン、トルエン、キシレン等の芳香族炭化水素類；ジエチルエーテル、テトラヒドロフラン、ジオキサン、モノグライム、ジグライム等のエーテル類；ジクロロメタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類；メタノール、エタノール等のアルコール類；ペンタン、ヘキサン、ヘプタン、リグロイン等の脂肪族炭化水素類；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非プロトン性極性溶媒；酢酸等の溶媒中又はこれらの混合溶媒中、水素化ホウ素ナトリウム、シアノ水素化ホウ素ナトリウム、水素化トリアセトキシホウ素ナトリウム、水素化トリ(ｓｅｃ－ブチル)ホウ素リチウム、水素化トリ(ｓｅｃ－ブチル)ホウ素カリウム等のヒドリド還元剤の存在下、（ｒ－４）で表されるアルデヒドを０℃～加熱還流下で１～１２時間反応させることにより、発明化合物（ｋ）を合成することができる。

(Wherein, R ¹ to R ¹⁴ , Ah, Bh and n are the same as defined above.)
Aromatic hydrocarbons such as benzene, toluene and xylene; diethyl ether, tetrahydrofuran, ethers such as dioxane, monoglyme and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane and ligroin; aprotic polar solvents such as N,N-dimethylformamide and dimethylsulfoxide; sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, triacetoxyborohydride, In the presence of a hydride reducing agent such as lithium (sec-butyl)borohydride or potassium tri(sec-butyl)borohydride, the aldehyde represented by (r-4) is reacted at 0°C to reflux with heating for 1 to 12 hours. The invention compound (k) can be synthesized by

(Method H) by S _n 2 reaction of the invention compound (f) or (g) obtained in (i) above (both together represented as (fg)) with an alkylating agent (r-1) , the invention compound (k) can be obtained.

（式中Ｒ^１～Ｒ^１４、Ｌ′、Ａｈ、Ｂｈ及びｎは前記と同じものを示す。）
上記（ｉ）で得られた発明化合物（ｆ）又は（ｇ）（両者を合わせて（ｆ－ｇ）と表す）に、ベンゼン、トルエン、キシレン等の芳香族炭化水素類；ジエチルエーテル、テトラヒドロフラン、ジオキサン、モノグライム、ジグライム等のエーテル類；メタノール、エタノール等のアルコール類；ジクロロメタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類；ペンタン、ヘキサン、ヘプタン、リグロイン等の脂肪族炭化水素類；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非プロトン性極性溶媒中、カリウムビス（トリメチルシリル）アミド（ＫＨＭＤＳ）、リチウムジイソプロピルアミド（ＬＤＡ）、水素化リチウム、水素化ナトリウム、水素化カリウム、ナトリウムメトキシド、ナトリウムエトキシド、ナトリウムｔｅｒｔ－ブトキシド、カリウムｔｅｒｔ－ブトキシド、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウム、酢酸ナトリウム等の無機塩基；トリメチルアミン、トリエチルアミン、トリブチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジメチルアミノピリジン、Ｎ－メチルピペリジン、Ｎ－メチルモルホリン、ジエチルアミン、シクロヘキシルアミン、プロカイン等の有機塩基等の無機塩基の存在下、ヨウ化カリウム又はヨウ化ナトリウム存在下又は非存在下、（ｒ－１）で表されるアルキル化剤と、室温～加熱還流下で１～２４時間反応させることで発明化合物（ｋ）を合成することができる。

(In the formula, R ¹ to R ¹⁴ , L', Ah, Bh and n are the same as above.)
Aromatic hydrocarbons such as benzene, toluene and xylene; diethyl ether, tetrahydrofuran, ethers such as dioxane, monoglyme and diglyme; alcohols such as methanol and ethanol; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; aliphatic hydrocarbons such as pentane, hexane, heptane and ligroin; Potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), lithium hydride, sodium hydride, potassium hydride, sodium methoxide in aprotic polar solvents such as N,N-dimethylformamide and dimethylsulfoxide. , sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, inorganic bases such as sodium acetate; trimethylamine, triethylamine, tributylamine, N, N- In the presence of an inorganic base such as diisopropylethylamine, pyridine, N,N-dimethylaniline, N,N-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, an organic base such as procaine, iodination The invention compound (k) can be synthesized by reacting an alkylating agent represented by (r-1) in the presence or absence of potassium or sodium iodide at room temperature to heating under reflux for 1 to 24 hours. can.

(Method I) Invention compound (k) can be obtained by reducing the amide moiety of invention compound (i) obtained in (iv) above.

（式中、Ｒ^１～Ｒ^１４、ｎは前記と同じものを示す。）
上記（ｉｖ）で得られた発明化合物（ｉ）に対し、ジエチルエーテル、テトラヒドロフラン、ジオキサン、モノグライム、ジグライム等のエーテル類中、水素化アルミニウムリチウム、ボラン－テトラヒドロフラン錯体、ボラン－ジメチルスルフィド錯体等の還元剤を、０℃～加熱還流下で１～２４時間反応させることにより、発明化合物（ｋ）を合成することができる。

(In the formula, R ¹ to R ¹⁴ and n are the same as above.)
Reduction of lithium aluminum hydride, borane-tetrahydrofuran complex, borane-dimethylsulfide complex, etc. in ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc. to the invention compound (i) obtained in the above (iv) The compound (k) of the present invention can be synthesized by reacting the agents at 0° C. to under reflux with heating for 1 to 24 hours.

(Method J) A ⁵ or B ⁵ obtained in (ii) above is NR ¹⁶ (R ¹⁶ is a C _1-10 alkyl group which may have a substituent, which may have a substituent represents an aralkyl group or a heteroaryl group which may have a substituent), and the other represents an invention compound (d-1) or (e-1) (both together (d ¹ -e ¹ ))) can also be used to synthesize invention compounds (f ¹ -g ¹ ).

（式中、Ｒ^１～Ｒ^１１及びＲ^１６は前記と同じものを示す。）

(In the formula, R ¹ to R ¹¹ and R ¹⁶ are the same as above.)

For the invention compound (d-1) or (e-1) obtained in (ii) above (both together represented as (d ¹ -e ¹ )), the same procedure as in the fourth step of (A method) The invention compound (f ¹ -g ¹ ) can be synthesized by performing the reaction.

(vi) In general formula (I) above, X is a nitrogen atom, either A or B is a methylene group, and the other is general formula (II) (Y is a carbonyl group, Z is NR ¹⁵ or an oxygen atom, m is 1 Shown) manufacturing method when showing

(Method K) Using the invention compound (f) or (g) obtained in (i) above (both collectively represented as (fg)), the invention compound (n) was obtained by the method described below. Obtainable.

（式中、Ａｈ又はＢｈのいずれかはＮＨ、他方はメチレン基、ＺはＮＲ^１５又は酸素原子を示し、Ｒ^１～Ｒ^１５、Ｌ′及びｎは前記と同じものを示し、Ｌ^－はそのカウンターアニオンを示す。）
（第一工程）
上記（ｉ）で得られた発明化合物（ｆ）又は（ｇ）（両者を合わせて（ｆ－ｇ）と表す）に、ベンゼン、トルエン、キシレン等の芳香族炭化水素類；ジエチルエーテル、テトラヒドロフラン、ジオキサン、モノグライム、ジグライム等のエーテル類；ジクロロメタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類；メタノール、エタノール等のアルコール類；ペンタン、ヘキサン、ヘプタン、リグロイン等の脂肪族炭化水素類；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非プロトン性極性溶媒中、Ｎ，Ｎ－ジメチルアミノピリジン，トリメチルアミン、トリエチルアミン、トリブチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、Ｎ，Ｎ－ジメチルアニリン、Ｎ－メチルピペリジン、Ｎ－メチルモルホリン、ジエチルアミン、シクロヘキシルアミン、プロカイン等の有機塩基；炭酸カリウム、炭酸リチウム等の無機塩基の存在下、カルボジイミダゾールを０℃～加熱還流下で１～１２時間反応させることにより、発明化合物（ｌ）を合成することができる。
（第二工程）
発明化合物（ｌ）に、ベンゼン、トルエン、キシレン等の芳香族炭化水素類；ジエチルエーテル、テトラヒドロフラン、ジオキサン、モノグライム、ジグライム等のエーテル類；ジクロロメタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類；メタノール、エタノール等のアルコール類；ペンタン、ヘキサン、ヘプタン、リグロイン等の脂肪族炭化水素類；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非プロトン性極性溶媒中、Ｎ，Ｎ－ジメチルアミノピリジン，トリメチルアミン、トリエチルアミン、トリブチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、Ｎ，Ｎ－ジメチルアニリン、Ｎ－メチルピペリジン、Ｎ－メチルモルホリン、ジエチルアミン、シクロヘキシルアミン、プロカイン等の有機塩基；炭酸カリウム、炭酸リチウム等の無機塩基の存在下又は非存在下、ヨウ化メチル、硫酸ジメチル、トリフルオロメタンスルホニルメタン、ｍｅｅｒｗｅｉｎ試薬等のメチル化剤を、０℃～加熱還流下で１２～４８時間反応させることにより、発明化合物（ｍ）を合成することができる。
（第三工程）
発明化合物（ｍ）にベンゼン、トルエン、キシレン等の芳香族炭化水素類；ジエチルエーテル、テトラヒドロフラン、ジオキサン、モノグライム、ジグライム等のエーテル類；ジクロロメタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類；ペンタン、ヘキサン、ヘプタン、リグロイン等の脂肪族炭化水素類；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非プロトン性極性溶媒中、Ｎ，Ｎ－ジメチルアミノピリジン、トリメチルアミン、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、トリブチルアミン、ピリジン、Ｎ，Ｎ－ジメチルアニリン、Ｎ－メチルピペリジン、Ｎ－メチルモルホリン、ジエチルアミン、シクロヘキシルアミン、プロカイン等の有機塩基；炭酸カリウム、炭酸リチウム等の無機塩基の存在下、（ｒ－５）で表されるアミン又は（ｒ－６）で表されるアルコールを、０℃～加熱還流下で１～１２時間反応させることにより、発明化合物（ｎ）を合成することができる。

(Wherein, either Ah or Bh is NH, the other is a methylene group, Z is NR ¹⁵ or an oxygen atom, R ¹ to R ¹⁵ , L' and n are the same as above, and L ^- indicates a counter anion.)
(First step)
Aromatic hydrocarbons such as benzene, toluene and xylene; diethyl ether, tetrahydrofuran, ethers such as dioxane, monoglyme and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane and ligroin; N,N-dimethylaminopyridine, trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N -Organic bases such as methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine and procaine; In the presence of inorganic bases such as potassium carbonate and lithium carbonate, carbodiimidazole is reacted at 0°C to under reflux with heating for 1 to 12 hours. Thus, invention compound (l) can be synthesized.
(Second step)
In invention compound (l), aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; Alcohols such as methanol and ethanol; Aliphatic hydrocarbons such as pentane, hexane, heptane and ligroin; N,N-dimethylaminopyridine in aprotic polar solvents such as acetonitrile, N,N-dimethylformamide and dimethylsulfoxide , trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, organic bases such as procaine; potassium carbonate, lithium carbonate In the presence or absence of an inorganic base such as, methyl iodide, dimethyl sulfate, trifluoromethanesulfonylmethane, a meerwein reagent such as a methylating agent, by reacting for 12 to 48 hours under heating from 0 ° C. to reflux, the invention Compound (m) can be synthesized.
(Third step)
Aromatic hydrocarbons such as benzene, toluene and xylene for the invention compound (m); Ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; Halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; Pentane , Hexane, heptane, ligroin and other aliphatic hydrocarbons; N,N-dimethylaminopyridine, trimethylamine, triethylamine, N,N- Diisopropylethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, organic bases such as procaine; in the presence of inorganic bases such as potassium carbonate and lithium carbonate, ( The compound (n) of the present invention can be synthesized by reacting the amine represented by r-5) or the alcohol represented by (r-6) at 0° C. to under reflux with heating for 1 to 12 hours.

(vii) production method when R ⁶ represents a hydroxy group in general formula (I)

(Method L) Invention compound (p) can be synthesized by dealkylation reaction of invention compound (o) obtained in (i) to (vi) above.

（式中、Ｒ^６ａはＣ_１－１０アルコキシ基を示し、Ｒ^１～Ｒ^１４、ｎ、ｍ、Ｙ及びＺは前記と同じものを示す。）
上記（ｉ）～（ｖｉ）で得られた発明化合物（ｏ）を、ジクロロメタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類；酢酸等のプロトン性有機溶媒；アセトニトリル等の非プロトン性極性溶媒中又は無溶媒中、三臭化ホウ素、トリメチルシリルヨージド、臭化水素、塩酸ピリジニウム等と、－３０～１８０℃で３０分～５時間反応させるか、あるいはＮ，Ｎ－ジメチルホルムアミド、ジメチルアセトアミド、Ｎ－メチルピロリドン、ジメチルスルホキシド等の非プロトン性極性溶媒中、カリウムｔｅｒｔ－ブトキシド、ナトリウムｔｅｒｔ－ブトキシド等の有機塩基存在下、１－プロパンチオール、１－ドデカンチオール等を１００℃～１８０℃で３０分～２４時間反応させることにより、発明化合物（ｐ）を合成することができる。

(Wherein, R ^6a represents a C _1-10 alkoxy group, and R ¹ to R ¹⁴ , n, m, Y and Z represent the same as above.)
The invention compound (o) obtained in (i) to (vi) above is dissolved in halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; protic organic solvents such as acetic acid; and aprotic polar solvents such as acetonitrile. Boron tribromide, trimethylsilyl iodide, hydrogen bromide, pyridinium hydrochloride or the like in medium or no solvent at -30 to 180°C for 30 minutes to 5 hours, or N,N-dimethylformamide, dimethylacetamide, In an aprotic polar solvent such as N-methylpyrrolidone or dimethylsulfoxide, in the presence of an organic base such as potassium tert-butoxide or sodium tert-butoxide, 1-propanethiol, 1-dodecanethiol or the like is reacted at 100°C to 180°C for 30 minutes. The invention compound (p) can be synthesized by reacting for minutes to 24 hours.

(viii) in the general formula (I), a production method when X represents N-oxide

(Method M) Invention compound (s) can be synthesized by oxidation reaction of invention compound (q) obtained in (i) to (vii) above.

（式中、Ｒ^１～Ｒ^１４、ｎ、ｍ、Ｙ及びＺは前記と同じものを示す。）
上記（ｉ）～（ｖｉｉ）で得られた発明化合物（ｑ）を、ジクロロメタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素溶媒中、過酸化水素（Ｈ_２Ｏ_２）水溶液又はｍ－クロロ過安息香酸（ｍＣＰＢＡ）等の酸化剤１～２当量を、０℃～室温で３０分～２４時間反応させることにより、発明化合物（ｓ）を合成することができる。

(Wherein, R ¹ to R ¹⁴ , n, m, Y and Z are the same as above.)
Invention compound (q) obtained in the above (i) to (vii) was added to a hydrogen peroxide (H ₂ O ₂ ) aqueous solution or m-chloroperoxide in a halogenated hydrocarbon solvent such as dichloromethane, chloroform and carbon tetrachloride. The invention compound (s) can be synthesized by reacting 1 to 2 equivalents of an oxidizing agent such as benzoic acid (mCPBA) at 0° C. to room temperature for 30 minutes to 24 hours.

The compounds obtained in each of the above steps can be purified by, for example, silica gel column chromatography, if necessary.
Furthermore, if necessary, an acid addition salt can be formed by a conventional method. For example, the compound (I) of the invention can be dissolved in an organic solvent such as ethyl acetate; , the compound (I) of the present invention is mixed with mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid, organic carboxylic acids such as formic acid, acetic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid and maleic acid, methanesulfonic acid and benzenesulfone. The reaction is carried out at room temperature or by heating as appropriate in the presence of an acid, an organic sulfonic acid such as p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid, or the like.

The azepane derivative represented by the general formula (I) and a pharmaceutically acceptable salt thereof are administered to humans together with a pharmaceutically acceptable carrier for parenteral administration, oral administration in solid or liquid form, etc. Compositions can be formulated. It can also be used in combination with other analgesics.
Solid formulations for oral administration include capsules, tablets, pills, powders, granules and the like. Excipients, disintegrants, binders, lubricants, pigments and the like can be used in preparing this solid preparation. Here, excipients such as lactose, D-mannitol, crystalline cellulose, and glucose, disintegrants such as starch and carboxymethylcellulose calcium (CMC-Ca), and lubricants such as magnesium stearate, Talc and the like, and binders include hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP) and the like. Buffering agents may also be used in the case of capsules, tablets and pills. Tablets and pills may be enteric-coated.

Forms of the composition of the present invention for injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of suitable non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, soothing, buffering, preserving and dispersing agents.
These compositions may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition which may be dissolved in the sterilizing agent or some other sterile injectable medium immediately prior to use. can be fungus.

Formulations for ophthalmic administration preferably contain solubilizers, preservatives, isotonic agents, thickeners and the like in addition to the compounds of the present invention.

Liquid formulations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used by those skilled in the art, such as water. Besides such inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and flavoring agents.

Formulations for rectal administration may preferably contain, in addition to the compounds of this invention, excipients such as cocoa butter or suppository waxes.

The dosage for adults is usually the active ingredient azepane derivative represented by the general formula (I), tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or The solvate is 0.01 μg to 1 g/day, preferably 0.0001 to 200 mg/day for injection, and 0.1 μg to 10 g/day, preferably 0.001 to 2000 mg/day for oral administration. The dosage can be increased or decreased depending on age, symptoms, and the like. Also, if desired, this daily dose can be divided and administered in 2 to 4 times.

Diseases and conditions associated with kappa opioid receptors include, for example, cardiovascular disorders, digestive disorders, blood disorders, respiratory disorders, liver disorders, nervous disorders, urinary disorders, pain, cough, pruritus, Examples include ischemic brain disease and drug dependence. Since the compounds of the present invention have high κ opioid receptor selectivity and potent agonist activity against κ opioid receptors, they are effective in treating, improving, and preventing these diseases and symptoms.

Next, the present invention will be described in more detail with reference examples, examples and test examples, but the present invention is not limited to these.

(Example 1)
(4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a-hydroxy-10-methoxy-1,2,3,4,4a,5,6,7-octahydro-4,13-methanobenzofuro [ Synthesis of 2,3-c]pyrido[4,3-d]azepin-8(8aH)-one

（方法１）
（４Ｒ，４ａＳ，７ａＲ，１２ｂＳ）－３－（シクロプロピルメチル）－４ａ－ヒドロキシ－９－メトキシ－２，３，４，４ａ，５，６－ヘキサヒドロ－１Ｈ－４，１２－メタノベンゾフロ［３，２－ｅ］イソキノリン－７（７ａＨ）－オン（Ｏｒｇａｎｉｃ Ｌｅｔｔｅｒｓ，２００９，１１，３，５３９に記載の方法で合成）（３００ｍｇ，０．８４ｍｍｏｌ）をポリリン酸（５ｇ）に懸濁後、内温５５－６０℃に加熱しアジ化ナトリウム（７８．５ｍｇ，１．２１ｍｍｏｌ）を加え、内温５８－６０℃で４５分間撹拌した。反応混合物を氷冷した２８％アンモニア水溶液に注ぎ、酢酸エチルで三回抽出した。合わせた抽出液を硫酸ナトリウムで乾燥後、減圧下にて濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（アミノ基担持シリカゲル、０－３％メタノール／クロロホルム）及び分取薄層クロマトグラフィー（クロロホルム：メタノール＝２０：１）で精製し、表題化合物（１７３．３ｍｇ，５５％）を無色固体として得た。
（方法２）
（４Ｒ，４ａＳ，７ａＲ，１２ｂＳ）－３－（シクロプロピルメチル）－４ａ－ヒドロキシ－９－メトキシ－２，３，４，４ａ，５，６－ヘキサヒドロ－１Ｈ－４，１２－メタノベンゾフロ［３，２－ｅ］イソキノリン－７（７ａＨ）－オン（Ｏｒｇａｎｉｃ Ｌｅｔｔｅｒｓ，２００９，１１，３，５３９に記載の方法で合成）（１.０ｇ，２．８１ｍｍｏｌ）をポリリン酸（１２．５ｇ）に懸濁後、内温６５－７０℃に加熱しアジドトリメチルシラン（１．１１ｍL，８．４４ｍｍｏｌ）を加え、内温６５－７０℃で３０分間撹拌した。反応混合物を氷冷した２８％アンモニア水溶液に注ぎ、クロロホルムで三回抽出した。合わせた抽出液を硫酸ナトリウムで乾燥後、減圧下にて濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（アミノ基担持シリカゲル、０－３％メタノール／酢酸エチル及び３５－１００％酢酸エチル／ヘプタン）で精製し、表題化合物（３６２．５ｍｇ，３５％）を無色アモルファスとして得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０９－０．１７（ｍ，２Ｈ），０．５１－０．５７（ｍ，２Ｈ），０．８０－０．９１（ｍ，１Ｈ），１．２８－１．３６（ｍ，１Ｈ），１．５９－１．６７（ｍ，１Ｈ），１．９２（ｄｄｄ，Ｊ＝６，１４，１４Ｈｚ，１Ｈ），２．２８－２．４２（ｍ，３Ｈ），２．４６（ｄｄｄ，Ｊ＝６，６，１３Ｈｚ，１Ｈ），２．６４（ｄｄ，Ｊ＝７，１９Ｈｚ，１Ｈ），２．７２（ｄｄ，Ｊ＝５，１１Ｈｚ，１Ｈ），２．８０－２．９９（ｍ，２Ｈ），３．０６－３．１７（ｍ，２Ｈ），３．８９（ｓ，３Ｈ），４．８６（ｓ，１Ｈ），４．９５（ｂｒ ｓ，１Ｈ），５．９５（ｔ，Ｊ＝７Ｈｚ，１Ｈ），６．６６（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７８（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．

(Method 1)
(4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-9-methoxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3, 2-e]isoquinolin-7(7aH)-one (Organic Letters, synthesized by the method described in 2009, 11, 3, 539) (300 mg, 0.84 mmol) was suspended in polyphosphoric acid (5 g), and then heated to internal temperature. The mixture was heated to 55-60°C, sodium azide (78.5 mg, 1.21 mmol) was added, and the mixture was stirred at an internal temperature of 58-60°C for 45 minutes. The reaction mixture was poured into an ice-cooled 28% aqueous ammonia solution and extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (amino group-supporting silica gel, 0-3% methanol/chloroform) and preparative thin layer chromatography (chloroform:methanol=20:1) to give the title compound (173. 3 mg, 55%) as a colorless solid.
(Method 2)
(4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-9-methoxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3, 2-e]isoquinolin-7(7aH)-one (Organic Letters, 2009, 11, 3, synthesized by the method described in 539) (1.0 g, 2.81 mmol) suspended in polyphosphoric acid (12.5 g) Then, the mixture was heated to an internal temperature of 65-70°C, azidotrimethylsilane (1.11 mL, 8.44 mmol) was added, and the mixture was stirred at an internal temperature of 65-70°C for 30 minutes. The reaction mixture was poured into an ice-cooled 28% aqueous ammonia solution and extracted with chloroform three times. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (amino group-supporting silica gel, 0-3% methanol/ethyl acetate and 35-100% ethyl acetate/heptane) to give the title compound (362.5 mg, 35%). Obtained as colorless amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09-0.17 (m, 2H), 0.51-0.57 (m, 2H), 0.80-0.91 (m , 1H), 1.28-1.36 (m, 1H), 1.59-1.67 (m, 1H), 1.92 (ddd, J = 6, 14, 14Hz, 1H), 2.28 -2.42 (m, 3H), 2.46 (ddd, J = 6, 6, 13Hz, 1H), 2.64 (dd, J = 7, 19Hz, 1H), 2.72 (dd, J = 5, 11Hz, 1H), 2.80-2.99 (m, 2H), 3.06-3.17 (m, 2H), 3.89 (s, 3H), 4.86 (s, 1H) , 4.95 (br s, 1 H), 5.95 (t, J=7 Hz, 1 H), 6.66 (d, J=8 Hz, 1 H), 6.78 (d, J=8 Hz, 1 H).

(Reference example 1)
(4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-1,2,3,4,4a,5,6,7-octahydro-4,13-methanobenzofuro[2, Synthesis of 3-c]pyrido[4,3-d]azepin-8(8aH)-one

実施例１で得られた化合物（１．３２ｇ，３．５８ｍｍｏｌ）のクロロホルム（２０ｍＬ）溶液に、氷冷下１Ｍ三臭化ホウ素－ジクロロメタン溶液（１７．９ｍＬ，１７．９ｍｍｏｌ）を加え、室温で１６時間撹拌した。反応混合物に氷冷下飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで三回抽出した。合わせた抽出液を硫酸ナトリウムで乾燥後、減圧下にて濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（０－５％メタノール／クロロホルム）で精製し、表題化合物（９０９．１ｍｇ，７２％）を無色固体として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ_３ОＤ）δ（ｐｐｍ）：０．１３－０．２０（ｍ，２Ｈ），０．５０－０．５９（ｍ，２Ｈ），０．８４－０．９５（ｍ，１Ｈ），１．３５－１．４３（ｍ，１Ｈ），１．５５－１．６２（ｍ，１Ｈ），１．７９－１．９０（ｍ，１Ｈ），２．２９－２．４７（ｍ，４Ｈ），２．６７（ｄｄ，Ｊ＝７，１９Ｈｚ，１Ｈ），２．６９－２．７５（ｍ，１Ｈ），２．８０－２．９１（ｍ，２Ｈ），３．１１（ｄ，Ｊ＝７Ｈｚ，１Ｈ），３．１５（ｄ，Ｊ＝５Ｈｚ，１Ｈ），４．７１（ｓ，１Ｈ），６．６０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６８（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．

To a solution of the compound obtained in Example 1 (1.32 g, 3.58 mmol) in chloroform (20 mL) was added 1 M boron tribromide-dichloromethane solution (17.9 mL, 17.9 mmol) under ice cooling, and the mixture was stirred at room temperature. Stirred for 16 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with chloroform three times. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (0-5% methanol/chloroform) to give the title compound (909.1 mg, 72%) as a colorless solid.

¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 0.13-0.20 (m, 2H), 0.50-0.59 (m, 2H), 0.84-0.95 ( m, 1H), 1.35-1.43 (m, 1H), 1.55-1.62 (m, 1H), 1.79-1.90 (m, 1H), 2.29-2. 47 (m, 4H), 2.67 (dd, J=7, 19Hz, 1H), 2.69-2.75 (m, 1H), 2.80-2.91 (m, 2H), 3. 11 (d, J = 7Hz, 1H), 3.15 (d, J = 5Hz, 1H), 4.71 (s, 1H), 6.60 (d, J = 8Hz, 1H), 6.68 ( d, J=8Hz, 1H).

(Example 2)
(4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-10-methoxy-1,2,3,4,6,7,8,8a-octahydro-4,13-methanobenzofuro[2,3- Synthesis of c]pyrido[4,3-d]azepin-4a(5H)-ol

実施例１で得られた化合物（１７２ｍｇ，０．４６ｍｍｏｌ）のテトラヒドロフラン（５ｍＬ）溶液に、０．９１Ｍボラン－テトラヒドロフラン錯体テトラヒドロフラン溶液（２．６ｍＬ，２．３２ｍｍｏｌ）を加え、１．５時間加熱還流した。反応混合液を放冷後、減圧下にて濃縮した。濃縮残渣に２Ｍ塩酸（４ｍＬ）を加え、１０分間加熱還流した。反応混合物を放冷後、飽和炭酸水素ナトリウム水溶液に注ぎ塩基性とし、クロロホルムで三回抽出した。合わせた抽出液を硫酸ナトリウムで乾燥後、減圧下にて濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（アミノ基担持シリカゲル、０－１％メタノール／クロロホルム）で精製し、表題化合物（１３４ｍｇ，８１％）を無色油状物質として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．１０－０．１５（ｍ，２Ｈ），０．５０－０．５８（ｍ，２Ｈ），０．８１－０．９０（ｍ，１Ｈ），１．３８－１．５９（ｍ，３Ｈ），２．２０－２．４２（ｍ，４Ｈ），２．５２－２．６５（ｍ，２Ｈ），２．８５（ｄｄｄ，Ｊ＝３，３，１４Ｈｚ，１Ｈ），２．９３（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．０２－３．０９（ｍ，１Ｈ），３．０３（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．１４（ｄｄ，Ｊ＝２，１５Ｈｚ，１Ｈ），３．３３－３．４３（ｍ，１Ｈ），３．８７（ｓ，３Ｈ），４．４７－４．５２（ｍ，１Ｈ），４．８２（ｂｒ ｓ，１Ｈ），６．５７（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．

To a tetrahydrofuran (5 mL) solution of the compound (172 mg, 0.46 mmol) obtained in Example 1 was added a 0.91 M borane-tetrahydrofuran complex tetrahydrofuran solution (2.6 mL, 2.32 mmol), and the mixture was heated under reflux for 1.5 hours. bottom. After allowing the reaction mixture to cool, it was concentrated under reduced pressure. 2M Hydrochloric acid (4 mL) was added to the concentrated residue, and the mixture was heated under reflux for 10 minutes. After the reaction mixture was allowed to cool, it was poured into a saturated aqueous solution of sodium hydrogencarbonate to make it basic, and the mixture was extracted with chloroform three times. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (amino group-supporting silica gel, 0-1% methanol/chloroform) to give the title compound (134 mg, 81%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10-0.15 (m, 2H), 0.50-0.58 (m, 2H), 0.81-0.90 (m , 1H), 1.38-1.59 (m, 3H), 2.20-2.42 (m, 4H), 2.52-2.65 (m, 2H), 2.85 (ddd, J = 3, 3, 14Hz, 1H), 2.93 (d, J = 6Hz, 1H), 3.02-3.09 (m, 1H), 3.03 (d, J = 18Hz, 1H), 3 .14 (dd, J=2, 15Hz, 1H), 3.33-3.43 (m, 1H), 3.87 (s, 3H), 4.47-4.52 (m, 1H), 4 .82 (br s, 1 H), 6.57 (d, J=8 Hz, 1 H), 6.72 (d, J=8 Hz, 1 H).

(Example 3)
(4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-1,2,3,4,6,7,8,8a-octahydro-4,13-methanobenzofuro[2,3-c]pyrido [ Synthesis of 4,3-d]azepine-4a,10(5H)-diol dihydrochloride (1) (4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-1,2,3,4, Synthesis of 6,7,8,8a-octahydro-4,13-methanobenzofuro[2,3-c]pyrido[4,3-d]azepine-4a,10(5H)-diol

実施例２に記載した方法に従い、参考例１で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０９－０．１６（ｍ，２Ｈ），０．４９－０．５７（ｍ，２Ｈ），０．７８－０．９０（ｍ，１Ｈ），１．３５－１．５１（ｍ，２Ｈ），１．５２－１．６１（ｍ，１Ｈ），２．２３－２．４３（ｍ，４Ｈ），２．５１（ｄｄ，Ｊ＝７，１９Ｈ，１Ｈ），２．５７－２．６７（ｍ，１Ｈ），２．８６－２．９５（ｍ，２Ｈ），３．０１－３．１１（ｍ，１Ｈ），３．０２（ｄ，Ｊ＝１９Ｈｚ，１Ｈ），３．１８（ｄ，Ｊ＝１５Ｈｚ，１Ｈ），３．７５－３．８５（ｍ，１Ｈ），４．５２（ｓ，１Ｈ），４．８７（ｂｒ ｓ，１Ｈ），６．４８（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６５（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．
ＭＳ（ＥＳＩ）： ｍ／ｚ ３４３．２４［Ｍ＋Ｈ］^＋
（２）（４Ｒ，４ａＳ，８ａＲ，１３ｂＳ）－３－（シクロプロピルメチル）－１，２，３，４，６，７，８，８ａ－オクタヒドロ－４，１３－メタノベンゾフロ［２，３－ｃ］ピリド［４，３－ｄ］アゼピン－４ａ，１０（５Ｈ）－ジオール二塩酸塩の合成

According to the method described in Example 2, the title compound was obtained from the compound obtained in Reference Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09-0.16 (m, 2H), 0.49-0.57 (m, 2H), 0.78-0.90 (m , 1H), 1.35-1.51 (m, 2H), 1.52-1.61 (m, 1H), 2.23-2.43 (m, 4H), 2.51 (dd, J = 7, 19H, 1H), 2.57-2.67 (m, 1H), 2.86-2.95 (m, 2H), 3.01-3.11 (m, 1H), 3.02 (d, J = 19 Hz, 1 H), 3.18 (d, J = 15 Hz, 1 H), 3.75-3.85 (m, 1 H), 4.52 (s, 1 H), 4.87 (br s, 1 H), 6.48 (d, J=8 Hz, 1 H), 6.65 (d, J=8 Hz, 1 H).
MS (ESI): m/z 343.24 [M+H] ⁺
(2) (4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-1,2,3,4,6,7,8,8a-octahydro-4,13-methanobenzofuro[2,3-c ]pyrido[4,3-d]azepine-4a,10(5H)-diol dihydrochloride

実施例３の（１）で得られた化合物（６．２ｍｇ，０．０１８ｍｍｏｌ）の酢酸エチル（１ｍＬ）溶液に、氷冷下１Ｍ塩酸－ジエチルエーテル溶液（１ｍＬ）を加え、１０分間撹拌した。析出した固体をろ取し、水を加え凍結後凍結乾燥器にて乾燥し、表題化合物（６．７ｍｇ，８９％）を微褐色固体として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ（ｐｐｍ）：０．４６－０．５８（ｍ，２Ｈ），０．７３－０．９０（ｍ，２Ｈ），１．０７－１．１８（ｍ，１Ｈ），１．７５－１．９９（ｍ，３Ｈ），２．７６（ｄｄｄ，Ｊ＝５，１３，１３Ｈｚ，１Ｈ），２．９１（ｄｄｄ，Ｊ＝４，１３，１３Ｈｚ，１Ｈ），３．０１－３．２５（ｍ，３Ｈ），３．３０－３．４７（ｍ，４Ｈ），３．５５（ｄｄ，Ｊ＝３，１５Ｈｚ，１Ｈ），３．６５（ｄｄ，Ｊ＝５，１５Ｈｚ，１Ｈ），３．９４（ｄ，Ｊ＝７Ｈｚ，１Ｈ），４．９２（ｄｄ，Ｊ＝３，５Ｈｚ，１Ｈ），６．７５（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．８１（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．

To a solution of the compound (6.2 mg, 0.018 mmol) obtained in Example 3 (1) in ethyl acetate (1 mL) was added 1 M hydrochloric acid-diethyl ether solution (1 mL) under ice cooling, and the mixture was stirred for 10 minutes. The precipitated solid was collected by filtration, water was added, and the solid was frozen and dried in a freeze dryer to give the title compound (6.7 mg, 89%) as a pale brown solid.

¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 0.46-0.58 (m, 2H), 0.73-0.90 (m, 2H), 1.07-1.18 ( m, 1H), 1.75-1.99 (m, 3H), 2.76 (ddd, J = 5, 13, 13Hz, 1H), 2.91 (ddd, J = 4, 13, 13Hz, 1H) ), 3.01-3.25 (m, 3H), 3.30-3.47 (m, 4H), 3.55 (dd, J = 3, 15Hz, 1H), 3.65 (dd, J = 5, 15Hz, 1H), 3.94 (d, J = 7Hz, 1H), 4.92 (dd, J = 3, 5Hz, 1H), 6.75 (d, J = 8Hz, 1H), 6 .81 (d, J=8 Hz, 1 H).

(Example 4)
(4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-10-methoxy-7-(2-(pyridin-2-yl)ethyl)-1,2,3,4,6,7,8 ,8a-octahydro-4,13-methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-4a(5H)-ol

実施例２で得られた化合物（１１ｍｇ，０．０３１ｍｍｏｌ）のエタノール（２ｍＬ）溶液に、酢酸（１７．７μＬ，０．３１ｍｍｏｌ）および２－ビニルピリジン（３３．１μＬ，０．３１ｍｍｏｌ）を加え、６時間加熱還流した。反応液を放冷後、減圧下濃縮した。得られた濃縮残渣を分取薄層クロマトグラフィー（クロロホルム：２Ｍアンモニア－メタノール＝２０：１）で精製し、表題化合物（１１．６ｍｇ，８２％）を無色油状物質として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０９－０．１５（ｍ，２Ｈ），０．４０－０．５５（ｍ，２Ｈ），０．７９－０．９１（ｍ，１Ｈ），１．３２－１．４０（ｍ，１Ｈ），１．４７－１．５５（ｍ，１Ｈ），１．７２（ｄｄｄ，Ｊ＝４，１３，１３Ｈｚ，１Ｈ），２．１８（ｄｄｄ，Ｊ＝３，１２，１２Ｈｚ，１Ｈ），２．２５－２．４３（ｍ，３Ｈ），２．５０－２．６５（ｍ，３Ｈ），２．８０－３．２０（ｍ，９Ｈ），３．８４（ｓ，３Ｈ），４．４８（ｄｄ，Ｊ＝４，５Ｈｚ，１Ｈ），４．８２（ｂｒ ｓ，１Ｈ），６．５６（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．０３－７．０８（ｍ，１Ｈ），７．１３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．４７－７．５４（ｍ，１Ｈ），８．４４－８．４９（ｍ，１Ｈ）．

Acetic acid (17.7 μL, 0.31 mmol) and 2-vinylpyridine (33.1 μL, 0.31 mmol) were added to an ethanol (2 mL) solution of the compound (11 mg, 0.031 mmol) obtained in Example 2, It was heated to reflux for 6 hours. After allowing the reaction solution to cool, it was concentrated under reduced pressure. The resulting concentrated residue was purified by preparative thin layer chromatography (chloroform:2M ammonia-methanol=20:1) to give the title compound (11.6 mg, 82%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09-0.15 (m, 2H), 0.40-0.55 (m, 2H), 0.79-0.91 (m , 1H), 1.32-1.40 (m, 1H), 1.47-1.55 (m, 1H), 1.72 (ddd, J = 4, 13, 13Hz, 1H), 2.18 (ddd, J = 3, 12, 12Hz, 1H), 2.25-2.43 (m, 3H), 2.50-2.65 (m, 3H), 2.80-3.20 (m, 9H), 3.84 (s, 3H), 4.48 (dd, J = 4, 5Hz, 1H), 4.82 (br s, 1H), 6.56 (d, J = 8Hz, 1H), 6.70 (d, J = 8Hz, 1H), 7.03-7.08 (m, 1H), 7.13 (d, J = 8Hz, 1H), 7.47-7.54 (m, 1H) ), 8.44-8.49 (m, 1H).

(Example 5)
(4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-7-(2-(pyridin-2-yl)ethyl)-1,2,3,4,6,7,8,8a-octahydro Synthesis of -4,13-methanobenzofuro[2,3-c]pyrido[4,3-d]azepine-4a,10(5H)-diol

参考例１に記載した方法に従い、実施例４で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．１０－０．１５（ｍ，２Ｈ），０．５０－０．５７（ｍ，２Ｈ），０．７９－０．９０（ｍ，１Ｈ），１．１６－１．２４（ｍ，１Ｈ），１．５５－１．６４（ｍ，１Ｈ），１．６６－１．７８（ｍ，１Ｈ），２．２６－２．３５（ｍ，３Ｈ），２．３６－２．４５（ｍ，２Ｈ），２．５０（ｄｄ，Ｊ＝７，１９Ｈｚ，１Ｈ），２．５８－２．７２（ｍ，３Ｈ），２．７９（ｄｄｄ，Ｊ＝Ｊ＝５，１１，１１Ｈｚ，１Ｈ），２．９１（ｄ，Ｊ＝７Ｈｚ，１Ｈ），３．０１（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．１６（ｄｄ，Ｊ＝２，１６Ｈｚ，１Ｈ），３．３５（ｄｄｄ，Ｊ＝２，１３，１３Ｈｚ，１Ｈ），３．４９－３．５９（ｍ，２Ｈ），４．５５（ｄｄ，Ｊ＝３，３Ｈｚ，１Ｈ），４．８４（ｂｒ ｓ，１Ｈ），６．５０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．８２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．１１－７．１９（ｍ，２Ｈ），７．５９（ｄｄｄ，Ｊ＝２，７，７Ｈｚ，１Ｈ），８．４８－８．５１（ｍ，１Ｈ）．

According to the method described in Reference Example 1, the title compound was obtained from the compound obtained in Example 4.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10-0.15 (m, 2H), 0.50-0.57 (m, 2H), 0.79-0.90 (m , 1H), 1.16-1.24 (m, 1H), 1.55-1.64 (m, 1H), 1.66-1.78 (m, 1H), 2.26-2.35 (m, 3H), 2.36-2.45 (m, 2H), 2.50 (dd, J=7, 19Hz, 1H), 2.58-2.72 (m, 3H), 2.79 (ddd, J = J = 5, 11, 11 Hz, 1 H), 2.91 (d, J = 7 Hz, 1 H), 3.01 (d, J = 18 Hz, 1 H), 3.16 (dd, J = 2, 16Hz, 1H), 3.35 (ddd, J = 2, 13, 13Hz, 1H), 3.49-3.59 (m, 2H), 4.55 (dd, J = 3, 3Hz, 1H) ), 4.84 (br s, 1H), 6.50 (d, J = 8Hz, 1H), 6.82 (d, J = 8Hz, 1H), 7.11-7.19 (m, 2H) , 7.59 (ddd, J=2, 7, 7 Hz, 1H), 8.48-8.51 (m, 1H).

(Example 6)
((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a-hydroxy-10-methoxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)(pyridin-2-yl)methanone

実施例２で得られた化合物（７．６ｍｇ，０．０２１ｍｍｏｌ）及びピコリン酸（３．９ｍｇ，０．０３２ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（７．４μＬ，０．０４３ｍｍｏｌ）及びＯ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムヘキサフルオロホスファート（１２．２ｍｇ，０．０３２ｍｍｏｌ）を加え、室温で２２時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで一回抽出した。有機層を飽和炭酸水素ナトリウム水溶液で二回洗浄し、硫酸ナトリウムで乾燥後、減圧下にて濃縮した。得られた粗生成物を分取薄層クロマトグラフィー（クロロホルム：メタノール＝１２：１）で精製し、表題化合物（８．４ｍｇ，８６％）を無色油状物質として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１６（ｍ，２Ｈ），０．４４－０．５９（ｍ，２Ｈ），０．７５－０．９４（ｍ，１Ｈ），１．３３－１．４８（ｍ，１Ｈ），１．５２－１．６２（ｍ，１Ｈ），１．８０－１．９１（ｍ，１Ｈ），２．０１－２．４０（ｍ，４Ｈ），２．５２－２．６８（ｍ，２Ｈ），２．８６－２．９０（ｍ，０．４Ｈ），２．９５－３．０６（ｍ，１．６Ｈ），３．１０－３．２９（ｍ，０．４Ｈ），３．４０－３．４８（ｍ，０．６Ｈ），３．５０－３．６８（ｍ，０．６Ｈ），３．６９－３．８１（ｍ，１Ｈ），３．７９（ｓ，１．８Ｈ），３．８８（ｓ，１．２Ｈ），４．００－４．１５（ｍ，０．４Ｈ），４．２５－４．３３（ｍ，０．６Ｈ），４．４０－４．６８（ｍ，２Ｈ），５．１５－５．２３（ｍ，０．４Ｈ），６．５９（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．６２（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．７４（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），７．２７－７．３６（ｍ，１Ｈ），７．５４（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），７．６５（ｄ，Ｊ＝７Ｈｚ，０．４Ｈ），７．７３－７．８２（ｍ，１Ｈ），８．５２－８．５７（ｍ，１Ｈ）．

N,N-Diisopropylethylamine (7 .4 μL, 0.043 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (12.2 mg, 0.032 mmol). and stirred at room temperature for 22 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted once with ethyl acetate. The organic layer was washed twice with a saturated aqueous sodium hydrogencarbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by preparative thin layer chromatography (chloroform:methanol=12:1) to give the title compound (8.4 mg, 86%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.16 (m, 2H), 0.44-0.59 (m, 2H), 0.75-0.94 (m , 1H), 1.33-1.48 (m, 1H), 1.52-1.62 (m, 1H), 1.80-1.91 (m, 1H), 2.01-2.40 (m, 4H), 2.52-2.68 (m, 2H), 2.86-2.90 (m, 0.4H), 2.95-3.06 (m, 1.6H), 3 .10-3.29 (m, 0.4H), 3.40-3.48 (m, 0.6H), 3.50-3.68 (m, 0.6H), 3.69-3. 81 (m, 1H), 3.79 (s, 1.8H), 3.88 (s, 1.2H), 4.00-4.15 (m, 0.4H), 4.25-4. 33 (m, 0.6H), 4.40-4.68 (m, 2H), 5.15-5.23 (m, 0.4H), 6.59 (d, J = 8Hz, 0.6H ), 6.62 (d, J = 8 Hz, 0.4 H), 6.71 (d, J = 8 Hz, 0.6 H), 6.74 (d, J = 8 Hz, 0.4 H), 7.27 -7.36 (m, 1H), 7.54 (d, J = 8Hz, 0.6H), 7.65 (d, J = 7Hz, 0.4H), 7.73-7.82 (m, 1H), 8.52-8.57 (m, 1H).

(Example 7)
((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro[2 Synthesis of ,3-c]pyrido[4,3-d]azepin-7(1H)-yl)(pyridin-2-yl)methanone

参考例１に記載した方法に従い、実施例６で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１７（ｍ，２Ｈ），０．４７－０．５８（ｍ，２Ｈ），０．７６－０．９２（ｍ，１Ｈ），１．２９－１．３５（ｍ，０．６Ｈ），１．４１－１．７２（ｍ，２．４Ｈ），２．１４－２．４２（ｍ，４Ｈ），２．５０－２．６７（ｍ，２Ｈ），２．８９（ｄ，Ｊ＝６Ｈｚ，０．４Ｈ），２．９５－３．０７（ｍ，１．６Ｈ），３．３５－３．４４（ｍ，０．６Ｈ），３．４８－３．５６（ｍ，０．４Ｈ），３．５８－３．６７（ｍ，０．４Ｈ），３．６９－３．７６（ｍ，０．６Ｈ），３．８０－３．９２（ｍ，０．４Ｈ），４．１２－４．２０（ｍ，０．６Ｈ），４．３２－４．４０（ｍ，０．４Ｈ），４．３８（ｓ，１Ｈ），４．８２（ｂｒ ｓ，１Ｈ），４．９７－５．０３（ｍ，０．６Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．５５（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７５（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７８（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．７８（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），７．２６－７．３２（ｍ，０．８Ｈ），７．３５－７．４０（ｍ，０．６Ｈ），７．４４（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），７．６８－７．７４（ｍ，０．４Ｈ），７．８１（ｄｄｄ，Ｊ＝Ｊ＝２，８，８Ｈｚ，０．６Ｈ），８．５１（ｄ，Ｊ＝５Ｈｚ，０．４Ｈ），８．６６（ｄ，Ｊ＝５Ｈｚ，０．６Ｈ）．

According to the method described in Reference Example 1, the title compound was obtained from the compound obtained in Example 6.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.17 (m, 2H), 0.47-0.58 (m, 2H), 0.76-0.92 (m , 1H), 1.29-1.35 (m, 0.6H), 1.41-1.72 (m, 2.4H), 2.14-2.42 (m, 4H), 2.50 -2.67 (m, 2H), 2.89 (d, J=6Hz, 0.4H), 2.95-3.07 (m, 1.6H), 3.35-3.44 (m, 0.6H), 3.48-3.56 (m, 0.4H), 3.58-3.67 (m, 0.4H), 3.69-3.76 (m, 0.6H), 3.80-3.92 (m, 0.4H), 4.12-4.20 (m, 0.6H), 4.32-4.40 (m, 0.4H), 4.38 (s , 1H), 4.82 (br s, 1H), 4.97-5.03 (m, 0.6H), 6.54 (d, J = 8Hz, 0.6H), 6.55 (d, J = 8Hz, 0.4H), 6.75 (d, J = 8Hz, 0.4H), 6.78 (d, J = 8Hz, 0.6H), 6.78 (d, J = 8Hz, 0 .6H), 7.26-7.32 (m, 0.8H), 7.35-7.40 (m, 0.6H), 7.44 (d, J = 8Hz, 0.6H), 7 .68-7.74 (m, 0.4H), 7.81 (ddd, J = J = 2, 8, 8Hz, 0.6H), 8.51 (d, J = 5Hz, 0.4H), 8.66 (d, J=5Hz, 0.6H).

(Example 8)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a-hydroxy-10-methoxy-2,3,4,4a,5,6,8,8a-octahydro-4,13 - Synthesis of methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(pyridin-2-yl)ethan-1-one

実施例６に記載した方法に従い、実施例２で得られた化合物及び２－（ピリジン－２－イル）酢酸塩酸塩より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１６（ｍ，２Ｈ），０．５０－０．５７（ｍ，２Ｈ），０．７９－０．９０（ｍ，１Ｈ），１．４０－１．９５（ｍ，３Ｈ），２．０５－２．１４（ｍ，０．４Ｈ），２．２０－２．４１（ｍ，３．６Ｈ），２．４９－２．６７（ｍ，２Ｈ），２．９１－３．０５（ｍ，２Ｈ），３．１０－３．３３（ｍ，１Ｈ），３．６４（ｄｄ，Ｊ＝２，１６Ｈｚ，０．６Ｈ），３．８６（ｓ，１．８Ｈ），３．８７（ｓ，１．２Ｈ），３．９２－４．０５（ｍ，１Ｈ），３．９３（ｄ，Ｊ＝１６Ｈｚ，０．６Ｈ），３．９７（ｄ，Ｊ＝１６Ｈｚ，０．４Ｈ），４．０５（ｄ，Ｊ＝１６Ｈｚ，０．４Ｈ），４．２０－４．３２（ｍ，０．８Ｈ），４．３２（ｄ，Ｊ＝１６Ｈｚ，０．６Ｈ），４．４０－４．５０（ｍ，０．６Ｈ），４．６２－４．６６（ｍ，０．６Ｈ），４．９０（ｄｄ，Ｊ＝５，１０Ｈｚ，０．４Ｈ），６．５７（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．５９（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），７．１２（ｄｄ，Ｊ＝５，７Ｈｚ，１Ｈ），７．１８－７．２６（ｍ，１Ｈ），７．５５－７．６２（ｍ，１Ｈ），８．４９－８．５４（ｍ，１Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 2 and 2-(pyridin-2-yl)acetic acid hydrochloride.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.16 (m, 2H), 0.50-0.57 (m, 2H), 0.79-0.90 (m , 1H), 1.40-1.95 (m, 3H), 2.05-2.14 (m, 0.4H), 2.20-2.41 (m, 3.6H), 2.49 -2.67 (m, 2H), 2.91-3.05 (m, 2H), 3.10-3.33 (m, 1H), 3.64 (dd, J = 2, 16Hz, 0.05). 6H), 3.86 (s, 1.8H), 3.87 (s, 1.2H), 3.92-4.05 (m, 1H), 3.93 (d, J = 16Hz, 0.8H). 6H), 3.97 (d, J=16Hz, 0.4H), 4.05 (d, J=16Hz, 0.4H), 4.20-4.32 (m, 0.8H), 4. 32 (d, J=16Hz, 0.6H), 4.40-4.50 (m, 0.6H), 4.62-4.66 (m, 0.6H), 4.90 (dd, J = 5, 10Hz, 0.4H), 6.57 (d, J = 8Hz, 0.6H), 6.59 (d, J = 8Hz, 0.4H), 6.71 (d, J = 8Hz, 0.6H), 6.72 (d, J = 8Hz, 0.4H), 7.12 (dd, J = 5, 7Hz, 1H), 7.18-7.26 (m, 1H), 7.12. 55-7.62 (m, 1H), 8.49-8.54 (m, 1H).

(Example 9)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(pyridin-2-yl)ethan-1-one

参考例１に記載した方法に従い、実施例８で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１９（ｍ，２Ｈ），０．４８－０．６０（ｍ，２Ｈ），０．７５－０．９３（ｍ，１Ｈ），１．１９－１．３０（ｍ，０．２Ｈ），１．３２－１．３９（ｍ，０．９Ｈ），１．４１－１．５０（ｍ，１H），１．６３－１．７３（ｍ，０．９H），２．１５－２．２１（ｍ，０．２Ｈ），２．２８－２．３５（ｍ，２．９Ｈ），２．３９（ｄｄ，Ｊ＝６，１２Ｈｚ，１Ｈ），２．４８（ｄｄ，Ｊ＝７，１９Ｈｚ，０．９Ｈ），２．５５－２．７０（ｍ，１Ｈ），２．７９－３．０９（ｍ，３Ｈ），３．３１－３．７４（ｍ，０．３Ｈ），３．６１（ｄ，Ｊ＝１６Ｈｚ，０．９Ｈ），３．６７（ｄｄ，Ｊ＝１，１６Ｈｚ，０．９Ｈ），３．８２（ｄ，Ｊ＝１５Ｈｚ，０．１Ｈ），３．９１（ｄ，Ｊ＝１５Ｈｚ，０．１Ｈ），４．２７－４．４１（ｍ，１．８Ｈ），４．６２－４．６８（ｍ，０．１Ｈ），４．６８（ｄｄ，Ｊ＝１，３Ｈｚ，０．９Ｈ），４．８６（ｂｒ ｓ，１Ｈ），４．９６（ｄ，Ｊ＝１６Ｈｚ，０．９Ｈ），６．４２（ｄ，Ｊ＝８Ｈｚ，０．１Ｈ），６．４７（ｄ，Ｊ＝８Ｈｚ，０．９Ｈ），６．７４（ｄ，Ｊ＝８Ｈｚ，０．１Ｈ），６．８１（ｄ，Ｊ＝８Ｈｚ，０．９Ｈ），６．９４－７．０５（ｍ，０．２Ｈ），７．２２（ｄｄｄ，Ｊ＝１，５，８Ｈｚ，０．９Ｈ），７．２６－７．２９（ｍ，０．９Ｈ），７．４６（ｄｄｄ，Ｊ＝２，８，８Ｈｚ，０．１Ｈ），７．６９（ｄｄｄ，Ｊ＝２，８，８Ｈｚ，０．９Ｈ），８．３７－８．４０（ｍ，０．１Ｈ），８．５０（ｄｄｄ，Ｊ＝１，２，５Ｈｚ，０．９Ｈ）．

According to the method described in Reference Example 1, the title compound was obtained from the compound obtained in Example 8.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.19 (m, 2H), 0.48-0.60 (m, 2H), 0.75-0.93 (m , 1H), 1.19-1.30 (m, 0.2H), 1.32-1.39 (m, 0.9H), 1.41-1.50 (m, 1H), 1.63 -1.73 (m, 0.9H), 2.15-2.21 (m, 0.2H), 2.28-2.35 (m, 2.9H), 2.39 (dd, J = 6, 12Hz, 1H), 2.48 (dd, J = 7, 19Hz, 0.9H), 2.55-2.70 (m, 1H), 2.79-3.09 (m, 3H), 3.31-3.74 (m, 0.3H), 3.61 (d, J = 16Hz, 0.9H), 3.67 (dd, J = 1, 16Hz, 0.9H), 3.82 (d, J = 15 Hz, 0.1 H), 3.91 (d, J = 15 Hz, 0.1 H), 4.27-4.41 (m, 1.8 H), 4.62-4.68 ( m, 0.1H), 4.68 (dd, J = 1, 3Hz, 0.9H), 4.86 (br s, 1H), 4.96 (d, J = 16Hz, 0.9H), 6 .42 (d, J=8 Hz, 0.1 H), 6.47 (d, J=8 Hz, 0.9 H), 6.74 (d, J=8 Hz, 0.1 H), 6.81 (d, J = 8Hz, 0.9H), 6.94-7.05 (m, 0.2H), 7.22 (ddd, J = 1, 5, 8Hz, 0.9H), 7.26-7.29 (m, 0.9H), 7.46 (ddd, J = 2, 8, 8Hz, 0.1H), 7.69 (ddd, J = 2, 8, 8Hz, 0.9H), 8.37- 8.40 (m, 0.1H), 8.50 (ddd, J = 1, 2, 5Hz, 0.9H).

(Example 10)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a-hydroxy-10-methoxy-2,3,4,4a,5,6,8,8a-octahydro-4,13 - Synthesis of methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)ethan-1-one

実施例６に記載した方法に従い、実施例２で得られた化合物及び２－（６－（トリフルオロメチル）ピリジン－２－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１９（ｍ，２Ｈ），０．４７－０．６１（ｍ，２Ｈ），０．７８－０．９２（ｍ，１Ｈ），１．４１－１．６６（ｍ，３Ｈ），２．１０（ｄｄｄ，Ｊ＝３，１２，１２Ｈｚ，０．４Ｈ），２．１８－２．４２（ｍ，３．６Ｈ），２．４８－２．６８（ｍ，２Ｈ），２．９４（ｄ，Ｊ＝６Ｈｚ，０．４Ｈ），２．９８（ｄ，Ｊ＝７Ｈｚ，０．６Ｈ），２．９９（ｄ，Ｊ＝１８Ｈｚ，０．４Ｈ），３．０３（ｄ，Ｊ＝１９Ｈｚ，０．６Ｈ），３．０９－３．２０（ｍ，０．６Ｈ），３．２８－３．４３（ｍ，０．４Ｈ），３．６５（ｄｄ，Ｊ＝２，１６Ｈｚ，０．６Ｈ），３．８４（ｓ，１．８Ｈ），３．８７（ｓ，１．２Ｈ），３．９３－４．１６（ｍ，１．８Ｈ），４．１１（ｄ，Ｊ＝１６Ｈｚ，０．６Ｈ），４．１９－４．２７（ｍ，０．８Ｈ），４．３３（ｄ，Ｊ＝１６Ｈｚ，０．６Ｈ），４．４５－４．５６（ｍ，０．６Ｈ），４．６５－４．７０（ｍ，０．６Ｈ），４．８４－４．９１（ｍ，０．４Ｈ），６．５８（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７０（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），７．３８（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），７．４８－７．５５（ｍ，０．４Ｈ），７．５２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．７５（ｄｄ，Ｊ＝８，８Ｈｚ，０．６Ｈ），７．７６（ｄｄ，Ｊ＝８，８Ｈｚ，０．４Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 2 and 2-(6-(trifluoromethyl)pyridin-2-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.19 (m, 2H), 0.47-0.61 (m, 2H), 0.78-0.92 (m , 1H), 1.41-1.66 (m, 3H), 2.10 (ddd, J = 3, 12, 12Hz, 0.4H), 2.18-2.42 (m, 3.6H) , 2.48-2.68 (m, 2H), 2.94 (d, J = 6Hz, 0.4H), 2.98 (d, J = 7Hz, 0.6H), 2.99 (d, J = 18Hz, 0.4H), 3.03 (d, J = 19Hz, 0.6H), 3.09-3.20 (m, 0.6H), 3.28-3.43 (m, 0 .4H), 3.65 (dd, J=2, 16Hz, 0.6H), 3.84 (s, 1.8H), 3.87 (s, 1.2H), 3.93-4.16 (m, 1.8H), 4.11 (d, J=16Hz, 0.6H), 4.19-4.27 (m, 0.8H), 4.33 (d, J=16Hz, 0.6H). 6H), 4.45-4.56 (m, 0.6H), 4.65-4.70 (m, 0.6H), 4.84-4.91 (m, 0.4H), 6. 58 (d, J = 8Hz, 1H), 6.70 (d, J = 8Hz, 0.4H), 6.72 (d, J = 8Hz, 0.6H), 7.38 (d, J = 8Hz , 0.6H), 7.48-7.55 (m, 0.4H), 7.52 (d, J = 8Hz, 1H), 7.75 (dd, J = 8, 8Hz, 0.6H) , 7.76(dd,J=8,8Hz,0.4H).

(Example 11)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)ethan-1-one

参考例１に記載した方法に従い、実施例１０で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．１６－０．３０（ｍ，２Ｈ），０．５５－０．６６（ｍ，２Ｈ），０．７８－１．０４（ｍ，１Ｈ），１．３８－１．７９（ｍ，３Ｈ），２．０８－２．７３（ｍ，６Ｈ），２．７３－２．９０（ｍ，１Ｈ），２．９６（ｄ，Ｊ＝１９Ｈｚ，０．４Ｈ），３．０２（ｄ，Ｊ＝１９Ｈｚ，０．６Ｈ），３．０７－３．３３（ｍ，１Ｈ），３．４６－３．８０（ｍ，１．８Ｈ），３．８８（ｄ，Ｊ＝１５Ｈｚ，０．４Ｈ），４．０３（ｄ，Ｊ＝１５Ｈｚ，０．４Ｈ），４．１２（ｄ，Ｊ＝１６Ｈｚ，０．６Ｈ），４．２１－４．２９（ｍ，０．６Ｈ），４．３７－４．４５（ｍ，０．６Ｈ），４．５１（ｄ，Ｊ＝１６Ｈｚ，０．６Ｈ），４．６８－４．７４（ｍ，１Ｈ），６．４２（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．５１（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．６４（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７８（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），７．３４（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），７．４６（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），７．４７（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），７．５７（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），７．７１（ｄｄ，Ｊ＝８，８Ｈｚ，０．４Ｈ），７．８１（ｄｄ，Ｊ＝８，８Ｈｚ，０．６Ｈ）．

According to the method described in Reference Example 1, the title compound was obtained from the compound obtained in Example 10.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.16-0.30 (m, 2H), 0.55-0.66 (m, 2H), 0.78-1.04 (m , 1H), 1.38-1.79 (m, 3H), 2.08-2.73 (m, 6H), 2.73-2.90 (m, 1H), 2.96 (d, J = 19Hz, 0.4H), 3.02 (d, J = 19Hz, 0.6H), 3.07-3.33 (m, 1H), 3.46-3.80 (m, 1.8H) , 3.88 (d, J = 15Hz, 0.4H), 4.03 (d, J = 15Hz, 0.4H), 4.12 (d, J = 16Hz, 0.6H), 4.21- 4.29 (m, 0.6H), 4.37-4.45 (m, 0.6H), 4.51 (d, J=16Hz, 0.6H), 4.68-4.74 (m , 1H), 6.42 (d, J = 8Hz, 0.4H), 6.51 (d, J = 8Hz, 0.6H), 6.64 (d, J = 8Hz, 0.4H), 6 .78 (d, J = 8Hz, 0.6H), 7.34 (d, J = 8Hz, 0.4H), 7.46 (d, J = 8Hz, 0.4H), 7.47 (d, J = 8Hz, 0.6H), 7.57 (d, J = 8Hz, 0.6H), 7.71 (dd, J = 8, 8Hz, 0.4H), 7.81 (dd, J = 8 , 8Hz, 0.6H).

(Example 12)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a-hydroxy-10-methoxy-2,3,4,4a,5,6,8,8a-octahydro-4,13 - Synthesis of methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(6-methoxypyridin-2-yl)ethan-1-one

実施例６に記載した方法に従い、実施例２で得られた化合物及び２－（６－メトキシピリジン－２－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）： ０．０９－０．１９（ｍ，２Ｈ），０．４９－０．６０（ｍ，２Ｈ），０．７８－０．９０（ｍ，１Ｈ），１．４０－１．６９（ｍ，３Ｈ），２．１０（ｄｄｄ，Ｊ＝３，１２，１２Ｈｚ，０．３Ｈ），２．１９－２．４２（ｍ，３．７Ｈ），２．４７－２．６７（ｍ，２Ｈ），２．９３（ｄ，Ｊ＝６Ｈｚ，０．３Ｈ），２．９７（ｄ，Ｊ＝６Ｈｚ，０．７Ｈ），２．９９（ｄ，Ｊ＝１８Ｈｚ，０．３Ｈ），３．０２（ｄ，Ｊ＝１８Ｈｚ，０．７Ｈ），３．１２－３．２４（ｍ，０．７Ｈ），３．２６－３．３８（ｍ，０．３Ｈ），３．５９－３．６９（ｍ，０．７Ｈ），３．６９（ｄ，Ｊ＝１５Ｈｚ，０．７Ｈ），３．８２（ｄ，Ｊ＝１５Ｈｚ，０．３Ｈ），３．８３－４．０８（ｍ，１Ｈ），３．８６（ｓ，２．１Ｈ），３．８７（ｓ，０．９Ｈ），３．８７（ｓ，０．９Ｈ），３．８９（ｓ，２．１Ｈ），３．９６（ｄ，Ｊ＝１５Ｈｚ，０．３Ｈ），４．２０－４．２９（ｍ，０．６Ｈ），４．３４（ｄ，Ｊ＝１５Ｈｚ，０．７Ｈ），４．５７－４．７０（ｍ，１．４Ｈ），４．８６－４．９２（ｍ，０．３Ｈ），６．５３－６．６１（ｍ，２Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．７５（ｄ，Ｊ＝７Ｈｚ，０．３Ｈ），６．８０（ｄ，Ｊ＝７Ｈｚ，０．７Ｈ），７．４３（ｄｄ，Ｊ＝７，７Ｈｚ，０．３Ｈ），７．４７（ｄｄ，Ｊ＝７，８Ｈｚ，０．７Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 2 and 2-(6-methoxypyridin-2-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09-0.19 (m, 2H), 0.49-0.60 (m, 2H), 0.78-0.90 (m , 1H), 1.40-1.69 (m, 3H), 2.10 (ddd, J = 3, 12, 12Hz, 0.3H), 2.19-2.42 (m, 3.7H) , 2.47-2.67 (m, 2H), 2.93 (d, J = 6Hz, 0.3H), 2.97 (d, J = 6Hz, 0.7H), 2.99 (d, J = 18Hz, 0.3H), 3.02 (d, J = 18Hz, 0.7H), 3.12-3.24 (m, 0.7H), 3.26-3.38 (m, 0 .3H), 3.59-3.69 (m, 0.7H), 3.69 (d, J = 15Hz, 0.7H), 3.82 (d, J = 15Hz, 0.3H), 3 .83-4.08 (m, 1H), 3.86 (s, 2.1H), 3.87 (s, 0.9H), 3.87 (s, 0.9H), 3.89 (s , 2.1H), 3.96 (d, J = 15Hz, 0.3H), 4.20-4.29 (m, 0.6H), 4.34 (d, J = 15Hz, 0.7H) , 4.57-4.70 (m, 1.4H), 4.86-4.92 (m, 0.3H), 6.53-6.61 (m, 2H), 6.71 (d, J = 8Hz, 0.7H), 6.72 (d, J = 8Hz, 0.3H), 6.75 (d, J = 7Hz, 0.3H), 6.80 (d, J = 7Hz, 0.3H) .7H), 7.43 (dd, J=7,7Hz, 0.3H), 7.47 (dd, J=7,8Hz, 0.7H).

