JP2022017604A - Morphinan derivative - Google Patents

Abstract

To provide a morphinan derivative that has an opioid κ receptor agonist effect.SOLUTION: The morphinan derivative is represented by general formula (I) in the figure. (In the formula, R1 to R11 each represent a hydrogen atom, a C1-6 alkyl group that may have a substituent, or the like; R12 and R13 each represent a hydrogen atom or the like; R14 represents a heteroaryl group or the like; X represents a nitrogen atom or the like; Y and Z each represent an oxygen atom or the like; m represents an integer from 0 to 1; and n represents an integer from 0 to 3.)SELECTED DRAWING: None

Description

The present invention relates to a morphinan derivative having an opioid κ receptor agonistic action.

Three types of opioid receptors are known: μ, δ, and κ. Morphine, which has a strong affinity for μ receptors, has long been used as an analgesic. However, opioid μ receptor agonists are known to cause adverse events such as dependence formation and respiratory depression via the μ receptor.
On the other hand, κ receptor agonists also have analgesic effects, but are known not to be involved in the adverse events seen in morphine.
On the other hand, κ receptor agonists are generally known to exhibit sedative and drug aversive effects. Nalfurafine (Patent Document 1) is the only κ receptor agonist that separates drug aversion.Since nalfurafine has a sedative effect at an analgesic dose, it has been approved as an antipruritic drug, but as an analgesic drug. Has not been approved. That is, there is still no opioid κ receptor-selective agonist approved as an analgesic.
Therefore, κ receptor-selective agonists that do not show sedative or drug aversive effects are expected to be excellent treatments, ameliorations, or preventive agents for diseases and symptoms related to opioid κ receptors such as analgesics.
In Patent Document 2, the following equation (A),

It is disclosed that the compound represented by is having opioid κ receptor agonist activity. However, its activity was not sufficient.
Further, in Patent Document 3, the following equation (B),

Compounds represented by are reported. It is stated that this compound has opioid κ receptor selective binding and analgesic activity. However, its analgesic activity was unsatisfactory.
Further, in Non-Patent Document 1, the compound (C) represented by the following formula is described.

Although disclosed to have extremely high activity, this compound was not sufficiently stable in vivo. When a compound is unstable in a living body, it is difficult to develop it as a drug due to reasons such as the expected medicinal effect not being exhibited and the influence of decomposition products on the living body. It is an important requirement.
None of the analgesics on the market yet have high opioid κ receptor agonist activity.
Therefore, a compound that exhibits selectivity and high activity for opioid κ receptors and is excellent in in vivo stability is desired in order to aim for analgesics.

International Publication No. 1993/5081 Pamphlet Japanese Unexamined Patent Publication No. 2008-179554 Japanese Patent No. 2525552

JNRC2016 36th Analgesic / Opioid Peptide Symposium Program / Abstracts, page 37, Analgesic / Opioid Peptide Study Group

An object of the present invention is to provide an agent effective for treating, ameliorating, or preventing various diseases and symptoms related to opioid kappa receptor, which have suppressed sedation and drug aversive effects.

Under such circumstances, as a result of diligent studies by the present inventors, a specific morphinan derivative has opioid κ receptor selectivity and strong agonist activity against opioid κ receptor, and is highly stable in vivo. It was found that the present invention was completed.
[1] That is, the present invention has the following general formula (I),

（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アリール基、置換委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、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、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アルコキシ基又はヒドロキシ基を示し、
Ｒ^８及びＲ^９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^８及びＲ^９が一緒になってカルボニル基、チオカルボニル基を示すかＲ^８及びＲ^９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^１０及びＲ^１１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^１０及びＲ^１１が一緒になってカルボニル基、チオカルボニル基を示すかＲ^１０及びＲ^１１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^１２及びＲ^１３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_２－６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、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し、
Ｘは窒素原子又はＮ－オキシドを示し、
Ｙは酸素原子又は硫黄原子を示し、
ＺはＮＲ^１５、酸素原子、結合手、―ＣＨ＝ＣＨ―又は―Ｃ≡Ｃ―を示し、
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、
実線と破線からなる二重線は単結合又は二重結合を示し
ｍは０～１の整数を示し、
ｎは０～３の整数を示す。）
で表されるモルヒナン誘導体、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物に関する。
［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］記載のモルヒナン誘導体、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物に関する。
［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］記載のモルヒナン誘導体、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物に関する。
［４］また本発明は、前記［１］～［３］記載のモルヒナン誘導体、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を有効成分として含有する医薬組成物に関する。
［５］また本発明は、オピオイドκ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［４］記載の医薬に関する。
［６］また本発明は、鎮痛薬である前記［４］又は［５］記載の医薬に関する。
［７］また本発明は、止痒薬である前記［４］又は［５］記載の医薬に関する。。

(In the formula, R ¹ has a hydrogen atom, a C _1-6 alkyl group which may have a substituent, a C _3-6 cycloalkyl group which may have a substituent, and a substituent. May be C _3-6 cycloalkyl C _1-6 alkyl group, aryl group which may have a substituent, heteroaryl group which may have a substituent, and aralkyl which may have a substituent. Group, heteroarylalkyl group which may have a substituent, C _2-6 alkenyl group which may have a substituent, C _2-6 alkynyl group which may have a substituent, substituent. Indicates an acyl or amino-protecting group that may have
R ² and R ³ are the same or different hydrogen atom, C _1-6 alkyl group which may have a substituent, C _1-6 alkoxy group which may have a substituent, a halogen atom and a hydroxy group. Alternatively, R ² and R ³ together indicate a carbonyl group or R ² and R ³ may be attached to indicate a cyclic ketal which may have a substituent.
R ⁴ and R ⁵ have the same or different hydrogen atom, a C _1-6 alkyl group which may have a substituent, a C _1-6 alkoxy group which may have a substituent, and a substituent. Indicates an amino group, a halogen atom or a hydroxy group which may be present.
R ⁶ is a hydrogen atom, a C _1-6 alkoxy group which may have a substituent, an amino group which may have a substituent, a halogen atom, a hydroxy group, a cyano group, a carboxy group and a carboxylic acid ester group. Alternatively, a carbamoyl group which may have a substituent is shown.
R ⁷ represents a hydrogen atom, a C _1-6 alkyl group which may have a substituent, a C _1-6 alkoxy group which may have a substituent, or a hydroxy group.
R ⁸ and R ⁹ are the same or different hydrogen atoms, C _1-6 alkyl groups which may have substituents, C _1-6 alkoxy groups which may have substituents, halogen atoms, hydroxy groups. Alternatively, R ⁸ and R ⁹ may be combined to indicate a carbonyl group, a thiocarbonyl group, or R ⁸ and R ⁹ may be bonded to have a substituent C _3-6 saturated hydrocarbon ring or substituent. Indicates a ring-shaped ketal that may have,
R ¹⁰ and R ¹¹ are the same or different hydrogen atom, C _1-6 alkyl group which may have a substituent, C _1-6 alkoxy group which may have a substituent, a halogen atom and a hydroxy group. Alternatively, R ¹⁰ and R ¹¹ together indicate a carbonyl group, a thiocarbonyl group, or R ¹⁰ and R ¹¹ may be bonded to have a substituent C _3-6 saturated hydrocarbon ring or substituent. Indicates a ring-shaped ketal that may have,
R ¹² and R ¹³ indicate the same or different C _1-6 alkyl groups that may have the same or different hydrogen atoms, substituents, or R ¹² and R ¹³ on the same carbon have a substituent. It indicates a C _3-6 saturated hydrocarbon ring which may be present, a saturated heterocyclic ring which may have a substituent, or when n is 2 to 3, adjacent sets of ^R12 are bonded to each other and substituted. It is possible to form a C _3-6 saturated hydrocarbon ring which may have a group or a saturated heterocyclic ring which may have a substituent.
R ¹⁴ is a hydrogen atom, a C _1-6 alkyl group which may have a substituent, a C _3-6 cycloalkyl group which may have a substituent, and C ₂ which may have a substituent. _-6 Alkenyl group, C _2-6 alkynyl group which may have a substituent, C _1-6 alkoxy group which may have a substituent, amino group which may have a substituent, halogen. An atom, a hydroxy group, a C _6-10 aryl group which may have a substituent, a heteroaryl group which may have a substituent, and a cyclic amino group which may have a substituent are shown.
X represents a nitrogen atom or N-oxide,
Y represents an oxygen atom or a sulfur atom.
Z indicates NR ¹⁵ , oxygen atom, bond, —CH = CH— or —C≡C—,
R ¹⁵ indicates a hydrogen atom, a C _1-6 alkyl group which may have a substituent, or indicates a nitrogen-containing saturated heterocycle in which R ¹⁵ and R ¹⁴ may be bonded and have a substituent. ,
A double line consisting of a solid line and a broken line indicates a single bond or a double bond, and m indicates an integer of 0 to 1.
n represents an integer of 0 to 3. )
It relates to a morphinan derivative represented by, a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof.
[2] Further, in the present invention, the morphinan derivative according to the above [1], which is a C _1-6 alkoxy group in which R ⁶ may have a hydroxy group or a substituent, a tautomer of the compound, and a steric isomer. With respect to the body, or its pharmaceutically acceptable salts or solvates thereof.
[3] In the present invention, the morphinan derivative according to the above [1] or [ ² ], wherein R6 is a hydroxy group, a tautomer of the compound, a stereoisomer, or a pharmaceutically acceptable salt thereof or the like. Regarding those solvates.
[4] Further, the present invention is effective for the morphinan derivative according to the above [1] to [3], a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof. The present invention relates to a pharmaceutical composition contained as an ingredient.
[5] The present invention also relates to the pharmaceutical agent according to the above [4], which is a therapeutic, ameliorating, or preventive agent for a disease related to opioid kappa receptor.
[6] The present invention also relates to the pharmaceutical product according to the above [4] or [5], which is an analgesic.
[7] The present invention also relates to the drug according to the above [4] or [5], which is an antipruritic drug. ..

Next, the present invention will be described in more detail.
Among the morphinan derivatives represented by the general formula (I), tautomers of the compound, stereoisomers, pharmaceutically acceptable salts thereof, or solvates thereof, the following are preferable. Be done.
The C _1-6 alkyl group in the C _1-6 alkyl group which may have the substituents represented by R ¹ to R ⁵ and R ⁷ to R ¹⁴ 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, preferably a methyl group, an ethyl group, a propyl group and the like, and more preferably a methyl group.

Examples of the C _3-6 cycloalkyl group in the C _3-6 cycloalkyl group which may have the substituents indicated by R ¹ and R ¹⁴ include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. However, a cyclopropyl group is preferable.

The substituents in the C _1-6 alkyl group which may have a substituent represented by R ¹ and the C _3-6 cycloalkyl group which may have a substituent include a methyl group, an ethyl group and a propyl group. C _1-6 alkyl groups such as groups, fluoromethyl groups, difluoromethyl groups, methyl halides such as trifluoromethyl groups, halogen atoms such as fluorine atoms and chlorine atoms, hydroxy groups, C _1-6 alkylamino groups, Di C _1-6 Amino group which may have a substituent such as an alkylamino group, an acylamino group, a protected amino group, a formyl group, an acetyl group, an acyl group such as a cyclopropylcarbonyl group and a benzoyl group, azetidinyl. Examples thereof include a cyclic amino group such as a group, a pyrrolidinyl group, a piperazinyl group and a morpholinyl group, and a cyclic lactam group such as β-lactam, γ-lactam and δ-lactam.

The C _1-6 alkoxy group in the C _1-6 alkoxy group which may have the substituents represented by R ² to R ¹¹ and R ¹⁴ includes a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group and a butoxy. Examples thereof include a group, an isobutoxy group and the like, and preferably a methoxy group.
Examples of the substituent include a C _1-6 alkoxy group such as a methoxy group and an ethoxy group, a halogen atom such as a phenoxy group, a fluorine atom and a chlorine atom, preferably a fluorine atom, specifically a fluoromethoxy group and the like. Examples thereof include a difluoromethoxy group, a trifluoromethoxy group and a 2,2,2-trifluoroethoxy group.

Examples of the aryl group in the aryl group which may have the substituent represented by R ¹ and R ¹⁴ include a phenyl group and a naphthyl group.

Examples of the heteroaryl group in the heteroaryl group which may have the substituents indicated by R ¹ and R ¹⁴ include a furanyl group, an imidazolyl group, a pyrazolyl group, a thienyl, an oxazolyl group, an isoxazolyl group, a thiazolyl group and an isoxazolyl group. 6-membered ring heteroaryl group, indrill group, benzoimidazolyl group, benzofuranyl group, benzothienyl group, benzoxazolyl group, benzothiazolyl group, etc. Examples thereof include a monocyclic or bicyclic heteroaryl group containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom such as a bicyclic heteroaryl group as a ring-constituting atom.
Further, a remutable substance may exist depending on the substituent on these heteroaryl groups. For example, when a hydroxy group is substituted on a pyridyl group, a 6-hydroxypyridine-2-yl group and the remutable body thereof are present. 6-oxo-1,6-dihydropyridine-2-yl group and 4-hydroxypyridine-2-yl group, and 4-oxo-1,4-dihydropyridine-2-yl group as their homomorphs are mentioned. Be done.

The aryl group which may have a substituent shown by R ¹ and R ¹⁴ and the heteroaryl group which may have a substituent may have 1 to 3 substituents on the ring. As the substituents, C _1-6 alkyl groups such as methyl group, ethyl group and propyl group, methyl halide groups such as fluoromethyl group, difluoromethyl group and trifluoromethyl group, hydroxymethyl group and droxyethyl group, Hydroxyalkyl groups such as 1-hydroxypropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, C _1-6 alkoxy group such as butoxy group, halogen atom such as fluorine atom and chlorine atom, hydroxy group, nitro group. , Cyan group, C _1-6 alkylamino group, diC _1-6 alkylamino group, acylamino group, amino group which may have a substituent such as a protected amino group, formyl group, acetyl group, cyclo Examples thereof include an acyl group such as a propylcarbonyl group and a benzoyl group, a cyclic amino group such as an azetidinyl group, a pyrrolidinyl group, a piperazinyl group and a morpholinyl group, and a cyclic lactam group such as β-lactam, γ-lactam and δ-lactam.

Examples of the C _{3-6 cycloalkyl in the C 3-6 cycloalkyl} C _1-6 alkyl group which may have the substituent represented by R ¹ include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and are preferable. Cyclopropyl and cyclobutyl are mentioned, and more preferably cyclopropyl is mentioned.
Moreover, as the C _1-6 alkyl group in the C _3-6 cycloalkyl C _1-6 alkyl group represented by R ¹ , the same thing as above can be mentioned.
Examples of the substituent include the same as the substituent in the C _3-6 cycloalkyl group which may have the above-mentioned substituent.

As the aralkyl group which may have the substituent represented by R ¹ , the aryl moiety has a carbon number of C _{6 to 10} and the alkylene moiety has a carbon number of C _{1 to 5} , and is substituted with, for example, phenyl or naphthyl. Examples thereof include a methyl group and an ethyl group, preferably a phenyl-substituted methyl group (benzyl group).

The heteroaryl moiety in the heteroarylalkyl group which may have a substituent represented by R ¹ includes 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as ring-constituting atoms. Heteroaryl can be mentioned, and examples of the alkyl moiety include C _1-6 alkyl groups such as a methyl group, an ethyl group and a propyl group, for example, (pyridine-2-yl) methyl group and (pyridine-3-yl). Methyl group, (pyridine-4-yl) methyl group, 2- (pyridine-2-yl) ethyl group, (fran-2-yl) methyl group, (fran-3-yl) methyl group, (imidazole-2-) Il) methyl group, (imidazole-4-yl) methyl group, (imidazole-5-yl) methyl group, (thiazol-2-yl) methyl group, (thiazol-4-yl) methyl group, (thiazol-5-yl) Monocyclic heteroarylalkyl groups such as yl) methyl group, (thiophene-2-yl) methyl group or 2- (thiophen-2-yl) ethyl group, (quinolin-3-yl) methyl group, (indol-3-3). Ill) Examples thereof include a bicyclic heteroarylalkyl group of a methyl group.

It may have a substituent on the aryl and the heteroaryl in the aralkyl group which may have the substituent represented by ^R1 and the heteroarylalkyl group which may have the substituent, and may have a substituent as the substituent. Examples thereof include the same as the substituent in the aryl group which may have a substituent and the heteroaryl group which may have a substituent.

Examples of the C _2-6 alkenyl group in the C _2-6 alkenyl group which may have the substituents indicated by R ¹ and R ¹⁴ include a linear or branched alkenyl group of C _2-6 . 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 groups and the like are alkenyl groups.

The C _2-6 alkynyl group in the C _2-6 alkynyl group which may have the substituents indicated by R ¹ and R ¹⁴ indicates a linear or branched alkynyl group of C _2-6 . For example, an ethynyl group, a propynyl group, a butynyl group and the like can be mentioned.

Examples of the group that can be substituted with such an alkenyl group and an alkynyl group include an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group and a propoxycarbonyl group, a benzyl group, a 2-phenylethyl group, a 3-phenylpropyl group and a 4-phenyl group. Aralkyl group such as butyl group, methoxy group, ethoxy group, propoxy group, alkoxy group such as butoxy group, aralkyloxy group such as benzyloxy group and 2 _- phenylethyloxy group, linear or branched chain of C1-6. Examples thereof include an amino group which may be substituted with an alkyl group, a halogen atom such as a fluorine atom and a chlorine atom, a carboxy group and a hydroxy group.

Examples of the acyl group which may have the substituent represented by R ¹ include a C _2-6 alkanoyl group such as a formyl group, an acetyl group, a propionyl group, a butanoyl group, a pentanoyl group and a hexanoyl group, and a cyclopropylcarbonyl group. C _4-7 cycloalkanoyl group such as cyclobutylcarbonyl group and cyclopentylcarbonyl group, aloyl group such as benzoyl group and naphthoyl group or floyl group, thiophenecarbonyl group, nicotinyl group, isonicotinoyyl group and other 5- to 6-membered heteroaroyl group. And so on.
Examples of the substituent in the C _2-6 alkanoyl group and the C _4-7 cycloalkanoyl group include the same as the substituent in the C _1-6 alkyl group which may have the above-mentioned substituent, and alloyl. Examples of the substituent in the group and the heteroaroyl group include the same as the substituent in the aryl group which may have the substituent and the heteroaryl group which may have the substituent.

The substituent in the carbamoyl group which may have a substituent represented by R ⁶ and the substituent in the amino group which may have a substituent represented by R ⁴ to R ⁶ and R ¹⁴ is a methyl group. , C _1-6 alkyl group which may have a linear or branched substituent such as ethyl group, propyl group, isopropyl group (as the substituent, hydroxy group, C _1-6 alkoxy group, fluorine atom, Examples thereof include a halogen atom such as a chlorine atom, an amino group, a cyano group, a heteroaryl group and the like), and these substituents may have 1 or 2.
In addition to the above, examples of the substituent in the amino group which may have the substituents shown in R ⁴ to R ⁶ and R ¹⁴ include the same amino protecting group as the amino protecting group shown in R ¹ . ..

Examples of the amino-protecting group represented by R ¹ include a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group, a tert-amyloxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group and p-. Chlorobenzyloxycarbonyl group, p-methoxybenzylcarbonyl group, p-nitrobenzyloxycarbonyl group, p-phenylazobenzyloxycarbonyl group, p-methoxyphenylazobenzyloxycarbonyl group, 3,5-dimethoxybenzyloxycarbonyl group, Carbamate protection of 3,4,5-trimethoxybenzyloxycarbonyl group, p-biphenylisopropyloxycarbonyl group, diisopropylmethyloxycarbonyl group, 2- (trimethylsilyl) ethoxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, etc. Group, p-toluenesulfonyl group, 2-nitrobenzenesulfonyl group and other sulfonamide-based protective groups, phthaloyl group and other imide-based protective groups, benzyl group, phenylethyl group, phenylpropyl group, trityl group, naphthylmethyl group and other _{C7 -19} Aralkyl groups are listed.

Examples of the halogen atom represented by ^R2 to ^R6 , ^R8 to ^R11 and ^R14 include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a fluorine atom, a chlorine atom, and more preferably a fluorine atom. Can be mentioned.

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

Examples of the cyclic amino group in the cyclic amino group which may have the substituent represented by R14 include an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a ^morphonyl group and a thiomorpholinyl group.
Examples of the substituent include a C _1-6 alkyl group such as a methyl group and an ethyl group, a C _1-6 alkoxy group such as a methoxy group, an ethoxy group and a propoxy group, a halogen atom such as a fluorine atom and a chlorine atom, and a hydroxy group. Can be mentioned.

It may have a substituent formed by bonding R ⁸ and R ⁹ , and may have a substituent formed by bonding R ¹⁰ and R ¹¹ to a C _3-6 saturated hydrocarbon ring. A good C _3-6 saturated hydrocarbon ring, with substituents formed by the bond of R ¹² and R ¹³ on the same carbon or the bond of adjacent sets of R ¹² to each other when n is 2-3. Examples of the C _3-6 saturated hydrocarbon ring in the C _3-6 saturated hydrocarbon ring may include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, and a cyclohexane ring.

As a saturated heterocycle which may have a substituent formed by bonding R ¹² and R ¹³ on the same carbon or by bonding adjacent sets of R ¹² to each other when n is 2 to 3. Examples thereof include saturated heterocycles having a 3- to 6-membered ring, such as cyclic amines such as aziridine, azetidine, pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine, and cyclic ethers such as epoxide, oxetane, tetrahydrofuran, tetrahydropyran and dioxane. Cyclic thioethers such as thietan, thiolan, and thian can be mentioned.
When the saturated heterocycle has a nitrogen atom as a constituent atom of the ring, it may have a substituent such as a C _1-6 alkyl group, an acyl group and an amino protecting group on nitrogen. These substituents are the same as described above.

Examples of the nitrogen-containing saturated heterocycle which may have a substituent formed by bonding R ¹⁴ and R ¹⁵ include a 3- to 6-membered nitrogen-containing saturated heterocycle, for example, aziridine, azetidine, and pyrrolidine. , Piperidine, piperazine, morpholine, thiomorpholine and the like.
These nitrogen-containing saturated heterocycles may be further fused with a saturated hydrocarbon, a saturated heterocycle, an unsaturated hydrocarbon or an unsaturated heterocycle, for example, decahydroquinoline, decahydroisoquinoline, indolin, isoindoline, 1 , 2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, benzomorpholin, benzothiomorpholin and the like.
When the nitrogen-containing heterocycle has a nitrogen atom as a constituent atom of the ring in addition to the nitrogen atom to which ^R15 is bonded, it has a substituent such as a C _1-6 alkyl group, an acyl group and an amino-protecting group. You may be doing it. These substituents are the same as described above.

A C _3-6 saturated hydrocarbon ring which may have a substituent formed by bonding R ¹² and R ¹³ on the same carbon, and formed by bonding R ¹² and R ¹³ on the same carbon. Saturated heterocycle which may have a substituent, and C _3-6 saturated which may have a substituent formed by bonding adjacent sets of ^R12 to each other when n is 2 to 3. The cyclic is the substituent in the saturated heterocycle which may have a hydrocarbon ring or a substituent and the nitrogen-containing saturated heterocycle which may have a substituent formed by combining R ¹⁴ and R ¹⁵ . The same as the substituent in the amino group can be mentioned.

Examples of the cyclic ketal that may have a substituent formed by binding R ² and R ³ , R ⁸ and R ⁹ and R ¹⁰ and R ¹¹ include dioxolane and dioxane. Examples of the substituent include C _1-6 alkyl groups such as a methyl group, an ethyl group and a propyl group.

X indicates a nitrogen atom or N-oxide, and a nitrogen atom is preferable.

Y represents an oxygen atom or a sulfur atom, and is preferably an oxygen atom.

Z represents NR ¹⁵ , oxygen atom, bond, —CH = CH— or —C≡C—, preferably NR ¹⁵ , oxygen atom, bond or ethylene.

m represents an integer of 0 to 1, preferably 1.

n represents an integer of 0 to 3, preferably 1.

In the preferred embodiment of the compound (I) used in the present invention, R ¹ may have a substituent C _1-6 alkyl group and may have a substituent C _3-6 cycloalkyl. It is a C _1-6 alkyl group, and R ² and R ³ may have the same or different hydrogen atom or substituent C _1-6 alkyl group, and may have a substituent C _{1- 6} An alkoxy group, a halogen atom, and a hydroxy group, and ^R4 and R5 may have the ^same or different hydrogen atom and substituent, and may have a C _1-6 alkyl group and substituent. C _1-6 alkoxy group, an amino group which may have a substituent, a halogen atom or a hydroxy group, and R ⁶ is a C _1-6 alkoxy group or a hydroxy group which may have a substituent. , R ⁷ is a hydrogen atom, a C _1-6 alkyl group which may have a substituent, a C _1-6 alkoxy group or a hydroxy group which may have a substituent, and R ⁸ and R ⁹ are. The same or different hydrogen atom, C _1-6 alkyl group which may have a substituent, C _1-6 alkoxy group which may have a substituent, a halogen atom or a hydroxy group, and R ¹⁰ and R ¹¹ is the same or different hydrogen atom, C _1-6 alkyl group which may have a substituent, C _1-6 alkoxy group which may have a substituent, a halogen atom, and a hydroxy group. R ¹² and R ¹³ are C _1-6 alkyl groups that may have the same or different hydrogen atoms or substituents, and R ¹⁴ is a C _6-10 aryl group that may have substituents, A heteroaryl group which may have a substituent or a cyclic amino group which may have a substituent, X is a nitrogen atom or an N-oxide, Y is an oxygen atom or a sulfur atom, and Z is. Is NR ¹⁵ , oxygen atom, bonder, —CH = CH— or —C≡C—, and ^R15 is a hydrogen atom, a C _1-6 alkyl group that may have a substituent, with a solid line. The double line consisting of a broken line is a single bond or a double bond, m is an integer of 0 or 1, and n is an integer of 0 to 3.

In a more preferred embodiment of the compound (I) used in the present invention, R ¹ may have a C _1-6 alkyl group which may have a substituent or a C _3-6 cycloalkyl which may have a substituent. C _1-6 alkyl groups, R ² and R ³ are C _1-6 alkyl groups that may have the same or different hydrogen atoms or substituents, and R ⁴ and R ⁵ are the same or different. A C _1-6 alkyl group which may have a hydrogen atom or a substituent, R ⁶ is a C _1-6 alkoxy group or a hydroxy group which may have a substituent, and R ⁷ is a hydrogen atom. , C _1-6 alkyl group which may have a substituent, C _1-6 alkoxy group or hydroxy group which may have a substituent, and R ⁸ and R ⁹ are the same or different hydrogen atoms. , A C _1-6 alkyl group which may have a substituent or a C _1-6 alkoxy group which may have a substituent, and R ¹⁰ and R ¹¹ are the same or different hydrogen atoms or substituents. Is a C _1-6 alkyl group that may have, and R ¹² and R ¹³ are C _1-6 alkyl groups that may have the same or different hydrogen atoms or substituents, where R ¹⁴ is. A C _6-10 aryl group which may have a substituent, a heteroaryl group which may have a substituent or a cyclic amino group which may have a substituent, and X is a nitrogen atom or N. -Oxide, Y is an oxygen atom or a sulfur atom, Z is an NR ¹⁵ , an oxygen atom, a bond or -CH = CH-, and R ¹⁵ is a hydrogen atom, which may have a substituent. A _1-6 alkyl group, a double line consisting of a solid line and a broken line is a single bond or a double bond, m is an integer of 0 or 1, and n is an integer of 0 to 3.

Further, as a preferred embodiment of the compound (I) used in the present invention, R ¹ may have a substituent C _1-6 alkyl group and may have a substituent C _3-6 cycloalkyl. C _1-6 alkyl groups, R ² and R ³ are C _1-6 alkyl groups that may have the same or different hydrogen atoms or substituents, and R ⁴ and R ⁵ are hydrogen atoms. , R ⁶ is a hydroxy group, R ⁷ is a hydrogen atom or a hydroxy group, and R ⁸ and R ⁹ are C _1-6 alkyl groups which may have the same or different hydrogen atoms or substituents. , R ¹⁰ and R ¹¹ are C _1-6 alkyl groups that may have the same or different hydrogen atoms or substituents, and R ¹² and R ¹³ have the same or different hydrogen atoms or substituents. May be a C _1-6 alkyl group, R ¹⁴ is a heteroaryl group which may have a substituent, X is a nitrogen atom, Y is an oxygen atom, Z is NR ¹⁵ , An oxygen atom, a bond or —CH = CH—, ^R15 is a C _1-6 alkyl group which may have a hydrogen atom or a substituent, and the double line consisting of a solid line and a broken line is a single bond. Yes, m is an integer of 0 or 1, and n is an integer of 0 to 1.

In the morphinan derivative represented by the above general formula (I), a homovariant of the compound, a steric isomer, or a pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt is preferably acid addition. Examples thereof include salts, and examples of the acid addition salt include (a) salts with mineral acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, (b) formic acid, acetic acid, citrate, trichloroacetic acid, trifluoroacetic acid, fumaric acid, and malein. Examples thereof include a salt with an organic carboxylic acid such as acid and tartrate acid, and a salt with a sulfonic acid such as (c) methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.

In the morphinan derivative represented by the general formula (I), a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a mixture thereof, the stereoisomers are cis and trans. Examples include isomers, racemates and optically active substances.

As a hydrate or solvate in the morphinan derivative represented by the general formula (I), a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof. Can also exist. Therefore, the compounds of the present invention include all their crystalline forms and hydrated or solvated products.

Next, a method for producing a morphinan derivative represented by the general formula (I), a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof will be shown.

(Method A) A 7-membered ring in the general formula (I) of the manufacturing method (method A-1) in which R ⁷ to R ¹¹ are hydrogen atoms, X is a nitrogen atom, and a double wire consisting of a solid line and a broken line is a single bond. When the nitrogen atom, which is a constituent atom of the above, is bonded to a benzyloxycarbonyl group (Cbz) or a hydrogen atom, the invention compounds (a-10) to (a-13) can be obtained by the methods described below.

（式中、Ｒ^１～Ｒ^６は前記と同様のものを示す。）

(In the formula, R ¹ to R ⁶ indicate the same as above.)

(First step)
Aromatic hydrocarbons such as benzene, toluene and xylene with 1 to 10 equivalents of the raw material (a-1) and 2-chloroacrylonitrile; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and jigglime; Halogenated hydrocarbons such as carbon tetrachloride, 1,2-dichloroethane; alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane and ligroin; acetonitrile, N, N-dimethylformamide, dimethyl In an aprotonic polar solvent such as sulfoxide, in the presence or absence of a base such as sodium hydrogen carbonate, lithium carbonate, sodium carbonate, potassium carbonate, etc., after reacting at 80 to 190 ° C. for 3 to 24 hours, or in a sealed tube. The compound (a-2) can be synthesized by hydrolysis after irradiating with a hydrocarbon by a hydrocarbon synthesizer to react. The hydrolysis reaction can be carried out using an acid or a base by a generally known method, but a base is preferable, for example, ethers such as tetrahydrofuran and dioxane; 1 to 10 mol in an alcohol solvent such as methanol and ethanol. It can be carried out by adding 1 to 6 equivalents of an inorganic basic aqueous solution such as / L lithium hydroxide, sodium hydroxide, or potassium hydroxide aqueous solution and reacting at room temperature to heating and reflux for 1 to 24 hours.
The starting material (a-1) can be synthesized by a generally known method. For example, J. Chem. Soc. C, 1966, 617 or J.M. Chem. Soc. C, 1969, 2569, J.M. Chem. Soc. Perkin Trans. It can be synthesized by the method described in I, 1994, 911.

(Second step)
Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; alcohols such as methanol, ethanol and 2-propanol; water, Solvents such as acetic acid; trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N, N in aprotonic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, etc. -Organic bases such as dimethylaminopyridine, N-methylpiperidin, N-methylmorpholin, diethylamine, cyclohexylamine, procaine, sodium methoxydo, sodium ethoxydo; lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide In the presence of an inorganic base such as, the compound (a-3) is reacted with hydroxylamine (for example, an aqueous hydroxylamine solution, a hydroxylamine hydrochloride, a hydroxylamine sulfate, etc.) at room temperature to heated reflux for 1 to 24 hours. ) Can be synthesized.

(Third step)
Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride. Classes; aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin; potassium bis (trimethylsilyl) amide (KHMDS) in aprotonic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, etc. , Lithium diisopropylamide (LDA) and other bases; trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N, N-dimethylaminopyridine, N-methylpiperidin, N-methylmorpholin, diethylamine, cyclohexylamine, Organic bases such as prokine, sodium methoxydo and sodium ethoxydo; reagents represented by L _- Cl or L2O in the presence of inorganic bases such as lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide. (L represents a methanesulfonyl group, a p-toluenesulfonyl group, a trifluoromethanesulfonyl group, a 2-nitrobenzenesulfonyl group, etc.) and a compound after reacting with the compound at −78 ° C. to heated reflux for 1 to 24 hours. (A-4) can be synthesized. The hydrolysis reaction can be carried out using an acid by a generally known method, for example, ethers such as tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and 2-propanol; acetonitrile, N, N-dimethylformamide and dimethyl. Aprotic polar solvent such as sulfoxide; 1 to 6 equivalents or an amount of an inorganic acidic aqueous solution such as sulfuric acid or 1 to 10 mol / L hydrochloric acid or sulfuric acid is added in a solvent such as acetic acid or in the absence of a solvent, and the mixture is heated at room temperature to reflux. This can be done by reacting for 1 to 24 hours.

(4th step)
In a hydrogen atmosphere or in the presence of potassium formate (1-5 equivalents) or the like, the compound (a-4) is an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; alcohols such as methanol, ethanol and 2-propanol; In a solvent such as water or acetic acid or in a mixed solvent thereof, a metal catalyst such as a nickel catalyst such as lane nickel, palladium-activated carbon (Pd / C) and a Pearlman catalyst (Pearlman's Catalyst: Pd (OH) ₂ ) and the like. The compound (a-5) can be synthesized by reacting in the presence of a platinum catalyst such as a palladium catalyst or an Adams'catalyst (PtO ₂ ) at room temperature to heating and reflux for 1 to 24 hours.

(Fifth step)
Arochemical hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; alcohols such as methanol, ethanol and 2-propanol; methylene chloride. , Hydrocarbons such as chloroform and carbon tetrachloride; aliphatic hydrocarbons such as pentane, hexane, heptane and ligroin; aprotonic polar solvents such as acetonitrile, N, N-dimethylformamide and dimethylsulfoxide; acetic acid and the like. In the solvent of, hydride reducing agents such as sodium hydride, sodium cyanohydride, sodium hydride triacetoxyboron, hydride tri (sec-butyl) boron lithium, hydride tri (sec-butyl) boron potassium, and the like. The compound (a-6) can be synthesized by reacting at −30 ° C. to heating and reflux for 1 to 24 hours.

(Sixth step)
The compound (a-6) is mixed with a reducing agent such as lithium aluminum hydride, borane-tetrahydrofuran complex, borane-dimethylsulfide in ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and jigglime, and heated at 0 ° C. to reflux. The compound (a-7) can be synthesized by reacting in 1 to 24 hours.

(7th step)
Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride. Kind; Aprotonic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide; In a solvent such as water or a mixed solvent thereof, trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N. , N-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, sodium methoxydo, sodium ethoxydo and other organic bases; sodium hydrogencarbonate, lithium carbonate, sodium carbonate, potassium carbonate, water The compound (a-8) can be synthesized by reacting with benzyl chloride at 0 ° C. to room temperature for 1 to 24 hours in the presence of an inorganic base such as sodium oxide or potassium hydroxide.

(8th step)
Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride. Classes; aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin; potassium bis (trimethylsilyl) amide (KHMDS), lithium diisopropylamide in aprotonic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, etc. Bases such as (LDA); trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N, N-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, sodium methoxy. Organic bases such as di, sodium ethoxydo, potassium ether-butoxide; in the presence of inorganic bases such as lithium hydride, sodium hydride, potassium hydride, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc. , L _— Cl or L2O (L indicates the same as above) by reacting with the compound (a-9) at −78 ° C. to heating and reflux for 1 to 24 hours. Can be synthesized.

(Ninth step)
Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride. Classes; aliphatic hydrocarbons such as pentane, hexane, heptane, ligroine; potassium bis (trimethylsilyl) amide (KHMDS), lithium diisopropylamide in aprotonic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, etc. Bases such as (LDA); trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N, N-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, sodium methoxy. De, sodium ethoxydo, potassium ether-organic bases such as butoxide; inorganic bases such as lithium hydride, sodium hydride, potassium hydride, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and- The invention compound (a-10) can be synthesized by reacting at 78 ° C. to heating and reflux for 1 to 24 hours.

(10th step)
Under a hydrogen atmosphere, the invention compound (a-10) is mixed with ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; alcohols such as methanol, ethanol and 2-propanol; in a solvent such as water and acetic acid or a mixture thereof. In the solvent, a metal catalyst such as a nickel catalyst such as Raney nickel, a palladium catalyst such as palladium-activated carbon (Pd / C) and a Pearlman catalyst (Pd (OH) ₂ ), or an Adams'catalyst: The invention compound (a-11) can be synthesized by reacting in the presence of a platinum catalyst such as PtO ₂ ) at room temperature to heating and reflux for 1 to 24 hours.

(11th step)
When R ⁶ is a C _1-6 alkoxy group, the invention compound (a-11) is used as a halogenated hydrocarbon such as methylene chloride, chloroform or carbon tetrachloride; an organic solvent such as acetic acid or ethyl acetate; or a non-acetaken or the like. React with boron tribromide, trimethylsilyl iodide, hydrogen bromide, pyridinium hydrochloride, etc. in a protonic polar solvent or no solvent at -30 to 180 ° C. for 30 minutes to 5 hours, or N, N-dimethylformamide. , 1-Propanethiol, 1-dodecanethiol, etc. in the presence of organic bases such as potassium tert-butoxide, sodium tert-butoxide, etc. in aprotonic polar solvents such as dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, etc. from 100 ° C. The invention compound (a-12) can be obtained by reacting at 180 ° C. for 30 minutes to 24 hours.

(Twelfth step)
When R ⁶ is a C _1-6 alkoxy group, the invention compound (a-13) can be obtained by carrying out the same reaction as in the eleventh step above with respect to the invention compound (a-10).

(13th step)
The invention compound (a-12) can be obtained by carrying out the same reaction as in the tenth step of the invention compound (a-13).
The compound (a-5) can also be synthesized by the method described below.

（式中、Ｒ^１～Ｒ^６及びＬは前記と同様のものを示す。）

(In the formula, R ¹ to R ⁶ and L indicate the same as described above.)

(First step)
In a hydrogen atmosphere or in the presence of potassium formate (1 to 5 equivalents) or the like, the compound (a-2) is an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; alcohols such as methanol, ethanol and 2-propanol; In a solvent such as water or acetic acid or a mixed solvent thereof, a metal catalyst such as a nickel catalyst such as lane nickel, palladium such as palladium-activated carbon (Pd / C) and a Pearlman catalyst (Pearlman's Catalyst: Pd (OH) ₂ ) The compound (a-14) can be synthesized by reacting in the presence of a catalyst or a platinum catalyst such as Adams'catalyst (PtO ₂ ) at room temperature to heating and reflux for 1 to 24 hours.

(Second step)
The compound (a-14) can be synthesized from the compound (a-2) in the same manner as in the second step in the synthesis of the compound (a-3).

(Third step) and (Fourth step)
The compound (a-15) is synthesized from the compound (a-3) in the same manner as in the third step in the synthesis of the compound (a-4) to synthesize the compound (a-16) and the compound (a-5). Can be done.

(Method A-2) In the general formula (I), when Z is a bond, -CH = CH- or -C≡C-, and m is 1, the invention compound (a-19) to the method described below. (A-22) can be obtained.

（式中、Ｍはハロゲン原子、Ｚは結合手、―ＣＨ＝ＣＨ―又は―Ｃ≡Ｃ―を示し、Ｒ^１～Ｒ^６、Ｒ^１２～Ｒ^１４、Ｙ、ｎは前記と同様のものを示す。）

( ^In the formula, M is a halogen atom, Z is a bond, —CH = CH— or —C≡C—, and ^R1 to R6, ^R12 to ^R14 , Y, and n are the same as above. show.)

(First step)
Aromatic hydrocarbons such as benzene, toluene and xylene to the inventive compound (a-11) obtained in (Method A-1); ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme: methylene chloride, chloroform. Hydrocarbons such as carbon tetrachloride: alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane and ligroin; aprotons such as acetonitrile, N, N-dimethylformamide and dimethylsulfoxide. In the sexual polar solvent, the acid halide represented by (a-18) is N, N-dimethylaminopyridine, trimethylamine, triethylamine, tributylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaniline, N. -Organic bases such as methylpiperidin, N-methylmorpholine, diethylamine, cyclocarbonate, prokine: Reaction in the presence or absence of inorganic bases such as potassium carbonate, lithium carbonate, 0 ° C. to heated reflux for 1 to 12 hours. Alternatively, the carboxylic acid represented by (a-17) can be replaced with O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU). ), O- (benzotriazole-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-triazine-2-yl) -4-methylmorpholinium chloride n hydrate The compound of invention (a-19) can be synthesized by reacting the compound (DMT-MM) in the presence or absence of a condensing agent at 0 ° C. to heating and refluxing for 1 to 12 hours. In addition, the invented compound (a-19) is an aromatic hydrocarbon such as benzene, toluene or xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; halogenation of methylene chloride, chloroform, carbon tetrachloride and the like. Hydrocarbons; among aliphatic hydrocarbons such as pentane, hexane, heptane, and ligroin, heat from 0 ° C. using a generally known sulfide agent such as diphosphorus pentasulfide, Lawesson's reagent, Davy reagent, Japanese reagent, and bereo reagent. It can be converted to the invention compound (a-20) by reacting under reflux for 1 to 12 hours.

(Second step)
When R ⁶ is a C _1-6 alkoxy group, the invention compound (a-19) or (a-20) is subjected to the same reaction as in the eleventh step of (Method A-1). a-21) or (a-22) can be obtained, respectively.

(Method A-3) In the general formula (I), when Y is an oxygen atom, Z is NR ¹⁵ or an oxygen atom, and m is 1, the invention compounds (a-23) and (a-24) are according to the methods described below. ) And (a-27) to (a-28) can be obtained.

（式中、ＺはＮＲ^１５又は酸素原子、メチル化剤（Ｍｅ-Ａ）におけるＡはハロゲン、トロフルオロメタンスルホネート等を示し、Ａ^-はそのカウンターアニオンを示し、Ｒ^１～Ｒ^６、Ｒ^１２～Ｒ^１５、Ｚ、ｎは前記と同様のものを示す。）

(In the formula, Z indicates NR ¹⁵ or oxygen atom, A in the methylating agent (Me-A) indicates halogen, trofluoromethanesulfonate, etc. ^, A- indicates its counter anion, R ¹ to R ⁶ , R ¹² ~ R ¹⁵ , Z, n indicate the same as above.)

(First step)
In the compound of invention (a-11) obtained in (Method A-1), aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme: methylene chloride, Halogenated hydrocarbons such as chloroform and carbon tetrachloride: alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane and ligroin; non-alkoxy, N, N-dimethylformamide, dimethylsulfoxide and the like. N, N-dimethylaminopyridine, trimethylamine, triethylamine, tributylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexyl in a protonic polar solvent. Organic bases such as amines and prokines: In the presence of inorganic bases such as potassium carbonate and lithium carbonate, the invention compound (a-23) is synthesized by reacting carbodiimidazole at 0 ° C. to heating and reflux for 1 to 12 hours. can do.

(Second step)
Aromatic hydrocarbons such as benzene, toluene and xylene in the compound of the invention (a-23); ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme: halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride. Hydrogens: Alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane and ligroins; N, N- in aprotonic polar solvents such as acetonitrile, N, N-dimethylformamide and dimethylsulfoxide. Organic bases such as dimethylaminopyridine, trimethylamine, triethylamine, tributylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, prokine: potassium carbonate , In the presence or absence of an inorganic base such as lithium carbonate, a methylating agent such as methyl iodide, dimethyl sulfate, trifluoromethanesulfonate, meerween reagent, etc. is reacted at 0 ° C. to heated reflux for 12 to 48 hours. , The invention compound (a-24) can be synthesized.

(Third step)
Aromatic hydrocarbons such as benzene, toluene and xylene to the compound (a-24) of the invention; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and jigglime; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride Classes; aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin; N, N-dimethylaminopyridine, trimethylamine, triethylamine, N in aprotonic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, etc. , N-diisopropylethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, prokine and other organic bases: presence of inorganic bases such as potassium carbonate and lithium carbonate The compound (a-27) of the invention is synthesized by reacting the amine represented by (a-25) or the alcohol represented by (a-26) below at 0 ° C. to heated reflux for 1 to 12 hours. can do.

(4th step),
When R ⁶ is a C _1-6 alkoxy group, the invention compound (a-28) can be obtained from the invention compound (a-27) in the same manner as in the eleventh step of (method A-1).

(Method A-4) When m is 0 and Z is a bond in the general formula (I) The invention compounds (a-30) to (a-31) can be obtained by the methods described below.

（式中、Ｒ^１～Ｒ^６、Ｒ^１２～Ｒ^１４、ｎは前記と同様のものを示す。）

(In the formula, R ¹ to R ⁶ , R ¹² to R ¹⁴ , and n indicate the same as described above.)

(First step)
In the compound of invention (a-11) obtained in (Method A-1), aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme: methylene chloride, Halogenated hydrocarbons such as chloroform and carbon tetrachloride: alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane and ligroin; non-alkoxy, N, N-dimethylformamide, dimethylsulfoxide and the like. Protonic polar solvent; in a solvent such as acetic acid or a mixed solvent thereof, sodium borohydride, sodium borohydride borohydride, sodium triacetoxyborohydride, tri (sec-butyl) boron borohydride, tri borohydride. The invented compound (a-30) is obtained by reacting the aldehyde represented by (a-23) at 0 ° C. to heating and refluxing for 1 to 12 hours in the presence of a hydride reducing agent such as (sec-butyl) potassium borohydride. Can be synthesized.

(Second step)
When R ⁶ is a C _1-6 alkoxy group, the invention compound (a-31) can be obtained from the invention compound (a-30) in the same manner as in the eleventh step of (method A-1).

(Method A-5) In the general formula (I), when m and n are 0, Z is a bond, and R ¹⁴ may have a substituent, C _6-10 aryl group or heteroaryl group may have the following. The invention compounds (a-32) to (a-33) can be obtained by the method described.

（式中、Ａは置換基を有していてもよいＣ_６－１０アリール基又はヘテロアリール基、ｈａｌはハロゲン原子を示し、Ｒ^１～Ｒ^６は前記と同様のものを示す。）

(In the formula, A indicates a C _6-10 aryl group or a heteroaryl group which may have a substituent, hal indicates a halogen atom, and R ¹ to R ⁶ indicate the same as described above.)

(First step)
In the compound of invention (a-11) obtained in (Method A-1), aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme: methylene chloride, Halogenated hydrocarbons such as chloroform and carbon tetrachloride: alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane and ligroin; non-polymers such as acetonitrile, N, N-dimethylformamide and dimethylsulfoxide. In a protonic polar solvent or in a mixed solvent thereof,
In the presence of palladium catalysts such as tetrakistriphenylphosphine palladium (0), palladium (II) acetate, bis (dibenzilidenacetone) palladium (0), bis (triphenylphosphine) palladium (0) dichloride, palladium (II) chloride or In the absence of (±) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP), 1,1'-bis (diphenylphosphino) ferrocene (dppff), 2-dicyclohexylphos Fino-2', 4', 6'-triisopropylbiphenyl (Xphos), 2-dicyclohexylphosphino-2', 6'-dimethoxybiphenyl (Sphos), 4,5'-bis (diphenylphosphino) -9, N, N-dimethylaminopyridine, trimethylamine, triethylamine, tributylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethyl in the presence or absence of a phosphorus ligand such as 9'-dimethylxanthene (xantphos). Organic bases such as aniline, N-methylpiperidin, N-methylmorpholin, diethylamine, cyclohexylamine, prokine, sodium methoxydo, sodium ethoxydo, sodium tert-butoxide, potassium tert-butoxide; inorganic bases such as potassium carbonate and lithium carbonate. The compound of invention (a-32) can be synthesized by reacting A-hal with A-hal at room temperature to heating and refluxing for 1 to 24 hours in the presence or absence of such a base.

(Second step)
When R ⁶ is a C _1-6 alkoxy group, the invention compound (a-33) can be obtained from the invention compound (a-32) in the same manner as in the eleventh step of (method A-1).

(Method B) In the general formula (I), R ⁷ is a hydroxy group, R ⁸ and R ⁹ are combined to form a carbonyl group, R ¹⁰ and R ¹¹ are hydrogen atoms, X is a nitrogen atom, and a solid line and a broken line are formed. Production method when the heavy wire is a single bond The invention compounds (b-1) to (b-2) can be obtained by the method described below.

（式中、Ｒ^１～Ｒ^６は前記と同様のものを示す。）

(In the formula, R ¹ to R ⁶ indicate the same as above.)

(First step)
The conversion of the compound (a-5) to the invention compound (b-1) can be carried out by a hydrolysis reaction of a cyano group. The hydrolysis reaction can be carried out using an acid or a base by a generally known method. In the case of acid hydrolysis, for example, ethers such as tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and 2-propanol; aprotonic polar solvents such as acetonitrile, N, N-dimethylformamide and dimethylsulfoxide; acetic acid and the like. 1 to 6 equivalents or an amount of an inorganic acidic aqueous solution such as 1 to 12 mol / L hydrochloric acid or sulfuric acid is added to the above solvent, a mixed solvent thereof, or no solvent, and the reaction is carried out at room temperature to heating and reflux for 1 to 24 hours. It can be done by letting it. In the case of hydrolysis with a base, for example, ethers such as tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and 2-propanol; aprotonic polar solvents such as dimethylsulfoxide; in a solvent such as water or a mixed solvent thereof. It can be carried out by reacting 1 to 6 equivalents of an inorganic base such as sodium hydroxide or potassium hydroxide or an aqueous solution thereof for 1 to 24 hours at room temperature to heating and reflux.

(Second step)
When R ⁶ is a C _1-6 alkoxy group, the invention compound (b-2) can be obtained from the invention compound (b-1) in the same manner as in the eleventh step of (method A-1).

(Method C) In the general formula (I), R ⁷ is a hydroxy group, R ⁸ to R ¹¹ are hydrogen atoms, X is a nitrogen atom, and a double wire consisting of a solid line and a broken line is a single bond. The invention compounds (c-1) to (c-3) can be obtained by the above-mentioned method.

（式中、Ｒ^１～Ｒ^６、Ｒ^１２～Ｒ^１４、Ｙ、Ｚ、ｍ、ｎは前記と同様のものを示す。）

(In the formula, R ¹ to R ⁶ , R ¹² to R ¹⁴ , Y, Z, m, and n indicate the same as described above.)

(First step)
In the compound of invention (b-1) obtained in (Method B), aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme: methylene chloride, chloroform, etc. Hydrocarbons such as carbon tetrachloride: Among aliphatic hydrocarbons such as pentane, hexane, heptane, and ligroin, a reducing agent such as borane-dimethylsulfide complex, borane-tetratetracomplex tetrahydrofuran solution or lithium aluminum hydride. The invention compound (c-1) can be synthesized by reacting at room temperature to heating and reflux for 2 to 24 hours.

(Second step)
The invention compound (c-2) can be synthesized by carrying out the same reaction with the invention compound (c-1) as described in the above (method A-2) to (method A-5). can.

(Third step)
When R ⁶ is a C _1-6 alkoxy group, the invention compound (c-3) can be obtained from the invention compound (c-2) in the same manner as in (method A-1).

(Method D) In the general formula (I), the invention compound (d-2) can be obtained by the method described below when X is an N oxide and the double bond consisting of a solid line and a broken line is a single bond. can.

