WO2020085234A1

WO2020085234A1 - Morphinan derivative

Info

Publication number: WO2020085234A1
Application number: PCT/JP2019/041076
Authority: WO
Inventors: 渡邉義一; 茂木雄三; 齊藤大祐; 林田康平; 山元広平
Original assignee: 日本ケミファ株式会社
Priority date: 2018-10-22
Filing date: 2019-10-18
Publication date: 2020-04-30
Also published as: JP2022017604A

Abstract

The present invention relates to a morphinan derivative that has an opioid κ receptor agonist effect and that is represented by general formula (I). (In the formula, R¹ indicates a hydrogen atom, a C_1-6 alkyl group that may have a substituent, or the like; R² and R³ are the same or different and each indicate a hydrogen atom, a C_1-6 alkyl group that may have a substituent, or the like; R⁴ and R⁵ are the same or different and each indicate a hydrogen atom, a C_1-6 alkyl group that may have a substituent, or the like; R⁶ indicates a hydrogen atom, a C_1-6 alkoxy group that may have a substituent, or the like; R⁷ indicates a hydrogen atom, a C_1-6 alkyl group that may have a substituent, or the like; R⁸ and R⁹ are the same or different and each indicate a hydrogen atom, a C_1-6 alkyl group that may have a substituent, or the like; R¹⁰ and R¹¹ are the same or different and each indicate a hydrogen atom, a C_1-6 alkyl group that may have a substituent, or the like; R¹² and R¹³ are the same or different and each indicate a hydrogen atom or the like; R¹⁴ indicates a heteroaryl group that may have a substituent or the like; X indicates a nitrogen atom or the like; Y indicates C=O or the like; Z indicates an oxygen atom or the like; a double line consisting of a solid line and a broken line indicates a single bond or the like; m indicates an integer of 0-1; and n indicates an integer of 0-3.) The present invention also relates to a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of said compound, or a solvate of said substances.

Description

Morphinan derivative

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

Three types of opioid receptors are known, μ, δ, and κ. Morphine, which has a strong affinity for the μ receptor, has long been used as an analgesic. However, μ opioid receptor agonists are known to cause adverse events such as dependence formation and respiratory depression via the μ opioid receptor.
On the other hand, kappa opioid receptor agonists also show an analgesic effect, but it is known that they do not participate in the adverse events seen in morphine.
On the other hand, kappa opioid receptor agonists are generally known to exhibit sedative action and drug aversion. The only kappa opioid receptor agonist that separates drug aversion is nalfurafine (Patent Document 1), but since nalfurafine exhibits a sedative effect at an analgesic dose, approval as an antipruritic drug was obtained, but an analgesic drug. Has not been approved. That is, there are still no kappa opioid receptor-selective agonists approved as analgesics.
Therefore, a κ receptor-selective agonist that does not exhibit sedative action or drug aversion is expected as an excellent therapeutic or ameliorating or preventive drug for diseases and symptoms related to κ opioid receptors such as analgesics.
In Patent Document 2, the following formula (A),

It is disclosed that the compound represented by the formula (1) has κ opioid receptor agonist activity. However, its activity was not sufficient.
Further, in Patent Document 3, the following formula (B),

The compound represented by is reported. It is described that this compound has a κ opioid receptor-selective binding and analgesic effect. However, its analgesic activity was not satisfactory.
Further, in Patent Document 4 and Non-Patent Document 1, a compound (C) represented by the following formula:

Although disclosed to have extremely high activity, this compound was not sufficiently stable in vivo. When a compound is unstable in vivo, it is difficult to develop it as a drug due to the fact that expected drug efficacy is not exerted and the effect of degradation products on the living body. It becomes an important requirement.
None of the analgesics on the market have high κ opioid receptor agonist activity.
Therefore, a compound that exhibits selectivity and high activity for the kappa opioid receptor and is excellent in stability in vivo is desired for the purpose of becoming an analgesic.

International publication 1993/5081 pamphlet JP, 2008-179554, A Japanese Patent No. 2525552 U.S. Patent No. 963460

An object of the present invention is to provide a medicine effective for treating, ameliorating, and preventing various diseases and symptoms related to the κ opioid receptor, in which sedation and drug aversion are suppressed.

Under such circumstances, the present inventors have conducted diligent studies, and as a result, specific morphinan derivatives have κ opioid receptor selectivity and strong agonist activity for κ opioid receptors, and have high in vivo stability. The present invention has been completed and the present invention has been completed.
[1] That is, the present invention provides the following general formula (I):