(Example 13)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(6-methoxypyridin-2-yl)ethan-1-one

参考例１に記載した方法に従い、実施例１２で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．２０（ｍ，２Ｈ），０．４６－０．６０（ｍ，２Ｈ），０．７６－０．９１（ｍ，１Ｈ），１．２４－１．２８（ｍ，１Ｈ），１．４２－１．６９（ｍ，２Ｈ），２．１３－２．４３（ｍ，５Ｈ），２．５５（ｄｄ，Ｊ＝７，１８Ｈｚ，０．５Ｈ），２．５６－２．６７（ｍ，１Ｈ），２．８６（ｄ，Ｊ＝６Ｈｚ，０．５Ｈ），２．９１－３．０４（ｍ，１．５Ｈ），３．０７－３．１７（ｍ，０．５Ｈ），３．４１－３．５７（ｍ，０．５Ｈ），３．５９－３．７３（ｍ，１．５Ｈ），３．７４（ｄ，Ｊ＝１５Ｈｚ，０．５Ｈ），３．８２（ｄ，Ｊ＝１５Ｈｚ，０．５Ｈ），３．８４（ｓ，１．５Ｈ），３．９１（ｓ，１．５Ｈ），３．９５（ｄ，Ｊ＝１５Ｈｚ，０．５Ｈ），４．２４－４．３４（ｍ，０．５Ｈ），４．３０（ｄ，Ｊ＝１５Ｈｚ，０．５Ｈ），４．６０－４．７４（ｍ，１．５Ｈ），６．４３（ｄ，Ｊ＝８Ｈｚ，０．５Ｈ），６．４６（ｄ，Ｊ＝８Ｈｚ，０．５Ｈ），６．５０（ｄ，Ｊ＝８Ｈｚ，０．５Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，０．５Ｈ），６．５８（ｄ，Ｊ＝８Ｈｚ，０．５Ｈ），６．５９（ｄ，Ｊ＝８Ｈｚ，０．５Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，０．５Ｈ），６．８５（ｄ，Ｊ＝７Ｈｚ，０．５Ｈ），７．３３（ｄｄ，Ｊ＝８，８Ｈｚ，０．５Ｈ），７．４９（ｄｄ，Ｊ＝７，８Ｈｚ，０．５Ｈ）．

According to the method described in Reference Example 1, the title compound was obtained from the compound obtained in Example 12.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.20 (m, 2H), 0.46-0.60 (m, 2H), 0.76-0.91 (m , 1H), 1.24-1.28 (m, 1H), 1.42-1.69 (m, 2H), 2.13-2.43 (m, 5H), 2.55 (dd, J = 7, 18Hz, 0.5H), 2.56-2.67 (m, 1H), 2.86 (d, J = 6Hz, 0.5H), 2.91-3.04 (m, 1. 5H), 3.07-3.17 (m, 0.5H), 3.41-3.57 (m, 0.5H), 3.59-3.73 (m, 1.5H), 3. 74 (d, J = 15Hz, 0.5H), 3.82 (d, J = 15Hz, 0.5H), 3.84 (s, 1.5H), 3.91 (s, 1.5H), 3.95 (d, J=15Hz, 0.5H), 4.24-4.34 (m, 0.5H), 4.30 (d, J=15Hz, 0.5H), 4.60-4 .74 (m, 1.5H), 6.43 (d, J = 8Hz, 0.5H), 6.46 (d, J = 8Hz, 0.5H), 6.50 (d, J = 8Hz, 0.5H), 6.54 (d, J = 8Hz, 0.5H), 6.58 (d, J = 8Hz, 0.5H), 6.59 (d, J = 8Hz, 0.5H), 6.71 (d, J = 8Hz, 0.5H), 6.85 (d, J = 7Hz, 0.5H), 7.33 (dd, J = 8, 8Hz, 0.5H), 7.49 (dd, J=7,8Hz, 0.5H).

(Example 14)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a-hydroxy-10-methoxy-2,3,4,4a,5,6,8,8a-octahydro-4,13 - Synthesis of methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(3-methoxypyridin-2-yl)ethan-1-one

実施例６に記載した方法に従い、実施例２で得られた化合物及び２－（３－メトキシピリジン－２－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）： ０．０９－０．１５（ｍ，２Ｈ），０．５０－０．５８（ｍ，２Ｈ），０．７９－０．９０（ｍ，１Ｈ），１．４３－１．７３（ｍ，３Ｈ），２．０３－２．１２（ｍ，０．４Ｈ），２．１８－２．４１（ｍ，３．６Ｈ），２．５３－２．６６（ｍ，２Ｈ），２．９４－３．０５（ｍ，２．４Ｈ），３．２０－３．３４（ｍ，１Ｈ），３．６０－３．７１（ｍ，０．６Ｈ），３．７９（ｓ，１．８Ｈ），３．８３（ｓ，１．２Ｈ），３．８６（ｓ，１．２Ｈ），３．８９（ｓ，１．８Ｈ），３．９３（ｄ，Ｊ＝１６Ｈｚ，０．６Ｈ），３．９７－４．０８（ｍ，１．４Ｈ），４．１８－４．３７（ｍ，１．４Ｈ），４．２８（ｄ，Ｊ＝１６Ｈｚ，０．６Ｈ），４．６２（ｄｄ，Ｊ＝２，４Ｈｚ，０．６Ｈ），４．９３（ｄｄ，Ｊ＝６，１１Ｈｚ，０．４Ｈ），６．５７（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．６１（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），７．０７－７．１７（ｍ，２Ｈ），８．１０（ｄｄ，Ｊ＝２，４Ｈｚ，０．６Ｈ），８．１４（ｄｄ，Ｊ＝２，４Ｈｚ，０．４Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 2 and 2-(3-methoxypyridin-2-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09-0.15 (m, 2H), 0.50-0.58 (m, 2H), 0.79-0.90 (m , 1H), 1.43-1.73 (m, 3H), 2.03-2.12 (m, 0.4H), 2.18-2.41 (m, 3.6H), 2.53 -2.66 (m, 2H), 2.94-3.05 (m, 2.4H), 3.20-3.34 (m, 1H), 3.60-3.71 (m, 0. 6H), 3.79 (s, 1.8H), 3.83 (s, 1.2H), 3.86 (s, 1.2H), 3.89 (s, 1.8H), 3.93 (d, J = 16Hz, 0.6H), 3.97-4.08 (m, 1.4H), 4.18-4.37 (m, 1.4H), 4.28 (d, J = 16Hz, 0.6H), 4.62 (dd, J = 2, 4Hz, 0.6H), 4.93 (dd, J = 6, 11Hz, 0.4H), 6.57 (d, J = 8Hz , 0.6H), 6.61 (d, J = 8Hz, 0.4H), 6.72 (d, J = 8Hz, 0.6H), 6.72 (d, J = 8Hz, 0.4H) , 7.07-7.17 (m, 2H), 8.10 (dd, J = 2, 4Hz, 0.6H), 8.14 (dd, J = 2, 4Hz, 0.4H).

(Example 15)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(3-methoxypyridin-2-yl)ethan-1-one

参考例１に記載した方法に従い、実施例１４で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．２０（ｍ，２Ｈ），０．４７－０．６０（ｍ，２Ｈ），０．７９－０．９２（ｍ，１Ｈ），１．２３－１．３８（ｍ，１Ｈ），１．４１－１．５０（ｍ，１Ｈ），１．５４－１．８４（ｍ，１Ｈ），２．１８－２．３６（ｍ，３Ｈ），２．４０（ｄｄ，Ｊ＝６，１３Ｈｚ，１Ｈ），２．４８（ｄｄ，Ｊ＝７，１９Ｈｚ，１Ｈ），２．５８－２．７０（ｍ，１Ｈ），２．８８（ｄ，Ｊ＝７Ｈｚ，０．１Ｈ），２．９４（ｄ，Ｊ＝７Ｈｚ，０．９Ｈ），２．９６－３．０６（ｍ，１Ｈ），３．００（ｄ，Ｊ＝１９Ｈｚ，１Ｈ），３．６２－３．６９（ｍ，１Ｈ），３．７９（ｓ，０．３Ｈ），３．８２（ｓ，２．７Ｈ），３．８９（ｄ，Ｊ＝１６Ｈｚ，０．１Ｈ），４．０１（ｄ，Ｊ＝１６Ｈｚ，０．９Ｈ），４．２８（ｄｄｄ，Ｊ＝３，３，１３Ｈｚ，１Ｈ），４．３５－４．４３（ｍ，１Ｈ），４．６１－４．６４（ｍ，０．１Ｈ），４．６５－４．７０（ｍ，０．９Ｈ），４．８０（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），４．８４（ｂｒ ｓ，１Ｈ），６．４４－６．４７（ｍ，０．１Ｈ），６．４８（ｄ，Ｊ＝８Ｈｚ，０．９Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．１Ｈ），６．８４（ｄ，Ｊ＝８Ｈｚ，０．９Ｈ），７．０５－７．０８（ｍ，０．２Ｈ），７．１９－７．２２（ｍ，１．８Ｈ），８．００－８．０３（ｍ，０．１Ｈ），８．０７－８．１３（ｍ，０．９Ｈ）．

According to the method described in Reference Example 1, the title compound was obtained from the compound obtained in Example 14.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.20 (m, 2H), 0.47-0.60 (m, 2H), 0.79-0.92 (m , 1H), 1.23-1.38 (m, 1H), 1.41-1.50 (m, 1H), 1.54-1.84 (m, 1H), 2.18-2.36 (m, 3H), 2.40 (dd, J = 6, 13Hz, 1H), 2.48 (dd, J = 7, 19Hz, 1H), 2.58-2.70 (m, 1H), 2 .88 (d, J = 7Hz, 0.1H), 2.94 (d, J = 7Hz, 0.9H), 2.96-3.06 (m, 1H), 3.00 (d, J = 19Hz, 1H), 3.62-3.69 (m, 1H), 3.79 (s, 0.3H), 3.82 (s, 2.7H), 3.89 (d, J = 16Hz, 0.1H), 4.01 (d, J = 16Hz, 0.9H), 4.28 (ddd, J = 3, 3, 13Hz, 1H), 4.35-4.43 (m, 1H), 4.61-4.64 (m, 0.1H), 4.65-4.70 (m, 0.9H), 4.80 (d, J=16Hz, 1H), 4.84 (br s, 1H), 6.44-6.47 (m, 0.1H), 6.48 (d, J = 8Hz, 0.9H), 6.73 (d, J = 8Hz, 0.1H), 6. 84 (d, J = 8Hz, 0.9H), 7.05-7.08 (m, 0.2H), 7.19-7.22 (m, 1.8H), 8.00-8.03 (m, 0.1H), 8.07-8.13 (m, 0.9H).

(Example 16)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a-hydroxy-10-methoxy-2,3,4,4a,5,6,8,8a-octahydro-4,13 - Synthesis of methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(pyrimidin-2-yl)ethan-1-one

実施例６に記載した方法に従い、実施例２で得られた化合物及び２－（ピリミジン－２－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）： ０．０９－０．１９（ｍ，２Ｈ），０．４７－０．６１（ｍ，２Ｈ），０．７７－０．９０（ｍ，１Ｈ），１．４３－１．６９（ｍ，３Ｈ），２．０８（ｄｄｄ，Ｊ＝４，１２，１２Ｈｚ，０．６Ｈ），２．２２－２．４１（ｍ，３．４Ｈ），２．５２－２．６７（ｍ，２Ｈ），２．８３－３．０５（ｍ，２．４Ｈ），３．１８－３．２７（ｍ，１Ｈ），３．６５（ｄｄ，Ｊ＝２，１７Ｈｚ，０．６Ｈ），３．８６（ｓ，１．２Ｈ），３．８８（ｓ，１．８Ｈ），３．９５－４．０６（ｍ，０．６Ｈ），３．９９（ｄ，Ｊ＝１５Ｈｚ，０．６Ｈ），４．２１（ｄ，Ｊ＝１６Ｈｚ，０．４Ｈ），４．２２（ｄ，Ｊ＝１６Ｈｚ，０．４Ｈ），４．２５－４．３４（ｍ，０．８Ｈ），４．３７－４．４７（ｍ，０．６Ｈ），４．６０－４．６６（ｍ，０．６Ｈ），４．６３（ｄ，Ｊ＝１５Ｈｚ，０．６Ｈ），４．９５（ｄｄ，Ｊ＝６，１１Ｈｚ，０．４Ｈ），６．５７（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．６１（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），７．１４（ｔ，Ｊ＝５Ｈｚ，０．６Ｈ），７．１７（ｔ，Ｊ＝５Ｈｚ，０．４Ｈ），８．６８（ｄ，Ｊ＝５Ｈｚ，１．２Ｈ），８．７２（ｄ，Ｊ＝５Ｈｚ，０．８Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 2 and 2-(pyrimidin-2-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09-0.19 (m, 2H), 0.47-0.61 (m, 2H), 0.77-0.90 (m , 1H), 1.43-1.69 (m, 3H), 2.08 (ddd, J = 4, 12, 12Hz, 0.6H), 2.22-2.41 (m, 3.4H) , 2.52-2.67 (m, 2H), 2.83-3.05 (m, 2.4H), 3.18-3.27 (m, 1H), 3.65 (dd, J = 2, 17Hz, 0.6H), 3.86 (s, 1.2H), 3.88 (s, 1.8H), 3.95-4.06 (m, 0.6H), 3.99 ( d, J = 15 Hz, 0.6 H), 4.21 (d, J = 16 Hz, 0.4 H), 4.22 (d, J = 16 Hz, 0.4 H), 4.25-4.34 (m , 0.8H), 4.37-4.47 (m, 0.6H), 4.60-4.66 (m, 0.6H), 4.63 (d, J = 15Hz, 0.6H) , 4.95 (dd, J=6, 11 Hz, 0.4 H), 6.57 (d, J=8 Hz, 0.6 H), 6.61 (d, J=8 Hz, 0.4 H), 6. 72 (d, J = 8Hz, 0.6H), 6.72 (d, J = 8Hz, 0.4H), 7.14 (t, J = 5Hz, 0.6H), 7.17 (t, J = 5Hz, 0.4H), 8.68 (d, J = 5Hz, 1.2H), 8.72 (d, J = 5Hz, 0.8H).

(Example 17)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(pyrimidin-2-yl)ethan-1-one

参考例１に記載した方法に従い、実施例１６で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１９（ｍ，２Ｈ），０．４７－０．６０（ｍ，２Ｈ），０．７８－０．９１（ｍ，１Ｈ），１．３０－１．３９（ｍ，１Ｈ），１．４１－１．５１（ｍ，１Ｈ），１．６２－１．７３（ｍ，１Ｈ），２．１６－２．４３（ｍ，４．１Ｈ），２．４８（ｄｄ，Ｊ＝７，１８Ｈｚ，０．９Ｈ），２．５６－２．７１（ｍ，１Ｈ），２．８８（ｄ，Ｊ＝６Ｈｚ，０．１Ｈ），２．９５（ｄ，Ｊ＝７Ｈｚ，０．９Ｈ），２．９７－３．１１（ｍ，１．１Ｈ），３．０２（ｄ，Ｊ＝１８Ｈｚ，０．９Ｈ），３．４８－３．８０（ｍ，１．２Ｈ），３．８９（ｄ，Ｊ＝１５Ｈｚ，０．９Ｈ），４．０２（ｄ，Ｊ＝１５Ｈｚ，０．１Ｈ），４．１３（ｄ，Ｊ＝１５Ｈｚ，０．１Ｈ），４．２６（ｄｄｄ，Ｊ＝３，３，１４Ｈｚ，０．９Ｈ），４．３３（ｄｄｄ，Ｊ＝１，３，１６Ｈｚ，０．９Ｈ），４．６６－４．７３（ｍ，１Ｈ），４．８５（ｂｒ ｓ，１Ｈ），５．１０（ｄ，Ｊ＝１５Ｈｚ，０．９Ｈ），６．４４（ｄ，Ｊ＝８Ｈｚ，０．１Ｈ），６．４９（ｄ，Ｊ＝８Ｈｚ，０．９Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．１Ｈ），６．８２（ｄ，Ｊ＝８Ｈｚ，０．９Ｈ），７．０９（ｔ，Ｊ＝５Ｈｚ，０．１Ｈ），７．２４（ｔ，Ｊ＝５Ｈｚ，０．９Ｈ），８．６２（ｄ，Ｊ＝５Ｈｚ，０．２Ｈ），８．７４（ｄ，Ｊ＝５Ｈｚ，１．８Ｈ）．

According to the method described in Reference Example 1, the title compound was obtained from the compound obtained in Example 16.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.19 (m, 2H), 0.47-0.60 (m, 2H), 0.78-0.91 (m , 1H), 1.30-1.39 (m, 1H), 1.41-1.51 (m, 1H), 1.62-1.73 (m, 1H), 2.16-2.43 (m, 4.1H), 2.48 (dd, J=7, 18Hz, 0.9H), 2.56-2.71 (m, 1H), 2.88 (d, J=6Hz, 0.9H). 1H), 2.95 (d, J=7Hz, 0.9H), 2.97-3.11 (m, 1.1H), 3.02 (d, J=18Hz, 0.9H), 3. 48-3.80 (m, 1.2H), 3.89 (d, J = 15Hz, 0.9H), 4.02 (d, J = 15Hz, 0.1H), 4.13 (d, J = 15Hz, 0.1H), 4.26 (ddd, J = 3, 3, 14Hz, 0.9H), 4.33 (ddd, J = 1, 3, 16Hz, 0.9H), 4.66- 4.73 (m, 1H), 4.85 (br s, 1H), 5.10 (d, J = 15Hz, 0.9H), 6.44 (d, J = 8Hz, 0.1H), 6 .49 (d, J=8 Hz, 0.9 H), 6.73 (d, J=8 Hz, 0.1 H), 6.82 (d, J=8 Hz, 0.9 H), 7.09 (t, J = 5Hz, 0.1H), 7.24 (t, J = 5Hz, 0.9H), 8.62 (d, J = 5Hz, 0.2H), 8.74 (d, J = 5Hz, 1 .8H).

(Example 18)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(thiazol-2-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（チアゾール－２－イル）酢酸ナトリウムより表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１７（ｍ，２Ｈ），０．４８－０．５７（ｍ，２Ｈ），０．７８－０．９１（ｍ，１Ｈ），１．３４－１．６８（ｍ，３Ｈ），２．１４－２．４２（ｍ，４Ｈ），２．４８（ｄｄ，Ｊ＝７，１８Ｈｚ，１Ｈ），２．５８－２．６９（ｍ，１Ｈ），２．８８－３．１２（ｍ，３Ｈ），３．４８－３．７５（ｍ，０．２Ｈ），３．７０（ｄｄ，Ｊ＝１，１６Ｈｚ，０．９Ｈ），３．７８（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），４．０８（ｄ，Ｊ＝１６Ｈｚ，０．１Ｈ），４．１６（ｄ，Ｊ＝１６Ｈｚ，０．１Ｈ），４．３０－４．３９（ｍ，１．８Ｈ），４．６４－４．６８（ｍ，０．９Ｈ），４．７３－４．８０（ｍ，０．１Ｈ），４．８７（ｂｒ ｓ，１Ｈ），５．２０（ｄ，Ｊ＝１６Ｈｚ，０．９Ｈ），６．４６（ｄ，Ｊ＝８Ｈｚ，０．９Ｈ），６．４７－６．５０（ｍ，０．１Ｈ），６．６９（ｄ，Ｊ＝８Ｈｚ，０．１Ｈ），６．７５（ｄ，Ｊ＝８Ｈｚ，０．９Ｈ），７．２０（ｄ，Ｊ＝３Ｈｚ，０．１Ｈ），７．３２（ｄ，Ｊ＝３Ｈｚ，０．９Ｈ），７．６３（ｄ，Ｊ＝３Ｈｚ，０．１Ｈ），７．７３（ｄ，Ｊ＝３Ｈｚ，０．９Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and sodium 2-(thiazol-2-yl)acetate.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.17 (m, 2H), 0.48-0.57 (m, 2H), 0.78-0.91 (m , 1H), 1.34-1.68 (m, 3H), 2.14-2.42 (m, 4H), 2.48 (dd, J = 7, 18Hz, 1H), 2.58-2 .69 (m, 1H), 2.88-3.12 (m, 3H), 3.48-3.75 (m, 0.2H), 3.70 (dd, J = 1, 16Hz, 0. 9H), 3.78 (d, J = 16Hz, 1H), 4.08 (d, J = 16Hz, 0.1H), 4.16 (d, J = 16Hz, 0.1H), 4.30- 4.39 (m, 1.8H), 4.64-4.68 (m, 0.9H), 4.73-4.80 (m, 0.1H), 4.87 (br s, 1H) , 5.20 (d, J = 16 Hz, 0.9 H), 6.46 (d, J = 8 Hz, 0.9 H), 6.47-6.50 (m, 0.1 H), 6.69 ( d, J = 8 Hz, 0.1 H), 6.75 (d, J = 8 Hz, 0.9 H), 7.20 (d, J = 3 Hz, 0.1 H), 7.32 (d, J = 3 Hz , 0.9H), 7.63 (d, J=3 Hz, 0.1 H), 7.73 (d, J=3 Hz, 0.9 H).

(Example 19)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a-hydroxy-10-methoxy-2,3,4,4a,5,6,8,8a-octahydro-4,13 - Synthesis of methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(thiazol-4-yl)ethan-1-one

実施例６に記載した方法に従い、実施例２で得られた化合物及び２－（チアゾール－４－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）： ０．０６－０．２０（ｍ，２Ｈ），０．４６－０．６１（ｍ，２Ｈ），０．７７－０．９１（ｍ，１Ｈ），１．４１－１．６８（ｍ，３Ｈ），２．１０（ｄｄｄ，Ｊ＝４，１２，１２Ｈｚ，０．４Ｈ），２．１７－２．４２（ｍ，３．６Ｈ），２．５０－２．６７（ｍ，２Ｈ），２．９１－３．０５（ｍ，２Ｈ），３．１０－３．２４（ｍ，０．６Ｈ），３．２５－３．３５（ｍ，０．４Ｈ），３．６０－３．７０（ｍ，１Ｈ），３．８１－４．０６（ｍ，１Ｈ），３．８５（ｓ，１．８Ｈ），３．８７（ｓ，１．２Ｈ），３．９０（ｄ，Ｊ＝１６Ｈｚ，０．６Ｈ），３．９６（ｄ，Ｊ＝１６Ｈｚ，０．４Ｈ），４．１２（ｄ，Ｊ＝１６Ｈｚ，０．４Ｈ），４．２０－４．３２（ｍ，０．８Ｈ），４．３７－４．５０（ｍ，０．６Ｈ），４．４１（ｄ，Ｊ＝１６Ｈｚ，０．６Ｈ），４．６０－４．６６（ｍ，０．６Ｈ），４．９０（ｄｄ，Ｊ＝５，９Ｈｚ，０．４Ｈ），６．５６（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．６１（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７０（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），７．０９（ｂｒ ｓ，０．４Ｈ），７．１５（ｓ，０．６Ｈ），８．７４（ｓ，１Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 2 and 2-(thiazol-4-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.20 (m, 2H), 0.46-0.61 (m, 2H), 0.77-0.91 (m , 1H), 1.41-1.68 (m, 3H), 2.10 (ddd, J = 4, 12, 12Hz, 0.4H), 2.17-2.42 (m, 3.6H) , 2.50-2.67 (m, 2H), 2.91-3.05 (m, 2H), 3.10-3.24 (m, 0.6H), 3.25-3.35 ( m, 0.4H), 3.60-3.70 (m, 1H), 3.81-4.06 (m, 1H), 3.85 (s, 1.8H), 3.87 (s, 1.2H), 3.90 (d, J = 16Hz, 0.6H), 3.96 (d, J = 16Hz, 0.4H), 4.12 (d, J = 16Hz, 0.4H), 4.20-4.32 (m, 0.8H), 4.37-4.50 (m, 0.6H), 4.41 (d, J=16Hz, 0.6H), 4.60-4 .66 (m, 0.6H), 4.90 (dd, J = 5, 9Hz, 0.4H), 6.56 (d, J = 8Hz, 0.6H), 6.61 (d, J = 8Hz, 0.4H), 6.70 (d, J = 8Hz, 0.6H), 6.73 (d, J = 8Hz, 0.4H), 7.09 (br s, 0.4H), 7 .15 (s, 0.6H), 8.74 (s, 1H).

(Example 20)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(thiazol-4-yl)ethan-1-one

参考例１に記載した方法に従い、実施例１９で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１９（ｍ，２Ｈ），０．４７－０．６０（ｍ，２Ｈ），０．７６－０．９０（ｍ，１Ｈ），１．３４－１．５５（ｍ，２Ｈ），１．５９－１．６９（ｍ，１Ｈ），２．１７－２．４３（ｍ，４．２Ｈ），２．４９（ｄｄ，Ｊ＝７，１９Ｈｚ，０．８Ｈ），２．５６－２．７０（ｍ，１Ｈ），２．８５（ｄ，Ｊ＝６Ｈｚ，０．２Ｈ），２．９４（ｄ，Ｊ＝７Ｈｚ，０．８Ｈ），２．９５（ｄ，Ｊ＝１８Ｈｚ，０．２Ｈ），３．０２（ｄ，Ｊ＝１９Ｈｚ，０．８Ｈ），３．０２－３．１２（ｍ，１Ｈ），３．４０－３．７４（ｍ，２Ｈ），３．７９（ｄ，Ｊ＝１６Ｈｚ，０．２Ｈ），４．０５（ｄ，Ｊ＝１６Ｈｚ，０．２Ｈ），４．２７－４．３５（ｍ，０．８Ｈ），４．３６－４．４４（ｍ，０．８Ｈ），４．６４－４．６７（ｍ，０．８Ｈ），４．６８－４．７２（ｍ，０．２Ｈ），４．８９（ｄ，Ｊ＝１６Ｈｚ，０．８Ｈ），４．９１（ｄ，Ｊ＝１６Ｈｚ，０．２Ｈ），６．４８（ｄ，Ｊ＝８Ｈｚ，０．８Ｈ），６．４９（ｄ，Ｊ＝８Ｈｚ，０．２Ｈ），６．７１－６．８１（ｍ，１．２Ｈ），７．２０（ｄ，Ｊ＝２Ｈｚ，０．８Ｈ），８．６３（ｄ，Ｊ＝２Ｈｚ，０．２Ｈ），８．８０（ｄ，Ｊ＝２Ｈｚ，０．８Ｈ）．
．

According to the method described in Reference Example 1, the title compound was obtained from the compound obtained in Example 19.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.19 (m, 2H), 0.47-0.60 (m, 2H), 0.76-0.90 (m , 1H), 1.34-1.55 (m, 2H), 1.59-1.69 (m, 1H), 2.17-2.43 (m, 4.2H), 2.49 (dd , J = 7, 19Hz, 0.8H), 2.56-2.70 (m, 1H), 2.85 (d, J = 6Hz, 0.2H), 2.94 (d, J = 7Hz, 0.8H), 2.95 (d, J = 18Hz, 0.2H), 3.02 (d, J = 19Hz, 0.8H), 3.02-3.12 (m, 1H), 3. 40-3.74 (m, 2H), 3.79 (d, J = 16Hz, 0.2H), 4.05 (d, J = 16Hz, 0.2H), 4.27-4.35 (m , 0.8H), 4.36-4.44 (m, 0.8H), 4.64-4.67 (m, 0.8H), 4.68-4.72 (m, 0.2H) , 4.89 (d, J=16 Hz, 0.8 H), 4.91 (d, J=16 Hz, 0.2 H), 6.48 (d, J=8 Hz, 0.8 H), 6.49 ( d, J = 8Hz, 0.2H), 6.71-6.81 (m, 1.2H), 7.20 (d, J = 2Hz, 0.8H), 8.63 (d, J = 2Hz , 0.2H), 8.80 (d, J=2Hz, 0.8H).
.

(Example 21)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(1H-pyrazol-1-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（１Ｈ－ピラゾール－１－イル）酢酸より表題化合物得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．２０（ｍ，２Ｈ），０．６０－０．７０（ｍ，２Ｈ），０．７５－０．９０（ｍ，１Ｈ），１．２０－１．３０（ｍ，１Ｈ），１．３０－１．５５（ｍ，２Ｈ），１．６０－１．７０（ｍ，１Ｈ），２．２５－２．５５（ｍ，４Ｈ），２．６０－２．７０（ｍ，１Ｈ），２．９０－３．１５（ｍ，３Ｈ），３．６５－３．８０（ｍ，２Ｈ），４．２０－４．３５（ｍ，２Ｈ），４．６０－４．７０（ｍ，２Ｈ），６．１９（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），６．３０（ｄ，Ｊ＝２Ｈｚ，１Ｈ），６．４９（ｄ，Ｊ＝８Ｈｚ，０．９Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，０．１Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．１Ｈ），６．８１（ｄ，Ｊ＝８Ｈｚ，０．９Ｈ），７．４１（ｓ，０．１Ｈ），７．４６（ｄ，Ｊ＝２Ｈｚ，０．９Ｈ），７．５２（ｓ，０．１Ｈ），７．５７（ｄ，Ｊ＝２Ｈｚ，０．９Ｈ），８．８２（ｂｒ＿ｓ，１Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 2-(1H-pyrazol-1-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.20 (m, 2H), 0.60-0.70 (m, 2H), 0.75-0.90 (m , 1H), 1.20-1.30 (m, 1H), 1.30-1.55 (m, 2H), 1.60-1.70 (m, 1H), 2.25-2.55 (m, 4H), 2.60-2.70 (m, 1H), 2.90-3.15 (m, 3H), 3.65-3.80 (m, 2H), 4.20-4 .35 (m, 2H), 4.60-4.70 (m, 2H), 6.19 (d, J = 16Hz, 1H), 6.30 (d, J = 2Hz, 1H), 6.49 (d, J = 8 Hz, 0.9 H), 6.54 (d, J = 8 Hz, 0.1 H), 6.72 (d, J = 8 Hz, 0.1 H), 6.81 (d, J = 8Hz, 0.9H), 7.41 (s, 0.1H), 7.46 (d, J = 2Hz, 0.9H), 7.52 (s, 0.1H), 7.57 (d, J=2Hz, 0.9H), 8.82(br_s, 1H).

(Example 22)
(4R,4aS,8aR,13bS)-7-(2-(1H-pyrazol-1-yl)ethyl)-3-(cyclopropylmethyl)-1,2,3,4,6,7,8,8a -Synthesis of octahydro-4,13-methanobenzofuro[2,3-c]pyrido[4,3-d]azepine-4a,10(5H)-diol

実施例２に記載した方法に従い、実施例２１で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．００－０．２０（ｍ，２Ｈ），０．５０－０．６０（ｍ，２Ｈ），０．７５－０．９０（ｍ，１Ｈ），１．２０－１．４０（ｍ，２Ｈ），１．５０－１．７０（ｍ，２Ｈ），２．２０－２．４５（ｍ，４Ｈ），２．４５－２．７０（ｍ，４Ｈ），２．８０－２．９５（ｍ，２Ｈ），２．９５－３．３０（ｍ，４Ｈ），４．０５－４．１５（ｍ，１Ｈ），４．４０－４．５０（ｍ，２Ｈ），６．１０－６．２５（ｍ，１Ｈ），６．５１（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７６（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．３１（ｄ，Ｊ＝２Ｈｚ，１Ｈ），７．４８（ｄ，Ｊ＝２Ｈｚ，１Ｈ）．

The title compound was obtained from the compound obtained in Example 21 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.20 (m, 2H), 0.50-0.60 (m, 2H), 0.75-0.90 (m , 1H), 1.20-1.40 (m, 2H), 1.50-1.70 (m, 2H), 2.20-2.45 (m, 4H), 2.45-2.70 (m, 4H), 2.80-2.95 (m, 2H), 2.95-3.30 (m, 4H), 4.05-4.15 (m, 1H), 4.40-4 .50 (m, 2H), 6.10-6.25 (m, 1H), 6.51 (d, J = 8Hz, 1H), 6.76 (d, J = 8Hz, 1H), 7.31 (d, J=2 Hz, 1 H), 7.48 (d, J=2 Hz, 1 H).

(Example 23)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(5-methyl-1H-pyrazol-1-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（５－メチル－１Ｈ－ピラゾール－１－イル）酢酸より表題化合物得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．１０－０．２０（ｍ，２Ｈ），０．５０－０．６０（ｍ，２Ｈ），０．８０－０．９５（ｍ，１Ｈ），１．３０－１．４０（ｍ，１Ｈ），１．４０－１．５５（ｍ，１Ｈ），１．６０－１．７５（ｍ，２Ｈ），２．２３（ｓ，３Ｈ），２．２５－２．６０（ｍ，５Ｈ），２．６０－２．７０（ｍ，１Ｈ），２．９０－３．１０（ｍ，３Ｈ），３．７０（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），４．２０－４．３０（ｍ，２Ｈ），４．５５（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），４．６６（ｓ，１Ｈ），６．０３（ｓ，１Ｈ），６．１３（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），６．４９（ｄ，Ｊ＝８Ｈｚ，１Ｈ）６．８３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．４４（ｓ，１Ｈ），９．２５（ｂｒ ｓ，１Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 2-(5-methyl-1H-pyrazol-1-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10-0.20 (m, 2H), 0.50-0.60 (m, 2H), 0.80-0.95 (m , 1H), 1.30-1.40 (m, 1H), 1.40-1.55 (m, 1H), 1.60-1.75 (m, 2H), 2.23 (s, 3H) ), 2.25-2.60 (m, 5H), 2.60-2.70 (m, 1H), 2.90-3.10 (m, 3H), 3.70 (d, J = 16Hz , 1H), 4.20-4.30 (m, 2H), 4.55 (d, J = 16Hz, 1H), 4.66 (s, 1H), 6.03 (s, 1H), 6. 13 (d, J = 16Hz, 1H), 6.49 (d, J = 8Hz, 1H) 6.83 (d, J = 8Hz, 1H), 7.44 (s, 1H), 9.25 (br s, 1H).

(Example 24)
(4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-7-(2-(5-methyl-1H-pyrazol-1-yl)ethyl)-1,2,3,4,6,7 ,8,8a-octahydro-4,13-methanobenzofuro[2,3-c]pyrido[4,3-d]azepine-4a,10(5H)-diol

実施例２に記載した方法に従い、実施例２３で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ（ｐｐｍ）：０．０５－０．１５（ｍ，２Ｈ），０．４５－０．５５（ｍ，２Ｈ），０．７５－０．９０（ｍ，１Ｈ），１．２０－１．３０（ｍ，１Ｈ），１．５７（ｄ，Ｊ＝１１Ｈｚ，１Ｈ），１．６５－１．７５（ｍ，１Ｈ），２．１９（ｓ，３Ｈ），２．２５－２．５５（ｍ，７Ｈ），２．５５－２．７０（ｍ，２Ｈ），２．７０－２．８０（ｍ，１Ｈ），２．９１（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．００（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．１５（ｄｄ，Ｊ＝２，１６Ｈｚ，１Ｈ），３．２５－３．４０（ｍ，１Ｈ），３．４１（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），３．９５－４．０５（ｍ，１Ｈ），４．４５－４．５５（ｍ，１Ｈ），４．６０－４．７０（ｍ，１Ｈ），５．９５（ｄ，Ｊ＝２Ｈｚ，１Ｈ），６．５０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．８０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．３８（ｄ，Ｊ＝２Ｈｚ，１Ｈ）．

The title compound was obtained from the compound obtained in Example 23 according to the method described in Example 2.

¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 0.05-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.75-0.90 ( m, 1H), 1.20-1.30 (m, 1H), 1.57 (d, J = 11Hz, 1H), 1.65-1.75 (m, 1H), 2.19 (s, 3H), 2.25-2.55 (m, 7H), 2.55-2.70 (m, 2H), 2.70-2.80 (m, 1H), 2.91 (d, J = 6Hz, 1H), 3.00 (d, J = 18Hz, 1H), 3.15 (dd, J = 2, 16Hz, 1H), 3.25-3.40 (m, 1H), 3.41 ( d, J=16 Hz, 1H), 3.95-4.05 (m, 1H), 4.45-4.55 (m, 1H), 4.60-4.70 (m, 1H), 5. 95 (d, J=2 Hz, 1 H), 6.50 (d, J=8 Hz, 1 H), 6.80 (d, J=8 Hz, 1 H), 7.38 (d, J=2 Hz, 1 H).