（式中、Ｒ^１～Ｒ^１４、Ｙ、Ｚ、ｍ、ｎは前記と同じ。）

(In the formula, R ¹ to R ¹⁴ , Y, Z, m, n are the same as above.)

(First step)
The invention compound (d-1) obtained by the methods described in (Method A-1) to (Method A-5), (Method B), and (Method C) can be used as methylene chloride, chloroform, carbon tetrachloride, or the like. 1 to 2 equivalents of an oxidizing agent such as an aqueous solution of hydrogen peroxide (H ₂ O ₂ ) or m-chloroperbenzoic acid (mCPBA) is reacted at 0 ° C. to room temperature for 30 minutes to 24 hours in the halogenated hydrocarbon solvent. Thereby, the invention compound (d-2) can be synthesized.

The compound obtained by each of the above steps can be purified, for example, by silica gel column chromatography, if necessary.
Further, if necessary, an acid addition salt can be formed by a conventional method. For example, the invention compound (I) can be contained in an organic solvent such as ethyl acetate: alcohols such as methanol and ethanol: or a polar solvent such as water. The compound (I) of the present invention is a mineral acid such as hydrochloric acid, sulfuric acid or phosphoric acid, an organic carboxylic acid such as formic acid, acetic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid or maleic acid, methanesulfonic acid or benzenesulfon. It is carried out by heating at room temperature or appropriately in the presence of an organic sulfonic acid such as an acid, p-toluene sulfonic acid, mesitylane sulfonic acid or naphthalene sulfonic acid.

The morphinan derivative represented by the above general formula (I), tautomer, stereoisomer of the compound, or a pharmaceutically acceptable salt thereof or a solvate thereof is orally administered to humans. The composition can be formulated with a pharmaceutically acceptable carrier for oral administration, etc. in solid or liquid form. It can also be used in combination with other analgesics.

Examples of the solid preparation for oral administration include capsules, tablets, pills, powders and granules. Excipients, disintegrants, binders, lubricants, dyes and the like can be used in the preparation of this solid preparation. Here, as an excipient, lactose, D-mannitol, crystalline cellulose, glucose and the like are used, starch, carboxymethyl cellulose calcium (CMC-Ca) and the like are used as a disintegrant, and magnesium stearate is used as a lubricant. Examples of the binder include hydroxypropyl cellulose (HPC), gelatin, polyvinylpyrrolidone (PVP) and the like. In the case of capsules, tablets and pills, a buffer may be further used. Tablets and pills may be enteric coated.

Forms of the compositions of the invention for injections include pharmaceutically acceptable sterile water 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 can also contain auxiliaries such as preservatives, wetting agents, emulsifiers, soothing agents, buffers, preservatives and dispersants.
These compositions are reduced, for example, by filtration through a bacterial retention filter or by mixing the sterilizer in the form of a sterile solid composition that can be dissolved in a sterilizer or some other sterilized injectable medium immediately prior to use. Can be fungus.

The preparation for eye drop administration is preferably added with a lysis aid, a preservative, an isotonic agent, a thickener and the like in addition to the compound of the present invention.

Liquid formulations for oral administration include inactive diluents commonly used by those of skill in the art, such as pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing water. In addition to such Inactive Diluents, the composition may also contain auxiliaries such as wetting agents, emulsifying and suspending agents, as well as sweetening, seasoning and flavoring agents.

The preparation for transrectal administration may preferably contain an excipient such as cocoa butter or a suppository wax in addition to the compound of the present invention.

The dose is usually the active ingredient, a morphinan derivative represented by the above general formula (I), a homovariant of the compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. The solvent mixture 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. It is administered, but it can be increased or decreased depending on age, symptoms, etc. Further, if desired, this daily dose may be administered in 2 to 4 divided doses.

Diseases and symptoms related to opioid κ receptors include, for example, cardiovascular disorders, digestive disorders, hematological disorders, respiratory disorders, liver disorders, nervous system disorders, urinary disorders, pain, coughing, pruritus, etc. Ischemic brain disease, drug dependence, etc. may be mentioned. Since the compound of the present invention has high opioid κ receptor selectivity and strong agonist activity against opioid κ receptors, it is effective for the treatment, amelioration, and prevention of these diseases and symptoms.

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

(Reference example 1)
(4R, 4aR, 7S, 7aR, 12bS) -3- (Cyclopropylmethyl) -7,9-dimethoxy-1,2,3,4,7,7a-Hexahydro-4a, 7-Etano-4,12- Synthesis of methanobenzoflo [3,2-e] isoquinoline-14-one (1)

（方法ａ）
（４Ｒ，７ａＲ，１２ｂＳ）－３－（シクロプロピルメチル）－７，９－ジメトキシ－２，３，４，７ａ－テトラヒドロ－１Ｈ－４，１２－メタノベンゾフロ［３，２－ｅ］イソキノリン（Ｊ．Ｃｈｅｍ．Ｓｏｃ．Ｃ，１９６６，６１７、Ｊ．Ｃｈｅｍ．Ｓｏｃ．Ｃ，１９６９，２５６９およびＪ．Ｃｈｅｍ．Ｓｏｃ．Ｐｅｒｋｉｎ Ｔｒａｎｓ．Ｉ，１９９４，９１１に記載の方法で合成）（２．０ｇ，５．６３ｍｍｏｌ）の１，２－ジクロロエタン（１０ｍＬ）溶液をマイクロウェーブ反応用のバイアルに入れ、２－クロロアクリロニトリル（４．５ｍＬ，５６．６ｍｍｏｌ）を加えて密封したものを３本用意した。マイクロフェーブ合成装置にて、それぞれマイクロウェーブを照射し、１８０°Ｃ、１０ｂａｒの条件下で３０分間反応させた。放冷後、３本のバイアルの内容物を合わせ、減圧下にて濃縮した。残渣をシリカゲルカラムクロマトグラフィー（２５－５０％酢酸エチル／ヘキサン）にて精製した。得られた濃縮残渣をエタノール（１４４ｍＬ）に溶解し、１Ｍ水酸化ナトリウム水溶液（３６ｍＬ）を加えて３時間加熱還流した。放冷後、水（２００ｍＬ）を加え、ジエチルエーテルで二回抽出した。有機層を飽和食塩水で２回洗浄し、硫酸マグネシウムで乾燥後、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（２５－５０％酢酸エチル／ヘキサン）で精製し、表題化合物（２．５ｇ，４４％）を無色アモルファスとして得た。

（方法ｂ）
（４Ｒ，７ａＲ，１２ｂＳ）－３－（シクロプロピルメチル）－７，９－ジメトキシ－２，３，４，７ａ－テトラヒドロ－１Ｈ－４，１２－メタノベンゾフロ［３，２－ｅ］イソキノリン（１９ｇ，５４ｍｍｏｌ）のキシレン（１８０ｍＬ）溶液に、炭酸水素ナトリウム（４２ｇ，５４０ｍｍｏｌ）及び２－クロロアクリロニトリル（３４．４ｍＬ，４３２ｍｍｏｌ）を加え、１４０°Ｃで６時間撹拌した。放冷後、反応液に水を加え酢酸エチルで二回抽出した。合わせた抽出物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。得られた粗生成物に対し、（方法ａ）と同様の加水分解反応を行うことで、表題化合物（１５．２ｇ，７１％）を淡黄色固体として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０８－０．２０（ｍ，２Ｈ），０．４５－０．６０（ｍ，２Ｈ），０．７７－０．９１（ｍ，１Ｈ），１．８７（ｄｄ，Ｊ＝３，１３Ｈｚ，１Ｈ），２．０７（ｄｄｄ，Ｊ＝５，１３，１３Ｈｚ，１Ｈ），２．１７（ｄ，Ｊ＝１９Ｈｚ，１Ｈ），２．３２－２．５５（ｍ，４Ｈ），２．７７（ｄｄ，Ｊ＝５，１２Ｈｚ，１Ｈ），３．１７（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．３２（ｄ，Ｊ＝１９Ｈｚ，１Ｈ），３．６３（ｓ，３Ｈ），３．６５（ｄ，Ｊ＝７Ｈｚ，１Ｈ），３．８３（ｓ，３Ｈ），４．６８（ｄ，Ｊ＝１Ｈｚ，１Ｈ），５．７０（ｄ，Ｊ＝９Ｈｚ，１Ｈ），５．８８－５．９３（ｍ，１Ｈ），６．５７（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６６（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．

(Method a)
(4R, 7aR, 12bS) -3- (Cyclopropylmethyl) -7,9-dimethoxy-2,3,4,7a-tetrahydro-1H-4,12-methanobenzoflo [3,2-e] isoquinoline (J. Synthesized by the method described in Chem. Soc. C, 1966, 617, J. Chem. Soc. C, 1969, 2569 and J. Chem. Soc. Perkin Trans. I, 1994, 911) (2.0 g, 5. A solution of 1,2-dichloroethane (10 mL) (63 mmol) was placed in a vial for a microwave reaction, 2-chloroacrylonitrile (4.5 mL, 56.6 mmol) was added, and three sealed bottles were prepared. Each of them was irradiated with microwaves in a microfave synthesizer and reacted at 180 ° C. and 10 bar for 30 minutes. After allowing to cool, the contents of the three vials were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25-50% ethyl acetate / hexane). The obtained concentrated residue was dissolved in ethanol (144 mL), a 1 M aqueous sodium hydroxide solution (36 mL) was added, and the mixture was heated under reflux for 3 hours. After allowing to cool, water (200 mL) was added, and the mixture was extracted twice with diethyl ether. The organic layer was washed twice with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (25-50% ethyl acetate / hexane) to give the title compound (2.5 g, 44%) as a colorless amorphous substance.

(Method b)
(4R, 7aR, 12bS) -3- (Cyclopropylmethyl) -7,9-dimethoxy-2,3,4,7a-tetrahydro-1H-4,12-methanobenzoflo [3,2-e] isoquinoline (19g, Sodium hydrogen carbonate (42 g, 540 mmol) and 2-chloroacrylonitrile (34.4 mL, 432 mmol) were added to a solution of (54 mmol) xylene (180 mL), and the mixture was stirred at 140 ° C. for 6 hours. After allowing to cool, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The combined extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was subjected to the same hydrolysis reaction as in (Method a) to give the title compound (15.2 g, 71%) as a pale yellow solid.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.77-0.91 (m) , 1H), 1.87 (dd, J = 3,13Hz, 1H), 2.07 (ddd, J = 5,13,13Hz, 1H), 2.17 (d, J = 19Hz, 1H), 2 .32-2.55 (m, 4H), 2.77 (dd, J = 5,12Hz, 1H), 3.17 (d, J = 18Hz, 1H), 3.32 (d, J = 19Hz, 1H), 3.63 (s, 3H), 3.65 (d, J = 7Hz, 1H), 3.83 (s, 3H), 4.68 (d, J = 1Hz, 1H), 5.70 (D, J = 9Hz, 1H), 5.88-5.93 (m, 1H), 6.57 (d, J = 8Hz, 1H), 6.66 (d, J = 8Hz, 1H).

(Reference example 2)
(4R, 4aR, 7R, 7aR, 12bS) -3- (Cyclopropylmethyl) -7,9-dimethoxy-1,2,3,4,7,7a-Hexahydro-4a, 7-Etano-4,12- Synthesis of methanobenzoflo [3,2-e] isoquinoline-14-one oxime (2)

化合物１（６．９３ｇ，１７．６ｍｍｏｌ）、ヒドロキシルアミン塩酸塩（２．９４ｇ，４２．３ｍｍｏｌ）及び２０％ナトリウムエトキシド－エタノール溶液（２０．４ｍＬ，５２．８ｍｍｏｌ）のエタノール（１１６ｍＬ）／水（５８ｍＬ）混合溶液を、５．５間加熱還流した。反応混合物を放冷後減圧下にて濃縮し、残渣に２Ｍ炭酸カリウム水溶液を加え酢酸エチルで三回抽出した。合わせた抽出物を硫酸ナトリウムで乾燥後、減圧下にて濃縮した。得られた濃縮残渣に対し精製操作は行わず、表題化合物の粗生成物（７．２２ｇ，定量的）を淡黄色固体として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．１１－０．１９（ｍ，２Ｈ），０．４７－０．５８（ｍ，２Ｈ），０．８３－０．９３（ｍ，１Ｈ），１．８０（ｄｄ，Ｊ＝２，１３Ｈｚ，１Ｈ），２．０２（ｄｄｄ，Ｊ＝６，１３，１３Ｈｚ，１Ｈ），２．１０（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），２．３４－２．４９（ｍ，４Ｈ），２．７５（ｄｄ，Ｊ＝５，１２Ｈｚ，１Ｈ），３．１４（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．６４（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．６６（ｓ，３Ｈ），３．７１（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．８３（ｓ，３Ｈ），４．６４（ｄ，Ｊ＝１Ｈｚ，１Ｈ），５．６２（ｄ，Ｊ＝９Ｈｚ，１Ｈ），６．００（ｄｄ，Ｊ＝１，９Ｈｚ，１Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．５７（ｂｒ ｓ，１Ｈ）．

Ethanol (116 mL) / water of compound 1 (6.93 g, 17.6 mmol), hydroxylamine hydrochloride (2.94 g, 42.3 mmol) and 20% sodium ethoxide-ethanol solution (20.4 mL, 52.8 mmol). The (58 mL) mixed solution was heated to reflux for 5.5 minutes. The reaction mixture was allowed to cool, then concentrated under reduced pressure, a 2M aqueous potassium carbonate solution was added to the residue, and the mixture was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. No purification operation was performed on the obtained concentrated residue, and a crude product (7.22 g, quantitative) of the title compound was obtained as a pale yellow solid.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.11-0.19 (m, 2H), 0.47-0.58 (m, 2H), 0.83-0.93 (m) , 1H), 1.80 (dd, J = 2,13Hz, 1H), 2.02 (ddd, J = 6,13,13Hz, 1H), 2.10 (d, J = 18Hz, 1H), 2 .34-2.49 (m, 4H), 2.75 (dd, J = 5,12Hz, 1H), 3.14 (d, J = 18Hz, 1H), 3.64 (d, J = 6Hz, 1H), 3.66 (s, 3H), 3.71 (d, J = 18Hz, 1H), 3.83 (s, 3H), 4.64 (d, J = 1Hz, 1H), 5.62 (D, J = 9Hz, 1H), 6.00 (dd, J = 1,9Hz, 1H), 6.54 (d, J = 8Hz, 1H), 6.63 (d, J = 8Hz, 1H) , 7.57 (br s, 1H).

(Reference example 3)
2-((4R, 4aR, 7aR, 12bS) -3- (cyclopropylmethyl) -9-methoxy-7-oxo-1,2,3,4,7,7a-hexahydro-4aH-4,12-methanobenzoflo) [3,2-e] Isoquinoline-4a-yl) Synthesis of acetonitrile (3)

氷冷下、化合物２（７００ｍｇ，１．７１ｍｍｏｌ）のジクロロメタン（６ｍＬ）溶液に、トリエチルアミン（４７７．７μＬ，３．４３ｍｍｏｌ）及び塩化メタンスルホニル（２６５．３μＬ，３．４３ｍｍｏｌ）を加え、室温で２０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、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後、減圧下にて濃縮した。得られた濃縮残渣をテトラヒドロフラン（１０ｍＬ）に溶解し、２Ｍ塩酸（８ｍＬ）を加え、室温で１６時間撹拌した。反応混合物を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。合わせた抽出物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（３０－６０％酢酸エチル／へプタン）で精製し、表題化合物（６２０．１ｍｇ，９６％）を無色固体として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．１１－０．１９（ｍ，２Ｈ），０．５２－０．６１（ｍ，２Ｈ），０．８０－０．９０（ｍ，１Ｈ），１．７１－１．７７（ｍ，１Ｈ），２．１４－２．２９（ｍ，２Ｈ），２．３４－２．４７（ｍ，３Ｈ），２．７８－２．８３（ｍ，１Ｈ），３．１１（ｄ，Ｊ＝１７Ｈｚ，１Ｈ），３．１４（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），３．３８（ｄ，Ｊ＝５Ｈｚ，１Ｈ），３．５５（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），３．８４（ｓ，３Ｈ），４．９３（ｓ，１Ｈ），６．２４（ｄ，Ｊ＝１１Ｈｚ，１Ｈ），６．６１（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６７（ｄ，Ｊ＝１１Ｈｚ，１Ｈ），６．６９（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．

Under ice-cooling, triethylamine (477.7 μL, 3.43 mmol) and methanesulfonyl chloride (265.3 μL, 3.43 mmol) were added to a solution of compound 2 (700 mg, 1.71 mmol) in dichloromethane (6 mL), and 20 at room temperature. Stir for minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained concentrated residue was dissolved in tetrahydrofuran (10 mL), 2M hydrochloric acid (8 mL) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution to make it basic, and the mixture was extracted three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (30-60% ethyl acetate / heptane) to give the title compound (620.1 mg, 96%) as a colorless solid.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.11-0.19 (m, 2H), 0.52-0.61 (m, 2H), 0.80-0.90 (m) , 1H), 1.71-1.77 (m, 1H), 2.14-2.29 (m, 2H), 2.34-2.47 (m, 3H), 2.78-2.83 (M, 1H), 3.11 (d, J = 17Hz, 1H), 3.14 (d, J = 16Hz, 1H), 3.38 (d, J = 5Hz, 1H), 3.55 (d) , J = 16Hz, 1H), 3.84 (s, 3H), 4.93 (s, 1H), 6.24 (d, J = 11Hz, 1H), 6.61 (d, J = 8Hz, 1H) ), 6.67 (d, J = 11Hz, 1H), 6.69 (d, J = 8Hz, 1H).

(Reference example 4)
2-((4R, 4aS, 7aR, 12bS) -3- (cyclopropylmethyl) -9-methoxy-7-oxo-1,2,3,4,5,6,7,7a-octahydro-4aH-4 , 12-Methylnobenzoflo [3,2-e] isoquinoline-4a-yl) Synthesis of acetonitrile (4)

化合物３（５．６４ｇ，１５ｍｍｏｌ）のエタノール（１５０ｍＬ）／テトラヒドロフラン（１５０ｍＬ）混合溶液に、１０％パラジウム－活性炭素（５５％ｗｅｔ）（１．５ｇ）を加え、水素雰囲気下、室温で４時間撹拌した。反応混合物をセライトろ過し、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（３０－６０％酢酸エチル／へプタン）で精製し、表題化合物（５．６７ｇ，１００％）を無色アモルファスとして得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．１０－０．２１（ｍ，２Ｈ），０．５０－０．５９（ｍ，２Ｈ），０．８２－０．９２（ｍ，１Ｈ），１．５２－１．６０（ｍ，１Ｈ），１．６９（ｄｄｄ，Ｊ＝４，１４，１４Ｈｚ，１Ｈ），１．９６－２．１８（ｍ，３Ｈ），２．３１－２．５３（ｍ，４Ｈ），２．５５－２．６４（ｍ，１Ｈ），２．７０－２．７８（ｍ，１Ｈ），２．９７（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），３．０２（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．３５（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．８９（ｓ，３Ｈ），４．０９（ｄｄ，Ｊ＝１，１６Ｈｚ，１Ｈ），４．６１（ｓ，１Ｈ），６．６７（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７０（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．

Add 10% palladium-active carbon (55% wet) (1.5 g) to a mixed solution of compound 3 (5.64 g, 15 mmol) in ethanol (150 mL) / tetrahydrofuran (150 mL), and add 10% palladium-active carbon (55% wet) (1.5 g) to the mixture under a hydrogen atmosphere at room temperature for 4 hours. Stirred. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (30-60% ethyl acetate / heptane) to give the title compound (5.67 g, 100%) as a colorless amorphous substance.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10-0.21 (m, 2H), 0.50-0.59 (m, 2H), 0.82-0.92 (m) , 1H), 1.52-1.60 (m, 1H), 1.69 (ddd, J = 4,14,14Hz, 1H), 1.96-2.18 (m, 3H), 2.31 -2.53 (m, 4H), 2.55-2.64 (m, 1H), 2.70-2.78 (m, 1H), 2.97 (d, J = 16Hz, 1H), 3 .02 (d, J = 18Hz, 1H), 3.35 (d, J = 6Hz, 1H), 3.89 (s, 3H), 4.09 (dd, J = 1,16Hz, 1H), 4 .61 (s, 1H), 6.67 (d, J = 8Hz, 1H), 6.70 (d, J = 8Hz, 1H).

(Reference example 5)
2-((4R, 4aS, 7S, 7aR, 12bS) -3- (cyclopropylmethyl) -7-hydroxy-9-methoxy-1,2,3,4,5,6,7,7a-octahydro-4aH -4,12-Methylanobenzoflo [3,2-e] isoquinoline-4a-yl) Synthesis of acetonitrile (5)

化合物４（１ｇ，２．６４ｍｍｏｌ）のテトラヒドロフラン（２６ｍＬ）溶液に、１Ｍ Ｌ－ｓｅｌｅｃｔｒｉｄｅ－テトラヒドロフラン溶液（５．３ｍＬ，５．２８ｍｍｏｌ）を加え、室温で２時間撹拌した。反応混合に水を加え、酢酸エチルで三回抽出した。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（０－７０％酢酸エチル／へプタン）で精製し、表題化合物（８２８．７ｍｇ，８２％）を無色固体として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１７（ｍ，２Ｈ），０．４９－０．６０（ｍ，２Ｈ），０．８５－０．９２（ｍ，１Ｈ），１．０９－１．１８（ｍ，１Ｈ），１．３８－１．４７（ｍ，１Ｈ），１．４９－１．５４（ｍ，１Ｈ），１．６７－１．８０（ｍ，２Ｈ），１．９９（ｄｄｄ，Ｊ＝５，１２，１２Ｈｚ，１Ｈ），２．２０（ｄｄｄ，Ｊ＝４，１２，１２Ｈｚ，１Ｈ），２．２７－２．４０（ｍ，４Ｈ），２．５６（ｄｄ，Ｊ＝６，１９Ｈｚ，１Ｈ），２．６７（ｄｄ，Ｊ＝５，１２Ｈｚ，１Ｈ），２．９８（ｄ，Ｊ＝１９Ｈｚ，１Ｈ），３．３８（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．８７（ｓ，３Ｈ），３．９９－４．０６（ｍ，２Ｈ），４．６０（ｄ，Ｊ＝５Ｈｚ，１Ｈ），６．６５（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７４（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．

A 1ML-selectride-tetrahydrofuran solution (5.3 mL, 5.28 mmol) was added to a solution of compound 4 (1 g, 2.64 mmol) in tetrahydrofuran (26 mL), and the mixture was stirred at room temperature for 2 hours. Water 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 obtained crude product was purified by silica gel column chromatography (0-70% ethyl acetate / heptane) to give the title compound (828.7 mg, 82%) as a colorless solid.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.17 (m, 2H), 0.49-0.60 (m, 2H), 0.85-0.92 (m) , 1H), 1.09-1.18 (m, 1H), 1.38-1.47 (m, 1H), 1.49-1.54 (m, 1H), 1.67-1.80 (M, 2H), 1.99 (ddd, J = 5,12,12Hz, 1H), 2.20 (ddd, J = 4,12,12Hz, 1H), 2.27-2.40 (m, 4H), 2.56 (dd, J = 6,19Hz, 1H), 2.67 (dd, J = 5,12Hz, 1H), 2.98 (d, J = 19Hz, 1H), 3.38 ( d, J = 6Hz, 1H), 3.87 (s, 3H), 3.99-4.06 (m, 2H), 4.60 (d, J = 5Hz, 1H), 6.65 (d, J = 8Hz, 1H), 6.74 (d, J = 8Hz, 1H).

(Reference example 6)
Benzyl (2-((4R, 4aS, 7S, 7aR, 12bS) -3- (cyclopropylmethyl) -7-hydroxy-9-methoxy-1,2,3,4,5,6,7,7a-octahydro Synthesis of -4aH-4,12-methanobenzoflo [3,2-e] isoquinoline-4a-yl) ethyl) carbamate (6)

化合物５（１．０８ｇ，２．８４ｍｍｏｌ）のテトラヒドロフラン（２８ｍＬ）溶液に、０．９４Ｍボラン－テトラヒドロフラン溶液（１５．１ｍＬ，１４．２ｍｍｏｌ）を加え、１時間加熱還流した。反応混合を放冷後、減圧下にて濃縮した。濃縮残渣に６Ｍ塩酸（１０ｍＬ）を加え、１５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、酢酸エチルで三回抽出した。合わせた抽出物を硫酸ナトリウムで乾燥後、減圧下にて濃縮した。得られた粗生成物のテトラヒドロフラン（１５ｍＬ）溶液に飽和炭酸水素ナトリウム水溶液（１５ｍＬ）及びクロロギ酸ベンジル（２．１ｍＬ，１４．８ｍｍｏｌ）を加え、室温で４．５時間撹拌した。反応混合物を酢酸エチルで三回抽出した。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（２０－６０％酢酸エチル／へプタン）で精製し、表題化合物（１．１６ｇ，７９％）を無色アモルファスとして得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０２－０．１０（ｍ，２Ｈ），０．３５－０．５１（ｍ，２Ｈ），０．７９－０．９０（ｍ，１Ｈ），０．９１－１．０４（ｍ，１Ｈ），１．１２－１．２２（ｍ，１Ｈ），１．３７－１．４９（ｍ，２Ｈ），１．５１－１．６９（ｍ，２Ｈ），２．０２－２．１５（ｍ，２Ｈ），２．２６（ｄｄｄ，Ｊ＝６，１３，１３Ｈｚ，１Ｈ），２．３９－２．４８（ｍ，３Ｈ），２．７５－２．８５（ｍ，２Ｈ），２．９２（ｄ，Ｊ＝１９Ｈｚ，１Ｈ），３．０６（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．２２－３．４２（ｍ，２Ｈ），３．８６（ｓ，３Ｈ），４．０４－４．１５（ｍ，１Ｈ），４．６１（ｄ，Ｊ＝５Ｈｚ，１Ｈ），５．０８（ｄ，Ｊ＝１２Ｈｚ，１Ｈ），５．１２（ｄ，Ｊ＝１２Ｈｚ，１Ｈ），５．３８（ｂｒ ｓ，１Ｈ），６．６０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．２７－７．４０（ｍ，５Ｈ）．

A 0.94M borane-tetrahydrofuran solution (15.1 mL, 14.2 mmol) was added to a solution of compound 5 (1.08 g, 2.84 mmol) in tetrahydrofuran (28 mL), and the mixture was heated under reflux for 1 hour. The reaction mixture was allowed to cool and then concentrated under reduced pressure. 6M Hydrochloric acid (10 mL) was added to the concentrated residue, and the mixture was heated under reflux for 15 minutes. The reaction mixture was allowed to cool, poured into saturated aqueous sodium hydrogen carbonate solution to make it basic, and extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution (15 mL) and benzyl chloroformate (2.1 mL, 14.8 mmol) were added to a solution of the obtained crude product in tetrahydrofuran (15 mL), and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (20-60% ethyl acetate / heptane) to give the title compound (1.16 g, 79%) as a colorless amorphous substance.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02-0.10 (m, 2H), 0.35-0.51 (m, 2H), 0.79-0.90 (m) , 1H), 0.91-1.04 (m, 1H), 1.12-1.22 (m, 1H), 1.37-1.49 (m, 2H), 1.51-1.69 (M, 2H), 2.02-2.15 (m, 2H), 2.26 (ddd, J = 6,13,13Hz, 1H), 2.39-2.48 (m, 3H), 2 .75-2.85 (m, 2H), 2.92 (d, J = 19Hz, 1H), 3.06 (d, J = 6Hz, 1H), 3.22-3.42 (m, 2H) , 3.86 (s, 3H), 4.04-4.15 (m, 1H), 4.61 (d, J = 5Hz, 1H), 5.08 (d, J = 12Hz, 1H), 5 .12 (d, J = 12Hz, 1H), 5.38 (br s, 1H), 6.60 (d, J = 8Hz, 1H), 6.71 (d, J = 8Hz, 1H), 7. 27-7.40 (m, 5H).

(Reference example 7)
(4R, 4aS, 7S, 7aR, 12bS) -4a- (2-(((Bendiroxy) carbonyl) amino) ethyl) -3- (cyclopropylmethyl) -9-methoxy-2,3,4,4a, 5 , 6,7,7a-Octahydro-1H-4,12-methanobenzoflo [3,2-e] Isoquinoline-7-yl methanesulfonate (7) synthesis

化合物６（１．１１ｇ，２．１４ｍｍｏｌ）のジクロロメタン（２１ｍＬ）溶液に、トリエチルアミン（５９８．７μＬ，４．２９ｍｍｏｌ）及び塩化メタンスルホニル（３３１．３μL，４．２９ｍｍｏｌ）を加え、室温で４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（３０－６０％酢酸エチル／へプタン）で精製し、表題化合物（１．２８ｇ，１００％）を無色アモルファスとして得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．１０（ｍ，２Ｈ），０．４１－０．５１（ｍ，２Ｈ），０．７９－０．８５（ｍ，１Ｈ），１．２５－１．６０（ｍ，５Ｈ），１．８０－１．９０（ｍ，１Ｈ），２．０５－２．２４（ｍ，３Ｈ），２．３６－２．４６（ｍ，２Ｈ），２．７０－２．８０（ｍ，１Ｈ），２．９０－３．００（ｍ，２Ｈ），３．０９（ｓ，３Ｈ），３．１０－３．１３（ｍ，１Ｈ），３．１９－３．４０（ｍ，２Ｈ），３．８６（ｓ，３Ｈ），４．６９（ｄ，Ｊ＝６Ｈｚ，１Ｈ），５．００－５．２３（ｍ，４Ｈ），６．６０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．２９－７．４１（ｍ，５Ｈ）．

Triethylamine (598.7 μL, 4.29 mmol) and methanesulfonyl chloride (331.3 μL, 4.29 mmol) were added to a solution of compound 6 (1.11 g, 2.14 mmol) in dichloromethane (21 mL), and the mixture was stirred at room temperature for 4 hours. did. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (30-60% ethyl acetate / heptane) to give the title compound (1.28 g, 100%) as a colorless amorphous substance.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.10 (m, 2H), 0.41-0.51 (m, 2H), 0.79-0.85 (m) , 1H), 1.25-1.60 (m, 5H), 1.80-1.90 (m, 1H), 2.05-2.24 (m, 3H), 2.36-2.46 (M, 2H), 2.70-2.80 (m, 1H), 2.90-3.00 (m, 2H), 3.09 (s, 3H), 3.10-3.13 (m) , 1H), 3.19-3.40 (m, 2H), 3.86 (s, 3H), 4.69 (d, J = 6Hz, 1H), 5.00-5.23 (m, 4H) ), 6.60 (d, J = 8Hz, 1H), 6.72 (d, J = 8Hz, 1H), 7.29-7.41 (m, 5H).

(Example 1)
Benzyl (4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carboxylate (8)

化合物７（１７３ｍｇ，０．２９ｍｍｏｌ）のテトラヒドロフラン（５ｍＬ）溶液に、カリウムｔeｒｔ－ブトキシド（３９ｍｇ，０．３５ｍｍｏｌ）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加え、酢酸エチルで三回抽出した。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（４０－８０％酢酸エチル／へプタン）で精製し、表題化合物（１０２．３ｍｇ，７１％）を無色アモルファスとして得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１５（ｍ，２Ｈ），０．４３－０．５２（ｍ，２Ｈ），０．７３－０．８３（ｍ，１Ｈ），１．００－１．１３（ｍ，１Ｈ），１．２１－１．５２（ｍ，４Ｈ），１．６１－１．７８（ｍ，１Ｈ），２．１４－２．４３（ｍ，５Ｈ），２．６２（ｄｄ，Ｊ=５，１１Ｈｚ，１Ｈ），２．７６－２．９０（ｍ，１Ｈ），２．９７（ｄ，Ｊ=１８Ｈｚ，１Ｈ），３．０１（ｄ，Ｊ=６Ｈｚ，１Ｈ），３．３４－３．４５（ｍ，１Ｈ），３．８６（ｓ，１．８Ｈ），３．８７（ｓ，１．２Ｈ），４．００－４．１５（ｍ，１Ｈ），４．２３－４．３５（ｍ，１Ｈ），４．４６－４．５６（ｍ，１Ｈ），５．１０－５．２３（ｍ，２Ｈ），６．５５－６．６１（ｍ，１Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．２９－７．４０（ｍ，５Ｈ）．

Potassium tert-butoxide (39 mg, 0.35 mmol) was added to a solution of compound 7 (173 mg, 0.29 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate 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 obtained crude product was purified by silica gel column chromatography (40-80% ethyl acetate / heptane) to give the title compound (102.3 mg, 71%) as a colorless amorphous substance.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.15 (m, 2H), 0.43-0.52 (m, 2H), 0.73-0.83 (m) , 1H), 1.00-1.13 (m, 1H), 1.21-1.52 (m, 4H), 1.61-1.78 (m, 1H), 2.14-2.43 (M, 5H), 2.62 (dd, J = 5,11Hz, 1H), 2.76-2.90 (m, 1H), 2.97 (d, J = 18Hz, 1H), 3.01 (D, J = 6Hz, 1H), 3.34-3.45 (m, 1H), 3.86 (s, 1.8H), 3.87 (s, 1.2H), 4.00-4 .15 (m, 1H), 4.23-4.35 (m, 1H), 4.46-4.56 (m, 1H), 5.10-15.23 (m, 2H), 6.55 -6.61 (m, 1H), 6.71 (d, J = 8Hz, 1H), 7.29-7.40 (m, 5H).

(Example 2)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-methoxy-1,2,3,4,6,7,8,8a-octahydro-5H-4a, 8-ethano- Synthesis of 4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine (9)

化合物８（６１４．９ｍｇ，１．２３ｍｍｏｌ）のメタノール（１２ｍＬ）溶液に、２０％水酸化パラジウム－活性炭素（５０％ｗｅｔ）（１２０ｍｇ）を加え、水素雰囲気下、室温で４０分撹拌した。反応混合物に２０％水酸化パラジウム－活性炭素（５０％ｗｅｔ）（３００ｍｇ）を追加し、更に２時間撹拌した。反応混合物をセライトろ過し、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（０－１０％ １０％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（４２２．２ｍｇ，９４％）を黒色油状物質として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１４（ｍ，２Ｈ），０．４２－０．５５（ｍ，２Ｈ），０．７６－０．８３（ｍ，１Ｈ），０．９９－１．０９（ｍ，１Ｈ），１．２５－１．４２（ｍ，３Ｈ），１．５０－１．５８（ｍ，１Ｈ），１．６１－１．６５（ｍ，１Ｈ），２．２１（ｄｄ，Ｊ=７，１２Ｈｚ，１Ｈ），２．２６－２．４１（ｍ，４Ｈ），２．５８－２．６５（ｍ，１Ｈ），２．７６－２．８６（ｍ，１Ｈ），２．９５（ｄ，Ｊ=１８Ｈｚ，１Ｈ），２．９６－３．０３（ｍ，２Ｈ），３．１２－３．２２（ｍ，２Ｈ），３．８６（ｓ，３Ｈ），４．５０－４．５２（ｍ，１Ｈ），６．５７（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．

20% Palladium hydroxide-activated carbon (50% wet) (120 mg) was added to a solution of compound 8 (614.9 mg, 1.23 mmol) in methanol (12 mL), and the mixture was stirred at room temperature for 40 minutes under a hydrogen atmosphere. 20% Palladium hydroxide-activated carbon (50% wet) (300 mg) was added to the reaction mixture, and the mixture was further stirred for 2 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-10% 10% ammonia-methanol / chloroform) to give the title compound (422.2 mg, 94%) as a black oily substance.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.14 (m, 2H), 0.42-0.55 (m, 2H), 0.76-0.83 (m) , 1H), 0.99-1.09 (m, 1H), 1.25-1.42 (m, 3H), 1.50-1.58 (m, 1H), 1.61-1.65 (M, 1H), 2.21 (dd, J = 7, 12Hz, 1H), 2.26-2.41 (m, 4H), 2.58-2.65 (m, 1H), 2.76 -2.86 (m, 1H), 2.95 (d, J = 18Hz, 1H), 2.96-3.03 (m, 2H), 3.12-3.22 (m, 2H), 3 .86 (s, 3H), 4.50-4.52 (m, 1H), 6.57 (d, J = 8Hz, 1H), 6.71 (d, J = 8Hz, 1H).

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

化合物９（１５５ｍｇ，０．４２ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（４ｍＬ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（３６８．３μＬ，２．１１ｍｍｏｌ）及びカルボニルジイミダゾール（３４２．９ｍｇ，２．１１ｍｍｏｌ）を加え、室温で二時間撹拌した。反応混合物に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液で三回洗浄した。有機層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（０－４％メタノール／クロロホルム）で精製し、表題化合物（１９８．３ｍｇ，１００％）を無色アモルファスとして得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１５（ｍ，２Ｈ），０．４４－０．５４（ｍ，２Ｈ），０．７２－０．８２（ｍ，１Ｈ），１．１１－１．２１（ｍ，１Ｈ），１．２５－１．３７（ｍ，１Ｈ），１．４３－１．５５（ｍ，２Ｈ），１．６２－１．６５（ｍ，１Ｈ），１．７２－１．８４（ｍ，１Ｈ），２．１７－２．４５（ｍ，５Ｈ），２．６６（ｄｄ，Ｊ＝５，１２Ｈｚ，１Ｈ），２．８９－２．９８（ｍ，１Ｈ），３．０１（ｄ，Ｊ=１８Ｈｚ，１Ｈ），３．０６（ｄ，Ｊ=６Ｈｚ，１Ｈ），３．５８－３．６７（ｍ，１Ｈ），３．８０－３．８７（ｍ，１Ｈ），３．８８（ｓ，３Ｈ），４．４６（ｂｒ ｓ，１Ｈ），４．６８（ｓ，１Ｈ），６．６２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７５（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．１０－７．１３（ｍ，１Ｈ），７．２４－７．２６（ｍ，１Ｈ），７．９１（ｓ，１Ｈ）．

N, N-diisopropylethylamine (368.3 μL, 2.11 mmol) and carbonyldiimidazole (342.9 mg, 2.11 mmol) in a solution of compound 9 (155 mg, 0.42 mmol) in N, N-dimethylformamide (4 mL). Was added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed three times with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-4% methanol / chloroform) to give the title compound (198.3 mg, 100%) as a colorless amorphous substance.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.15 (m, 2H), 0.44-0.54 (m, 2H), 0.72-0.82 (m) , 1H), 1.11-1.21 (m, 1H), 1.25-1.37 (m, 1H), 1.43-1.55 (m, 2H), 1.62-1.65 (M, 1H), 1.72-1.84 (m, 1H), 2.17-2.45 (m, 5H), 2.66 (dd, J = 5,12Hz, 1H), 2.89 -2.98 (m, 1H), 3.01 (d, J = 18Hz, 1H), 3.06 (d, J = 6Hz, 1H), 3.58-3.67 (m, 1H), 3 .80-3.87 (m, 1H), 3.88 (s, 3H), 4.46 (br s, 1H), 4.68 (s, 1H), 6.62 (d, J = 8Hz, 1H), 6.75 (d, J = 8Hz, 1H), 7.10-7.13 (m, 1H), 7.24-7.26 (m, 1H), 7.91 (s, 1H) ..

(Example 4)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,6,7,8,8a-octahydro-5H-4a, 8 -Synthesis of ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carbonyl) -3-methyl-1H-imidazole-3-ium iodide (11)

化合物１０（１９４．８ｍｇ，０．４２ｍｍｏｌ）のアセトニトリル（５ｍＬ）溶液に、ヨウ化メチル（７９０．３μＬ，１２．７ｍｍｏｌ）を加え、室温で１７時間撹拌した。反応混合物を減圧下にて濃縮した。得られた濃縮残渣に対し精製操作は行わず、表題化合物の粗生成物（２５５．４ｍｇ，定量的）を無色アモルファスとして得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．１４（ｍ，２Ｈ），０．４２－０．５４（ｍ，２Ｈ），０．７０－０．８２（ｍ，１Ｈ），１．０７－１．１８（ｍ，１Ｈ），１．３７－１．７１（ｍ，４Ｈ），１．９６－２．１２（ｍ，１Ｈ），２．２０－２．３７（ｍ，４Ｈ），２．４３（ｄｄ，Ｊ＝６，１８Ｈｚ，１Ｈ），２．６５（ｄ，Ｊ＝８Ｈｚ，１Ｈ），２．８６－２．９９（ｍ，１Ｈ），２．９９（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．１０（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．８８（ｓ，３Ｈ），３．９０－４．００（ｍ，１Ｈ），４．０７－４．２４（ｍ，１Ｈ），４．２７（ｓ，３Ｈ），４．３６（ｂｒ ｓ，１Ｈ），４．６９（ｂｒ ｓ，１Ｈ），６．６３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７５（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．３３－７．３７（ｍ，１Ｈ），７．６６－７．７０（ｍ，１Ｈ），１０．６４（ｂｒ ｓ，１Ｈ）．

Methyl iodide (790.3 μL, 12.7 mmol) was added to a solution of compound 10 (194.8 mg, 0.42 mmol) in acetonitrile (5 mL), and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure. No purification operation was performed on the obtained concentrated residue, and a crude product (255.4 mg, quantitative) of the title compound was obtained as a colorless amorphous substance.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.14 (m, 2H), 0.42-0.54 (m, 2H), 0.70-0.82 (m) , 1H), 1.07-1.18 (m, 1H), 1.37-1.71 (m, 4H), 1.96-2.12 (m, 1H), 2.20-2.37 (M, 4H), 2.43 (dd, J = 6,18Hz, 1H), 2.65 (d, J = 8Hz, 1H), 2.86-2.99 (m, 1H), 2.99 (D, J = 18Hz, 1H), 3.10 (d, J = 6Hz, 1H), 3.88 (s, 3H), 3.90-4.00 (m, 1H), 4.07-4 .24 (m, 1H), 4.27 (s, 3H), 4.36 (br s, 1H), 4.69 (br s, 1H), 6.63 (d, J = 8Hz, 1H), 6.75 (d, J = 8Hz, 1H), 7.33-7.37 (m, 1H), 7.66-7.70 (m, 1H), 10.64 (br s, 1H).

(Reference example 8)
Synthesis of tert-butyl (2-((methylamino) methyl) pyridin-3-yl) carbamate (12)

ｔｅｒｔ－ブチル （２－ホルミルピリジン－３－イル）カーバメート（１３４ｍｇ，０．６０ｍｍｏｌ）のメタノール（１．５ｍＬ）溶液に、氷冷下２Ｍメチルアミン－メタノール溶液（０．３６ｍＬ，０．７２ｍｍｏｌ）を加え、室温で２．５時間撹拌した。反応混合物に、氷冷下水素化ホウ素ナトリウム（３４．７ｍｇ，０．９２ｍｍｏｌ）を加え、室温で３．５時間撹拌した。反応混合物に水を加え、クロロホルムで三回抽出した。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。得られた濃縮残渣に対し精製操作は行わず、表題化合物の粗生成物（１４５ｍｇ，定量的）を淡黄色油状物として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．５４（ｓ，９Ｈ），２．４５（ｓ，３Ｈ），４．０４（ｓ，２Ｈ），７．１８（ｄｄ，Ｊ＝５，８Ｈｚ，１Ｈ），８．１３（ｄ，Ｊ＝５Ｈｚ，１Ｈ），８．３４（ｄ，Ｊ＝８Ｈｚ，１Ｈ），９．９２（ｂｒ ｓ，１Ｈ）．

A 2M methylamine-methanol solution (0.36 mL, 0.72 mmol) under ice-cooling was added to a methanol (1.5 mL) solution of tert-butyl (2-formylpyridine-3-yl) carbamate (134 mg, 0.60 mmol). In addition, the mixture was stirred at room temperature for 2.5 hours. Sodium borohydride (34.7 mg, 0.92 mmol) under ice-cooling was added to the reaction mixture, and the mixture was stirred at room temperature for 3.5 hours. Water was added to the reaction mixture, and the mixture was extracted three times with chloroform. The combined extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. No purification operation was performed on the obtained concentrated residue, and a crude product (145 mg, quantitative) of the title compound was obtained as a pale yellow oil.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 1.54 (s, 9H), 2.45 (s, 3H), 4.04 (s, 2H), 7.18 (dd, J = 5,8Hz, 1H), 8.13 (d, J = 5Hz, 1H), 8.34 (d, J = 8Hz, 1H), 9.92 (br s, 1H).

(Example 5)
tert-Butyl (2-(((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-N-methyl-1,2,3,4,6,7,8, 8a-Octahydro-5H-4a, 8-Etano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carboxamide) methyl) pyridine-3-yl) carbamate (13) Synthesis of

化合物１１（１５ｍｇ，０．０２５ｍｍｏｌ）、化合物１２（１２．３ｍｇ，０．０５２ｍｍｏｌ）及びトリエチルアミン（２１μＬ，０．１５ｍｍｏｌ）のテトラヒドロフラン（１．５ｍＬ）溶液を、室温で２１．５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、クロロホルムで三回抽出した。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（０－５％メタノール／クロロホルム）で精製し、表題化合物（１６．１ｍｇ，定量的）を無色油状物質として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１５（ｍ，２Ｈ），０．４５－０．５３（ｍ，２Ｈ），０．７４－０．８４（ｍ，１Ｈ），１．０４－１．１０（ｍ，１Ｈ），１．２５－１．７１（ｍ，１４Ｈ），２．２０－２．４２（ｍ，５Ｈ），２．６０－２．６４（ｍ，１Ｈ），２．８５－２．９４（ｍ，１Ｈ），２．９４（ｓ，３Ｈ），２．９８（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０５（ｄ，Ｊ=６Ｈｚ，１Ｈ），３．４１（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，１Ｈ），３．５４（ｄｄｄ，Ｊ＝４，４，１４Ｈｚ，１Ｈ），３．８７（ｓ，３Ｈ），４．０９－４．１２（ｍ，１Ｈ），４．５２（ｓ，２Ｈ），４．５９（ｓ，１Ｈ），６．５８（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．２２（ｄｄ，Ｊ＝４，８Ｈｚ，１Ｈ），８．２０（ｄｄ，Ｊ＝１，４Ｈｚ，１Ｈ），８．４２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），１０．１（ｓ，１Ｈ）．

A solution of compound 11 (15 mg, 0.025 mmol), compound 12 (12.3 mg, 0.052 mmol) and triethylamine (21 μL, 0.15 mmol) in tetrahydrofuran (1.5 mL) was stirred at room temperature for 21.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted three times with chloroform. The combined extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-5% methanol / chloroform) to give the title compound (16.1 mg, quantitative) as a colorless oily substance.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.15 (m, 2H), 0.45-0.53 (m, 2H), 0.74-0.84 (m) , 1H), 1.04-1.10 (m, 1H), 1.25-1.71 (m, 14H), 2.20-2.42 (m, 5H), 2.60-2.64 (M, 1H), 2.85-2.94 (m, 1H), 2.94 (s, 3H), 2.98 (d, J = 18Hz, 1H), 3.05 (d, J = 6Hz) , 1H), 3.41 (ddd, J = 4,11,14Hz, 1H), 3.54 (ddd, J = 4,4,14Hz, 1H), 3.87 (s, 3H), 4.09 -4.12 (m, 1H), 4.52 (s, 2H), 4.59 (s, 1H), 6.58 (d, J = 8Hz, 1H), 6.72 (d, J = 8Hz) , 1H), 7.22 (dd, J = 4.8Hz, 1H), 8.20 (dd, J = 1,4Hz, 1H), 8.42 (d, J = 8Hz, 1H), 10.1 (S, 1H).

(Example 6)
(4R, 4aS, 8R, 8aR, 13bS) -N-((3-acetamidopyridin-2-yl) methyl) -3- (cyclopropylmethyl) -10-methoxy-N-methyl-1,2, 3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (14) Synthesis of

化合物１３（１６．１ｍｇ，０．０２５ｍｍｏｌ）のジクロロメタン（１ｍＬ）溶液に、氷冷下トリフルオロ酢酸（０．５ｍＬ）を加え、室温で４．５時間撹拌した。反応混合物を減圧濃縮後、クロロホルムを加え飽和炭酸水素ナトリウム水溶液で三回、飽和食塩水で一回洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧下にて濃縮した。得られた粗生成物及びトリエチルアミン（３４μL，０．２５ｍｍｏｌ）のジクロロメタン（１．５ｍL）溶液に、氷冷下、塩化アセチル（１７μL，０．２４ｍｍｏｌ）を加え、室温で２０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、クロロホルムで三回抽出した。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（０－５％メタノール／クロロホルム）で精製し、表題化合物（９．８ｍｇ，６９％）を淡黄色油状物質として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１５（ｍ，２Ｈ），０．４５－０．５４（ｍ，２Ｈ），０．７５－０．８４（ｍ，１Ｈ），１．０５－１．１２（ｍ，１Ｈ），１．２５－１．７１（ｍ，５Ｈ），２．１３－２．４３（ｍ，８Ｈ），２．６１－２．６５（ｍ，１Ｈ），２．８６－２．９５（ｍ，４Ｈ），２．９９（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０７（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．４２（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，１Ｈ），３．５５（ｄｄｄ，Ｊ＝４，４，１４Ｈｚ，１Ｈ），３．８７（ｓ，３Ｈ），４．０９－４．１２（ｍ，１Ｈ），４．５１（ｄ，Ｊ＝１４Ｈｚ，１Ｈ），４．６０（ｄ，Ｊ＝１４Ｈｚ，１Ｈ），４．６１（ｓ，１Ｈ），６．６０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．２６（ｄｄ，Ｊ＝５，８Ｈｚ，１Ｈ），８．２５（ｄｄ，Ｊ＝１，５Ｈｚ，１Ｈ），８．７１（ｄｄ，Ｊ＝１，８Ｈｚ，１Ｈ），１１．４（ｓ，１Ｈ）．

Trifluoroacetic acid (0.5 mL) under ice-cooling was added to a solution of compound 13 (16.1 mg, 0.025 mmol) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated under reduced pressure, chloroform was added, and the mixture was washed three times with saturated aqueous sodium hydrogen carbonate solution and once with saturated brine. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. Acetyl chloride (17 μL, 0.24 mmol) was added to a solution of the obtained crude product and triethylamine (34 μL, 0.25 mmol) in dichloromethane (1.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 20 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted three times with chloroform. The combined extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-5% methanol / chloroform) to give the title compound (9.8 mg, 69%) as a pale yellow oily substance.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.15 (m, 2H), 0.45-0.54 (m, 2H), 0.75-0.84 (m) , 1H), 1.05-1.12 (m, 1H), 1.25-1.71 (m, 5H), 2.13-2.43 (m, 8H), 2.61-2.65 (M, 1H), 2.86-2.95 (m, 4H), 2.99 (d, J = 18Hz, 1H), 3.07 (d, J = 6Hz, 1H), 3.42 (ddd) , J = 4,11,14Hz, 1H), 3.55 (ddd, J = 4,4,14Hz, 1H), 3.87 (s, 3H), 4.09-4.12 (m, 1H) , 4.51 (d, J = 14Hz, 1H), 4.60 (d, J = 14Hz, 1H), 4.61 (s, 1H), 6.60 (d, J = 8Hz, 1H), 6 .73 (d, J = 8Hz, 1H), 7.26 (dd, J = 5,8Hz, 1H), 8.25 (dd, J = 1,5Hz, 1H), 8.71 (dd, J = 1.8Hz, 1H), 11.4 (s, 1H).