(In the formula, R ¹ 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, or a substituent C _3-6 cycloalkyl C _1-6 alkyl group, aryl group optionally having substituent (s), heteroaryl group optionally having substituent (s), aralkyl optionally having substituent (s) Group, heteroarylalkyl group optionally having substituent (s), C _2-6 alkenyl group optionally having substituent (s), C _2-6 alkynyl group optionally having substituent (s), substituent (s) Represents an acyl group or an amino protecting group which may have,
R ² and R ³ are the same or different and each is 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, a halogen atom, a hydroxy group. Or R ² and R ³ together represent a carbonyl group or a thiocarbonyl group, or R ² and R ³ are bonded to each other to represent a cyclic ketal which may have a substituent,
R ⁴ and R ⁵ are the same or different and each have 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, and a substituent. Optionally represents an amino group, a halogen atom or a hydroxy group,
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, a carboxylic acid ester group Or a carbamoyl group which may have a substituent,
R ⁷ represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _1-6 alkoxy group or a hydroxy group,
R ⁸ and R ⁹ are the same or different and each is 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, a halogen atom or a hydroxy group. Or R ⁸ and R ⁹ together represent a carbonyl group or a thiocarbonyl group, or R ⁸ and R ⁹ are bonded to each other to form a C _3-6 saturated hydrocarbon ring which may have a substituent or a substituent. Indicates a cyclic ketal that may have,
R ¹⁰ and R ¹¹ are the same or different and each is 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, a halogen atom, a hydroxy group. Or R ¹⁰ and R ¹¹ together represent a carbonyl group or a thiocarbonyl group, or R ¹⁰ and R ¹¹ are bonded to each other to form a C _3-6 saturated hydrocarbon ring which may have a substituent or a substituent. Indicates a cyclic ketal that may have,
R ¹² and R ¹³ are the same or different and each represent a hydrogen atom, an optionally substituted C _1-6 alkyl group, or R ¹² and R ¹³ together represent a carbonyl group or a thiocarbonyl group. Or R ¹² and R ¹³ on the same carbon are bonded to each other to represent a C _3-6 saturated hydrocarbon ring which may have a substituent, a saturated heterocyclic ring which may have a substituent, or n In the case where is 2 to 3, a pair of adjacent R ¹² is bonded to form a C _3-6 saturated hydrocarbon ring which may have a substituent or a saturated heterocycle which may have a substituent. Can be formed,
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, or a C ₂ which may have a substituent. _-4 alkenyl group, optionally substituted C _2-4 alkynyl group, optionally substituted C _1-6 alkoxy group, optionally substituted amino group, 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 or a saturated heterocyclic group which may have a substituent,
X represents a nitrogen atom or N-oxide,
Y represents C = O, C = S, C = NR ¹⁶ or SO ₂ ,
R ¹⁶ represents a hydrogen atom or an optionally substituted C _1-6 alkyl group,
Z represents NR ¹⁵ , an oxygen atom, a bond, an ethenylene group which may have a substituent or an ethynylene group,
R ¹⁵ represents a hydrogen atom, a C _1-6 alkyl group which may have a substituent, or a nitrogen-containing saturated heterocycle which may have a substituent by the combination of R ¹⁵ and R ^14. ,
A double line consisting of a solid line and a broken line represents a single bond or a double bond, and m represents an integer of 0 to 1,
n represents an integer of 0 to 3. )
And a tautomer, a stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof.
[2] The present invention also provides the morphinan derivative according to the above [1], wherein R ⁶ is a hydroxy group or a C _1-6 alkoxy group which may have a substituent, a tautomer of the compound, and stereoisomerism. The present invention relates to the body, a pharmaceutically acceptable salt thereof, or a solvate thereof.
[3] The present invention also provides the morphinan derivative according to the above [1] or [2], wherein R ⁶ is a hydroxy group, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or Regarding their solvates.
[4] The present invention also provides the morphinan derivative according to any one of the above [1] to [3], wherein R ⁷ is a hydrogen atom, a tautomer, a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof. Or, it relates to a solvate thereof.
[5] The present invention also provides the morphinan derivative according to any one of the above [1] to [5], wherein Z is NR ¹⁵ , an oxygen atom, a bond or an ethenylene group which may have a substituent. The present invention relates to a pharmaceutical composition containing a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
[6] The present invention also provides the morphinan derivative according to any one of the above [1] to [5], wherein Z is either NR ¹⁵ or a bond, a tautomer, a stereoisomer of the compound, or a pharmaceutical thereof. Relates to a pharmaceutical composition containing a pharmaceutically acceptable salt or a solvate thereof as an active ingredient.
[7] The present invention also provides that R ¹⁴ is an amino group which may have a substituent, a C _6-10 aryl group which may have a substituent, and a heteroaryl which may have a substituent. Or a saturated heterocyclic group which may have a substituent, the morphinan derivative according to any one of the above [1] to [6], a tautomer or stereoisomer of the compound, or a pharmaceutical thereof. Relates to a pharmaceutical composition containing a pharmaceutically acceptable salt or a solvate thereof as an active ingredient.
[8] The present invention also provides the morphinan derivative according to the above [7], wherein the C _6-10 aryl group which may have a substituent according to the above [7] is a phenyl group, a tautomer of the compound, The present invention relates to a pharmaceutical composition containing a stereoisomer, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
[9] The present invention also provides that the heteroaryl group optionally having a substituent described in [7] above is a furanyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group. , 1,3,4-thiadiazolyl group, isothiazolyl group, triazolyl group, pyridyl group, pyridazinyl group, pyrazinyl group, pyrimidyl group, 2-oxopyridyl group, 4-oxopyridyl group, 2-oxopyrazinyl group, quinolyl group, isoquinolyl group , Indolyl group, indazolyl group, benzofuranyl group, benzothienyl group, benzoxazolyl group, benzothiazolyl group, imidazopyridinyl group, imidazo [1,2-a] pyrimidyl group, pyrazolopyridinyl group, purine, adenine Or guanine, the morphinan derivative according to the above [7], Tautomers of the object, stereoisomer, or a pharmaceutical composition containing as an active ingredient a pharmaceutically acceptable salt or solvate thereof.
[10] The present invention also provides the morphinan derivative according to the above [7], wherein the saturated heterocyclic group optionally having a substituent according to the above [7] is a cyclic amino group, a tautomer of the compound, The present invention relates to a pharmaceutical composition containing a stereoisomer, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
[11] The present invention also provides that the cyclic amino group which may have a substituent as described in [10] above is an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, an azepanyl group, a morpholinyl group, a thiomorpholinyl group, 7- Azabicyclo [2.2.1] heptyl group, 3-oxa-8-azabicyclo [2.2.2] octyl group, 3-oxa-8-azabicyclo [3.2.1] octyl group, 8-azabicyclo [3 1.2.1] A morphinan derivative according to the above [10], which is any of octyl groups, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof or a solvate thereof. The present invention relates to a pharmaceutical composition containing as an ingredient.
[12] The present invention also provides the morphinan derivative according to any one of the above [1] to [11], wherein X is a nitrogen atom, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof. Or, it relates to a pharmaceutical composition containing a solvate thereof as an active ingredient.
[13] The present invention also provides the morphinan derivative according to any one of the above [1] to [12], wherein Y is C═O, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable form thereof. The present invention relates to a pharmaceutical composition containing a salt or a solvate thereof as an active ingredient.
[14] The present invention also provides the morphinan derivative according to any one of the above [1] to [13], a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Relates to a pharmaceutical composition containing as an active ingredient.
[15] The present invention also relates to the medicament according to the above [14], which is a therapeutic, ameliorating, or prophylactic agent for diseases associated with κ opioid receptors.
[16] The present invention also relates to the medicament according to [14] or [15] above, which is an analgesic drug.
[17] The present invention also relates to the medicine according to the above [14] or [15], which is an antipruritic drug.