(Example 25)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(4-methyl-1H-pyrazol-1-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（４－メチル－１Ｈ－ピラゾール－１－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１９（ｍ，２Ｈ），０．５０－０．５９（ｍ，２Ｈ），０．７９－０．９０（ｍ，１Ｈ），１．３２－１．４０（ｍ，１Ｈ），１．４１－１．５１（ｍ，１Ｈ），１．６０－１．７０（ｍ，１Ｈ），２．０６（ｓ，３Ｈ），２．２７－２．４２（ｍ，４Ｈ），２．４８（ｄｄ，Ｊ＝７，１８Ｈｚ，１Ｈ），２．５９－２．７０（ｍ，１Ｈ），２．９４（ｄ，Ｊ＝７Ｈｚ，１Ｈ），３．０１（ｄ，Ｊ＝１９Ｈｚ，１Ｈ），３．０２－３．１０（ｍ，１Ｈ），３．６９（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），４．１６－４．２９（ｍ，２Ｈ），４．５５（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），４．６２－４．６６（ｍ，１Ｈ），６．１０（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），６．４８（ｄ，Ｊ＝８Ｈｚ，０．９Ｈ），６．５３（ｄ，Ｊ＝８Ｈｚ，０．１Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．１Ｈ），６．８１（ｄ，Ｊ＝８Ｈｚ，０．９Ｈ），７．２３（ｓ，１Ｈ），７．３５（ｓ，１Ｈ），８．９７（ｂｒ ｓ，１Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 2-(4-methyl-1H-pyrazol-1-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.19 (m, 2H), 0.50-0.59 (m, 2H), 0.79-0.90 (m , 1H), 1.32-1.40 (m, 1H), 1.41-1.51 (m, 1H), 1.60-1.70 (m, 1H), 2.06 (s, 3H) ), 2.27-2.42 (m, 4H), 2.48 (dd, J = 7, 18Hz, 1H), 2.59-2.70 (m, 1H), 2.94 (d, J = 7Hz, 1H), 3.01 (d, J = 19Hz, 1H), 3.02-3.10 (m, 1H), 3.69 (d, J = 16Hz, 1H), 4.16-4 .29 (m, 2H), 4.55 (d, J=16Hz, 1H), 4.62-4.66 (m, 1H), 6.10 (d, J=16Hz, 1H), 6.48 (d, J = 8 Hz, 0.9 H), 6.53 (d, J = 8 Hz, 0.1 H), 6.73 (d, J = 8 Hz, 0.1 H), 6.81 (d, J = 8Hz, 0.9H), 7.23 (s, 1H), 7.35 (s, 1H), 8.97 (br s, 1H).

(Example 26)
(4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-7-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-1,2,3,4,6,7 ,8,8a-octahydro-4,13-methanobenzofuro[2,3-c]pyrido[4,3-d]azepine-4a,10(5H)-diol

実施例２に記載した方法に従い、実施例２５で得られた化合物より表題化合物を得た。

The title compound was obtained from the compound obtained in Example 25 according to the method described in Example 2.

(Example 27)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a-hydroxy-10-methoxy-2,3,4,4a,5,6,8,8a-octahydro-4,13 - Synthesis of methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(1-methyl-1H-imidazol-4-yl)ethan-1-one

実施例６に記載した方法に従い、実施例２で得られた化合物および２－（１－メチル－１Ｈ－イミダゾール－４－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０９－０．１６（ｍ，２Ｈ），０．５０－０．５７（ｍ，２Ｈ），０．７７－０．９３（ｍ，１Ｈ），１．４０－１．６７（ｍ，３Ｈ），２．０３－２．１３（ｍ，０．４Ｈ），２．１８－２．４１（ｍ，３．６Ｈ），２．５１－２．６６（ｍ，２Ｈ），２．９２－３．００（ｍ，１Ｈ），３．００（ｄ，Ｊ＝１９Ｈｚ，１Ｈ），３．１２－３．２３（ｍ，０．６Ｈ），３．２６－３．３６（ｍ，０．４Ｈ），３．５２（ｄ，Ｊ＝１６Ｈｚ，０．６Ｈ），３．５９－３．６７（ｍ，０．６Ｈ），３．６１（ｓ，１．８Ｈ），３．６２（ｓ，１．２Ｈ），３．７１（ｄ，Ｊ＝１７Ｈｚ，０．４Ｈ），３．７８－３．８９（ｍ，０．４Ｈ），３．８４（ｓ，１．８Ｈ），３．８７（ｓ，１．２Ｈ），３．９７－４．２６（ｍ，１．８Ｈ），４．１９（ｄ，Ｊ＝１６Ｈｚ，０．６Ｈ），４．４５－４．５５（ｍ，０．６Ｈ），４．６０－４．６５（ｍ，０．６Ｈ），４．８７－４．９４（ｍ，０．４Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．６０（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．６８（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７７（ｓ，０．６Ｈ），６．７９（ｓ，０．４Ｈ），７．３２（ｓ，１Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 2 and 2-(1-methyl-1H-imidazol-4-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09-0.16 (m, 2H), 0.50-0.57 (m, 2H), 0.77-0.93 (m , 1H), 1.40-1.67 (m, 3H), 2.03-2.13 (m, 0.4H), 2.18-2.41 (m, 3.6H), 2.51 -2.66 (m, 2H), 2.92-3.00 (m, 1H), 3.00 (d, J=19Hz, 1H), 3.12-3.23 (m, 0.6H) , 3.26-3.36 (m, 0.4H), 3.52 (d, J = 16Hz, 0.6H), 3.59-3.67 (m, 0.6H), 3.61 ( s, 1.8H), 3.62 (s, 1.2H), 3.71 (d, J=17Hz, 0.4H), 3.78-3.89 (m, 0.4H), 3. 84 (s, 1.8H), 3.87 (s, 1.2H), 3.97-4.26 (m, 1.8H), 4.19 (d, J=16Hz, 0.6H), 4.45-4.55 (m, 0.6H), 4.60-4.65 (m, 0.6H), 4.87-4.94 (m, 0.4H), 6.54 (d , J = 8Hz, 0.6H), 6.60 (d, J = 8Hz, 0.4H), 6.68 (d, J = 8Hz, 0.6H), 6.72 (d, J = 8Hz, 0.4H), 6.77 (s, 0.6H), 6.79 (s, 0.4H), 7.32 (s, 1H).

(Example 28)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(1-methyl-1H-imidazol-4-yl)ethan-1-one

参考例１に記載した方法に従い、実施例２７で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０９－０．１７（ｍ，２Ｈ），０．５０－０．５７（ｍ，２Ｈ），０．７９－０．９３（ｍ，１Ｈ），１．３２－１．５３（ｍ，２Ｈ），１．５７－１．６９（ｍ，１Ｈ），２．２５－２．３５（ｍ，３Ｈ），２．３９（ｄｄ，Ｊ＝６，１３Ｈｚ，１Ｈ），２．４７（ｄｄ，Ｊ＝７，１９Ｈｚ，１Ｈ），２．５７－２．６８（ｍ，１Ｈ），２．９３（ｄ，Ｊ＝７Ｈｚ，１Ｈ），２．９６－３．０７（ｍ，１Ｈ），３．００（ｄ，Ｊ＝１９Ｈｚ，１Ｈ），３．２３（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），３．５３－３．７５（ｍ，１Ｈ），３．６３（ｓ，３Ｈ），４．２７－４．４５（ｍ，２Ｈ），４．６０－４．６４（ｍ，１Ｈ），４．６８（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），６．４５（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７７（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７９（ｓ，１Ｈ），７．３９（ｓ，１Ｈ）．

According to the method described in Reference Example 1, the title compound was obtained from the compound obtained in Example 27.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09-0.17 (m, 2H), 0.50-0.57 (m, 2H), 0.79-0.93 (m , 1H), 1.32-1.53 (m, 2H), 1.57-1.69 (m, 1H), 2.25-2.35 (m, 3H), 2.39 (dd, J = 6, 13Hz, 1H), 2.47 (dd, J = 7, 19Hz, 1H), 2.57-2.68 (m, 1H), 2.93 (d, J = 7Hz, 1H), 2 .96-3.07 (m, 1H), 3.00 (d, J=19Hz, 1H), 3.23 (d, J=16Hz, 1H), 3.53-3.75 (m, 1H) , 3.63 (s, 3H), 4.27-4.45 (m, 2H), 4.60-4.64 (m, 1H), 4.68 (d, J = 16Hz, 1H), 6 .45 (d, J=8 Hz, 1 H), 6.77 (d, J=8 Hz, 1 H), 6.79 (s, 1 H), 7.39 (s, 1 H).

(Example 29)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(1-methyl-1H-pyrazol-3-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（１－メチル－１Ｈ－ピラゾール－３－イル）酢酸塩酸塩より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．２５（ｍ
，２Ｈ），０．４５－０．６２（ｍ，２Ｈ），０．７７－０．９９（ｍ，１Ｈ），１．１７－２．５４（ｍ，８Ｈ），２．５６－２．７２（ｍ，１Ｈ），２．８５－３．１４（ｍ，３Ｈ），３．２６－４．１２（ｍ，６Ｈ），４．２５－４．４７（ｍ，２Ｈ），４．６０－４．８３（ｍ，２Ｈ），５．８６－５．９５（ｍ，０．１Ｈ），６．２３（ｄ，Ｊ＝２Ｈｚ，０．９Ｈ），６．３７－６．５３（ｍ，１Ｈ），６．６６－６．７９（ｍ，１Ｈ）６．９８－７．７５（ｍ，１Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 2-(1-methyl-1H-pyrazol-3-yl)acetic acid hydrochloride.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.25 (m
, 2H), 0.45-0.62 (m, 2H), 0.77-0.99 (m, 1H), 1.17-2.54 (m, 8H), 2.56-2.72 (m, 1H), 2.85-3.14 (m, 3H), 3.26-4.12 (m, 6H), 4.25-4.47 (m, 2H), 4.60-4 .83 (m, 2H), 5.86-5.95 (m, 0.1H), 6.23 (d, J=2Hz, 0.9H), 6.37-6.53 (m, 1H) , 6.66-6.79 (m, 1H) 6.98-7.75 (m, 1H).

(Example 30)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)ethane- Synthesis of 1-ones

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（１－メチル－５－（トリフルオロメチル）－１Ｈ－ピラゾール－３－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．２２（ｍ，２Ｈ），０．４６－０．６２（ｍ，２Ｈ），０．７７－０．９４（ｍ，１Ｈ），１．１１－２．７２（ｍ，９Ｈ），２．８８－３．１５（ｍ，３Ｈ），３．３２－４．０４（ｍ，６Ｈ），４．２４－４．４４（ｍ，２Ｈ），４．５６－４．８５（ｍ，２Ｈ），６．３８－６．５４（ｍ，１．２Ｈ），６．５８－６．７９（ｍ，１．８Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 2-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)acetic acid. Obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.22 (m, 2H), 0.46-0.62 (m, 2H), 0.77-0.94 (m , 1H), 1.11-2.72 (m, 9H), 2.88-3.15 (m, 3H), 3.32-4.04 (m, 6H), 4.24-4.44 (m, 2H), 4.56-4.85 (m, 2H), 6.38-6.54 (m, 1.2H), 6.58-6.79 (m, 1.8H).

(Example 31)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(1H-pyrazol-3-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（１Ｈ－ピラゾール－３－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）： ０．００－０．１５（ｍ，２Ｈ），０．４５－０．６０（ｍ，２Ｈ），０．７５－０．９５（ｍ，１Ｈ），１．３０－１．８０（ｍ，３Ｈ），２．２０－２．７０（ｍ，７Ｈ），２．９０－３．１０（ｍ，３Ｈ），３．４５－３．５５（ｍ，１Ｈ），３．６０－３．９０（ｍ，２．２Ｈ），４．３０－４．４５（ｍ，１．８Ｈ），４．６０－４．７５（ｍ，１．８Ｈ），４．８９（ｂｒ＿ｓ、０．２Ｈ），６．０１（ｓ，０．２Ｈ），６．３０（ｄ，Ｊ＝２Ｈｚ，０．８Ｈ），６．４４（ｄ，Ｊ＝８Ｈｚ，０．８Ｈ），６．５２（ｄ，Ｊ＝８Ｈｚ，０．２Ｈ），６．６５－６．７５（ｍ，１Ｈ），７．４２（ｓ，０．２Ｈ），７．５０（ｄ，Ｊ＝２Ｈｚ，０．８Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 2-(1H-pyrazol-3-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.95 (m , 1H), 1.30-1.80 (m, 3H), 2.20-2.70 (m, 7H), 2.90-3.10 (m, 3H), 3.45-3.55 (m, 1H), 3.60-3.90 (m, 2.2H), 4.30-4.45 (m, 1.8H), 4.60-4.75 (m, 1.8H) , 4.89 (br_s, 0.2H), 6.01 (s, 0.2H), 6.30 (d, J=2Hz, 0.8H), 6.44 (d, J=8Hz, 0.8H). 8H), 6.52 (d, J = 8Hz, 0.2H), 6.65-6.75 (m, 1H), 7.42 (s, 0.2H), 7.50 (d, J = 2Hz, 0.8H).

(Example 32)
(4R,4aS,8aR,13bS)-7-(2-(1H-pyrazol-3-yl)ethyl)-3-(cyclopropylmethyl)-1,2,3,4,6,7,8,8a -Synthesis of octahydro-4,13-methanobenzofuro[2,3-c]pyrido[4,3-d]azepine-4a,10(5H)-diol

実施例２に記載した方法に従い、実施例３１で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．００－０．２５（ｍ，２Ｈ），０．４５－０．６５（ｍ，２Ｈ），０．７０－１．００（ｍ，１Ｈ），１．２０－１．７０（ｍ，３Ｈ），２．００－３．５０（ｍ，１７Ｈ），４．５２（ｂｒ ｓ，１Ｈ），５．９６（ｓ，１Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．８５（ｂｒ ｓ，１Ｈ），７．４０（ｓ，１Ｈ）．

The title compound was obtained from the compound obtained in Example 31 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.25 (m, 2H), 0.45-0.65 (m, 2H), 0.70-1.00 (m , 1H), 1.20-1.70 (m, 3H), 2.00-3.50 (m, 17H), 4.52 (br s, 1H), 5.96 (s, 1H), 6 .54 (d, J=8 Hz, 1 H), 6.85 (br s, 1 H), 7.40 (s, 1 H).

(Example 33)
(E)-1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a-hydroxy-10-methoxy-2,3,4,4a,5,6,8,8a-octahydro -4,13-methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-3-(furan-3-yl)prop-2-en-1-one synthesis

実施例６に記載した方法に従い、実施例２で得られた化合物及び（Ｅ）－３－（フラン－３－イル）アクリル酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１６（ｍ，２Ｈ），０．４８－０．５９（ｍ，２Ｈ），０．７７－０．９２（ｍ，１Ｈ），１．４６－１．６１（ｍ，２Ｈ），１．６２－１．７３（ｍ，１Ｈ），２．０７－２．１４（ｍ，０．２Ｈ），２．１６－２．２６（ｍ，１Ｈ），２．２８－２．４１（ｍ，２．８Ｈ），２．５２－２．６６（ｍ，２Ｈ），２．９３－３．０７（ｍ，２Ｈ），３．１８－３．３８（ｍ，１Ｈ），３．５６（ｓ，２．４Ｈ），３．６４（ｄ，Ｊ＝１６Ｈｚ，０．８Ｈ），３．８７（ｓ，０．６Ｈ），４．１０－４．２１（ｍ，０．２Ｈ），４．２２－４．５０（ｍ，２Ｈ），４．６０－４．６７（ｍ，０．８Ｈ），４．９１－５．００（ｍ，０．２Ｈ），６．５２（ｄ，Ｊ＝８Ｈｚ，０．８Ｈ），６．５６－６．７９（ｍ，２．４Ｈ），７．０１（ｄ，Ｊ＝１６Ｈｚ，０．８Ｈ），７．３８－７．４７（ｍ，１．８Ｈ），７．５６（ｄ，Ｊ＝１６Ｈｚ，０．２Ｈ），７．６０（ｓ，１Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 2 and (E)-3-(furan-3-yl)acrylic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.16 (m, 2H), 0.48-0.59 (m, 2H), 0.77-0.92 (m , 1H), 1.46-1.61 (m, 2H), 1.62-1.73 (m, 1H), 2.07-2.14 (m, 0.2H), 2.16-2 .26 (m, 1H), 2.28-2.41 (m, 2.8H), 2.52-2.66 (m, 2H), 2.93-3.07 (m, 2H), 3 .18-3.38 (m, 1H), 3.56 (s, 2.4H), 3.64 (d, J=16Hz, 0.8H), 3.87 (s, 0.6H), 4 .10-4.21 (m, 0.2H), 4.22-4.50 (m, 2H), 4.60-4.67 (m, 0.8H), 4.91-5.00 ( m, 0.2H), 6.52 (d, J = 8Hz, 0.8H), 6.56-6.79 (m, 2.4H), 7.01 (d, J = 16Hz, 0.8H) ), 7.38-7.47 (m, 1.8H), 7.56 (d, J=16Hz, 0.2H), 7.60 (s, 1H).

(Example 34)
(E)-1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4 ,13-methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-3-(furan-3-yl)prop-2-en-1-one

参考例１に記載した方法に従い、実施例３３で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０８－０．１５（ｍ，２Ｈ），０．４９－０．５７（ｍ，２Ｈ），０．７７－０．９０（ｍ，１Ｈ），１．４４－１．７２（ｍ，３Ｈ），１．８２－１．９６（ｍ，０．６Ｈ），２．１２－２．４１（ｍ，４Ｈ），２．５０－２．６６（ｍ，２Ｈ），２．９２－３．０５（ｍ，２Ｈ），３．２０－３．３２（ｍ，０．４Ｈ），３．４７－３．５７（ｍ，０．４Ｈ），３．６７（ｄ，Ｊ＝１６Ｈｚ，０．６Ｈ），３．７７－４．００（ｍ，０．８Ｈ），４．２２－４．３８（ｍ，１．２Ｈ），４．６０－４．６８（ｍ，０．６Ｈ），４．８０－４．８９（ｍ，０．４Ｈ），６．４３－６．５６（ｍ，２Ｈ），６．６０（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７１（ｓ，０．６Ｈ），６．７２（ｓ，０．４Ｈ），６．９３（ｄ，Ｊ＝１６Ｈｚ，０．６Ｈ），７．３６－７．４５（ｍ，１．６Ｈ），７．４９（ｄ，Ｊ＝１５Ｈｚ，０．４Ｈ），７．５９（ｓ，１Ｈ）．

According to the method described in Reference Example 1, the title compound was obtained from the compound obtained in Example 33.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08-0.15 (m, 2H), 0.49-0.57 (m, 2H), 0.77-0.90 (m , 1H), 1.44-1.72 (m, 3H), 1.82-1.96 (m, 0.6H), 2.12-2.41 (m, 4H), 2.50-2 .66 (m, 2H), 2.92-3.05 (m, 2H), 3.20-3.32 (m, 0.4H), 3.47-3.57 (m, 0.4H) , 3.67 (d, J=16Hz, 0.6H), 3.77-4.00 (m, 0.8H), 4.22-4.38 (m, 1.2H), 4.60- 4.68 (m, 0.6H), 4.80-4.89 (m, 0.4H), 6.43-6.56 (m, 2H), 6.60 (d, J=8Hz, 0 .4H), 6.71 (s, 0.6H), 6.72 (s, 0.4H), 6.93 (d, J = 16Hz, 0.6H), 7.36-7.45 (m , 1.6 H), 7.49 (d, J=15 Hz, 0.4 H), 7.59 (s, 1 H).

(Example 35)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(1H-indazol-3-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（１Ｈ－インダゾール－３－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．００－０．１５（ｍ，２Ｈ），０．４５－０．６０（ｍ，２Ｈ），０．７０－０．９５（ｍ，１Ｈ），１．２０－１．７０（ｍ，３Ｈ），２．１０－２．５５（ｍ，７Ｈ），２．６０－２．７０（ｍ，１Ｈ），２．８５－３．１５（ｍ，３Ｈ），３．７０－３．７５（ｍ，１Ｈ），３．８５（ｄ，Ｊ＝１５Ｈｚ，０．８Ｈ），３．９８（ｄ，Ｊ＝１５Ｈｚ，０．２Ｈ），４．０８（ｄ，Ｊ＝１５Ｈｚ，０．２Ｈ），４．３８（ｄ，Ｊ＝１５Ｈｚ，１Ｈ），４．５１（ｄ，Ｊ＝１５Ｈｚ，１Ｈ），４．６９（ｂｒ ｓ，０．８Ｈ），４．７５（ｂｒ ｓ，０．２Ｈ），４．９７（ｄ，Ｊ＝１５Ｈｚ，０．８Ｈ），６．４５（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６４（ｄ，Ｊ＝８Ｈｚ，０．２Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．８Ｈ），７．１０－７．２０（ｍ，１Ｈ），７．３０－７．４５（ｍ，２Ｈ），７．６７（ｄ，Ｊ＝８Ｈｚ，０．２Ｈ），７．７７（ｄ，Ｊ＝８Ｈｚ，０．８Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 2-(1H-indazol-3-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.60 (m, 2H), 0.70-0.95 (m , 1H), 1.20-1.70 (m, 3H), 2.10-2.55 (m, 7H), 2.60-2.70 (m, 1H), 2.85-3.15 (m, 3H), 3.70-3.75 (m, 1H), 3.85 (d, J = 15Hz, 0.8H), 3.98 (d, J = 15Hz, 0.2H), 4 .08 (d, J=15 Hz, 0.2 H), 4.38 (d, J=15 Hz, 1 H), 4.51 (d, J=15 Hz, 1 H), 4.69 (br s, 0.8 H ), 4.75 (br s, 0.2H), 4.97 (d, J = 15Hz, 0.8H), 6.45 (d, J = 8Hz, 1H), 6.64 (d, J = 8Hz, 0.2H), 6.73 (d, J = 8Hz, 0.8H), 7.10-7.20 (m, 1H), 7.30-7.45 (m, 2H), 7. 67 (d, J=8 Hz, 0.2 H), 7.77 (d, J=8 Hz, 0.8 H).

(Example 36)
(4R,4aS,8aR,13bS)-7-(2-(1H-indazol-3-yl)ethyl)-3-(cyclopropylmethyl)-1,2,3,4,6,7,8,8a -Synthesis of octahydro-4,13-methanobenzofuro[2,3-c]pyrido[4,3-d]azepine-4a,10(5H)-diol

実施例２に記載した方法に従い、実施例３５で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．００－０．２５（ｍ，２Ｈ），０．４５－０．６５（ｍ，２Ｈ），０．７５－１．００（ｍ，１Ｈ），１．２０－１．８０（ｍ，３Ｈ），２．２０－３．５０（ｍ，１８Ｈ），４．５３（ｂｒ ｓ，１Ｈ），６．５２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．８１（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．０７（ｔ，Ｊ＝８Ｈｚ，１Ｈ），７．３２（ｔ，Ｊ＝８Ｈｚ，１Ｈ），７．５７（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．６１（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．

The title compound was obtained from the compound obtained in Example 35 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.25 (m, 2H), 0.45-0.65 (m, 2H), 0.75-1.00 (m , 1H), 1.20-1.80 (m, 3H), 2.20-3.50 (m, 18H), 4.53 (br s, 1H), 6.52 (d, J = 8Hz, 1H), 6.81 (d, J = 8Hz, 1H), 7.07 (t, J = 8Hz, 1H), 7.32 (t, J = 8Hz, 1H), 7.57 (d, J = 8 Hz, 1 H), 7.61 (d, J = 8 Hz, 1 H).

(Example 37)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(imidazo[1,2-a]pyridin-2-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（イミダゾ［１，２－ａ］ピリジン－２－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．２１（ｍ，２Ｈ），０．４６－０．６０（ｍ，２Ｈ），０．７８－０．９３（ｍ，１Ｈ），１．２０－１．７５（ｍ，３Ｈ），２．１０－２．６８（ｍ，６Ｈ），２．８０－３．１５（ｍ，３Ｈ），３．４２－４．０１（ｍ，２Ｈ），４．３０－４．５１（ｍ，２Ｈ），４．６６（ｓ，１Ｈ），４．８９（ｄ，Ｊ＝１６Ｈｚ，１Ｈ）６．１９（ｄ，Ｊ＝８Ｈｚ，０．１Ｈ），６．４５（ｄ，Ｊ＝８Ｈｚ，０．９Ｈ），６．５９（ｄ，Ｊ＝８Ｈｚ，０．１Ｈ），６．６９－６．８４（ｍ，１．９Ｈ），７．０６－７．２２（ｍ，１Ｈ），７．４２（ｄ，Ｊ＝９Ｈｚ，０．１Ｈ），７．５０（ｓ，１Ｈ），７．６７（ｄ，Ｊ＝９Ｈｚ，０．９Ｈ），７．９８－８．１０（ｍ，１Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 2-(imidazo[1,2-a]pyridin-2-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.21 (m, 2H), 0.46-0.60 (m, 2H), 0.78-0.93 (m , 1H), 1.20-1.75 (m, 3H), 2.10-2.68 (m, 6H), 2.80-3.15 (m, 3H), 3.42-4.01 (m, 2H), 4.30-4.51 (m, 2H), 4.66 (s, 1H), 4.89 (d, J = 16Hz, 1H) 6.19 (d, J = 8Hz, 0.1H), 6.45 (d, J = 8Hz, 0.9H), 6.59 (d, J = 8Hz, 0.1H), 6.69-6.84 (m, 1.9H), 7.06-7.22 (m, 1H), 7.42 (d, J = 9Hz, 0.1H), 7.50 (s, 1H), 7.67 (d, J = 9Hz, 0.9H ), 7.98-8.10 (m, 1H).

(Example 38)
(4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-7-(2-(isoquinolin-3-yl)ethyl)-1,2,3,4,6,7,8,8a-octahydro Synthesis of -4,13-methanobenzofuro[2,3-c]pyrido[4,3-d]azepine-4a,10(5H)-diol

実施例３の（１）で得られた化合物（６．６ｍｇ，０．０２ｍｍｏｌ）および２－（イソキノリン－３－イル）アセタルデヒド（１７．１ｍｇ，０．１０ｍｍｏｌ）のクロロホルム（１．０ｍＬ）溶液に、氷浴下、水素化トリアセトキシホウ素ナトリウム（２１．２ｍｇ，０．１ｍｍｏｌ）を加え、室温で１６時間撹拌した。反応液を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、水及び飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧下にて濃縮した。得られた粗生成物を分取薄層クロマトグラフィー（クロロホルム：２Ｍアンモニア－メタノール溶液＝９２：８）で精製し、表題化合物（９．５ｍｇ，９８％）を無色アモルファスとして得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０８－０．１８（ｍ，２Ｈ），０．４６－０．５９（ｍ，２Ｈ），０．７６－０．９４（ｍ，１Ｈ），１．０５－１．３７（ｍ，１Ｈ），１．５４－１．８０（ｍ，２Ｈ），２．１７－２．７９（ｍ，８Ｈ），２．８０（ｄｔ，Ｊ＝５，１１Ｈｚ，１Ｈ），２．８９－２．９９（ｍ，２Ｈ），３．０１（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．１８（ｄｄ，Ｊ＝２，１６Ｈｚ，１Ｈ），３．２９－３．４０（ｍ，１Ｈ），３．５２－３．６７（ｍ，２Ｈ），４．５４－４．５９（ｍ，１Ｈ），６．４９（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．８１（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．４８（ｓ，１Ｈ），７．５１－７．５７（ｍ，１Ｈ），７．６５（ｄｄｄ，Ｊ＝１，７，８Ｈｚ，１Ｈ），７．７２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．９４（ｄ，Ｊ＝８Ｈｚ，１Ｈ），９．１８（ｓ，１Ｈ）．

In a chloroform (1.0 mL) solution of the compound (6.6 mg, 0.02 mmol) obtained in Example 3 (1) and 2-(isoquinolin-3-yl)acetaldehyde (17.1 mg, 0.10 mmol) , under an ice bath, sodium triacetoxyborohydride (21.2 mg, 0.1 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by preparative thin layer chromatography (chloroform:2M ammonia-methanol solution=92:8) to give the title compound (9.5 mg, 98%) as a colorless amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08-0.18 (m, 2H), 0.46-0.59 (m, 2H), 0.76-0.94 (m , 1H), 1.05-1.37 (m, 1H), 1.54-1.80 (m, 2H), 2.17-2.79 (m, 8H), 2.80 (dt, J = 5, 11Hz, 1H), 2.89-2.99 (m, 2H), 3.01 (d, J = 18Hz, 1H), 3.18 (dd, J = 2, 16Hz, 1H), 3 .29-3.40 (m, 1H), 3.52-3.67 (m, 2H), 4.54-4.59 (m, 1H), 6.49 (d, J=8Hz, 1H) , 6.81 (d, J = 8Hz, 1H), 7.48 (s, 1H), 7.51-7.57 (m, 1H), 7.65 (ddd, J = 1, 7, 8Hz, 1 H), 7.72 (d, J=8 Hz, 1 H), 7.94 (d, J=8 Hz, 1 H), 9.18 (s, 1 H).

(Example 39)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-3-(pyridin-2-yl)propan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び３－（ピリジン－２－イル）プロパン酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．１０－０．１９（ｍ，２Ｈ），０．４９－０．５９（ｍ，２Ｈ），０．７９－０．９１（ｍ，１Ｈ），１．４１－１．４９（ｍ，１Ｈ），１．５３－１．６９（ｍ，２Ｈ），２．１２－２．４１（ｍ，５Ｈ），２．５４（ｄｄ，Ｊ＝７，１８Ｈｚ，１Ｈ），２．５９－２．６８（ｍ，１Ｈ），２．７５（ｄｄｄ，Ｊ＝３，１３，１３Ｈｚ，１Ｈ），２．９１－３．０５（ｍ，３Ｈ），３．１０（ｄｄｄ，Ｊ＝６，１３，１３Ｈｚ，１Ｈ），３．５３－３．６０（ｍ，１Ｈ），３．６１（ｄｄｄ，Ｊ＝３，１２，１５Ｈｚ，１Ｈ），４．２４－４．３３（ｍ，１Ｈ），４．４１－４．４９（ｍ，１Ｈ），４．５５－４．５９（ｍ，１Ｈ），６．５０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６９（ｄ，Ｊ＝８Ｈｚ，０．１Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．９Ｈ），７．１８－７．２３（ｍ，１Ｈ），７．２４（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．６４－７．７０（ｍ，１Ｈ），８．４５－８．４８（ｍ，０．１Ｈ），８．５９（ｄ，Ｊ＝５Ｈｚ，０．９Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 3-(pyridin-2-yl)propanoic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10-0.19 (m, 2H), 0.49-0.59 (m, 2H), 0.79-0.91 (m , 1H), 1.41-1.49 (m, 1H), 1.53-1.69 (m, 2H), 2.12-2.41 (m, 5H), 2.54 (dd, J = 7, 18Hz, 1H), 2.59-2.68 (m, 1H), 2.75 (ddd, J = 3, 13, 13Hz, 1H), 2.91-3.05 (m, 3H) , 3.10 (ddd, J=6, 13, 13 Hz, 1 H), 3.53-3.60 (m, 1 H), 3.61 (ddd, J=3, 12, 15 Hz, 1 H), 4. 24-4.33 (m, 1H), 4.41-4.49 (m, 1H), 4.55-4.59 (m, 1H), 6.50 (d, J=8Hz, 1H), 6.69 (d, J = 8Hz, 0.1H), 6.73 (d, J = 8Hz, 0.9H), 7.18-7.23 (m, 1H), 7.24 (d, J = 8Hz, 1H), 7.64-7.70 (m, 1H), 8.45-8.48 (m, 0.1H), 8.59 (d, J = 5Hz, 0.9H).

(Example 40)
2-cyclohexyl-1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4 ,13-methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及びシクロヘキシル酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．２２（ｍ，２Ｈ），０．４４－０．５９（ｍ，２Ｈ），０．６０－１．８５（ｍ，１４Ｈ），１．８８－２．７３（ｍ，１０Ｈ），２．８６－３．０６（ｍ，２Ｈ），３．０９－４．４１（ｍ，４Ｈ），４．５０－４．８３（ｍ，１Ｈ），６．３５－６．５７（ｍ，１．３Ｈ），６．６９（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in (1) of Example 3 and cyclohexylacetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.22 (m, 2H), 0.44-0.59 (m, 2H), 0.60-1.85 (m , 14H), 1.88-2.73 (m, 10H), 2.86-3.06 (m, 2H), 3.09-4.41 (m, 4H), 4.50-4.83 (m, 1H), 6.35-6.57 (m, 1.3H), 6.69 (d, J=8Hz, 0.7H).

(Example 41)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(pyrrolidin-1-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（ピロリジン－１－イル）酢酸塩酸塩より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．２１（ｍ，２Ｈ），０．４６－０．６３（ｍ，２Ｈ），０．７５－０．９７（ｍ，１Ｈ），１．１５－３．２７（ｍ，２２Ｈ），３．３４－３．８０（ｍ，２Ｈ），３．９９－４．３４（ｍ，２Ｈ），４．５１－５．１１（ｍ，１Ｈ），６．４１－６．５７（ｍ，１Ｈ），６．６３－６．８０（ｍ，１Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 2-(pyrrolidin-1-yl)acetic acid hydrochloride.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.21 (m, 2H), 0.46-0.63 (m, 2H), 0.75-0.97 (m , 1H), 1.15-3.27 (m, 22H), 3.34-3.80 (m, 2H), 3.99-4.34 (m, 2H), 4.51-5.11 (m, 1H), 6.41-6.57 (m, 1H), 6.63-6.80 (m, 1H).