(Example 7)
(4R, 4aS, 8R, 8aR, 13bS) -N-((3-acetamidopyridin-2-yl) methyl) -3- (cyclopropylmethyl) -10-hydroxy-N-methyl-1,2, 3,4,5,6,8,8a-Octahydro-7H-4a, 8-Etano-4,13-Methylnobenzoflo [2,3-c] Pyridine [4,3-d] Azepine-7-Carboxamide (15) Synthesis of

化合物１４（９．８ｍｇ，０．０１７ｍｍｏｌ）のジクロロメタン（１．５ｍＬ）溶液に、氷冷下１Ｍ三臭化ホウ素－ジクロロメタン溶液（６０μＬ，０．０６ｍｍｏｌ）を加え、室温で１７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、クロロホルムで三回抽出した。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分取薄層クロマトグラフィー（クロロホルム：メタノール＝９６：４、二回）で精製し、表題化合物（６．７ｍｇ，７０％）を無色油状物質として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１５（ｍ，２Ｈ），０．４５－０．５４（ｍ，２Ｈ），０．７４－０．８４（ｍ，１Ｈ），１．０４－１．１２（ｍ，１Ｈ），１．２５－１．７２（ｍ，５Ｈ），２．２１－２．４０（ｍ，８Ｈ），２．６１－２．６５（ｍ，１Ｈ），２．８５－２．９３（ｍ，４Ｈ），２．９６（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０６（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．４３（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，１Ｈ），３．５５（ｄｄｄ，Ｊ＝４，４，１４Ｈｚ，１Ｈ），４．０６－４．０９（ｍ，１Ｈ），４．５３（ｄ，Ｊ＝１４Ｈｚ，１Ｈ），４．６０（ｓ，１Ｈ），４．６４（ｄ，Ｊ＝１４Ｈｚ，１Ｈ），６．５３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．２７（ｄｄ，Ｊ＝５，８Ｈｚ，１Ｈ），８．２６（ｄｄ，Ｊ＝１，５Ｈｚ，１Ｈ），８．７４（ｄｄ，Ｊ＝１，８Ｈｚ，１Ｈ），１１．３（ｓ，１Ｈ）．

To a solution of compound 14 (9.8 mg, 0.017 mmol) in dichloromethane (1.5 mL) was added a 1 M boron tribromide-dichloromethane solution (60 μL, 0.06 mmol) under ice-cooling, and the mixture was stirred at room temperature for 17 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted three times with chloroform. The combined extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: methanol = 96: 4, twice) to obtain the title compound (6.7 mg, 70%) as a colorless oily substance.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.15 (m, 2H), 0.45-0.54 (m, 2H), 0.74-0.84 (m) , 1H), 1.04-1.12 (m, 1H), 1.25-1.72 (m, 5H), 2.21-2.40 (m, 8H), 2.61-2.65 (M, 1H), 2.85-2.93 (m, 4H), 2.96 (d, J = 18Hz, 1H), 3.06 (d, J = 6Hz, 1H), 3.43 (ddd) , J = 4,11,14Hz, 1H), 3.55 (ddd, J = 4,4,14Hz, 1H), 4.06-4.09 (m, 1H), 4.53 (d, J = 14Hz, 1H), 4.60 (s, 1H), 4.64 (d, J = 14Hz, 1H), 6.53 (d, J = 8Hz, 1H), 6.70 (d, J = 8Hz, 1H), 7.27 (dd, J = 5,8Hz, 1H), 8.26 (dd, J = 1,5Hz, 1H), 8.74 (dd, J = 1,8Hz, 1H), 11. 3 (s, 1H).

(Example 8)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -N- (2-Fluoro-6-Hydroxybenzyl) -10-Hydroxy-N-Methyl-1,2,3,4,5 , 6,8,8a-Octahydro-7H-4a, 8-Etano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] synthesis of azepine-7-carboxamide (16)

化合物１１（１３．８ｍｇ，０．０２３ｍｍｏｌ）及び１－（２－フルオロ－６－メトキシフェニル）－Ｎ－メチルメタンアミン（１１．６ｍｇ，０．０６９ｍｍｏｌ）のジクロロメタン（１ｍＬ）溶液に、トリエチルアミン（９．６μＬ，０．０６９ｍｍｏＬ）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、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。得られた粗生成物のジクロロメタン（１ｍL）溶液に、氷冷下、１Ｍ三臭化ホウ素－ジクロロメタン溶液（２４０μＬ，０．２４ｍｍｏＬ）を加え、室温で２時間撹拌した。反応混合物に２８％アンモニア水溶液を加え、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分取薄層クロマトグラフィー（クロロホルム：メタノール＝９６：４）で精製し、表題化合物（１０．６ｍｇ，８７％）を無色固体として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１５（ｍ，２Ｈ），０．４１－０．５３（ｍ，２Ｈ），０．７３－０．８２（ｍ，１Ｈ），１．０１－１．１０（ｍ，１Ｈ），１．２１－１．３０（ｍ，１Ｈ），１．３３－１．５５（ｍ，３Ｈ），１．５７－１．７０（ｍ，１Ｈ），２．１２－２．４０（ｍ，５Ｈ），２．５２－２．６６（ｍ，１Ｈ），２．８２（ｓ，３Ｈ），２．８５－２．９８（ｍ，２Ｈ），３．０２（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．３８－３．４７（ｍ，１Ｈ），３．５５－３．６２（ｍ，１Ｈ），４．０５（ｂｒ ｓ，１Ｈ），４．３５（ｄ，Ｊ＝１５Ｈｚ，１Ｈ），４．４５（ｄ，Ｊ＝１５Ｈｚ，１Ｈ），４．６４（ｂｒ ｓ，１Ｈ），６．４９－６．６１（ｍ，２Ｈ），６．６５－６．７８（ｍ，２Ｈ），７．０９－７．１７（ｍ，１Ｈ）．

Triethylamine (9) in a solution of compound 11 (13.8 mg, 0.023 mmol) and 1- (2-fluoro-6-methoxyphenyl) -N-methylmethaneamine (11.6 mg, 0.069 mmol) in dichloromethane (1 mL). (0.6 μL, 0.069 mmoL) was added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. A 1M boron tribromide-dichloromethane solution (240 μL, 0.24 mmoL) was added to a solution of the obtained crude product in dichloromethane (1 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. A 28% aqueous ammonia solution was added to the reaction mixture, and the mixture was extracted three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: methanol = 96: 4) to give the title compound (10.6 mg, 87%) as a colorless solid.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.15 (m, 2H), 0.41-0.53 (m, 2H), 0.73-0.82 (m) , 1H), 1.01-1.10 (m, 1H), 1.21-1.30 (m, 1H), 1.33-1.55 (m, 3H), 1.57-1.70 (M, 1H), 2.12-2.40 (m, 5H), 2.52-2.66 (m, 1H), 2.82 (s, 3H), 2.85-2.98 (m) , 2H), 3.02 (d, J = 6Hz, 1H), 3.38-3.47 (m, 1H), 3.55-3.62 (m, 1H), 4.05 (br s, 1H), 4.35 (d, J = 15Hz, 1H), 4.45 (d, J = 15Hz, 1H), 4.64 (br s, 1H), 6.49-6.61 (m, 2H) ), 6.65-6.78 (m, 2H), 7.09-7.17 (m, 1H).

(Reference example 9)
Synthesis of 6- (trifluoromethyl) picoline aldehyde (17)

（６－（トリフルオロメチル）ピリジン－２－イル）メタノール（ＷＯ２０１００５９３９３に記載の方法により合成）（９４４ｍｇ，５．２８ｍｍｏｌ）の酢酸エチル（２０ｍＬ）溶液に、二酸化マンガン（４．６２ｇ，５３．１ｍｍｏｌ）を加えて、２．５時間加熱還流した。放冷後、セライトろ過し、ろ液を減圧下にて濃縮し、表題化合物（６７３ｍｇ，７２％）を黄色油状物として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：７．９３（ｄｄ，Ｊ＝１，８Ｈｚ，１Ｈ），８．１０（ｄｄ，Ｊ＝８，８Ｈｚ，１Ｈ），８．１６（ｄｄ，Ｊ＝１，８Ｈｚ，１Ｈ），１０．１（ｓ，１Ｈ）．

Manganese dioxide (4.62 g, 53.1 mmol) in a solution of methanol (synthesized by the method described in WO20100059393) (944 mg, 5.28 mmol) in ethyl acetate (20 mL) (6- (trifluoromethyl) pyridin-2-yl) methanol. ) Was added, and the mixture was heated under reflux for 2.5 hours. After allowing to cool, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (673 mg, 72%) as a yellow oil.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.93 (dd, J = 1,8 Hz, 1H), 8.10 (dd, J = 8,8 Hz, 1H), 8.16 (dd) , J = 1.8Hz, 1H), 10.1 (s, 1H).

(Reference example 10)
Synthesis of N-methyl-1- (6- (trifluoromethyl) pyridin-2-yl) methaneamine (18)

参考例８に記載した方法に従い、化合物１７より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．４５（ｓ，３Ｈ），３．９５（ｓ，２Ｈ），７．５３－７．５７（ｍ，２Ｈ），７．８３（ｄｄ，Ｊ＝８，８Ｈｚ，１Ｈ）．

The title compound was obtained from compound 17 according to the method described in Reference Example 8.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.45 (s, 3H), 3.95 (s, 2H), 7.53-7.57 (m, 2H), 7.83 ( dd, J = 8,8 Hz, 1H).

(Example 9)
(4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-N-methyl-N-((6- (trifluoromethyl) pyridin-2-yl) methyl) -1, 2,3,4,5,6,8,8a-Octahydro-7H-4a, 8-Etano-4,13-Methylnobenzoflo [2,3-c] Pyridine [4,3-d] Azepine-7-Carboxamide ( 19) Synthesis

実施例８に記載した方法に従い、化合物１１及び化合物１８より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１５（ｍ，２Ｈ），０．４２－０．５２（ｍ，２Ｈ），０．７１－０．８０（ｍ，１Ｈ），０．９９－１．０７（ｍ，１Ｈ），１．１９－１．６５（ｍ，５Ｈ），２．１５－２．３７（ｍ，５Ｈ），２．５４－２．６２（ｍ，１Ｈ），２．７８－２．８６（ｍ，１Ｈ），２．８８（ｓ，３Ｈ），２．９２（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０１（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．３５－３．４４（ｍ，１Ｈ），３．６１－３．７０（ｍ，１Ｈ），４．１０－４．１３（ｍ，１Ｈ），４．５３（ｄ，Ｊ＝１７Ｈｚ，１Ｈ），４．５６（ｄ，Ｊ＝１７Ｈｚ，１Ｈ），４．６０（ｓ，１Ｈ），６．４８（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．５６（ｄｄ，Ｊ＝８，８Ｈｚ，２Ｈ），７．８２（ｄｄ，Ｊ＝８，８Ｈｚ，１Ｈ）．

The title compound was obtained from compound 11 and compound 18 according to the method described in Example 8.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.15 (m, 2H), 0.42-0.52 (m, 2H), 0.71-0.80 (m) , 1H), 0.99-1.07 (m, 1H), 1.19-1.65 (m, 5H), 2.15-2.37 (m, 5H), 2.54-2.62 (M, 1H), 2.78-2.86 (m, 1H), 2.88 (s, 3H), 2.92 (d, J = 18Hz, 1H), 3.01 (d, J = 6Hz) , 1H), 3.35-3.44 (m, 1H), 3.61-3.70 (m, 1H), 4.10-4.13 (m, 1H), 4.53 (d, J) = 17Hz, 1H), 4.56 (d, J = 17Hz, 1H), 4.60 (s, 1H), 6.48 (d, J = 8Hz, 1H), 6.73 (d, J = 8Hz) , 1H), 7.56 (dd, J = 8,8Hz, 2H), 7.82 (dd, J = 8,8Hz, 1H).

(Reference example 11)
Synthesis of 2-((Methylamino) Methyl) Pyridine-3-ol (20)

参考例８に記載した方法に従い、３－ヒドロキシピコリンアルデヒド（ＷＯ２００２０２２６００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）：２．５２（ｓ，３Ｈ），４．１８（ｓ，２Ｈ），５．１０－６．００（ｍ，２Ｈ），７．０９－７．１０（ｍ，２Ｈ），８．００－８．０１（ｍ，１Ｈ）．

The title compound was obtained from 3-hydroxypicoline aldehyde (synthesized by the method described in WO2002022600) according to the method described in Reference Example 8.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 2.52 (s, 3H), 4.18 (s, 2H), 5.10-16.00 (m, 2H), 7.09- 7.10 (m, 2H), 8.00-8.01 (m, 1H).

(Example 10)
(4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-N-((3-hydroxypyridin-2-yl) methyl) -N-methyl-1,2,3 Synthesis of 4,5,6,8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (21)

実施例８に記載した方法に従い、化合物１１及び化合物２０より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１５（ｍ，２Ｈ），０．４２－０．５３（ｍ，２Ｈ），０．７３－０．８３（ｍ，１Ｈ），１．０２－１．１４（ｍ，１Ｈ），１．２２－１．７１（ｍ，５Ｈ），２．２０－２．４１（ｍ，５Ｈ），２．６０－２．６７（ｍ，１Ｈ），２．８５－３．００（ｍ，２Ｈ），２．９４（ｓ，３Ｈ），３．０４（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．３９－３．５０（ｍ，１Ｈ），３．５７－３．６５（ｍ，１Ｈ），４．０２－４．０６（ｍ，１Ｈ），４．３９（ｄ，Ｊ＝１４Ｈｚ，１Ｈ），４．６３（ｄ，Ｊ＝１４Ｈｚ，１Ｈ），４．６５（ｓ，１Ｈ），６．５３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．１８（ｄｄ，Ｊ＝５，８Ｈｚ，１Ｈ），７．２５－７．２８（ｍ，１Ｈ），８．０６（ｄｄ，Ｊ＝１，５Ｈｚ，１Ｈ），１１．５（ｂｒ ｓ，１Ｈ）．

The title compound was obtained from compound 11 and compound 20 according to the method described in Example 8.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.15 (m, 2H), 0.42-0.53 (m, 2H), 0.73-0.83 (m) , 1H), 1.02-1.14 (m, 1H), 1.22-1.71 (m, 5H), 2.20-2.41 (m, 5H), 2.60-2.67 (M, 1H), 2.85-3.00 (m, 2H), 2.94 (s, 3H), 3.04 (d, J = 6Hz, 1H), 3.39-3.50 (m) , 1H), 3.57-3.65 (m, 1H), 4.02-4.06 (m, 1H), 4.39 (d, J = 14Hz, 1H), 4.63 (d, J) = 14Hz, 1H), 4.65 (s, 1H), 6.53 (d, J = 8Hz, 1H), 6.71 (d, J = 8Hz, 1H), 7.18 (dd, J = 5) , 8Hz, 1H), 7.25-7.28 (m, 1H), 8.06 (dd, J = 1,5Hz, 1H), 11.5 (br s, 1H).

(Reference example 12)
Synthesis of tert-butylmethyl (pyrimidine-2-ylmethyl) carbamate (22)

ｔｅｒｔ－ブチル（ピリミジン－２－イルメチル）カーバメート（ＷＯ２０１３０１３２３８に記載の方法により合成）（４９４ｍｇ，２．３６ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（８ｍＬ）溶液に、氷冷下で水素化ナトリウム（５５％オイルディスパージョン）（１２６ｍｇ，２．８９ｍｍｏｌ）を加え、１０分間撹拌した。反応混合物に、ヨウ化メチル（４４１μＬ，７．０８ｍｍｏｌ）を加え、室温で２４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（１５－７０％酢酸エチル／ヘプタン）で精製し、表題化合物（３６３ｍｇ，６９％）を黄色油状物として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．３３－１．５０（ｍ，９Ｈ），２．９９－３．０４（ｍ，３Ｈ），４．６０－４．７０（ｍ，２Ｈ），７．１７－７．１８（ｍ，１Ｈ），８．７０－８．７１（ｍ，２Ｈ）．

Sodium hydride (55%) in N, N-dimethylformamide (8 mL) solution of tert-butyl (pyrimidine-2-ylmethyl) carbamate (synthesized by the method described in WO201301328) (494 mg, 2.36 mmol) under ice-cooling. (Oil dispersion) (126 mg, 2.89 mmol) was added, and the mixture was stirred for 10 minutes. Methyl iodide (441 μL, 7.08 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 24 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (15-70% ethyl acetate / heptane) to give the title compound (363 mg, 69%) as a yellow oil.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.33-1.50 (m, 9H), 2.99-3.04 (m, 3H), 4.60-4.70 (m) , 2H), 7.17-7.18 (m, 1H), 8.70-8.71 (m, 2H).

(Reference example 13)
Synthesis of N-Methyl-1- (pyrimidine-2-yl) methaneamine dihydrochloride (23)

化合物２２（３６３ｍｇ，１．６３ｍｍｏｌ）のメタノール（５ｍＬ）溶液に、３Ｍ塩化水素－１，４－ジオキサン溶液（５ｍＬ）を加え、室温で４．５時間撹拌した。反応混合物を減圧下にて濃縮後、凍結乾燥し、表題化合物（３４２ｍｇ，定量的）を淡黄色固体として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ（ｐｐｍ）：２．８５（ｓ，３Ｈ），４．４７（ｓ，２Ｈ），７．４５－７．４９（ｍ，１Ｈ），８．８１－８．８５（ｍ，２Ｈ）．

A 3M hydrogen chloride-1,4-dioxane solution (5 mL) was added to a solution of compound 22 (363 mg, 1.63 mmol) in methanol (5 mL), and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated under reduced pressure and then lyophilized to give the title compound (342 mg, quantitative) as a pale yellow solid.

^{1 1} H-NMR (400 MHz, CD ₃ OD) δ (ppm): 2.85 (s, 3H), 4.47 (s, 2H), 7.45-7.49 (m, 1H), 8.81 -8.85 (m, 2H).

(Example 11)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-Hydroxy-N-Methyl-N- (Pyrimidine-2-ylmethyl) -1,2,3,4,5,6 Synthesis of 8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (24)

実施例８に記載した方法に従い、化合物１１及び化合物２３より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１４（ｍ，２Ｈ），０．４２－０．５３（ｍ，２Ｈ），０．７２－０．８３（ｍ，１Ｈ），０．９９－１．０９（ｍ，１Ｈ），１．１９－１．４２（ｍ，３Ｈ），１．４８－１．５４（ｍ，１Ｈ），１．６３－１．７６（ｍ，１Ｈ），２．１８－２．３９（ｍ，５Ｈ），２．５６－２．６６（ｍ，１Ｈ），２．８２－２．９３（ｍ，１Ｈ），２．９４（ｄ，Ｊ＝１７Ｈｚ，１Ｈ），２．９６（ｓ，３Ｈ），３．０１（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．４２（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，１Ｈ），３．７３（ｄｄｄ，Ｊ＝４，５，１４Ｈｚ，１Ｈ），４．１０－４．１５（ｍ，１Ｈ），４．５８（ｄ，Ｊ＝１７Ｈｚ，１Ｈ），４．６５（ｄ，Ｊ＝１７Ｈｚ，１Ｈ），４．７１（ｓ，１Ｈ），６．５１（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６９（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．２０（ｄｄ，Ｊ＝５，５Ｈｚ，１Ｈ），８．７３（ｄ，Ｊ＝５Ｈｚ，２Ｈ）．

The title compound was obtained from compound 11 and compound 23 according to the method described in Example 8.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.14 (m, 2H), 0.42-0.53 (m, 2H), 0.72-0.83 (m) , 1H), 0.99-1.09 (m, 1H), 1.19-1.42 (m, 3H), 1.48-1.54 (m, 1H), 1.63-1.76 (M, 1H), 2.18-2.39 (m, 5H), 2.56-2.66 (m, 1H), 2.82-2.93 (m, 1H), 2.94 (d). , J = 17Hz, 1H), 2.96 (s, 3H), 3.01 (d, J = 6Hz, 1H), 3.42 (ddd, J = 4,11,14Hz, 1H), 3.73 (Ddd, J = 4,5,14Hz, 1H), 4.10-4.15 (m, 1H), 4.58 (d, J = 17Hz, 1H), 4.65 (d, J = 17Hz, 1H), 4.71 (s, 1H), 6.51 (d, J = 8Hz, 1H), 6.69 (d, J = 8Hz, 1H), 7.20 (dd, J = 5,5Hz, 1H), 8.73 (d, J = 5Hz, 2H).

(Example 12)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-Hydroxy-N-Methyl-N- (Pyrimidine-4-ylmethyl) -1,2,3,4,5,6 Synthesis of 8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (25)

実施例８に記載した方法に従い、化合物１１及びＮ－メチル－１－（ピリミジン－４－イル）メタンアミン二塩酸塩より表題化合物を得た。
^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１７（ｍ，２Ｈ），０．４３－０．５５（ｍ，２Ｈ），０．７２－０．８３（ｍ，１Ｈ），１．０２－１．１２（ｍ，１Ｈ），１．２３－１．４６（ｍ，３Ｈ），１．５１－１．８０（ｍ，２Ｈ），２．１７－２．４１（ｍ，５Ｈ），２．５９－２．６６（ｍ，１Ｈ），２．８３－３．００（ｍ，２Ｈ），２．９２（ｓ，３Ｈ），３．０４（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．３７－３．４８（ｍ，１Ｈ），３．６１－３．６９（ｍ，１Ｈ），４．０５－４．１１（ｍ，１Ｈ），４．４６（ｓ，２Ｈ），４．６４（ｓ，１Ｈ），５．４２（ｂｒ ｓ，１Ｈ），６．５３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．３９（ｄ，Ｊ＝６Ｈｚ，１Ｈ），８．７３（ｄ，Ｊ＝６Ｈｚ，１Ｈ），９．１７（ｓ，１Ｈ）．

The title compound was obtained from compound 11 and N-methyl-1- (pyrimidine-4-yl) methaneamine dihydrochloride according to the method described in Example 8.
^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.17 (m, 2H), 0.43-0.55 (m, 2H), 0.72-0.83 (m) , 1H), 1.02-1.12 (m, 1H), 1.23-1.46 (m, 3H), 1.51-1.80 (m, 2H), 2.17-2.41 (M, 5H), 2.59-2.66 (m, 1H), 2.83-3.00 (m, 2H), 2.92 (s, 3H), 3.04 (d, J = 6Hz) , 1H), 3.37-3.48 (m, 1H), 3.61-3.69 (m, 1H), 4.05-4.11 (m, 1H), 4.46 (s, 2H) ), 4.64 (s, 1H), 5.42 (br s, 1H), 6.53 (d, J = 8Hz, 1H), 6.70 (d, J = 8Hz, 1H), 7.39. (D, J = 6Hz, 1H), 8.73 (d, J = 6Hz, 1H), 9.17 (s, 1H).

(Example 13)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-Hydroxy-N-Methyl-N- (Pyrimidine-5-ylmethyl) -1,2,3,4,5,6 Synthesis of 8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (26)

実施例８に記載した方法に従い、化合物１１及びＮ－メチル－１－（ピリミジン－５－イル）メタンアミン二塩酸塩より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１５（ｍ，２Ｈ），０．４３－０．５４（ｍ，２Ｈ），０．７４－０．８４（ｍ，１Ｈ），１．０２－１．１３（ｍ，１Ｈ），１．２２－１．４５（ｍ，３Ｈ），１．５０－１．５６（ｍ，１Ｈ），１．６２－１．７３（ｍ，１Ｈ），２．１６－２．４１（ｍ，５Ｈ），２．６２（ｄｄ，Ｊ＝５，１２Ｈｚ，１Ｈ），２．８０－２．９５（ｍ，１Ｈ），２．８２（ｓ，３Ｈ），２．９５（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０４（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．４１（ｄｄｄ，Ｊ＝４，１２，１６Ｈｚ，１Ｈ），３．６６（ｄｄｄ，Ｊ＝３，５，１４Ｈｚ，１Ｈ），４．０３－４．０７（ｍ，１Ｈ），４．３４（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），４．３８（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），４．５７（ｓ，１Ｈ），６．５３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，１Ｈ），８．７６（ｓ，２Ｈ），９．１６（ｓ，１Ｈ）．

The title compound was obtained from compound 11 and N-methyl-1- (pyrimidine-5-yl) methaneamine dihydrochloride according to the method described in Example 8.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.15 (m, 2H), 0.43-0.54 (m, 2H), 0.74-0.84 (m) , 1H), 1.02-1.13 (m, 1H), 1.22-1.45 (m, 3H), 1.50-1.56 (m, 1H), 1.62-1.73 (M, 1H), 2.16-2.41 (m, 5H), 2.62 (dd, J = 5,12Hz, 1H), 2.80-2.95 (m, 1H), 2.82 (S, 3H), 2.95 (d, J = 18Hz, 1H), 3.04 (d, J = 6Hz, 1H), 3.41 (ddd, J = 4,12,16Hz, 1H), 3 .66 (ddd, J = 3,5,14Hz, 1H), 4.03-4.07 (m, 1H), 4.34 (d, J = 16Hz, 1H), 4.38 (d, J = 16Hz, 1H), 4.57 (s, 1H), 6.53 (d, J = 8Hz, 1H), 6.71 (d, J = 8Hz, 1H), 8.76 (s, 2H), 9 .16 (s, 1H).

(Reference example 14)
Synthesis of tert-butylmethyl (pyrazine-2-ylmethyl) carbamate (27)

参考例１２に記載した方法に従い、ｔｅｒｔ－ブチル（ピラジン－２－イルメチル）カーバメート（ＷＯ２０１２１２２４２２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）：１．４４－１．５０（ｍ，９Ｈ），２．９４－３．００（ｍ，３Ｈ），４．５４－４．６０（ｍ，２Ｈ），８．４９－８．５７（ｍ，３Ｈ）．

The title compound was obtained from tert-butyl (pyrazine-2-ylmethyl) carbamate (synthesized by the method described in WO2012122422) according to the method described in Reference Example 12.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.44-1.50 (m, 9H), 2.94-3.00 (m, 3H), 4.54-4.60 (m) , 2H), 8.49-8.57 (m, 3H).

(Reference example 15)
Synthesis of N-Methyl-1- (pyrazine-2-yl) methaneamine dihydrochloride (28)

参考例１３に記載した方法に従い、化合物２７より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ（ｐｐｍ）：２．８４（ｓ，３Ｈ），４．４９（ｓ，２Ｈ），８．６７（ｄ，Ｊ＝２Ｈｚ，１Ｈ），８．７５－８．７８（ｍ，２Ｈ）．

The title compound was obtained from compound 27 according to the method described in Reference Example 13.

^{1 1} H-NMR (400 MHz, CD ₃ OD) δ (ppm): 2.84 (s, 3H), 4.49 (s, 2H), 8.67 (d, J = 2Hz, 1H), 8.75 -8.78 (m, 2H).

(Example 14)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-Hydroxy-N-Methyl-N- (Pyrazine-2-ylmethyl) -1,2,3,4,5,6 Synthesis of 8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (29)

実施例８に記載した方法に従い、化合物１１及び化合物２８より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１６（ｍ，２Ｈ），０．４２－０．５４（ｍ，２Ｈ），０．７２－０．８４（ｍ，１Ｈ），１．０１－１．１１（ｍ，１Ｈ），１．２２－１．４４（ｍ，３Ｈ），１．５０－１．５７（ｍ，１Ｈ），１．６０－１．７９（ｍ，１Ｈ），２．１７－２．４１（ｍ，５Ｈ），２．５９－２．６６（ｍ，１Ｈ），２．８１－２．９５（ｍ，１Ｈ），２．９１（ｓ，３Ｈ），２．９５（ｄ，Ｊ＝１９Ｈｚ，１Ｈ），３．０３（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．４２（ｄｄｄ，Ｊ＝４，１２，１５Ｈｚ，１Ｈ），３．６９（ｄｄｄ，Ｊ＝４，４，１４Ｈｚ，１Ｈ），４．０４－４．１０（ｍ，１Ｈ），４．５３（ｓ，２Ｈ），４．６３（ｓ，１Ｈ），５．４７（ｂｒ ｓ，１Ｈ），６．５２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），８．５０（ｄ，Ｊ＝３Ｈｚ，１Ｈ），８．５３－８．５５（ｍ，１Ｈ），８．６８（ｓ，１Ｈ）．

The title compound was obtained from compound 11 and compound 28 according to the method described in Example 8.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.16 (m, 2H), 0.42-0.54 (m, 2H), 0.72-0.84 (m) , 1H), 1.01-1.11 (m, 1H), 1.22-1.44 (m, 3H), 1.50-1.57 (m, 1H), 1.60-1.79 (M, 1H), 2.17-2.41 (m, 5H), 2.59-2.66 (m, 1H), 2.81-2.95 (m, 1H), 2.91 (s) , 3H), 2.95 (d, J = 19Hz, 1H), 3.03 (d, J = 6Hz, 1H), 3.42 (ddd, J = 4,12,15Hz, 1H), 3.69 (Ddd, J = 4,4,14Hz, 1H), 4.04-4.10 (m, 1H), 4.53 (s, 2H), 4.63 (s, 1H), 5.47 (br) s, 1H), 6.52 (d, J = 8Hz, 1H), 6.70 (d, J = 8Hz, 1H), 8.50 (d, J = 3Hz, 1H), 8.53-8. 55 (m, 1H), 8.68 (s, 1H).

(Reference example 16)
Synthesis of N-Methyl-1- (pyridazine-3-yl) methaneamine (30)

参考例８に記載した方法に従い、ピリダジン－３－カルバルデヒドより表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．５１（ｓ，３Ｈ），４．０９（ｓ，２Ｈ），７．４５（ｄｄ，Ｊ＝５，８Ｈｚ，１Ｈ），７．５７（ｄｄ，Ｊ＝２，８Ｈｚ，１Ｈ）９．１１（ｄｄ，Ｊ＝２，５Ｈｚ，１Ｈ）．

The title compound was obtained from pyridazine-3-carbaldehyde according to the method described in Reference Example 8.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.51 (s, 3H), 4.09 (s, 2H), 7.45 (dd, J = 5,8 Hz, 1H), 7. 57 (dd, J = 2.8Hz, 1H) 9/11 (dd, J = 2.5Hz, 1H).

(Example 15)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-Hydroxy-N-Methyl-N- (Pyridazine-3-ylmethyl) -1,2,3,4,5,6 Synthesis of 8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (31)

実施例８に記載した方法に従い、化合物１１及び化合物３０より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１６（ｍ，２Ｈ），０．４３－０．５４（ｍ，２Ｈ），０．７２－０．８３（ｍ，１Ｈ），１．０１－１．１１（ｍ，１Ｈ），１．２２－１．４５（ｍ，３Ｈ），１．５０－１．５７（ｍ，１Ｈ），１．６０－１．７３（ｍ，１Ｈ），２．１８－２．４１（ｍ，５Ｈ），２．５８－２．６５（ｍ，１Ｈ），２．８２－２．９９（ｍ，２Ｈ），２．９２（ｓ，３Ｈ），３．０４（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．４２（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，１Ｈ），３．６３（ｄｄｄ，Ｊ＝４，４，１４Ｈｚ，１Ｈ），４．０５－４．１０（ｍ，１Ｈ），４．６１（ｓ，１Ｈ），４．６７（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），４．７２（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），６．５２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．４９（ｄｄ，Ｊ＝５，９Ｈｚ，１Ｈ），７．７１（ｄｄ，Ｊ＝２，９Ｈｚ，１Ｈ），９．１２（ｄｄ，Ｊ＝２，５Ｈｚ，１Ｈ）．

The title compound was obtained from compound 11 and compound 30 according to the method described in Example 8.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.16 (m, 2H), 0.43-0.54 (m, 2H), 0.72-0.83 (m) , 1H), 1.01-1.11 (m, 1H), 1.22-1.45 (m, 3H), 1.50-1.57 (m, 1H), 1.60-1.73 (M, 1H), 2.18-2.41 (m, 5H), 2.58-2.65 (m, 1H), 2.82-2.99 (m, 2H), 2.92 (s) , 3H), 3.04 (d, J = 6Hz, 1H), 3.42 (ddd, J = 4,11,14Hz, 1H), 3.63 (ddd, J = 4,4,14Hz, 1H) , 4.05-4.10 (m, 1H), 4.61 (s, 1H), 4.67 (d, J = 16Hz, 1H), 4.72 (d, J = 16Hz, 1H), 6 .52 (d, J = 8Hz, 1H), 6.71 (d, J = 8Hz, 1H), 7.49 (dd, J = 5,9Hz, 1H), 7.71 (dd, J = 2, 9Hz, 1H), 9.12 (dd, J = 2.5Hz, 1H).

(Example 16)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-Hydroxy-N-Methyl-N- ((6-oxo-1,6-dihydropyridine-2-yl) methyl) -1 , 2,3,4,5,6,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carboxamide Synthesis of (32)

実施例８に記載した方法に従い、化合物１１及び６－（（メチルアミノ）メチル）ピリジン－２（１Ｈ）－オン（ＷＯ２０１５０５０７９８に記載の方法により合成）より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ_６）δ（ｐｐｍ）：０．０４－０．１１（ｍ，２Ｈ），０．４０－０．４８（ｍ，２Ｈ），０．７３－０．８０（ｍ，１Ｈ），０．８８－０．９６（ｍ，１Ｈ），１．１３－１．３９（ｍ，４Ｈ），１．６２－１．６９（ｍ，１Ｈ），２．１０－２．３９（ｍ，５Ｈ），２．４９－２．５６（ｍ，１Ｈ），２．６１－２．７８（ｍ，１Ｈ），２．７２（ｓ，３Ｈ），２．８６（ｄ，Ｊ＝１９Ｈｚ，１Ｈ），２．９８（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．１８－３．４９（ｍ，１Ｈ），３．５２－３．６３（ｍ，１Ｈ），３．８９（ｓ，１Ｈ），４．０３（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），４．０８（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），４．４９（ｓ，１Ｈ），６．１３（ｄ，Ｊ＝７Ｈｚ，１Ｈ），６．２３（ｄ，Ｊ＝９Ｈｚ，１Ｈ），６．４５（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．５７（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．４０（ｄｄ，Ｊ＝６，９Ｈｚ，１Ｈ）．

The title compound was obtained from compounds 11 and 6-((methylamino) methyl) pyridine-2 (1H) -one (synthesized by the method described in WO2015050798) according to the method described in Example 8.

^{1 1} H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 0.04-0.11 (m, 2H), 0.40-0.48 (m, 2H), 0.73-0.80 (M, 1H), 0.88-0.96 (m, 1H), 1.13-1.39 (m, 4H), 1.62-1.69 (m, 1H), 2.10-2 .39 (m, 5H), 2.49-2.56 (m, 1H), 2.61-2.78 (m, 1H), 2.72 (s, 3H), 2.86 (d, J) = 19Hz, 1H), 2.98 (d, J = 6Hz, 1H), 3.18-3.49 (m, 1H), 3.52-3.63 (m, 1H), 3.89 (s) , 1H), 4.03 (d, J = 16Hz, 1H), 4.08 (d, J = 16Hz, 1H), 4.49 (s, 1H), 6.13 (d, J = 7Hz, 1H) ), 6.23 (d, J = 9Hz, 1H), 6.45 (d, J = 8Hz, 1H), 6.57 (d, J = 8Hz, 1H), 7.40 (dd, J = 6). , 9Hz, 1H).

(Reference example 17)
Synthesis of N-methyl-1- (1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol-2-yl) methaneamine (33)

参考例８に記載した方法に従い、１－（（２－（トリメチルシリル）エトキシ）メチル）－１Ｈ－イミダゾール－２－カルバルデヒド（Ｊｏｕｒｎａｌ ｏｆ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ ２００６，７１，８８０７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）：－０．０１（ｓ，９Ｈ），０．９０（ｔ，Ｊ＝８Ｈｚ，２Ｈ），２．４４（ｓ，３Ｈ），３．５０（ｔ，Ｊ＝８Ｈｚ，２Ｈ），３．８６（ｓ，２Ｈ），５．３３（ｓ，２Ｈ），６．９６（ｓ，２Ｈ）．

Titled from 1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole-2-carbaldehyde (synthesized by the method described in Journal of Organic Chemistry 2006, 71, 8807) according to the method described in Reference Example 8. The compound was obtained.
^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): -0.01 (s, 9H), 0.90 (t, J = 8Hz, 2H), 2.44 (s, 3H), 3.50 (T, J = 8Hz, 2H), 3.86 (s, 2H), 5.33 (s, 2H), 6.96 (s, 2H).

(Example 17)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-Methoxy-N-Methyl-N-((1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole- 2-yl) Methyl) -1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3 -D] Synthesis of azepine-7-carboxamide (34)

実施例５に記載した方法に従い、化合物１１及び化合物３３より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）： －０．０１（ｓ，９Ｈ），０．００－０．１５（ｍ，２Ｈ），０．４０－０．５０（ｍ，２Ｈ），０．７０－０．８５（ｍ，１Ｈ），０．８５－０．９５（ｍ，２Ｈ），１．００－１．１０（ｍ，１Ｈ），１．２０-１．８０（ｍ，４Ｈ），２．２０－２．４５（ｍ，６Ｈ），２．５５－２．６５（ｍ，１Ｈ），２．８０－２．９０（ｍ，１Ｈ），２．８９（ｓ，３Ｈ），２．９６（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０３（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．３０－３．４０（ｍ，１Ｈ），３．４０-３．５０（ｍ，２Ｈ），３．５０－３．６０（ｍ，１Ｈ），３．８７（ｓ，３Ｈ），４．００－４．１０（ｍ，１Ｈ），４．４７（ｄ，Ｊ＝１５Ｈｚ，１Ｈ），４．５４（ｄ，Ｊ＝１５Ｈｚ，１Ｈ），４．６０－４．７０（ｍ，１Ｈ），５．３４（ｄ，Ｊ＝１０Ｈｚ，１Ｈ），５．３７（ｄ，Ｊ＝１０Ｈｚ，１Ｈ），６．５８（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．９６－７．００（ｍ，２Ｈ）．

The title compound was obtained from compound 11 and compound 33 according to the method described in Example 5.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): -0.01 (s, 9H), 0.00-0.15 (m, 2H), 0.40-0.50 (m, 2H) , 0.70-0.85 (m, 1H), 0.85-0.95 (m, 2H), 1.00-1.10 (m, 1H), 1.20-1.80 (m, 4H), 2.20-2.45 (m, 6H), 2.55-2.65 (m, 1H), 2.80-2.90 (m, 1H), 2.89 (s, 3H) , 2.96 (d, J = 18Hz, 1H), 3.03 (d, J = 6Hz, 1H), 3.30-3.40 (m, 1H), 3.40-3.50 (m, 2H), 3.50-3.60 (m, 1H), 3.87 (s, 3H), 4.00-4.10 (m, 1H), 4.47 (d, J = 15Hz, 1H) , 4.54 (d, J = 15Hz, 1H), 4.60-4.70 (m, 1H), 5.34 (d, J = 10Hz, 1H), 5.37 (d, J = 10Hz, 1H), 6.58 (d, J = 8Hz, 1H), 6.71 (d, J = 8Hz, 1H), 6.96-7.00 (m, 2H).

(Example 18)
(4R, 4aS, 8R, 8aR, 13bS) -N-((1H-imidazol-2-yl) methyl) -3- (cyclopropylmethyl) -10-hydroxy-N-methyl-1,2,3,4 , 5,6,8,8a-Octahydro-7H-4a, 8-Etano-4,13-Methylnobenzoflo [2,3-c] pyrido [4,3-d] Synthesis of azepine-7-carboxamide (35)

実施例７に記載した方法に従い、化合物３４より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）： ０．００－０．２０（ｍ，２Ｈ），０．４０－０．６０（ｍ，２Ｈ），０．７５－０．９０（ｍ，１Ｈ），１．００－１．１５（ｍ，１Ｈ），１．２０-２．００（ｍ，８Ｈ），２．２０－２．５０（ｍ，３Ｈ），２．６０－２．８０（ｍ，１Ｈ），２．８３（ｓ，３Ｈ），２．９７（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．００－３．２０（ｍ，１Ｈ），３．４３（ｄｔ，Ｊ＝４，１２Ｈｚ，１Ｈ），３．６０－３．７０（ｍ，１Ｈ），４．００－４．１０（ｍ，１Ｈ），４．１９（ｄ，Ｊ＝１５Ｈｚ，１Ｈ），４．４１（ｄ，Ｊ＝１５Ｈｚ，１Ｈ），４．６０－４．７０（ｍ，１Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．９９（ｓ，２Ｈ）．

The title compound was obtained from compound 34 according to the method described in Example 7.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.00-0.20 (m, 2H), 0.40-0.60 (m, 2H), 0.75-0.90 (m) , 1H), 1.00-1.15 (m, 1H), 1.20-2.00 (m, 8H), 2.20-2.50 (m, 3H), 2.60-2.80 (M, 1H), 2.83 (s, 3H), 2.97 (d, J = 18Hz, 1H), 3.00-3.20 (m, 1H), 3.43 (dt, J = 4) , 12Hz, 1H), 3.60-3.70 (m, 1H), 4.00-4.10 (m, 1H), 4.19 (d, J = 15Hz, 1H), 4.41 (d) , J = 15Hz, 1H), 4.60-4.70 (m, 1H), 6.54 (d, J = 8Hz, 1H), 6.73 (d, J = 8Hz, 1H), 6.99 (S, 2H).

(Example 19)
(4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-N-methyl-N-((1-methyl-1H-imidazol-2-yl) methyl) -1,2 , 3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (36) ) Synthesis

実施例５に記載した方法に従い、化合物１１およびＮ－メチル－１－（１－メチル－１Ｈ－イミダゾール－２－イル）メタンアミンより表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）： ０．００－０．１５（ｍ，２Ｈ），０．４０－０．５５（ｍ，２Ｈ），０．７０－０．８５（ｍ，１Ｈ），１．０７（ｔ，Ｊ＝１２Ｈｚ，１Ｈ），１．２０－１．５０（ｍ，３Ｈ），１．５０－１．６０（ｍ，１Ｈ），２．２０－２．４５（ｍ，５Ｈ），２．６０－２．７０（ｍ，１Ｈ），２．８０－２．９３（ｍ，１Ｈ），２．８７（ｓ，３Ｈ），２．９７（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０５（ｄ，Ｊ＝５Ｈｚ，１Ｈ），３．３９（ｄｔ，Ｊ＝４，１１Ｈｚ，１Ｈ），３．５５－３．６５（ｍ，１Ｈ），３．６６（ｓ，３Ｈ），３．７０（ｓ，１Ｈ），３．８７（ｓ，３Ｈ），４．００－４．１０（ｍ，１Ｈ），４．４２（ｄ，Ｊ＝１５Ｈｚ，１Ｈ），４．５３（ｄ，Ｊ＝１５Ｈｚ，１Ｈ），４．５８－４．６２（ｍ，１Ｈ），６．５８（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．８５（ｄ，Ｊ＝１Ｈｚ，１Ｈ），６．９６（ｄ，Ｊ＝１Ｈｚ，１Ｈ）．

The title compound was obtained from compound 11 and N-methyl-1- (1-methyl-1H-imidazol-2-yl) methaneamine according to the method described in Example 5.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.55 (m, 2H), 0.70-0.85 (m) , 1H), 1.07 (t, J = 12Hz, 1H), 1.20-1.50 (m, 3H), 1.50-1.60 (m, 1H), 2.20-2.45 (M, 5H), 2.60-2.70 (m, 1H), 2.80-2.93 (m, 1H), 2.87 (s, 3H), 2.97 (d, J = 18Hz) , 1H), 3.05 (d, J = 5Hz, 1H), 3.39 (dt, J = 4,11Hz, 1H), 3.55-3.65 (m, 1H), 3.66 (s) , 3H), 3.70 (s, 1H), 3.87 (s, 3H), 4.00-4.10 (m, 1H), 4.42 (d, J = 15Hz, 1H), 4. 53 (d, J = 15Hz, 1H), 4.58-4.62 (m, 1H), 6.58 (d, J = 8Hz, 1H), 6.72 (d, J = 8Hz, 1H), 6.85 (d, J = 1Hz, 1H), 6.96 (d, J = 1Hz, 1H).

(Example 20)
(4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-N-methyl-N-((1-methyl-1H-imidazol-2-yl) methyl) -1,2 , 3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (37) ) Synthesis

実施例７に記載した方法に従い、化合物３６より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）： ０．００－０．１５（ｍ，２Ｈ），０．４０－０．５５（ｍ，２Ｈ），０．７０－０．９０（ｍ，２Ｈ），１．００－２．００（ｍ，６Ｈ），２．１５－２．４５（ｍ，４Ｈ），２．５５－２．６５（ｍ，１Ｈ），２．８６（ｓ，３Ｈ），２．８０－３．１０（ｍ，３Ｈ），３．４９（ｓ，３Ｈ），３．３０－３．７０（ｍ，２Ｈ），４．０４（ｓ，１Ｈ），４．４４（ｄ，Ｊ＝１４Ｈｚ，１Ｈ），４．５１（ｄ，Ｊ＝１４Ｈｚ，１Ｈ），４．６１（ｓ，１Ｈ），６．５２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．８６（ｄ，Ｊ＝１Ｈｚ，１Ｈ），６．９７（ｄ，Ｊ＝１Ｈｚ，１Ｈ）．

The title compound was obtained from compound 36 according to the method described in Example 7.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.55 (m, 2H), 0.70-0.90 (m) , 2H), 1.00-2.00 (m, 6H), 2.15-2.45 (m, 4H), 2.55-2.65 (m, 1H), 2.86 (s, 3H) ), 2.80-3.10 (m, 3H), 3.49 (s, 3H), 3.30-3.70 (m, 2H), 4.04 (s, 1H), 4.44 ( d, J = 14Hz, 1H), 4.51 (d, J = 14Hz, 1H), 4.61 (s, 1H), 6.52 (d, J = 8Hz, 1H), 6.70 (d, J = 8Hz, 1H), 6.86 (d, J = 1Hz, 1H), 6.97 (d, J = 1Hz, 1H).

(Example 21)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-Methoxy-N-Methyl-N- ((1-Methyl-1H-Pyrazole-3-yl) Methyl) -1,2 , 3,4,5,6,8,8a-Octahydro-7H-4a, 8-Etano-4,13-Methylnobenzoflo [2,3-c] Pyrazole [4,3-d] Azepine-7-Carboxamide (38) ) Synthesis

実施例５に記載した方法に従い、化合物１１及びＮ－メチル－１－（１－メチル－１Ｈ－ピラゾール－３－イル）メタンアミン（Ｊｏｕｒｎａｌ оｆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ ２０１７，６０，９７２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）：０．０７－０．１５（ｍ，２Ｈ），０．４４－０．５３（ｍ，２Ｈ），０．７５－０．８４（ｍ，１Ｈ），１．０２－１．０８（ｍ，１Ｈ），１．２６－１．７８（ｍ，５Ｈ），２．２０－２．４１（ｍ，５Ｈ），２．５８－２．６６（ｍ，１Ｈ），２．８０（ｓ，３Ｈ），２．８３－２．９３（ｍ，１Ｈ），２．９７（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０３（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．４０（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，１Ｈ），３．６５（ｄｄｄ，Ｊ＝４，４，１４Ｈｚ，１Ｈ），３．８７（ｓ，６Ｈ），４．０９－４．１１（ｍ，１Ｈ），４．３２（ｓ，２Ｈ），４．６２（ｓ，１Ｈ），６．２１（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．５７（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７１（ｄ，Ｊ＝２Ｈｚ，１Ｈ），７．２９（ｄ，Ｊ＝２Ｈｚ，１Ｈ）．

From compound 11 and N-methyl-1- (1-methyl-1H-pyrazole-3-yl) methaneamine (synthesized by the method described in Journal оf Medicinal Chemistry 2017, 60, 972) according to the method described in Example 5. The title compound was obtained.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.15 (m, 2H), 0.44-0.53 (m, 2H), 0.75-0.84 (m) , 1H), 1.02-1.08 (m, 1H), 1.26-1.78 (m, 5H), 2.20-2.41 (m, 5H), 2.58-2.66 (M, 1H), 2.80 (s, 3H), 2.83-2.93 (m, 1H), 2.97 (d, J = 18Hz, 1H), 3.03 (d, J = 6Hz) , 1H), 3.40 (ddd, J = 4,11,14Hz, 1H), 3.65 (ddd, J = 4,4,14Hz, 1H), 3.87 (s, 6H), 4.09 -4.11 (m, 1H), 4.32 (s, 2H), 4.62 (s, 1H), 6.21 (d, J = 8Hz, 1H), 6.57 (d, J = 8Hz) , 1H), 6.71 (d, J = 2Hz, 1H), 7.29 (d, J = 2Hz, 1H).

(Example 22)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-Hydroxy-N-Methyl-N- ((1-Methyl-1H-Pyrazole-3-yl) Methyl) -1,2 , 3,4,5,6,8,8a-Octahydro-7H-4a, 8-Etano-4,13-Methylnobenzoflo [2,3-c] Pyrazole [4,3-d] Azepine-7-Carboxamide (39) ) Synthesis

実施例７に記載した方法に従い、化合物３８より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１３（ｍ，２Ｈ），０．４３－０．５３（ｍ，２Ｈ），０．７３－０．８２（ｍ，１Ｈ），１．０１－１．０８（ｍ，１Ｈ），１．２４－１．７２（ｍ，５Ｈ），２．１８－２．３９（ｍ，５Ｈ），２．５９－２．６４（ｍ，１Ｈ），２．７９（ｓ，３Ｈ），２．８３－２．９１（ｍ，１Ｈ），２．９５（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０２（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．４１（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，１Ｈ），３．６８（ｄｄｄ，Ｊ＝４，４，１４Ｈｚ，１Ｈ），３．８８（ｓ，３Ｈ），４．０８－４．１１（ｍ，１Ｈ），４．２９（ｄ，Ｊ＝１５Ｈｚ，１Ｈ），４．３３（ｄ，Ｊ＝１５Ｈｚ，１Ｈ），４．６５（ｓ，１Ｈ），６．２２（ｄ，Ｊ＝２Ｈｚ，１Ｈ），６．５２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．３０（ｄ，Ｊ＝２Ｈｚ，１Ｈ）．

The title compound was obtained from compound 38 according to the method described in Example 7.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.13 (m, 2H), 0.43-0.53 (m, 2H), 0.73-0.82 (m) , 1H), 1.01-1.08 (m, 1H), 1.24-1.72 (m, 5H), 2.18-2.39 (m, 5H), 2.59-2.64 (M, 1H), 2.79 (s, 3H), 2.83-2.91 (m, 1H), 2.95 (d, J = 18Hz, 1H), 3.02 (d, J = 6Hz) , 1H), 3.41 (ddd, J = 4,11,14Hz, 1H), 3.68 (ddd, J = 4,4,14Hz, 1H), 3.88 (s, 3H), 4.08 -4.11 (m, 1H), 4.29 (d, J = 15Hz, 1H), 4.33 (d, J = 15Hz, 1H), 4.65 (s, 1H), 6.22 (d) , J = 2Hz, 1H), 6.52 (d, J = 8Hz, 1H), 6.70 (d, J = 8Hz, 1H), 7.30 (d, J = 2Hz, 1H).

(Reference Example 18)
Synthesis of N-Methyl-1- (oxazole-2-yl) methaneamine (40)

参考例８に記載した方法に従い、オキサゾール－２－カルバルデヒドより表題化合物を得た。


^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．４７（ｓ，３Ｈ），３．９０（ｓ，２Ｈ），７．０７（ｓ，１Ｈ），７．６２（ｓ，１Ｈ）．

The title compound was obtained from oxazole-2-carbaldehyde according to the method described in Reference Example 8.


^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 2.47 (s, 3H), 3.90 (s, 2H), 7.07 (s, 1H), 7.62 (s, 1H) ..