Next, the present invention will be described in more detail.
Of the morphinan derivatives represented by the above general formula (I), tautomers, stereoisomers of the compounds, or pharmaceutically acceptable salts thereof or solvates thereof, preferably the following are mentioned. To be
The C _1-6 alkyl group in the C _1-6 alkyl group which may have a substituent represented by R ¹ to R ⁵ and R ⁷ to R ¹⁶ includes a methyl group, an ethyl group, a propyl group and an isopropyl group. , A butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, and other linear or branched alkyl groups are preferred, and a methyl group, an ethyl group, a propyl group are preferred, and a methyl group is more preferred. Can be mentioned.

Examples of the C _3-6 cycloalkyl group in the C _3-6 cycloalkyl group which may have a substituent represented by R ¹ and R ¹⁴ include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. And preferably a cyclopropyl group.

The substituent in the C _1-6 alkyl group which may have a substituent and the C _3-6 cycloalkyl group which may have a substituent, which is represented by R ¹ , is a methyl group, an ethyl group or a propyl group. C _1-6 alkyl group such as group, fluoromethyl group, difluoromethyl group, halogenated methyl group such as trifluoromethyl group, halogen atom such as fluorine atom and chlorine atom, hydroxy group, C _1-6 alkylamino group, Di C _1-6 alkylamino group, acylamino group, amino group which may have a substituent such as protected amino group, formyl group, acetyl group, cyclopropylcarbonyl group, acyl group such as benzoyl group, azetidinyl Group, a pyrrolidinyl group, a piperazinyl group, a cyclic amino group such as morpholinyl group, a lactam group such as β-lactam, γ-lactam, and δ-lactam. That.

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

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

Examples of the heteroaryl group represented by R ¹ and R ¹⁴ which may have a substituent include a furanyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group and a thiazolyl group. Group, 5-membered heteroaryl group such as isothiazolyl group, triazolyl group and tetrazolyl group; 6 such as pyridyl group, pyridazinyl group, pyrazinyl group, pyrimidyl group, 2-oxopyridyl group, 4-oxopyridyl group and 2-oxopyrazinyl group Membered ring heteroaryl group; quinolyl group, isoquinolyl group, quinazolyl group, quinoxalyl group, indolyl group, indazolyl group, isoindazolyl group, benzimidazolyl group, benzofuranyl group, benzothienyl group, benzoxazolyl group, benzothiazolyl group, imidazopyridydi group Group, pyrazolopyridinyl group, 2-oxoquinolinyl group, purine base such as purine, adenine, guanine; dihydrobenzofuranyl group, chromanyl group, bicyclic heteroaryl group such as dihydrobenzodioxanyl group, etc. Examples thereof include monocyclic or bicyclic heteroaryl groups containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom as ring-constituting atoms.
Preferred heteroaryl groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,3,4-thiadiazolyl, isothiazolyl, triazolyl, pyridyl, pyridazinyl. Group, pyrazinyl group, pyrimidyl group, 2-oxopyridyl group, 4-oxopyridyl group, 2-oxopyrazinyl group, quinolyl group, isoquinolyl group, indolyl group, indazolyl group, benzofuranyl group, benzothienyl group, benzoxazolyl group, Examples thereof include a benzothiazolyl group, an imidazopyridinyl group, an imidazo [1,2-a] pyrimidyl group, a pyrazolopyridinyl group, purine, adenine, and guanine. More preferred are a furanyl group, a thienyl group, a pyrrolyl group, and an imidazolyl group. Group, pyrazolyl , Oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyridyl group, pyridazinyl group, pyrazinyl group, pyrimidyl group, 2-oxopyridyl group, 2-oxopyrazinyl group, indolyl group, indazolyl group, benzoxazolyl group, pyrazolo group Examples include a pyridinyl group.
Further, tautomers may exist depending on the substituents on these heteroaryl groups. For example, when a hydroxy group is substituted on the pyridyl group, the 6-hydroxypyridin-2-yl group and its tautomer 6-oxo-1,6-dihydropyridin-2-yl group and 4-hydroxypyridin-2-yl group and 4-oxo-1,4-dihydropyridin-2-yl group as its tautomer To be