(Example 42)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a-hydroxy-10-methoxy-2,3,4,4a,5,6,8,8a-octahydro-4,13 - Synthesis of methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(piperidin-1-yl)ethan-1-one

実施例６に記載した方法に従い、実施例２で得られた化合物及び２－（ピペリジン－１－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．２０（ｍ，２Ｈ），０．４８－０．５９（ｍ，２Ｈ），０．７７－２．０４（ｍ，１１Ｈ），２．０６－２．７１（ｍ，１０Ｈ），２．９０－３．９３（ｍ，９Ｈ），３．９８－４．２０（ｍ，０．６Ｈ），４．２５－４．５５（ｍ，０．４Ｈ），４．６３－４．７４（ｍ，０．６Ｈ），４．７８－４．９２（ｍ，０．４Ｈ），６．４８－６．６２（ｍ，１Ｈ），６．６３－６．７４（ｍ，１Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 2 and 2-(piperidin-1-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.20 (m, 2H), 0.48-0.59 (m, 2H), 0.77-2.04 (m , 11H), 2.06-2.71 (m, 10H), 2.90-3.93 (m, 9H), 3.98-4.20 (m, 0.6H), 4.25-4 .55 (m, 0.4H), 4.63-4.74 (m, 0.6H), 4.78-4.92 (m, 0.4H), 6.48-6.62 (m, 1H), 6.63-6.74 (m, 1H).

(Example 43)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(piperidin-1-yl)ethan-1-one

参考例１に記載した方法に従い、実施例４２で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０３－０．２２（ｍ，２Ｈ），０．４６－０．６２（ｍ，２Ｈ），０．７７－０．９７（ｍ，１Ｈ），１．０８－３．３３（ｍ，２４Ｈ），３．３６－３．９１（ｍ，２Ｈ），３．９７－５．０５（ｍ，３Ｈ），６．３４－６．５０（ｍ，１Ｈ），６．５７－６．７３（ｍ，１Ｈ）．

According to the method described in Reference Example 1, the title compound was obtained from the compound obtained in Example 42.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.22 (m, 2H), 0.46-0.62 (m, 2H), 0.77-0.97 (m , 1H), 1.08-3.33 (m, 24H), 3.36-3.91 (m, 2H), 3.97-5.05 (m, 3H), 6.34-6.50 (m, 1H), 6.57-6.73 (m, 1H).

(Example 44)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-((R)-morpholin-3-yl)ethan-1-one

実施例３の（１）で得られた化合物（１０ｍｇ，０．０２９ｍｍｏｌ）及び（Ｒ）－２－（４－（ｔｅｒｔ－ブトキシカルボニル）モルホリン－３－イル）酢酸（１１ｍｇ，０．０４４ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（１５μＬ，０．０８８ｍｍｏｌ）及びＯ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムヘキサフルオロホスファート（ＨＡＴＵ）（１４ｍｇ，０．０３８ｍｍｏｌ）を加え、室温で２時間撹拌した後に炭酸カリウム（５０ｍｇ，０．３６ｍｍｏｌ）のメタノール懸濁液（１ｍＬ）を加え、室温で３０分間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで三回抽出した。有機層を水で１回洗浄し、硫酸ナトリウムで乾燥後、減圧下にて濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（１－１０％メタノール／クロロホルム）で精製し、表題化合物のＢｏｃ保護体（１６ｍｇ）を淡黄色ガム状物質として得た。得られた表題化合物のＢｏｃ保護体をクロロホルム（１ｍＬ）に溶解し、氷冷下トリフルオロ酢酸（０．５ｍＬ）を加え、室温で２時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで三回抽出した。合わせた抽出液を硫酸ナトリウムで乾燥後、減圧下にて濃縮した。得られた粗生成物を分取薄層クロマトグラフィー（クロロホルム：２Mアンモニア－メタノール溶液＝１０：１）で精製し、表題化合物（８．８ｍｇ，６７％）を淡黄色ガム状物質として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．２０（ｍ，２Ｈ），０．４７－０．６２（ｍ，２Ｈ），０．７４－０．９６（ｍ，１Ｈ），１．１６－３．０７（ｍ，１５Ｈ），３．０８－３．２０（ｍ，０．６Ｈ），３．２２－３．３７（ｍ，１Ｈ），３．４２－３．９８（ｍ，６Ｈ），４．０８－４．３４（ｍ，１．４Ｈ），４．５０－４．９８（ｍ，２Ｈ），６．４４－６．５５（ｍ，１Ｈ），６．６５－６．７４（ｍ，１Ｈ）．

The compound (10 mg, 0.029 mmol) obtained in Example 3 (1) and (R)-2-(4-(tert-butoxycarbonyl)morpholin-3-yl)acetic acid (11 mg, 0.044 mmol) N,N-diisopropylethylamine (15 μL, 0.088 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′- were added to a solution of N,N-dimethylformamide (1 mL). Tetramethyluronium hexafluorophosphate (HATU) (14 mg, 0.038 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Stir for 30 minutes. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic layer was washed once with water, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (1-10% methanol/chloroform) to give the Boc protected form of the title compound (16 mg) as a pale yellow gummy substance. The obtained Boc-protected form of the title compound was dissolved in chloroform (1 mL), trifluoroacetic acid (0.5 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (chloroform:2M ammonia-methanol solution=10:1) to give the title compound (8.8 mg, 67%) as a pale yellow gummy substance.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.20 (m, 2H), 0.47-0.62 (m, 2H), 0.74-0.96 (m , 1H), 1.16-3.07 (m, 15H), 3.08-3.20 (m, 0.6H), 3.22-3.37 (m, 1H), 3.42-3 .98 (m, 6H), 4.08-4.34 (m, 1.4H), 4.50-4.98 (m, 2H), 6.44-6.55 (m, 1H), 6 .65-6.74 (m, 1H).

(Example 45)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-((S)-morpholin-3-yl)ethan-1-one

実施例４４に記載した方法に従い、実施例３の（１）で得られた化合物及び（Ｓ）－２－（４－（ｔｅｒｔ－ブトキシカルボニル）モルホリン－３－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．２２（ｍ，２Ｈ），０．４７－０．６３（ｍ，２Ｈ），０．７８－０．９６（ｍ，１Ｈ），１．１４－２．４５（ｍ，８Ｈ），２．５１（ｄｄ，Ｊ＝７，１８Ｈｚ，１Ｈ），２．５８－２．７１（ｍ，１Ｈ），２．８２（ｄ，Ｊ＝１２Ｈｚ，１Ｈ），２．８７－３．１４（ｍ，４Ｈ），３．２４－３．３５（ｍ，１Ｈ），３．３６－３．７０（ｍ，４Ｈ），３．７６（ｄｄ，Ｊ＝３，１１Ｈｚ，１Ｈ），３．８６（ｄｄ，Ｊ＝２，１１Ｈｚ，１Ｈ），４．０８－４．３７（ｍ，２Ｈ），４．５９（ｓ，１Ｈ），４．７９（ｂｒ ｓ，１Ｈ），６．４９（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７５（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．

According to the method described in Example 44, the title compound was obtained from the compound obtained in (1) of Example 3 and (S)-2-(4-(tert-butoxycarbonyl)morpholin-3-yl)acetic acid. .

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.22 (m, 2H), 0.47-0.63 (m, 2H), 0.78-0.96 (m , 1H), 1.14-2.45 (m, 8H), 2.51 (dd, J = 7, 18Hz, 1H), 2.58-2.71 (m, 1H), 2.82 (d , J = 12 Hz, 1H), 2.87-3.14 (m, 4H), 3.24-3.35 (m, 1H), 3.36-3.70 (m, 4H), 3.76 (dd, J = 3, 11 Hz, 1H), 3.86 (dd, J = 2, 11 Hz, 1H), 4.08-4.37 (m, 2H), 4.59 (s, 1H), 4 .79 (br s, 1 H), 6.49 (d, J=8 Hz, 1 H), 6.75 (d, J=8 Hz, 1 H).

(Example 46)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-((R)-4-methylmorpholin-3-yl)ethan-1-one

実施例４４で得られた化合物（６．５ｍｇ，０．０１４ｍｍｏｌ）のメタノール（０．５ｍＬ）溶液に酢酸（４．７μＬ，０．０８３ｍｍｏｌ）及び３６％ホルムアルデヒド水溶液（３．２μＬ，０．０４２ｍｍｏｌ）を加え、室温で３０分間撹拌した後にトリアセトキシ水素化ホウ素ナトリウム（８．８ｍｇ，０．０４２ｍｍｏｌ）を加え、室温で２１時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで三回抽出した。合わせた抽出液を硫酸ナトリウムで乾燥後、減圧下にて濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（アミノ基担持シリカゲル、０－４％メタノール／クロロホルム）で精製し、表題化合物（４．８ｍｇ，７２％）を淡黄色ガム状物質として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．２４（ｍ，２Ｈ），０．４５－０．６３（ｍ，２Ｈ），０．７７－０．９５（ｍ，１Ｈ），１．１１－２．８８（ｍ，１６．４Ｈ），２．８９－３．１０（ｍ，２．８Ｈ），３．１７－３．５０（ｍ，２．８Ｈ），３．５６－４．００（ｍ，４．４Ｈ），４．３３（ｄ，Ｊ＝１５Ｈｚ，０．８Ｈ），４．４１（ｄ，Ｊ＝１４Ｈｚ，０．８Ｈ），４．５３－４．８４（ｍ，１Ｈ），６．４２－６．５５（ｍ，１Ｈ），６．６３－６．７５（ｍ，１Ｈ）．

A methanol (0.5 mL) solution of the compound (6.5 mg, 0.014 mmol) obtained in Example 44 was added with acetic acid (4.7 μL, 0.083 mmol) and 36% aqueous formaldehyde solution (3.2 μL, 0.042 mmol). was added, and the mixture was stirred at room temperature for 30 minutes, then sodium triacetoxyborohydride (8.8 mg, 0.042 mmol) was added, and the mixture was stirred at room temperature for 21 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (amino group-supporting silica gel, 0-4% methanol/chloroform) to give the title compound (4.8 mg, 72%) as a pale yellow gummy substance.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.24 (m, 2H), 0.45-0.63 (m, 2H), 0.77-0.95 (m , 1H), 1.11-2.88 (m, 16.4H), 2.89-3.10 (m, 2.8H), 3.17-3.50 (m, 2.8H), 3 .56-4.00 (m, 4.4H), 4.33 (d, J=15Hz, 0.8H), 4.41 (d, J=14Hz, 0.8H), 4.53-4. 84 (m, 1H), 6.42-6.55 (m, 1H), 6.63-6.75 (m, 1H).

(Example 47)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-((S)-4-methylmorpholin-3-yl)ethan-1-one

実施例４６に記載した方法に従い、実施例４５で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．２０（ｍ，２Ｈ），０．４６－０．６３（ｍ，２Ｈ），０．７６－０．９５（ｍ，１Ｈ），１．１７－３．２８（ｍ，２１Ｈ），３．３０－３．４４（ｍ，１Ｈ），３．４６－３．９９（ｍ，４．３Ｈ），４．０７－５．１３（ｍ，２．７Ｈ），６．４５－６．５６（ｍ，１Ｈ），６．６７－６．７８（ｍ，１Ｈ）．

The title compound was obtained from the compound obtained in Example 45 according to the method described in Example 46.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.20 (m, 2H), 0.46-0.63 (m, 2H), 0.76-0.95 (m , 1H), 1.17-3.28 (m, 21H), 3.30-3.44 (m, 1H), 3.46-3.99 (m, 4.3H), 4.07-5 .13 (m, 2.7H), 6.45-6.56 (m, 1H), 6.67-6.78 (m, 1H).

(Example 48)
2-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-1-(piperidin-1-yl)ethan-1-one

実施例３の（１）で得られた化合物（９．９ｍｇ，０．０３ｍｍｏｌ）のアセトニトリル（１．０ｍＬ）溶液にＮ，Ｎ－ジイソプロピルエチルアミン（１０．５μＬ，０．０４５ｍｍｏｌ）及び２－クロロ－１－（ピペリジン－１－イル）エタン－１－オン（ＷＯ２０１８１４８５７６に記載の方法で合成）を加え、６０℃で４時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えクロロホルムで三回抽出した。合わせた抽出物を硫酸ナトリウムで乾燥し、減圧下濃縮した。得られた粗生成物を分取薄層クロマトグラフィー（クロロホルム：２Ｍアンモニア－メタノール溶液＝５０：３）で精製し、表題化合物（１１．５ｍｇ，８５％）を無色アモルファスとして得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０８－０．１８（ｍ，２Ｈ），０．４９－０．５６（ｍ，２Ｈ），０．７７－０．９２（ｍ，１Ｈ），１．２１－１．８６（ｍ，１０Ｈ），２．１５－２．７０（ｍ，６Ｈ），２．８９－３．４９（ｍ，１０Ｈ），３．５５－３．６９（ｍ，１Ｈ），４．４４－４．５０（ｍ，１Ｈ），６．５１（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．

N,N-diisopropylethylamine (10.5 μL, 0.045 mmol) and 2-chloro- 1-(Piperidin-1-yl)ethan-1-one (synthesized by the method described in WO2018148576) was added and stirred at 60° C. for 4 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform three times. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by preparative thin layer chromatography (chloroform:2M ammonia-methanol solution=50:3) to give the title compound (11.5 mg, 85%) as a colorless amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08-0.18 (m, 2H), 0.49-0.56 (m, 2H), 0.77-0.92 (m , 1H), 1.21-1.86 (m, 10H), 2.15-2.70 (m, 6H), 2.89-3.49 (m, 10H), 3.55-3.69 (m, 1H), 4.44-4.50 (m, 1H), 6.51 (d, J=8Hz, 1H), 6.71 (d, J=8Hz, 1H).

(Example 49)
(4R,4aR,8aR,13bS)-3-(cyclopropylmethyl)-10-methoxy-1,2,3,4,4a,5,6,7-octahydro-4,13-methanobenzofuro[2,3- Synthesis of c]pyrido[4,3-d]azepin-8(8aH)-one

実施例１に記載した方法に従い、（４Ｒ，４ａＲ，７ａＲ，１２ｂＳ）－３－（シクロプロピルメチル）－９－メトキシ－２，３，４，４ａ，５，６－ヘキサヒドロ－１Ｈ－４，１２－メタノベンゾフロ［３，２－ｅ］イソキノリン－７（７ａＨ）－オン（Ｈｅｔｅｒｏｃｙｃｌｅｓ，２００６，６９，２７１に記載の方法で合成より表題化合物を無色アモルファスとして得た。
^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１５（ｍ，２Ｈ），０．４５－０．６０（ｍ，２Ｈ），０．７０－０．９０（ｍ，２Ｈ），１．６０－１．９０（ｍ，２Ｈ），２．１０－２．２０（ｍ，１Ｈ），２．２０－２．３０（ｍ，１Ｈ），２．３５－２．５５（ｍ，４Ｈ），２．７０－２．９０（ｍ，３Ｈ），２．９２（ｄ，Ｊ＝１９Ｈｚ，１Ｈ），３．４４（ｄｄ，Ｊ＝２，７Ｈｚ，１Ｈ），３．８８（ｓ，３Ｈ），４．９４（ｓ，１Ｈ），６．１０－６．２５（ｍ，１Ｈ），６．６６（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７８（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．

(4R,4aR,7aR,12bS)-3-(cyclopropylmethyl)-9-methoxy-2,3,4,4a,5,6-hexahydro-1H-4,12 according to the method described in Example 1 -methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (Heterocycles, 2006, 69, 271) to obtain the title compound as a colorless amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.15 (m, 2H), 0.45-0.60 (m, 2H), 0.70-0.90 (m , 2H), 1.60-1.90 (m, 2H), 2.10-2.20 (m, 1H), 2.20-2.30 (m, 1H), 2.35-2.55 (m, 4H), 2.70-2.90 (m, 3H), 2.92 (d, J=19Hz, 1H), 3.44 (dd, J=2,7Hz, 1H), 3.88 (s, 3H), 4.94 (s, 1H), 6.10-6.25 (m, 1H), 6.66 (d, J = 8Hz, 1H), 6.78 (d, J = 8Hz , 1H).

(Example 50)
(4R,4aR,8aR,13bS)-3-(cyclopropylmethyl)-10-methoxy-1,2,3,4,4a,5,6,7,8,8a-decahydro-4,13-methanobenzofuro [ Synthesis of 2,3-c]pyrido[4,3-d]azepine

実施例２に記載した方法に従い、実施例４９で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．１０－０．２０（ｍ，２Ｈ），０．５０－０．６０（ｍ，２Ｈ），０．８０－０．９５（ｍ，１Ｈ），１．２０－１．４５（ｍ，２Ｈ），１．７３（ｍ，２Ｈ），２．００－２．１０（ｍ，１Ｈ），２．１５－２．３０（ｍ，１Ｈ），２．３０－２．５５（ｍ，４Ｈ），２．６０－２．７０（ｍ，１Ｈ），２．７５（ｄｄ，Ｊ＝４，１２Ｈｚ，１Ｈ），２．８０－２．９５（ｍ，２Ｈ），２．９５－３．０５（ｍ，１Ｈ），３．１５－３．４０（ｍ，２Ｈ），３．８８（ｓ，３Ｈ），４．５４（ｄｄ，Ｊ＝４，６Ｈｚ，１Ｈ），６．５９（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．

The title compound was obtained from the compound obtained in Example 49 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10-0.20 (m, 2H), 0.50-0.60 (m, 2H), 0.80-0.95 (m , 1H), 1.20-1.45 (m, 2H), 1.73 (m, 2H), 2.00-2.10 (m, 1H), 2.15-2.30 (m, 1H) ), 2.30-2.55 (m, 4H), 2.60-2.70 (m, 1H), 2.75 (dd, J = 4, 12Hz, 1H), 2.80-2.95 (m, 2H), 2.95-3.05 (m, 1H), 3.15-3.40 (m, 2H), 3.88 (s, 3H), 4.54 (dd, J=4 , 6 Hz, 1 H), 6.59 (d, J=8 Hz, 1 H), 6.73 (d, J=8 Hz, 1 H).

(Example 51)
1-((4R,4aR,8aR,13bS)-3-(cyclopropylmethyl)-10-methoxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro[2 ,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(pyridin-2-yl)ethan-1-one

実施例６に記載した方法に従い、実施例５０で得られた化合物および２－（ピリジン－２－イル）酢酸塩酸塩より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．１０－０．２５（ｍ，２Ｈ），０．６０－０．７５（ｍ，２Ｈ），０．８０－１．００（ｍ，１Ｈ），１．２０－１．４０（ｍ，２Ｈ），１．４０－１．６０（ｍ，１Ｈ），１．６０－１．８０（ｍ，１Ｈ），１．８０－２．００（ｍ，１Ｈ），２．１０－２．２５（ｍ，１Ｈ），２．２５－２．６５（ｍ，４Ｈ），２．７０－２．９５（ｍ，３Ｈ），３．２５－３．４５（ｍ，２Ｈ），３．６５－４．０５（ｍ，２Ｈ），３．８８（ｓ，３Ｈ），４．１２（ｄ，Ｊ＝１６Ｈｚ，０．５Ｈ），４．２０－４．３５（ｍ，０．５Ｈ），４．６５－４．７５（ｍ，０．５Ｈ），４．８５（ｄｄ，Ｊ＝６，１１Ｈｚ，０．５Ｈ），６．６３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．１５－７．２５（ｍ，１Ｈ），７．２５－７．３５（ｍ，１Ｈ），７．６０－７．７５（ｍ，１Ｈ），８．５０－８．６０（ｍ，１Ｈ）．

The title compound was obtained from the compound obtained in Example 50 and 2-(pyridin-2-yl)acetic acid hydrochloride according to the method described in Example 6.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10-0.25 (m, 2H), 0.60-0.75 (m, 2H), 0.80-1.00 (m , 1H), 1.20-1.40 (m, 2H), 1.40-1.60 (m, 1H), 1.60-1.80 (m, 1H), 1.80-2.00 (m, 1H), 2.10-2.25 (m, 1H), 2.25-2.65 (m, 4H), 2.70-2.95 (m, 3H), 3.25-3 .45 (m, 2H), 3.65-4.05 (m, 2H), 3.88 (s, 3H), 4.12 (d, J=16Hz, 0.5H), 4.20-4 .35 (m, 0.5H), 4.65-4.75 (m, 0.5H), 4.85 (dd, J = 6, 11Hz, 0.5H), 6.63 (d, J = 8Hz, 1H), 6.73 (d, J = 8Hz, 1H), 7.15-7.25 (m, 1H), 7.25-7.35 (m, 1H), 7.60-7. 75 (m, 1H), 8.50-8.60 (m, 1H).

(Example 52)
1-((4R,4aR,8aR,13bS)-3-(cyclopropylmethyl)-10-hydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro[2 ,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(pyridin-2-yl)ethan-1-one

参考例１に記載した方法に従い、実施例５１で得られた化合物より表題化合物を得た。
^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．１０－０．２５（ｍ，２Ｈ），０．５０－０．６５（ｍ，２Ｈ），０．８０－１．００（ｍ，１Ｈ），１．００－１．１５（ｍ，１Ｈ），１．２０－１．５０（ｍ，２Ｈ），１．５０－２．６０（ｍ，６Ｈ），２．６０－２．７０（ｍ，１Ｈ），２．８０－２．９０（ｍ，２Ｈ），３．３０－３．５０（ｍ，２Ｈ），３．６０－３．７０（ｍ，１Ｈ），４．２０－４．４０（ｍ，２Ｈ），４．７０－４．９０（ｍ，２Ｈ），６．５０（ｄ，Ｊ＝８Ｈｚ，０．８Ｈ），６．５２（ｄ，Ｊ＝８Ｈｚ，０．２Ｈ），６．７０（ｄ，Ｊ＝８Ｈｚ，０．２Ｈ），６．８０（ｄ，Ｊ＝８Ｈｚ，０．８Ｈ），７．１０－７．２５（ｍ，１Ｈ），７．２８（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．６０－７．８０（ｍ，１Ｈ），８．５０－８．５５（ｍ，１Ｈ）．

According to the method described in Reference Example 1, the title compound was obtained from the compound obtained in Example 51.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10-0.25 (m, 2H), 0.50-0.65 (m, 2H), 0.80-1.00 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.50 (m, 2H), 1.50-2.60 (m, 6H), 2.60-2.70 (m, 1H), 2.80-2.90 (m, 2H), 3.30-3.50 (m, 2H), 3.60-3.70 (m, 1H), 4.20-4 .40 (m, 2H), 4.70-4.90 (m, 2H), 6.50 (d, J = 8Hz, 0.8H), 6.52 (d, J = 8Hz, 0.2H) , 6.70 (d, J = 8 Hz, 0.2 H), 6.80 (d, J = 8 Hz, 0.8 H), 7.10-7.25 (m, 1 H), 7.28 (d, J=8 Hz, 1 H), 7.60-7.80 (m, 1 H), 8.50-8.55 (m, 1 H).

(Example 53)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(1-methyl-1H-imidazol-2-yl)ethan-1-one

２－（１－メチル－１Ｈ－イミダゾール－２－イル）酢酸エチル塩酸塩（１０ｍｇ，０．０５０ｍｍｏｌ）のメタノール（１ｍＬ）溶液に、水酸化リチウム一水和物（６．３ｍｇ，０．１５ｍｍｏｌ）及び水（０．１ｍＬ）を加え、室温で１７時間撹拌した後、減圧下にて濃縮した。得られた残渣と実施例３の（１）で得られた化合物（７．０ｍｇ，０．０２０ｍｍｏｌ）をＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）溶解し、Ｎ，Ｎ－ジイソプロピルエチルアミン（１７μＬ，０．１０ｍｍｏｌ）及びＯ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムヘキサフルオロホスファート（ＨＡＴＵ）（１０ｍｇ，０．０２７ｍｍｏｌ）を加え、室温で１７時間撹拌した。その後炭酸カリウム（２８ｍｇ，０．２０ｍｍｏｌ）のメタノール（１ｍＬ）懸濁液を加え、室温で１時間撹拌した。反応混合物に水を加え、酢酸エチルで三回抽出した。有機層を水で１回洗浄し、硫酸ナトリウムで乾燥後、減圧下にて濃縮した。得られた粗生成物を分取薄層クロマトグラフィー（クロロホルム：２Mアンモニア－メタノール溶液＝１０：１）で精製し、表題化合物（２．８ｍｇ，３０％）を淡黄色固体として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０３－０．２３（ｍ，２Ｈ），０．４４－０．６２（ｍ，２Ｈ），０．６８－２．０８（ｍ，３Ｈ），２．１１－２．７１（ｍ，６Ｈ），２．８１－３．１４（ｍ，３Ｈ），３．２９－３．８６（ｍ，６Ｈ），４．１８－４．４６（ｍ，２Ｈ），４．５４－４．９６（ｍ，２Ｈ），５．０１－５．１５（ｍ，１Ｈ），６．４７（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７６－６．８６（ｍ，２Ｈ），６．９２－７．０２（ｍ，１Ｈ）．

2-(1-Methyl-1H-imidazol-2-yl) ethyl acetate hydrochloride (10 mg, 0.050 mmol) in methanol (1 mL), lithium hydroxide monohydrate (6.3 mg, 0.15 mmol) and water (0.1 mL) were added, and the mixture was stirred at room temperature for 17 hours and then concentrated under reduced pressure. The obtained residue and the compound (7.0 mg, 0.020 mmol) obtained in (1) of Example 3 were dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethylamine (17 μL, 0.05 μL) was added. 10 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (10 mg, 0.027 mmol) were added and Stirred for 17 hours. After that, a suspension of potassium carbonate (28 mg, 0.20 mmol) in methanol (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate three times. The organic layer was washed once with water, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by preparative thin layer chromatography (chloroform:2M ammonia-methanol solution=10:1) to give the title compound (2.8 mg, 30%) as a pale yellow solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.23 (m, 2H), 0.44-0.62 (m, 2H), 0.68-2.08 (m , 3H), 2.11-2.71 (m, 6H), 2.81-3.14 (m, 3H), 3.29-3.86 (m, 6H), 4.18-4.46 (m, 2H), 4.54-4.96 (m, 2H), 5.01-5.15 (m, 1H), 6.47 (d, J=8Hz, 1H), 6.76-6 .86 (m, 2H), 6.92-7.02 (m, 1H).

(Example 54)
2-chloro-1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4 ,13-methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)ethan-1-one

実施例３の（１）で得られた化合物（１５ｍｇ，０．０４２ｍｍｏｌ）のクロロホルム（１ｍＬ）溶液に、氷冷下Ｎ，Ｎ－ジイソプロピルエチルアミン（２２μＬ，０．１３ｍｍｏｌ）及びクロロアセチルクロリド（５．２μＬ，０．０６６ｍｍｏｌ）を加え、室温で１９時間撹拌した。その後、炭酸カリウム（６１ｍｇ，０．４４ｍｍｏｌ）のメタノール（１ｍＬ）懸濁液を加え、室温で１時間撹拌した。氷冷下、反応混合物に水を加え、酢酸エチルで三回抽出した。合わせた抽出液を硫酸ナトリウムで乾燥後、減圧下にて濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（０－１０％メタノール／クロロホルム）で精製し、表題化合物（１５ｍｇ，８０％）を淡黄色フィルム状物質として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．２３（ｍ，２Ｈ），０．４７－０．６４（ｍ，２Ｈ），０．７７－０．９３（ｍ，１Ｈ），１．０７－２．４４（ｍ，７Ｈ），２．４７－２．７４（ｍ，２Ｈ），２．８９－３．０６（ｍ，２Ｈ），３．１５（ｄｄ，Ｊ＝１３，１３Ｈｚ，０．４Ｈ），３．２５－４．３４（ｍ，５．６Ｈ），４．５１－４．６６（ｍ，１Ｈ），４．７４－５．２１（ｍ，１Ｈ），６．４８（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．５５（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．６１（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ）．

To a solution of the compound (15 mg, 0.042 mmol) obtained in Example 3 (1) in chloroform (1 mL) was added N,N-diisopropylethylamine (22 μL, 0.13 mmol) and chloroacetyl chloride (5. 2 μL, 0.066 mmol) was added and stirred at room temperature for 19 hours. After that, a suspension of potassium carbonate (61 mg, 0.44 mmol) in methanol (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture under ice-cooling, and the mixture was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (0-10% methanol/chloroform) to give the title compound (15 mg, 80%) as a pale yellow film-like substance.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.23 (m, 2H), 0.47-0.64 (m, 2H), 0.77-0.93 (m , 1H), 1.07-2.44 (m, 7H), 2.47-2.74 (m, 2H), 2.89-3.06 (m, 2H), 3.15 (dd, J = 13, 13Hz, 0.4H), 3.25-4.34 (m, 5.6H), 4.51-4.66 (m, 1H), 4.74-5.21 (m, 1H) , 6.48 (d, J=8 Hz, 0.4 H), 6.55 (d, J=8 Hz, 0.6 H), 6.61 (d, J=8 Hz, 0.4 H), 6.71 ( d, J=8Hz, 0.6H).

(Example 55)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(3,3-difluoropyrrolidin-1-yl)ethan-1-one

実施例５４で得られた化合物（５．１ｍｇ，０．０１２ｍｍｏｌ）のアセトニトリル（１ｍＬ）溶液にＮ，Ｎ－ジイソプロピルエチルアミン（２１μＬ，０．１２ｍｍｏｌ）、３，３－ジフルオロピロリジン塩酸塩（５．２ｍｇ，０．０３７ｍｍｏｌ）及びヨウ化ナトリウム（１．８ｍｇ，０．０１２ｍｍｏｌ）を加え室温で１７時間撹拌した。反応混合物に水を加え、酢酸エチルで三回抽出した。合わせた抽出液を硫酸ナトリウムで乾燥後、減圧下にて濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（１－８％２Mアンモニア－メタノール／クロロホルム）で精製し、表題化合物（３．５ｍｇ，５９％）を淡黄色ガム状物質として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．２１（ｍ，２Ｈ），０．４５－０．６３（ｍ，２Ｈ），０．７７－０．９６（ｍ，１Ｈ），１．０７－２．７２（ｍ，１４Ｈ），２．８５－４．４４（ｍ，１０Ｈ），４．５４－４．７９（ｍ，１Ｈ），６．４４－６．５６（ｍ，１Ｈ），６．６３－６．７４（ｍ，１Ｈ）．

N,N-diisopropylethylamine (21 μL, 0.12 mmol), 3,3-difluoropyrrolidine hydrochloride (5.2 mg , 0.037 mmol) and sodium iodide (1.8 mg, 0.012 mmol) were added and stirred at room temperature for 17 hours. Water was added to the reaction mixture and extracted with ethyl acetate three times. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (1-8% 2M ammonia-methanol/chloroform) to give the title compound (3.5 mg, 59%) as a pale yellow gum.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.21 (m, 2H), 0.45-0.63 (m, 2H), 0.77-0.96 (m , 1H), 1.07-2.72 (m, 14H), 2.85-4.44 (m, 10H), 4.54-4.79 (m, 1H), 6.44-6.56 (m, 1H), 6.63-6.74 (m, 1H).

(Example 56)
2-chloro-1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a-hydroxy-10-methoxy-2,3,4,4a,5,6,8,8a-octahydro Synthesis of -4,13-methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)ethan-1-one

実施例５４に記載した方法に従い、実施例２で得られた化合物及びクロロアセチルクロリドより表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．２０（ｍ，２Ｈ），０．４５－０．６２（ｍ，２Ｈ），０．７６－０．９４（ｍ，１Ｈ），１．１６－１．９４（ｍ，３Ｈ），２．００－２．４３（ｍ，４Ｈ），２．４８－２．７０（ｍ，２Ｈ），２．０８－３．２１（ｍ，３Ｈ），３．３１（ｄｄ，Ｊ＝６，１３Ｈｚ，０．３Ｈ），３．６５（ｄ，Ｊ＝１６Ｈｚ，０．７Ｈ），３．７２－４．３９（ｍ，６．４Ｈ），４．５１－４．６６（ｍ，１．３Ｈ），４．９５（ｄｄ，Ｊ＝６，１１Ｈｚ，０．３Ｈ），６．４９－６．７７（ｍ，２Ｈ）．

The title compound was obtained from the compound obtained in Example 2 and chloroacetyl chloride according to the method described in Example 54.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.20 (m, 2H), 0.45-0.62 (m, 2H), 0.76-0.94 (m , 1H), 1.16-1.94 (m, 3H), 2.00-2.43 (m, 4H), 2.48-2.70 (m, 2H), 2.08-3.21 (m, 3H), 3.31 (dd, J=6, 13Hz, 0.3H), 3.65 (d, J=16Hz, 0.7H), 3.72-4.39 (m, 6. 4H), 4.51-4.66 (m, 1.3H), 4.95 (dd, J=6, 11Hz, 0.3H), 6.49-6.77 (m, 2H).

(Example 57)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a-hydroxy-10-methoxy-2,3,4,4a,5,6,8,8a-octahydro-4,13 - methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-((2R,6S)-2,6-dimethylpiperidin-1-yl)ethane-1 -Synthesis of on

実施例５５に記載した方法に従い、実施例５６で得られた化合物及びｃｉｓ－２，６－ジメチルピペリジンより表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０３－０．２３（ｍ，２Ｈ），０．４７－０．６４（ｍ，２Ｈ），０．７６－２．８６（ｍ，２２Ｈ），２．９２－３．３９（ｍ，４Ｈ），３．４４－４．４９（ｍ，９Ｈ），４．５３－４．６５（ｍ，０．４Ｈ），４．８６（ｄｄ，Ｊ＝６，１０Ｈｚ，０．６Ｈ），６．５５（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．５９－６．６８（ｍ，１Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ）．

According to the method described in Example 55, the title compound was obtained from the compound obtained in Example 56 and cis-2,6-dimethylpiperidine.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.23 (m, 2H), 0.47-0.64 (m, 2H), 0.76-2.86 (m , 22H), 2.92-3.39 (m, 4H), 3.44-4.49 (m, 9H), 4.53-4.65 (m, 0.4H), 4.86 (dd , J = 6, 10Hz, 0.6H), 6.55 (d, J = 8Hz, 0.4H), 6.59-6.68 (m, 1H), 6.72 (d, J = 8Hz, 0.6H).

(Example 58)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-((2R,6S)-2,6-dimethylpiperidin-1-yl)ethan-1-one Synthesis of

参考例１に記載した方法に従い、実施例５７で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０３－０．２５（ｍ，２Ｈ），０．４３－０．６１（ｍ，２Ｈ），０．６２－２．７１（ｍ，２３Ｈ），２．７８－３．８７（ｍ，８Ｈ），３．９５－４．４０（ｍ，１Ｈ），４．４５－５．０３（ｍ，２Ｈ），６．４１－６．５４（ｍ，１Ｈ），６．６２－６．７５（ｍ，１Ｈ）．

According to the method described in Reference Example 1, the title compound was obtained from the compound obtained in Example 57.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.25 (m, 2H), 0.43-0.61 (m, 2H), 0.62-2.71 (m , 23H), 2.78-3.87 (m, 8H), 3.95-4.40 (m, 1H), 4.45-5.03 (m, 2H), 6.41-6.54 (m, 1H), 6.62-6.75 (m, 1H).