(Example 23)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-Methoxy-N-Methyl-N- (Oxazole-2-ylmethyl) -1,2,3,4,5,6 Synthesis of 8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (41)

実施例５に記載した方法に従い、化合物１１及び化合物４０より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１４（ｍ，２Ｈ），０．４４－０．５３（ｍ，２Ｈ），０．７４－０．８４（ｍ，１Ｈ），１．０４－１．１０（ｍ，１Ｈ），１．２６－１．７２（ｍ，５Ｈ），２．２１－２．４２（ｍ，５Ｈ），２．５８－２．６６（ｍ，１Ｈ），２．８６－２．９４（ｍ，４Ｈ），２．９７（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０４（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．４３（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，１Ｈ），３．６８（ｄｄｄ，Ｊ＝４，４，１４Ｈｚ，１Ｈ），３．８７（ｓ，３Ｈ），４．０９－４．１２（ｍ，１Ｈ），４．４４（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），４．４９（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），４．６４－４．６５（ｍ，１Ｈ），６．５８（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．０８（ｄ，Ｊ＝１Ｈｚ，１Ｈ），７．６４（ｄ，Ｊ＝１Ｈｚ，１Ｈ）．

The title compound was obtained from compound 11 and compound 40 according to the method described in Example 5.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.14 (m, 2H), 0.44-0.53 (m, 2H), 0.74-0.84 (m) , 1H), 1.04-1.10 (m, 1H), 1.26-1.72 (m, 5H), 2.21-2.42 (m, 5H), 2.58-2.66 (M, 1H), 2.86-2.94 (m, 4H), 2.97 (d, J = 18Hz, 1H), 3.04 (d, J = 6Hz, 1H), 3.43 (ddd) , J = 4,11,14Hz, 1H), 3.68 (ddd, J = 4,4,14Hz, 1H), 3.87 (s, 3H), 4.09-4.12 (m, 1H) , 4.44 (d, J = 16Hz, 1H), 4.49 (d, J = 16Hz, 1H), 4.64-4.65 (m, 1H), 6.58 (d, J = 8Hz, 1H), 6.72 (d, J = 8Hz, 1H), 7.08 (d, J = 1Hz, 1H), 7.64 (d, J = 1Hz, 1H).

(Example 24)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-Hydroxy-N-Methyl-N- (Oxazole-2-ylmethyl) -1,2,3,4,5,6 Synthesis of 8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (42)

実施例７に記載した方法に従い、化合物４１より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１４（ｍ，２Ｈ），０．４４－０．５２（ｍ，２Ｈ），０．７５－０．８２（ｍ，１Ｈ），１．０３－１．０９（ｍ，１Ｈ），１．２４－１．７２（ｍ，５Ｈ），２．２０－２．３９（ｍ，５Ｈ），２．６０－２．６４（ｍ，１Ｈ），２．８４－２．９１（ｍ，４Ｈ），２．９５（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０３（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．４０－３．４８（ｍ，１Ｈ），３．６７－３．７３（ｍ，１Ｈ），４．０８－４．１１（ｍ，１Ｈ），４．４６（ｓ，２Ｈ），４．６６（ｓ，１Ｈ），６．５２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．１０（ｓ，１Ｈ），７．６５（ｓ，１Ｈ）．

The title compound was obtained from compound 41 according to the method described in Example 7.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.14 (m, 2H), 0.44-0.52 (m, 2H), 0.75-0.82 (m) , 1H), 1.03-1.09 (m, 1H), 1.24-1.72 (m, 5H), 2.20-2.39 (m, 5H), 2.60-2.64 (M, 1H), 2.84-2.91 (m, 4H), 2.95 (d, J = 18Hz, 1H), 3.03 (d, J = 6Hz, 1H), 3.40-3 .48 (m, 1H), 3.67-3.73 (m, 1H), 4.08-4.11 (m, 1H), 4.46 (s, 2H), 4.66 (s, 1H) ), 6.52 (d, J = 8Hz, 1H), 6.70 (d, J = 8Hz, 1H), 7.10 (s, 1H), 7.65 (s, 1H).

(Reference example 19)
Synthesis of N-Methyl-1- (oxazole-4-yl) methaneamine (43)

参考例８に記載した方法に従い、オキサゾール－４－カルバルデヒドより表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．４６（ｓ，３Ｈ），３．７１（ｓ，２Ｈ），７．５７（ｄ，Ｊ＝１Ｈｚ，１Ｈ），７．８５（ｓ，１Ｈ）．

The title compound was obtained from oxazole-4-carbaldehyde according to the method described in Reference Example 8.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 2.46 (s, 3H), 3.71 (s, 2H), 7.57 (d, J = 1Hz, 1H), 7.85 ( s, 1H).

(Example 25)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-Hydroxy-N-Methyl-N- (Oxazole-4-ylmethyl) -1,2,3,4,5,6 Synthesis of 8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (44)

実施例８に記載した方法に従い、化合物１１及び化合物４３より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１７（ｍ，２Ｈ），０．４２－０．５４（ｍ，２Ｈ），０．７２－０．８３（ｍ，１Ｈ），１．００－１．１０（ｍ，１Ｈ），１．１９－１．４４（ｍ，３Ｈ），１．４９－１．５６（ｍ，１Ｈ），１．５８－１．８０（ｍ，１Ｈ），２．１６－２．４１（ｍ，５Ｈ），２．５８－２．６５（ｍ，１Ｈ），２．８１－２．９４（ｍ，１Ｈ），２．８６（ｓ，３Ｈ），２．９５（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０２（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．４１（ｄｄｄ，Ｊ＝４，１２，１５Ｈｚ，１Ｈ），３．７０（ｄｄｄ，Ｊ＝４，４，１４Ｈｚ，１Ｈ），４．０６－４．１１（ｍ，１Ｈ），４．２２（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），４．２８（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），４．６２（ｓ，１Ｈ），５．２８（ｂｒ ｓ，１Ｈ），６．５２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．８０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．６８（ｓ，１Ｈ），７．８７（ｓ，１Ｈ）．

The title compound was obtained from compound 11 and compound 43 according to the method described in Example 8.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.05-0.17 (m, 2H), 0.42-0.54 (m, 2H), 0.72-0.83 (m) , 1H), 1.00-1.10 (m, 1H), 1.19-1.44 (m, 3H), 1.49-1.56 (m, 1H), 1.58-1.80 (M, 1H), 2.16-2.41 (m, 5H), 2.58-2.65 (m, 1H), 2.81-2.94 (m, 1H), 2.86 (s) , 3H), 2.95 (d, J = 18Hz, 1H), 3.02 (d, J = 6Hz, 1H), 3.41 (ddd, J = 4,12,15Hz, 1H), 3.70 (Ddd, J = 4,4,14Hz, 1H), 4.06-4.11 (m, 1H), 4.22 (d, J = 16Hz, 1H), 4.28 (d, J = 16Hz, 1H), 4.62 (s, 1H), 5.28 (br s, 1H), 6.52 (d, J = 8Hz, 1H), 6.80 (d, J = 8Hz, 1H), 7. 68 (s, 1H), 7.87 (s, 1H).

(Example 26)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-Methoxy-N-Methyl-N- (Thiazole-2-ylmethyl) -1,2,3,4,5,6 Synthesis of 8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (45)

実施例５に記載した方法に従い、化合物１１及びＮ－メチル－１－（チアゾール－２－イル）メタンアミン（Ｂｉｏｏｒｇａｎｉｃ ＆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ Ｌｅｔｔｅｒｓ ２０１５，２５，２０３７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）：０．０７－０．１５（ｍ，２Ｈ），０．４４－０．５３（ｍ，２Ｈ），０．７４－０．８４（ｍ，１Ｈ），１．０４－１．１１（ｍ，１Ｈ），１．２５－１．７３（ｍ，５Ｈ），２．２１－２．４２（ｍ，５Ｈ），２．６１－２．６６（ｍ，１Ｈ），２．８７－２．９３（ｍ，４Ｈ），２．９８（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０５（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．４４（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，１Ｈ），３．６７（ｄｄｄ，Ｊ＝４，４，１４Ｈｚ，１Ｈ），３．８７（ｓ，３Ｈ），４．１１－４．１３（ｍ，１Ｈ），４．５９－４．７１（ｍ，３Ｈ），６．５８（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．３１（ｄ，Ｊ＝３Ｈｚ，１Ｈ），７．７１（ｄ，Ｊ＝３Ｈｚ，１Ｈ）．

The title compound was obtained from compound 11 and N-methyl-1- (thiazole-2-yl) methaneamine (synthesized by the method described in Bioorganic & Medicinal Chemistry Letters 2015, 25, 2037) according to the method described in Example 5. ..

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.15 (m, 2H), 0.44-0.53 (m, 2H), 0.74-0.84 (m) , 1H), 1.04-1.11 (m, 1H), 1.25-1.73 (m, 5H), 2.21-2.42 (m, 5H), 2.61-2.66 (M, 1H), 2.87-2.93 (m, 4H), 2.98 (d, J = 18Hz, 1H), 3.05 (d, J = 6Hz, 1H), 3.44 (ddd) , J = 4,11,14Hz, 1H), 3.67 (ddd, J = 4,4,14Hz, 1H), 3.87 (s, 3H), 4.11-4.13 (m, 1H) , 4.59-4.71 (m, 3H), 6.58 (d, J = 8Hz, 1H), 6.72 (d, J = 8Hz, 1H), 7.31 (d, J = 3Hz, 1H), 7.71 (d, J = 3Hz, 1H).

(Example 27)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-Hydroxy-N-Methyl-N- (Thiazole-2-ylmethyl) -1,2,3,4,5,6 Synthesis of 8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (46)

実施例７に記載した方法に従い、化合物４５より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１６（ｍ，２Ｈ），０．４４－０．５３（ｍ，２Ｈ），０．７５－０．８４（ｍ，１Ｈ），１．０４－１．１０（ｍ，１Ｈ），１．２５－１．４５（ｍ，３Ｈ），１．５２－１．５７（ｍ，１Ｈ），１．６６－１．７２（ｍ，１Ｈ），２．２１－２．４２（ｍ，５Ｈ），２．６０－２．６７（ｍ，１Ｈ），２．８４－２．９２（ｍ，４Ｈ），２．９６（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０５（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．４５（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，１Ｈ），３．６７－３．７４（ｍ，１Ｈ），４．０９－４．１２（ｍ，１Ｈ），４．６１－４．７０（ｍ，３Ｈ），６．５３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．３２（ｄ，Ｊ＝３Ｈｚ，１Ｈ），７．７３（ｄ，Ｊ＝３Ｈｚ，１Ｈ）．

The title compound was obtained from compound 45 according to the method described in Example 7.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.16 (m, 2H), 0.44-0.53 (m, 2H), 0.75-0.84 (m) , 1H), 1.04-1.10 (m, 1H), 1.25-1.45 (m, 3H), 1.52-1.57 (m, 1H), 1.66-1.72 (M, 1H), 2.21-2.42 (m, 5H), 2.60-2.67 (m, 1H), 2.84-2.92 (m, 4H), 2.96 (d). , J = 18Hz, 1H), 3.05 (d, J = 6Hz, 1H), 3.45 (ddd, J = 4,11,14Hz, 1H), 3.67-3.74 (m, 1H) , 4.09-4.12 (m, 1H), 4.61-4.70 (m, 3H), 6.53 (d, J = 8Hz, 1H), 6.71 (d, J = 8Hz, 1H), 7.32 (d, J = 3Hz, 1H), 7.73 (d, J = 3Hz, 1H).

(Example 28)
Benzyl (4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carboxylate (47)

化合物８（１４ｍｇ，０．０２８ｍｍｏｌ）のジクロロメタン（３ｍＬ）溶液に、－４０°Ｃで１Ｍ三臭化ホウ素－ジクロロメタン溶液（８４μＬ，０．０８４ｍｍｏＬ）を加え、同温で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、酢酸エチルで二回抽出した。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：メタノール＝９５：５）で精製し、表題化合物（３．３ｍｇ，２４％）を無色油状物として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．１７（ｍ，２Ｈ），０．４２－０．５３（ｍ，２Ｈ），０．７０－０．９３（ｍ，１Ｈ），０．９９－１．１２（ｍ，１Ｈ）， １．１８－１．７６（ｍ，５Ｈ）， ２．１４－２．４１（ｍ，５Ｈ），２．５７－２．６７（ｍ，１Ｈ）， ２．７４－３．０５（ｍ，３Ｈ），３．３０－３．４４（ｍ，１Ｈ），４．０２－４．３２（ｍ，２Ｈ），４．４４－４．９０（ｍ，２Ｈ），５．１０－５．２５（ｍ，２Ｈ），６．４８－６．５６（ｍ，１Ｈ），６．６４－６．７３（ｍ，１Ｈ），７．２６－７．４５（ｍ，５Ｈ）．

To a solution of compound 8 (14 mg, 0.028 mmol) in dichloromethane (3 mL) was added a 1 M boron tribromide-dichloromethane solution (84 μL, 0.084 mmoL) at −40 ° C., and the mixture was stirred at the same temperature for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: methanol = 95: 5) to give the title compound (3.3 mg, 24%) as a colorless oil.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.17 (m, 2H), 0.42-0.53 (m, 2H), 0.70-0.93 (m) , 1H), 0.99-1.12 (m, 1H), 1.18-1.76 (m, 5H), 2.14-2.41 (m, 5H), 2.57-2.67 (M, 1H), 2.74-3.05 (m, 3H), 3.30-3.44 (m, 1H), 4.02-4.32 (m, 2H), 4.44-4 .90 (m, 2H), 5.10-15.25 (m, 2H), 6.48-6.56 (m, 1H), 6.64-6.73 (m, 1H), 7.26 -7.45 (m, 5H).

(Example 29)
Phenyl (4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carboxylate (48)

化合物９（１２．０ｍｇ，０．０３３ｍｍｏｌ）のテトラヒドロフラン（１ｍＬ）溶液に、０°ＣでＮ，Ｎ－ジイソプロピルエチルアミン（３０．０μＬ，０．１７ｍｍｏｌ）及びクロロギ酸フェニル（１２．５μＬ，０．０９９ｍｍｏｌ）を加え、同温で１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。合わせた抽出物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（ヘプタン：酢酸エチル＝６７：３３）で精製し、表題化合物（１５．９ｍｇ，定量的）を無色油状物質として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１６（ｍ，２Ｈ），０．４４－０．５６（ｍ，２Ｈ），０．７５－０．８６（ｍ，１Ｈ），１．０７－１．１８（ｍ，１Ｈ），１．３０－１．４０（ｍ，１Ｈ），１．４０－１．５１（ｍ，２Ｈ），１．５２－１．６７（ｍ，１Ｈ），１．７２－１．８５（ｍ，１Ｈ），２．２２－２．４１（ｍ，４Ｈ），２．４２（ｄｄ，Ｊ＝６，１８Ｈｚ，１Ｈ），２．６１－２．７１（ｍ，１Ｈ），２．８７－３．０１（ｍ，１Ｈ）３．００（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０４－３．０９（ｍ，１Ｈ），３．４５（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，０．７Ｈ），３．５８（ｄｄｄ，Ｊ＝４，１２，１４Ｈｚ，０．３Ｈ），３．８７（ｓ，３Ｈ），４．１３－４．２５（ｍ，１Ｈ），４．３３－４．３８（ｍ，０．３Ｈ），４．４２－４．４８（ｍ，０．７Ｈ），４．６３（ｓ，０．３Ｈ），４．６６（ｓ，０．７Ｈ），６．５９（ｄ，Ｊ＝９Ｈｚ，０．３Ｈ），６．６２（ｄ，Ｊ＝９Ｈｚ，０．７Ｈ），６．７３（ｄ，Ｊ＝９Ｈｚ，０．３Ｈ），６．７４（ｄ，Ｊ＝９Ｈｚ，０．７Ｈ），７．１０－７．１５（ｍ，２Ｈ），７，１９（ｄｄ，Ｊ＝７，７Ｈｚ，１Ｈ），７．３２－７．３９（ｍ，２Ｈ）．

N, N-diisopropylethylamine (30.0 μL, 0.17 mmol) and phenylchloroformate (12.5 μL, 0.099 mmol) in a solution of compound 9 (12.0 mg, 0.033 mmol) in tetrahydrofuran (1 mL) at 0 ° C. ) Was added, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate 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 obtained crude product was purified by preparative thin layer chromatography (heptane: ethyl acetate = 67: 33) to give the title compound (15.9 mg, quantitative) as a colorless oily substance.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.16 (m, 2H), 0.44-0.56 (m, 2H), 0.75-0.86 (m) , 1H), 1.07-1.18 (m, 1H), 1.30-1.40 (m, 1H), 1.40-1.51 (m, 2H), 1.52-1.67 (M, 1H), 1.72-1.85 (m, 1H), 2.22-2.41 (m, 4H), 2.42 (dd, J = 6,18Hz, 1H), 2.61 -2.71 (m, 1H), 2.87-3.01 (m, 1H) 3.00 (d, J = 18Hz, 1H), 3.04-3.09 (m, 1H), 3. 45 (ddd, J = 4,11,14Hz, 0.7H), 3.58 (ddd, J = 4,12,14Hz, 0.3H), 3.87 (s, 3H), 4.13-4 .25 (m, 1H), 4.33-4.38 (m, 0.3H), 4.42-4.48 (m, 0.7H), 4.63 (s, 0.3H), 4 .66 (s, 0.7H), 6.59 (d, J = 9Hz, 0.3H), 6.62 (d, J = 9Hz, 0.7H), 6.73 (d, J = 9Hz, 0.3H), 6.74 (d, J = 9Hz, 0.7H), 7.10-7.15 (m, 2H), 7,19 (dd, J = 7,7Hz, 1H), 7. 32-7.39 (m, 2H).

(Example 30)
Phenyl (4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carboxylate (49)

実施例７に記載した方法に従い、化合物４８より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１７（ｍ，２Ｈ），０．４４－０．５５（ｍ，２Ｈ），０．７４－０．８６（ｍ，１Ｈ），１．０６－１．１７（ｍ，１Ｈ），１．２４－１．４９（ｍ，３Ｈ），１．５５－１．６１（ｍ，１Ｈ），１．７１－１．８５（ｍ，１Ｈ），２．２２－２．４４（ｍ，５Ｈ），２．６１－２．７１（ｍ，１Ｈ），２．８６－３．０１（ｍ，１Ｈ），２．９８（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０３－３．０９（ｍ，１Ｈ），３．４６（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，０．６Ｈ），３．５４（ｄｄｄ，Ｊ＝３，１１，１４Ｈｚ，０．４Ｈ），４．１１－４．３２（ｍ，１．４Ｈ），４．３５－４．４１（ｍ，０．６Ｈ），４．６１（ｓ，０．４Ｈ），４．６５（ｓ，０．６Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．５５（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．７０（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），７．１１－７．１７（ｍ，２Ｈ），７．２０（ｔ，Ｊ＝７Ｈｚ，１Ｈ），７．３７（ｔ，Ｊ＝８Ｈｚ，２Ｈ）．

The title compound was obtained from compound 48 according to the method described in Example 7.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.17 (m, 2H), 0.44-0.55 (m, 2H), 0.74-0.86 (m) , 1H), 1.06-1.17 (m, 1H), 1.24-1.49 (m, 3H), 1.55-1.61 (m, 1H), 1.71-1.85 (M, 1H), 2.22-2.44 (m, 5H), 2.61-2.71 (m, 1H), 2.86-3.01 (m, 1H), 2.98 (d) , J = 18Hz, 1H), 3.03-3.09 (m, 1H), 3.46 (ddd, J = 4,11,14Hz, 0.6H), 3.54 (ddd, J = 3, 11, 14Hz, 0.4H), 4.11-4.32 (m, 1.4H), 4.35-4.41 (m, 0.6H), 4.61 (s, 0.4H), 4.65 (s, 0.6H), 6.54 (d, J = 8Hz, 0.4H), 6.55 (d, J = 8Hz, 0.6H), 6.70 (d, J = 8Hz) , 0.6H), 6.71 (d, J = 8Hz, 0.4H), 7.11-7.17 (m, 2H), 7.20 (t, J = 7Hz, 1H), 7.37 (T, J = 8Hz, 2H).

(Example 31)
Oxazole-2-ylmethyl (4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a , 8-Etano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] synthesis of azepine-7-carboxylate (50)

化合物１１（９．８ｍｇ，０．０１６ｍｍｏｌ）、オキサゾール－２－イルメタノール（１７．２ｍｇ，０．１７ｍｍｏｌ）及びトリエチルアミン（２２μＬ，０．１６ｍｍｏｌ）のテトラヒドロフラン（１．５ｍＬ）溶液を、室温で６５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、クロロホルムで三回抽出した。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（０－５％メタノール／クロロホルム）で精製し、表題化合物（６．４ｍｇ，８１％）を無色油状物質として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１４（ｍ，２Ｈ），０．４４－０．５２（ｍ，２Ｈ），０．７４－０．８３（ｍ，１Ｈ），１．０４－１．１１（ｍ，１Ｈ），１．２６－１．９０（ｍ，５Ｈ），２．１８－２．４２（ｍ，５Ｈ），２．６０－２．６６（ｍ，１Ｈ），２．８０－２．９１（ｍ，１Ｈ），２．９７（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０２（ｄ，Ｊ＝７Ｈｚ，１Ｈ），３．３６－３．４４（ｍ，１Ｈ），３．８５（ｓ，２．１Ｈ），３．８７（ｓ，０．９Ｈ），３．９０－４．０５（ｍ，０．３Ｈ），４．０９－４．１５（ｍ，０．７Ｈ），４．２２－４．２５（ｍ，０．７Ｈ），４．２９－４．３２（ｍ，０．３Ｈ），４．５４（ｓ，１Ｈ），５．２４（ｓ，２Ｈ），６．５７－６．６０（ｍ，１Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．１２（ｓ，０．７Ｈ），７．１４（ｓ，０．３Ｈ），７．６６（ｓ，０．７Ｈ），７．６８（ｓ，０．３Ｈ）．

A solution of compound 11 (9.8 mg, 0.016 mmol), oxazole-2-ylmethanol (17.2 mg, 0.17 mmol) and triethylamine (22 μL, 0.16 mmol) in tetrahydrofuran (1.5 mL) at room temperature for 65 hours. Stirred. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted three times with chloroform. The combined extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-5% methanol / chloroform) to give the title compound (6.4 mg, 81%) as a colorless oily substance.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.14 (m, 2H), 0.44-0.52 (m, 2H), 0.74-0.83 (m) , 1H), 1.04-1.11 (m, 1H), 1.26-1.90 (m, 5H), 2.18-2.42 (m, 5H), 2.60-2.66 (M, 1H), 2.80-2.91 (m, 1H), 2.97 (d, J = 18Hz, 1H), 3.02 (d, J = 7Hz, 1H), 3.36-3 .44 (m, 1H), 3.85 (s, 2.1H), 3.87 (s, 0.9H), 3.90-4.05 (m, 0.3H), 4.09-4 .15 (m, 0.7H), 4.22-4.25 (m, 0.7H), 4.29-4.32 (m, 0.3H), 4.54 (s, 1H), 5 .24 (s, 2H), 6.57-6.60 (m, 1H), 6.72 (d, J = 8Hz, 1H), 7.12 (s, 0.7H), 7.14 (s) , 0.3H), 7.66 (s, 0.7H), 7.68 (s, 0.3H).

(Example 32)
Oxazole-2-ylmethyl (4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a , 8-Etano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] synthesis of azepine-7-carboxylate (51)

化合物５０（６．４ｍｇ，０．０１３ｍｍｏｌ）のジクロロメタン（１．５ｍＬ）溶液に、氷冷下１Ｍ三臭化ホウ素－ジクロロメタン溶液（５０μＬ，０．０５ｍｍｏｌ）を加え、０℃で３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、クロロホルムで三回抽出した。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分取薄層クロマトグラフィー（クロロホルム：メタノール＝９６：４、二回）で精製し、表題化合物（３．１ｍｇ，５０％）を無色固体として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１２（ｍ，２Ｈ），０．４４－０．５２（ｍ，２Ｈ），０．７３－０．８２（ｍ，１Ｈ），１．０３－１．０９（ｍ，１Ｈ），１．２６－１．７２（ｍ，５Ｈ），２．１８－２．３９（ｍ，５Ｈ），２．５８－２．６６（ｍ，１Ｈ），２．７８－２．９０（ｍ，１Ｈ），２．９５（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０１（ｄ，Ｊ＝７Ｈｚ，１Ｈ），３．３４－３．４４（ｍ，１Ｈ），４．０２－４．２４（ｍ，２Ｈ），４．５４（ｓ，１Ｈ），５．２４（ｓ，０．８Ｈ），５．２７（ｓ，１．２Ｈ），６．５３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６９（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），７．１４（ｓ，０．６Ｈ），７．１５（ｓ，０．４Ｈ），７．６７（ｓ，０．６Ｈ），７．６８（ｓ，０．４Ｈ）．

To a solution of compound 50 (6.4 mg, 0.013 mmol) in dichloromethane (1.5 mL) was added a 1 M boron tribromide-dichloromethane solution (50 μL, 0.05 mmol) under ice-cooling, and the mixture was stirred at 0 ° C. for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted three times with chloroform. The combined extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: methanol = 96: 4, twice) to give the title compound (3.1 mg, 50%) as a colorless solid.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.12 (m, 2H), 0.44-0.52 (m, 2H), 0.73-0.82 (m) , 1H), 1.03-1.09 (m, 1H), 1.26-1.72 (m, 5H), 2.18-2.39 (m, 5H), 2.58-2.66 (M, 1H), 2.78-2.90 (m, 1H), 2.95 (d, J = 18Hz, 1H), 3.01 (d, J = 7Hz, 1H), 3.34-3 .44 (m, 1H), 4.02-4.24 (m, 2H), 4.54 (s, 1H), 5.24 (s, 0.8H), 5.27 (s, 1.2H) ), 6.53 (d, J = 8Hz, 1H), 6.69 (d, J = 8Hz, 0.6H), 6.71 (d, J = 8Hz, 0.4H), 7.14 (s). , 0.6H), 7.15 (s, 0.4H), 7.67 (s, 0.6H), 7.68 (s, 0.4H).

(Example 33)
Oxazole-5-ylmethyl (4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a , 8-Etano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] synthesis of azepine-7-carboxylate (52)

実施例３１に記載した方法に従い、化合物１１及びオキサゾール－５－イルメタノール（ＷＯ２０１５１３８８９５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）：０．０６－０．１３（ｍ，２Ｈ），０．４３－０．５３（ｍ，２Ｈ），０．７３－０．８２（ｍ，１Ｈ），１．０１－１．１１（ｍ，１Ｈ），１．２４－１．７５（ｍ，５Ｈ），２．１３－２．４２（ｍ，５Ｈ），２．５９－２．６５（ｍ，１Ｈ），２．７６－２．８９（ｍ，１Ｈ），２．９７（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０１（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．３７（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，１Ｈ），３．８６（ｓ，１．８Ｈ），３．８８（ｓ，１．２Ｈ），３．９３－３．９９（ｍ，０．４Ｈ），４．０７－４．１４（ｍ，０．６Ｈ），４．１６－４．１９（ｍ，０．６Ｈ），４．２８－４．３２（ｍ，０．４Ｈ），４．４０－４．４３（ｍ，０．６Ｈ），４．５１－４．５３（ｍ，０．４Ｈ），５．１２－５．２３（ｍ，２Ｈ），６．５７（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．５９（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．１４（ｓ，１Ｈ），７．８８（ｓ，０．６Ｈ），７．８９（ｓ，０．４Ｈ）．

The title compound was obtained from compound 11 and oxazole-5-ylmethanol (synthesized by the method described in WO2015138895) according to the method described in Example 31.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.13 (m, 2H), 0.43-0.53 (m, 2H), 0.73-0.82 (m) , 1H), 1.01-1.11 (m, 1H), 1.24-1.75 (m, 5H), 2.13-2.42 (m, 5H), 2.59-2.65 (M, 1H), 2.76-2.89 (m, 1H), 2.97 (d, J = 18Hz, 1H), 3.01 (d, J = 6Hz, 1H), 3.37 (ddd) , J = 4,11,14Hz, 1H), 3.86 (s, 1.8H), 3.88 (s, 1.2H), 3.93-3.99 (m, 0.4H), 4 .07-4.14 (m, 0.6H), 4.16-4.19 (m, 0.6H), 4.28-4.32 (m, 0.4H), 4.40-4. 43 (m, 0.6H), 4.51-4.53 (m, 0.4H), 5.12-5.23 (m, 2H), 6.57 (d, J = 8Hz, 0.4H) ), 6.59 (d, J = 8Hz, 0.6H), 6.72 (d, J = 8Hz, 1H), 7.14 (s, 1H), 7.88 (s, 0.6H), 7.89 (s, 0.4H).

(Example 34)
Oxazole-5-ylmethyl (4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a , 8-Etano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] synthesis of azepine-7-carboxylate (53)

実施例３２に記載した方法に従い、化合物５２より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１３（ｍ，２Ｈ），０．４３－０．５３（ｍ，２Ｈ），０．７３－０．８２（ｍ，１Ｈ），１．０１－１．１１（ｍ，１Ｈ），１．２４－１．７２（ｍ，５Ｈ），２．１３－２．４０（ｍ，５Ｈ），２．５９－２．６５（ｍ，１Ｈ），２．７４－２．８９（ｍ，１Ｈ），２．９５（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０１（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．３０－３．４３（ｍ，１Ｈ），３．９５－４．０２（ｍ，０．４Ｈ），４．０７－４．１５（ｍ，１．２Ｈ），４．２０－４．２４（ｍ，０．４Ｈ），４．３９－４．４１（ｍ，０．６Ｈ），４．４９－４．５２（ｍ，０．４Ｈ），５．１３－５．２６（ｍ，２Ｈ），６．５３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６９（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），７．１７（ｓ，１Ｈ），７．９０（ｓ，０．４Ｈ），７．９１（ｓ，０．６Ｈ）．

The title compound was obtained from compound 52 according to the method described in Example 32.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.13 (m, 2H), 0.43-0.53 (m, 2H), 0.73-0.82 (m) , 1H), 1.01-1.11 (m, 1H), 1.24-1.72 (m, 5H), 2.13-2.40 (m, 5H), 2.59-2.65 (M, 1H), 2.74-2.89 (m, 1H), 2.95 (d, J = 18Hz, 1H), 3.01 (d, J = 6Hz, 1H), 3.30-3 .43 (m, 1H), 3.95-4.02 (m, 0.4H), 4.07-4.15 (m, 1.2H), 4.20-4.24 (m, 0. 4H), 4.39-4.41 (m, 0.6H), 4.49-4.52 (m, 0.4H), 5.13-5.26 (m, 2H), 6.53 ( d, J = 8Hz, 1H), 6.69 (d, J = 8Hz, 0.6H), 6.71 (d, J = 8Hz, 0.4H), 7.17 (s, 1H), 7. 90 (s, 0.4H), 7.91 (s, 0.6H).

(Example 35)
Thiazole-2-ylmethyl (4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a , 8-Etano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] synthesis of azepine-7-carboxylate (54)

実施例３１に記載した方法に従い、化合物１１及びチアゾール－２－イルメタノール（ＷＯ２０１４０６６７９５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）：０．０６－０．１５（ｍ，２Ｈ），０．４４－０．５３（ｍ，２Ｈ），０．７５－０．８４（ｍ，１Ｈ），１．０４－１．１３（ｍ，１Ｈ），１．２６－１．７５（ｍ，５Ｈ），２．１６－２．４２（ｍ，５Ｈ），２．５９－２．６７（ｍ，１Ｈ），２．８０－２．９３（ｍ，１Ｈ），２．９８（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０３（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．３８－３．４８（ｍ，１Ｈ），３．８６（ｓ，１．８Ｈ），３．８８（ｓ，１．２Ｈ），４．０１－４．１８（ｍ，１Ｈ），４．２５－４．３４（ｍ，１Ｈ），４．５４（ｓ，１Ｈ），５．４１－５．５１（ｍ，２Ｈ），６．５８（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．５９（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．３４（ｄ，Ｊ＝３Ｈｚ，０．６Ｈ），７．３６（ｄ，Ｊ＝３Ｈｚ，０．４Ｈ），７．７７（ｄ，Ｊ＝３Ｈｚ，０．６Ｈ），７．７９（ｄ，Ｊ＝３Ｈｚ，０．４Ｈ）．

The title compound was obtained from compound 11 and thiazole-2-ylmethanol (synthesized by the method described in WO2014066795) according to the method described in Example 31.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.15 (m, 2H), 0.44-0.53 (m, 2H), 0.75-0.84 (m) , 1H), 1.04-1.13 (m, 1H), 1.26-1.75 (m, 5H), 2.16-2.42 (m, 5H), 2.59-2.67 (M, 1H), 2.80-2.93 (m, 1H), 2.98 (d, J = 18Hz, 1H), 3.03 (d, J = 6Hz, 1H), 3.38-3 .48 (m, 1H), 3.86 (s, 1.8H), 3.88 (s, 1.2H), 4.01-4.18 (m, 1H), 4.25-4.34 (M, 1H), 4.54 (s, 1H), 5.41-5.51 (m, 2H), 6.58 (d, J = 8Hz, 0.4H), 6.59 (d, J) = 8Hz, 0.6H), 6.72 (d, J = 8Hz, 1H), 7.34 (d, J = 3Hz, 0.6H), 7.36 (d, J = 3Hz, 0.4H) , 7.77 (d, J = 3Hz, 0.6H), 7.79 (d, J = 3Hz, 0.4H).

(Example 36)
Thiazole-2-ylmethyl (4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a , 8-Etano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] synthesis of azepine-7-carboxylate (55)

実施例３２に記載した方法に従い、化合物５４より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１５（ｍ，２Ｈ），０．４３－０．５３（ｍ，２Ｈ），０．７４－０．８３（ｍ，１Ｈ），１．０３－１．１２（ｍ，１Ｈ），１．２５－１．７４（ｍ，５Ｈ），２．１８－２．４１（ｍ，５Ｈ），２．５９－２．６７（ｍ，１Ｈ），２．７９－２．９１（ｍ，１Ｈ），２．９６（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０３（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．３６－３．４６（ｍ，１Ｈ），４．０５－４．３２（ｍ，２Ｈ），４．５３（ｓ，１Ｈ），５．４１－５．５５（ｍ，２Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７０（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），７．３５－７．３９（ｍ，１Ｈ），７．７８－７．８２（ｍ，１Ｈ）．

The title compound was obtained from compound 54 according to the method described in Example 32.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.15 (m, 2H), 0.43-0.53 (m, 2H), 0.74-0.83 (m) , 1H), 1.03-1.12 (m, 1H), 1.25-1.74 (m, 5H), 2.18-2.41 (m, 5H), 2.59-2.67 (M, 1H), 2.79-2.91 (m, 1H), 2.96 (d, J = 18Hz, 1H), 3.03 (d, J = 6Hz, 1H), 3.36-3 .46 (m, 1H), 4.05-4.32 (m, 2H), 4.53 (s, 1H), 5.41-5.55 (m, 2H), 6.54 (d, J) = 8Hz, 1H), 6.70 (d, J = 8Hz, 0.6H), 6.72 (d, J = 8Hz, 0.4H), 7.35-7.39 (m, 1H), 7 .78-7.82 (m, 1H).

(Example 37)
Pyrimidine-2-ylmethyl (4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a , 8-Etano-4,13-Metanobenzoflo [2,3-c] Pyrimidine [4,3-d] Synthesis of azepine-7-carboxylate (56)

実施例３１に記載した方法に従い、化合物１１及び２－ピリミジンメタノールより表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１９（ｍ，２Ｈ），０．４３－０．５４（ｍ，２Ｈ），０．７４－０．９２（ｍ，２Ｈ），１．０１－１．８２（ｍ，５Ｈ），２．１４－２．４５（ｍ，５Ｈ），２．５７－２．６９（ｍ，１Ｈ），２．８１－３．０７（ｍ，３Ｈ），３．２５－３．６２（ｍ，１Ｈ），３．８２－３．８９（ｍ，３Ｈ），４．１０－４．６６（ｍ，２Ｈ），４．８３－５．０２（ｍ，１Ｈ），５．２２－５．５３（ｍ，２Ｈ），６．５５－６．６４（ｍ，１Ｈ），６．６９－６．７４（ｍ，１Ｈ），７．１６－７．２６（ｍ，１Ｈ），８．６７－８．７７（ｍ，２Ｈ）．

The title compound was obtained from Compound 11 and 2-pyrimidinemethanol according to the method described in Example 31.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.19 (m, 2H), 0.43-0.54 (m, 2H), 0.74-0.92 (m) , 2H), 1.01-1.82 (m, 5H), 2.14-2.45 (m, 5H), 2.57-2.69 (m, 1H), 2.81-3.07 (M, 3H), 3.25-3.62 (m, 1H), 3.82-3.89 (m, 3H), 4.10-4.66 (m, 2H), 4.83-5 .02 (m, 1H), 5.22-5.53 (m, 2H), 6.55-6.64 (m, 1H), 6.69-6.74 (m, 1H), 7.16 -7.26 (m, 1H), 8.67-8.77 (m, 2H).

(Example 38)
Pyrimidine-2-ylmethyl (4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a , 8-Etano-4,13-Metanobenzoflo [2,3-c] Pyrimidine [4,3-d] Synthesis of azepine-7-carboxylate (57)

実施例３２に記載した方法に従い、化合物５６より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１８（ｍ，２Ｈ），０．４１－０．５４（ｍ，２Ｈ），０．７０－０．９３（ｍ，１Ｈ），１．０１－１．８３（ｍ，６Ｈ），２．１４－２．４５（ｍ，５Ｈ），２．５８－２．７１（ｍ，１Ｈ），２．８０－３．０９（ｍ，３Ｈ），３．２６－３．６０（ｍ，１Ｈ），４．１５－４．３３（ｍ，２Ｈ），４．５５－５．０６（ｍ，２Ｈ），５．２２－５．５９（ｍ，２Ｈ）６．４９－６．５７（ｍ，１Ｈ），６．６５－６．７４（ｍ，１Ｈ），７．１５－７．２９（ｍ，１Ｈ），８．６８－８．７４（ｍ，２Ｈ）．

The title compound was obtained from compound 56 according to the method described in Example 32.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.18 (m, 2H), 0.41-0.54 (m, 2H), 0.70-0.93 (m) , 1H), 1.01-1.83 (m, 6H), 2.14-2.45 (m, 5H), 2.58-2.71 (m, 1H), 2.80-3.09 (M, 3H), 3.26-3.60 (m, 1H), 4.15-4.33 (m, 2H), 4.55-5.06 (m, 2H), 5.22-5 .59 (m, 2H) 6.49-6.57 (m, 1H), 6.65-6.74 (m, 1H), 7.15-7.29 (m, 1H), 8.68- 8.74 (m, 2H).

(Example 39)
2- (Hydroxymethyl) Pyridine-3-yl (4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-Hydroxy-1,2,3,4,5,6,8,8a -Synthesis of Octahydro-7H-4a, 8-Etano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carboxylate (58)

化合物１１（１０ｍｇ，０．０１７ｍｍｏｌ）、３－ヒドロキシ－２－ピリジンメタノール塩酸塩（１１ｍｇ，０．０６６ｍｍｏｌ）及びトリエチルアミン（２３μＬ，０．１７ｍｍｏｌ）のテトラヒドロフラン（１ｍＬ）溶液を、室温で７０時間撹拌した。反応混合物に水を加え、酢酸エチルで二回抽出した。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（２－８％メタノール／クロロホルム）で精製し、２－（ヒドロキシメチル）ピリジン－３－イル （４Ｒ，４ａＳ，８Ｒ，８ａＲ，１３ｂＳ）－３－（シクロプロピルメチル）－１０－メトキシ－１，２，３，４，５，６，８，８ａ－オクタヒドロ－７Ｈ－４ａ，８－エタノ－４，１３－メタノベンゾフロ［２，３－ｃ］ピリド［４，３－ｄ］アゼピン－７－カルボキシレートの粗体（８．３ｍｇ）を無色油状物として得た。その後、実施例３２に記載した方法に従い、得られた粗体より表題化合物（２．４ｍｇ，２９％）を無色油状物質として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．１８（ｍ，２Ｈ），０．４３－０．５７（ｍ，２Ｈ），０．７４－０．９４（ｍ，１Ｈ），１．０７－１．８７（ｍ，６Ｈ），２．１９－２．４５（ｍ，５Ｈ），２．６１－２．７２（ｍ，１Ｈ），２．８６－３．１１（ｍ，３Ｈ），３．４１－３．６６（ｍ，１Ｈ），４．０６－４．３７（ｍ，３Ｈ），４．５４－４．８７（ｍ，４Ｈ），６．５２－６．６０（ｍ，１Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．２４－７．３３（ｍ，１Ｈ），７．５４－７．６２（ｍ，１Ｈ），８．４２－８．４７（ｍ，１Ｈ）．

A solution of compound 11 (10 mg, 0.017 mmol), 3-hydroxy-2-pyridinemethanol hydrochloride (11 mg, 0.066 mmol) and triethylamine (23 μL, 0.17 mmol) in tetrahydrofuran (1 mL) was stirred at room temperature for 70 hours. .. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (2-8% methanol / chloroform) and 2- (hydroxymethyl) pyridine-3-yl (4R, 4aS, 8R, 8aR, 13bS) -3-( Cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4] , 3-d] A crude product of azepine-7-carboxylate (8.3 mg) was obtained as a colorless oil. Then, according to the method described in Example 32, the title compound (2.4 mg, 29%) was obtained as a colorless oily substance from the obtained crude product.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.04-0.18 (m, 2H), 0.43-0.57 (m, 2H), 0.74-0.94 (m) , 1H), 1.07-1.87 (m, 6H), 2.19-2.45 (m, 5H), 2.61-2.72 (m, 1H), 2.86-3.11 (M, 3H), 3.41-3.66 (m, 1H), 4.06-4.37 (m, 3H), 4.54-4.87 (m, 4H), 6.52-6 .60 (m, 1H), 6.72 (d, J = 8Hz, 1H), 7.24-7.33 (m, 1H), 7.54-7.62 (m, 1H), 8.42 -8.47 (m, 1H).

(Example 40)
(4R, 4aS, 8R, 8aR, 13bS) -7-Benzyl-3- (cyclopropylmethyl) -1,2,3,4,6,7,8,8a-octahydro-5H-4a, 8-ethano- Synthesis of 4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-10-ol (59)

実施例３２に記載した方法に従い、化合物４７より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１５（ｍ，２Ｈ），０．４１－０．５４（ｍ，２Ｈ），０．７３－０．８５（ｍ，１Ｈ），０．８９－０．９９（ｍ，１Ｈ），１．００－１．１１（ｍ，１Ｈ），１．１６－１．２８（ｍ，１Ｈ），１．２９－１．３８（ｍ，１Ｈ），１．４９－１．７０（ｍ，２Ｈ），２．２２（ｄｄ，Ｊ＝７，１２Ｈｚ，１Ｈ），２．２５－２．４７（ｍ，４Ｈ），２．６３（ｄｄ，Ｊ＝５，１２Ｈｚ，１Ｈ），２．７４－２．８８（ｍ，４Ｈ），２．９３（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），２．９８（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．６６（ｄ，Ｊ＝１４Ｈｚ，１Ｈ），３．７７（ｄ，Ｊ＝１４Ｈｚ，１Ｈ），４．５５（ｓ，１Ｈ），６．４８（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６４（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．２０－７．４０（ｍ，５Ｈ）．

The title compound was obtained from compound 47 according to the method described in Example 32.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.15 (m, 2H), 0.41-0.54 (m, 2H), 0.73-0.85 (m) , 1H), 0.89-0.99 (m, 1H), 1.00-1.11 (m, 1H), 1.16-1.28 (m, 1H), 1.29-1.38 (M, 1H), 1.49-1.70 (m, 2H), 2.22 (dd, J = 7,12Hz, 1H), 2.25-2.47 (m, 4H), 2.63 (Dd, J = 5,12Hz, 1H), 2.74-2.88 (m, 4H), 2.93 (d, J = 18Hz, 1H), 2.98 (d, J = 6Hz, 1H) , 3.66 (d, J = 14Hz, 1H), 3.77 (d, J = 14Hz, 1H), 4.55 (s, 1H), 6.48 (d, J = 8Hz, 1H), 6 .64 (d, J = 8Hz, 1H), 7.20-7.40 (m, 5H).

(Example 41)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -1,2,3,4,6,7,8,8a-Octahydro-5H-4a, 8-Etano-4,13- Synthesis of methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-10-ol (60)

実施例２に記載した方法に従い、化合物５９より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ（ｐｐｍ）：０．１２－０．２２（ｍ，２Ｈ），０．４６－０．５８（ｍ，２Ｈ），０．７９－０．９２（ｍ，１Ｈ），１．１１－１．２１（ｍ，１Ｈ），１．３０－１．４５（ｍ，２Ｈ），１．４９－１．６１（ｍ，１Ｈ），１．６９（ｄｄｄ，Ｊ＝５，５，１６Ｈｚ，１Ｈ），１．７５－１．８８（ｍ，１Ｈ），２．２９－２．４５（ｍ，４Ｈ），２．５０（ｄｄ，Ｊ＝６，１９Ｈｚ，１Ｈ），２．６８－２．８１（ｍ，１Ｈ），３．０３（ｄ，Ｊ＝１９Ｈｚ，１Ｈ），３．０３－３．１４（ｍ，１Ｈ），３．１９－３．４０（ｍ，３Ｈ），３．６２（ｄ，Ｊ＝２Ｈｚ，１Ｈ），４．７３（ｓ，１Ｈ），６．５７（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６７（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．

The title compound was obtained from compound 59 according to the method described in Example 2.

^{1 1} H-NMR (400 MHz, CD ₃ OD) δ (ppm): 0.12-0.22 (m, 2H), 0.46-0.58 (m, 2H), 0.79-0.92 ( m, 1H), 1.11-1.21 (m, 1H), 1.30-1.45 (m, 2H), 1.49-1.61 (m, 1H), 1.69 (ddd, J = 5,5,16Hz, 1H), 1.75-1.88 (m, 1H), 2.29-2.45 (m, 4H), 2.50 (dd, J = 6,19Hz, 1H) ), 2.68-2.81 (m, 1H), 3.03 (d, J = 19Hz, 1H), 3.03-3.14 (m, 1H), 3.19-3.40 (m) , 3H), 3.62 (d, J = 2Hz, 1H), 4.73 (s, 1H), 6.57 (d, J = 8Hz, 1H), 6.67 (d, J = 8Hz, 1H) ).

(Example 42)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (3-fluoropyridin-2-yl) methanone (61)

化合物９（１０ｍｇ，０．０２７ｍｍｏｌ）、３－フルオロピコリン酸（１１．５ｍｇ，０．０８２ｍｍｏｌ）、Ｎ，Ｎ－ジメチルアミノピリジン（１．８ｍｇ，０．０１４ｍｍｏｌ），１－ヒドロキシベンズトリアゾール一水和物（１１．１ｍｇ，０．０８２ｍｍｏｌ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（１４．３μＬ，０．０８２ｍｍｏｌ）及び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（１５．７ｍｇ，０．０８２ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）溶液を、室温で２．５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＝９７：３）で精製し、表題化合物（１５ｍｇ，定量的）を無色油状物質として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１２（ｍ，２Ｈ），０．４３－０．５２（ｍ，２Ｈ），０．７１－０．８６（ｍ，１Ｈ），１．０５－１．２０（ｍ，１Ｈ），１．２３－１．３５（ｍ，２Ｈ），１．５０－１．６１（ｍ，２Ｈ），１．６８－１．８６（ｍ，１Ｈ），２．１９－２．４４（ｍ，５Ｈ），２．６１－２．６８（ｍ，１Ｈ），２．８３－２．９２（ｍ，０．７Ｈ），２．９７－３．０４（ｍ，０．３Ｈ），２．９９（ｄ，Ｊ＝１９Ｈｚ，１Ｈ），３．０４（ｄ，Ｊ＝６Ｈｚ，０．７Ｈ），３．０８（ｄ，Ｊ＝６Ｈｚ，０．３Ｈ），３．３９－３．６２（ｍ，１．７Ｈ），３．７８－３．８２（ｍ，０．３Ｈ），３．７９（ｓ，０．９Ｈ），３．９０（ｓ，２．１Ｈ），４．５１（ｄｄｄ，Ｊ＝５，５，１４Ｈｚ，０．３Ｈ），４．６８－４．７１（ｍ，０．３Ｈ），４．７３－４．７５（ｍ，０．７Ｈ），４．８０－４．８３（ｍ，０．７Ｈ），６．６０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６８（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．７４（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），７．３３－７．４０（ｍ，１Ｈ），７．４６－７．５３（ｍ，１Ｈ），８．４４（ｄｄｄ，Ｊ＝１，１，５Ｈｚ，０．３Ｈ），８．４７（ｄｄｄ，Ｊ＝１，１，５Ｈｚ，０．７Ｈ）．

Compound 9 (10 mg, 0.027 mmol), 3-fluoropicolinic acid (11.5 mg, 0.082 mmol), N, N-dimethylaminopyridine (1.8 mg, 0.014 mmol), 1-hydroxybenztriazole monohydration. (11.1 mg, 0.082 mmol), N, N-diisopropylethylamine (14.3 μL, 0.082 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (15.7 mg, 0. A solution of N, N-dimethylformamide (1 mL) (082 mmol) was stirred at room temperature for 2.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: methanol = 97: 3) to give the title compound (15 mg, quantitative) as a colorless oily substance.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.12 (m, 2H), 0.43-0.52 (m, 2H), 0.71-0.86 (m) , 1H), 1.05-1.20 (m, 1H), 1.23-1.35 (m, 2H), 1.50-1.61 (m, 2H), 1.68-1.86 (M, 1H), 2.19-2.44 (m, 5H), 2.61-2.68 (m, 1H), 2.83-2.92 (m, 0.7H), 2.97 -3.04 (m, 0.3H), 2.99 (d, J = 19Hz, 1H), 3.04 (d, J = 6Hz, 0.7H), 3.08 (d, J = 6Hz, 0.3H), 3.39-3.62 (m, 1.7H), 3.78-3.82 (m, 0.3H), 3.79 (s, 0.9H), 3.90 ( s, 2.1H), 4.51 (ddd, J = 5,5,14Hz, 0.3H), 4.68-4.71 (m, 0.3H), 4.73-4.75 (m) , 0.7H), 4.80-4.83 (m, 0.7H), 6.60 (d, J = 8Hz, 1H), 6.68 (d, J = 8Hz, 0.3H), 6 .74 (d, J = 8Hz, 0.7H), 7.33-7.40 (m, 1H), 7.46-7.53 (m, 1H), 8.44 (ddd, J = 1, 1,5Hz, 0.3H), 8.47 (ddd, J = 1,1,5Hz, 0.7H).