The optionally substituted aryl group and the optionally substituted heteroaryl group represented by R ¹ and R ¹⁴ may have 1 to 3 substituents on the ring. As the substituent thereof, a linear or branched C _1-6 alkyl group such as methyl group, ethyl group, propyl group, isopropyl group; halogenated methyl group such as fluoromethyl group, difluoromethyl group, trifluoromethyl group, etc. Hydroxyalkyl group such as hydroxymethyl group, hydroxyethyl group, 1-hydroxypropyl group; linear or branched C _1-6 alkoxy group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group; cyclo fluorine atom, a halogen atom such as a chlorine atom; propyl group, a cyclopentyl group, C _3-6 cycloalkyl groups such as cyclohexyl group hydroxy group, Toromoto, cyano group; C _1-6 alkylamino group, di C _1-6 alkylamino group, an acylamino group, a protected substituent or protecting an amino group which may have a group such as an amino group; a formyl group , Acyl groups such as acetyl group, cyclopropylcarbonyl group and benzoyl group; cyclic amino groups such as azetidinyl group, pyrrolidinyl group, piperazinyl group and morpholinyl group; lactam groups such as β-lactam, γ-lactam and δ-lactam; The amino protecting group described in [0030] and the like can be mentioned.

The C _3-6 cycloalkyl C _1-6 alkyl group in the C _3-6 cycloalkyl C _1-6 alkyl group which may have a substituent represented by R ¹ includes a cyclopropylmethyl group and a cyclopropylethyl group. Group, cyclopropylpropyl group, cyclobutylmethyl group, cyclobutylethyl group, cyclopentylmethyl group, cyclopentylethyl group, cyclopentylpropyl group, cyclohexylmethyl group, cyclohexylethyl group, cyclohexylpropyl group and the like, preferably cyclopropylmethyl group Group, cyclopropylethyl group, cyclobutylmethyl group, cyclobutylethyl group, cyclopentylmethyl group, cyclopentylethyl group, more preferably cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, most preferably Mashiku can be mentioned cyclopropylmethyl group. As the _{C 1-6} alkyl group in the _{C 3-6} cycloalkyl _{C 1-6} alkyl group represented by ^{R 1,} include those similar to the aforementioned.
As the substituent, the same substituents as those for the above-mentioned optionally substituted C _3-6 cycloalkyl group can be mentioned.

The aralkyl group which may have a substituent represented by R ¹ has an aryl moiety having a carbon number of C _{6 to 10} and an alkylene moiety having a carbon number of C _{1 to 5,} and is substituted with, for example, phenyl or naphthyl. And a methyl group (benzyl group) substituted with phenyl are preferred.

The heteroaryl moiety in the optionally substituted heteroarylalkyl group represented by R ¹ includes 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom as ring-constituting atoms. Examples of the heteroaryl include C _1-6 alkyl groups such as a methyl group, an ethyl group and a propyl group, and examples of the alkyl moiety include (pyridin-2-yl) methyl group and (pyridin-3-yl). Methyl group, (pyridin-4-yl) methyl group, 2- (pyridin-2-yl) ethyl group, (furan-2-yl) methyl group, (furan-3-yl) methyl group, (imidazol-2- (Il) methyl group, (imidazol-4-yl) methyl group, (imidazol-5-yl) methyl group, (thiazol-2-yl) methyl group, (thiazol-4-yl) A monocyclic heteroarylalkyl group such as tyl group, (thiazol-5-yl) methyl group, (thiophen-2-yl) methyl group or 2- (thiophen-2-yl) ethyl group, (quinolin-3-yl) Examples thereof include a bicyclic heteroarylalkyl group such as a methyl group and a (indol-3-yl) methyl group.

The aralkyl group which may have a substituent and the heteroarylalkyl group which may have a substituent represented by R ¹ may have a substituent on the aryl and the heteroaryl, and as the substituent, Are the same as the above-mentioned substituents 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 a substituent represented by R ¹ and R ¹⁴ include a C _2-6 linear or branched alkenyl group, Allyl group, vinyl group, 1-propenyl group, 2-butenyl group, 3-butenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group And alkenyl groups such as 5-hexenyl group.

The C _2-6 alkynyl group in the C _2-6 alkynyl group which may have a substituent represented by R ¹ and R ¹⁴ is a C _2-6 linear or branched alkynyl group. Examples include ethynyl group, propynyl group, butynyl group and the like.