(Example 59)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(5-methylthiazol-2-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（５－メチルチアゾール－２－イル）酢酸ナトリウムより表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０３－０．２１（ｍ，２Ｈ），０．４２－０．６２（ｍ，２Ｈ），０．７６－０．９５（ｍ，１Ｈ），１．０６－３．１５（ｍ，１５．６Ｈ），３．２７－３．８３（ｍ，２．４Ｈ），３．８９－４．４８（ｍ，２Ｈ），４．５０－４．８５（ｍ，１Ｈ），５．０１－５．１８（ｍ，１Ｈ）６．３７－６．５８（ｍ，１Ｈ），６．６５－６．８２（ｍ，１Ｈ），７．２０－７．３８（ｍ，１Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and sodium 2-(5-methylthiazol-2-yl)acetate.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.21 (m, 2H), 0.42-0.62 (m, 2H), 0.76-0.95 (m , 1H), 1.06-3.15 (m, 15.6H), 3.27-3.83 (m, 2.4H), 3.89-4.48 (m, 2H), 4.50 -4.85 (m, 1H), 5.01-5.18 (m, 1H) 6.37-6.58 (m, 1H), 6.65-6.82 (m, 1H), 7. 20-7.38 (m, 1H).

(Example 60)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(2-methylthiazol-4-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（２－メチルチアゾール－４－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１９（ｍ，２Ｈ），０．４９－０．５８（ｍ，２Ｈ），０．７８－０．９２（ｍ，１Ｈ），１．２１－１．５５（ｍ，２Ｈ），１．６１－１．７１（ｍ，１Ｈ），２．１５－２．３６（ｍ，３．４Ｈ），２．３９（ｄｄ，Ｊ＝６，１２Ｈｚ，０．８Ｈ），２．４９（ｄｄ，Ｊ＝７，１９Ｈｚ，０．８Ｈ），２．５７－２．６９（ｍ，１Ｈ），２．６２（ｓ，０．６Ｈ），２．７６（ｓ，２．４Ｈ），２．８７（ｄ，Ｊ＝６Ｈｚ，０．２Ｈ），２．９４（ｄ，Ｊ＝７Ｈｚ，０．８Ｈ），２．９７－３．０９（ｍ，２Ｈ），３．４３－３．７２（ｍ，１．４Ｈ），３．４６（ｄ，Ｊ＝１６Ｈｚ，０．８Ｈ），３．７０（ｄ，Ｊ＝１６Ｈｚ，０．２Ｈ），３．９２（ｄ，Ｊ＝１６Ｈｚ，０．２Ｈ），４．２６－４．４０（ｍ，１．６Ｈ），４．６２－４．６７（ｍ，０．８Ｈ），４．６９－４．７４（ｍ，０．２Ｈ），４．８６（ｄ，Ｊ＝１６Ｈｚ，０．８Ｈ），６．４６－６．５１（ｍ，０．４Ｈ），６．４８（ｄ，Ｊ＝８Ｈｚ，０．８Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．２Ｈ），６．８０（ｄ，Ｊ＝８Ｈｚ，０．８Ｈ），６．９２（ｓ，０．８Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 2-(2-methylthiazol-4-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.19 (m, 2H), 0.49-0.58 (m, 2H), 0.78-0.92 (m , 1H), 1.21-1.55 (m, 2H), 1.61-1.71 (m, 1H), 2.15-2.36 (m, 3.4H), 2.39 (dd , J = 6, 12 Hz, 0.8H), 2.49 (dd, J = 7, 19 Hz, 0.8H), 2.57-2.69 (m, 1H), 2.62 (s, 0.8H). 6H), 2.76 (s, 2.4H), 2.87 (d, J=6Hz, 0.2H), 2.94 (d, J=7Hz, 0.8H), 2.97-3. 09 (m, 2H), 3.43-3.72 (m, 1.4H), 3.46 (d, J = 16Hz, 0.8H), 3.70 (d, J = 16Hz, 0.2H ), 3.92 (d, J=16Hz, 0.2H), 4.26-4.40 (m, 1.6H), 4.62-4.67 (m, 0.8H), 4.69 -4.74 (m, 0.2H), 4.86 (d, J = 16Hz, 0.8H), 6.46-6.51 (m, 0.4H), 6.48 (d, J = 8Hz, 0.8H), 6.73 (d, J = 8Hz, 0.2H), 6.80 (d, J = 8Hz, 0.8H), 6.92 (s, 0.8H).

(Example 61)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(2-phenylthiazol-4-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（２－フェニルチアゾール－４－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１６（ｍ，２Ｈ），０．４６－０．５９（ｍ，２Ｈ），０．７５－０．９３（ｍ，１Ｈ），１．２３－１．６９（ｍ，３Ｈ），２．１２－２．４２（ｍ，５Ｈ），２．５３（ｄｄ，Ｊ＝６，１９Ｈｚ，０．６Ｈ），２．５３－２．６９（ｍ，０．８Ｈ），２．８３（ｄ，Ｊ＝７Ｈｚ，０．４Ｈ），２．９１（ｄ，Ｊ＝１９Ｈｚ，０．４Ｈ），２．９７（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），３．００（ｄ，Ｊ＝１９Ｈｚ，０．６Ｈ），３．０５－３．１６（ｍ，０．６Ｈ），３．４１－３．５６（ｍ，０．４Ｈ），３．６１－３．７３（ｍ，１．４Ｈ），３．７７（ｄ，Ｊ＝１６Ｈｚ，０．４Ｈ），３．９８（ｄ，Ｊ＝１６Ｈｚ，０．６Ｈ），４．０９（ｄ，Ｊ＝１６Ｈｚ，０．４Ｈ），４．２６－４．３４（ｍ，０．６Ｈ），４．４０－４．４９（ｍ，０．６Ｈ），４．６０（ｄ，Ｊ＝１６Ｈｚ，０．６Ｈ），４．６５－４．７３（ｍ，１Ｈ），６．４１（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．４６（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．６５（ｓ，０．４Ｈ），６．６９（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），７．１３（ｓ，０．６Ｈ），７．３７－７．４９（ｍ，３Ｈ），７．８２－７．８９（ｍ，０．８Ｈ），７．９０－７．９６（ｍ，１．２Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 2-(2-phenylthiazol-4-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.16 (m, 2H), 0.46-0.59 (m, 2H), 0.75-0.93 (m , 1H), 1.23-1.69 (m, 3H), 2.12-2.42 (m, 5H), 2.53 (dd, J = 6, 19Hz, 0.6H), 2.53 -2.69 (m, 0.8H), 2.83 (d, J = 7Hz, 0.4H), 2.91 (d, J = 19Hz, 0.4H), 2.97 (d, J = 8Hz, 0.6H), 3.00 (d, J = 19Hz, 0.6H), 3.05-3.16 (m, 0.6H), 3.41-3.56 (m, 0.4H) ), 3.61-3.73 (m, 1.4H), 3.77 (d, J = 16Hz, 0.4H), 3.98 (d, J = 16Hz, 0.6H), 4.09 (d, J = 16Hz, 0.4H), 4.26-4.34 (m, 0.6H), 4.40-4.49 (m, 0.6H), 4.60 (d, J = 16Hz, 0.6H), 4.65-4.73 (m, 1H), 6.41 (d, J = 8Hz, 0.4H), 6.46 (d, J = 8Hz, 0.6H), 6.65 (s, 0.4H), 6.69 (d, J = 8Hz, 0.4H), 6.72 (d, J = 8Hz, 0.6H), 7.13 (s, 0.6H ), 7.37-7.49 (m, 3H), 7.82-7.89 (m, 0.8H), 7.90-7.96 (m, 1.2H).

(Example 62)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(oxazol-2-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（オキサゾール－２－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１９（ｍ，２Ｈ），０．４７－０．５９（ｍ，２Ｈ），０．７８－０．９２（ｍ，１Ｈ），１．２１－１．５４（ｍ，２Ｈ），１．５８－１．６９（ｍ，１Ｈ），２．１２－２．４２（ｍ，４．１Ｈ），２．４４－２．５５（ｍ，０．１Ｈ），２．４８（ｄｄ，Ｊ＝７，１９Ｈｚ，０．９Ｈ），２．５８－２．７０（ｍ，１Ｈ），２．９１－３．１１（ｍ，１．１Ｈ），２．９４（ｄ，Ｊ＝７Ｈｚ，０．９Ｈ），３．０２（ｄ，Ｊ＝１９Ｈｚ，０．９Ｈ），３．６１－３．８９（ｍ，１．２Ｈ），３．６５（ｄ，Ｊ＝１６Ｈｚ，０．９Ｈ），３．９１（ｄ，Ｊ＝１６Ｈｚ，０．１Ｈ），３．９５（ｄ，Ｊ＝１６Ｈｚ，０．１Ｈ），４．２２－４．３４（ｍ，１．８Ｈ），４．６２－４．６６（ｍ，０．９Ｈ），４．７８－４．８４（ｍ，０．１Ｈ），４．９８（ｄ，Ｊ＝１６Ｈｚ，０．９Ｈ），６．４９（ｄ，Ｊ＝８Ｈｚ，０．９Ｈ），６．５３（ｄ，Ｊ＝８Ｈｚ，０．１Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．１Ｈ），６．８１（ｄ，Ｊ＝８Ｈｚ，０．９Ｈ），７．００（ｓ，０．１Ｈ），７．１１（ｓ，０．９Ｈ），７．５３（ｓ，０．１Ｈ），７．６４（ｓ，０．９Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 2-(oxazol-2-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.19 (m, 2H), 0.47-0.59 (m, 2H), 0.78-0.92 (m , 1H), 1.21-1.54 (m, 2H), 1.58-1.69 (m, 1H), 2.12-2.42 (m, 4.1H), 2.44-2 .55 (m, 0.1H), 2.48 (dd, J=7, 19Hz, 0.9H), 2.58-2.70 (m, 1H), 2.91-3.11 (m, 1.1H), 2.94 (d, J = 7Hz, 0.9H), 3.02 (d, J = 19Hz, 0.9H), 3.61-3.89 (m, 1.2H), 3.65 (d, J = 16Hz, 0.9H), 3.91 (d, J = 16Hz, 0.1H), 3.95 (d, J = 16Hz, 0.1H), 4.22-4 .34 (m, 1.8H), 4.62-4.66 (m, 0.9H), 4.78-4.84 (m, 0.1H), 4.98 (d, J = 16Hz, 0.9H), 6.49 (d, J = 8Hz, 0.9H), 6.53 (d, J = 8Hz, 0.1H), 6.72 (d, J = 8Hz, 0.1H), 6.81 (d, J = 8Hz, 0.9H), 7.00 (s, 0.1H), 7.11 (s, 0.9H), 7.53 (s, 0.1H), 7. 64 (s, 0.9H).

(Example 63)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(4-methylthiazol-2-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（４－メチルチアゾール－２－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．２１（ｍ
，２Ｈ），０．４７－０．６２（ｍ，２Ｈ），０．７７－０．９７（ｍ，１Ｈ），１．１６－２．７２（ｍ，１３Ｈ），２．８７－３．１７（ｍ，３Ｈ），３．３２－３．９０（ｍ，２Ｈ），３．９７－４．５１（ｍ，２Ｈ），４．５９－４．８６（ｍ，１Ｈ），５．１１－５．２４（ｍ，１Ｈ），６．４２－６．５８（ｍ，１Ｈ），６．６３－６．９０（ｍ，２Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 2-(4-methylthiazol-2-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.21 (m
, 2H), 0.47-0.62 (m, 2H), 0.77-0.97 (m, 1H), 1.16-2.72 (m, 13H), 2.87-3.17 (m, 3H), 3.32-3.90 (m, 2H), 3.97-4.51 (m, 2H), 4.59-4.86 (m, 1H), 5.11-5 .24 (m, 1H), 6.42-6.58 (m, 1H), 6.63-6.90 (m, 2H).

(Example 64)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(1-hydroxycyclohexyl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（１－ヒドロキシシクロヘキシル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．２１（ｍ，２Ｈ），０．４４－０．６２（ｍ，２Ｈ），０．７７－０．９７（ｍ，１Ｈ），１．１１－２．７１（ｍ，２０Ｈ），２．８１－３．２１（ｍ，２．６Ｈ），３．２４－４．４５（ｍ，３．４Ｈ），４．４４－５．１０（ｍ，２Ｈ），６．４８（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．５３（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．６４－６．７５（ｍ，２Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in (1) of Example 3 and 2-(1-hydroxycyclohexyl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.21 (m, 2H), 0.44-0.62 (m, 2H), 0.77-0.97 (m , 1H), 1.11-2.71 (m, 20H), 2.81-3.21 (m, 2.6H), 3.24-4.45 (m, 3.4H), 4.44 -5.10 (m, 2H), 6.48 (d, J = 8Hz, 0.4H), 6.53 (d, J = 8Hz, 0.6H), 6.64-6.75 (m, 2H).

(Example 65)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(3,3-difluoropiperidin-1-yl)ethan-1-one

実施例５５に記載した方法に従い、実施例５４で得られた化合物及び３，３－ジフルオロピペリジン塩酸塩より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０３－０．２１（ｍ，２Ｈ），０．４６－０．６３（ｍ，２Ｈ），０．７５－１．９７（ｍ，９Ｈ），２．０２－２．６９（ｍ，８Ｈ），２．７１－３．２６（ｍ，４Ｈ），３．３１－３．７９（ｍ，４Ｈ），３．８９－４．４７（ｍ，２Ｈ），４．６１－４．８６（ｍ，１Ｈ），６．４４－６．５６（ｍ，１Ｈ），６．６４（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．６８（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ）．

According to the method described in Example 55, the title compound was obtained from the compound obtained in Example 54 and 3,3-difluoropiperidine hydrochloride.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.21 (m, 2H), 0.46-0.63 (m, 2H), 0.75-1.97 (m , 9H), 2.02-2.69 (m, 8H), 2.71-3.26 (m, 4H), 3.31-3.79 (m, 4H), 3.89-4.47 (m, 2H), 4.61-4.86 (m, 1H), 6.44-6.56 (m, 1H), 6.64 (d, J=8Hz, 0.3H), 6.68 (d, J=8Hz, 0.7H).

(Example 66)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(oxazol-4-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（オキサゾール－４－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．２０（ｍ，２Ｈ），０．４８－０．６１（ｍ，２Ｈ），０．７９－０．９０（ｍ，１Ｈ），１．２２－１．６８（ｍ，３Ｈ），１．９９－２．０６（ｍ，０．２Ｈ），２．１２－２．４２（ｍ，４Ｈ），２．４５－２．５５（ｍ，０．２Ｈ），２．４９（ｄｄ，Ｊ＝７，１９Ｈｚ，０．８Ｈ），２．５８－２．７０（ｍ，１Ｈ），２．９１－３．１２（ｍ，１．２Ｈ），２．９５（ｄ，Ｊ＝７Ｈｚ，０．８Ｈ），３．０２（ｄ，Ｊ＝１９Ｈｚ，０．８Ｈ），３．４０（ｄ，Ｊ＝１６Ｈｚ，０．８Ｈ），３．４７－３．５６（ｍ，０．２Ｈ），３．６０－３．８２（ｍ，１．６Ｈ），４．２７－４．４２（ｍ，１．６Ｈ），４．５３（ｄ，Ｊ＝１６Ｈｚ，０．８Ｈ），４．６１－４．６６（ｍ，０．８Ｈ），４．７５－５．０１（ｍ，１．２Ｈ），６．４８（ｄ，Ｊ＝８Ｈｚ，０．８Ｈ），６．４９－６．５３（ｍ，０．２Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．２Ｈ），６．７７（ｄ，Ｊ＝８Ｈｚ，０．８Ｈ），７．４９（ｓ，０．２Ｈ），７．６２（ｓ，０．８Ｈ），７．７７（ｓ，０．２Ｈ），７．９３（ｓ，０．８Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 2-(oxazol-4-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.20 (m, 2H), 0.48-0.61 (m, 2H), 0.79-0.90 (m , 1H), 1.22-1.68 (m, 3H), 1.99-2.06 (m, 0.2H), 2.12-2.42 (m, 4H), 2.45-2 .55 (m, 0.2H), 2.49 (dd, J=7, 19Hz, 0.8H), 2.58-2.70 (m, 1H), 2.91-3.12 (m, 1.2H), 2.95 (d, J = 7Hz, 0.8H), 3.02 (d, J = 19Hz, 0.8H), 3.40 (d, J = 16Hz, 0.8H), 3.47-3.56 (m, 0.2H), 3.60-3.82 (m, 1.6H), 4.27-4.42 (m, 1.6H), 4.53 (d , J = 16Hz, 0.8H), 4.61-4.66 (m, 0.8H), 4.75-5.01 (m, 1.2H), 6.48 (d, J = 8Hz, 0.8H), 6.49-6.53 (m, 0.2H), 6.72 (d, J = 8Hz, 0.2H), 6.77 (d, J = 8Hz, 0.8H), 7.49 (s, 0.2H), 7.62 (s, 0.8H), 7.77 (s, 0.2H), 7.93 (s, 0.8H).

(Example 67)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-3-(4-methyl-1H-pyrazol-1-yl)propan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び３－（４－メチル－１Ｈ－ピラゾール－１－イル）プロパン酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．１０－０．２０（ｍ，２Ｈ），０．５０－０．６０（ｍ，２Ｈ），０．７５－０．９０（ｍ，１Ｈ），１．２０－１．９０（ｍ，４Ｈ），２．０４（ｓ，０．３Ｈ），２．０５（ｓ，２．７Ｈ），２．２０－２．４０（ｍ，４Ｈ），２．４５－２．７０（ｍ，３Ｈ），２．９０－３．１０（ｍ，３Ｈ），３．５８（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），３．７５－３．８５（ｍ，１Ｈ），４．００－４．１０（ｍ，１Ｈ），４．２０－４．４５（ｍ，３Ｈ），４．５８（ｓ，１Ｈ），６．４５－６．５５（ｍ，１Ｈ），６．６５－６．７５（ｍ，１Ｈ），７．１６（ｓ，０．９Ｈ），７．２１（ｓ，０．１Ｈ），７．４０（ｓ，１Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in (1) of Example 3 and 3-(4-methyl-1H-pyrazol-1-yl)propanoic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10-0.20 (m, 2H), 0.50-0.60 (m, 2H), 0.75-0.90 (m , 1H), 1.20-1.90 (m, 4H), 2.04 (s, 0.3H), 2.05 (s, 2.7H), 2.20-2.40 (m, 4H) ), 2.45-2.70 (m, 3H), 2.90-3.10 (m, 3H), 3.58 (d, J = 16Hz, 1H), 3.75-3.85 (m , 1H), 4.00-4.10 (m, 1H), 4.20-4.45 (m, 3H), 4.58 (s, 1H), 6.45-6.55 (m, 1H) ), 6.65-6.75 (m, 1H), 7.16 (s, 0.9H), 7.21 (s, 0.1H), 7.40 (s, 1H).

(Example 68)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(4,4-difluoropiperidin-1-yl)ethan-1-one

実施例５５に記載した方法に従い、実施例５４で得られた化合物及び４，４－ジフルオロピペリジンより表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．２３（ｍ，２Ｈ），０．４３－０．６３（ｍ，２Ｈ），０．７７－０．９９（ｍ，１Ｈ），１．０５－２．７０（ｍ，１７Ｈ），２．７１－３．９４（ｍ，７Ｈ），４．０３－５．０５（ｍ，３Ｈ），６．３５－６．５２（ｍ，１Ｈ），６．５７－６．７２（ｍ，１Ｈ）．

According to the method described in Example 55, the title compound was obtained from the compound obtained in Example 54 and 4,4-difluoropiperidine.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.23 (m, 2H), 0.43-0.63 (m, 2H), 0.77-0.99 (m , 1H), 1.05-2.70 (m, 17H), 2.71-3.94 (m, 7H), 4.03-5.05 (m, 3H), 6.35-6.52 (m, 1H), 6.57-6.72 (m, 1H).

(Example 69)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)propan-1-one synthesis

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び３－（４－（トリフルオロメチル）－１Ｈ－ピラゾール－１－イル）プロパン酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．１０－０．２０（ｍ，２Ｈ），０．５０－０．６０（ｍ，２Ｈ），０．７５－０．９５（ｍ，１Ｈ），１．２０－１．９０（ｍ，７Ｈ），２．２０－２．４０（ｍ，３Ｈ），２．４５－２．６５（ｍ，２Ｈ），２．９０－３．１０（ｍ，２．８Ｈ），３．１５－３．３０（ｍ，０．２Ｈ），３．６１（ｄ，Ｊ＝１４Ｈｚ，０．８Ｈ），３．７０－３．９０（ｍ，０．８Ｈ），４．１５－４．５５（ｍ，３．４Ｈ），４．６０（ｓ，１Ｈ），６．５０（ｄ，Ｊ＝８Ｈｚ，０．８Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，０．２Ｈ），６．６９（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．６７（ｓ，０．２Ｈ），７．７２（ｓ，０．８Ｈ），７．８０（ｓ，０．８Ｈ），７．８４（ｓ，０．２Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in (1) of Example 3 and 3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)propanoic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10-0.20 (m, 2H), 0.50-0.60 (m, 2H), 0.75-0.95 (m , 1H), 1.20-1.90 (m, 7H), 2.20-2.40 (m, 3H), 2.45-2.65 (m, 2H), 2.90-3.10 (m, 2.8H), 3.15-3.30 (m, 0.2H), 3.61 (d, J=14Hz, 0.8H), 3.70-3.90 (m, 0.8H) 8H), 4.15-4.55 (m, 3.4H), 4.60 (s, 1H), 6.50 (d, J = 8Hz, 0.8H), 6.54 (d, J = 8Hz, 0.2H), 6.69 (d, J = 8Hz, 1H), 7.67 (s, 0.2H), 7.72 (s, 0.8H), 7.80 (s, 0.8H). 8H), 7.84 (s, 0.2H).

(Example 70)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-3-(1H-pyrazol-1-yl)propan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び３－（１Ｈ－ピラゾール－１－イル）プロパン酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．１０－０．２０（ｍ，２Ｈ），０．５０－０．６０（ｍ，２Ｈ），０．７５－０．９５（ｍ，１Ｈ），１．２０－１．９０（ｍ，５Ｈ），２．２０－２．４５（ｍ，３．３Ｈ），２．４５－２．７０（ｍ，２．７Ｈ），２．９０－３．１０（ｍ，３Ｈ），３．５９（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），３．８０－３．９０（ｍ，１Ｈ），４．１０－４．２０（ｍ，２Ｈ），４．２４（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），４．３５－４．５０（ｍ，１Ｈ），４．６０（ｓ，１Ｈ），６．１９（ｔ，Ｊ＝２Ｈｚ，０．１Ｈ），６．２３（ｔ，Ｊ＝２Ｈｚ，０．９Ｈ），６．４５－６．６０（ｍ，１Ｈ），６．６５－６．８０（ｍ，１Ｈ），７．４０（ｄ，Ｊ＝２Ｈｚ，０．９Ｈ），７．４４（ｄ，Ｊ＝２Ｈｚ，０．１Ｈ），７．４７（ｄ，Ｊ＝２Ｈｚ，０．１Ｈ），７．６２（ｄ，Ｊ＝２Ｈｚ，０．９Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 3-(1H-pyrazol-1-yl)propanoic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10-0.20 (m, 2H), 0.50-0.60 (m, 2H), 0.75-0.95 (m , 1H), 1.20-1.90 (m, 5H), 2.20-2.45 (m, 3.3H), 2.45-2.70 (m, 2.7H), 2.90 -3.10 (m, 3H), 3.59 (d, J=16Hz, 1H), 3.80-3.90 (m, 1H), 4.10-4.20 (m, 2H), 4 .24 (d, J=16 Hz, 1 H), 4.35-4.50 (m, 1 H), 4.60 (s, 1 H), 6.19 (t, J=2 Hz, 0.1 H), 6 .23 (t, J = 2Hz, 0.9H), 6.45-6.60 (m, 1H), 6.65-6.80 (m, 1H), 7.40 (d, J = 2Hz, 0.9 H), 7.44 (d, J=2 Hz, 0.1 H), 7.47 (d, J=2 Hz, 0.1 H), 7.62 (d, J=2 Hz, 0.9 H).

(Example 71)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(2,2-dimethylpyrrolidin-1-yl)ethan-1-one

実施例５５に記載した方法に従い、実施例５４で得られた化合物及び２，２－ジメチルピロリジン塩酸塩より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０３－０．２６（ｍ，２Ｈ），０．４６－０．６４（ｍ，２Ｈ），０．７２－３．３２（ｍ，２６Ｈ），３．３５－４．０３（ｍ，２．６Ｈ），４．２４－４．４１（ｍ，０．４Ｈ），４．４６－５．０９（ｍ，３Ｈ），６．４０－６．５５（ｍ，１Ｈ），６．６０－６．７７（ｍ，１Ｈ）．

According to the method described in Example 55, the title compound was obtained from the compound obtained in Example 54 and 2,2-dimethylpyrrolidine hydrochloride.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.26 (m, 2H), 0.46-0.64 (m, 2H), 0.72-3.32 (m , 26H), 3.35-4.03 (m, 2.6H), 4.24-4.41 (m, 0.4H), 4.46-5.09 (m, 3H), 6.40 -6.55 (m, 1H), 6.60-6.77 (m, 1H).

(Example 72)
2-(azetidin-1-yl)-1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8 ,8a-octahydro-4,13-methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)ethan-1-one

実施例５５に記載した方法に従い、実施例５４で得られた化合物及びアゼチジン塩酸塩より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．２２（ｍ，２Ｈ），０．４６－０．６３（ｍ，２Ｈ），０．７８－０．９７（ｍ，１Ｈ），１．１７－２．８５（ｍ，１２Ｈ），２．８７－３．１９（ｍ，３Ｈ），３．２０－３．７９（ｍ，５Ｈ），３．８８－４．３６（ｍ，３Ｈ），４．４６－４．７９（ｍ，１Ｈ），６．４５－６．５７（ｍ，１Ｈ），６．６８（ｄ，Ｊ＝８Ｈｚ，０．１Ｈ），６．８１（ｄ，Ｊ＝８Ｈｚ，０．９Ｈ）．

The title compound was obtained from the compound obtained in Example 54 and azetidine hydrochloride according to the method described in Example 55.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.22 (m, 2H), 0.46-0.63 (m, 2H), 0.78-0.97 (m , 1H), 1.17-2.85 (m, 12H), 2.87-3.19 (m, 3H), 3.20-3.79 (m, 5H), 3.88-4.36 (m, 3H), 4.46-4.79 (m, 1H), 6.45-6.57 (m, 1H), 6.68 (d, J=8Hz, 0.1H), 6.81 (d, J=8Hz, 0.9H).

(Example 73)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(5-methylthiazol-4-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（５－メチルチアゾール－４－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１９（ｍ，２Ｈ），０．４７－０．６０（ｍ，２Ｈ），０．７８－０．９０（ｍ，１Ｈ），１．２３－１．５３（ｍ，２Ｈ），１．５９－１．７０（ｍ，１Ｈ），２．１２－２．４３（ｍ，４．４Ｈ），２．３９（ｓ，２．７Ｈ），２．４４－２．５６（ｍ，０．１Ｈ），２．４８（ｄｄ，Ｊ＝７，１９Ｈｚ，０．９Ｈ），２．５７－２．６９（ｍ，１Ｈ），２．９０（ｄ，Ｊ＝６Ｈｚ，０．１Ｈ），２．９２－３．０９（ｍ，１Ｈ），２．９５（ｄ，Ｊ＝７Ｈｚ，０．９Ｈ），３．０１（ｄ，Ｊ＝１９Ｈｚ，０．９Ｈ），３．４７（ｄ，Ｊ＝１６Ｈｚ，０．９Ｈ），３．６２－３．７５（ｍ，１．３Ｈ），３．８５（ｄ，Ｊ＝１５Ｈｚ，０．１Ｈ），４．２９－４．３６（ｍ，０．９Ｈ），４．３８－４．４６（ｍ，０．９Ｈ），４．６４－４．６７（ｍ，０．９Ｈ），４．６８－４．７３（ｍ，０．１Ｈ），４．９０（ｄ，Ｊ＝１６Ｈｚ，０．９Ｈ），６．４４－６．５０（ｍ，０．１Ｈ），６．４７（ｄ，Ｊ＝８Ｈｚ，０．９Ｈ），６．７０（ｄ，Ｊ＝８Ｈｚ，０．１Ｈ），６．７９（ｄ，Ｊ＝８Ｈｚ，０．９Ｈ），８．４２（ｓ，０．１Ｈ），８．５８（ｓ，０．９Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 2-(5-methylthiazol-4-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.19 (m, 2H), 0.47-0.60 (m, 2H), 0.78-0.90 (m , 1H), 1.23-1.53 (m, 2H), 1.59-1.70 (m, 1H), 2.12-2.43 (m, 4.4H), 2.39 (s , 2.7H), 2.44-2.56 (m, 0.1H), 2.48 (dd, J = 7, 19Hz, 0.9H), 2.57-2.69 (m, 1H) , 2.90 (d, J = 6 Hz, 0.1 H), 2.92-3.09 (m, 1 H), 2.95 (d, J = 7 Hz, 0.9 H), 3.01 (d, J = 19Hz, 0.9H), 3.47 (d, J = 16Hz, 0.9H), 3.62-3.75 (m, 1.3H), 3.85 (d, J = 15Hz, 0 .1H), 4.29-4.36 (m, 0.9H), 4.38-4.46 (m, 0.9H), 4.64-4.67 (m, 0.9H), 4 .68-4.73 (m, 0.1H), 4.90 (d, J=16Hz, 0.9H), 6.44-6.50 (m, 0.1H), 6.47 (d, J = 8Hz, 0.9H), 6.70 (d, J = 8Hz, 0.1H), 6.79 (d, J = 8Hz, 0.9H), 8.42 (s, 0.1H), 8.58 (s, 0.9H).

(Example 74)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(2-azaspiro[3.3]heptan-2-yl)-ethan-1-one synthesis

実施例５５に記載した方法に従い、実施例５４で得られた化合物及び２－アザスピロ［３．３］ヘプタンシュウ酸塩より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０３－０．３２（ｍ，２Ｈ），０．４３－０．６７（ｍ，２Ｈ），０．７６－１．０１（ｍ，１Ｈ），１．１５－３．８６（ｍ，２４Ｈ），３．９１－４．３９（ｍ，３Ｈ），４．４５－５．２１（ｍ，２Ｈ），６．４２－６．６２（ｍ，１Ｈ），６．７０（ｄ，Ｊ＝８Ｈｚ，０．１Ｈ），６．７９（ｄ，Ｊ＝８Ｈｚ，０．９Ｈ）．

According to the method described in Example 55, the title compound was obtained from the compound obtained in Example 54 and 2-azaspiro[3.3]heptane oxalate.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.32 (m, 2H), 0.43-0.67 (m, 2H), 0.76-1.01 (m , 1H), 1.15-3.86 (m, 24H), 3.91-4.39 (m, 3H), 4.45-5.21 (m, 2H), 6.42-6.62 (m, 1 H), 6.70 (d, J=8 Hz, 0.1 H), 6.79 (d, J=8 Hz, 0.9 H).

(Example 75)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-((S)-2-methylpyrrolidin-1-yl)ethan-1-one

実施例５５に記載した方法に従い、実施例５４で得られた化合物及び（Ｓ）－２－メチルピロリジン塩酸塩より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．２０（ｍ，２Ｈ），０．４５－０．６１（ｍ，２Ｈ），０．７７－２．７１（ｍ，２０Ｈ），２．７７－３．１８（ｍ，３Ｈ），３．３６－３．８６（ｍ，２．６Ｈ），３．８９－４．３４（ｍ，２．４Ｈ），４．４８－５．１３（ｍ，２Ｈ），６．４２－６．５４（ｍ，１Ｈ），６．６８（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ）．

According to the method described in Example 55, the title compound was obtained from the compound obtained in Example 54 and (S)-2-methylpyrrolidine hydrochloride.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.20 (m, 2H), 0.45-0.61 (m, 2H), 0.77-2.71 (m , 20H), 2.77-3.18 (m, 3H), 3.36-3.86 (m, 2.6H), 3.89-4.34 (m, 2.4H), 4.48 −5.13 (m, 2H), 6.42-6.54 (m, 1H), 6.68 (d, J=8Hz, 0.4H), 6.71 (d, J=8Hz, 0.4H) 6H).

(Example 76)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-((S)-3-methylpyrrolidin-1-yl)ethan-1-one

実施例５５に記載した方法に従い、実施例５４で得られた化合物及び（Ｓ）－３－メチルピロリジン塩酸塩より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．２０（ｍ，２Ｈ），０．４５－０．６１（ｍ，２Ｈ），０．７８－３．１６（ｍ，２３．４Ｈ），３．２８－３．７７（ｍ，２．６Ｈ），３．９０－４．３４（ｍ，２Ｈ），４．４８－５．０７（ｍ，２Ｈ），６．４３－６．５３（ｍ，１Ｈ），６．６７（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ）．

According to the method described in Example 55, the title compound was obtained from the compound obtained in Example 54 and (S)-3-methylpyrrolidine hydrochloride.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.61 (m, 2H), 0.78-3.16 (m , 23.4H), 3.28-3.77 (m, 2.6H), 3.90-4.34 (m, 2H), 4.48-5.07 (m, 2H), 6.43 -6.53 (m, 1H), 6.67 (d, J = 8Hz, 0.4H), 6.71 (d, J = 8Hz, 0.6H).