(Example 43)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (3-fluoropyridin-2-yl) methanone (62)

実施例７に記載した方法に従い、化合物６１より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１５（ｍ，２Ｈ），０．４０－０．５２（ｍ，２Ｈ），０．６９－０．７８（ｍ，１Ｈ），１．１４－１．１８（ｍ，１Ｈ），１．２４－１．３４（ｍ，２Ｈ），１．４６－１．８８（ｍ，３Ｈ），２．１７－２．４０（ｍ，５Ｈ），２．６０－２．６７（ｍ，１Ｈ），２．８０－２．９１（ｍ，０．８Ｈ），２．９２－３．００（ｍ，０．２Ｈ），２．９７（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０３（ｄ，Ｊ＝６Ｈｚ，０．８Ｈ），３．０７（ｄ，Ｊ＝６Ｈｚ，０．２Ｈ），３．３９－３．５８（ｍ，１．８Ｈ），３．６９－３．７２（ｍ，０．２Ｈ），４．５１－４．５８（ｍ，０．２Ｈ），４．６８－４．７０（ｍ，０．２Ｈ），４．７１－４．７６（ｍ，１．６Ｈ），６．５２（ｄ，Ｊ＝８Ｈｚ，０．２Ｈ），６．５５（ｄ，Ｊ＝８Ｈｚ，０．８Ｈ），６．６４（ｄ，Ｊ＝８Ｈｚ，０．２Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．８Ｈ），７．３９（ｄｄｄ，Ｊ＝４，４，８Ｈｚ，１Ｈ）， ７．５２（ｄｄｄ，Ｊ＝１，８，８Ｈｚ，１Ｈ），８．１４（ｄｄｄ，Ｊ＝１，１，４Ｈｚ，０．２Ｈ），８．４９（ｄｄｄ，Ｊ＝１，１，４Ｈｚ，０．８Ｈ），

The title compound was obtained from compound 61 according to the method described in Example 7.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.05-0.15 (m, 2H), 0.40-0.52 (m, 2H), 0.69-0.78 (m) , 1H), 1.14-1.18 (m, 1H), 1.24-1.34 (m, 2H), 1.46-1.88 (m, 3H), 2.17-2.40 (M, 5H), 2.60-2.67 (m, 1H), 2.80-2.91 (m, 0.8H), 2.92-3.00 (m, 0.2H), 2 .97 (d, J = 18Hz, 1H), 3.03 (d, J = 6Hz, 0.8H), 3.07 (d, J = 6Hz, 0.2H), 3.39-3.58 ( m, 1.8H), 3.69-3.72 (m, 0.2H), 4.51-4.58 (m, 0.2H), 4.68-4.70 (m, 0.2H) ), 4.71-4.76 (m, 1.6H), 6.52 (d, J = 8Hz, 0.2H), 6.55 (d, J = 8Hz, 0.8H), 6.64 (D, J = 8Hz, 0.2H), 6.73 (d, J = 8Hz, 0.8H), 7.39 (ddd, J = 4,4,8Hz, 1H), 7.52 (ddd, J = 1,8,8Hz, 1H), 8.14 (ddd, J = 1,1,4Hz, 0.2H), 8.49 (ddd, J = 1,1,4Hz, 0.8H),

(Example 44)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano -4,13-Metanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (pyrimidine-2-yl) synthesis of methanone (63)

化合物９（１４ｍｇ，０．０３８ｍｍｏｌ）、ピリミジン－２－カルボン酸（１４．２ｍｇ，０．１１ｍｍｏｌ）、Ｎ，Ｎ－ジメチルアミノピリジン（２．３ｍｇ，０．０１９ｍｍｏｌ），１－ヒドロキシベンズトリアゾール一水和物（１７．５ｍｇ，０．１１ｍｍｏｌ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（２０μＬ，０．１１ｍｍｏｌ）及び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（２２ｍｇ，０．１１ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）溶液を、室温で１５時間撹拌した。反応混合物に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液で三回、飽和食塩水で一回洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧下にて濃縮した。得られた粗生成物のジクロロメタン（１ｍL）溶液に、氷冷下、１Ｍ三臭化ホウ素－ジクロロメタン溶液（２００μＬ，０．２０ｍｍｏＬ）を加え、室温で１時間撹拌した。反応混合物に２８％アンモニア水溶液を加え、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（０－１０％メタノール／クロロホルム）で精製し、表題化合物（９．２ｍｇ，５３％）を無色油状物質として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．１５（ｍ，２Ｈ），０．４０－０．５５（ｍ，２Ｈ），０．７０－０．８６（ｍ，１Ｈ），１．０４－１．３３（ｍ，３Ｈ），１．４５－１．６１（ｍ，２Ｈ），１．６９－１．８７（ｍ，１Ｈ），２．１８－２．４１（ｍ，５Ｈ），２．６０－２．６９（ｍ，１Ｈ），２．８６－２．９９（ｍ，１Ｈ），２．９６（ｄ，Ｊ＝１９Ｈｚ，１Ｈ），３．０４（ｄ，Ｊ＝６Ｈｚ，０．７Ｈ），３．０８（ｄ，Ｊ＝６Ｈｚ，０．３Ｈ），３．３８－３．５４（ｍ，１．７Ｈ），３．６４－３．６８（ｍ，０．３Ｈ），４．５４－４．６１（ｍ，０．３Ｈ），４．６９－４．７５（ｍ，０．７Ｈ），４．７５（ｓ，０．７Ｈ），４．８４（ｓ，０．３Ｈ），６．５１（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．６５（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），７．３７（ｔ，Ｊ＝５Ｈｚ，１Ｈ），８．８４（ｄ，Ｊ＝５Ｈｚ，０．６Ｈ），８．８５（ｄ，Ｊ＝５Ｈｚ，１．４Ｈ）．

Compound 9 (14 mg, 0.038 mmol), pyrimidin-2-carboxylic acid (14.2 mg, 0.11 mmol), N, N-dimethylaminopyridine (2.3 mg, 0.019 mmol), 1-hydroxybenztriazole monohydrate. Japanese products (17.5 mg, 0.11 mmol), N, N-diisopropylethylamine (20 μL, 0.11 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (22 mg, 0.11 mmol). The N, N-dimethylformamide (1 mL) solution was stirred at room temperature for 15 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed three times with saturated aqueous sodium hydrogen carbonate solution and once with saturated brine. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. A 1M boron tribromide-dichloromethane solution (200 μL, 0.20 mmoL) was added to a solution of the obtained crude product in dichloromethane (1 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. A 28% aqueous ammonia solution was added to the reaction mixture, and the mixture was extracted three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-10% methanol / chloroform) to give the title compound (9.2 mg, 53%) as a colorless oily substance.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.04-0.15 (m, 2H), 0.40-0.55 (m, 2H), 0.70-0.86 (m) , 1H), 1.04-1.33 (m, 3H), 1.45-1.61 (m, 2H), 1.69-1.87 (m, 1H), 2.18-2.41 (M, 5H), 2.60-2.69 (m, 1H), 2.86-2.99 (m, 1H), 2.96 (d, J = 19Hz, 1H), 3.04 (d) , J = 6Hz, 0.7H), 3.08 (d, J = 6Hz, 0.3H), 3.38-3.54 (m, 1.7H), 3.64-3.68 (m, 0.3H), 4.54-4.61 (m, 0.3H), 4.69-4.75 (m, 0.7H), 4.75 (s, 0.7H), 4.84 ( s, 0.3H), 6.51 (d, J = 8Hz, 0.3H), 6.54 (d, J = 8Hz, 0.7H), 6.65 (d, J = 8Hz, 0.3H) ), 6.73 (d, J = 8Hz, 0.7H), 7.37 (t, J = 5Hz, 1H), 8.84 (d, J = 5Hz, 0.6H), 8.85 (d). , J = 5Hz, 1.4H).

(Example 45)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (pyrimidine-4-yl) methanone (64)

化合物６０（５．７ｍｇ，０．０１６ｍｍｏｌ）、ピリミジン－４－カルボン酸（６ｍｇ，０．０４９ｍｍｏｌ）、Ｎ，Ｎ－ジメチルアミノピリジン（１．１ｍｇ，０．００８ｍｍｏｌ），１－ヒドロキシベンズトリアゾール一水和物（６．６ｍｇ，０．０４９ｍｍｏｌ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（８．４μＬ，０．０４９ｍｍｏｌ）及び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（８．３ｍｇ，０．０４９ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（０．５ｍＬ）溶液を、室温で１時間撹拌した。反応混合物に２Ｍ水酸化ナトリウム水溶液を加え、１時間撹拌した。反応混合物をクロロホルムで三回抽出後、合わせた抽出物を硫酸ナトリウムで乾燥し、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＝９７：３）で精製し、表題化合物（５．９ｍｇ，８０％）を無色油状物質として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１５（ｍ，２Ｈ），０．４３－０．５４（ｍ，２Ｈ），０．７１－０．８１（ｍ，１Ｈ），１．０４－１．１８（ｍ，１Ｈ），１．２５－１．３９（ｍ，２Ｈ），１．４６－１．８４（ｍ，３Ｈ），２．２０－２．４３（ｍ，５Ｈ），２．６１－２．６８（ｍ，１Ｈ），２．８９－２．９９（ｍ，１Ｈ），２．９７（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０６（ｄ，Ｊ＝６Ｈｚ，０．７Ｈ），３．０８（ｄ，Ｊ＝６Ｈｚ，０．３Ｈ），３．４３－３．５８（ｍ，１Ｈ），３．６７－３．７６（ｍ，０．７Ｈ），３．９２－３．９６（ｍ，０．３Ｈ），４．４９－４．５６（ｍ，０．３Ｈ），４．６５－４．７１（ｍ，１．４Ｈ），４．８９－４．９２（ｍ，０．３Ｈ），５．２８（ｂｒ ｓ，１Ｈ），６．５３（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．５６（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．６７（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），７．５８（ｄｄ，Ｊ＝１，５Ｈｚ，０．７Ｈ），７．６１（ｄｄ，Ｊ＝１，５Ｈｚ，０．３Ｈ），８．８９（ｄ，Ｊ＝５Ｈｚ，０．７Ｈ），８．９０（ｄ，Ｊ＝５Ｈｚ，０．３Ｈ），９．２８（ｂｒ ｓ，０．７Ｈ），９．３２（ｄ，Ｊ＝１Ｈｚ，０．３Ｈ）．

Compound 60 (5.7 mg, 0.016 mmol), pyrimidin-4-carboxylic acid (6 mg, 0.049 mmol), N, N-dimethylaminopyridine (1.1 mg, 0.008 mmol), 1-hydroxybenztriazole monohydrate. Japanese product (6.6 mg, 0.049 mmol), N, N-diisopropylethylamine (8.4 μL, 0.049 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (8.3 mg, 0). A solution of N, N-dimethylformamide (0.5 mL) (0.049 mmol) was stirred at room temperature for 1 hour. A 2M aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was stirred for 1 hour. The reaction mixture was extracted three times with chloroform, and the combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: methanol = 97: 3) to give the title compound (5.9 mg, 80%) as a colorless oily substance.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.15 (m, 2H), 0.43-0.54 (m, 2H), 0.71-0.81 (m) , 1H), 1.04-1.18 (m, 1H), 1.25-1.39 (m, 2H), 1.46-1.84 (m, 3H), 2.20-2.43 (M, 5H), 2.61-2.68 (m, 1H), 2.89-2.99 (m, 1H), 2.97 (d, J = 18Hz, 1H), 3.06 (d) , J = 6Hz, 0.7H), 3.08 (d, J = 6Hz, 0.3H), 3.43-3.58 (m, 1H), 3.67-3.76 (m, 0. 7H), 3.92-3.96 (m, 0.3H), 4.49-4.56 (m, 0.3H), 4.65-4.71 (m, 1.4H), 4. 89-4.92 (m, 0.3H), 5.28 (br s, 1H), 6.53 (d, J = 8Hz, 0.3H), 6.56 (d, J = 8Hz, 0. 7H), 6.67 (d, J = 8Hz, 0.3H), 6.73 (d, J = 8Hz, 0.7H), 7.58 (dd, J = 1,5Hz, 0.7H), 7.61 (dd, J = 1,5Hz, 0.3H), 8.89 (d, J = 5Hz, 0.7H), 8.90 (d, J = 5Hz, 0.3H), 9.28 (Br s, 0.7H), 9.32 (d, J = 1Hz, 0.3H).

(Example 46)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (pyrimidine-5-yl) methanone (65)

実施例４２に記載した方法に従い、化合物９及びピリミジン－５－カルボン酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１６（ｍ，２Ｈ），０．４３－０．５５（ｍ，２Ｈ），０．７１－０．８２（ｍ，１Ｈ），１．１０－１．４３（ｍ，３Ｈ），１．５０－１．８５（ｍ，３Ｈ），２．１５－２．４１（ｍ，４Ｈ），２．４２（ｄｄ，Ｊ＝６，１８Ｈｚ，１Ｈ），２．６６（ｄｄ，Ｊ＝５，１２Ｈｚ，１Ｈ），２．８３－２．９４（ｍ，１Ｈ），３．０１（ｄ，Ｊ＝１９Ｈｚ，１Ｈ），３．０５（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．５７－３．６７（ｍ，２Ｈ），３．９０（ｓ，３Ｈ），４．６６（ｓ，１Ｈ），４．７６－４．８２（ｍ，１Ｈ），６．６２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７６（ｄ，Ｊ＝８Ｈｚ，１Ｈ），８．８３（ｓ，２Ｈ），９．２８（ｓ，１Ｈ）．

The title compound was obtained from compound 9 and pyrimidine-5-carboxylic acid according to the method described in Example 42.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.16 (m, 2H), 0.43-0.55 (m, 2H), 0.71-0.82 (m) , 1H), 1.10-1.43 (m, 3H), 1.50-1.85 (m, 3H), 2.15-2.41 (m, 4H), 2.42 (dd, J) = 6,18Hz, 1H), 2.66 (dd, J = 5,12Hz, 1H), 2.83-2.94 (m, 1H), 3.01 (d, J = 19Hz, 1H), 3 .05 (d, J = 6Hz, 1H), 3.57-3.67 (m, 2H), 3.90 (s, 3H), 4.66 (s, 1H), 4.76-4.82 (M, 1H), 6.62 (d, J = 8Hz, 1H), 6.76 (d, J = 8Hz, 1H), 8.83 (s, 2H), 9.28 (s, 1H).

(Example 47)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (pyrimidine-5-yl) methanone (65)

実施例７に記載した方法に従い、化合物６５より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．１５（ｍ，２Ｈ），０．４２－０．５４（ｍ，２Ｈ），０．７０－０．８１（ｍ，１Ｈ），１．１１－１．２１（ｍ，１Ｈ），１．２２－１．３４（ｍ，１Ｈ），１．３４－１．４２（ｍ，１Ｈ），１．４８－１．５９（ｍ，１Ｈ），１．６２（ｄｄ，Ｊ＝２，１４Ｈｚ，１Ｈ），１．７３－１．８５（ｍ，１Ｈ），２．１３－２．４４（ｍ，５Ｈ），２．６５（ｄｄ，Ｊ＝４，１１Ｈｚ，１Ｈ），２．８１－２．９２（ｍ，１Ｈ），２．９８（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０３（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．５２－３．７０（ｍ，２Ｈ），４．６４（ｓ，１Ｈ），４．６８－４．７４（ｍ，１Ｈ），６．５５（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７４（ｄ，Ｊ＝８Ｈｚ，１Ｈ），８．８４（ｓ，２Ｈ），９．２９（ｓ，１Ｈ）．

The title compound was obtained from compound 65 according to the method described in Example 7.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.15 (m, 2H), 0.42-0.54 (m, 2H), 0.70-0.81 (m) , 1H), 1.11-1.21 (m, 1H), 1.22-1.34 (m, 1H), 1.34-1.42 (m, 1H), 1.48-1.59 (M, 1H), 1.62 (dd, J = 2,14Hz, 1H), 1.73-1.85 (m, 1H), 2.13-2.44 (m, 5H), 2.65 (Dd, J = 4,11Hz, 1H), 2.81-2.92 (m, 1H), 2.98 (d, J = 18Hz, 1H), 3.03 (d, J = 6Hz, 1H) , 3.52-3.70 (m, 2H), 4.64 (s, 1H), 4.68-4.74 (m, 1H), 6.55 (d, J = 8Hz, 1H), 6 .74 (d, J = 8Hz, 1H), 8.84 (s, 2H), 9.29 (s, 1H).

(Example 48)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (pyridazine-3-yl) methanone (67)

実施例４５に記載した方法に従い、化合物６０およびピリダジン－３－カルボン酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．００－０．１８（ｍ，２Ｈ），０．４５－０．５５（ｍ，２Ｈ），０．７０－１．００（ｍ，２Ｈ），１．１０－１．２０（ｍ，１Ｈ），１．２０－１．９０（ｍ，４Ｈ），２．２０－２．４５（ｍ，５Ｈ），２．６０－２．７０（ｍ，１Ｈ），２．９５－３．１０（ｍ，３Ｈ），３．４０－３．７０（ｍ，１Ｈ），３．８５－４．００（ｍ，０．７Ｈ），４．１３（ｓ，０．３Ｈ），４．５０－４．６５（ｍ，０．３Ｈ），４．７０－４．８０（ｍ，１．４Ｈ），５．０１（ｓ，０．３Ｈ），６．５０－６．６０（ｍ，１Ｈ），６．６７（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），７．６０－７．６５（ｍ，１Ｈ），７．８０－７．９０（ｍ，１Ｈ）９．２３－９．２８（ｍ，１Ｈ）．

The title compound was obtained from compound 60 and pyridazine-3-carboxylic acid according to the method described in Example 45.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.00-0.18 (m, 2H), 0.45-0.55 (m, 2H), 0.70-1.00 (m) , 2H), 1.10-1.20 (m, 1H), 1.20-1.90 (m, 4H), 2.20-2.45 (m, 5H), 2.60-2.70 (M, 1H), 2.95-3.10 (m, 3H), 3.40-3.70 (m, 1H), 3.85-4.00 (m, 0.7H), 4.13 (S, 0.3H), 4.50-4.65 (m, 0.3H), 4.70-4.80 (m, 1.4H), 5.01 (s, 0.3H), 6 .50-6.60 (m, 1H), 6.67 (d, J = 8Hz, 0.3H), 6.73 (d, J = 8Hz, 0.7H), 7.60-7.65 ( m, 1H), 7.80-7.90 (m, 1H) 9.23-9.28 (m, 1H).

(Example 49)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (pyridazine-4-yl) methanone (68)

実施例４５に記載した方法に従い、化合物６０およびピリダジン－４－カルボン酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．００－０．２０（ｍ，２Ｈ）， ０．４０－０．６０（ｍ，２Ｈ），０．６０－１．００（ｍ，４Ｈ），１．００－２．００（ｍ，３Ｈ），２．２２－２．５０（ｍ，５Ｈ），２．６０－２．７０（ｍ，１Ｈ），２．８０－２．９０（ｍ，１Ｈ），２．９０－３．２０（ｍ，２Ｈ），３．４０－３．７０（ｍ，２Ｈ），，４．６０－４．８０（ｍ，２Ｈ），６．５６（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７５（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．４５－７．６０（ｍ，１Ｈ），９．２０－９．２８（ｍ，１Ｈ），９．２８－９．６０（ｍ，１Ｈ）．

The title compound was obtained from compound 60 and pyridazine-4-carboxylic acid according to the method described in Example 45.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.00-0.20 (m, 2H), 0.40-0.60 (m, 2H), 0.60-1.00 (m) , 4H), 1.00-2.00 (m, 3H), 2.22-2.50 (m, 5H), 2.60-2.70 (m, 1H), 2.80-2.90 (M, 1H), 2.90-3.20 (m, 2H), 3.40-3.70 (m, 2H), 4.60-4.80 (m, 2H), 6.56 ( d, J = 8Hz, 1H), 6.75 (d, J = 8Hz, 1H), 7.45-7.60 (m, 1H), 9.20-9.28 (m, 1H), 9. 28-9.60 (m, 1H).

(Example 50)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (pyrazine-2-yl) methanone (69)

実施例４２に記載した方法に従い、化合物９及びピラジン－２－カルボン酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）： ０．００－０．１５（ｍ，２Ｈ），０．４０－０．７０（ｍ，２Ｈ），０．７０－１．００（ｍ，１Ｈ），１．００-２．００（ｍ，６Ｈ），２．１０－２．５０（ｍ，５Ｈ），２．５５－２．７０（ｍ，１Ｈ），２．８０－３．２０（ｍ，２．７Ｈ），３．６０－４．００（ｍ，２Ｈ），３．７９（ｓ，０．９Ｈ），３．９０（ｓ，２．１Ｈ），４．１２（ｓ，０．３Ｈ），４．４０－４．６０（ｍ，０．３Ｈ），４．７２（ｓ，０．７Ｈ），４．８７（ｓ，１Ｈ），６．５５－６．６５（ｍ，１Ｈ），６．６９（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．７５（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），７．５５－７．６５（ｍ，１Ｈ），７．７４（ｄｔ，Ｊ＝２，８Ｈｚ，０．３Ｈ），７．８２（ｄｔ，Ｊ＝２，８Ｈｚ，０．７Ｈ），９．２０－９．３０（ｍ，１Ｈ）．

The title compound was obtained from compound 9 and pyrazine-2-carboxylic acid according to the method described in Example 42.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.70 (m, 2H), 0.70-1.00 (m) , 1H), 1.00-2.00 (m, 6H), 2.10-2.50 (m, 5H), 2.55-2.70 (m, 1H), 2.80-3.20 (M, 2.7H), 3.60-4.00 (m, 2H), 3.79 (s, 0.9H), 3.90 (s, 2.1H), 4.12 (s, 0) .3H), 4.40-4.60 (m, 0.3H), 4.72 (s, 0.7H), 4.87 (s, 1H), 6.55-6.65 (m, 1H) ), 6.69 (d, J = 8Hz, 0.3H), 6.75 (d, J = 8Hz, 0.7H), 7.55-7.65 (m, 1H), 7.74 (dt). , J = 2.8Hz, 0.3H), 7.82 (dt, J = 2.8Hz, 0.7H), 9.20-9.30 (m, 1H).

(Example 51)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano -4,13-Metanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (pyrazine-2-yl) synthesis of methanone (70)

実施例７に記載した方法に従い、化合物６９より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）： ０．００－０．１５（ｍ，２Ｈ），０．４０－０．５５（ｍ，２Ｈ），０．７０－１．００（ｍ，１．３Ｈ），１．００－１．９０（ｍ，５．４Ｈ），２．２０－２．４５（ｍ，５．３Ｈ），２．６０－２．７０（ｍ，１Ｈ），２．８８－３．１０（ｍ，３Ｈ），３．４０－３．６０（ｍ，１Ｈ），３．７０－３．８０（ｍ，０．７Ｈ），４．０１（ｓ，０．３Ｈ），４．５０－４．６０（ｍ，０．３Ｈ），４．６８（ｓ，０．７Ｈ），４．７２（ｓ，０．７Ｈ），４．９２（ｓ，０．３Ｈ），６．５０－６．５８（ｍ，１Ｈ），６．６７（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），８．５５－８．６５（ｍ，２Ｈ），８．８９（ｄ，Ｊ＝１Ｈｚ，０．７Ｈ），８．９４（ｄ，Ｊ＝１Ｈｚ，０．３Ｈ）．

The title compound was obtained from compound 69 according to the method described in Example 7.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.55 (m, 2H), 0.70-1.00 (m) , 1.3H), 1.00-1.90 (m, 5.4H), 2.20-2.45 (m, 5.3H), 2.60-2.70 (m, 1H), 2 .88-3.10 (m, 3H), 3.40-3.60 (m, 1H), 3.70-3.80 (m, 0.7H), 4.01 (s, 0.3H) , 4.50-4.60 (m, 0.3H), 4.68 (s, 0.7H), 4.72 (s, 0.7H), 4.92 (s, 0.3H), 6 .50-6.58 (m, 1H), 6.67 (d, J = 8Hz, 0.3H), 6.73 (d, J = 8Hz, 0.7H), 8.55-8.65 ( m, 2H), 8.89 (d, J = 1Hz, 0.7H), 8.94 (d, J = 1Hz, 0.3H).

(Example 52)
6-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,6,7,8a-octahydro-5H-4a, 8 -Synthesis of ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carbonyl) pyridin-2 (1H) -one (71)

実施例４２に記載した方法に従い、化合物９及び６－オキソ－１，６－ジヒドロピリジン－２－カルボン酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１２（ｍ，２Ｈ），０．４３－０．５２（ｍ，２Ｈ），０．７２－０．８２（ｍ，１Ｈ），１．０８－１．１８（ｍ，１Ｈ），１．２２－１．５９（ｍ，４Ｈ），１．７２－１．８７（ｍ，１Ｈ），２．２０－２．４５（ｍ，５Ｈ），２．５９－２．６６（ｍ，１Ｈ），２．８５－２．９６（ｍ，１Ｈ），２．９９（ｄ，Ｊ＝１９Ｈｚ，１Ｈ），３．０６（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．５６－３．６６（ｍ，１Ｈ），３．７２－３．８４（ｍ，１Ｈ），３．８８（ｓ，３Ｈ），４．６２－４．７３（ｍ，２Ｈ），６．３６（ｄ，Ｊ＝６Ｈｚ，１Ｈ），６．６０（ｄ，Ｊ＝９Ｈｚ，１Ｈ），６．６１（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７４（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．４３（ｄｄ，Ｊ＝６，９Ｈｚ，１Ｈ）．

The title compound was obtained from compound 9 and 6-oxo-1,6-dihydropyridine-2-carboxylic acid according to the method described in Example 42.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.12 (m, 2H), 0.43-0.52 (m, 2H), 0.72-0.82 (m) , 1H), 1.08-1.18 (m, 1H), 1.22-1.59 (m, 4H), 1.72-1.87 (m, 1H), 2.20-2.45 (M, 5H), 2.59-2.66 (m, 1H), 2.85-2.96 (m, 1H), 2.99 (d, J = 19Hz, 1H), 3.06 (d). , J = 6Hz, 1H), 3.56-3.66 (m, 1H), 3.72-3.84 (m, 1H), 3.88 (s, 3H), 4.62-4.73 (M, 2H), 6.36 (d, J = 6Hz, 1H), 6.60 (d, J = 9Hz, 1H), 6.61 (d, J = 8Hz, 1H), 6.74 (d). , J = 8Hz, 1H), 7.43 (dd, J = 6,9Hz, 1H).

(Example 53)
6-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,6,7,8,8a-octahydro-5H-4a, 8 -Synthesis of ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carbonyl) pyridin-2 (1H) -one (72)

実施例７に記載した方法に従い、化合物７０より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１３（ｍ，２Ｈ），０．４１－０．５１（ｍ，２Ｈ），０．６９－０．８１（ｍ，１Ｈ），１．０３－１．７９（ｍ，６Ｈ），２．１０－２．４０（ｍ，５Ｈ），２．５３－２．６３（ｍ，１Ｈ），２．７５－２．９０（ｍ，１Ｈ），２．９３（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０２（ｄ，Ｊ＝５Ｈｚ，１Ｈ），３．４６－３．６０（ｍ，２Ｈ），３．７５－３．９０（ｍ，１Ｈ），４．４８－４．７０（ｍ，１Ｈ），６．３２（ｂｒ ｓ，１Ｈ），６．５１（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６３（ｂｒ ｓ，１Ｈ），６．７４（ｂｒ ｓ，１Ｈ），７．３８（ｂｒ ｓ，１Ｈ）．

The title compound was obtained from compound 70 according to the method described in Example 7.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.13 (m, 2H), 0.41-0.51 (m, 2H), 0.69-0.81 (m) , 1H), 1.03-1.79 (m, 6H), 2.10-2.40 (m, 5H), 2.53-2.63 (m, 1H), 2.75-2.90 (M, 1H), 2.93 (d, J = 18Hz, 1H), 3.02 (d, J = 5Hz, 1H), 3.46-3.60 (m, 2H), 3.75-3 .90 (m, 1H), 4.48-4.70 (m, 1H), 6.32 (br s, 1H), 6.51 (d, J = 8Hz, 1H), 6.63 (br s) , 1H), 6.74 (br s, 1H), 7.38 (br s, 1H).

(Example 54)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (6-hydroxypyridin-3-yl) methanone (73)

実施例４２に記載した方法に従い、化合物９及び６－ヒドロキシニコチン酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１４（ｍ，２Ｈ），０．４４－０．５４（ｍ，２Ｈ），０．７４－０．８３（ｍ，１Ｈ），１．０８－１．１７（ｍ，１Ｈ），１．２２－１．３６（ｍ，１Ｈ），１．３７－１．６３（ｍ，３Ｈ），１．６６－１．７８（ｍ，１Ｈ），２．１５－２．４５（ｍ，５Ｈ），２．６５（ｄｄ，Ｊ＝５，１１Ｈｚ，１Ｈ），２．８１－２．９２（ｍ，１Ｈ），２．９９（ｄ，Ｊ＝１９Ｈｚ，１Ｈ），３．０６（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．５４－３．６４（ｍ，１Ｈ），３．７５－３．８８（ｍ，１Ｈ），３．８８（ｓ，３Ｈ），４．５０－４．７３（ｍ，２Ｈ），６．６０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６１（ｄ，Ｊ＝１０Ｈｚ，１Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．５８（ｄ，Ｊ＝１０Ｈｚ，０．４Ｈ），７．５９（ｄ，Ｊ＝１０Ｈｚ，０．６Ｈ），７．６５（ｓ，０．６Ｈ），７．６６（ｓ，０．４Ｈ）．

The title compound was obtained from compounds 9 and 6-hydroxynicotinic acid according to the method described in Example 42.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.14 (m, 2H), 0.44-0.54 (m, 2H), 0.74-0.83 (m) , 1H), 1.08-1.17 (m, 1H), 1.22-1.36 (m, 1H), 1.37-1.63 (m, 3H), 1.66-1.78 (M, 1H), 2.15-2.45 (m, 5H), 2.65 (dd, J = 5,11Hz, 1H), 2.81-2.92 (m, 1H), 2.99 (D, J = 19Hz, 1H), 3.06 (d, J = 6Hz, 1H), 3.54-3.64 (m, 1H), 3.75-3.88 (m, 1H), 3 .88 (s, 3H), 4.50-4.73 (m, 2H), 6.60 (d, J = 8Hz, 1H), 6.61 (d, J = 10Hz, 1H), 6.73 (D, J = 8Hz, 1H), 7.58 (d, J = 10Hz, 0.4H), 7.59 (d, J = 10Hz, 0.6H), 7.65 (s, 0.6H) , 7.66 (s, 0.4H).

(Example 55)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (6-hydroxypyridin-3-yl) methanone (74)

実施例７に記載した方法に従い、化合物７３より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．１４（ｍ，２Ｈ），０．４３－０．５３（ｍ，２Ｈ），０．７１－０．９０（ｍ，１Ｈ），１．０７－１．１４（ｍ，１Ｈ），１．２０－１．３３（ｍ，１Ｈ），１．３５－１．６１（ｍ，３Ｈ），１．６３－１．７７（ｍ，１Ｈ），２．１４－２．４２（ｍ，５Ｈ），２．５９－２．６７（ｍ，１Ｈ），２．７７－２．８９（ｍ，１Ｈ），２．９６（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０４（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．５１－３．６６（ｍ，１Ｈ），３．７５－３．９３（ｍ，１Ｈ），４．２６－４．３２（ｍ，０．３Ｈ），４．４１－４．６０（ｍ，１．７Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６２（ｄ，Ｊ＝１０Ｈｚ，１Ｈ），６．７４（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．５９（ｄｄ，Ｊ＝２，１０Ｈｚ，１Ｈ），７．８１（ｂｒ ｓ，１Ｈ）．

The title compound was obtained from compound 73 according to the method described in Example 7.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.14 (m, 2H), 0.43-0.53 (m, 2H), 0.71-0.90 (m) , 1H), 1.07-1.14 (m, 1H), 1.20-1.33 (m, 1H), 1.35-1.61 (m, 3H), 1.63-1.77 (M, 1H), 2.14-2.42 (m, 5H), 2.59-2.67 (m, 1H), 2.77-2.89 (m, 1H), 2.96 (d). , J = 18Hz, 1H), 3.04 (d, J = 6Hz, 1H), 3.51-3.66 (m, 1H), 3.75-3.93 (m, 1H), 4.26 -4.32 (m, 0.3H), 4.41-4.60 (m, 1.7H), 6.54 (d, J = 8Hz, 1H), 6.62 (d, J = 10Hz, 1H), 6.74 (d, J = 8Hz, 1H), 7.59 (dd, J = 2,10Hz, 1H), 7.81 (br s, 1H).

(Example 56)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (2-hydroxypyridin-3-yl) methanone (75)

実施例４２に記載した方法に従い、化合物９及び２－ヒドロキシニコチン酸より表題化合物を得た。


^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１６（ｍ，２Ｈ），０．４１－０．５５（ｍ，２Ｈ），０．６９－０．７８（ｍ，１Ｈ），１．０７－１．１６（ｍ，１Ｈ），１．２３－１．３６（ｍ，２Ｈ），１．４７－１．６２（ｍ，２Ｈ），１．６９－１．８０（ｍ，１Ｈ），２．１５－２．４６（ｍ，５Ｈ），２．５６－２．６７（ｍ，１Ｈ），２．９１－３．１４（ｍ，３Ｈ），３．４３－３．６２（ｍ，１．８Ｈ），３．７９（ｓ，０．６Ｈ），３．８９（ｓ，２．４Ｈ），３．９０－３．９３（ｍ，０．２Ｈ），４．４１－４．５９（ｍ，０．２Ｈ），４．６３－４．６９（ｍ，１Ｈ），４．７７（ｓ，０．８Ｈ），６．２９－６．３６（ｍ，１Ｈ），６．５９（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６９（ｄ，Ｊ＝８Ｈｚ，０．２Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．８Ｈ），７．５１－７．６１（ｍ，２Ｈ）．

The title compound was obtained from compound 9 and 2-hydroxynicotinic acid according to the method described in Example 42.


^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.16 (m, 2H), 0.41-0.55 (m, 2H), 0.69-0.78 (m) , 1H), 1.07-1.16 (m, 1H), 1.23-1.36 (m, 2H), 1.47-1.62 (m, 2H), 1.69-1.80 (M, 1H), 2.15-2.46 (m, 5H), 2.56-2.67 (m, 1H), 2.91-3.14 (m, 3H), 3.43-3 .62 (m, 1.8H), 3.79 (s, 0.6H), 3.89 (s, 2.4H), 3.90-3.93 (m, 0.2H), 4.41 -4.59 (m, 0.2H), 4.63-4.69 (m, 1H), 4.77 (s, 0.8H), 6.29-6.36 (m, 1H), 6 .59 (d, J = 8Hz, 1H), 6.69 (d, J = 8Hz, 0.2H), 6.73 (d, J = 8Hz, 0.8H), 7.51-7.61 ( m, 2H).

(Example 57)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (2-hydroxypyridin-3-yl) methanone (76)

実施例７に記載した方法に従い、化合物７５より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ（ｐｐｍ）：０．０６－０．１６（ｍ，２Ｈ），０．４４－０．５３（ｍ，２Ｈ），０．７４－０．８３（ｍ，１Ｈ），１．０７－１．１５（ｍ，１Ｈ），１．２５－１．５３（ｍ，４Ｈ），１．７３－１．８５（ｍ，１Ｈ），２．２２－２．４３（ｍ，５Ｈ），２．６１－２．６７（ｍ，１Ｈ），２．８２－２．９９（ｍ，１Ｈ），２．９７（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０６（ｄ，Ｊ＝６Ｈｚ，０．８Ｈ），３．１３（ｄ，Ｊ＝６Ｈｚ，０．２Ｈ），３．４８－３．６４（ｍ，２Ｈ），４．５０－４．６０（ｍ，２Ｈ），６．４３－６．４９（ｍ，１Ｈ），６．５１（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．５８（ｄ，Ｊ＝８Ｈｚ，０．２Ｈ），６．６３（ｄ，Ｊ＝８Ｈｚ，０．８Ｈ），７．５４（ｄ，Ｊ＝６Ｈｚ，１Ｈ），７．６０－７．７３（ｍ，１Ｈ）．

The title compound was obtained from compound 75 according to the method described in Example 7.

^{1 1} H-NMR (400 MHz, CD ₃ OD) δ (ppm): 0.06-0.16 (m, 2H), 0.44-0.53 (m, 2H), 0.74-0.83 ( m, 1H), 1.07-1.15 (m, 1H), 1.25-1.53 (m, 4H), 1.73-1.85 (m, 1H), 2.22-2. 43 (m, 5H), 2.61-2.67 (m, 1H), 2.82-2.99 (m, 1H), 2.97 (d, J = 18Hz, 1H), 3.06 ( d, J = 6Hz, 0.8H), 3.13 (d, J = 6Hz, 0.2H), 3.48-3.64 (m, 2H), 4.50-4.60 (m, 2H) ), 6.43-6.49 (m, 1H), 6.51 (d, J = 8Hz, 1H), 6.58 (d, J = 8Hz, 0.2H), 6.63 (d, J) = 8Hz, 0.8H), 7.54 (d, J = 6Hz, 1H), 7.60-7.73 (m, 1H).

(Example 58)
6-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,6,7,8a-octahydro-5H-4a, 8 -Synthesis of ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carbonyl) -1-methylpyridine-2 (1H) -one (77)

実施例４２に記載した方法に従い、化合物９及び１－メチル－６－オキソ－１，６－ジヒドロピリジン－２－カルボン酸（ＷＯ２０１６１４８２３２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）：０．０６－０．１７（ｍ，２Ｈ），０．４３－０．５６（ｍ，２Ｈ），０．７０－０．８４（ｍ，１Ｈ），１．１２－１．８０（ｍ，６Ｈ），１．９８－２．４９（ｍ，５Ｈ），２．６４（ｄｄ，Ｊ＝５，１２Ｈｚ，１Ｈ），２．７６－２．８８（ｍ，１Ｈ），２．９７－３．０２（ｍ，１Ｈ），，３．０３（ｄ，Ｊ＝６Ｈｚ，０．４Ｈ），３．０８（ｄ，Ｊ＝７Ｈｚ，０．６Ｈ），３．４５－３．６０（ｍ，２Ｈ），３．４７（ｓ，１．８Ｈ），３．５７（ｓ，１．２Ｈ），３．９０（ｓ，３Ｈ），４．５５－４．５８（ｍ，０．６Ｈ），４．６０－４．６３（ｍ，０．４Ｈ），４．６８－４．７５（ｍ，１Ｈ），６．０９（ｄｄ，Ｊ＝１，７Ｈｚ，０．４Ｈ），６．１３（ｄｄ，Ｊ＝１，７Ｈｚ，０．６Ｈ），６．５６－６．６５（ｍ，２Ｈ），７．２６（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．３２（ｄｄ，Ｊ＝７，９Ｈｚ，０．４Ｈ），７．３７（ｄｄ，Ｊ＝７，９Ｈｚ，０．６Ｈ）．

The title compound was obtained from compound 9 and 1-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (synthesized by the method described in WO2016148232) according to the method described in Example 42.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.17 (m, 2H), 0.43-0.56 (m, 2H), 0.70-0.84 (m) , 1H), 1.12-1.80 (m, 6H), 1.98-2.49 (m, 5H), 2.64 (dd, J = 5,12Hz, 1H), 2.76-2 .88 (m, 1H), 2.97-3.02 (m, 1H), 3.03 (d, J = 6Hz, 0.4H), 3.08 (d, J = 7Hz, 0.6H) ), 3.45-3.60 (m, 2H), 3.47 (s, 1.8H), 3.57 (s, 1.2H), 3.90 (s, 3H), 4.55- 4.58 (m, 0.6H), 4.60-4.63 (m, 0.4H), 4.68-4.75 (m, 1H), 6.09 (dd, J = 1,7Hz) , 0.4H), 6.13 (dd, J = 1,7Hz, 0.6H), 6.56-6.65 (m, 2H), 7.26 (d, J = 8Hz, 1H), 7 .32 (dd, J = 7.9Hz, 0.4H), 7.37 (dd, J = 7.9Hz, 0.6H).

(Example 59)
6-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,6,7,8,8a-octahydro-5H-4a, 8 -Synthesis of ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-carbonyl) -1-methylpyridine-2 (1H) -one (78)

実施例７に記載した方法に従い、化合物７７より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）： ０．０５－０．１６（ｍ，２Ｈ），０．４２－０．５６（ｍ，２Ｈ），０．６９－０．８１（ｍ，１Ｈ），１．１１－１．４３（ｍ，３Ｈ），１．４５－１．８１（ｍ，３Ｈ），２．０３－２．４４（ｍ，５Ｈ），２．６０－２．７０（ｍ，１Ｈ），２．７５－２．８６（ｍ，１Ｈ），２．９７（ｄ，Ｊ＝１８Ｈｚ，０．４Ｈ），２．９８（ｄ，Ｊ＝１８Ｈｚ，０．６Ｈ），３．０２（ｄ，Ｊ＝６Ｈｚ，０．４Ｈ），３．０８（ｄ，Ｊ＝６Ｈｚ，０．６Ｈ），３．４６－３．６１（ｍ，２Ｈ），３．４８（ｓ，１．８Ｈ），３．５９（ｓ，１．２Ｈ），４．５３－４．５７（ｍ，０．６Ｈ），４．６０－４．６７（ｍ，１．４Ｈ），５．５０（ｂｒ ｓ，１Ｈ），６．１０（ｄｄ，Ｊ＝１，７Ｈｚ，０．４Ｈ），６．１４（ｄｄ，Ｊ＝１，７Ｈｚ，０．６Ｈ），６．５６（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６３（ｄｄ，Ｊ＝１，９Ｈｚ，０．４Ｈ），６．６３（ｄｄ，Ｊ＝１，９Ｈｚ，０．６Ｈ），６．７５（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７５（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），７．３４（ｄｄ，Ｊ＝７，９Ｈｚ，０．４Ｈ），７．３８（ｄｄ，Ｊ＝７，９Ｈｚ，０．６Ｈ）．

The title compound was obtained from compound 77 according to the method described in Example 7.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.05-0.16 (m, 2H), 0.42-0.56 (m, 2H), 0.69-0.81 (m) , 1H), 1.11-1.43 (m, 3H), 1.45-1.81 (m, 3H), 2.03-2.44 (m, 5H), 2.60-2.70 (M, 1H), 2.75-2.86 (m, 1H), 2.97 (d, J = 18Hz, 0.4H), 2.98 (d, J = 18Hz, 0.6H), 3 .02 (d, J = 6Hz, 0.4H), 3.08 (d, J = 6Hz, 0.6H), 3.46-3.61 (m, 2H), 3.48 (s, 1. 8H), 3.59 (s, 1.2H), 4.53-4.57 (m, 0.6H), 4.60-4.67 (m, 1.4H), 5.50 (br s) , 1H), 6.10 (dd, J = 1,7Hz, 0.4H), 6.14 (dd, J = 1,7Hz, 0.6H), 6.56 (d, J = 8Hz, 1H) , 6.63 (dd, J = 1,9Hz, 0.4H), 6.63 (dd, J = 1,9Hz, 0.6H), 6.75 (d, J = 8Hz, 0.4H), 6.75 (d, J = 8Hz, 0.6H), 7.34 (dd, J = 7, 9Hz, 0.4H), 7.38 (dd, J = 7.9Hz, 0.6H).

(Example 60)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (oxazole-2-yl) metanone (79)

化合物９（７．５ｍｇ，０．０２１ｍｍｏｌ）及びオキサゾール－２－カルボン酸（１１．７ｍｇ，０．１０ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（１．５ｍL）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（３５μL，０．２０ｍｍｏｌ）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）（１７．７ｍｇ，０．０４７ｍｍｏｌ）を加え、室温で３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（０－５％メタノール／クロロホルム）で精製し、表題化合物（７．２ｍｇ，７６％）を淡黄色油状物質として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１５（ｍ，２Ｈ），０．４３－０．５４（ｍ，２Ｈ），０．７４－０．８５（ｍ，１Ｈ），１．０９－１．８３（ｍ，６Ｈ），２．１７－２．４７（ｍ，５Ｈ），２．６０－２．６７（ｍ，１Ｈ），２．８９－３．１０（ｍ，３Ｈ），３．４９（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，０．３Ｈ），３．７９（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，０．７Ｈ），３．８６（ｓ，０．９Ｈ），３．８９（ｓ，２．１Ｈ），４．４７－４．５５（ｍ，０．３Ｈ），４．６３－４．６７（ｍ，０．７Ｈ），４．６９－４．７７（ｍ，１．３Ｈ），４．８１－４．８４（ｍ，０．７Ｈ），６．６０（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．６１（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．７４（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），７．２６－７．３０（ｍ，１Ｈ），７．７５－７．７７（ｍ，１Ｈ）．

N, N-diisopropylethylamine (35 μL) in an N, N-dimethylformamide (1.5 mL) solution of compound 9 (7.5 mg, 0.021 mmol) and oxazole-2-carboxylic acid (11.7 mg, 0.10 mmol). , 0.20 mmol) and O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU) (17.7 mg, 0.047 mmol) Was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-5% methanol / chloroform) to give the title compound (7.2 mg, 76%) as a pale yellow oily substance.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.15 (m, 2H), 0.43-0.54 (m, 2H), 0.74-0.85 (m) , 1H), 1.09-1.83 (m, 6H), 2.17-2.47 (m, 5H), 2.60-2.67 (m, 1H), 2.89-3.10 (M, 3H), 3.49 (ddd, J = 4,11,14Hz, 0.3H), 3.79 (ddd, J = 4,11,14Hz, 0.7H), 3.86 (s, 0.9H), 3.89 (s, 2.1H), 4.47-4.55 (m, 0.3H), 4.63-4.67 (m, 0.7H), 4.69- 4.77 (m, 1.3H), 4.81-4.84 (m, 0.7H), 6.60 (d, J = 8Hz, 0.7H), 6.61 (d, J = 8Hz) , 0.3H), 6.73 (d, J = 8Hz, 0.3H), 6.74 (d, J = 8Hz, 0.7H), 7.26-7.30 (m, 1H), 7 .75-7.77 (m, 1H).

(Example 61)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (oxazole-2-yl) metanone (80)

実施例７に記載した方法に従い、化合物７９より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１５（ｍ，２Ｈ），０．４１－０．５３（ｍ，２Ｈ），０．７２－０．８５（ｍ，１Ｈ），１．０７－１．８２（ｍ，６Ｈ），２．１７－２．４２（ｍ，５Ｈ），２．６０－２．６８（ｍ，１Ｈ），２．９０－３．０９（ｍ，３Ｈ），３．４１（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，０．４Ｈ），３．７５（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，０．６Ｈ），４．５７－４．８８（ｍ，３Ｈ），６．５５（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），７．２７（ｓ，０．６Ｈ），７．３４（ｓ，０．４Ｈ），７．７８（ｓ，０．６Ｈ），７．８０（ｓ，０．４Ｈ）．

The title compound was obtained from compound 79 according to the method described in Example 7.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.15 (m, 2H), 0.41-0.53 (m, 2H), 0.72-0.85 (m) , 1H), 1.07-1.82 (m, 6H), 2.17-2.42 (m, 5H), 2.60-2.68 (m, 1H), 2.90-3.09 (M, 3H), 3.41 (ddd, J = 4,11,14Hz, 0.4H), 3.75 (ddd, J = 4,11,14Hz, 0.6H), 4.57-4. 88 (m, 3H), 6.55 (d, J = 8Hz, 1H), 6.71 (d, J = 8Hz, 0.4H), 6.73 (d, J = 8Hz, 0.6H), 7.27 (s, 0.6H), 7.34 (s, 0.4H), 7.78 (s, 0.6H), 7.80 (s, 0.4H).

(Example 62)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (oxazole-4-yl) methanone (81)

実施例６０に記載した方法に従い、化合物９及びオキサゾール－４－カルボン酸より表題化合物を得た。


^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１５（ｍ，２Ｈ），０．４３－０．５３（ｍ，２Ｈ），０．７５－０．８５（ｍ，１Ｈ），１．０７－１．１８（ｍ，１Ｈ），１．２６－１．８０（ｍ，５Ｈ），２．１８－２．４４（ｍ，５Ｈ），２．６０－２．６７（ｍ，１Ｈ），２．８６－３．１０（ｍ，３Ｈ），３．３６－３．４６（ｍ，０．４Ｈ），３．６９－３．７８（ｍ，０．６Ｈ），３．８６（ｓ，１．２Ｈ），３．８９（ｓ，１．８Ｈ），４．４６－４．８２（ｍ，３Ｈ），６．５９（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．６１（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７４（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），７．８９（ｓ，０．６Ｈ），７．９１（ｓ，０．４Ｈ），８．２０（ｓ，１Ｈ）．

The title compound was obtained from compound 9 and oxazole-4-carboxylic acid according to the method described in Example 60.


¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.15 (m, 2H), 0.43-0.53 (m, 2H), 0.75-0.85 (m) , 1H), 1.07-1.18 (m, 1H), 1.26-1.80 (m, 5H), 2.18-2.44 (m, 5H), 2.60-2.67 (M, 1H), 2.86-3.10 (m, 3H), 3.36-3.46 (m, 0.4H), 3.69-3.78 (m, 0.6H), 3 .86 (s, 1.2H), 3.89 (s, 1.8H), 4.46-4.82 (m, 3H), 6.59 (d, J = 8Hz, 0.6H), 6 .61 (d, J = 8Hz, 0.4H), 6.73 (d, J = 8Hz, 0.4H), 6.74 (d, J = 8Hz, 0.6H), 7.89 (s, 0.6H), 7.91 (s, 0.4H), 8.20 (s, 1H).

(Example 63)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (oxazole-4-yl) metanone (82)

実施例７に記載した方法に従い、化合物８１より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１４（ｍ，２Ｈ），０．４３－０．５３（ｍ，２Ｈ），０．７４－０．８４（ｍ，１Ｈ），１．０６－１．１６（ｍ，１Ｈ），１．２５－１．８０（ｍ，５Ｈ），２．１８－２．４１（ｍ，５Ｈ），２．６０－２．６７（ｍ，１Ｈ），２．８３－３．０９（ｍ，３Ｈ），３．３４（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，０．４Ｈ），３．６９（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，０．６Ｈ），４．５４－４．８３（ｍ，３Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．５５（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），７．９０（ｓ，０．６Ｈ），７．９５（ｓ，０．４Ｈ），８．２１（ｓ，０．６Ｈ），８．２７（ｓ，０．４Ｈ）．

The title compound was obtained from compound 81 according to the method described in Example 7.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.14 (m, 2H), 0.43-0.53 (m, 2H), 0.74-0.84 (m) , 1H), 1.06-1.16 (m, 1H), 1.25-1.80 (m, 5H), 2.18-2.41 (m, 5H), 2.60-2.67 (M, 1H), 2.83-3.09 (m, 3H), 3.34 (ddd, J = 4,11,14Hz, 0.4H), 3.69 (ddd, J = 4,11, 14Hz, 0.6H), 4.54-4.83 (m, 3H), 6.54 (d, J = 8Hz, 0.6H), 6.55 (d, J = 8Hz, 0.4H), 6.71 (d, J = 8Hz, 0.4H), 6.72 (d, J = 8Hz, 0.6H), 7.90 (s, 0.6H), 7.95 (s, 0.4H) ), 8.21 (s, 0.6H), 8.27 (s, 0.4H).

(Example 64)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (isoxazole-5-yl) metanone (83)

実施例６０に記載した方法に従い、化合物９及びイソキサゾール－５－カルボン酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１５（ｍ，２Ｈ），０．４４－０．５４（ｍ，２Ｈ），０．７４－０．８５（ｍ，１Ｈ），１．１０－１．８１（ｍ，６Ｈ），２．１７－２．４６（ｍ，５Ｈ），２．６１－２．６８（ｍ，１Ｈ），２．９３－３．１１（ｍ，３Ｈ），３．６３（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，１Ｈ），３．８６－３．９６（ｍ，３．７Ｈ），４．１８－４．２１（ｍ，０．３Ｈ），４．２６－４．３４（ｍ，０．３Ｈ），４．６０－４．６３（ｍ，０．７Ｈ），４．６７－４．６９（ｍ，０．３Ｈ），４．７１－４．７４（ｍ，０．７Ｈ），６．６１（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．６２（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．７２－６．７７（ｍ，２Ｈ），８．３１（ｄ，Ｊ＝２Ｈｚ，０．３Ｈ），８．３２（ｄ，Ｊ＝２Ｈｚ，０．７Ｈ）．

The title compound was obtained from compound 9 and isoxazole-5-carboxylic acid according to the method described in Example 60.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.15 (m, 2H), 0.44-0.54 (m, 2H), 0.74-0.85 (m) , 1H), 1.10-1.81 (m, 6H), 2.17-2.46 (m, 5H), 2.61-2.68 (m, 1H), 2.93-3.11 (M, 3H), 3.63 (ddd, J = 4,11,14Hz, 1H), 3.86-3.96 (m, 3.7H), 4.18-4.21 (m, 0. 3H), 4.26-4.34 (m, 0.3H), 4.60-4.63 (m, 0.7H), 4.67-4.69 (m, 0.3H), 4. 71-4.74 (m, 0.7H), 6.61 (d, J = 8Hz, 0.7H), 6.62 (d, J = 8Hz, 0.3H), 6.72-6.77 (M, 2H), 8.31 (d, J = 2Hz, 0.3H), 8.32 (d, J = 2Hz, 0.7H).