Examples of the group capable of substituting the alkenyl group and alkynyl group include alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group and propoxycarbonyl group; benzyl group, 2-phenylethyl group, 3-phenylpropyl group, 4-phenyl Aralkyl group such as butyl group; alkoxy group such as methoxy group, ethoxy group, propoxy group, butoxy group; aralkyloxy group such as benzyloxy group and 2-phenylethyloxy group; C _1-6 straight or branched chain 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 optionally substituted acyl group represented by R ¹ include a formyl group; a C _2-6 alkanoyl group such as an acetyl group, a propionyl group, a butanoyl group, a pentanoyl group and a hexanoyl group; a cyclopropylcarbonyl group; C _4-7 cycloalkanoyl group such as cyclobutylcarbonyl group and cyclopentylcarbonyl group; aroyl group or furoyl group such as benzoyl group and naphthoyl group; heteroaroyl group having 5 to 6 membered ring such as thiophencarbonyl group, nicotinyl group and isonicotinoyl group Etc.
In addition, examples of the substituent in the C _2-6 alkanoyl group and C _4-7 cycloalkanoyl group include the same as the above-mentioned substituents in the C _1-6 alkyl group which may have a substituent. Examples of the substituent in the group and the heteroaroyl group include the same substituents as those in the aryl group which may have a substituent and the heteroaryl group which may have a substituent.

Examples of the substituent in the amino group which may have a substituent represented by substituents and R ^{4 ~} R ⁶ and R ¹⁴ in the carbamoyl group which may have a substituent group represented by R ^6, a methyl group , A C _1-6 alkyl group which may have a linear or branched substituent such as an ethyl group, a propyl group and an isopropyl group (the substituent is a hydroxy group, a C _1-6 alkoxy group, a fluorine atom, Halogen atom such as chlorine atom, amino group, cyano group, heteroaryl group, and the like.), And may have 1 or 2 of these substituents.
Further, examples of the substituent in the amino group which may have a substituent represented by R ⁴ to R ⁶ and R ¹⁴ include the same amino protecting group as the amino protecting group represented by R ¹ in addition to the above. To be

Examples of the amino protecting group represented by R ¹ include methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group, tert-amyloxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, p- Chlorobenzyloxycarbonyl group, p-methoxybenzylcarbonyl group, p-nitrobenzyloxycarbonyl group, p-phenylazobenzyloxycarbonyl group, p-methoxyphenylazobenzyloxycarbonyl group, 3,5-dimethoxybenzyloxycarbonyl group, 3,4,5-trimethoxybenzyloxycarbonyl group, p-biphenylisopropyloxycarbonyl group, diisopropylmethyloxycarbonyl group, 2- (trimethylsilyl) ethoxycarbonyl group, 9-fluorenyl Carbamate-based protecting groups such as rumethyloxycarbonyl group; Sulfonamide-based protecting groups such as p-toluenesulfonyl group and 2-nitrobenzenesulfonyl group; Imide-based protecting groups such as phthaloyl group; benzyl group, phenylethyl group, phenylpropyl group, Examples thereof include C _7-19 aralkyl groups such as trityl group and naphthylmethyl group; and acetal-based protecting groups such as methoxymethyl group and 2- (trimethylsilyl) ethoxymethyl group.

Examples of the halogen atom represented by R ² to R ⁶ , R ⁸ to R ¹¹ and R ¹⁴ 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. Is mentioned.

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

Examples of the saturated heterocyclic group represented by R ¹⁴ which may have a substituent include a cyclic amino group, a lactam group and a cyclic ether group.
Examples of the cyclic amino group are an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, an azepanyl group, a morpholinyl group and a thiomorpholinyl group, a 7-azabicyclo [2.2.1] heptyl group, 3-oxa-8-azabicyclo [2. 2.2] octyl group, 3-oxa-8-azabicyclo [3.2.1] octyl group, azabicyclo [2.2.2] octyl group, 2-oxa-6-azaspiro [3.3] heptyl group, etc. Is mentioned.
Examples of the lactam group include β-lactam, γ-lactam, δ-lactam and the like.
Examples of the cyclic ether group include an oxetanyl group, a tetrahydrofuranyl group and a tetrahydropyranyl group.
Preferred saturated heterocyclic groups include cyclic amino groups, and preferred cyclic amino groups include azetidinyl groups, pyrrolidinyl groups, piperidinyl groups, piperazinyl groups, azepanyl groups, morpholinyl groups and thiomorpholinyl groups, 7-azabicyclo [2.2.1]. ] Heptyl group, 3-oxa-8-azabicyclo [2.2.2] octyl group, 3-oxa-8-azabicyclo [3.2.1], and more preferably pyrrolidinyl group, piperidinyl group, azepanyl group , And a morpholinyl group.
As the substituent, a linear or branched C _1-6 alkyl group such as a methyl group, an ethyl group, a propyl group or an isopropyl group; a linear chain such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group or a butoxy group Or a branched C _1-6 alkoxy group; a C _3-6 cycloalkyl group such as a cyclopropyl group, a cyclopentyl group, a cyclohexyl group; a halogen atom such as a fluorine atom and a chlorine atom; a formyl group, an acetyl group, a cyclopropylcarbonyl group, Acyl group such as benzoyl group; C _3-6 cycloalkyl C _1-6 alkyl group such as cyclopropylmethyl group, cyclopropylethyl group, and cyclopropylpropyl group; aralkyl group such as benzyl group, pyridine, pyridazine, and pyrimidine hetero Aryl group; examples thereof include the amino protecting group described in paragraph [0030].

R ⁸ and R ⁹ may have a substituent formed by bonding, and a C _3-6 saturated hydrocarbon ring, and R ¹⁰ and R ¹¹ may have a substituent formed by bonding. A good C _3-6 saturated hydrocarbon ring, having a substituent formed by the combination of R ¹² and R ¹³ on the same carbon, or a pair of adjacent R ¹² bonded together when n is 2 to 3 the C _3-6 saturated hydrocarbon ring of which may C _3-6 saturated hydrocarbon ring optionally, cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring.