(Example 77)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-((R)-2-methylpyrrolidin-1-yl)ethan-1-one

実施例５５に記載した方法に従い、実施例５４で得られた化合物及び（Ｒ）－２－メチルピロリジン塩酸塩より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．２１（ｍ，２Ｈ），０．４７－０．６２（ｍ，２Ｈ），０．７７－２．４４（ｍ，１９．３Ｈ），２．４６－２．７３（ｍ，３Ｈ），２．８８－３．３６（ｍ，３Ｈ），３．３８－４．２２（ｍ，２．７Ｈ），４．３９－４．９６（ｍ，２Ｈ），６．４１－６．５２（ｍ，１Ｈ），６．６２（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．６６（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ）．

According to the method described in Example 55, the title compound was obtained from the compound obtained in Example 54 and (R)-2-methylpyrrolidine hydrochloride.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.21 (m, 2H), 0.47-0.62 (m, 2H), 0.77-2.44 (m , 19.3H), 2.46-2.73 (m, 3H), 2.88-3.36 (m, 3H), 3.38-4.22 (m, 2.7H), 4.39 −4.96 (m, 2H), 6.41-6.52 (m, 1H), 6.62 (d, J=8Hz, 0.3H), 6.66 (d, J=8Hz, 0.3H) 7H).

(Example 78)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-((R)-3-methylpyrrolidin-1-yl)ethan-1-one

実施例５５に記載した方法に従い、実施例５４で得られた化合物及び（Ｒ）－３－メチルピロリジン塩酸塩より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．２０（ｍ，２Ｈ），０．４５－０．６２（ｍ，２Ｈ），０．７７－２．８６（ｍ，２０Ｈ），２．８８－３．２１（ｍ，４Ｈ），３．２５－３．７９（ｍ，２Ｈ），３．９７－４．３３（ｍ，２Ｈ），４．５２－４．７３（ｍ，１Ｈ），６．４５－６．５２（ｍ，１Ｈ），６．６７（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ）．

According to the method described in Example 55, the title compound was obtained from the compound obtained in Example 54 and (R)-3-methylpyrrolidine hydrochloride.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.20 (m, 2H), 0.45-0.62 (m, 2H), 0.77-2.86 (m , 20H), 2.88-3.21 (m, 4H), 3.25-3.79 (m, 2H), 3.97-4.33 (m, 2H), 4.52-4.73 (m, 1H), 6.45-6.52 (m, 1H), 6.67 (d, J=8Hz, 0.4H), 6.73 (d, J=8Hz, 0.6H).

(Example 79)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-3-(pyridin-3-yl)propan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び３－（ピリジン－３－イル）プロピオン酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．１０－０．１５（ｍ，２Ｈ），０．５１－０．５６（ｍ，２Ｈ），０．８０－０．８８（ｍ，１Ｈ），１．４２－１．６３（ｍ，３Ｈ），１．８４－１．９６（ｍ，０．４Ｈ），２．１１－２．４０（ｍ，４Ｈ），２．４６－３．０９（ｍ，８Ｈ），３．１５－３．３０（ｍ，１Ｈ），３．５４（ｄ，Ｊ＝１５Ｈｚ，０．６Ｈ），３．７５－３．９６（ｍ，０．８Ｈ），４．１８（ｄ，Ｊ＝１５Ｈｚ，０．６Ｈ），４．３３－４．３６（ｍ，０．６Ｈ），４．５６（ｓ，０．６Ｈ），４．８２（ｄｄ，Ｊ＝４，８Ｈｚ，０．４Ｈ），６．４３（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．５３（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．６４（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），７．１６－７．２２（ｍ，１Ｈ），７．５２－７．５４（ｍ，０．４Ｈ），７．６０－７．６２（ｍ，０．６Ｈ），８．３６－８．３７（ｍ，０．６Ｈ），８．４３（ｄｄ，Ｊ＝１，５Ｈｚ，０．４Ｈ），８．４５（ｓ，０．４Ｈ），８．５２（ｓ，０．６Ｈ）.

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 3-(pyridin-3-yl)propionic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10-0.15 (m, 2H), 0.51-0.56 (m, 2H), 0.80-0.88 (m , 1H), 1.42-1.63 (m, 3H), 1.84-1.96 (m, 0.4H), 2.11-2.40 (m, 4H), 2.46-3 .09 (m, 8H), 3.15-3.30 (m, 1H), 3.54 (d, J=15Hz, 0.6H), 3.75-3.96 (m, 0.8H) , 4.18 (d, J = 15Hz, 0.6H), 4.33-4.36 (m, 0.6H), 4.56 (s, 0.6H), 4.82 (dd, J = 4, 8 Hz, 0.4 H), 6.43 (d, J = 8 Hz, 0.6 H), 6.53 (d, J = 8 Hz, 0.4 H), 6.64 (d, J = 8 Hz, 0 .6H), 6.72 (d, J=8Hz, 0.4H), 7.16-7.22 (m, 1H), 7.52-7.54 (m, 0.4H), 7.60 -7.62 (m, 0.6H), 8.36-8.37 (m, 0.6H), 8.43 (dd, J = 1, 5Hz, 0.4H), 8.45 (s, 0.4H), 8.52 (s, 0.6H).

(Example 80)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-3-(pyridin-4-yl)propan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び３－（ピリジン－４－イル）プロピオン酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．１０－０．１５（ｍ，２Ｈ），０．５１－０．５６（ｍ，２Ｈ），０．８０－０．９０（ｍ，１Ｈ），１．４５－１．６８（ｍ，３Ｈ），１．８６－１．９５（ｍ，０．３Ｈ），２．１１－２．４０（ｍ，４Ｈ），２．４５－２．６３（ｍ，２Ｈ），２．６８－３．０９（ｍ，６Ｈ），３．１６－３．３０（ｍ，１Ｈ），３．５８（ｄ，Ｊ＝１６Ｈｚ，０．７Ｈ），３．７６－３．９４（ｍ，０．６Ｈ），４．２４（ｄ，Ｊ＝１６Ｈｚ，０．７Ｈ），４．３８－４．４１（ｍ，０．７Ｈ），４．５９（ｓ，０．７Ｈ），４．８０（ｄｄ，Ｊ＝４，８Ｈｚ，０．３Ｈ），６．４５（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．６３（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），７．１２－７．１５（ｍ，２Ｈ），８．３２（ｄ，Ｊ＝６Ｈｚ，１．４Ｈ），８．４７（ｄ，Ｊ＝６Ｈｚ，０．６Ｈ）.

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 3-(pyridin-4-yl)propionic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10-0.15 (m, 2H), 0.51-0.56 (m, 2H), 0.80-0.90 (m , 1H), 1.45-1.68 (m, 3H), 1.86-1.95 (m, 0.3H), 2.11-2.40 (m, 4H), 2.45-2 .63 (m, 2H), 2.68-3.09 (m, 6H), 3.16-3.30 (m, 1H), 3.58 (d, J=16Hz, 0.7H), 3 .76-3.94 (m, 0.6H), 4.24 (d, J=16Hz, 0.7H), 4.38-4.41 (m, 0.7H), 4.59 (s, 0.7H), 4.80 (dd, J = 4, 8Hz, 0.3H), 6.45 (d, J = 8Hz, 0.7H), 6.54 (d, J = 8Hz, 0.3H) ), 6.63 (d, J = 8Hz, 0.7H), 6.72 (d, J = 8Hz, 0.3H), 7.12-7.15 (m, 2H), 8.32 (d , J=6Hz, 1.4H), 8.47 (d, J=6Hz, 0.6H).

(Example 81)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(pyridin-3-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（ピリジン－３－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．１０－０．１５（ｍ，２Ｈ），０．５１－０．５６（ｍ，２Ｈ），０．８０－０．９０（ｍ，１Ｈ），１．３９－１．６９（ｍ，３Ｈ），２．１３－２．６６（ｍ，６．３Ｈ），２．８８－３．１２（ｍ，２．７Ｈ），３．４０－３．４４（ｍ，０．３Ｈ），３．６２－３．７６（ｍ，２．７Ｈ），４．３５（ｄ，Ｊ＝１７Ｈｚ，２Ｈ），４．６６（ｂｒ ｓ，０．７Ｈ），４．７４－４．７８（ｍ，０．３Ｈ），６．４４（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．５１（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．６６（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），７．１４－７．１７（ｍ，０．３Ｈ），７．２１－７．２４（ｍ，０．７Ｈ），７．３５－７．４０（ｍ，０．３Ｈ），７．５７（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ）８．３７－８．４３（ｍ，１．３Ｈ），８．５７（ｓ，０．７Ｈ）.

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 2-(pyridin-3-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10-0.15 (m, 2H), 0.51-0.56 (m, 2H), 0.80-0.90 (m , 1H), 1.39-1.69 (m, 3H), 2.13-2.66 (m, 6.3H), 2.88-3.12 (m, 2.7H), 3.40 -3.44 (m, 0.3H), 3.62-3.76 (m, 2.7H), 4.35 (d, J=17Hz, 2H), 4.66 (br s, 0.7H) ), 4.74-4.78 (m, 0.3H), 6.44 (d, J = 8Hz, 0.7H), 6.51 (d, J = 8Hz, 0.3H), 6.66 (d, J = 8Hz, 0.7H), 6.73 (d, J = 8Hz, 0.3H), 7.14-7.17 (m, 0.3H), 7.21-7.24 ( m, 0.7H), 7.35-7.40 (m, 0.3H), 7.57 (d, J = 8Hz, 0.7H) 8.37-8.43 (m, 1.3H) , 8.57(s, 0.7H).

(Example 82)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(pyridin-4-yl)ethan-1-one

According to the method described in Example 6, the title compound was obtained from the compound obtained in (1) of Example 3 and 2-(pyridin-4-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10-0.15 (m, 2H), 0.50-0.57 (m, 2H), 0.77-0.90 (m , 1H), 1.31-1.70 (m, 3H), 2.14-2.65 (m, 6.4H), 2.88 (d, J = 6Hz, 0.4H), 2.94 -3.02 (m, 1.6H), 3.11 (t, J = 13Hz, 0.6H), 3.38 (d, J = 15Hz, 0.4H), 3.62-3.77 ( m, 3H), 4.30 (d, J = 15Hz, 1H), 4.37 (d, J = 15Hz, 0.6H), 4.62-4.64 (m, 0.6H), 4. 72-4.75 (m, 0.4H), 6.43 (d, J = 8Hz, 0.6H), 6.53 (d, J = 8Hz, 0.4H), 6.64 (d, J = 8Hz, 0.6H), 6.76 (d, J = 8Hz, 0.4H), 6.96-6.97 (m, 1H), 7.20-7.22 (m, 1H), 8 .33-8.34 (m, 1H), 8.42-8.43 (m, 1H).

(Example 83)
2-cyclopentyl-1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4 ,13-methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－シクロペンチル酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．２０（ｍ，２Ｈ），０．４６－０．６２（ｍ，２Ｈ），０．７７－２．７３（ｍ，２１．７Ｈ），２．９１－３．０６（ｍ，２Ｈ），３．０７－３．２５（ｍ，０．３Ｈ），３．３３－４．３４（ｍ，３Ｈ），４．５３－４．８２（ｍ，１Ｈ），４．１３（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ）６．４７－６．５９（ｍ，１Ｈ），６．６９（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 2-cyclopentylacetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.20 (m, 2H), 0.46-0.62 (m, 2H), 0.77-2.73 (m , 21.7H), 2.91-3.06 (m, 2H), 3.07-3.25 (m, 0.3H), 3.33-4.34 (m, 3H), 4.53 -4.82 (m, 1H), 4.13 (d, J = 8Hz, 0.3H) 6.47-6.59 (m, 1H), 6.69 (d, J = 8Hz, 0.7H) ).

(Example 84)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethane- Synthesis of 1-ones

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（４－メチル－３－（トリフルオロメチル）－１Ｈ－ピラゾール－１－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ（ｐｐｍ）：０．１５－０．１９（ｍ，２Ｈ），０．５０－０．５８（ｍ，２Ｈ），０．８５－０．９７（ｍ，１Ｈ），１．３９－１．５８（ｍ，３Ｈ），２．１３－２．４５（ｍ，７Ｈ），２．５２－２．７１（ｍ，２Ｈ），３．０２－３．１８（ｍ，３Ｈ），３．６７－４．３４（ｍ，３Ｈ），４．６９－４．７６（ｍ，１Ｈ），５．２４（ｄ，Ｊ＝１７Ｈｚ，１Ｈ），５．５０（ｄ，Ｊ＝１７Ｈｚ，１Ｈ），６．５２（ｄ，Ｊ＝８Ｈｚ，０．８Ｈ），６．５６（ｄ，Ｊ＝８Ｈｚ，０．２Ｈ），６．６３（ｄ，Ｊ＝８Ｈｚ，０．２Ｈ），６．６６（ｄ，Ｊ＝８Ｈｚ，０．８Ｈ），７．４３（ｓ，１Ｈ）.

According to the method described in Example 6, the title compound was obtained from the compound obtained in (1) of Example 3 and 2-(4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid. Obtained.

¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 0.15-0.19 (m, 2H), 0.50-0.58 (m, 2H), 0.85-0.97 ( m, 1H), 1.39-1.58 (m, 3H), 2.13-2.45 (m, 7H), 2.52-2.71 (m, 2H), 3.02-3. 18 (m, 3H), 3.67-4.34 (m, 3H), 4.69-4.76 (m, 1H), 5.24 (d, J = 17Hz, 1H), 5.50 ( d, J = 17 Hz, 1 H), 6.52 (d, J = 8 Hz, 0.8 H), 6.56 (d, J = 8 Hz, 0.2 H), 6.63 (d, J = 8 Hz, 0 .2H), 6.66 (d, J = 8Hz, 0.8H), 7.43 (s, 1H).

(Example 85)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-((R)-2-(trifluoromethyl)pyrrolidin-1-yl)ethan-1-one Synthesis of

実施例５５に記載した方法に従い、実施例５４で得られた化合物及び（Ｒ）－２－（トリフルオロメチル）ピロリジン塩酸塩より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．２０（ｍ，２Ｈ），０．４６－０．６２（ｍ，２Ｈ），０．７６－０．９５（ｍ，１Ｈ），１．１６－２．４２（ｍ，１１．６Ｈ），２．４６－２．６８（ｍ，２Ｈ），２．７８（ｄｄ，Ｊ＝８，１６Ｈｚ，０．４Ｈ），２．８９－３．１５（ｍ，４Ｈ），３．２２－４．１８（ｍ，５．６Ｈ），４．２７（ｄ，Ｊ＝１４Ｈｚ，０．４Ｈ），４．５０－４．９６（ｍ，２Ｈ），６．４２－６．５６（ｍ，１Ｈ），６．６４（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．６９（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ）．

According to the method described in Example 55, the title compound was obtained from the compound obtained in Example 54 and (R)-2-(trifluoromethyl)pyrrolidine hydrochloride.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.20 (m, 2H), 0.46-0.62 (m, 2H), 0.76-0.95 (m , 1H), 1.16-2.42 (m, 11.6H), 2.46-2.68 (m, 2H), 2.78 (dd, J = 8, 16Hz, 0.4H), 2 .89-3.15 (m, 4H), 3.22-4.18 (m, 5.6H), 4.27 (d, J = 14Hz, 0.4H), 4.50-4.96 ( m, 2H), 6.42-6.56 (m, 1H), 6.64 (d, J=8Hz, 0.4H), 6.69 (d, J=8Hz, 0.6H).

(Example 86)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-((S)-3-fluoropyrrolidin-1-yl)ethan-1-one

実施例５５に記載した方法に従い、実施例５４で得られた化合物及び（Ｓ）－３－フルオロピロリジン塩酸塩より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．２０（ｍ，２Ｈ），０．４５－０．６０（ｍ，２Ｈ），０．７７－０．９３（ｍ，１Ｈ），１．１８－２．４３（ｍ，１１．５Ｈ），２．４４－３．７９（ｍ，９．５Ｈ），３．９９－４．３５（ｍ，２Ｈ），４．５３－４．５４（ｍ，１Ｈ），４．８８－５．３２（ｍ，１Ｈ），６．４３－６．５５（ｍ，１Ｈ），６．６４－６．７３（ｍ，１Ｈ）．

According to the method described in Example 55, the title compound was obtained from the compound obtained in Example 54 and (S)-3-fluoropyrrolidine hydrochloride.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.77-0.93 (m , 1H), 1.18-2.43 (m, 11.5H), 2.44-3.79 (m, 9.5H), 3.99-4.35 (m, 2H), 4.53 -4.54 (m, 1H), 4.88-5.32 (m, 1H), 6.43-6.55 (m, 1H), 6.64-6.73 (m, 1H).

(Example 87)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-((R)-3-fluoropyrrolidin-1-yl)ethan-1-one

実施例５５に記載した方法に従い、実施例５４で得られた化合物及び（Ｒ）－３－フルオロピロリジン塩酸塩より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．２２（ｍ，２Ｈ），０．４５－０．６０（ｍ，２Ｈ），０．７６－０．９３（ｍ，１Ｈ），１．１５－２．７０（ｍ，１３．５Ｈ），２．７４－３．１９（ｍ，５Ｈ），３．２５（ｄ，Ｊ＝１５Ｈｚ，０．５Ｈ），３．３７－３．７６（ｍ，２．５Ｈ），３．９１（ｄ，Ｊ＝１４Ｈｚ，０．５Ｈ），４．０３－４．３４（ｍ，１Ｈ），４．５３－４．８０（ｍ，１Ｈ），４．８９－５．３１（ｍ，１Ｈ），６．４３－６．５６（ｍ，１Ｈ），６．６８（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．

According to the method described in Example 55, the title compound was obtained from the compound obtained in Example 54 and (R)-3-fluoropyrrolidine hydrochloride.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.22 (m, 2H), 0.45-0.60 (m, 2H), 0.76-0.93 (m , 1H), 1.15-2.70 (m, 13.5H), 2.74-3.19 (m, 5H), 3.25 (d, J = 15Hz, 0.5H), 3.37 -3.76 (m, 2.5H), 3.91 (d, J=14Hz, 0.5H), 4.03-4.34 (m, 1H), 4.53-4.80 (m, 1H), 4.89-5.31 (m, 1H), 6.43-6.56 (m, 1H), 6.68 (d, J=8Hz, 1H).

(Example 88)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)ethan-1-one Synthesis of

実施例５５に記載した方法に従い、実施例５４で得られた化合物及び（Ｓ）－２－（トリフルオロメチル）ピロリジン塩酸塩より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０３－０．２２（ｍ，２Ｈ），０．４６－０．６１（ｍ，２Ｈ），０．７６－２．８４（ｍ，１６Ｈ），２．８９－３．０７（ｍ，２Ｈ），３．０９－３．８３（ｍ，６Ｈ），３．８９－４．９６（ｍ，３Ｈ），６．４２－６．５３（ｍ，１Ｈ），６．６６（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．

According to the method described in Example 55, the title compound was obtained from the compound obtained in Example 54 and (S)-2-(trifluoromethyl)pyrrolidine hydrochloride.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.22 (m, 2H), 0.46-0.61 (m, 2H), 0.76-2.84 (m , 16H), 2.89-3.07 (m, 2H), 3.09-3.83 (m, 6H), 3.89-4.96 (m, 3H), 6.42-6.53 (m, 1H), 6.66 (d, J=8Hz, 1H).

(Example 89)
(4R,4aS,8aR,13bS)-3-benzyl-4a,10-dihydroxy-1,2,3,4,4a,5,6,7-octahydro-4,13-methanobenzofuro[2,3-c] Synthesis of pyrido[4,3-d]azepin-8(8aH)-one

実施例３の方法２に記載した方法に従い、（４Ｒ，４ａＳ，７ａＲ，１２ｂＳ）－３－ベンジル－４ａ，９－ジヒドロキシ－２，３，４，４ａ，５，６－ヘキサヒドロ－１Ｈ－４，１２－メタノベンゾフロ［３，２－ｅ］イソキノリン－７（７ａＨ）－オン（Ｂｉｏｏｒｇａｎｉｃ ＆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ Ｌｅｔｔｅｒｓ，２０１４，２４，３５９２に記載の方法で合成）より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．２９－１．４１（ｍ，１Ｈ），１．５８－１．８１（ｍ，２Ｈ），２．２７－２．４５（ｍ，２Ｈ），２．５０－２．５８（ｍ，１Ｈ），２．６３（ｄｄ，Ｊ＝７，１９Ｈｚ，１Ｈ），２．８１－２．９６（ｍ，２Ｈ），３．０１－３．１３（ｍ，１Ｈ），３．２４（ｄ，Ｊ＝１９Ｈｚ，１Ｈ），３．６２（ｓ，２Ｈ），４．８７（ｓ，１Ｈ），６．３３－６．４２（ｍ，１Ｈ），６．６３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７８（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．２６－７．３８（ｍ，５Ｈ）．

(4R,4aS,7aR,12bS)-3-benzyl-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-1H-4, according to the method described in Method 2 of Example 3, The title compound was obtained from 12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (synthesized by the method described in Bioorganic & Medicinal Chemistry Letters, 2014, 24, 3592).

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.29-1.41 (m, 1H), 1.58-1.81 (m, 2H), 2.27-2.45 (m , 2H), 2.50-2.58 (m, 1H), 2.63 (dd, J = 7, 19Hz, 1H), 2.81-2.96 (m, 2H), 3.01-3 .13 (m, 1H), 3.24 (d, J=19Hz, 1H), 3.62 (s, 2H), 4.87 (s, 1H), 6.33-6.42 (m, 1H ), 6.63 (d, J=8 Hz, 1 H), 6.78 (d, J=8 Hz, 1 H), 7.26-7.38 (m, 5 H).

(Example 90)
(4R,4aS,8aR,13bS)-3-benzyl-1,2,3,4,6,7,8,8a-octahydro-4,13-methanobenzofuro[2,3-c]pyrido[4,3- d] Synthesis of azepine-4a,10(5H)-diol

実施例２に記載した方法に従い、実施例８９で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．１７－１．８９（ｍ，３Ｈ），２．２５（ｄｔ，Ｊ＝５，１２Ｈｚ，１Ｈ），２．３５（ｄｔ，Ｊ＝３，１２Ｈｚ，１Ｈ），２．４８（ｄｄ，Ｊ＝５，１２Ｈｚ，１Ｈ），２．５６（ｄｄ，Ｊ＝７，１８Ｈｚ，１Ｈ），２．７１（ｄ，Ｊ＝７Ｈｚ，１Ｈ），２．８１－２．９１（ｍ，１Ｈ），２．９６－３．０７（ｍ，１Ｈ），３．１１－３．２４（ｍ，２Ｈ），３．６１（ｓ，２Ｈ），３．６６－３．７６（ｍ，１Ｈ），４．４７－４．５２（ｍ，１Ｈ），４．７４（ｂｒ ｓ，１Ｈ），６．５３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６６（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．２１－７．３８（ｍ，５Ｈ）．
^ｄ

The title compound was obtained from the compound obtained in Example 89 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.17-1.89 (m, 3H), 2.25 (dt, J = 5, 12 Hz, 1H), 2.35 (dt, J = 3, 12Hz, 1H), 2.48 (dd, J = 5, 12Hz, 1H), 2.56 (dd, J = 7, 18Hz, 1H), 2.71 (d, J = 7Hz, 1H) , 2.81-2.91 (m, 1H), 2.96-3.07 (m, 1H), 3.11-3.24 (m, 2H), 3.61 (s, 2H), 3 .66-3.76 (m, 1H), 4.47-4.52 (m, 1H), 4.74 (br s, 1H), 6.53 (d, J=8Hz, 1H), 6. 66 (d, J=8Hz, 1H), 7.21-7.38 (m, 5H).
^d

(Example 91)
1-((4R,4aS,8aR,13bS)-3-benzyl-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro[2,3 Synthesis of c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(pyridin-2-yl)ethan-1-one

実施例６に記載した方法に従い、実施例９０で得られた化合物及び２－（ピリジン－２－イル）酢酸塩酸塩より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．１９－１．５０（ｍ，４Ｈ），２．１３－２．５６（ｍ，３Ｈ），２．５９－２．６４（ｍ，０．１Ｈ），（ｄ，Ｊ＝７Ｈｚ，０．９Ｈ），２．９２－３．２４（ｍ，２Ｈ），３．５４－３．６８（ｍ，４Ｈ），３．７８－３．９２（ｍ，０．２Ｈ），４．２０－４．４０（ｍ，１．８Ｈ），４．６５（ｓ，１Ｈ），４．９４（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），６．４６－６．５２（ｍ，１Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．１Ｈ），６．８２（ｄ，Ｊ＝８Ｈｚ，０．９Ｈ），６．９３－７．５３（ｍ，７．１Ｈ），７．６７（ｄｄｄ，Ｊ＝２，８，８Ｈｚ，０．９Ｈ），８．３５－８．４０（ｍ，０．１Ｈ），８．４８（ｄ，Ｊ＝４Ｈｚ，０．９Ｈ）．

The title compound was obtained from the compound obtained in Example 90 and 2-(pyridin-2-yl)acetic acid hydrochloride according to the method described in Example 6.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.19-1.50 (m, 4H), 2.13-2.56 (m, 3H), 2.59-2.64 (m , 0.1H), (d, J=7Hz, 0.9H), 2.92-3.24 (m, 2H), 3.54-3.68 (m, 4H), 3.78-3. 92 (m, 0.2H), 4.20-4.40 (m, 1.8H), 4.65 (s, 1H), 4.94 (d, J = 16Hz, 1H), 6.46- 6.52 (m, 1H), 6.72 (d, J = 8Hz, 0.1H), 6.82 (d, J = 8Hz, 0.9H), 6.93-7.53 (m, 7 .1H), 7.67 (ddd, J = 2, 8, 8Hz, 0.9H), 8.35-8.40 (m, 0.1H), 8.48 (d, J = 4Hz, 0.9H). 9H).

(Example 92)
1-((4R,4aS,8aR,13bS)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro[2,3-c]pyride Synthesis of [4,3-d]azepin-7(1H)-yl)-2-(pyridin-2-yl)ethan-1-one

実施例９１で得られた化合物（２０ｍｇ，０．０４０ｍｍｏｌ）のメタノール（１．０ｍＬ）溶液にパラジウム／炭素（パラジウム１０％、約５５％水湿潤品、１０ｍｇ）を加え、水素雰囲気化室温で２０時間撹拌した。反応液をセライトにてろ過後、減圧下にて濃縮した。得られた粗生成物を分取薄層クロマトグラフィー（酢酸エチル：２Ｍアンモニア－メタノール溶液＝１０：１）で精製し、表題化合物（９．１ｍｇ，５６％）を無色アモルファスとして得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．２０－１．７１（ｍ，３Ｈ），２．１４－２．４０（ｍ，１Ｈ），２．５９－３．１２（ｍ，６Ｈ），３．５８－５．００（ｍ，６Ｈ），６．４８（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．２Ｈ），６．８１（ｄ，Ｊ＝８Ｈｚ，０．８Ｈ），６．８２－７．５４（ｍ，２．２Ｈ），７．６９（ｄｄｄ，Ｊ＝２，８，８Ｈｚ，０．８Ｈ），８．４０（ｄ，Ｊ＝４Ｈｚ，０．２Ｈ），８．５０（ｄ，Ｊ＝４Ｈｚ，０．８Ｈ）．

Palladium/carbon (10% palladium, about 55% wet with water, 10 mg) was added to a solution of the compound (20 mg, 0.040 mmol) obtained in Example 91 in methanol (1.0 mL), and the mixture was stirred at room temperature for 20 minutes under a hydrogen atmosphere. Stirred for an hour. The reaction solution was filtered through celite and then concentrated under reduced pressure. The resulting crude product was purified by preparative thin layer chromatography (ethyl acetate:2M ammonia-methanol solution=10:1) to give the title compound (9.1 mg, 56%) as a colorless amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.20-1.71 (m, 3H), 2.14-2.40 (m, 1H), 2.59-3.12 (m , 6H), 3.58-5.00 (m, 6H), 6.48 (d, J = 8Hz, 1H), 6.72 (d, J = 8Hz, 0.2H), 6.81 (d , J = 8Hz, 0.8H), 6.82-7.54 (m, 2.2H), 7.69 (ddd, J = 2, 8, 8Hz, 0.8H), 8.40 (d, J=4 Hz, 0.2 H), 8.50 (d, J=4 Hz, 0.8 H).

(Example 93)
2-(azepan-1-yl)-1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8 ,8a-octahydro-4,13-methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（アゼパン－１－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．２０（ｍ，２Ｈ），０．４４－０．６０（ｍ，２Ｈ），０．７６－０．９４（ｍ，１Ｈ），１．１５－２．８６（ｍ，２２Ｈ），２．８８－３．７９（ｍ，６Ｈ），４．０４－４．４９（ｍ，１Ｈ），４．５６－５．０１（ｍ，２Ｈ），６．４１－６．５４（ｍ，１Ｈ），６．６０－６．７１（ｍ，１Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 2-(azepan-1-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.20 (m, 2H), 0.44-0.60 (m, 2H), 0.76-0.94 (m , 1H), 1.15-2.86 (m, 22H), 2.88-3.79 (m, 6H), 4.04-4.49 (m, 1H), 4.56-5.01 (m, 2H), 6.41-6.54 (m, 1H), 6.60-6.71 (m, 1H).

(Example 94)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)ethane-1- Composite on

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び（４－イソプロピル－１Ｈ－１，２，３－トリアゾール－１－イル）酢酸（Ｊｏｕｒｎａｌ ｏｆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ ２０１８, ６１, ８７９７に記載の方法により合成）より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０９－０．１４（ｍ，２Ｈ），０．５０－０．５５（ｍ，２Ｈ），０．７６－０．８７（ｍ，１Ｈ），１．２１－１．５９（ｍ，９Ｈ），２．０８－２．５７（ｍ，５Ｈ），２．８５－３．６５（ｍ，７Ｈ），４．１３－５．１４（ｍ，４Ｈ），５．８５－５．８９（ｍ，０．５Ｈ），６．３６－６．３９（ｍ，１Ｈ），６．５８－６．６３（ｍ，１Ｈ），７．３８（ｓ，０．５Ｈ）.

According to the method described in Example 6, the compound obtained in (1) of Example 3 and (4-isopropyl-1H-1,2,3-triazol-1-yl)acetic acid (Journal of Medicinal Chemistry 2018, 61 , 8797) to obtain the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09-0.14 (m, 2H), 0.50-0.55 (m, 2H), 0.76-0.87 (m , 1H), 1.21-1.59 (m, 9H), 2.08-2.57 (m, 5H), 2.85-3.65 (m, 7H), 4.13-5.14 (m, 4H), 5.85-5.89 (m, 0.5H), 6.36-6.39 (m, 1H), 6.58-6.63 (m, 1H), 7.38 (s, 0.5H).

(Reference example 2)
Synthesis of 3-(chloromethyl)-5-methylisothiazole

（５－メチルイソチアゾール－３－イル）メタノール（１０３ｍｇ，０．７９７ｍｍｏｌ）のトルエン（３ｍＬ）溶液に、塩化チオニル（０．１２ｍＬ，１．７ｍｍｏｌ）を加え、８０℃で５時間撹拌した。室温まで放冷後、反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで３回抽出した。合わせた抽出液を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧下にて濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（４－２５％酢酸エチル／へプタン）で精製し、表題化合物（６９．７ｍｇ，５９％）を淡褐色油状物として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．５８（ｓ，３Ｈ），４．６２（ｓ，２Ｈ），７．０５（ｓ，１Ｈ）.

Thionyl chloride (0.12 mL, 1.7 mmol) was added to a solution of (5-methylisothiazol-3-yl)methanol (103 mg, 0.797 mmol) in toluene (3 mL), and the mixture was stirred at 80° C. for 5 hours. After cooling to room temperature, saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The combined extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (4-25% ethyl acetate/heptane) to give the title compound (69.7 mg, 59%) as a pale brown oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.58 (s, 3H), 4.62 (s, 2H), 7.05 (s, 1H).

(Reference example 3)
Synthesis of 2-(5-methylisothiazol-3-yl)acetonitrile

参考例２で得られた化合物（６９．７ｍｇ，０．４７２ｍｍｏｌ）のジメチルスルホキシド（１．５ｍＬ）溶液に、シアン化ナトリウム（６９．４ｍｇ，１．４２ｍｍｏｌ）を加え、室温で１．５時間、５０℃で１７時間撹拌した。室温まで放冷後、反応混合物に水を加え、ｔｅｒｔ－ブチルメチルエーテルで３回抽出した。合わせた抽出液を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧下にて濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（１９－４０％酢酸エチル／へプタン）で精製し、表題化合物（４２．９ｍｇ，６６％）を無色油状物として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．５９（ｓ，３Ｈ），３．８６（ｓ，２Ｈ），７．０１（ｓ，１Ｈ）.

Sodium cyanide (69.4 mg, 1.42 mmol) was added to a dimethylsulfoxide (1.5 mL) solution of the compound (69.7 mg, 0.472 mmol) obtained in Reference Example 2, and the mixture was stirred at room temperature for 1.5 hours. Stir at 50° C. for 17 hours. After allowing to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted three times with tert-butyl methyl ether. The combined extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (19-40% ethyl acetate/heptane) to give the title compound (42.9 mg, 66%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.59 (s, 3H), 3.86 (s, 2H), 7.01 (s, 1H).

(Reference example 4)
Synthesis of 2-(5-methylisothiazol-3-yl)acetic acid

参考例３で得られた化合物（４２．９ｍｇ，０．３１０ｍｍｏｌ）の酢酸（１ｍＬ）溶液に６Ｎ塩酸（０．５ｍＬ）を加え、９０℃で４．５時間撹拌した。室温まで放冷後、反応液を減圧下にて濃縮した。得られた残渣に水を加え、酢酸エチルで３回抽出した。合わせた抽出液を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧下にて濃縮し、表題化合物（４２．９ｍｇ，８８％）を淡褐色結晶として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．５９（ｓ，３Ｈ），３．８８（ｓ，２Ｈ），６．９１（ｓ，１Ｈ）.

6N Hydrochloric acid (0.5 mL) was added to a solution of the compound (42.9 mg, 0.310 mmol) obtained in Reference Example 3 in acetic acid (1 mL), and the mixture was stirred at 90° C. for 4.5 hours. After allowing to cool to room temperature, the reaction solution was concentrated under reduced pressure. Water was added to the resulting residue, and the mixture was extracted with ethyl acetate three times. The combined extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (42.9 mg, 88%) as pale brown crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.59 (s, 3H), 3.88 (s, 2H), 6.91 (s, 1H).