(Example 65)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (isoxazole-5-yl) metanone (84)

実施例７に記載した方法に従い、化合物８３より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１５（ｍ，２Ｈ），０．４４－０．５４（ｍ，２Ｈ），０．７３－０．８３（ｍ，１Ｈ），１．０９－１．８１（ｍ，６Ｈ），２．１８－２．４２（ｍ，５Ｈ），２．６２－２．６７（ｍ，１Ｈ），２．８９－３．１０（ｍ，３Ｈ），３．４４－３．６７（ｍ，１Ｈ），３．９１－３．９８（ｍ，０．７Ｈ），４．１８－４．２１（ｍ，０．３Ｈ），４．４１－４．４９（ｍ，０．３Ｈ），４．５９－４．６１（ｍ，０．７Ｈ），４．６４－４．６７（ｍ，０．７Ｈ），４．７１－４．７３（ｍ，０．３Ｈ），６．５６（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７０－６．７６（ｍ，２Ｈ），８．３３（ｄ，Ｊ＝２Ｈｚ，０．７Ｈ），８．３５（ｄ，Ｊ＝２Ｈｚ，０．３Ｈ）．

The title compound was obtained from compound 83 according to the method described in Example 7.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.15 (m, 2H), 0.44-0.54 (m, 2H), 0.73-0.83 (m) , 1H), 1.09-1.81 (m, 6H), 2.18-2.42 (m, 5H), 2.62-2.67 (m, 1H), 2.89-3.10 (M, 3H), 3.44-3.67 (m, 1H), 3.91-3.98 (m, 0.7H), 4.18-4.21 (m, 0.3H), 4 .41-4.49 (m, 0.3H), 4.59-4.61 (m, 0.7H), 4.64-4.67 (m, 0.7H), 4.71-4. 73 (m, 0.3H), 6.56 (d, J = 8Hz, 1H), 6.70-6.76 (m, 2H), 8.33 (d, J = 2Hz, 0.7H), 8.35 (d, J = 2Hz, 0.3H).

(Example 66)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano -4,13-Metanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (thiazole-2-yl) synthesis of methanone (85)

実施例４５に記載した方法に従い、化合物６０及びチアゾール－２－カルボン酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１７（ｍ，２Ｈ），０．４２－０．５６（ｍ，２Ｈ），０．７２－０．９７（ｍ，１Ｈ），１．０７－１．９０（ｍ，６Ｈ），２．１４－２．４９（ｍ，５Ｈ），２．５９－２．６８（ｍ，１Ｈ），２．８４－３．１２（ｍ，３Ｈ），３．３３－３．９０（ｍ，１Ｈ），４．５５－５．０１（ｍ，３Ｈ），５．２１－５．３６（ｍ，１Ｈ），６．５５（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６９－６．７６（ｍ，１Ｈ），７．５０－７．６０（ｍ，１Ｈ），７．９１（ｄ，Ｊ＝３Ｈｚ，０．６Ｈ），７．９９（ｄ，Ｊ＝３Ｈｚ，０．４Ｈ）．

The title compound was obtained from compound 60 and thiazole-2-carboxylic acid according to the method described in Example 45.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.17 (m, 2H), 0.42-0.56 (m, 2H), 0.72-0.97 (m) , 1H), 1.07-1.90 (m, 6H), 2.14-2.49 (m, 5H), 2.59-2.68 (m, 1H), 2.84-3.12 (M, 3H), 3.33-3.90 (m, 1H), 4.55-5.01 (m, 3H), 5.21-5.36 (m, 1H), 6.55 (d) , J = 8Hz, 1H), 6.69-6.76 (m, 1H), 7.50-7.60 (m, 1H), 7.91 (d, J = 3Hz, 0.6H), 7 .99 (d, J = 3Hz, 0.4H).

(Reference example 20)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -7- (Thiazole-4-carbonyl) -1,2,3,4,6,7,8,8a-Octahydro-5H- Synthesis of 4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-10-ylthiazole-4-carboxylate (86)

実施例４２に記載した方法に従い、化合物６０及びチアゾール－４－カルボン酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１７（ｍ，２Ｈ），０．４２－０．５５（ｍ，２Ｈ），０．７２－０．９３（ｍ，１Ｈ），１．０５－１．８６（ｍ，６Ｈ），２．２０－２．５１（ｍ，５Ｈ），２．６２－２．７１（ｍ，１Ｈ），２．８６－３．１６（ｍ，３Ｈ），３．４０－３．７２（ｍ，１Ｈ），４．０７－４．９８（ｍ，３Ｈ），６．６８（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．９１－７．０３（ｍ，１Ｈ），７．８７－８．００（ｍ，１Ｈ），８．４１－８．５０（ｍ，１Ｈ），８．７４－８．８４（ｍ，１Ｈ），８．８９－８．９５（ｍ，１Ｈ）．

The title compound was obtained from compound 60 and thiazole-4-carboxylic acid according to the method described in Example 42.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.17 (m, 2H), 0.42-0.55 (m, 2H), 0.72-0.93 (m) , 1H), 1.05-1.86 (m, 6H), 2.20-2.51 (m, 5H), 2.62-2.71 (m, 1H), 2.86-3.16 (M, 3H), 3.40-3.72 (m, 1H), 4.07-4.98 (m, 3H), 6.68 (d, J = 8Hz, 1H), 6.91-7 .03 (m, 1H), 7.87-8.00 (m, 1H), 8.41-8.50 (m, 1H), 8.74-8.84 (m, 1H), 8.89 -8.95 (m, 1H).

(Example 67)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (thiazole-4-yl) metanone (87)

化合物８６（７．５ｍｇ，０．０１３ｍｍｏｌ）のメタノール（１ｍＬ）溶液に、２Ｍ水酸化ナトリウム水溶液（０．１ｍＬ，０．１０ｍｍｏｌ）を加え、室温で１時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、クロロホルム／メタノール混合溶媒で三回抽出した。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：メタノール＝９１：９）で精製し、表題化合物（５．６ｍｇ，９２％）を無色粉末として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１７（ｍ，２Ｈ），０．４２－０．５４（ｍ，２Ｈ），０．７１－０．９０（ｍ，１Ｈ），１．０３－１．８９（ｍ，６Ｈ），２．１７－２．４１（ｍ，５Ｈ），２．５９－２．６８（ｍ，１Ｈ），２．８６－３．１１（ｍ，３Ｈ），３．３１－３．８１（ｍ，１Ｈ），４．１８－４．２９（ｍ，０．７Ｈ），４．４５－４．９６（ｍ，３．３Ｈ），６．５５（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６６－６．７５（ｍ，１Ｈ），７．９３（ｄ，Ｊ＝２Ｈｚ，０．７Ｈ），８．０４（ｄ，Ｊ＝２Ｈｚ，０．３Ｈ），８．８２（ｄ，Ｊ＝２Ｈｚ，０．７Ｈ），８．８７（ｄ，Ｊ＝２Ｈｚ，０．３Ｈ）．

A 2M aqueous sodium hydroxide solution (0.1 mL, 0.10 mmol) was added to a solution of compound 86 (7.5 mg, 0.013 mmol) in methanol (1 mL), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted three times with a mixed chloroform / methanol solvent. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: methanol = 91: 9) to obtain the title compound (5.6 mg, 92%) as a colorless powder.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.05-0.17 (m, 2H), 0.42-0.54 (m, 2H), 0.71-0.90 (m) , 1H), 1.03-1.89 (m, 6H), 2.17-2.41 (m, 5H), 2.59-2.68 (m, 1H), 2.86-3.11 (M, 3H), 3.31-3.81 (m, 1H), 4.18-4.29 (m, 0.7H), 4.45-4.96 (m, 3.3H), 6 .55 (d, J = 8Hz, 1H), 6.66-6.75 (m, 1H), 7.93 (d, J = 2Hz, 0.7H), 8.04 (d, J = 2Hz, 0.3H), 8.82 (d, J = 2Hz, 0.7H), 8.87 (d, J = 2Hz, 0.3H).

(Example 68)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (thiazole-5-yl) methanone (88)

化合物６０（７．０ｍｇ，０．０２０ｍｍｏｌ）、チアゾール－５－カルボン酸（１３ｍｇ，０．１０ｍｍｏｌ）、Ｎ，Ｎ－ジメチルアミノピリジン（１．０ｍｇ，０．０１０ｍｍｏｌ），１－ヒドロキシベンズトリアゾール一水和物（９．０ｍｇ，０．０６０ｍｍｏｌ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（２０μＬ，０．１２ｍｍｏｌ）及び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（１１ｍｇ，０．０６０ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）溶液を、室温で終夜撹拌した。反応混合物に炭酸カリウム（５０ｍｇ，０．３６ｍｍｏｌ）のメタノール溶液（１ｍＬ）を加え、１時間撹拌した。反応混合物をクロロホルムで三回抽出後、合わせた抽出物を硫酸ナトリウムで乾燥し、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＝１５：１）で精製し、表題化合物（６．３ｍｇ，６８％）を無色固体として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１８（ｍ，２Ｈ），０．４３－０．５４（ｍ，２Ｈ），０．７１－０．９２（ｍ，１Ｈ），１．０８－１．８５（ｍ，６Ｈ），２．１７－２．４３（ｍ，５Ｈ），２．６０－２．６９（ｍ，１Ｈ），２．８２－３．１４（ｍ，３Ｈ），３．４５－３．８２（ｍ，１Ｈ），３．９０－４．１６（ｍ，１Ｈ），４．５５－４．９６（ｍ，３Ｈ），６．５６（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），８．０６－８．２６（ｍ，１Ｈ），８．９０（ｓ，１Ｈ）．

Compound 60 (7.0 mg, 0.020 mmol), thiazole-5-carboxylic acid (13 mg, 0.10 mmol), N, N-dimethylaminopyridine (1.0 mg, 0.010 mmol), 1-hydroxybenztriazole monohydrate. Japanese products (9.0 mg, 0.060 mmol), N, N-diisopropylethylamine (20 μL, 0.12 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (11 mg, 0.060 mmol). The N, N-dimethylformamide (1 mL) solution was stirred overnight at room temperature. A methanol solution (1 mL) of potassium carbonate (50 mg, 0.36 mmol) was added to the reaction mixture, and the mixture was stirred for 1 hour. The reaction mixture was extracted three times with chloroform, and the combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: methanol = 15: 1) to give the title compound (6.3 mg, 68%) as a colorless solid.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.05-0.18 (m, 2H), 0.43-0.54 (m, 2H), 0.71-0.92 (m) , 1H), 1.08-1.85 (m, 6H), 2.17-2.43 (m, 5H), 2.60-2.69 (m, 1H), 2.82-3.14 (M, 3H), 3.45-3.82 (m, 1H), 3.90-4.16 (m, 1H), 4.55-4.96 (m, 3H), 6.56 (d) , J = 8Hz, 1H), 6.73 (d, J = 8Hz, 1H), 8.06-8.26 (m, 1H), 8.90 (s, 1H).

(Example 69)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano -4,13-Metanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (isothiazole-4-yl) synthesis of methanone (89)

実施例６８に記載した方法に従い、化合物６０及びイソチアゾール－４－カルボン酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１７（ｍ，２Ｈ），０．４２－０．５５（ｍ，２Ｈ），０．６９－０．９１（ｍ，１Ｈ），１．０６－１．８６（ｍ，６Ｈ），２．１５－２．４５（ｍ，５Ｈ），２．６２－２．７１（ｍ，１Ｈ），２．７９－３．１２（ｍ，３Ｈ），３．３３－３．６７（ｍ，１Ｈ），３．７２－４．０６（ｍ，１Ｈ），４．３８－５．００（ｍ，３Ｈ），６．５６（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６６－６．７７（ｍ，１Ｈ），８．６０－８．７３（ｍ，１Ｈ），８．８０－８．９３（ｍ，１Ｈ）．

The title compound was obtained from compound 60 and isothiazole-4-carboxylic acid according to the method described in Example 68.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.17 (m, 2H), 0.42-0.55 (m, 2H), 0.69-0.91 (m) , 1H), 1.06-1.86 (m, 6H), 2.15-2.45 (m, 5H), 2.62-2.71 (m, 1H), 2.79-3.12 (M, 3H), 3.33-3.67 (m, 1H), 3.72-4.06 (m, 1H), 4.38-5.00 (m, 3H), 6.56 (d) , J = 8Hz, 1H), 6.66-6.77 (m, 1H), 8.60-8.73 (m, 1H), 8.80-8.93 (m, 1H).

(Example 70)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (isothiazole-5-yl) methanone (90)

実施例６０に記載した方法に従い、化合物９及びイソチアゾール－５－カルボン酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．１５（ｍ，２Ｈ），０．４１－０．５６（ｍ，２Ｈ），０．７０－０．９０（ｍ，１Ｈ），
１．０７－１．８９（ｍ，６Ｈ），２．１２－２．４８（ｍ，５Ｈ），２．６０－２．７０（ｍ，１Ｈ），２．７９－３．１９（ｍ，３Ｈ），３．４５－３．６８（ｍ，１Ｈ），３．７６－４．８５（ｍ，６Ｈ），６．５７－６．６６（ｍ，１Ｈ），６．６９－６．７８（ｍ，１Ｈ），７．３２－７．５１（ｍ，１Ｈ），８．４４－８．５２（ｍ，１Ｈ）．

The title compound was obtained from compound 9 and isothiazole-5-carboxylic acid according to the method described in Example 60.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.15 (m, 2H), 0.41-0.56 (m, 2H), 0.70-0.90 (m) , 1H),
1.07-1.89 (m, 6H), 2.12-2.48 (m, 5H), 2.60-2.70 (m, 1H), 2.79-3.19 (m, 3H) ), 3.45-3.68 (m, 1H), 3.76-4.85 (m, 6H), 6.57-6.66 (m, 1H), 6.69-6.78 (m). , 1H), 7.32-7.51 (m, 1H), 8.44-8.52 (m, 1H).

(Example 71)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (isothiazole-5-yl) methanone (91)

実施例７に記載した方法に従い、化合物９０より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－１．７８（ｍ，２Ｈ），０．４２－０．５５（ｍ，２Ｈ），０．７０－０．９３（ｍ，１Ｈ），１．０７－１．８２（ｍ，６Ｈ），２．１４－２．４４（ｍ，５Ｈ），２．６０－２．７１（ｍ，１Ｈ），２．７７－３．１４（ｍ，３Ｈ），３．４１－３．９３（ｍ，２Ｈ），４．４０－４．９２（ｍ，３Ｈ），６．５６（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６７－６．７７（ｍ，１Ｈ），７．３５－７．５５（ｍ，１Ｈ），８．４６－８．５３（ｍ，１Ｈ）．

The title compound was obtained from compound 90 according to the method described in Example 7.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-1.78 (m, 2H), 0.42-0.55 (m, 2H), 0.70-0.93 (m) , 1H), 1.07-1.82 (m, 6H), 2.14-2.44 (m, 5H), 2.60-2.71 (m, 1H), 2.77-3.14 (M, 3H), 3.41-3.93 (m, 2H), 4.40-4.92 (m, 3H), 6.56 (d, J = 8Hz, 1H), 6.67-6 .77 (m, 1H), 7.35-7.55 (m, 1H), 8.46-8.53 (m, 1H).

(Example 72)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano -4,13-Metanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (1H-indole-2-yl) Synthesis of methanone (92)

実施例６０に記載した方法に従い、化合物９及び１Ｈ－インドール－２－カルボン酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．１８（ｍ，２Ｈ），０．４４－０．５７（ｍ，２Ｈ），０．７５－０．９２（ｍ，１Ｈ），１．０７－１．８９（ｍ，６Ｈ），２．１２－２．４９（ｍ，５Ｈ），２．５８－２．７０（ｍ，１Ｈ），２．８２－３．１６（ｍ，３Ｈ），３．３２－３．５２（ｍ，０．４Ｈ），３．７５－３．９９（ｍ，３．６Ｈ），４．５２－４．８７（ｍ，３Ｈ），６．５５－６．６８（ｍ，１Ｈ），６．７１－６．８１（ｍ，１Ｈ），６．８４－７．３３（ｍ，３Ｈ），７．４２（ｄ，Ｊ＝７Ｈｚ，１Ｈ），７．６０－７．８３（ｍ，１Ｈ），９．０１－９．４２（ｍ，１Ｈ）．

The title compound was obtained from compound 9 and 1H-indole-2-carboxylic acid according to the method described in Example 60.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.04-0.18 (m, 2H), 0.44-0.57 (m, 2H), 0.75-0.92 (m) , 1H), 1.07-1.89 (m, 6H), 2.12-2.49 (m, 5H), 2.58-2.70 (m, 1H), 2.82-3.16 (M, 3H), 3.32-3.52 (m, 0.4H), 3.75-3.99 (m, 3.6H), 4.52-4.87 (m, 3H), 6 .55-6.68 (m, 1H), 6.71-6.81 (m, 1H), 6.84-7.33 (m, 3H), 7.42 (d, J = 7Hz, 1H) , 7.60-7.83 (m, 1H), 9.01-9.42 (m, 1H).

(Example 73)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano -4,13-Metanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (1H-indole-2-yl) Synthesis of methanone (93)

実施例７に記載した方法に従い、化合物９２より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１８（ｍ，２Ｈ），０．４３－０．５６（ｍ，２Ｈ），０．７５－０．９０（ｍ，１Ｈ），１．０９－１．８６（ｍ，６Ｈ），２．１７－２．４７（ｍ，５Ｈ），２．５９－２．７１（ｍ，１Ｈ），２．８３－３．１５（ｍ，３Ｈ），３．２３－３．８９（ｍ，１Ｈ），４．５０－４．９４（ｍ，４Ｈ），６．５４－６．６２（ｍ，１Ｈ），６．７４（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．８４－７．３５（ｍ，３Ｈ），７．４０－７．４７（ｍ，１Ｈ），７．６２－７．８３（ｍ，１Ｈ），８．９５－９．５０（ｍ，１Ｈ）．

The title compound was obtained from compound 92 according to the method described in Example 7.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.18 (m, 2H), 0.43-0.56 (m, 2H), 0.75-0.90 (m) , 1H), 1.09-1.86 (m, 6H), 2.17-2.47 (m, 5H), 2.59-2.71 (m, 1H), 2.83-3.15 (M, 3H), 3.23-3.89 (m, 1H), 4.50-4.94 (m, 4H), 6.54-6.62 (m, 1H), 6.74 (d). , J = 8Hz, 1H), 6.84-7.35 (m, 3H), 7.40-7.47 (m, 1H), 7.62-7.83 (m, 1H), 8.95 -9.50 (m, 1H).

(Example 74)
(5-Chloropyrimidine-2-yl) ((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a -Synthesis of octahydro-7H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) metanone (94)

実施例６０に記載した方法に従い、化合物９及び５－クロロピリミジン－２－カルボン酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０３－０．１６（ｍ，２Ｈ），０．４１－０．５６（ｍ，２Ｈ），０．７０－０．９３（ｍ，１Ｈ），１．０４－１．９０（ｍ，５Ｈ），２．１１－２．４５（ｍ，６Ｈ），２．５９－２．６９（ｍ，１Ｈ），２．７６－３．１２（ｍ，３Ｈ），３．３４－３．５６（ｍ，１．６Ｈ），３．６８－３．７５（ｍ，０．４Ｈ），３．８１（ｓ，１．２Ｈ），３．９０（ｓ，１．８Ｈ），４．４９－４．６０（ｍ，０．４Ｈ），４．６８－４．８７（ｍ，１．６Ｈ），６．５７－６．６２（ｍ，１Ｈ），６．７０（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ）．６．７５（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），８．７４－８．８２（ｍ，２Ｈ）．

The title compound was obtained from compound 9 and 5-chloropyrimidine-2-carboxylic acid according to the method described in Example 60.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.03-0.16 (m, 2H), 0.41-0.56 (m, 2H), 0.70-0.93 (m) , 1H), 1.04-1.90 (m, 5H), 2.11-2.45 (m, 6H), 2.59-2.69 (m, 1H), 2.76-3.12 (M, 3H), 3.34-3.56 (m, 1.6H), 3.68-3.75 (m, 0.4H), 3.81 (s, 1.2H), 3.90 (S, 1.8H), 4.49-4.60 (m, 0.4H), 4.68-4.87 (m, 1.6H), 6.57-6.62 (m, 1H) , 6.70 (d, J = 8Hz, 0.4H). 6.75 (d, J = 8Hz, 0.6H), 8.74-8.82 (m, 2H).

(Example 75)
(5-Chloropyrimidine-2-yl) ((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a -Synthesis of octahydro-7H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) methanone (95)

実施例７に記載した方法に従い、化合物９４より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０３－０．１６（ｍ，２Ｈ），０．４０－０．５５（ｍ，２Ｈ），０．６５－０．９６（ｍ，１Ｈ），１．０３－１．９１（ｍ，５Ｈ），２．０７－２．４４（ｍ，６Ｈ），２．５８－２．６９（ｍ，１Ｈ），２．８４－３．１１（ｍ，３Ｈ），３．３６－３．６６（ｍ，２Ｈ），４．４６－５．００（ｍ，３Ｈ），６．５０－６．５８（ｍ，１Ｈ），６．６５（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），８．７７－８．１２（ｍ，１Ｈ）．

The title compound was obtained from compound 94 according to the method described in Example 7.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.03-0.16 (m, 2H), 0.40-0.55 (m, 2H), 0.65-0.96 (m) , 1H), 1.03-1.91 (m, 5H), 2.07-2.44 (m, 6H), 2.58-2.69 (m, 1H), 2.84-3.11 (M, 3H), 3.36-3.66 (m, 2H), 4.46-5.00 (m, 3H), 6.50-6.58 (m, 1H), 6.65 (d) , J = 8Hz, 0.3H), 6.73 (d, J = 8Hz, 0.7H), 8.77-8.12 (m, 1H).

(Example 76)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (5-fluoropyrimidine-2-yl) methanone (96)

実施例６０に記載した方法に従い、化合物９及び５－フルオロピリミジン－２－カルボン酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０３－０．１８（ｍ，２Ｈ），０．４１－０．５７（ｍ，２Ｈ），０．６９－０．９２（ｍ，１Ｈ），１．０５－１．９２（ｍ，６Ｈ），２．１３－２．４７（ｍ，５Ｈ），２．８５－３．１４（ｍ，３Ｈ），２．５８－２．６９（ｍ，１Ｈ），３．３５－３．５９（ｍ，１．６Ｈ），３．６７－３．７３（ｍ，０．４Ｈ），３．８０（ｓ，１．２Ｈ），３．９０（ｓ，１．８Ｈ），４．４９－４．６０（ｍ，０．４Ｈ），４．６９－４．８６（ｍ，１．６Ｈ），６．５７－６．６３（ｍ，１Ｈ），６．７０（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７５（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），８．６４－８．７１（ｍ，２Ｈ）．

The title compound was obtained from compound 9 and 5-fluoropyrimidine-2-carboxylic acid according to the method described in Example 60.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.03-0.18 (m, 2H), 0.41-0.57 (m, 2H), 0.69-0.92 (m) , 1H), 1.05-1.92 (m, 6H), 2.13-2.47 (m, 5H), 2.85-3.14 (m, 3H), 2.58-2.69 (M, 1H), 3.35-3.59 (m, 1.6H), 3.67-3.73 (m, 0.4H), 3.80 (s, 1.2H), 3.90 (S, 1.8H), 4.49-4.60 (m, 0.4H), 4.69-4.86 (m, 1.6H), 6.57-6.63 (m, 1H) , 6.70 (d, J = 8Hz, 0.4H), 6.75 (d, J = 8Hz, 0.6H), 8.64-8.71 (m, 2H).

(Example 77)
((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) (5-fluoropyrimidine-2-yl) metanone (97)

実施例７に記載した方法に従い、化合物９６より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１７（ｍ，２Ｈ），０．４１－０．５６（ｍ，２Ｈ），０．６８－０．９４（ｍ，１Ｈ），１．０３－１．８７（ｍ，６Ｈ），２．１３－２．４４（ｍ，５Ｈ），２．５８－２．７１（ｍ，１Ｈ），２．８４－３．１２（ｍ，３Ｈ），３．３４－３．６９（ｍ，２Ｈ），４．３８－４．９２（ｍ，３Ｈ），６．５０－６．５８（ｍ，１Ｈ），６．６５（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），８．６６－８．７３（ｍ，２Ｈ）．

The title compound was obtained from compound 96 according to the method described in Example 7.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.05-0.17 (m, 2H), 0.41-0.56 (m, 2H), 0.68-0.94 (m) , 1H), 1.03-1.87 (m, 6H), 2.13-2.44 (m, 5H), 2.58-2.71 (m, 1H), 2.84-3.12 (M, 3H), 3.34-3.69 (m, 2H), 4.38-4.92 (m, 3H), 6.50-6.58 (m, 1H), 6.65 (d) , J = 8Hz, 0.3H), 6.73 (d, J = 8Hz, 0.7H), 8.66-8.73 (m, 2H).

(Example 78)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Synthesis of ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (pyrimidine-2-yl) ethane-1-one (98)

実施例４４に記載した方法に従い、化合物９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）：０．０６－０．１３（ｍ，２Ｈ），０．４３－０．５１（ｍ，２Ｈ），０．７０－０．８１（ｍ，１Ｈ），１．０３－１．１２（ｍ，１Ｈ），１．１７－１．３３（ｍ，１Ｈ），１．３４－１．５４（ｍ，３Ｈ），１．６０－１．７５（ｍ，１Ｈ），２．１１－２．４２（ｍ，５Ｈ），２．５５－２．７２（ｍ，１．７Ｈ），２．７９－２．８９（ｍ，０．３Ｈ），２．９０－３．０５（ｍ，２Ｈ），３．３７－３．５５（ｍ，１Ｈ），３．７４－３．８３（ｍ，０．７Ｈ），４．１７－４．３１（ｍ，２Ｈ），４．３３－４．４２（ｍ，０．３Ｈ）４．５５－４．６１（ｍ，２Ｈ），６．５０（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．５２（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．６９（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．７０（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），７．１９－７．２３（ｍ，１Ｈ），８．７２（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），８．７４（ｄ，Ｊ＝８Ｈｚ，１．４Ｈ）．

The title compound was obtained from compounds 9 and 2- (pyrimidine-2-yl) acetic acid according to the method described in Example 44.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.13 (m, 2H), 0.43-0.51 (m, 2H), 0.70-0.81 (m) , 1H), 1.03-1.12 (m, 1H), 1.17-1.33 (m, 1H), 1.34-1.54 (m, 3H), 1.60-1.75 (M, 1H), 2.11-2.42 (m, 5H), 2.55-2.72 (m, 1.7H), 2.79-2.89 (m, 0.3H), 2 .90-3.05 (m, 2H), 3.37-1.55 (m, 1H), 3.74-3.83 (m, 0.7H), 4.17-4.31 (m, 2H), 4.33-4.42 (m, 0.3H) 4.55-4.61 (m, 2H), 6.50 (d, J = 8Hz, 0.7H), 6.52 (d) , J = 8Hz, 0.3H), 6.69 (d, J = 8Hz, 0.3H), 6.70 (d, J = 8Hz, 0.7H), 7.19-7.23 (m, 1H), 8.72 (d, J = 8Hz, 0.6H), 8.74 (d, J = 8Hz, 1.4H).

(Example 79)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Synthesis of ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (pyrimidine-5-yl) ethane-1-one (99)

実施例４４に記載した方法に従い、化合物９及び２－（ピリミジン－５－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），０．４４－０．５５（ｍ，２Ｈ），０．７２－０．８５（ｍ，１Ｈ），１．０６－１．１８（ｍ，１Ｈ），１．１９－１．８８（ｍ，５Ｈ），１．９６－２．１３（ｍ，１Ｈ），２．１８－２．４７（ｍ，４Ｈ），２．５８－２．７０（ｍ，１Ｈ），２．７４－２．９０（ｍ，１Ｈ），２．９４－３．１０（ｍ，２Ｈ），３．３７（ｄｄｄ，Ｊ＝５，１１，１５Ｈｚ，０．５Ｈ），３．５６（ｄｄｄ，Ｊ＝４，１１，１５Ｈｚ，０．５Ｈ），３．７１－３．８２（ｍ，０．５Ｈ），３．７６（ｓ，２Ｈ），３．８７（ｓ，１．５Ｈ），３．８９（ｓ，１．５Ｈ），４．０７－４．１２（ｍ，０．５Ｈ），４．４１（ｄｄｄ，Ｊ＝５，５，１４Ｈｚ，０．５Ｈ），４．５０（ｓ，１Ｈ），４．６０－４．６５（ｍ，０．５Ｈ），６．５８（ｄ，Ｊ＝８Ｈｚ，０．５Ｈ），６．６５（ｄ，Ｊ＝８Ｈｚ，０．５Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．５Ｈ），６．７６（ｄ，Ｊ＝８Ｈｚ，０．５Ｈ），８．６８（ｓ，２Ｈ），９．１３（ｓ，０．５Ｈ），９．１４（ｓ，０．５Ｈ）．

The title compound was obtained from compounds 9 and 2- (pyrimidine-5-yl) acetic acid according to the method described in Example 44.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.16 (m, 2H), 0.44-0.55 (m, 2H), 0.72-0.85 (m) , 1H), 1.06-1.18 (m, 1H), 1.19-1.88 (m, 5H), 1.96-2.13 (m, 1H), 2.18-2.47 (M, 4H), 2.58-2.70 (m, 1H), 2.74-2.90 (m, 1H), 2.94-3.10 (m, 2H), 3.37 (ddd) , J = 5,11,15Hz, 0.5H), 3.56 (ddd, J = 4,11,15Hz, 0.5H), 3.71-3.82 (m, 0.5H), 3. 76 (s, 2H), 3.87 (s, 1.5H), 3.89 (s, 1.5H), 4.07-4.12 (m, 0.5H), 4.41 (ddd, J = 5,5,14Hz, 0.5H), 4.50 (s, 1H), 4.60-4.65 (m, 0.5H), 6.58 (d, J = 8Hz, 0.5H) ), 6.65 (d, J = 8Hz, 0.5H), 6.73 (d, J = 8Hz, 0.5H), 6.76 (d, J = 8Hz, 0.5H), 8.68. (S, 2H), 9.13 (s, 0.5H), 9.14 (s, 0.5H).

(Example 80)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Synthesis of ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (pyrimidine-5-yl) ethane-1-one (100)

実施例７に記載した方法に従い、化合物９９より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１６（ｍ，２Ｈ），０．４３－０．５５（ｍ，２Ｈ），０．７１－０．８３（ｍ，１Ｈ），１．０６－１．１９（ｍ，１Ｈ），１．２０－１．７７（ｍ，５Ｈ），２．０９（ｄｄｄ，Ｊ＝６，１２，１２Ｈｚ，１Ｈ），２．１６－２．４５（ｍ，４Ｈ），２．５８－２．６９（ｍ，１Ｈ），２．７２－２．９１（ｍ，１Ｈ），２．９６（ｄ，Ｊ＝１９Ｈｚ，０．７Ｈ），２．９８（ｄ，Ｊ＝１８Ｈｚ，０．３Ｈ），３．０３（ｄ，Ｊ＝６Ｈｚ，０．７Ｈ），３．０６（ｄ，Ｊ＝６Ｈｚ，０．３Ｈ），３．４５（ｄｄｄ，Ｊ＝５，１１，１５Ｈｚ，０．３Ｈ），３．５８（ｄｄｄ，Ｊ＝４，１２，１５Ｈｚ，０．７Ｈ），３．７２－３．８６（ｍ，０．７Ｈ），３．７７（ｓ，１．４Ｈ），３．７８（ｓ，０．６Ｈ），４．０４－４．０８（ｍ，０．３Ｈ），４．３２（ｄｄｄ，Ｊ＝５，５，１４Ｈｚ，０．３Ｈ），４．４７（ｓ，０．７Ｈ），４．４９（ｓ，０．３Ｈ），４．５１－４．５７（ｍ，０．７Ｈ），５．１０（ｂｒ ｓ，０．７Ｈ），５．２９（ｂｒ ｓ，０．３Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．５８（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），８．６９（ｓ，１．４Ｈ），８．７０（ｓ，０．６Ｈ），９．１３（ｓ，０．３Ｈ），９．１５（ｓ，０．７Ｈ）．

The title compound was obtained from compound 99 according to the method described in Example 7.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.16 (m, 2H), 0.43-0.55 (m, 2H), 0.71-0.83 (m) , 1H), 1.06-1.19 (m, 1H), 1.20-1.77 (m, 5H), 2.09 (ddd, J = 6,12,12Hz, 1H), 2.16 -2.45 (m, 4H), 2.58-2.69 (m, 1H), 2.72-2.91 (m, 1H), 2.96 (d, J = 19Hz, 0.7H) , 2.98 (d, J = 18Hz, 0.3H), 3.03 (d, J = 6Hz, 0.7H), 3.06 (d, J = 6Hz, 0.3H), 3.45 ( ddd, J = 5,11,15Hz, 0.3H), 3.58 (ddd, J = 4,12,15Hz, 0.7H), 3.72-3.86 (m, 0.7H), 3 .77 (s, 1.4H), 3.78 (s, 0.6H), 4.04-4.08 (m, 0.3H), 4.32 (ddd, J = 5,5,14Hz, 0.3H), 4.47 (s, 0.7H), 4.49 (s, 0.3H), 4.51-4.57 (m, 0.7H), 5.10 (br s, 0) .7H), 5.29 (br s, 0.3H), 6.54 (d, J = 8Hz, 0.7H), 6.58 (d, J = 8Hz, 0.3H), 6.72 ( d, J = 8Hz, 0.7H), 6.73 (d, J = 8Hz, 0.3H), 8.69 (s, 1.4H), 8.70 (s, 0.6H), 9. 13 (s, 0.3H), 9.15 (s, 0.7H).

(Example 81)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Synthesis of ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (pyrazine-2-yl) ethane-1-one (101)

実施例４５に記載した方法に従い、化合物６０及び２－（ピラジン－２－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１４（ｍ，２Ｈ），０．４４－０．５２（ｍ，２Ｈ），０．７３－０．８０（ｍ，１Ｈ），１．０３－１．１５（ｍ，１Ｈ），１．１９－１．２９（ｍ，１Ｈ），１．３０－１．５６（ｍ，３Ｈ），１．６０－１．７５（ｍ，１Ｈ），２．０８（ｄｄｄ，Ｊ＝６，１３，１３Ｈｚ，１Ｈ），２．２０－２．４３（ｍ，４Ｈ），２．５７－２．７５（ｍ，１．７Ｈ），２．８１－２．９０（ｍ，０．３Ｈ），２．９４（ｄ，Ｊ＝１８Ｈｚ，０．７Ｈ），２．９７（ｄ，Ｊ＝１８Ｈｚ，０．３Ｈ），２．９９（ｄ，Ｊ＝６Ｈｚ，０．７Ｈ），３．０５（ｄ，Ｊ＝６Ｈｚ，０．３Ｈ），３．４３（ｄｄｄ，Ｊ＝４，１０，１４Ｈｚ，０．３Ｈ），３．５５（ｄｄｄ，Ｊ＝４，１２，１５Ｈｚ，０．７Ｈ），３．８６－３．９３（ｍ，０．７Ｈ），４．０１（ｄ，Ｊ＝１５Ｈｚ，１Ｈ），４．０６（ｄ，Ｊ＝１５Ｈｚ，１Ｈ），４．２０－４．２３（ｍ，０．３Ｈ），４．３２（ｄｄｄ，Ｊ＝５，５，１５Ｈｚ，０．３Ｈ），４．４８－４．５２（ｍ，０．７Ｈ），４．５３－４．５７（ｍ，０．７Ｈ），４．５８－４．６１（ｍ，０．３Ｈ），６．５２（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．５６（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．７０（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），８．４６－８．５２（ｍ，１．３Ｈ），８．５３－８．５５（ｍ，０．７Ｈ），８．６５－８．６７（ｍ，１Ｈ）．

The title compound was obtained from compound 60 and 2- (pyrazine-2-yl) acetic acid according to the method described in Example 45.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.14 (m, 2H), 0.44-0.52 (m, 2H), 0.73-0.80 (m) , 1H), 1.03-1.15 (m, 1H), 1.19-1.29 (m, 1H), 1.30-1.56 (m, 3H), 1.60-1.75 (M, 1H), 2.08 (ddd, J = 6,13,13Hz, 1H), 2.20-2.43 (m, 4H), 2.57-2.75 (m, 1.7H) , 2.81-2.90 (m, 0.3H), 2.94 (d, J = 18Hz, 0.7H), 2.97 (d, J = 18Hz, 0.3H), 2.99 ( d, J = 6Hz, 0.7H), 3.05 (d, J = 6Hz, 0.3H), 3.43 (ddd, J = 4,10,14Hz, 0.3H), 3.55 (dddd) , J = 4,12,15Hz, 0.7H), 3.86-3.93 (m, 0.7H), 4.01 (d, J = 15Hz, 1H), 4.06 (d, J = 15Hz, 1H), 4.20-4.23 (m, 0.3H), 4.32 (ddd, J = 5,5,15Hz, 0.3H), 4.48-4.52 (m, 0) .7H), 4.53-4.57 (m, 0.7H), 4.58-4.61 (m, 0.3H), 6.52 (d, J = 8Hz, 0.7H), 6 .56 (d, J = 8Hz, 0.3H), 6.70 (d, J = 8Hz, 0.7H), 6.71 (d, J = 8Hz, 0.3H), 8.46-8. 52 (m, 1.3H), 8.53-8.55 (m, 0.7H), 8.65-8.67 (m, 1H).

(Example 82)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Etano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (1H-imidazol-2-yl) ethane-1-one (102) Synthetic

実施例６０に記載した方法に従い、化合物９及び２－（１Ｈ－イミダゾール－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）：０．００－０．１５（ｍ，２Ｈ），０．４５－０．６５（ｍ，２Ｈ），０．７０－０．８５（ｍ，１Ｈ），１．００－１．１５（ｍ，１Ｈ），１．２０－２．００（ｍ，６Ｈ），２．００－２．１０（ｍ，０．６Ｈ），２．１０－２．４５（ｍ，４．４Ｈ），２．５５－２．６７（ｍ，１Ｈ），２．６７－２．８８（ｍ，１Ｈ），２．９０－３．０８（ｍ，２Ｈ），３．３０－３．４０（ｍ，０．４Ｈ），３．５０－３．６０（ｍ，０．６Ｈ），３．７０－４．００（ｍ，５．６Ｈ），４．１０－４．２０（ｓ，０．４Ｈ），４．３０－４．４３（ｍ，０．４Ｈ），４．４８（ｓ，１Ｈ），４．６０－４．６５（ｓ，０．６Ｈ），６．５７（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．６２（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７０－６．７６（ｍ，１Ｈ），６．９３（ｓ，０．４Ｈ），６．９６（ｓ，０．６Ｈ），７．５８（ｓ，０．４Ｈ），７．５９（ｓ，０．６Ｈ）．

The title compound was obtained from compounds 9 and 2- (1H-imidazol-2-yl) acetate according to the method described in Example 60.


¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.65 (m, 2H), 0.70-0.85 (m) , 1H), 1.00-1.15 (m, 1H), 1.20-2.00 (m, 6H), 2.00-2.10 (m, 0.6H), 2.10-2 .45 (m, 4.4H), 2.55-2.67 (m, 1H), 2.67-2.88 (m, 1H), 2.90-3.08 (m, 2H), 3 .30-3.40 (m, 0.4H), 3.50-3.60 (m, 0.6H), 3.70-4.00 (m, 5.6H), 4.10-4. 20 (s, 0.4H), 4.30-4.43 (m, 0.4H), 4.48 (s, 1H), 4.60-4.65 (s, 0.6H), 6. 57 (d, J = 8Hz, 0.6H), 6.62 (d, J = 8Hz, 0.4H), 6.70-6.76 (m, 1H), 6.93 (s, 0.4H) ), 6.96 (s, 0.6H), 7.58 (s, 0.4H), 7.59 (s, 0.6H).

(Example 83)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Etano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (1H-imidazol-2-yl) ethane-1-one dihydrochloride ( 103) Synthesis

実施例７に記載した方法に従い、化合物１０２（１１．０ｍｇ，０．０２３ｍｍｏｌ）より表題化合物のフリー体を得た。得られたフリー体をメタノール（１ｍＬ）に溶解し、氷冷下２Ｍ塩酸－メタノール溶液（１００μＬ）を滴下し３０分間撹拌した。反応混合物を減圧下にて濃縮後、濃縮残渣を凍結乾燥器にて乾燥し、表題化合物（２．５ｍｇ，２０％）を淡黄色結晶として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ（ｐｐｍ）：０．４６－０．５６（ｍ，１Ｈ），０．５８－０．６８（ｍ，１Ｈ），０．６８－０．８０（ｍ，１Ｈ），０．８０－１．００（ｍ，２Ｈ），１．０６－１．７４（ｍ，６Ｈ），１．７４－１．９６（ｍ，１Ｈ），２．４５－２．６５（ｍ，１Ｈ），２．７５－２．８５（ｍ，０．７Ｈ），２．９５－３．２０（ｍ，３Ｈ），３．２０－３．５０（ｍ，３．３Ｈ），３．６５－３．８０（ｍ，０．７Ｈ），４．００－４．２０（ｍ，３．６Ｈ），４．４５－４．５５（ｍ，１．７Ｈ），６．５０－６．８０（ｍ，２Ｈ），７．４２（ｓ，１Ｈ），８．７９（ｓ，１Ｈ）．

A free form of the title compound was obtained from compound 102 (11.0 mg, 0.023 mmol) according to the method described in Example 7. The obtained free form was dissolved in methanol (1 mL), a 2M hydrochloric acid-methanol solution (100 μL) was added dropwise under ice-cooling, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the concentrated residue was dried in a lyophilizer to give the title compound (2.5 mg, 20%) as pale yellow crystals.

¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 0.46-0.56 (m, 1H), 0.58-0.68 (m, 1H), 0.68-0.80 ( m, 1H), 0.80-1.00 (m, 2H), 1.06-1.74 (m, 6H), 1.74-1.96 (m, 1H), 2.45-2. 65 (m, 1H), 2.75-2.85 (m, 0.7H), 2.95-3.20 (m, 3H), 3.20-3.50 (m, 3.3H), 3.65-3.80 (m, 0.7H), 4.00-4.20 (m, 3.6H), 4.45-4.55 (m, 1.7H), 6.50-6 .80 (m, 2H), 7.42 (s, 1H), 8.79 (s, 1H).

(Example 84)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Synthesis of ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (isoxazole-3-yl) ethane-1-one (104)

実施例４２に記載した方法に従い、化合物９及び２－（イソキサゾール－３－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１６（ｍ，２Ｈ），０．４３－０．５４（ｍ，２Ｈ），０．７２－０．８５（ｍ，１Ｈ），１．０３－１．１６（ｍ，１Ｈ），１．１８－１．８２（ｍ，５Ｈ），１．９８－２．１３（ｍ，１Ｈ），２．１７－２．４６（ｍ，４Ｈ），２．５５－２．６８（ｍ，１Ｈ），２．６９－２．７９（ｍ，０．６Ｈ），２．８０－２．９０（ｍ，０．４Ｈ），２．９２－３．０３（ｍ，１．６Ｈ），３．０６（ｄ，Ｊ＝６Ｈｚ，０．４Ｈ），３．３５－３．４５（ｍ，０．４Ｈ），３．５０－３．６０（ｍ，０．６Ｈ），３．７８－３．９７（ｍ，２．６Ｈ），３．８７（ｓ，３Ｈ），４．１１－４．１６（ｓ，０．４Ｈ），４．３１－４．３９（ｍ，０．４Ｈ），４．４８（ｓ，０．６Ｈ），４．５２（ｓ，０．４Ｈ），４．５９－４．６４（ｍ，０．６Ｈ），６．４６（ｓ，１Ｈ），６．５７（ｄ，Ｊ＝９Ｈｚ，０．６Ｈ），６．６３（ｄ，Ｊ＝９Ｈｚ，０．４Ｈ），６．７２（ｄ，Ｊ＝９Ｈｚ，０．６Ｈ），６．７５（ｄ，Ｊ＝９Ｈｚ，０．４Ｈ），８．３６（ｓ，０．４Ｈ），８．４０（ｓ，０．６Ｈ）．

The title compound was obtained from compounds 9 and 2- (isoxazole-3-yl) acetic acid according to the method described in Example 42.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.05-0.16 (m, 2H), 0.43-0.54 (m, 2H), 0.72-0.85 (m) , 1H), 1.03-1.16 (m, 1H), 1.18-1.82 (m, 5H), 1.98-2.13 (m, 1H), 2.17-2.46 (M, 4H), 2.55-2.68 (m, 1H), 2.69-2.79 (m, 0.6H), 2.80-2.90 (m, 0.4H), 2 .92-3.03 (m, 1.6H), 3.06 (d, J = 6Hz, 0.4H), 3.35-3.45 (m, 0.4H), 3.50-3. 60 (m, 0.6H), 3.78-3.97 (m, 2.6H), 3.87 (s, 3H), 4.11-4.16 (s, 0.4H), 4. 31-4.39 (m, 0.4H), 4.48 (s, 0.6H), 4.52 (s, 0.4H), 4.59-4.64 (m, 0.6H), 6.46 (s, 1H), 6.57 (d, J = 9Hz, 0.6H), 6.63 (d, J = 9Hz, 0.4H), 6.72 (d, J = 9Hz, 0) .6H), 6.75 (d, J = 9Hz, 0.4H), 8.36 (s, 0.4H), 8.40 (s, 0.6H).

(Example 85)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Synthesis of ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (isoxazole-3-yl) ethane-1-one (105)

実施例７に記載した方法に従い、化合物１０４より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１８（ｍ，２Ｈ），０．４１－０．５５（ｍ，２Ｈ），０．７１－０．８４（ｍ，１Ｈ），１．０１－１．１６（ｍ，１Ｈ），１．１６－１．５４（ｍ，４Ｈ），１．５６－１．７３（ｍ，１Ｈ），２．０１－２．１２（ｍ，０．８Ｈ），２．１３－２．４３（ｍ，４．２Ｈ），２．５１－２．６６（ｍ，１Ｈ），２．６７－２．７７（ｍ，０．８Ｈ），２．７８－２．８９（ｍ，０．２Ｈ），２．９０－３．０７（ｍ，２Ｈ），３．４０（ｓ，Ｊ＝４，４，１０，１４Ｈｚ，０．２Ｈ），３．５４（ｄ，Ｊ＝３，３，１１，１４Ｈｚ，０．８Ｈ），３．７９－３．９９（ｍ，２．８Ｈ），４．０９－４．１５（ｍ，０．２Ｈ），４．２８－４．３８（ｍ，０．２Ｈ），４．４６（ｓ，０．８Ｈ），４．４８（ｓ，０．２Ｈ），４．５１－４．５８（ｍ，０．８Ｈ），６．４３－６．５８（ｍ，２Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），８，３８（ｓ，１Ｈ）．

The title compound was obtained from compound 104 according to the method described in Example 7.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.05-0.18 (m, 2H), 0.41-0.55 (m, 2H), 0.71-0.84 (m) , 1H), 1.01-1.16 (m, 1H), 1.16-1.54 (m, 4H), 1.56-1.73 (m, 1H), 2.01-2.12 (M, 0.8H), 2.13-2.43 (m, 4.2H), 2.51-2.66 (m, 1H), 2.67-2.77 (m, 0.8H) , 2.78-2.89 (m, 0.2H), 2.90-3.07 (m, 2H), 3.40 (s, J = 4,4,10,14Hz, 0.2H), 3.54 (d, J = 3,3,11,14Hz, 0.8H), 3.79-3.99 (m, 2.8H), 4.09-4.15 (m, 0.2H) , 4.28-4.38 (m, 0.2H), 4.46 (s, 0.8H), 4.48 (s, 0.2H), 4.51-4.58 (m, 0. 8H), 6.43-6.58 (m, 2H), 6.72 (d, J = 8Hz, 1H), 8,38 (s, 1H).

(Example 86)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Synthesis of ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (oxazole-4-yl) ethane-1-one (106)

実施例６０に記載した方法に従い、化合物９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）：０．０５－０．１７（ｍ，２Ｈ），０．４３－０．５５（ｍ，２Ｈ），０．７３－０．９０（ｍ，１Ｈ），１．０５－１．８１（ｍ，６Ｈ），１．９６－２．５１（ｍ，５Ｈ），２．５５－２．６９（ｍ，１Ｈ），２．７５－２．８９（ｍ，１Ｈ），２．９１－３．１２（ｍ，２Ｈ），３．３０－３．９６（ｍ，６．６Ｈ），４．１６－４．２２（ｍ，０．４Ｈ），４．３３－４．６７（ｍ，２Ｈ），６．５４－６．６５（ｍ，１Ｈ），６．６９－６．７８（ｍ，１Ｈ），７．６７－７．７５（ｍ，１Ｈ），７．７９－７．８８（ｍ，１Ｈ）．

The title compound was obtained from compounds 9 and 2- (oxazole-4-yl) acetic acid according to the method described in Example 60.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.17 (m, 2H), 0.43-0.55 (m, 2H), 0.73-0.90 (m) , 1H), 1.05-1.81 (m, 6H), 1.96-2.51 (m, 5H), 2.55-2.69 (m, 1H), 2.75-2.89 (M, 1H), 2.91-3.12 (m, 2H), 3.30-3.96 (m, 6.6H), 4.16-4.22 (m, 0.4H), 4 .33-4.67 (m, 2H), 6.54-6.65 (m, 1H), 6.69-6.78 (m, 1H), 7.67-7.75 (m, 1H) , 7.79-7.88 (m, 1H).

(Example 87)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Synthesis of ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (oxazole-4-yl) ethane-1-one (107)

実施例７に記載した方法に従い、化合物１０６より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１７（ｍ，２Ｈ），０．４３－０．５７（ｍ，２Ｈ），０．７１－０．９１（ｍ，１Ｈ），１．０２－１．７９（ｍ，６Ｈ），２．０４－２．４５（ｍ，５Ｈ），２．５６－２．６９（ｍ，１Ｈ），２．７２－３．１０（ｍ，３Ｈ），３．３３－３．６３（ｍ，１Ｈ），３．６７－３．９６（ｍ，２．８Ｈ），４．１３－４．２１（ｍ，０．２Ｈ），４．３０－５．０４（ｍ，３Ｈ），６．５０－６．５９（ｍ，１Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．７３（ｓ，１Ｈ），７．８２－７．９０（ｍ，１Ｈ）．

The title compound was obtained from compound 106 according to the method described in Example 7.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.17 (m, 2H), 0.43-0.57 (m, 2H), 0.71-0.91 (m) , 1H), 1.02-1.79 (m, 6H), 2.04-2.45 (m, 5H), 2.56-2.69 (m, 1H), 2.72-3.10 (M, 3H), 3.33-3.63 (m, 1H), 3.67-3.96 (m, 2.8H), 4.13-4.21 (m, 0.2H), 4 .30-5.04 (m, 3H), 6.50-6.59 (m, 1H), 6.71 (d, J = 8Hz, 1H), 7.73 (s, 1H), 7.82 -7.90 (m, 1H).

(Example 88)
2- (Benzo [d] Oxazole-2-yl) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-methoxy-1,2,3,4,5 , 6,8,8a-Octahydro-7H-4a, 8-Etano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) ethane-1-one (108) ) Synthesis

実施例６０に記載した方法に従い、化合物９及び２－（ベンゾ［ｄ］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）：０．０３－０．１９（ｍ，２Ｈ），０．４０－０．５５（ｍ，２Ｈ），０．６７－０．９３（ｍ，１Ｈ），１．０４－１．８２（ｍ，６Ｈ），２．０７－２．４８（ｍ，５Ｈ），２．５３－３．１２（ｍ，４Ｈ），３．３１－３．９２（ｍ，５Ｈ），４．０４－４．４４（ｍ，２．４Ｈ），４．５５－４．６８（ｍ，１．６Ｈ），６．５７（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．６４（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．６９－６．７６（ｍ，１Ｈ），７．１５－７．３７（ｍ，２Ｈ），７．４８－７．５７（ｍ，１Ｈ），７．６６－７．７４（ｍ，１Ｈ）．

The title compound was obtained from compounds 9 and 2- (benzo [d] oxazol-2-yl) acetic acid according to the method described in Example 60.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.03-0.19 (m, 2H), 0.40-0.55 (m, 2H), 0.67-0.93 (m) , 1H), 1.04-1.82 (m, 6H), 2.07-2.48 (m, 5H), 2.53-3.12 (m, 4H), 3.31-3.92 (M, 5H), 4.04-4.44 (m, 2.4H), 4.55-4.68 (m, 1.6H), 6.57 (d, J = 8Hz, 0.6H) , 6.64 (d, J = 8Hz, 0.4H), 6.69-6.76 (m, 1H), 7.15-7.37 (m, 2H), 7.48-7.57 ( m, 1H), 7.66-7.74 (m, 1H).