A saturated heterocyclic ring which may have a substituent formed by the combination of R ¹² and R ¹³ on the same carbon or the combination of adjacent sets of R ¹² when n is 2 to 3; Examples of the saturated heterocyclic group in the saturated heterocyclic group which may have a substituent represented by R ¹⁴ include a 3- to 6-membered saturated heterocyclic group, and examples thereof include aziridine, azetidine, pyrrolidine, piperidine, piperazine, Examples thereof include cyclic amines such as morpholine and thiomorpholine, cyclic ethers such as epoxide, oxetane, tetrahydrofuran, tetrahydropyran and dioxane, and cyclic thioethers such as thietane, thiolane and thiane.
When a nitrogen atom is contained as a ring-constituting atom among these saturated heterocycles, a substituent such as a C _1-6 alkyl group, an acyl group or an amino-protecting group may be present on the nitrogen. These substituents are the same as the above-mentioned substituents in the cyclic amino group.

Examples of the nitrogen-containing saturated heterocyclic ring which may be formed by the combination of R ¹⁴ and R ¹⁵ include a 3- to 6-membered nitrogen-containing saturated heterocyclic ring, and examples thereof include aziridine, azetidine and pyrrolidine. And cyclic amino groups such as piperidine, piperazine, azepane, morpholine and thiomorpholine.
These nitrogen-containing saturated heterocycles may be further condensed with saturated hydrocarbons, saturated heterocycles, unsaturated hydrocarbons or unsaturated heterocycles such as decahydroquinoline, decahydroisoquinoline, indoline, isoindoline, 1 2,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, benzomorpholine, benzothiomorpholine and the like.
When these nitrogen-containing heterocycles have a nitrogen atom as a ring-constituting atom in addition to the nitrogen atom to which R ¹⁵ is bonded, they have a substituent such as a C _1-6 alkyl group, an acyl group and an amino-protecting group. You may have. These substituents are the same as the above-mentioned substituents in the cyclic amino group.

A C _3-6 saturated hydrocarbon ring which may have a substituent formed by combining R ¹² and R ¹³ on the same carbon, and is formed by combining R ¹² and R ¹³ on the same carbon. Saturated heterocyclic ring optionally having substituent (s), C _3-6 saturated optionally having substituent (s) formed by bonding a pair of adjacent R ¹² 's when n is 2 to 3. A hydrocarbon ring or a saturated heterocycle which may have a substituent and a nitrogen-containing saturated heterocycle which may have a substituent formed by the combination of R ¹⁴ and R ¹⁵ are the above-mentioned cyclic groups. Examples thereof are the same as the substituents on the amino group.

Examples of the cyclic ketal which may have a substituent formed by combining 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 a C _1-6 alkyl group such as a methyl group, an ethyl group and a propyl group.

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

Y represents C = O, C = S, C = NR ¹⁶ or SO ₂ , and preferably C = O.

Z represents NR ¹⁵ , an oxygen atom, a bond, an ethenylene group which may have a substituent or an ethynylene group, and is preferably NR ¹⁵ , an oxygen atom, a bond or ethylene. Examples of the substituent in the ethenylene group which may have a substituent include those described in paragraph [0027].

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

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

In a preferred embodiment of the compound (I) used in the present invention, R ¹ is a C _1-6 alkyl group which may have a substituent or a C _3-6 cycloalkyl which may have a substituent. A C _1-6 alkyl group, wherein R ² and R ³ are the same or different and are a hydrogen atom or a C _1-6 alkyl group which may have a substituent, and C _{1 -which} may have a substituent. ₆ alkoxy group, halogen atom, hydroxy group or R ² and R ³ are taken together to form a carbonyl group, and R ⁴ and R ⁵ are the same or different and are each a hydrogen atom or C _{1 -which} may have a substituent. _{A 6} alkyl group, a C _1-6 alkoxy group which may have a substituent, an amino group which may have a substituent, a halogen atom or a hydroxy group, and R ⁶ has a substituent Also with a C _1-6 alkoxy group or hydroxy group R ⁷ is 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, and R ⁸ and R ⁹ Are the same or different and each is 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, a halogen atom, a hydroxy group or R ⁸ and R ⁹ together are a carbonyl group, and R ¹⁰ and R ¹¹ are the same or different and each is a hydrogen atom, a C _1-6 alkyl group which may have a substituent, or a C which may have a substituent. _1-6 alkoxy group, a halogen atom, a hydroxy group, R ¹² and R ¹³ are the same or different and are a hydrogen atom or a C _1-6 alkyl group which may have a substituent, and R ¹⁴ is a substituent. which may have a _{C 6-10} aryl , 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, and Y is C═O or C═S. And Z is NR ¹⁵ , an oxygen atom, a bond, an ethenylene group which may have a substituent or an ethynylene group, and R ¹⁵ is a hydrogen atom, a C _1-6 alkyl group which may have a substituent. The double line consisting of the solid line and the 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 is a C _1-6 alkyl group which may have a substituent or a C _3-6 cycloalkyl which may have a substituent. A C _1-6 alkyl group, R ² and R ³ are the same or different and are a C _1-6 alkyl group _optionally having a hydrogen atom or a substituent, and R ⁴ and R ⁵ are the same or different. It is a hydrogen atom or a C _1-6 alkyl group which may have a substituent, R ⁶ is a C _1-6 alkoxy group which may have a substituent or a hydroxy group, and R ⁷ is 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, wherein R ⁸ and R ⁹ are the same or different and each is a hydrogen atom. , optionally substituted C _1-6 alkyl group or Have a substituent is also a C _1-6 alkoxy group, R ¹⁰ and R ¹¹ are each independently hydrogen or optionally substituted C _1-6 alkyl radical, R ¹² and R ¹³ are the same or different and each is a hydrogen atom or a C _1-6 alkyl group which may have a substituent, and R ¹⁴ is a C _6-10 aryl group which may have a substituent, and a substituent. A heteroaryl group which may have a group or a cyclic amino group which may have a substituent, X is a nitrogen atom or an N-oxide, Y is C═O or C═S, Z is NR ¹⁵ , an oxygen atom, a bond or an ethenylene group which may have a substituent, R ¹⁵ is a hydrogen atom, a C _1-6 alkyl group which may have a substituent, and A double line composed of a broken line is a single bond or a double bond, and m is 0 or 1. A number, n represents include when an integer of 0-3.