(Example 95)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(5-methylisothiazol-3-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び参考例４で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０８－０．１４（ｍ，２Ｈ），０．４９－０．５７（ｍ，２Ｈ），０．７９－０．９４（ｍ，１Ｈ），１．２６－１．６５（ｍ，３Ｈ），２．１８－２．６４（ｍ，９Ｈ），２．８３－３．０９（ｍ，３Ｈ），３．３６－３．９４（ｍ，３Ｈ），４．３０－４．３８（ｍ，１Ｈ），４．６４－４．９４（ｍ，２Ｈ），６．４０（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．４５（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．６３（ｓ，０．４Ｈ），６．７３－６．７５（ｍ，１Ｈ），６．９５（ｓ，０．６Ｈ）.

According to the method described in Example 6, the title compound was obtained from the compound obtained in (1) of Example 3 and the compound obtained in Reference Example 4.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08-0.14 (m, 2H), 0.49-0.57 (m, 2H), 0.79-0.94 (m , 1H), 1.26-1.65 (m, 3H), 2.18-2.64 (m, 9H), 2.83-3.09 (m, 3H), 3.36-3.94 (m, 3H), 4.30-4.38 (m, 1H), 4.64-4.94 (m, 2H), 6.40 (d, J=8Hz, 0.4H), 6.45 (d, J = 8Hz, 0.6H), 6.63 (s, 0.4H), 6.73-6.75 (m, 1H), 6.95 (s, 0.6H).

(Example 96)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(furan-2-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び２－（フラン－２－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．２０（ｍ，２Ｈ），０．４４－０．６０（ｍ，２Ｈ），０．７５－０．９２（ｍ，１Ｈ），１．１６－２．６９（ｍ，９．６Ｈ），２．８３－３．０５（ｍ，２Ｈ），３．１４（ｄｄ，Ｊ＝１３，１３Ｈｚ，０．４Ｈ），３．４３（ｄ，Ｊ＝１３Ｈｚ，０．６Ｈ），３．５６－３．９９（ｍ，３Ｈ），４．０７－４．１８（ｍ，０．６Ｈ），４．２２－４．３８（ｍ，０．８Ｈ），４．５６－４．６５（ｍ，０．４Ｈ），４．７０－４．８５（ｍ，０．６Ｈ），５．８６－５．９９（ｍ，０．６Ｈ），６．１４－６．２３（ｍ，１Ｈ），６．３０（ｄｄ，Ｊ＝２，３Ｈｚ，０．４Ｈ），６．４６（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．５２（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．６１（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），７．１８－７．３６（ｍ，１Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 2-(furan-2-yl)acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.20 (m, 2H), 0.44-0.60 (m, 2H), 0.75-0.92 (m , 1H), 1.16-2.69 (m, 9.6H), 2.83-3.05 (m, 2H), 3.14 (dd, J = 13, 13Hz, 0.4H), 3 .43 (d, J = 13Hz, 0.6H), 3.56-3.99 (m, 3H), 4.07-4.18 (m, 0.6H), 4.22-4.38 ( m, 0.8H), 4.56-4.65 (m, 0.4H), 4.70-4.85 (m, 0.6H), 5.86-5.99 (m, 0.6H) ), 6.14-6.23 (m, 1H), 6.30 (dd, J = 2, 3Hz, 0.4H), 6.46 (d, J = 8Hz, 0.4H), 6.52 (d, J = 8Hz, 0.6H), 6.61 (d, J = 8Hz, 0.4H), 6.73 (d, J = 8Hz, 0.6H), 7.18-7.36 ( m, 1H).

(Reference example 5)
Synthesis of 2-(5-methylisoxazol-3-yl)acetic acid

参考例４に記載した方法に従い、２－（５－メチルイソキサゾール－３－イル）アセトニトリルより表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．４３（ｓ，３Ｈ），３．７６（ｓ，２Ｈ），６．０６（ｓ，１Ｈ）.

According to the method described in Reference Example 4, the title compound was obtained from 2-(5-methylisoxazol-3-yl)acetonitrile.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.43 (s, 3H), 3.76 (s, 2H), 6.06 (s, 1H).

(Example 97)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(5-methylisoxazol-3-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び参考例５で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．１１－０．１４（ｍ，２Ｈ），０．５１－０．５７（ｍ，２Ｈ），０．７９－０．９０（ｍ，１Ｈ），１．３８－１．６０（ｍ，３Ｈ），２．１４－２．４１（ｍ，７Ｈ），２．４８（ｄｄ，Ｊ＝７，１９Ｈｚ，１Ｈ），２．６０－２．７０（ｍ，１Ｈ），２．９１－３．１０（ｍ，３Ｈ），３．４８（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），３．６１－３．８３（ｍ，２Ｈ），４．３２－４．３８（ｍ，１Ｈ），４．５６（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），４．６２（ｂｒ ｓ，０．７Ｈ），４．７７（ｂｒ ｓ，０．３Ｈ），５．８３（ｓ，０．３Ｈ），６．１０（ｓ，０．７Ｈ），６．４６（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．４９（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ）.

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and the compound obtained in Reference Example 5.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.11-0.14 (m, 2H), 0.51-0.57 (m, 2H), 0.79-0.90 (m , 1H), 1.38-1.60 (m, 3H), 2.14-2.41 (m, 7H), 2.48 (dd, J = 7, 19Hz, 1H), 2.60-2 .70 (m, 1H), 2.91-3.10 (m, 3H), 3.48 (d, J=16Hz, 1H), 3.61-3.83 (m, 2H), 4.32 −4.38 (m, 1H), 4.56 (d, J=16Hz, 1H), 4.62 (br s, 0.7H), 4.77 (br s, 0.3H), 5.83 (s, 0.3H), 6.10 (s, 0.7H), 6.46 (d, J = 8Hz, 0.7H), 6.49 (d, J = 8Hz, 0.3H), 6 .72 (d, J = 8Hz, 0.7H), 6.73 (d, J = 8Hz, 0.3H).

(Example 98)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-3-(thiazol-2-yl)propan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び３－（チアゾール－２－イル）プロパン酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．２２（ｍ，２Ｈ），０．４４－０．６２（ｍ，２Ｈ），０．７４－２．０８（ｍ，４Ｈ），２．１１－２．４２（ｍ，４Ｈ），２．４３－２．８１（ｍ，３Ｈ），２．８７－３．１７（ｍ，４Ｈ），３．１９－３．４４（ｍ，１Ｈ），３．４７－３．９６（ｍ，２Ｈ），４．２１－４．４８（ｍ，２Ｈ），４．５５－４．８７（ｍ，１Ｈ），６．４３－６．５７（ｍ，１Ｈ），６．６７－６．７８（ｍ，１Ｈ），７．１５－７．２９（ｍ，１Ｈ），７．６５（ｄ，Ｊ＝３Ｈｚ，０．１Ｈ），７．７６（ｄ，Ｊ＝３Ｈｚ，０．９Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and 3-(thiazol-2-yl)propanoic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.22 (m, 2H), 0.44-0.62 (m, 2H), 0.74-2.08 (m , 4H), 2.11-2.42 (m, 4H), 2.43-2.81 (m, 3H), 2.87-3.17 (m, 4H), 3.19-3.44 (m, 1H), 3.47-3.96 (m, 2H), 4.21-4.48 (m, 2H), 4.55-4.87 (m, 1H), 6.43-6 .57 (m, 1H), 6.67-6.78 (m, 1H), 7.15-7.29 (m, 1H), 7.65 (d, J=3Hz, 0.1H), 7 .76 (d, J=3Hz, 0.9H).

(Reference example 6)
Synthesis of (5-ethylisoxazol-3-yl)methanol

５－エチルイソキサゾール－３－カルボン酸エチル（ＷＯ２０１６０４０５１５に記載の方法により合成）（４１０ｍｇ，２．４２ｍｍｏｌ）のテトラヒドロフラン（４．８ｍＬ）溶液に、氷冷下、４Ｍ水素化ホウ素リチウム－テトラヒドロフラン溶液（１．２１ｍＬ，４．８４ｍｍｏｌ）を加え、室温で２４．５時間撹拌した。反応混合物に水を加え、酢酸エチルで３回抽出した。合わせた抽出液を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧下にて濃縮し、表題化合物（１９５ｍｇ，６３％）を淡黄色油状物として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．３０（ｔ，ｄ＝８Ｈｚ，３Ｈ），２．７７（ｑ，ｄ＝８Ｈｚ，２Ｈ），４．７３（ｓ，２Ｈ），６．０３（ｓ，１Ｈ）.

To a solution of ethyl 5-ethylisoxazole-3-carboxylate (synthesized by the method described in WO2016040515) (410 mg, 2.42 mmol) in tetrahydrofuran (4.8 mL) under ice cooling, a 4 M lithium borohydride-tetrahydrofuran solution was added. (1.21 mL, 4.84 mmol) was added and stirred at room temperature for 24.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The combined extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (195 mg, 63%) as a pale yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.30 (t, d = 8 Hz, 3H), 2.77 (q, d = 8 Hz, 2H), 4.73 (s, 2H), 6.03 (s, 1H).

(Reference example 7)
Synthesis of 3-(chloromethyl)-5-ethylisoxazole

参考例２に記載した方法に従い、参考例６で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．３１（ｔ，ｄ＝８Ｈｚ，３Ｈ），２．７７（ｑ，ｄ＝８Ｈｚ，２Ｈ），４．５６（ｓ，２Ｈ），６．１０（ｓ，１Ｈ）.

According to the method described in Reference Example 2, the title compound was obtained from the compound obtained in Reference Example 6.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.31 (t, d = 8 Hz, 3H), 2.77 (q, d = 8 Hz, 2H), 4.56 (s, 2H), 6.10 (s, 1H).

(Reference example 8)
Synthesis of 2-(5-ethylisoxazol-3-yl)acetonitrile

参考例３に記載した方法に従い、参考例７で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．３１（ｔ，ｄ＝８Ｈｚ，３Ｈ），２．７９（ｑ，ｄ＝８Ｈｚ，２Ｈ），３．７８（ｓ，２Ｈ），６．１０（ｓ，１Ｈ）.

According to the method described in Reference Example 3, the title compound was obtained from the compound obtained in Reference Example 7.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.31 (t, d = 8 Hz, 3H), 2.79 (q, d = 8 Hz, 2H), 3.78 (s, 2H), 6.10 (s, 1H).

(Reference example 9)
Synthesis of 2-(5-ethylisoxazol-3-yl)acetic acid

参考例４に記載した方法に従い、参考例８で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．３０（ｔ，ｄ＝８Ｈｚ，３Ｈ），２．７７（ｑ，ｄ＝８Ｈｚ，２Ｈ），３．７７（ｓ，２Ｈ），６．０５（ｓ，１Ｈ）.

According to the method described in Reference Example 4, the title compound was obtained from the compound obtained in Reference Example 8.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.30 (t, d = 8 Hz, 3H), 2.77 (q, d = 8 Hz, 2H), 3.77 (s, 2H), 6.05 (s, 1H).

(Example 99)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(5-ethylisoxazol-3-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び参考例９で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．１１－０．１５（ｍ，２Ｈ），０．５１－０．５６（ｍ，２Ｈ），０．７９－０．８８（ｍ，１Ｈ），１．２３－１．２９（ｍ，３Ｈ），１．３８－１．６２（ｍ，３Ｈ），２．１４－２．４１（ｍ，４Ｈ），２．４５－２．５２（ｍ，１Ｈ），２．６０－２．７８（ｍ，３Ｈ），２．８８－３．１１（ｍ，３Ｈ），３．５１（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），３．６２－３．８２（ｍ，２Ｈ），４．３２－４．３９（ｍ，１Ｈ），４．５５（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），４．６３（ｂｒ ｓ，０．７Ｈ），４．７３－４．７８（ｍ，０．３Ｈ），５．８４（ｓ，０．３Ｈ），６．１０（ｓ，０．７Ｈ），６．４６（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．４９（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，１Ｈ）.

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and the compound obtained in Reference Example 9.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.11-0.15 (m, 2H), 0.51-0.56 (m, 2H), 0.79-0.88 (m , 1H), 1.23-1.29 (m, 3H), 1.38-1.62 (m, 3H), 2.14-2.41 (m, 4H), 2.45-2.52 (m, 1H), 2.60-2.78 (m, 3H), 2.88-3.11 (m, 3H), 3.51 (d, J=16Hz, 1H), 3.62-3 .82 (m, 2H), 4.32-4.39 (m, 1H), 4.55 (d, J=16Hz, 1H), 4.63 (br s, 0.7H), 4.73- 4.78 (m, 0.3H), 5.84 (s, 0.3H), 6.10 (s, 0.7H), 6.46 (d, J=8Hz, 0.7H), 6. 49 (d, J = 8Hz, 0.3H), 6.72 (d, J = 8Hz, 1H).

(Reference example 10)
Synthesis of (E)-3-(5-methylisothiazol-3-yl)ethyl acrylate

カリウムｔｅｒｔ－ブトキシド（１０６ｍｇ，０．９４ｍｍｏｌ）のテトラヒドロフラン（１ｍＬ）懸濁液に、氷浴下ホスホノ酢酸トリエチル（１８９μＬ，０．９４ｍｍｏｌ）を滴下し、３０分間同温で撹拌した。その後、５－メチルイソチアゾール－３－カルバルデヒド（１００ｍｇ，０．７９ｍｍｏｌ）のＴＨＦ（１ｍＬ）溶液を滴下し、室温で５時間撹拌した。氷浴下、反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで三回抽出した。合わせた抽出液を硫酸ナトリウムで乾燥後、減圧下にて濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（１－１０％酢酸エチル／ヘプタン）で精製し、表題化合物（１４３ｍｇ，９２％）を無色油状物質として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．３３（ｔ，Ｊ＝７Ｈｚ，３Ｈ），２．５９（ｓ，３Ｈ），４．２７（ｑ，Ｊ＝７Ｈｚ，２Ｈ），６．５６（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），７．１５（ｓ，１Ｈ），７．６５（ｄ，Ｊ＝１６Ｈｚ，１Ｈ）．

To a suspension of potassium tert-butoxide (106 mg, 0.94 mmol) in tetrahydrofuran (1 mL), triethyl phosphonoacetate (189 μL, 0.94 mmol) was added dropwise in an ice bath, and the mixture was stirred at the same temperature for 30 minutes. After that, a THF (1 mL) solution of 5-methylisothiazole-3-carbaldehyde (100 mg, 0.79 mmol) was added dropwise, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture in an ice bath, and the mixture was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (1-10% ethyl acetate/heptane) to give the title compound (143 mg, 92%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.33 (t, J=7 Hz, 3 H), 2.59 (s, 3 H), 4.27 (q, J=7 Hz, 2 H), 6.56 (d, J=16 Hz, 1 H), 7.15 (s, 1 H), 7.65 (d, J=16 Hz, 1 H).

(Reference example 11)
Synthesis of (E)-3-(5-methylisothiazol-3-yl)acrylic acid

参考例１０で得られた化合物（１４３ｍｇ，０．７３ｍｍｏｌ）のテトラヒドロフラン（１ｍＬ）溶液に、２Ｍ水酸化ナトリウム水溶液（０．７３ｍＬ，１．４５ｍｍｏｌ）を加え、室温で５時間撹拌した。反応混合物に２Ｍ塩酸（０．７３ｍＬ，１．４５ｍｍｏｌ）を加え、酢酸エチルで三回抽出した。合わせた抽出液を硫酸ナトリウムで乾燥後、減圧下にて濃縮し、表題化合物（１２２ｍｇ，９９％）を白色粉末として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ_６）δ（ｐｐｍ）：２．５７（ｓ，３Ｈ），６．６１（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），７．４２（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），７，５８（ｓ，１Ｈ），１２．７１（ｂｒ ｓ，１Ｈ）．

A 2M sodium hydroxide aqueous solution (0.73 mL, 1.45 mmol) was added to a tetrahydrofuran (1 mL) solution of the compound (143 mg, 0.73 mmol) obtained in Reference Example 10, and the mixture was stirred at room temperature for 5 hours. 2M Hydrochloric acid (0.73 mL, 1.45 mmol) was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (122 mg, 99%) as a white powder.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.57 (s, 3H), 6.61 (d, J = 16Hz, 1H), 7.42 (d, J = 16Hz, 1H ), 7, 58 (s, 1H), 12.71 (br s, 1H).

(Example 100)
(E)-1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4 , 13-methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-3-(5-methylisothiazol-3-yl)prop-2-en-1- Composite on

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び参考例１１で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０３－０．１９（ｍ，２Ｈ），０．４５－０．６０（ｍ，２Ｈ），０．７６－１．８３（ｍ，４Ｈ），２．０８－２．４３（ｍ，４Ｈ），２．４７－２．６９（ｍ，５Ｈ），２．８９－３．０５（ｍ，２Ｈ），３．０７－３．２１（ｍ，１Ｈ），３．６６（ｄ，Ｊ＝１７Ｈｚ，１Ｈ），４．３７－４．５５（ｍ，２Ｈ），４．６０－４．７４（ｍ，１Ｈ），５．８８（ｂｒ ｓ，１Ｈ），６．３９－６．６２（ｍ，２Ｈ），６．９７－７．０８（ｍ，１Ｈ），７．４９－７．５５（ｍ，１Ｈ），７．７０（ｄ，Ｊ＝１５Ｈｚ，１Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in (1) of Example 3 and the compound obtained in Reference Example 11.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.19 (m, 2H), 0.45-0.60 (m, 2H), 0.76-1.83 (m , 4H), 2.08-2.43 (m, 4H), 2.47-2.69 (m, 5H), 2.89-3.05 (m, 2H), 3.07-3.21 (m, 1H), 3.66 (d, J=17Hz, 1H), 4.37-4.55 (m, 2H), 4.60-4.74 (m, 1H), 5.88 (br s, 1H), 6.39-6.62 (m, 2H), 6.97-7.08 (m, 1H), 7.49-7.55 (m, 1H), 7.70 (d, J=15Hz, 1H).

(Example 101)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-3-(5-methylisothiazol-3-yl)propan-1-one

実施例１００で得られた化合物（５．６ｍｇ，０．０１１ｍｍｏｌ）のメタノール（１ｍＬ）溶液に、パラジウム／炭素（パラジウム１０％、約５５％水湿潤品、１０ｍｇ）（５．６ｍｇ）を加え、水素雰囲気下、室温で２１時間撹拌した。反応混合物をメンブレンフィルターでろ過し、ろ液を減圧下にて濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（１－６％メタノール／クロロホルム）で精製し、表題化合物（３．８ｍｇ，７０％）を淡黄色ガム状物質として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．２１（ｍ，２Ｈ），０．４８－０．６４（ｍ，２Ｈ），０．７７－２．０８（ｍ，４Ｈ），２．０９－２．７３（ｍ，１０Ｈ），２．７５－３．４４（ｍ，５Ｈ），３．４７－３．９８（ｍ，２Ｈ），４．０８－４．５１（ｍ，２Ｈ），４．５４－４．８６（ｍ，１Ｈ），６．４１－６．５７（ｍ，１Ｈ），６．６７－６．８４（ｍ，２Ｈ）．

To a methanol (1 mL) solution of the compound (5.6 mg, 0.011 mmol) obtained in Example 100 was added palladium/carbon (palladium 10%, about 55% wet, 10 mg) (5.6 mg), Under a hydrogen atmosphere, the mixture was stirred at room temperature for 21 hours. The reaction mixture was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (1-6% methanol/chloroform) to give the title compound (3.8 mg, 70%) as a pale yellow gum.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.21 (m, 2H), 0.48-0.64 (m, 2H), 0.77-2.08 (m , 4H), 2.09-2.73 (m, 10H), 2.75-3.44 (m, 5H), 3.47-3.98 (m, 2H), 4.08-4.51 (m, 2H), 4.54-4.86 (m, 1H), 6.41-6.57 (m, 1H), 6.67-6.84 (m, 2H).

(Reference example 12)
Synthesis of isothiazol-3-ylmethylmethanesulfonic acid

イソチアゾール－３－イルメタノール（ＷＯ２０１８１６０８７８に記載の方法により合成）（６１．４ｍｇ，０．５３３ｍｍｏｌ）のテトラヒドロフラン（２ｍＬ）溶液に無水メタンスルホン酸（１４１ｍｇ，０．８０９ｍｍｏｌ）およびＮ，Ｎ－ジイソプロピルエチルアミン（１８３μＬ，１．０６ｍｍｏｌ）を加え、室温で１．５時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで３回抽出した。合わせた抽出液を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧下にて濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（４９－７０％酢酸エチル／へプタン）で精製し、表題化合物（７１．０ｍｇ，６９％）を淡褐色油状物として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．０６（ｓ，３Ｈ），５．４０（ｓ，２Ｈ），７．３９（ｄ，Ｊ＝５Ｈｚ，１Ｈ），８．７３（ｄ，Ｊ＝５Ｈｚ，１Ｈ）.

To a solution of isothiazol-3-ylmethanol (synthesized by the method described in WO2018160878) (61.4 mg, 0.533 mmol) in tetrahydrofuran (2 mL) was added methanesulfonic anhydride (141 mg, 0.809 mmol) and N,N-diisopropylethylamine. (183 μL, 1.06 mmol) was added and stirred at room temperature for 1.5 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The combined extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (49-70% ethyl acetate/heptane) to give the title compound (71.0 mg, 69%) as a pale brown oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.06 (s, 3H), 5.40 (s, 2H), 7.39 (d, J = 5Hz, 1H), 8.73 ( d, J=5Hz, 1H).

(Reference example 13)
Synthesis of 2-(isothiazol-3-yl)acetonitrile

参考例１２で得られた化合物（７１．０ｍｇ，０．３６７ｍｍｏｌ）のジメチルスルホキシド（２ｍＬ）溶液に、シアン化ナトリウム（５３．４ｍｇ，１．０９ｍｍｏｌ）を加え、７０℃で１８．５時間撹拌した。室温まで放冷後、反応混合物に水を加え、ｔｅｒｔ－ブチルメチルエーテルで３回抽出した。合わせた抽出液を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧下にて濃縮し、表題化合物（３０．０ｍｇ，６６％）を褐色油状物として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．９８（ｓ，２Ｈ），７．３２（ｄ，Ｊ＝５Ｈｚ，１Ｈ），８．７４（ｄ，Ｊ＝５Ｈｚ，１Ｈ）.

Sodium cyanide (53.4 mg, 1.09 mmol) was added to a dimethylsulfoxide (2 mL) solution of the compound (71.0 mg, 0.367 mmol) obtained in Reference Example 12, and the mixture was stirred at 70°C for 18.5 hours. . After allowing to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted three times with tert-butyl methyl ether. The combined extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (30.0 mg, 66%) as a brown oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.98 (s, 2H), 7.32 (d, J = 5Hz, 1H), 8.74 (d, J = 5Hz, 1H).

(Reference example 14)
Synthesis of 2-(isothiazol-3-yl)acetic acid

参考例４に記載した方法に従い、参考例１３で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：４．００（ｓ，２Ｈ），７．２２（ｄ，Ｊ＝５Ｈｚ，１Ｈ），８．７１（ｄ，Ｊ＝５Ｈｚ，１Ｈ）.

According to the method described in Reference Example 4, the title compound was obtained from the compound obtained in Reference Example 13.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 4.00 (s, 2H), 7.22 (d, J = 5Hz, 1H), 8.71 (d, J = 5Hz, 1H).

(Example 102)
1-((4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a,10-dihydroxy-2,3,4,4a,5,6,8,8a-octahydro-4,13-methanobenzofuro Synthesis of [2,3-c]pyrido[4,3-d]azepin-7(1H)-yl)-2-(isothiazol-3-yl)ethan-1-one

実施例６に記載した方法に従い、実施例３の（１）で得られた化合物及び参考例１４で得られた化合物より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．１０－０．１５（ｍ，２Ｈ），０．５０－０．５６（ｍ，２Ｈ），０．７８－０．８９（ｍ，１Ｈ），１．２９－１．６３（ｍ，３Ｈ），２．１５－２．４１（ｍ，４．３Ｈ），２．４８（ｄｄ，Ｊ＝７，１８Ｈｚ，０．７Ｈ），２．５７－２．６４（ｍ，１Ｈ），２．８４－３．１０（ｍ，２．７Ｈ），３．６０－３．８２（ｍ，２．３Ｈ），４．０４（ｄ，Ｊ＝１５Ｈｚ，０．３Ｈ），４．３０－４．４０（ｍ，１．４Ｈ），４．６６－４．９０（ｍ，２．３Ｈ），６．４４－６．４７（ｍ，１Ｈ），６．７４－６．７８（ｍ，１Ｈ），６．９０（ｂｒ ｓ，０．３Ｈ），７．２５（ｄ，Ｊ＝５Ｈｚ，０．７Ｈ），８．３９（ｄ，Ｊ＝５Ｈｚ，０．３Ｈ），８．５８（ｄ，Ｊ＝５Ｈｚ，０．７Ｈ）．

According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 3 (1) and the compound obtained in Reference Example 14.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10-0.15 (m, 2H), 0.50-0.56 (m, 2H), 0.78-0.89 (m , 1H), 1.29-1.63 (m, 3H), 2.15-2.41 (m, 4.3H), 2.48 (dd, J = 7, 18Hz, 0.7H), 2 .57-2.64 (m, 1H), 2.84-3.10 (m, 2.7H), 3.60-3.82 (m, 2.3H), 4.04 (d, J = 15Hz, 0.3H), 4.30-4.40 (m, 1.4H), 4.66-4.90 (m, 2.3H), 6.44-6.47 (m, 1H), 6.74-6.78 (m, 1H), 6.90 (br s, 0.3H), 7.25 (d, J = 5Hz, 0.7H), 8.39 (d, J = 5Hz, 0.3H), 8.58 (d, J=5Hz, 0.7H).

(Test example 1)
Opioid receptor function test
The functional activity of the compounds of the present invention on κ opioid receptors was investigated.
Method: Lance Ultra cAMP kit (PerkinElmer) was used and carried out according to the predetermined method. In the evaluation of agonist activity, human kappa opioid receptor-expressing CHO cells (Catalog No. CT6606, accession No. NM_000912) and a test compound were mixed in the presence of 10 μM forskolin in an assay buffer (1×HBSS, 5 mM HEPES, pH 7.4). , 0.5 mM IBMX (Isobutylmethylxanthine), 0.1% BSA) for 30 minutes. Subsequently, the cAMP detection reagent in the kit was added, and after 1 hour, time-resolved fluorescence measurement was performed using an EnVision plate reader (PerkinElmer). Evaluation of test compounds was carried out at concentrations ranging from 10 ⁻¹⁴ to 10 ⁻⁷ M for κ opioid receptor function assays.

^１）塩酸塩を用いた。

表１に示すとおり、本発明の化合物はκオピオイド受容体に対して強力なアゴニスト活性を示すことが確認された。

¹⁾ Hydrochloride was used.

As shown in Table 1, it was confirmed that the compounds of the present invention exhibit potent agonistic activity on the κ opioid receptor.

(Test example 2)
Metabolic stability test
Human liver microsomes and the test compound were allowed to react for a predetermined period of time (0 to 30 minutes), and the rate of residual unchanged test compound in the reaction sample was determined. Assuming that the residual rate of the unchanged drug at 0 hour reaction time is 100%, the residual rate after incubation is plotted log-linearly against time, and the regression line (y = 100 ^{e −kt} , k = slope of the straight line: elimination rate constant). was obtained, and the metabolic clearance CL _int (mL/min/kg) was calculated using the following formula.

CL _int * = k (-min) x 45 (mg MS protein/g liver) x 21 (g liver/kg)/MS protein (mg MS protein/mL)

*: Yamazaki S.T. ; Skaptason J.; Romero D, Vekich S.; Jones HM. Tan W.; Wilner KD. Koudriakova T.; Drug Metab. Dispos. 2011 Mar;39(3):383-93.

^１）塩酸塩を用いた。

表２に示すとおり、本発明の化合物は優れた代謝安定性を示した。

¹⁾ Hydrochloride was used.

As shown in Table 2, the compounds of the invention exhibited excellent metabolic stability.

(Test example 3)
Mouse acetic acid writhing test
The analgesic activity of test compounds was evaluated by the acetic acid writhing test. For the experiment, male ICR mice were used and acclimated to a plastic open field for 30 minutes before starting the test. After acclimatization, the mice were subcutaneously or orally administered a test compound (30-300 μg/kg) or water for injection, and then returned to the open field. Thirty minutes after administration of the test compound, an additional 0.6% aqueous solution of acetic acid was administered intraperitoneally to the same mice. Ten minutes after administration of 0.6% acetic acid aqueous solution, the number of writhing reactions induced in mice (writhing reactions such as pressing the abdominal cavity against the floor and stretching) was counted for 10 minutes. The analgesic effect of the test compound was evaluated in comparison with the water-administered group). The results are listed in Table 3.

^１）塩酸塩を用いた。
^２）ライジング抑制作用は、抑制率に従って以下のように分類した。
４０≦％＜６０：＋、６０≦％＜８０：＋＋、８０≦％：＋＋＋
^３）Ｎ．Ｃ．：ｎｏｔ ｃａｌｃｕｌａｔｅｄ

被験化合物^１）
表３に示す通り、本発明の化合物は強力な鎮痛作用を示すことが確認された。

¹⁾ Hydrochloride was used.
²⁾ Rising suppression action was classified as follows according to the suppression rate.
40 ≤ % < 60: +, 60 ≤ % < 80: ++, 80 ≤ %: +++
³⁾ N. C. : not calculated

Test compound ¹⁾
As shown in Table 3, it was confirmed that the compounds of the present invention exhibit potent analgesic action.

Claims (13)

the following general formula (I),

(In the formula, R ¹ is a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, a substituted optionally substituted C _3-6 cycloalkyl C _1-6 alkyl group, optionally substituted C _6-10 aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group optionally having substituent(s), heteroarylalkyl group optionally having substituent(s), C _2-6 alkenyl group optionally having substituent(s), C _2-6 alkynyl optionally having substituent(s) a group, an optionally substituted acyl group or an amino-protecting group,
R ² and R ³ are the same or different, hydrogen atom, optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, halogen atom, hydroxy group or R ² and R ³ together represent a carbonyl group, or R ² and R ³ combine to have an optionally substituted C _3-6 saturated hydrocarbon ring or substituent shows a good cyclic ketal,
R ⁴ and R ⁵ are the same or different and have a hydrogen atom, optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, substituted represents an optional amino group, a protected amino group, a halogen atom or a hydroxy group,
R ⁶ is a hydrogen atom, an optionally substituted C _1-6 alkoxy group, an optionally substituted amino group, a protected amino group, a halogen atom, a hydroxy group, a cyano group, a carboxy represents a carbamoyl group which may have a group, a carboxylic acid ester group or a substituent,
R ⁷ and R ⁸ are the same or different, hydrogen atom, optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, halogen atom, hydroxy group or R ⁷ and R ⁸ together represent a carbonyl group or a thiocarbonyl group, or R ⁷ and R ⁸ combine to represent an optionally substituted C _3-6 saturated hydrocarbon ring or substituent indicates a cyclic ketal that may have
R ⁹ and R ¹⁰ are the same or different, hydrogen atom, optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, halogen atom, hydroxy group or R ⁹ and R ¹⁰ together represent a carbonyl group or a thiocarbonyl group, or R ⁹ and R ¹⁰ combine to represent an optionally substituted C _3-6 saturated hydrocarbon ring or substituent indicates a cyclic ketal that may have
R ¹¹ is a hydrogen atom, optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, optionally substituted aralkyloxy group , an optionally substituted amino group, a protected amino group, a halogen atom, a hydroxy group or a cyano group,
A and B are different methylene groups, carbonyl groups or the following general formula (II):

(R ¹² and R ¹³ are the same or different and represent a hydrogen atom, an optionally substituted C _1-6 alkyl group, or R ¹² and R ¹³ on the same carbon are bonded to have a substituent A C _3-6 saturated hydrocarbon ring which may be substituted, a saturated heterocyclic ring which may have a substituent, or when n is 2 to 3, a pair of adjacent R ¹² are bonded together can form an optionally substituted C _3-6 saturated hydrocarbon ring or an optionally substituted saturated heterocyclic ring,
R ¹⁴ is a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _{2 -4} alkenyl group, optionally substituted C _2-6 alkynyl group, optionally substituted C _1-6 alkoxy group, optionally substituted amino group, protected amino group, halogen atom, hydroxy group, optionally substituted _C6-10 aryl group, optionally substituted heteroaryl group, optionally substituted cyclic Indicates an amino group. ) represents a group represented by (provided that either A or B represents formula (II)),
X represents a nitrogen atom or N-oxide,
Y represents an optionally substituted methylene group, a carbonyl group or a thiocarbonyl group,
Z represents NR ¹⁵ , an oxygen atom, a bond, an optionally substituted ethenylene group or an ethynylene group (however, when m is 0, n is 0 and Z does not represent NR ¹⁵ ),
R ¹⁵ represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, or R ¹⁵ and R ¹⁴ combine to represent an optionally substituted nitrogen-containing saturated heterocyclic ring ,
m represents an integer of 0 to 1,
n represents an integer of 0-3.
(However, when Z is a bond, m and n do not indicate 0 at the same time.))
Azepane derivatives represented by and pharmaceutically acceptable salts thereof. The azepane derivative and its pharmaceutically acceptable salt according to claim 1, wherein R ⁶ is a hydroxy group or a C _1-6 alkoxy group which may have a substituent. The azepane derivative and its pharmaceutically acceptable salt according to claim 1 or ² , wherein R6 is a hydroxy group. The azepane according to any one of claims 1 to 3, wherein R ¹ is an optionally substituted C _1-6 alkyl group or an optionally substituted C _3-6 cycloalkyl C _1-6 alkyl group. Derivatives and pharmaceutically acceptable salts thereof. The azepane derivative and its pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein Z is a bond. The azepane derivative and its pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein n is 1 to 3. The azepane derivative and its pharmaceutically acceptable salt according to any one of claims 1 to 6, wherein R ¹⁴ is an optionally substituted heteroaryl group. The azepane derivatives and pharmaceutically acceptable salts thereof according to any one of claims 1 to 7, wherein A represents a group represented by the general formula (II) according to claim 1 and B represents a methylene group. The azepane derivative and its pharmaceutically acceptable salt according to any one of claims 1 to 8, wherein R ¹¹ is a hydroxy group. A pharmaceutical composition comprising the azepane derivative according to any one of claims 1 to 9 and a pharmaceutically acceptable salt thereof as an active ingredient. 11. The medicament according to claim 10, which is a therapeutic, ameliorating or preventive agent for diseases associated with κ opioid receptors. The medicament according to claim 10 or 11, which is an analgesic. The medicine according to claim 10 or 11, which is an antipruritic.