(Example 89)
2- (Benzo [d] Oxazole-2-yl) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-Hydroxy-1,2,3,4,5 , 6,8,8a-Octahydro-7H-4a, 8-Etano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) ethane-1-one (109) ) Synthesis

実施例７に記載した方法に従い、化合物１０８より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０２－０．１７（ｍ，２Ｈ），０．４０－０．５４（ｍ，２Ｈ），０．６５－０．９５（ｍ，１Ｈ），１．０１－１．８２（ｍ，６Ｈ），２．０６－２．４５（ｍ，５Ｈ），２．５４－３．１０（ｍ，４Ｈ），３．３６－３．６４（ｍ，１Ｈ），３．７７－３．９２（ｍ，０．８Ｈ），４．０７－４．８０（ｍ，５．２Ｈ），６．５２（ｄ，Ｊ＝８Ｈｚ，０．８Ｈ），６．５７（ｄ，Ｊ＝８Ｈｚ，０．２Ｈ），６．６７－６．７４（ｍ，１Ｈ），７．２６－７．３７（ｍ，２Ｈ），７．４９－７．５７（ｍ，１Ｈ），７．６７－７．７４（ｍ，１Ｈ）．

The title compound was obtained from compound 108 according to the method described in Example 7.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02-0.17 (m, 2H), 0.40-0.54 (m, 2H), 0.65-0.95 (m) , 1H), 1.01-1.82 (m, 6H), 2.06-2.45 (m, 5H), 2.54-3.10 (m, 4H), 3.36-3.64 (M, 1H), 3.77-3.92 (m, 0.8H), 4.07-4.80 (m, 5.2H), 6.52 (d, J = 8Hz, 0.8H) , 6.57 (d, J = 8Hz, 0.2H), 6.67-6.74 (m, 1H), 7.26-7.37 (m, 2H), 7.49-7.57 ( m, 1H), 7.67-7.74 (m, 1H).

(Example 90)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Etano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (1H-indole-3-yl) ethane-1-on (110) Synthetic

実施例６０に記載した方法に従い、化合物９及び２－（１Ｈ－インドール－３－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０３－０．１６（ｍ，２Ｈ），０．３８－０．５４（ｍ，２Ｈ），０．６７－１．８９（ｍ，６Ｈ），２．１３－２．６８（ｍ，７Ｈ），２．７７－３．０８（ｍ，３Ｈ），３．２２－３．５１（ｍ，１Ｈ），３．７５－４．００（ｍ，５．７Ｈ），４．１８－４．２５（ｍ，０．３Ｈ），４．３８－４．５３（ｍ，１．３Ｈ），４．６５－４．７２（ｍ，０．７Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．６１（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．６６－６．７７（ｍ，１Ｈ），７．０６－７．３９（ｍ，４Ｈ），７．５８－７．７１（ｍ，１Ｈ），７．９９－８．３３（ｍ，１Ｈ）．

The title compound was obtained from compounds 9 and 2- (1H-indole-3-yl) acetic acid according to the method described in Example 60.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.03-0.16 (m, 2H), 0.38-0.54 (m, 2H), 0.67-1.89 (m) , 6H), 2.13-2.68 (m, 7H), 2.77-3.08 (m, 3H), 3.22-3.51 (m, 1H), 3.75-4.00 (M, 5.7H), 4.18-4.25 (m, 0.3H), 4.38-4.53 (m, 1.3H), 4.65-4.72 (m, 0. 7H), 6.54 (d, J = 8Hz, 0.7H), 6.61 (d, J = 8Hz, 0.3H), 6.66-6.77 (m, 1H), 7.06- 7.39 (m, 4H), 7.58-7.71 (m, 1H), 7.99-8.33 (m, 1H).

(Example 91)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Etano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (1H-indole-3-yl) ethane-1-on (111) Synthetic

実施例７に記載した方法に従い、化合物１１０より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０２－０．１８（ｍ，２Ｈ），０．３９－０．５４（ｍ，２Ｈ），０．６５－１．７９（ｍ，８Ｈ），２．１０－２．６７（ｍ，６Ｈ），２．７５－３．１０（ｍ，２Ｈ），３．２６－３．５３（ｍ，１Ｈ），３．７８－４．０１（ｍ，３Ｈ），４．４１－５．１８（ｍ，３Ｈ），６．４５－６．５８（ｍ，１Ｈ），６．６９（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．１０－７．４３（ｍ，４Ｈ），７．６４－７．７３（ｍ，１Ｈ），８．０５－８．２０（ｍ，１Ｈ）．

The title compound was obtained from compound 110 according to the method described in Example 7.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02-0.18 (m, 2H), 0.39-0.54 (m, 2H), 0.65-1.79 (m) , 8H), 2.10-2.67 (m, 6H), 2.75-3.10 (m, 2H), 3.26-3.53 (m, 1H), 3.78-4.01 (M, 3H), 4.41-5.18 (m, 3H), 6.45-6.58 (m, 1H), 6.69 (d, J = 8Hz, 1H), 7.10-7 .43 (m, 4H), 7.64-7.73 (m, 1H), 8.05-8.20 (m, 1H).

(Example 92)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Synthesis of ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (thiazole-2-yl) ethane-1-one (112)

実施例６０に記載した方法に従い、化合物９及び２－（チアゾール－２－イル）酢酸（Ｂｉｏｏｒｇａｎｉｃ ＆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ Ｌｅｔｔｅｒｓ ２０１０，２０，７４１４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）：０．０７－０．１４（ｍ，２Ｈ），０．４４－０．５４（ｍ，２Ｈ），０．７３－０．８４（ｍ，１Ｈ），１．０４－１．１６（ｍ，１Ｈ），１．１９－１．７６（ｍ，５Ｈ），２．０５（ｄｄｄ，Ｊ＝５，１２，１２Ｈｚ，０．６Ｈ），２．１８－２．４５（ｍ，４．４Ｈ），２．５７－２．７５（ｍ，１．６Ｈ），２．８２－３．０７（ｍ，２．４Ｈ），３．４５（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，０．４Ｈ），３．５７（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，０．６Ｈ），３．８５－３．９３（ｍ，３．６Ｈ），４．１８－４．２８（ｍ，２．４Ｈ），４．３３－４．３９（ｍ，０．４Ｈ），４．５１－４．５５（ｍ，１Ｈ），４．６２－４．６５（ｍ，０．６Ｈ），６．５７（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．６２（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．７４（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），７．２９（ｄ，Ｊ＝３Ｈｚ，０．４Ｈ），７．３２（ｄ，Ｊ＝３Ｈｚ，０．６Ｈ），７．７１（ｄ，Ｊ＝３Ｈｚ，０．４Ｈ），７．７５（ｄ，Ｊ＝３Ｈｚ，０．６Ｈ）．

The title compound was obtained from Compounds 9 and 2- (thiazole-2-yl) acetic acid (synthesized by the method described in Bioorganic & Medicinal Chemistry Letters 2010, 20, 7414) according to the method described in Example 60.


¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.14 (m, 2H), 0.44-0.54 (m, 2H), 0.73-0.84 (m) , 1H), 1.04-1.16 (m, 1H), 1.19-1.76 (m, 5H), 2.05 (ddd, J = 5,12,12Hz, 0.6H), 2 .18-2.45 (m, 4.4H), 2.57-2.75 (m, 1.6H), 2.82-3.07 (m, 2.4H), 3.45 (ddd, J = 4,11,14Hz, 0.4H), 3.57 (ddd, J = 4,11,14Hz, 0.6H), 3.85-3.93 (m, 3.6H), 4.18 -4.28 (m, 2.4H), 4.33-4.39 (m, 0.4H), 4.51-4.55 (m, 1H), 4.62-4.65 (m, 0.6H), 6.57 (d, J = 8Hz, 0.6H), 6.62 (d, J = 8Hz, 0.4H), 6.72 (d, J = 8Hz, 0.6H), 6.74 (d, J = 8Hz, 0.4H), 7.29 (d, J = 3Hz, 0.4H), 7.32 (d, J = 3Hz, 0.6H), 7.71 (d) , J = 3Hz, 0.4H), 7.75 (d, J = 3Hz, 0.6H).

(Example 93)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Synthesis of ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (thiazole-2-yl) ethane-1-one (113)

実施例７に記載した方法に従い、化合物１１２より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１３（ｍ，２Ｈ），０．４３－０．５３（ｍ，２Ｈ），０．７２－０．８２（ｍ，１Ｈ），１．０３－１．１４（ｍ，１Ｈ），１．１９－１．７２（ｍ，５Ｈ），２．０５（ｄｄｄ，Ｊ＝６，１３，１３Ｈｚ，０．７Ｈ），２．１３－２．４１（ｍ，４．３Ｈ），２．５５－２．７３（ｍ，１．７Ｈ），２．８０－３．０５（ｍ，２．３Ｈ），３．４５（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，０．３Ｈ），３．５６（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，０．７Ｈ），３．８８－３．９４（ｍ，０．７Ｈ），４．１８－４．３６（ｍ，２．６Ｈ），４．４８－４．５１（ｍ，１Ｈ），４．５４－４．５７（ｍ，０．７Ｈ），６．５２（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．３２（ｄ，Ｊ＝３Ｈｚ，０．３Ｈ），７．３３（ｄ，Ｊ＝３Ｈｚ，０．７Ｈ），７．７３（ｄ，Ｊ＝３Ｈｚ，０．３Ｈ），７．７５（ｄ，Ｊ＝３Ｈｚ，０．７Ｈ）．

The title compound was obtained from compound 112 according to the method described in Example 7.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.13 (m, 2H), 0.43-0.53 (m, 2H), 0.72-0.82 (m) , 1H), 1.03-1.14 (m, 1H), 1.19-1.72 (m, 5H), 2.05 (ddd, J = 6,13,13Hz, 0.7H), 2 .13-2.41 (m, 4.3H), 2.55-2.73 (m, 1.7H), 2.80-3.05 (m, 2.3H), 3.45 (ddd, J = 4,11,14Hz, 0.3H), 3.56 (ddd, J = 4,11,14Hz, 0.7H), 3.88-3.94 (m, 0.7H), 4.18 -4.36 (m, 2.6H), 4.48-4.51 (m, 1H), 4.54-4.57 (m, 0.7H), 6.52 (d, J = 8Hz, 0.7H), 6.54 (d, J = 8Hz, 0.3H), 6.71 (d, J = 8Hz, 1H), 7.32 (d, J = 3Hz, 0.3H), 7. 33 (d, J = 3Hz, 0.7H), 7.73 (d, J = 3Hz, 0.3H), 7.75 (d, J = 3Hz, 0.7H).

(Example 94)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Synthesis of ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (thiazole-5-yl) ethane-1-one (114)

実施例６０に記載した方法に従い、化合物９及び２－（チアゾール－５－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０３－０．１７（ｍ，２Ｈ），０．４２－０．５６（ｍ，２Ｈ），０．７１－０．９２（ｍ，１Ｈ），１．０３－１．７９（ｍ，５Ｈ），１．９４－２．４７（ｍ，６Ｈ），２．５５－３．０９（ｍ，４Ｈ），３．２８－４．１２（ｍ，７Ｈ），４．３９－４．６６（ｍ，２Ｈ），６．５７（ｄ，Ｊ＝８Ｈｚ，０．５Ｈ），６．６４（ｄ，Ｊ＝０．５Ｈ），６．６８－６．８０（ｍ，１Ｈ），７．２３（ｓ，１Ｈ），８．７１－８．７９（ｍ，１Ｈ）．

The title compound was obtained from compounds 9 and 2- (thiazole-5-yl) acetic acid according to the method described in Example 60.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.17 (m, 2H), 0.42-0.56 (m, 2H), 0.71-0.92 (m) , 1H), 1.03-1.79 (m, 5H), 1.94-2.47 (m, 6H), 2.55-3.09 (m, 4H), 3.28-4.12 (M, 7H), 4.39-4.66 (m, 2H), 6.57 (d, J = 8Hz, 0.5H), 6.64 (d, J = 0.5H), 6.68 -6.80 (m, 1H), 7.23 (s, 1H), 8.71-8.79 (m, 1H).

(Example 95)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Synthesis of ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (thiazole-5-yl) ethane-1-one (115)

実施例７に記載した方法に従い、化合物１１４より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０３－０．１７（ｍ，２Ｈ），０．４３－０．５６（ｍ，２Ｈ），０．７０－０．９５（ｍ，１Ｈ），１．０３－１．７８（ｍ，５Ｈ），１．９７－２．４５（ｍ，６Ｈ），２．５４－３．１３（ｍ，４Ｈ），３．３４－３．６３（ｍ，１Ｈ），３．７２－３．８５（ｍ，０．６Ｈ），３．９６－４．１０（ｍ，２Ｈ），４．３３－５．１４（ｍ，３．４Ｈ），６．４９－６．６１（ｍ，１Ｈ），６．６８－６．７６（ｍ，１Ｈ），７．７０－７．７８（ｍ，１Ｈ），８．７４－８．８０（ｍ，１Ｈ）．

The title compound was obtained from compound 114 according to the method described in Example 7.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.17 (m, 2H), 0.43-0.56 (m, 2H), 0.70-0.95 (m) , 1H), 1.03-1.78 (m, 5H), 1.97-2.45 (m, 6H), 2.54-3.13 (m, 4H), 3.34-3.63 (M, 1H), 3.72-3.85 (m, 0.6H), 3.96-4.10 (m, 2H), 4.33-5.14 (m, 3.4H), 6 .49-6.61 (m, 1H), 6.68-6.76 (m, 1H), 7.70-7.78 (m, 1H), 8.74-8.80 (m, 1H) ..

(Example 96)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Synthesis of ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (thiazole-4-yl) ethane-1-one (116)

実施例６０に記載した方法に従い、化合物９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）：０．０６－０．１５（ｍ，２Ｈ），０．４４－０．５２（ｍ，２Ｈ），０．７３－０．８３（ｍ，１Ｈ），１．０４－１．９０（ｍ，６Ｈ），２．０４（ｄｄｄ，Ｊ＝６，１３，１３Ｈｚ，０．６Ｈ），２．２０－２．４４（ｍ，４．４Ｈ），２．５７－２．６９（ｍ，１．６Ｈ），２．８０－３．０７（ｍ，２．４Ｈ），３．３５－３．４３（ｍ，０．４Ｈ），３．５１－３．５８（ｍ，０．６Ｈ），３．８７（ｓ，３Ｈ），３．８９－４．０９（ｍ，２．６Ｈ），４．２４－４．２８（ｍ，０．４Ｈ），４．３７－４．４３（ｍ，０．４Ｈ），４．５１－４．５７（ｍ，１Ｈ），４．６２－４．６５（ｍ，０．６Ｈ），６．５６（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．６２（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．７４（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），７．２３（ｓ，０．４Ｈ），７．２７（ｓ，０．６Ｈ），８．７５（ｄ，Ｊ＝２Ｈｚ，０．４Ｈ），８．８０（ｄ，Ｊ＝２Ｈｚ，０．６Ｈ）．

The title compound was obtained from compounds 9 and 2- (thiazole-4-yl) acetic acid according to the method described in Example 60.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.15 (m, 2H), 0.44-0.52 (m, 2H), 0.73-0.83 (m) , 1H), 1.04-1.90 (m, 6H), 2.04 (ddd, J = 6,13,13Hz, 0.6H), 2.20-2.44 (m, 4.4H) , 2.57-2.69 (m, 1.6H), 2.80-3.07 (m, 2.4H), 3.35-3.43 (m, 0.4H), 3.51- 3.58 (m, 0.6H), 3.87 (s, 3H), 3.89-4.09 (m, 2.6H), 4.24-4.28 (m, 0.4H), 4.37-4.43 (m, 0.4H), 4.51-4.57 (m, 1H), 4.62-4.65 (m, 0.6H), 6.56 (d, J) = 8Hz, 0.6H), 6.62 (d, J = 8Hz, 0.4H), 6.72 (d, J = 8Hz, 0.6H), 6.74 (d, J = 8Hz, 0. 4H), 7.23 (s, 0.4H), 7.27 (s, 0.6H), 8.75 (d, J = 2Hz, 0.4H), 8.80 (d, J = 2Hz, 0.6H).

(Example 97)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Synthesis of ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (thiazole-4-yl) ethane-1-one (117)

実施例７に記載した方法に従い、化合物１１６より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１３（ｍ，２Ｈ），０．４３－０．５２（ｍ，２Ｈ），０．７３－０．８１（ｍ，１Ｈ），１．０２－１．１２（ｍ，１Ｈ），１．１８－１．７１（ｍ，５Ｈ），２．０４（ｄｄｄ，Ｊ＝５，１３，１３Ｈｚ，０．７Ｈ），２．１７－２．４１（ｍ，４．３Ｈ），２．５６－２．６７（ｍ，１．７Ｈ），２．７９－３．０５（ｍ，２．３Ｈ），３．３５－３．４２（ｍ，０．３Ｈ），３．４９－３．５６（ｍ，０．７Ｈ），３．９２－４．１５（ｍ，２．７Ｈ），４．２４－４．２７（ｍ，０．３Ｈ），４．３４－４．４１（ｍ，０．３Ｈ），４．４９－４．５８（ｍ，１．７Ｈ），６．５１（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．７０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．２６－７．２９（ｍ，１Ｈ），８．７７（ｄ，Ｊ＝２Ｈｚ，０．３Ｈ），８．８０（ｄ，Ｊ＝２Ｈｚ，０．７Ｈ）．

The title compound was obtained from compound 116 according to the method described in Example 7.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.05-0.13 (m, 2H), 0.43-0.52 (m, 2H), 0.73-0.81 (m) , 1H), 1.02-1.12 (m, 1H), 1.18-1.71 (m, 5H), 2.04 (ddd, J = 5,13,13Hz, 0.7H), 2 .17-2.41 (m, 4.3H), 2.56-2.67 (m, 1.7H), 2.79-3.05 (m, 2.3H), 3.35-3. 42 (m, 0.3H), 3.49-3.56 (m, 0.7H), 3.92-4.15 (m, 2.7H), 4.24-4.27 (m, 0) .3H), 4.34-4.41 (m, 0.3H), 4.49-4.58 (m, 1.7H), 6.51 (d, J = 8Hz, 0.7H), 6 .54 (d, J = 8Hz, 0.3H), 6.70 (d, J = 8Hz, 1H), 7.26-7.29 (m, 1H), 8.77 (d, J = 2Hz, 0.3H), 8.80 (d, J = 2Hz, 0.7H).

(Example 98)
2- (5-Chloropyrimidine-2-yl) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5, 6,8,8a-Octahydro-7H-4a, 8-Etano-4,13-Metanobenzoflo [2,3-c] Pyrimidine [4,3-d] Azepine-7-yl) Ethane-1-one (118) Synthesis of

実施例６０に記載した方法に従い、化合物９及び２－（５－クロロピリミジン－２－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１７（ｍ，２Ｈ），０．４３－０．５５（ｍ，２Ｈ），０．７１－０．９２（ｍ，１Ｈ），１．０３－１．８０（ｍ，６Ｈ），２．１１－２．４８（ｍ，５Ｈ），２．５７－３．１０（ｍ，４Ｈ），３．３３－３．６２（ｍ，１Ｈ），３．７０－３．８０（ｍ，０．６Ｈ），３．８７（ｓ，３Ｈ），４．０６－４．２３（ｍ，２．４Ｈ），４．３４－４．４６（ｍ，０．４Ｈ），４．５４－４．６９（ｍ，１．６Ｈ），６．５７（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．６３（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．６８－６．７７（ｍ，１Ｈ），８．６４－８．７１（ｍ，２Ｈ）．

The title compound was obtained from compounds 9 and 2- (5-chloropyrimidine-2-yl) acetic acid according to the method described in Example 60.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.17 (m, 2H), 0.43-0.55 (m, 2H), 0.71-0.92 (m) , 1H), 1.03-1.80 (m, 6H), 2.11-2.48 (m, 5H), 2.57-3.10 (m, 4H), 3.33-3.62 (M, 1H), 3.70-3.80 (m, 0.6H), 3.87 (s, 3H), 4.06-4.23 (m, 2.4H), 4.34-4 .46 (m, 0.4H), 4.54-4.69 (m, 1.6H), 6.57 (d, J = 8Hz, 0.6H), 6.63 (d, J = 8Hz, 0.4H), 6.68-6.77 (m, 1H), 8.64-8.71 (m, 2H).

(Example 99)
2- (5-Chloropyrimidine-2-yl) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5, 6,8,8a-Octahydro-7H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) ethane-1-one (119) Synthesis of

実施例７に記載した方法に従い、化合物１１８より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０３－０．１９（ｍ，２Ｈ），０．４３－０．５５（ｍ，２Ｈ），０．７２－０．９４（ｍ，１Ｈ），１．０１－１．９０（ｍ，６Ｈ），２．１１－２．４５（ｍ，５Ｈ），２．５８－３．１１（ｍ，４Ｈ），３．３５－３．５９（ｍ，１Ｈ），３．７０－３．８２（ｍ，０．８Ｈ），４．０４－４．２５（ｍ，２Ｈ），４．３０－４．４２（ｍ，０．２Ｈ），４．４８－４．８５（ｍ，３Ｈ），６．５０－６．５８（ｍ，１Ｈ），６．６８－６．７３（ｍ，１Ｈ），８．６７（ｓ，０．４Ｈ），８．６９（ｓ，１．６Ｈ）．

The title compound was obtained from compound 118 according to the method described in Example 7.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.19 (m, 2H), 0.43-0.55 (m, 2H), 0.72-0.94 (m) , 1H), 1.01-1.90 (m, 6H), 2.11-2.45 (m, 5H), 2.58-3.11 (m, 4H), 3.35-3.59 (M, 1H), 3.70-3.82 (m, 0.8H), 4.04-4.25 (m, 2H), 4.30-4.42 (m, 0.2H), 4 .48-4.85 (m, 3H), 6.50-6.58 (m, 1H), 6.68-6.73 (m, 1H), 8.67 (s, 0.4H), 8 .69 (s, 1.6H).

(Example 100)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Etano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (1H-imidazol-1-yl) ethane-1-one (120) Synthetic

実施例４５に記載した方法に従い、化合物６０及び２－（１Ｈ－イミダゾール－１－イル）酢酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．００－０．１５（ｍ，２Ｈ），０．４２－０．５５（ｍ，２Ｈ），０．７２－０．９２（ｍ，２Ｈ），１．０５－１．８０（ｍ，６Ｈ），１．９５－２．４５（ｍ，４Ｈ），２．６０－２．７０（ｍ，１Ｈ），２．７５－３．１０（ｍ，３Ｈ），３．５０－３．７０（ｍ，１．７Ｈ），３．９０（ｓ，０．３Ｈ），４．１５－４．３５（ｍ，０．３Ｈ），４．３５－４．５０（ｍ，１．７Ｈ），４．８０－５．００（ｍ，２Ｈ），６．５３（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．５７（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．７０－６．８０（ｍ，１Ｈ），６．９０－７．００（ｍ，１Ｈ），７．０５－７．１５（ｍ，１Ｈ），７．５８（ｓ，０．７Ｈ），７．６３（ｓ，０．３Ｈ）．

The title compound was obtained from compounds 60 and 2- (1H-imidazol-1-yl) acetic acid according to the method described in Example 45.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.42-0.55 (m, 2H), 0.72-0.92 (m) , 2H), 1.05-1.80 (m, 6H), 1.95-2.45 (m, 4H), 2.60-2.70 (m, 1H), 2.75-3.10 (M, 3H), 3.50-3.70 (m, 1.7H), 3.90 (s, 0.3H), 4.15-4.35 (m, 0.3H), 4.35 -4.50 (m, 1.7H), 4.80-5.00 (m, 2H), 6.53 (d, J = 8Hz, 0.7H), 6.57 (d, J = 8Hz, 0.3H), 6.70-6.80 (m, 1H), 6.90-7.00 (m, 1H), 7.05-7.15 (m, 1H), 7.58 (s, 0.7H), 7.63 (s, 0.3H).

(Example 101)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Etano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (1H-pyrazole-1-yl) ethane-1-one (121) Synthetic

実施例６０に記載した方法に従い、化合物９及び化合物２－（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）：０．００－０．１５（ｍ，２Ｈ），０．４５－０．５５（ｍ，２Ｈ），０．７０－０．８５（ｍ，１Ｈ），１．００－１．８０（ｍ，４．３Ｈ），２．００－２．１５（ｍ，０．７Ｈ），２．１５－２．４５（ｍ，５Ｈ），２．５５－２．７５（ｍ，２Ｈ），２．８０－３．１０（ｍ，３Ｈ），３．４０－３．６０（ｍ，１Ｈ），３．７５－３．８３（ｍ，０．７Ｈ），３．８６（ｓ，０．９Ｈ），３．８８（ｓ，２．１Ｈ），４．０８（ｓ，０．３Ｈ），４．２０－４．３２（ｍ，０．３Ｈ），４．４８（ｓ，０．７Ｈ），４．５５－４．６５（ｍ，１Ｈ），５．０４（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），５．１０（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），６．３０－６．３８（ｍ，１Ｈ），６．５７（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．６３（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．７０－６．７８（ｍ，１Ｈ），７．５０－７．６０（ｍ，２Ｈ）．

The title compound was obtained from compound 9 and compound 2- (1H-pyrazole-1-yl) acetic acid according to the method described in Example 60.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.70-0.85 (m) , 1H), 1.00-1.80 (m, 4.3H), 2.00-2.15 (m, 0.7H), 2.15-2.45 (m, 5H), 2.55 -2.75 (m, 2H), 2.80-3.10 (m, 3H), 3.40-3.60 (m, 1H), 3.75-3.83 (m, 0.7H) , 3.86 (s, 0.9H), 3.88 (s, 2.1H), 4.08 (s, 0.3H), 4.20-4.32 (m, 0.3H), 4 .48 (s, 0.7H), 4.55-4.65 (m, 1H), 5.04 (d, J = 16Hz, 1H), 5.10 (d, J = 16Hz, 1H), 6 .30-6.38 (m, 1H), 6.57 (d, J = 8Hz, 0.7H), 6.63 (d, J = 8Hz, 0.3H), 6.70-6.78 ( m, 1H), 7.50-7.60 (m, 2H).

(Example 102)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Etano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (1H-pyrazole-1-yl) ethane-1-one (122) Synthetic

実施例７に記載した方法に従い、化合物１２１より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．００－０．２０（ｍ，２Ｈ），０．４０－０．５５（ｍ，２Ｈ），０．７０－０．８５（ｍ，１Ｈ），１．００－１．８０（ｍ，６Ｈ），２．００－２．４５（ｍ，５．３Ｈ），２．５５－２．７５（ｍ，１．７Ｈ），２．７５－３．０５（ｍ，２．３Ｈ），３．４０－３．５５（ｍ，０．７Ｈ），３．７５－３．８５（ｍ，０．７Ｈ），４．０７（ｓ，０．３Ｈ），４．２０－４．３５（ｍ，０．３Ｈ），４．４０－４．５５（ｍ，１．７Ｈ），５．０４（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），５．１６（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），６．３０－６．３８（ｍ，１Ｈ），６．５１（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．５５（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．６６－６．７４（ｍ，１Ｈ），７．５２－７．５８（ｍ，２Ｈ）．

The title compound was obtained from compound 121 according to the method described in Example 7.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.00-0.20 (m, 2H), 0.40-0.55 (m, 2H), 0.70-0.85 (m) , 1H), 1.00-1.80 (m, 6H), 2.00-2.45 (m, 5.3H), 2.55-2.75 (m, 1.7H), 2.75 -3.05 (m, 2.3H), 3.40-3.55 (m, 0.7H), 3.75-3.85 (m, 0.7H), 4.07 (s, 0. 3H), 4.20-4.35 (m, 0.3H), 4.40-4.55 (m, 1.7H), 5.04 (d, J = 16Hz, 1H), 5.16 ( d, J = 16Hz, 1H), 6.30-6.38 (m, 1H), 6.51 (d, J = 8Hz, 0.7H), 6.55 (d, J = 8Hz, 0.3H) ), 6.66-6.74 (m, 1H), 7.52-7.58 (m, 2H).

(Example 103)
(E) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8a-octahydro-7H -4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -3- (pyrimidine-2-yl) prop-2-en-1 -On (123) synthesis

実施例４２に記載した方法に従い、化合物９及び（Ｅ）－３－（ピリミジン－２－イル）アクリル酸（ＷＯ２０１８０５０６５６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）：０．０７－０．１５（ｍ，２Ｈ），０．４５－０．５３（ｍ，２Ｈ），０．７５－０．８５（ｍ，１Ｈ），１．０８－１．１６（ｍ，１Ｈ），１．２２－１．３８（ｍ，２Ｈ），１．４５－１．５５（ｍ，２Ｈ），１．６８－１．７９（ｍ，１Ｈ），２．１３－２．４６（ｍ，５Ｈ），２．５９－２．６８（ｍ，１Ｈ），２．８７－２．９９（ｍ，１．６Ｈ），３．００－３．０９（ｍ，１．４Ｈ），３．５０（ｄｄｄ，Ｊ＝４，１０，１４Ｈｚ，０．６Ｈ），３．６４（ｄｄｄ，Ｊ＝４，１１，１４Ｈｚ，０．４Ｈ），３．８９（ｓ，３Ｈ），３．９８－４．０５（ｍ，０．４Ｈ），４．３０－４．３２（ｍ，０．６Ｈ），４．４０－４．４８（ｍ，０．６Ｈ），４．５８（ｓ，０．６Ｈ），４．６１（ｓ，０．４Ｈ），４．７３－４．７８（ｍ，０．４Ｈ），６．５８（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．６３（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．７４（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７５（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），７．１７－７．２１（ｍ，１Ｈ），７．５９（ｄ，Ｊ＝１５Ｈｚ，０．４Ｈ），７．７２（ｄ，Ｊ＝１５Ｈｚ，０．６Ｈ），７．７９（ｄ，Ｊ＝１５Ｈｚ，０．４Ｈ），７．８１（ｄ，Ｊ＝１５Ｈｚ，０．６Ｈ），８．７５（ｄ，Ｊ＝４Ｈｚ，１．２Ｈ），８．７６（ｄ，Ｊ＝４Ｈｚ，０．８Ｈ）．

The title compound was obtained from compound 9 and (E) -3- (pyrimidine-2-yl) acrylic acid (synthesized by the method described in WO2018050656) according to the method described in Example 42.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.15 (m, 2H), 0.45-0.53 (m, 2H), 0.75-0.85 (m) , 1H), 1.08-1.16 (m, 1H), 1.22-1.38 (m, 2H), 1.45-1.55 (m, 2H), 1.68-1.79 (M, 1H), 2.13-2.46 (m, 5H), 2.59-2.68 (m, 1H), 2.87-2.99 (m, 1.6H), 3.00 -3.09 (m, 1.4H), 3.50 (ddd, J = 4,10,14Hz, 0.6H), 3.64 (ddd, J = 4,11,14Hz, 0.4H), 3.89 (s, 3H), 3.98-4.05 (m, 0.4H), 4.30-4.32 (m, 0.6H), 4.40-4.48 (m, 0) .6H), 4.58 (s, 0.6H), 4.61 (s, 0.4H), 4.73-4.78 (m, 0.4H), 6.58 (d, J = 8Hz) , 0.4H), 6.63 (d, J = 8Hz, 0.6H), 6.74 (d, J = 8Hz, 0.4H), 6.75 (d, J = 8Hz, 0.6H) , 7.17-7.21 (m, 1H), 7.59 (d, J = 15Hz, 0.4H), 7.72 (d, J = 15Hz, 0.6H), 7.79 (d, J = 15Hz, 0.4H), 7.81 (d, J = 15Hz, 0.6H), 8.75 (d, J = 4Hz, 1.2H), 8.76 (d, J = 4Hz, 0) .8H).

(Example 104)
(E) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H -4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -3- (pyrimidine-2-yl) prop-2-en-1 -On (124) synthesis

実施例７に記載した方法に従い、化合物１２３より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１２（ｍ，２Ｈ），０．４５－０．５３（ｍ，２Ｈ），０．７３－０．８９（ｍ，１Ｈ），１．０７－１．１５（ｍ，２Ｈ），１．２４－１．３３（ｍ，２Ｈ），１．３９－１．５１（ｍ，２Ｈ），１．６８－１．７８（ｍ，１Ｈ），２．１４－２．４３（ｍ，５Ｈ），２．６０－２．６７（ｍ，１Ｈ），２．８５－２．９３（ｍ，１Ｈ），２．９７（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０３（ｄ，Ｊ＝６Ｈｚ，０．６Ｈ），３．０６（ｄ，Ｊ＝６Ｈｚ，０．４Ｈ），４．０１－４．０９（ｍ，０．４Ｈ），４．２５－４．２９（ｍ，０．６Ｈ）４．３９－４．４６（ｍ，０．４Ｈ），４．５７－４．６０（ｍ，１Ｈ），４．６７－４．６９（ｍ，０．６Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．５６（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），７．２１（ｔ，Ｊ＝５Ｈｚ，１Ｈ），７．６０（ｄ，Ｊ＝１５Ｈｚ，０．６Ｈ），７．７３（ｄ，Ｊ＝１５Ｈｚ，０．４Ｈ），７．８０（ｄ，Ｊ＝１５Ｈｚ，０．６Ｈ），７．８１（ｄ，Ｊ＝１５Ｈｚ，０．４Ｈ），８．７７（ｄ，Ｊ＝５Ｈｚ，１．２Ｈ），８．７８（ｄ，Ｊ＝５Ｈｚ，０．８Ｈ）．

The title compound was obtained from compound 123 according to the method described in Example 7.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.12 (m, 2H), 0.45-0.53 (m, 2H), 0.73-0.89 (m) , 1H), 1.07-1.15 (m, 2H), 1.24-1.33 (m, 2H), 1.39-1.51 (m, 2H), 1.68-1.78 (M, 1H), 2.14-2.43 (m, 5H), 2.60-2.67 (m, 1H), 2.85-2.93 (m, 1H), 2.97 (d). , J = 18Hz, 1H), 3.03 (d, J = 6Hz, 0.6H), 3.06 (d, J = 6Hz, 0.4H), 4.01-4.09 (m, 0. 4H), 4.25-4.29 (m, 0.6H) 4.39-4.46 (m, 0.4H), 4.57-4.60 (m, 1H), 4.67-4 .69 (m, 0.6H), 6.54 (d, J = 8Hz, 0.4H), 6.56 (d, J = 8Hz, 0.6H), 6.71 (d, J = 8Hz, 0.4H), 6.73 (d, J = 8Hz, 0.6H), 7.21 (t, J = 5Hz, 1H), 7.60 (d, J = 15Hz, 0.6H), 7. 73 (d, J = 15Hz, 0.4H), 7.80 (d, J = 15Hz, 0.6H), 7.81 (d, J = 15Hz, 0.4H), 8.77 (d, J) = 5Hz, 1.2H), 8.78 (d, J = 5Hz, 0.8H).

(Example 105)
(E) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H -4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -3- (fran-3-yl) prop-2-en-1 -On (125) synthesis

実施例４４に記載した方法に従い、化合物９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），０．４２－０．５５（ｍ，２Ｈ），０．７３－０．８５（ｍ，１Ｈ），１．０６－１．１５（ｍ，１Ｈ），１．２３－１．３９（ｍ，１Ｈ），１．４０－１．５７（ｍ，３Ｈ），１．６５－１．７８（ｍ，１Ｈ），２．１１－２．４３（ｍ，５Ｈ），２．５７－２．６８（ｍ，１Ｈ），２．８１－２．９１（ｍ，１Ｈ），２．９６（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０３－３．０７（ｍ，１Ｈ），３．３９－３．４９（ｍ，０．５Ｈ），３．５３－３．６３（ｍ，０．５Ｈ），３．９３－４．０１（ｍ，０．５Ｈ），４．１６－４．２２（ｍ，０．５Ｈ），４．４１－４．４８（ｍ，０．５Ｈ），４．５２－４．５９（ｍ，１Ｈ），４．６６（ｓ，０．５Ｈ），６．５１－６．７６（ｍ，４Ｈ），７．４３（ｓ，１Ｈ），７．５８（ｄ，Ｊ＝１６Ｈｚ，０．５Ｈ），７．６４（ｄ，Ｊ＝６Ｈｚ，１Ｈ），７．６８（ｄ，Ｊ＝１５Ｈｚ，０．５Ｈ）．

The title compound was obtained from compound 9 and (E) -3- (fran-3-yl) acrylic acid according to the method described in Example 44.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.16 (m, 2H), 0.42-0.55 (m, 2H), 0.73-0.85 (m) , 1H), 1.06-1.15 (m, 1H), 1.23-1.39 (m, 1H), 1.40-1.57 (m, 3H), 1.65-1.78 (M, 1H), 2.11-2.43 (m, 5H), 2.57-2.68 (m, 1H), 2.81-2.91 (m, 1H), 2.96 (d). , J = 18Hz, 1H), 3.03-3.07 (m, 1H), 3.39-3.49 (m, 0.5H), 3.53-3.63 (m, 0.5H) , 3.93-4.01 (m, 0.5H), 4.16-4.22 (m, 0.5H), 4.41-4.48 (m, 0.5H), 4.52- 4.59 (m, 1H), 4.66 (s, 0.5H), 6.51-6.76 (m, 4H), 7.43 (s, 1H), 7.58 (d, J = 16Hz, 0.5H), 7.64 (d, J = 6Hz, 1H), 7.68 (d, J = 15Hz, 0.5H).

(Example 106)
(E) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8a-octahydro-7H -4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -3- (oxazole-2-yl) prop-2-en-1 -Synthesis of on (126)

実施例６０に記載した方法に従い、化合物９及び（Ｅ）－３－（オキサゾール－２－イル）アクリル酸（ＵＳ２００７０１６７４２６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）：０．０７－０．１５（ｍ，２Ｈ），０．４５－０．５４（ｍ，２Ｈ），０．７５－０．８５（ｍ，１Ｈ），１．０９－１．７７（ｍ，６Ｈ），２．１２－２．４５（ｍ，５Ｈ），２．６０－２．６６（ｍ，１Ｈ），２．８６－２．９４（ｍ，１Ｈ），２．９７－３．０８（ｍ，２Ｈ），３．４４－３．６７（ｍ，０．６Ｈ），３．６０－３．６７（ｍ，０．４Ｈ），３．８９（ｓ，３Ｈ），３．９３－３．９８（ｍ，０．４Ｈ），４．２２－４．２５（ｍ，０．６Ｈ），４．４１－４．４７（ｍ，０．６Ｈ），４．５３－４．５８（ｍ，１Ｈ），４．７１－４．７４（ｍ，０．４Ｈ），６．５９（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．６３（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．７４（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７６（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），７．２３－７．６９（ｍ，４Ｈ）．

The title compound was obtained from compound 9 and (E) -3- (oxazole-2-yl) acrylic acid (synthesized by the method described in US20070167426) according to the method described in Example 60.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.15 (m, 2H), 0.45-0.54 (m, 2H), 0.75-0.85 (m) , 1H), 1.09-1.77 (m, 6H), 2.12-2.45 (m, 5H), 2.60-2.66 (m, 1H), 2.86-2.94 (M, 1H), 2.97-3.08 (m, 2H), 3.44-3.67 (m, 0.6H), 3.60-3.67 (m, 0.4H), 3 .89 (s, 3H), 3.93-3.98 (m, 0.4H), 4.22-4.25 (m, 0.6H), 4.41-4.47 (m, 0. 6H), 4.53-4.58 (m, 1H), 4.71-4.74 (m, 0.4H), 6.59 (d, J = 8Hz, 0.4H), 6.63 ( d, J = 8Hz, 0.6H), 6.74 (d, J = 8Hz, 0.4H), 6.76 (d, J = 8Hz, 0.6H), 7.23-7.69 (m) , 4H).

(Example 107)
(E) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H -4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -3- (oxazole-2-yl) prop-2-en-1 -On (127) synthesis

実施例７に記載した方法に従い、化合物１２６より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１４（ｍ，２Ｈ），０．４５－０．５３（ｍ，２Ｈ），０．７５－０．８６（ｍ，１Ｈ），１．０９－１．１５（ｍ，１Ｈ），１．２５－１．７８（ｍ，５Ｈ），２．１２－２．４３（ｍ，５Ｈ），２．６０－２．６６（ｍ，１Ｈ），２．８４－２．９２（ｍ，１Ｈ），２．９７（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０３（ｄ，Ｊ＝６Ｈｚ，０．６Ｈ），３．０６（ｄ，Ｊ＝６Ｈｚ，０．４Ｈ），３．４６－３．５３（ｍ，０．４Ｈ），３．５８－３．６６（ｍ，０．６Ｈ），３．９５－４．０１（ｍ，０．６Ｈ），４．１８－４．２１（ｍ，０．４Ｈ），４．３８－４．４４（ｍ，０．４Ｈ），４．５２－４．５６（ｍ，１Ｈ），４．６３－４．６６（ｍ，０．６Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．５６（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），７．２６－７．２７（ｍ，１Ｈ），７．３４（ｄ，Ｊ＝１５Ｈｚ，０．４Ｈ），７．３７（ｄ，Ｊ＝１５Ｈｚ，０．４Ｈ），７．４５（ｄ，Ｊ＝１５Ｈｚ，０．６Ｈ），７．５６（ｄ，Ｊ＝１５Ｈｚ，０．６Ｈ），７．７０（ｓ，１Ｈ）．

The title compound was obtained from compound 126 according to the method described in Example 7.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.14 (m, 2H), 0.45-0.53 (m, 2H), 0.75-0.86 (m) , 1H), 1.09-1.15 (m, 1H), 1.25-1.78 (m, 5H), 2.12-2.43 (m, 5H), 2.60-2.66 (M, 1H), 2.84-2.92 (m, 1H), 2.97 (d, J = 18Hz, 1H), 3.03 (d, J = 6Hz, 0.6H), 3.06 (D, J = 6Hz, 0.4H), 3.46-3.53 (m, 0.4H), 3.58-3.66 (m, 0.6H), 3.95-4.01 ( m, 0.6H), 4.18-4.21 (m, 0.4H), 4.38-4.44 (m, 0.4H), 4.52-4.56 (m, 1H), 4.63-4.66 (m, 0.6H), 6.54 (d, J = 8Hz, 0.4H), 6.56 (d, J = 8Hz, 0.6H), 6.72 (d) , J = 8Hz, 0.4H), 6.73 (d, J = 8Hz, 0.6H), 7.26-7.27 (m, 1H), 7.34 (d, J = 15Hz, 0. 4H), 7.37 (d, J = 15Hz, 0.4H), 7.45 (d, J = 15Hz, 0.6H), 7.56 (d, J = 15Hz, 0.6H), 7. 70 (s, 1H).

(Example 108)
(E) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8a-octahydro-7H -4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -3- (oxazole-4-yl) prop-2-en-1 -On (128) synthesis

実施例４２に記載した方法に従い、化合物９及び（Ｅ）－３－（オキサゾール－４－イル）アクリル酸（ＷＯ２０１５１９１９０７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）：０．０５－０．１６（ｍ，２Ｈ），０．４３－０．５５（ｍ，２Ｈ），０．７２－０．８５（ｍ，１Ｈ），１．０６－１．５７（ｍ，５Ｈ），１．６６－１．９０（ｍ，１Ｈ），２．１１－２．４７（ｍ，５Ｈ），２．５８－２．６８（ｍ，１Ｈ），２．８４－３．１０（ｍ，３Ｈ），３．５３（ｄｄｄ，Ｊ＝４，１０，１５Ｈｚ，０．５Ｈ），３．６２（ｄｄｄ，Ｊ＝４，１１，１５Ｈｚ，０．５Ｈ），３．８９（ｓ，３Ｈ），４．０２（ｄｄｄ，Ｊ＝４，４，１４Ｈｚ，０．５Ｈ），４．２６－４．３１（ｍ，０．５Ｈ），４．３７（ｄｄｄ，Ｊ＝５，５，１４Ｈｚ，０．５Ｈ），４．５７（ｓ，０．５Ｈ），４．５８（ｓ，０．５Ｈ），４．７２－４．７７（ｍ，０．５Ｈ），６．５８（ｄ，Ｊ＝８Ｈｚ，０．５Ｈ），６．６２（ｄ，Ｊ＝８Ｈｚ，０．５Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．５Ｈ），６．７５（ｄ，Ｊ＝８Ｈｚ，０．５Ｈ），７．２１（ｄ，Ｊ＝１５Ｈｚ，０．５Ｈ），７．２４（ｄ，Ｊ＝１５Ｈｚ，０．５Ｈ），７．５５（ｄ，Ｊ＝１５Ｈｚ，０．５Ｈ），７．６１（ｄ，Ｊ＝１５Ｈｚ，０．５Ｈ），７．７７（ｓ，０．５Ｈ），７．７８（ｓ，０．５Ｈ），７．８７（ｓ，０．５Ｈ），７．９０（ｓ，０．５Ｈ）．

The title compound was obtained from compound 9 and (E) -3- (oxazole-4-yl) acrylic acid (synthesized by the method described in WO2015191907) according to the method described in Example 42.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.05-0.16 (m, 2H), 0.43-0.55 (m, 2H), 0.72-0.85 (m) , 1H), 1.06-1.57 (m, 5H), 1.66-1.90 (m, 1H), 2.11-2.47 (m, 5H), 2.58-2.68 (M, 1H), 2.84-3.10 (m, 3H), 3.53 (ddd, J = 4,10,15Hz, 0.5H), 3.62 (ddd, J = 4,11, 15Hz, 0.5H), 3.89 (s, 3H), 4.02 (ddd, J = 4,4,14Hz, 0.5H), 4.26-4.31 (m, 0.5H), 4.37 (ddd, J = 5,5,14Hz, 0.5H), 4.57 (s, 0.5H), 4.58 (s, 0.5H), 4.72-4.77 (m) , 0.5H), 6.58 (d, J = 8Hz, 0.5H), 6.62 (d, J = 8Hz, 0.5H), 6.73 (d, J = 8Hz, 0.5H) , 6.75 (d, J = 8Hz, 0.5H), 7.21 (d, J = 15Hz, 0.5H), 7.24 (d, J = 15Hz, 0.5H), 7.55 ( d, J = 15Hz, 0.5H), 7.61 (d, J = 15Hz, 0.5H), 7.77 (s, 0.5H), 7.78 (s, 0.5H), 7. 87 (s, 0.5H), 7.90 (s, 0.5H).

(Example 109)
(E) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H -4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -3- (oxazole-4-yl) prop-2-en-1 -On (129) synthesis

実施例７に記載した方法に従い、化合物１２８より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１５（ｍ，２Ｈ），０．４３－０．５４（ｍ，２Ｈ），０．７３－０．８３（ｍ，１Ｈ），１．０５－１．１５（ｍ，１Ｈ），１．２３－１．７８（ｍ，５Ｈ），２．１１－２．４３（ｍ，５Ｈ），２．５８－２．６６（ｍ，１Ｈ），２．８２－２．９３（ｍ，１Ｈ），２．９６（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０２（ｄ，Ｊ＝６Ｈｚ，０．６Ｈ），３．０５（ｄ，Ｊ＝６Ｈｚ，０．４Ｈ），３．４８（ｄｄｄ，Ｊ＝５，１１，１５Ｈｚ，０．４Ｈ），３．６０（ｄｄｄ，Ｊ＝４，１２，１６Ｈｚ，０．６Ｈ），４．０５（ｄｄｄ，Ｊ＝３，４，１５Ｈｚ，０．６Ｈ），４．２２－４．２７（ｍ，０．４Ｈ），４．４１（ｄｄｄ，Ｊ＝５，５，１４Ｈｚ，０．４Ｈ），４．５３－４．５９（ｍ，１Ｈ），４．６４－４．６８（ｍ，０．６Ｈ），５．１５（ｂｒ ｓ，１Ｈ），６．５３（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．５５（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），７．２３（ｄ，Ｊ＝１５Ｈｚ，０．４Ｈ），７．２６（ｄ，Ｊ＝１５Ｈｚ，０．６Ｈ），７．５５（ｄ，Ｊ＝１５Ｈｚ，０．６Ｈ），７．６２（ｄ，Ｊ＝１５Ｈｚ，０．４Ｈ），７．７９（ｓ，０．６Ｈ），７．８１（ｓ，０．４Ｈ），７．９１（ｓ，０．６Ｈ），７．９２（ｓ，０．４Ｈ）．

The title compound was obtained from compound 128 according to the method described in Example 7.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.15 (m, 2H), 0.43-0.54 (m, 2H), 0.73-0.83 (m) , 1H), 1.05-1.15 (m, 1H), 1.23-1.78 (m, 5H), 2.11-2.43 (m, 5H), 2.58-2.66 (M, 1H), 2.82-2.93 (m, 1H), 2.96 (d, J = 18Hz, 1H), 3.02 (d, J = 6Hz, 0.6H), 3.05 (D, J = 6Hz, 0.4H), 3.48 (ddd, J = 5,11,15Hz, 0.4H), 3.60 (ddd, J = 4,12,16Hz, 0.6H), 4.05 (ddd, J = 3,4,15Hz, 0.6H), 4.22-4.27 (m, 0.4H), 4.41 (ddd, J = 5,5,14Hz, 0. 4H), 4.53-4.59 (m, 1H), 4.64-4.68 (m, 0.6H), 5.15 (br s, 1H), 6.53 (d, J = 8Hz) , 0.6H), 6.55 (d, J = 8Hz, 0.4H), 6.72 (d, J = 8Hz, 0.4H), 6.72 (d, J = 8Hz, 0.6H) , 7.23 (d, J = 15Hz, 0.4H), 7.26 (d, J = 15Hz, 0.6H), 7.55 (d, J = 15Hz, 0.6H), 7.62 ( d, J = 15Hz, 0.4H), 7.79 (s, 0.6H), 7.81 (s, 0.4H), 7.91 (s, 0.6H), 7.92 (s, 0.4H).

(Example 110)
(E) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8a-octahydro-7H -4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -3- (thiazole-2-yl) prop-2-en-1 -On (130) synthesis

実施例６０に記載した方法に従い、化合物９及び（Ｅ）－３－（チアゾール－２－イル）アクリル酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１５（ｍ，２Ｈ），０．４５－０．５３（ｍ，２Ｈ），０．７６－０．８４（ｍ，１Ｈ），１．１０－１．７６（ｍ，６Ｈ），２．１２－２．４５（ｍ，５Ｈ），２．６０－２．６７（ｍ，１Ｈ），２．８８－３．０８（ｍ，３Ｈ），３．５２－３．６８（ｍ，１Ｈ），３．８９（ｓ，３Ｈ），３．９６－４．０３（ｍ，０．５Ｈ），４．２５－４．２９（ｍ，０．５Ｈ），４．３４－４．４０（ｍ，０．５Ｈ），４．５６－４．５９（ｍ，１Ｈ），４．７２－４．７６（ｍ，０．５Ｈ），６．５９（ｄ，Ｊ＝８Ｈｚ，０．５Ｈ），６．６３（ｄ，Ｊ＝８Ｈｚ，０．５Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，０．５Ｈ），６．７５（ｄ，Ｊ＝８Ｈｚ，０．５Ｈ），７．３０－７．４１（ｍ，２Ｈ），７．６３－７．９０（ｍ，２Ｈ）．

The title compound was obtained from compound 9 and (E) -3- (thiazole-2-yl) acrylic acid according to the method described in Example 60.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.15 (m, 2H), 0.45-0.53 (m, 2H), 0.76-0.84 (m) , 1H), 1.10-1.76 (m, 6H), 2.12-2.45 (m, 5H), 2.60-2.67 (m, 1H), 2.88-3.08 (M, 3H), 3.52-3.68 (m, 1H), 3.89 (s, 3H), 3.96-4.03 (m, 0.5H), 4.25-4.29 (M, 0.5H), 4.34-4.40 (m, 0.5H), 4.56-4.59 (m, 1H), 4.72-4.76 (m, 0.5H) , 6.59 (d, J = 8Hz, 0.5H), 6.63 (d, J = 8Hz, 0.5H), 6.73 (d, J = 8Hz, 0.5H), 6.75 ( d, J = 8Hz, 0.5H), 7.30-7.41 (m, 2H), 7.63-7.90 (m, 2H).