Further, as a preferred embodiment of the compound (I) used in the present invention, R ¹ is a C _1-6 alkyl group which may have a substituent or a C _3-6 cycloalkyl which may have a substituent. A C _1-6 alkyl group, R ² and R ³ are the same or different and are a hydrogen atom or a C _1-6 alkyl group which may have a substituent, more preferably a hydrogen atom, and R ⁴ and R 3 ⁵ is a hydrogen atom, R ⁶ is a hydroxy group, R ⁷ is a hydrogen atom or a hydroxy group, and R ⁸ and R ⁹ are the same or different and may be a hydrogen atom or a C ₁ group which may have a substituent. _-6 alkyl group, more preferably a hydrogen atom, R ¹⁰ and R ¹¹ are the same or different, a hydrogen atom or a C _1-6 alkyl group _optionally having a substituent, more preferably a hydrogen atom, R ¹² and R ¹³ are the same or Differently, a hydrogen atom or a C _1-6 alkyl group which may have a substituent, more preferably a hydrogen atom, R ¹⁴ is a heteroaryl group which may have a substituent, and X is nitrogen. An atom, Y is C = O, Z is NR ¹⁵ or a bond, more preferably a bond, and R ¹⁵ is a hydrogen atom or a C _1-6 alkyl group _optionally having a substituent. And a double line consisting of a solid line and a broken line is a single bond, m is an integer of 0 or 1, and n is an integer of 0 or 1.

In the morphinan derivative represented by the general formula (I), the tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt is preferably acid addition. Examples of the acid addition salt include (a) salts with mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid, (ro) formic acid, acetic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid and maleic acid. Examples thereof include salts with organic carboxylic acids such as acids and tartaric acid, and (c) salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.

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

In the morphinan derivative represented by the above general formula (I), a tautomer, a stereoisomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, as a hydrate or a solvate. Can also exist. Accordingly, the compounds of this invention include all crystalline forms and hydrates or solvates thereof.

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

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

(In the formula, R ¹ to R ⁶ have the same meanings as described above.)