(Example 111)
(E) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H -4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -3- (thiazole-2-yl) prop-2-en-1 -On (131) synthesis

実施例７に記載した方法に従い、化合物１３０より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１４（ｍ，２Ｈ），０．４５－０．５３（ｍ，２Ｈ），０．７５－０．８３（ｍ，１Ｈ），１．０９－１．１５（ｍ，１Ｈ），１．２５－１．７５（ｍ，５Ｈ），２．１２－２．４２（ｍ，５Ｈ），２．６０－２．６６（ｍ，１Ｈ），２．８４－２．９３（ｍ，１Ｈ），２．９７（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０３（ｄ，Ｊ＝６Ｈｚ，０．６Ｈ），３．０６（ｄ，Ｊ＝６Ｈｚ，０．４Ｈ），３．４８－３．６６（ｍ，１Ｈ），３．９９－４．０５（ｍ，０．６Ｈ），４．２２－４．２４（ｍ，０．４Ｈ），４．３６－４．４２（ｍ，０．４Ｈ），４．５４－４．５７（ｍ，１Ｈ），４．６５－４．６８（ｍ，０．６Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．５５（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），７．３６－７．４３（ｍ，２Ｈ），７．７４（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），７．８５（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），７．９１－７．９３（ｍ，１Ｈ）．

The title compound was obtained from compound 130 according to the method described in Example 7.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.14 (m, 2H), 0.45-0.53 (m, 2H), 0.75-0.83 (m) , 1H), 1.09-1.15 (m, 1H), 1.25-1.75 (m, 5H), 2.12-2.42 (m, 5H), 2.60-2.66 (M, 1H), 2.84-2.93 (m, 1H), 2.97 (d, J = 18Hz, 1H), 3.03 (d, J = 6Hz, 0.6H), 3.06 (D, J = 6Hz, 0.4H), 3.48-3.66 (m, 1H), 3.99-4.05 (m, 0.6H), 4.22-4.24 (m, 0.4H), 4.36-4.42 (m, 0.4H), 4.54-4.57 (m, 1H), 4.65-4.68 (m, 0.6H), 6. 54 (d, J = 8Hz, 0.6H), 6.55 (d, J = 8Hz, 0.4H), 6.71 (d, J = 8Hz, 0.4H), 6.72 (d, J) = 8Hz, 0.6H), 7.36-743 (m, 2H), 7.74 (d, J = 8Hz, 0.6H), 7.85 (d, J = 8Hz, 0.4H) , 7.91-7.93 (m, 1H).

(Example 112)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Synthesis of ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -3-phenylprop-2-in-1-one (130)

実施例４４に記載した方法に従い、化合物９及び３－フェニルプロピオール酸より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１５（ｍ，２Ｈ），０．４３－０．５４（ｍ，２Ｈ），０．７４－０．８４（ｍ，１Ｈ），１．０８－１．１７（ｍ，１Ｈ），１．２５－１．３５（ｍ，１Ｈ），１．４０－１．５８（ｍ，２Ｈ），１．６６－１．８４（ｍ，２Ｈ），２．１６－２．４２（ｍ，５Ｈ），２．６０－２．６８（ｍ，１Ｈ），２．８２－２．９８（ｍ，１Ｈ），２．９７（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０６（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．３８（ｄｄｄ，Ｊ＝５，１１，１５Ｈｚ，０．４Ｈ），３．７０（ｄｄｄ，Ｊ＝４，１１，１５Ｈｚ，０．６Ｈ），４．３６－４．４５（ｍ，１Ｈ），４．５４－４．５９（ｍ，１．６Ｈ），４．６４－４．６６（ｍ，０．４Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，０．６Ｈ），６．５６（ｄ，Ｊ＝８Ｈｚ，０．４Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．３６－７．４６（ｍ，３Ｈ），７．５５－７．６３（ｍ，２Ｈ）．

The title compound was obtained from compound 9 and 3-phenylpropiolic acid according to the method described in Example 44.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.15 (m, 2H), 0.43-0.54 (m, 2H), 0.74-0.84 (m) , 1H), 1.08-1.17 (m, 1H), 1.25-1.35 (m, 1H), 1.40-1.58 (m, 2H), 1.66-1.84 (M, 2H), 2.16-2.42 (m, 5H), 2.60-2.68 (m, 1H), 2.82-2.98 (m, 1H), 2.97 (d). , J = 18Hz, 1H), 3.06 (d, J = 6Hz, 1H), 3.38 (ddd, J = 5,11,15Hz, 0.4H), 3.70 (ddd, J = 4, 11,15Hz, 0.6H), 4.36-4.45 (m, 1H), 4.54-4.59 (m, 1.6H), 4.64-4.66 (m, 0.4H) ), 6.54 (d, J = 8Hz, 0.6H), 6.56 (d, J = 8Hz, 0.4H), 6.73 (d, J = 8Hz, 1H), 7.36-7. .46 (m, 3H), 7.55-7.63 (m, 2H).

(Example 113)
(4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-7- (3-phenylpropyl) -1,2,3,4,6,7,8,8a-octahydro Synthesis of -5H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine (133)

化合物９（１３．５ｍｇ，０．０３７ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）溶液に、炭酸カリウム（２５．７ｍｇ，０．１９ｍｍｏｌ）及び３－フェニルプロピルブロミド（１７μＬ，０．１１ｍｍｏｌ）を加え、室温で３時間撹拌した。反応混合物に、炭酸カリウム（２６．９ｍｇ，０．１９ｍｍｏｌ）及び３－フェニルプロピルブロミド（１７μＬ，０．１１ｍｍｏｌ）を追加し、更に室温で２３時間撹拌した。反応混合物に水（２ｍＬ）を加え、酢酸エチルで三回抽出した。合わせた抽出液を水で二回、飽和食塩水で一回洗浄し、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＝９５：５）で精製し、表題化合物（６．２ｍｇ，３５％）を無色油状物質として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１５（ｍ，２Ｈ），０．４２－０．５４（ｍ，２Ｈ），０．７４－０．８５（ｍ，１Ｈ），０．９１－１．０１（ｍ，１Ｈ），１．１６－１．３６（ｍ，３Ｈ），１．４９－１．５５（ｍ，１Ｈ），１．５６－１．６９（ｍ，１Ｈ），１．７６－１．８５（ｍ，２Ｈ），２．２１（ｄｄ，Ｊ＝７，１３Ｈｚ，１Ｈ），２．２４－２．４３（ｍ，４Ｈ），２．５３（ｔ，Ｊ＝７Ｈｚ，２Ｈ），２．５８－２．６７（ｍ，１Ｈ），２．６４（ｔ，Ｊ＝７Ｈｚ，２Ｈ），２．６８－２．９１（ｍ，４Ｈ），２．９５（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），２．９９（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．８５（ｓ，３Ｈ），４．５５（ｓ，１Ｈ），６．５５（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．１４－７．２２（ｍ，３Ｈ），７．２４－７．３２（ｍ，２Ｈ）．

Potassium carbonate (25.7 mg, 0.19 mmol) and 3-phenylpropyl bromide (17 μL, 0.11 mmol) are added to a solution of compound 9 (13.5 mg, 0.037 mmol) in N, N-dimethylformamide (1 mL). , Stirred at room temperature for 3 hours. Potassium carbonate (26.9 mg, 0.19 mmol) and 3-phenylpropyl bromide (17 μL, 0.11 mmol) were added to the reaction mixture, and the mixture was further stirred at room temperature for 23 hours. Water (2 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed twice with water and once with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: methanol = 95: 5) to give the title compound (6.2 mg, 35%) as a colorless oily substance.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.15 (m, 2H), 0.42-0.54 (m, 2H), 0.74-0.85 (m) , 1H), 0.91-1.01 (m, 1H), 1.16-1.36 (m, 3H), 1.49-1.55 (m, 1H), 1.56-1.69 (M, 1H), 1.76-1.85 (m, 2H), 2.21 (dd, J = 7,13Hz, 1H), 2.24-2.43 (m, 4H), 2.53 (T, J = 7Hz, 2H), 2.58-2.67 (m, 1H), 2.64 (t, J = 7Hz, 2H), 2.68-2.91 (m, 4H), 2 .95 (d, J = 18Hz, 1H), 2.99 (d, J = 6Hz, 1H), 3.85 (s, 3H), 4.55 (s, 1H), 6.55 (d, J) = 8Hz, 1H), 6.70 (d, J = 8Hz, 1H), 7.14-7.22 (m, 3H), 7.24-7.32 (m, 2H).

(Example 114)
(4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -7- (3-phenylpropyl) -1,2,3,4,6,7,8a-octahydro-5H-4a , 8-Etano-4,13-Metanobenzoflo [2,3-c] pyrido [4,3-d] Synthesis of azepine-10-ol (134)

実施例７に記載した方法に従い、化合物１３３より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１６（ｍ，２Ｈ），０．４２－０．５４（ｍ，２Ｈ），０．７３－０．８５（ｍ，１Ｈ），０．９０－０．９９（ｍ，１Ｈ），１．０４－１．２３（ｍ，２Ｈ），１．２４－１．３６（ｍ，１Ｈ），１．４９－１．５５（ｍ，１Ｈ），１．５８－１．６８（ｍ，１Ｈ），１．８２（ｔｔ，Ｊ＝７，７Ｈｚ，２Ｈ），２．２０（ｄｄ，Ｊ＝７，１３Ｈｚ，１Ｈ），２．２５－２．４２（ｍ，４Ｈ），２．５５（ｔ，Ｊ＝７Ｈｚ，２Ｈ），２．５７－２．６８（ｍ，３Ｈ），２．６９－２．８７（ｍ，４Ｈ），２．９３（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），２．９９（ｄ，Ｊ＝６Ｈｚ，１Ｈ），４．５６（ｓ，１Ｈ），６．５０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６６（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．１５－７．２２（ｍ，３Ｈ），７．２４－７．３２（ｍ，２Ｈ）．

The title compound was obtained from compound 133 according to the method described in Example 7.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.16 (m, 2H), 0.42-0.54 (m, 2H), 0.73-0.85 (m) , 1H), 0.90-0.99 (m, 1H), 1.04-1.23 (m, 2H), 1.24-1.36 (m, 1H), 1.49-1.55 (M, 1H), 1.58-1.68 (m, 1H), 1.82 (tt, J = 7,7Hz, 2H), 2.20 (dd, J = 7,13Hz, 1H), 2 .25-2.42 (m, 4H), 2.55 (t, J = 7Hz, 2H), 2.57-2.68 (m, 3H), 2.69-2.87 (m, 4H) , 2.93 (d, J = 18Hz, 1H), 2.99 (d, J = 6Hz, 1H), 4.56 (s, 1H), 6.50 (d, J = 8Hz, 1H), 6 .66 (d, J = 8Hz, 1H), 7.15-7.22 (m, 3H), 7.24-7.32 (m, 2H).

(Example 115)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-Methoxy-7- (Pyrimidine-2-ylmethyl) -1,2,3,4,6,7,8,8a- Synthesis of Octahydro-5H-4a, 8-Etano-4,13-Methylbenzoflo [2,3-c] Pyrimidine [4,3-d] Azepine (135)

化合物９（１４ｍｇ，０．０３８ｍｍｏｌ）のジクロロメタン（１ｍＬ）溶液に、ピリミジン－２－カルバルデヒド（２０．６ｍｇ，０．１９ｍｍｏｌ）及び水素化トリアセトキシホウ素ナトリウム（４０．５ｍｇ，０．１９ｍｍｏｌ）を加え、室温で二時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、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（１５．３ｍｇ，８７％）を淡黄色油状物質として得た。
^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１４（ｍ，２Ｈ），０．４３－０．５２（ｍ，２Ｈ），０．７５－０．８５（ｍ，１Ｈ），０．９４－１．１４（ｍ，２Ｈ），１．２０－１．２９（ｍ，１Ｈ），１．３４－１．４５（ｍ，１Ｈ），１．５２（ｄｄｄ，Ｊ＝３，１３Ｈｚ，１Ｈ），１．６６－１．７５（ｍ，１Ｈ），２．１８－２．４０（ｍ，４Ｈ），２．４７（ｄｄｄ，Ｊ＝６，１３，１３Ｈｚ，１Ｈ），２．６２（ｄｄ，Ｊ＝５，１１Ｈｚ，１Ｈ），２．９０－３．０２（ｍ，６Ｈ），３．８１（ｓ，３Ｈ），４．００（ｄ，Ｊ＝１５Ｈｚ，１Ｈ），４．０５（ｄ，Ｊ＝１５Ｈｚ，１Ｈ），４．７３（ｓ，１Ｈ），６．５５（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６７（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．１７（ｔ，Ｊ＝５Ｈｚ，１Ｈ），８．７２（ｄ，Ｊ＝５Ｈｚ，２Ｈ）．

Pyrimidine-2-carbaldehyde (20.6 mg, 0.19 mmol) and sodium borohydride triacetoxyboron (40.5 mg, 0.19 mmol) are added to a solution of compound 9 (14 mg, 0.038 mmol) in dichloromethane (1 mL). , Stirred for 2 hours at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-5% methanol / chloroform) to give the title compound (15.3 mg, 87%) as a pale yellow oily substance.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.14 (m, 2H), 0.43-0.52 (m, 2H), 0.75-0.85 (m) , 1H), 0.94-1.14 (m, 2H), 1.20-1.29 (m, 1H), 1.34-1.45 (m, 1H), 1.52 (ddd, J) = 3,13Hz, 1H), 1.66-1.75 (m, 1H), 2.18-2.40 (m, 4H), 2.47 (ddd, J = 6,13,13Hz, 1H) , 2.62 (dd, J = 5,11Hz, 1H), 2.90-3.02 (m, 6H), 3.81 (s, 3H), 4.00 (d, J = 15Hz, 1H) , 4.05 (d, J = 15Hz, 1H), 4.73 (s, 1H), 6.55 (d, J = 8Hz, 1H), 6.67 (d, J = 8Hz, 1H), 7 .17 (t, J = 5Hz, 1H), 8.72 (d, J = 5Hz, 2H).

(Example 116)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -7- (Pyrimidine-2-ylmethyl) -1,2,3,4,6,7,8,8a-Octahydro-5H- Synthesis of 4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-10-ol (136)

実施例７に記載した方法に従い、化合物１３５より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０５－０．１４（ｍ，２Ｈ），０．４０－０．５３（ｍ，２Ｈ），０．７３－０．８３（ｍ，１Ｈ），０．９１－１．０７（ｍ，２Ｈ），１．１６－１．２９（ｍ，１Ｈ），１．３２－１．４２（ｍ，１Ｈ），１．４６－１．５４（ｍ，１Ｈ），１．６１－１．７１（ｍ，１Ｈ），２．１８－２．４７（ｍ，５Ｈ），２．６０（ｄｄ，Ｊ＝５，９Ｈｚ，１Ｈ），２．８２－３．０１（ｍ，６Ｈ），４．０１（ｄ，Ｊ＝１５Ｈｚ，１Ｈ），４．０４（ｄ，Ｊ＝１５Ｈｚ，１Ｈ），４．６８（ｓ，１Ｈ），６．４８（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．６５（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．１９（ｔ，Ｊ＝５Ｈｚ，１Ｈ），８．７３（ｄ，Ｊ＝５Ｈｚ，２Ｈ）．

The title compound was obtained from compound 135 according to the method described in Example 7.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.05-0.14 (m, 2H), 0.40-0.53 (m, 2H), 0.73-0.83 (m) , 1H), 0.91-1.07 (m, 2H), 1.16-1.29 (m, 1H), 1.32-1.42 (m, 1H), 1.46-1.54 (M, 1H), 1.61-1.71 (m, 1H), 2.18-2.47 (m, 5H), 2.60 (dd, J = 5,9Hz, 1H), 2.82 -3.01 (m, 6H), 4.01 (d, J = 15Hz, 1H), 4.04 (d, J = 15Hz, 1H), 4.68 (s, 1H), 6.48 (d) , J = 8Hz, 1H), 6.65 (d, J = 8Hz, 1H), 7.19 (t, J = 5Hz, 1H), 8.73 (d, J = 5Hz, 2H).

(Example 117)
(4R, 4aS, 8R, 8aR, 13bS) -7- (5-bromopyrimidine-2-yl) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,6,7,8 , 8a-Octahydro-5H-4a, 8-Etano-4,13-Metanobenzoflo [2,3-c] Pyrimidine [4,3-d] Synthesis of azepine (137)

化合物９（５．０ｍｇ，０．０１４ｍｍｏｌ）のアセトニトリル（０．５ｍＬ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（１０．０μＬ，０．０５６ｍｍｏｌ）及び５－ブロモ－２－クロロピリミジン（８．０ｍｇ，０．０４２ｍｍｏｌ）を加え８０°Ｃで１６時間撹拌した。反応混合物に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液で三回洗浄した。有機層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（１０－２０％酢酸エチル／ヘプタン）で精製し、表題化合物（６．６ｍｇ，９３％）を淡黄色アモルファスとして得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．００－０．２０（ｍ，２Ｈ），０．４０－０．６０（ｍ，２Ｈ），０．７０－０．９０（ｍ，１Ｈ），１．００－１．２０（ｍ，１Ｈ），１．２０－１．８０（ｍ，５Ｈ），２．００－２．５０（ｍ，５Ｈ），２．５９（ｄｄ，Ｊ＝６，１１Ｈｚ，１Ｈ），２．７０－２．９０（ｍ，１Ｈ），２．９８（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０４（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．４０－３．５５（ｍ，１Ｈ），３．８７（ｓ，３Ｈ），４．４７（ｓ，１Ｈ），４．６０－４．７０（ｍ，２Ｈ），６．５８（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，１Ｈ），８．２８（ｓ，２Ｈ）．

N, N-diisopropylethylamine (10.0 μL, 0.056 mmol) and 5-bromo-2-chloropyrimidine (8.0 mg, 8.0 mg,) in an acetonitrile (0.5 mL) solution of compound 9 (5.0 mg, 0.014 mmol). 0.042 mmol) was added, and the mixture was stirred at 80 ° C. for 16 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed three times with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (10-20% ethyl acetate / heptane) to give the title compound (6.6 mg, 93%) as a pale yellow amorphous substance.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.00-0.20 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m) , 1H), 1.00-1.20 (m, 1H), 1.20-1.80 (m, 5H), 2.00-2.50 (m, 5H), 2.59 (dd, J) = 6,11Hz, 1H), 2.70-2.90 (m, 1H), 2.98 (d, J = 18Hz, 1H), 3.04 (d, J = 6Hz, 1H), 3.40 -3.55 (m, 1H), 3.87 (s, 3H), 4.47 (s, 1H), 4.60-4.70 (m, 2H), 6.58 (d, J = 8Hz) , 1H), 6.72 (d, J = 8Hz, 1H), 8.28 (s, 2H).

(Example 118)
(4R, 4aS, 8R, 8aR, 13bS) -7- (5-bromopyrimidine-2-yl) -3- (cyclopropylmethyl) -1,2,3,4,6,7,8,8a-octahydro Synthesis of -5H-4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-10-ol (138)

実施例７に記載した方法に従い、化合物１３７より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．００－０．２０（ｍ，２Ｈ），０．４０－０．６０（ｍ，２Ｈ），０．７０－０．９０（ｍ，１Ｈ），１．００－２．４０（ｍ，１１Ｈ），２．６１（ｄｄ，Ｊ＝４，１１Ｈｚ，１Ｈ），２．７０－２．９０（ｍ，１Ｈ），２．９７（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０５（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．３０－３．５０（ｍ，１Ｈ），４．４５（ｓ，１Ｈ），４．５７（ｓ，１Ｈ），４．７０－４．９０（ｍ，１Ｈ），６．５５（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，１Ｈ），８．３３（ｓ，２Ｈ）．

The title compound was obtained from compound 137 according to the method described in Example 7.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.00-0.20 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m) , 1H), 1.00-2.40 (m, 11H), 2.61 (dd, J = 4,11Hz, 1H), 2.70-2.90 (m, 1H), 2.97 (d) , J = 18Hz, 1H), 3.05 (d, J = 6Hz, 1H), 3.30-3.50 (m, 1H), 4.45 (s, 1H), 4.57 (s, 1H) ), 4.70-4.90 (m, 1H), 6.55 (d, J = 8Hz, 1H), 6.71 (d, J = 8Hz, 1H), 8.33 (s, 2H).

(Example 119)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-Methoxy-7- (pyrimidine-2-yl) -1,2,3,4,6,7,8,8a- Synthesis of Octahydro-5H-4a, 8-Etano-4,13-Methylbenzoflo [2,3-c] Pyrimidine [4,3-d] Azepine (139)

実施例１１７に記載した方法に従い、化合物９及び２－クロロピリミジンより表題化合物を得た。
^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．００－０．２０（ｍ，２Ｈ），０．４０－０．６０（ｍ，２Ｈ），０．７０－０．９０（ｍ，１Ｈ），１．００－１．２０（ｍ，１Ｈ），１．２０－１．９０（ｍ，５Ｈ），２．１０－２．５０（ｍ，５Ｈ），２．５０－２．６５（ｍ，１Ｈ），２．７０－２．９０（ｍ，１Ｈ），２．９８（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０４（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．５１（ｔ，Ｊ＝１２Ｈｚ，１Ｈ），３．８８（ｓ，３Ｈ），４．５３（ｓ，１Ｈ），４．７５（ｓ，２Ｈ），６．４５（ｔ，Ｊ＝５Ｈｚ，１Ｈ），６．５８（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），８．３０（ｄ，Ｊ＝５Ｈｚ，２Ｈ）．

The title compound was obtained from compound 9 and 2-chloropyrimidine according to the method described in Example 117.
^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.00-0.20 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m) , 1H), 1.00-1.20 (m, 1H), 1.20-1.90 (m, 5H), 2.10-2.50 (m, 5H), 2.50-2.65 (M, 1H), 2.70-2.90 (m, 1H), 2.98 (d, J = 18Hz, 1H), 3.04 (d, J = 6Hz, 1H), 3.51 (t) , J = 12Hz, 1H), 3.88 (s, 3H), 4.53 (s, 1H), 4.75 (s, 2H), 6.45 (t, J = 5Hz, 1H), 6. 58 (d, J = 8Hz, 1H), 6.73 (d, J = 8Hz, 1H), 8.30 (d, J = 5Hz, 2H).

(Example 120)
(4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -7- (pyrimidine-2-yl) -1,2,3,4,6,7,8a-octahydro-5H- Synthesis of 4a, 8-ethano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-10-ol (140)

実施例７に記載した方法に従い、化合物１３９より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．００－０．２０（ｍ，２Ｈ），０．４０－０．６０（ｍ，２Ｈ），０．７０－０．９０（ｍ，１Ｈ），１．１２（ｔ，Ｊ＝１２Ｈｚ，１Ｈ），１．２０－１．７０（ｍ，４Ｈ），１．７９（ｔ，Ｊ＝１１Ｈｚ，１Ｈ），２．１０－２．５０（ｍ，５Ｈ），２．６０（ｄｄ，Ｊ＝６，１０Ｈｚ，１Ｈ），２．８３（ｄｔ，Ｊ＝５，１３Ｈｚ，１Ｈ），２．９６（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．０５（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．４０－３．５０（ｍ，１Ｈ），４．５０－４．６０（ｍ，１Ｈ），４．６５（ｑ，Ｊ＝３Ｈｚ，１Ｈ），４．８３（ｄｑ，Ｊ＝３，１４Ｈｚ，１Ｈ），６．４８（ｔ，Ｊ＝５Ｈｚ，１Ｈ），６．５４（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７１（ｄ，Ｊ＝８Ｈｚ，１Ｈ），８．３５（ｄ，Ｊ＝５Ｈｚ，２Ｈ）．

The title compound was obtained from compound 139 according to the method described in Example 7.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.20 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m) , 1H), 1.12 (t, J = 12Hz, 1H), 1.20-1.70 (m, 4H), 1.79 (t, J = 11Hz, 1H), 2.10-2.50 (M, 5H), 2.60 (dd, J = 6,10Hz, 1H), 2.83 (dt, J = 5,13Hz, 1H), 2.96 (d, J = 18Hz, 1H), 3 0.05 (d, J = 6Hz, 1H), 3.40-3.50 (m, 1H), 4.50-4.60 (m, 1H), 4.65 (q, J = 3Hz, 1H) , 4.83 (dq, J = 3,14Hz, 1H), 6.48 (t, J = 5Hz, 1H), 6.54 (d, J = 8Hz, 1H), 6.71 (d, J = 8Hz, 1H), 8.35 (d, J = 5Hz, 2H).

(Reference Example 21)
(4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -7- (2- (pyrimidine-2-yl) acetyl) -1,2,3,4,6,7,8,8a -Synthesis of Octahydro-5H-4a, 8-Etano-4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-10-yltrifluoromethanesulfonate (141)

化合物９８（３５ｍｇ，０．０７４ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（０．７ｍＬ）溶液に、炭酸カリウム（３１ｍｇ，０．２２ｍｍｏｌ）及びN-フェニルビス(トリフルオロメタンスルホンイミド)（７９ｍｇ，０．２２ｍｍｏｌ）を加え、室温で３０分撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、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（０－１０％メタノール／クロロホルム）で精製し、表題化合物（３６ｍｇ，８１％）を無色アモルファスとして得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０４－０．１７（ｍ，２Ｈ），０．４２－０．５８（ｍ，２Ｈ），０．６１－１．８３（ｍ，７Ｈ），２．０９－３．１４（ｍ，９Ｈ），３．３０－３．９１（ｍ，１．７Ｈ），４．００－４．４９（ｍ，２．３Ｈ），４．６０－４．７９（ｍ，２Ｈ），６．６４（ｄ，Ｊ＝８Ｈｚ，０．７Ｈ），６．６９（ｄ，Ｊ＝８Ｈｚ，０．３Ｈ），６．９８（ｄ，Ｊ＝８Ｈｚ，１Ｈ），７．１２－７．４１（ｍ，１Ｈ），８．６７－８．７９（ｍ，２Ｈ）．

Potassium carbonate (31 mg, 0.22 mmol) and N-phenylbis (trifluoromethanesulfonimide) (79 mg, 0.22 mmol) in a solution of compound 98 (35 mg, 0.074 mmol) in N, N-dimethylformamide (0.7 mL). ) Was added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-10% methanol / chloroform) to give the title compound (36 mg, 81%) as a colorless amorphous substance.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.17 (m, 2H), 0.42-0.58 (m, 2H), 0.61-1.83 (m) , 7H), 2.09-3.14 (m, 9H), 3.30-3.91 (m, 1.7H), 4.00-4.49 (m, 2.3H), 4.60 -4.79 (m, 2H), 6.64 (d, J = 8Hz, 0.7H), 6.69 (d, J = 8Hz, 0.3H), 6.98 (d, J = 8Hz, 1H), 7.12-7.41 (m, 1H), 8.67-8.79 (m, 2H).

(Example 121)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano-4) , 13-Methylnobenzoflo [2,3-c] pyrido [4,3-d] azepine-7-yl) -2- (pyrimidine-2-yl) ethane-1-one (142) synthesis

化合物１４１（３６ｍｇ，０．０６ｍｍｏｌ）、１，３－ビス（ジフェニルホスフィノ）プロパン（２．５ｍｇ，０．００６ｍｍｏｌ）及び酢酸パラジウム（１．３ｍｇ，０．００６ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（０．６ｍＬ）溶液に、トリエチルシラン（２４μL，０．１５ｍｍｏｌ）を加え、６０℃で１０分撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで３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）で精製した。得られた固体に１M塩酸を加え酢酸エチルで３回洗浄後、水層に炭酸カリウムを加えｐH１０とした。その後酢酸エチルにて３回抽出を行い、有機層を飽和食塩水で洗浄した。有機層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＝９５：５）で精製し、表題化合物（１５．４ｍｇ，５６％）を無色アモルファスとして得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０２－０．１８（ｍ，２Ｈ），０．３８－０．５７（ｍ，２Ｈ），０．６８－１．８８（ｍ，７Ｈ），２．０６－３．１２（ｍ，９Ｈ），３．３５－３．６２（ｍ，１Ｈ），３．６７－３．８７（ｍ，０．７Ｈ），４．０２－４．４４（ｍ，２．３Ｈ），４．４５－４．６９（ｍ，２Ｈ），６．４９－６．７３（ｍ，２Ｈ），６．９９－７．１１（ｍ，１Ｈ），７．１４－７．２５（ｍ，１Ｈ），８．６５－８．８１（ｍ，２Ｈ）．

N, N-dimethylformamide of compound 141 (36 mg, 0.06 mmol), 1,3-bis (diphenylphosphino) propane (2.5 mg, 0.006 mmol) and palladium acetate (1.3 mg, 0.006 mmol). Triethylsilane (24 μL, 0.15 mmol) was added to the 0.6 mL) solution, and the mixture was stirred at 60 ° C. for 10 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-10% methanol / chloroform). 1M Hydrochloric acid was added to the obtained solid, and the mixture was washed with ethyl acetate three times, and then potassium carbonate was added to the aqueous layer to give a pH of 10. Then, extraction was performed three times with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: 2M ammonia-methanol solution = 95: 5) to give the title compound (15.4 mg, 56%) as a colorless amorphous substance.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02-0.18 (m, 2H), 0.38-0.57 (m, 2H), 0.68-1.88 (m) , 7H), 2.06-3.12 (m, 9H), 3.35-3.62 (m, 1H), 3.67-3.87 (m, 0.7H), 4.02-4 .44 (m, 2.3H), 4.45-4.69 (m, 2H), 6.49-6.73 (m, 2H), 6.99-7.11 (m, 1H), 7 .14-7.25 (m, 1H), 8.65-8.81 (m, 2H).

(Reference example 22)
(4R, 4aS, 7S, 7aR, 12bS) -3- (Cyclopropylmethyl) -7,9-dimethoxy-1,2,3,4,7,7a-Hexahydro-4a, 7-Etano-4,12- Synthesis of methanobenzoflo [3,2-e] isoquinoline-6 (5H) -on (143)

化合物１（２．３５ｇ，５．９７ｍｍｏｌ）のエタノール（６０ｍＬ）溶液に、５％パラジウム－活性炭素（１．２ｇ）を加え、水素雰囲気下、７０°Ｃで１９時間撹拌した。反応液を放冷後、セライトろ過した。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（０－２％メタノール／クロロホルム）で精製し、表題化合物（２．２９ｇ，９７％）を無色固体として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１３（ｍ，２Ｈ），０．４５－０．５５（ｍ，２Ｈ），０．７５－０．８４（ｍ，１Ｈ），０．９７－１．０６（ｍ，１Ｈ），１．２６（ｄｄｄ，Ｊ＝６，１３，１３Ｈｚ，１Ｈ），１．５０－１．５７（ｍ，１Ｈ），１．６８（ｄｄ，Ｊ＝３，１３Ｈｚ，１Ｈ），１．７１－１．８１（ｍ，１Ｈ），２．０２（ｄｄｄ，Ｊ＝６，１３，１３Ｈｚ，１Ｈ），２．２２（ｄ，Ｊ＝２０Ｈｚ，１Ｈ），２．３０－２．４１（ｍ，４Ｈ），２．７１（ｄｄ，Ｊ＝６，１２Ｈｚ，１Ｈ），３．０７（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．１３（ｄ，Ｊ＝７Ｈｚ，１Ｈ），３．５１（ｄｄ，Ｊ＝４，２０Ｈｚ，１Ｈ），３．５３（ｓ，３Ｈ），３．８９（ｓ，３Ｈ），４．６０（ｄ，Ｊ＝２Ｈｚ，１Ｈ），６．６３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７６（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．

5% Palladium-active carbon (1.2 g) was added to a solution of compound 1 (2.35 g, 5.97 mmol) in ethanol (60 mL), and the mixture was stirred at 70 ° C. for 19 hours under a hydrogen atmosphere. After allowing the reaction solution to cool, it was filtered through Celite. The filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-2% methanol / chloroform) to give the title compound (2.29 g, 97%) as a colorless solid.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.13 (m, 2H), 0.45-0.55 (m, 2H), 0.75-0.84 (m) , 1H), 0.97-1.06 (m, 1H), 1.26 (ddd, J = 6,13,13Hz, 1H), 1.50-1.57 (m, 1H), 1.68 (Dd, J = 3,13Hz, 1H), 1.71-1.81 (m, 1H), 2.02 (ddd, J = 6,13,13Hz, 1H), 2.22 (d, J = 20Hz, 1H), 2.30-2.41 (m, 4H), 2.71 (dd, J = 6,12Hz, 1H), 3.07 (d, J = 18Hz, 1H), 3.13 ( d, J = 7Hz, 1H), 3.51 (dd, J = 4,20Hz, 1H), 3.53 (s, 3H), 3.89 (s, 3H), 4.60 (d, J = 2Hz, 1H), 6.63 (d, J = 8Hz, 1H), 6.76 (d, J = 8Hz, 1H).

(Reference example 23)
(4R, 4aS, 7R, 7aR, 12bS) -3- (Cyclopropylmethyl) -7,9-dimethoxy-1,2,3,4,7,7a-Hexahydro-4a, 7-Etano-4,12- Synthesis of methanobenzoflo [3,2-e] isoquinoline-6 (5H) -one oxime (144)

参考例２に記載した方法に従い、化合物１４３より表題化合物を得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０８－０．１５（ｍ，２Ｈ），０．４６－０．５６（ｍ，２Ｈ），０．８０－０．９５（ｍ，２Ｈ），１１０－１．２０（ｍ，１Ｈ），１．５５－１．７４（ｍ，３Ｈ），２．０１（ｄｄｄ，Ｊ＝６，１３，１３Ｈｚ，１Ｈ），２．２６－２．３８（ｍ，５Ｈ），２．６９（ｄｄ，Ｊ＝６，１２Ｈｚ，１Ｈ），３．０４（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．１５（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．５５（ｓ，３Ｈ），３．７０（ｄｄ，Ｊ＝４，２１Ｈｚ，１Ｈ），３．８９（ｓ，３Ｈ），４．６０（ｄ，Ｊ＝２Ｈｚ，１Ｈ），６．６０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），８．３０（ｂｒ ｓ，１Ｈ）．

The title compound was obtained from compound 143 according to the method described in Reference Example 2.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08-0.15 (m, 2H), 0.46-0.56 (m, 2H), 0.80-0.95 (m) , 2H), 110-1.20 (m, 1H), 1.55-1.74 (m, 3H), 2.01 (ddd, J = 6,13,13Hz, 1H), 2.26-2 .38 (m, 5H), 2.69 (dd, J = 6,12Hz, 1H), 3.04 (d, J = 18Hz, 1H), 3.15 (d, J = 6Hz, 1H), 3 .55 (s, 3H), 3.70 (dd, J = 4,21Hz, 1H), 3.89 (s, 3H), 4.60 (d, J = 2Hz, 1H), 6.60 (d) , J = 8Hz, 1H), 6.73 (d, J = 8Hz, 1H), 8.30 (br s, 1H).

(Reference Example 24)
2-((4R, 4aS, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-1,2,3,4,5,7a-hexahydro-4aH-4,12-methanobenzoflo [3] , 2-e] Isoquinoline-4a-yl) Synthesis of acetonitrile (145)

氷冷下、化合物１４４（３０ｍｇ，０．０７３ｍｍｏｌ）のジクロロメタン（１ｍＬ）溶液に、トリエチルアミン（２０．４μＬ，０．１５ｍｍｏｌ）及び塩化メタンスルホニル（１１．３μＬ，０．１５ｍｍｏｌ）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、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（１２－３３％酢酸エチル／へプタン）で精製し、表題化合物（２７．５ｍｇ，９６％）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），０．５０－０．６１（ｍ，２Ｈ），０．８６－０．９５（ｍ，１Ｈ），１．５５－１．６２（ｍ，１Ｈ），１．９０－２．０１（ｍ，２Ｈ），２．１１（ｄｄ，Ｊ＝６，１６Ｈｚ，１Ｈ），２．２０（ｄｄｄ，Ｊ＝４，１２，１２Ｈｚ，１Ｈ），２．３１（ｄｄ，Ｊ＝７，１３Ｈｚ，１Ｈ），２．４０（ｄｄ，Ｊ＝６，１３Ｈｚ，１Ｈ），２．５３（ｄｄ，Ｊ＝６，１８Ｈｚ，１Ｈ），２．６１（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），２．６７（ｄｄ，Ｊ＝５，１２Ｈｚ，１Ｈ），３．０１（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３．４７（ｄ，Ｊ＝６Ｈｚ，１Ｈ），３．５２（ｓ，３Ｈ），３．７１（ｄｄ，Ｊ＝２，１６Ｈｚ，１Ｈ），３．８４（ｓ，３Ｈ），４．６７－４．７１（ｍ，１Ｈ），４．７１（ｄ，Ｊ＝１Ｈｚ，１Ｈ），６．６３（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７２（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．

Under ice-cooling, triethylamine (20.4 μL, 0.15 mmol) and methanesulfonyl chloride (11.3 μL, 0.15 mmol) were added to a solution of compound 144 (30 mg, 0.073 mmol) in dichloromethane (1 mL) and 30 at room temperature. Stir for minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (12-33% ethyl acetate / heptane) to give the title compound (27.5 mg, 96%) as a colorless amorphous substance.

^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08-0.18 (m, 2H), 0.50-0.61 (m, 2H), 0.86-0.95 (m) , 1H), 1.55-1.62 (m, 1H), 1.90-2.01 (m, 2H), 2.11 (dd, J = 6,16Hz, 1H), 2.20 (ddd) , J = 4,12,12Hz, 1H), 2.31 (dd, J = 7,13Hz, 1H), 2.40 (dd, J = 6,13Hz, 1H), 2.53 (dd, J = 6,18Hz, 1H), 2.61 (d, J = 16Hz, 1H), 2.67 (dd, J = 5,12Hz, 1H), 3.01 (d, J = 18Hz, 1H), 3. 47 (d, J = 6Hz, 1H), 3.52 (s, 3H), 3.71 (dd, J = 2,16Hz, 1H), 3.84 (s, 3H), 4.67-4. 71 (m, 1H), 4.71 (d, J = 1Hz, 1H), 6.63 (d, J = 8Hz, 1H), 6.72 (d, J = 8Hz, 1H).

(Example 122)
(4R, 4aS, 8S, 8aR, 13bS) -3- (Cyclopropylmethyl) -8-hydroxy-10-methoxy-1,2,3,4,8,8a-hexahydro-5H-4a, 8-ethano- Synthesis of 4,13-methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-6 (7H) -on (146)

（方法ａ）
化合物４（２１９．６ｍｇ，０．５８ｍｍｏｌ）の６Ｍ塩酸（５ｍＬ）溶液を、７０℃で１時間撹拌した。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、酢酸エチルで三回抽出した。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（０－４％メタノール／クロロホルム）で精製し、表題化合物（１２０．９ｍｇ，５３％）を無色固体として得た。

（方法ｂ）
化合物１４５（３０ｍｇ，０．０７６ｍｍｏｌ）のテトラヒドロフラン（１ｍＬ）溶液に、濃塩酸（１ｍＬ）を加え、室温で１時間及び５０℃で２時間撹拌した。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、酢酸エチルで三回抽出した。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（０－６％メタノール／クロロホルム）で精製し、表題化合物（２４．８ｍｇ，８２％）を無色固体として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０７－０．１３（ｍ，２Ｈ），０．４７－０．５４（ｍ，２Ｈ），０．７７－０．８４（ｍ，１Ｈ），１．２３－１．５０（ｍ，３Ｈ），１．５６－１．６３（ｍ，１Ｈ），１．７９－１．８７（ｍ，１Ｈ），２．１９－２．２６（ｍ，２Ｈ），２．２７－２．３０（ｍ，２Ｈ），２．３７（ｄ，Ｊ＝１９Ｈｚ，１Ｈ），２．４７（ｄｄ，Ｊ＝６，１８Ｈｚ，１Ｈ），２．６３－２．７２（ｍ，１Ｈ），２．９８（ｄ，Ｊ＝２０Ｈｚ，１Ｈ），３．０１（ｄ，Ｊ＝７Ｈｚ，１Ｈ），３．３６（ｓ，１Ｈ），３．８８（ｓ，３Ｈ），４．０３（ｄｄ，Ｊ＝３，２０Ｈｚ，１Ｈ），４．４１（ｄ，Ｊ＝１Ｈｚ，１Ｈ），６．１２（ｂｒ ｓ，１Ｈ），６．６６（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７７（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．

(Method a)
A 6M hydrochloric acid (5 mL) solution of compound 4 (219.6 mg, 0.58 mmol) was stirred at 70 ° C. for 1 hour. The reaction mixture was allowed to cool, poured into saturated aqueous sodium hydrogen carbonate solution to make it basic, and extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-4% methanol / chloroform) to give the title compound (120.9 mg, 53%) as a colorless solid.

(Method b)
Concentrated hydrochloric acid (1 mL) was added to a solution of compound 145 (30 mg, 0.076 mmol) in tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for 1 hour and at 50 ° C. for 2 hours. The reaction mixture was allowed to cool, poured into saturated aqueous sodium hydrogen carbonate solution to make it basic, and extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-6% methanol / chloroform) to give the title compound (24.8 mg, 82%) as a colorless solid.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.07-0.13 (m, 2H), 0.47-0.54 (m, 2H), 0.77-0.84 (m) , 1H), 1.23-1.50 (m, 3H), 1.56-1.63 (m, 1H), 1.79-1.87 (m, 1H), 2.19-2.26 (M, 2H), 2.27-2.30 (m, 2H), 2.37 (d, J = 19Hz, 1H), 2.47 (dd, J = 6,18Hz, 1H), 2.63 -2.72 (m, 1H), 2.98 (d, J = 20Hz, 1H), 3.01 (d, J = 7Hz, 1H), 3.36 (s, 1H), 3.88 (s) , 3H), 4.03 (dd, J = 3,20Hz, 1H), 4.41 (d, J = 1Hz, 1H), 6.12 (br s, 1H), 6.66 (d, J = 8Hz, 1H), 6.77 (d, J = 8Hz, 1H).

(Example 123)
(4R, 4aS, 8S, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-Methoxy-1,2,3,4,6,7-Hexahydro-5H-4a, 8-Etano-4,13- Synthesis of methanobenzoflo [2,3-c] pyrido [4,3-d] azepine-8 (8aH) -ol (147)

化合物１４６（２０ｍｇ，０．０５０ｍｍｏｌ）のテトラヒドロフラン（３ｍＬ）溶液に、０．９４ｍｏｌ／Ｌ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（３１９μＬ，０．３０ｍｍｏｌ）を加え、４時間加熱還流した。反応混合物を放冷後減圧下にて濃縮し、得られた濃縮残渣に６Ｍ塩酸（３ｍＬ）を加え、１時間加熱還流した。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、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で二回洗浄し、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＝９５：５）で精製し、表題化合物（１３．５ｍｇ，７０％）を無色固体として得た。

^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：０．０６－０．１５（ｍ，２Ｈ），０．４４－０．５３（ｍ，２Ｈ），０．７３－０．８２（ｍ，１Ｈ），１．０３－１．１２（ｍ，１Ｈ），１．２４－１．３７（ｍ，３Ｈ），１．５３－１．８１（ｍ，３Ｈ），２．１７－２．３９（ｍ，５Ｈ），２．５８－２．６５（ｍ，１Ｈ），２．６９－２．７９（ｍ，２Ｈ），２．９５（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），２．９８－３．０５（ｍ，２Ｈ），３．１６－３．２７（ｍ，１Ｈ），３．８６（ｓ，３Ｈ），４．１７（ｄ，Ｊ＝２Ｈｚ，１Ｈ），６．６０（ｄ，Ｊ＝８Ｈｚ，１Ｈ），６．７３（ｄ，Ｊ＝８Ｈｚ，１Ｈ）．

A 0.94 mol / L borane-tetrahydrofuran complex tetrahydrofuran solution (319 μL, 0.30 mmol) was added to a solution of compound 146 (20 mg, 0.050 mmol) in tetrahydrofuran (3 mL), and the mixture was heated under reflux for 4 hours. The reaction mixture was allowed to cool and then concentrated under reduced pressure. 6M hydrochloric acid (3 mL) was added to the obtained concentrated residue, and the mixture was heated under reflux for 1 hour. The reaction mixture was allowed to cool, poured into saturated aqueous sodium hydrogen carbonate solution to make it basic, and extracted with ethyl acetate. The organic layer was washed twice with saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: methanol = 95: 5) to give the title compound (13.5 mg, 70%) as a colorless solid.

^{1 1} H-NMR (400MHz, CDCl ₃ ) δ (ppm): 0.06-0.15 (m, 2H), 0.44-0.53 (m, 2H), 0.73-0.82 (m) , 1H), 1.03-1.12 (m, 1H), 1.24-1.37 (m, 3H), 1.53-1.81 (m, 3H), 2.17-2.39 (M, 5H), 2.58-2.65 (m, 1H), 2.69-2.79 (m, 2H), 2.95 (d, J = 18Hz, 1H), 2.98-3 0.05 (m, 2H), 3.16-3.27 (m, 1H), 3.86 (s, 3H), 4.17 (d, J = 2Hz, 1H), 6.60 (d, J) = 8Hz, 1H), 6.73 (d, J = 8Hz, 1H).

(Test Example 1)
Opioid receptor function test
The functional activity of the compound of the present invention on the kappa opioid receptor was investigated.
Method: A Lance Ultra cAMP kit (PerkinElmer) was used, and the procedure was carried out according to a predetermined method. In the evaluation of agonist activity, human opioid κ receptor-expressing CHO cells (Catalog No. CT6666, accession No. NM_000912) and the test compound were used 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 one hour later, time-resolved fluorescence measurement was performed using an EnVision plate reader (PerkinElmer). The evaluation of the test compound was carried out in the kappa opioid receptor function test in the concentration range of ^10-14 to ^10-7 M.

表１に示すとおり、本発明の化合物は、オピオイドκ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。

As shown in Table 1, it was confirmed that the compound of the present invention exhibits strong agonist activity against opioid κ receptor.

(Test Example 2)
Metabolic stability test
(Test method)
Human liver microsomes and the test substance were reacted for a certain period of time (0 to 60 minutes), and the residual amount of the test substance in the reaction sample was measured to determine the residual rate. The residual rate of the unchanged form at 0 hours of reaction time is set to 100%, the residual rate after incubation is log-liner plotted with respect to time, and the regression line (y = 100e- ^kt , k = slope of a line: disappearance rate constant). Was calculated, and the metabolic clearance CL _int (mL / min / kg) was calculated using the following formula.
Further, as a comparative compound, the compound (C) described in paragraph number [0007] was used for comparison. The comparative compound (C) was synthesized by the method described in Non-Patent Document 1 and the like.

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

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

(Test results)
The test results are shown in Table 2.

以上の結果より、本発明化合物は比較化合物に対し優れた代謝安定性を示した。以上のことより、本発明化合物の優れたオピオイドκアゴニスト活性及び代謝安定性が確認された。

From the above results, the compound of the present invention showed excellent metabolic stability with respect to the comparative compound. From the above, the excellent opioid κ agonist activity and metabolic stability of the compound of the present invention were confirmed.

Claims (7)

The following general formula (I),

(In the formula, R ¹ has a hydrogen atom, a C _1-6 alkyl group which may have a substituent, a C _3-6 cycloalkyl group which may have a substituent, and a substituent. May be C _3-6 cycloalkyl C _1-6 alkyl group, aryl group which may have a substituent, heteroaryl group which may have a substituent, and aralkyl which may have a substituent. Group, heteroarylalkyl group which may have a substituent, C _2-6 alkenyl group which may have a substituent, C _2-6 alkynyl group which may have a substituent, substituent. Indicates an acyl or amino-protecting group that may have
R ² and R ³ are the same or different hydrogen atom, C _1-6 alkyl group which may have a substituent, C _1-6 alkoxy group which may have a substituent, a halogen atom and a hydroxy group. Alternatively, R ² and R ³ together indicate a carbonyl group or R ² and R ³ may be attached to indicate a cyclic ketal which may have a substituent.
R ⁴ and R ⁵ have the same or different hydrogen atom, a C _1-6 alkyl group which may have a substituent, a C _1-6 alkoxy group which may have a substituent, and a substituent. Indicates an amino group, a halogen atom or a hydroxy group which may be present.
R ⁶ is a hydrogen atom, a C _1-6 alkoxy group which may have a substituent, an amino group which may have a substituent, a halogen atom, a hydroxy group, a cyano group, a carboxy group and a carboxylic acid ester group. Alternatively, the carbamoyl group which may have a substituent is shown.
R ⁷ represents a hydrogen atom, a C _1-6 alkyl group which may have a substituent, a C _1-6 alkoxy group which may have a substituent, or a hydroxy group.
R ⁸ and R ⁹ are the same or different hydrogen atoms, C _1-6 alkyl groups which may have substituents, C _1-6 alkoxy groups which may have substituents, halogen atoms, hydroxy groups. Alternatively, R ⁸ and R ⁹ may be combined to indicate a carbonyl group, a thiocarbonyl group, or R ⁸ and R ⁹ may be bonded to have a substituent C _3-6 saturated hydrocarbon ring or substituent. Indicates a ring-shaped ketal that may have,
R ¹⁰ and R ¹¹ are the same or different hydrogen atom, C _1-6 alkyl group which may have a substituent, C _1-6 alkoxy group which may have a substituent, a halogen atom and a hydroxy group. Alternatively, R ¹⁰ and R ¹¹ together indicate a carbonyl group, a thiocarbonyl group, or R ¹⁰ and R ¹¹ may be bonded to have a substituent C _3-6 saturated hydrocarbon ring or substituent. Indicates a ring-shaped ketal that may have,
R ¹² and R ¹³ indicate the same or different C _1-6 alkyl groups that may have the same or different hydrogen atoms, substituents, or R ¹² and R ¹³ on the same carbon have a substituent. It indicates a C _3-6 saturated hydrocarbon ring which may be present, a saturated heterocyclic ring which may have a substituent, or when n is 2 to 3, adjacent sets of ^R12 are bonded to each other and substituted. It is possible to form a C _3-6 saturated hydrocarbon ring which may have a group or a saturated heterocyclic ring which may have a substituent.
R ¹⁴ is a hydrogen atom, a C _1-6 alkyl group which may have a substituent, a C _3-6 cycloalkyl group which may have a substituent, and C ₂ which may have a substituent. _-4 Alkenyl group, C _2-4 alkynyl group which may have a substituent, C _1-6 alkoxy group which may have a substituent, amino group which may have a substituent, halogen. An atom, a hydroxy group, a C _6-10 aryl group which may have a substituent, a heteroaryl group which may have a substituent, and a cyclic amino group which may have a substituent are shown.
X represents a nitrogen atom or N-oxide,
Y represents an oxygen atom or a sulfur atom.
Z indicates NR ¹⁵ , oxygen atom, bond, —CH = CH— or —C≡C—,
R ¹⁵ indicates a hydrogen atom, a C _1-6 alkyl group which may have a substituent, or indicates a nitrogen-containing saturated heterocycle in which R ¹⁵ and R ¹⁴ may be bonded and have a substituent. ,
A double line consisting of a solid line and a broken line indicates a single bond or a double bond, and m indicates an integer of 0 to 1.
n represents an integer of 0 to 3. )
A morphinan derivative represented by, a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof. The morphinan derivative according to claim 1, wherein R ⁶ is a C _1-6 alkoxy group which may have a hydroxy group or a substituent, a tautomer of the compound, a steric isomer, or a pharmaceutically acceptable thereof. Salts or solvates thereof. The morphinan derivative according to claim 1 or 2, wherein R ⁶ is a hydroxy group, a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof. A pharmaceutical composition containing the morphinan derivative according to any one of claims 1 to 3, a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. .. The medicine according to claim 4, which is a therapeutic, ameliorating, or prophylactic agent for a disease related to an opioid kappa receptor. The drug according to claim 4 or 5, which is an analgesic. The drug according to claim 4 or 5, which is an antipruritic drug.