(First step)
1 to 10 equivalents of the starting material (a-1) and 2-chloroacrylonitrile are used as aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; dichloromethane, chloroform, tetra Halogenated hydrocarbons such as carbon chloride and 1,2-dichloroethane; alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin; acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide Etc. in an aprotic polar solvent in the presence or absence of a base such as sodium hydrogen carbonate, lithium carbonate, sodium carbonate or potassium carbonate at 80 to 190 ° C. for 3 to 24 hours, or in a sealed tube, By microwave synthesizer After reacting by irradiating Lee black wave, it is possible to synthesize a compound (a-2) by hydrolysis. 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 of lithium hydroxide, sodium hydroxide or potassium hydroxide aqueous solution and reacting at room temperature to under 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. Chem. Soc. C, 1969, 2569, J. Chem. Soc. Perkin Trans. It can be synthesized by the method described in I, 1994, 911.
(Second step)
Compound (a-2), aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; alcohols such as methanol, ethanol, 2-propanol; water, Solvents such as acetic acid; trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N, N in aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide or mixed solvents thereof. -Organic bases such as dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, sodium methoxide, sodium ethoxide; lithium carbonate, sodium carbonate, potassium carbonate Reacting with hydroxylamine (eg, hydroxylamine aqueous solution, hydroxylamine hydrochloride, hydroxylamine sulfate, etc.) in the presence of an inorganic base such as sodium hydroxide or potassium hydroxide at room temperature to under reflux for 1 to 24 hours. Thus, the compound (a-3) can be synthesized.
(Third step)
Compound (a-3), aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc. Aliphatic hydrocarbons such as pentane, hexane, heptane, and ligroin; potassium bis (trimethylsilyl) amide (KHMDS) in an aprotic polar solvent such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide or in the absence of solvent. Bases such as lithium diisopropylamide (LDA); trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N, N-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, die Triethanolamine, organic bases cyclohexylamine, procaine, such as sodium methoxide, sodium ethoxide; lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide in the presence of an inorganic base such as potassium hydroxide, L-Cl or L ₂ O After reacting with a reagent represented by (wherein L represents a methanesulfonyl group, a p-toluenesulfonyl group, a trifluoromethanesulfonyl group, a 2-nitrobenzenesulfonyl group, etc.) at -78 ° C to under heating under reflux for 1 to 24 hours. The compound (a-4) can be synthesized by hydrolysis. 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. An aprotic polar solvent such as sulfoxide; 1 to 6 equivalents or a solvent amount of 1 to 10 mol / L of an inorganic acidic aqueous solution such as hydrochloric acid or sulfuric acid is added to a solvent such as acetic acid or no solvent, and the mixture is heated at room temperature to under reflux. It can be carried out by reacting for 1 to 24 hours.
(Fourth step)
Compound (a-4) is converted to diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme or the like ether under a hydrogen atmosphere or in the presence of potassium formate (1 to 5 equivalents) or the like; alcohols such as methanol, ethanol or 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 Raney nickel, a palladium-activated carbon (Pd / C) and a Pearlman's catalyst (Pearlman's Catalyst: Pd (OH) ₂ ) Compound (a-5) can be synthesized by reacting at room temperature to reflux for 1 to 24 hours in the presence of a platinum catalyst such as a palladium catalyst or an Adams 'catalyst (Adams' Catalyst: PtO ₂ ).
(Fifth step)
Compound (a-5), aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; alcohols such as methanol, ethanol, 2-propanol; dichloromethane, Chloroform, carbon tetrachloride, etc., halogenated hydrocarbons; pentane, hexane, heptane, ligroin, etc., aliphatic hydrocarbons; acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, etc., aprotic polar solvent; acetic acid, etc. A hydride reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium tri (sec-butyl) borohydride, potassium tri (sec-butyl) borohydride in a solvent, 30 ℃ ~ heating under reflux Compound (a-6) can be synthesized by reacting under the conditions of 1 to 24 hours.
(Sixth step)
The compound (a-6) is heated at 0 ° C. to reflux with a reducing agent such as lithium aluminum hydride, borane-tetrahydrofuran complex or borane-dimethyl sulfide complex in ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme or diglyme. Compound (a-7) can be synthesized by reacting under the conditions of 1 to 24 hours.
(Seventh step)
Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride Aprotic polar solvent such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide; in a solvent such as water or a mixed solvent thereof, trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N, Organic bases such as N-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, sodium methoxide, sodium ethoxide; sodium hydrogen carbonate, lithium carbonate, sodium carbonate Compound (a-8) can be synthesized by reacting with benzyl chloroformate in the presence of an inorganic base such as lithium, potassium carbonate, sodium hydroxide or potassium hydroxide at 0 ° C. to room temperature for 1 to 24 hours. it can.
(Eighth process)
Compound (a-8) as aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc. Aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin; aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, potassium bis (trimethylsilyl) amide (KHMDS), lithium diisopropylamide ( LDA) and the like; trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N, N-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, Organic bases such as chlorhexylamine, procaine, sodium methoxide, sodium ethoxide, potassium tert-butoxide; lithium hydride, sodium hydride, potassium hydride, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, hydroxide Reacting with a reagent represented by L-Cl or L ₂ O (L is the same as above) in the presence of an inorganic base such as potassium at -78 ° C to under heating under reflux for 1 to 24 hours. Then, the compound (a-9) can be synthesized.
(9th step)
Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride Aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin; aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, potassium bis (trimethylsilyl) amide (KHMDS), lithium diisopropylamide ( LDA) and the like; trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N, N-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, Organic bases such as chlorhexylamine, procaine, sodium methoxide, sodium ethoxide, potassium tert-butoxide; lithium hydride, sodium hydride, potassium hydride, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, hydroxide The compound (a-10) of the invention can be synthesized by reacting with an inorganic base such as potassium at -78 ° C to under reflux with heating for 1 to 24 hours.
(10th process)
In a hydrogen atmosphere, the invention compound (a-10) is treated with an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; an alcohol such as methanol, ethanol, 2-propanol; a solvent such as water or acetic acid, or a mixture thereof. In a solvent, a metal catalyst, for example, a nickel catalyst such as Raney nickel, a palladium catalyst such as palladium-activated carbon (Pd / C) and Pearlman's catalyst (Pearlman's Catalyst: Pd (OH) ₂ ), or an Adams catalyst (Adams' Catalyst: Inventive compound (a-11) can be synthesized by reacting in the presence of a platinum catalyst such as PtO ₂ ) at room temperature to under reflux for 1 to 24 hours.
(Eleventh step)
When R ⁶ is a C _1-6 alkoxy group, the invention compound (a-11) is treated with halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; organic solvents such as acetic acid and ethyl acetate; aprotons such as acetonitrile. In a polar solvent or without solvent, it is reacted with boron tribromide, trimethylsilyl iodide, hydrogen bromide, pyridinium hydrochloride or the like at -30 to 180 ° C for 30 minutes to 5 hours, or N, N-dimethylformamide, 100-180 ° C. of 1-propanethiol, 1-dodecanethiol and the like in the presence of an organic base such as potassium tert-butoxide and sodium tert-butoxide in an aprotic polar solvent such as dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide. The compound of the invention (a-12) is obtained by reacting at 30 ° C. for 30 minutes to 24 hours. It is possible to obtain.
(Twelfth step)
When R ⁶ is a C _1-6 alkoxy group, the invention compound (a-13) can be obtained by subjecting the invention compound (a-10) to the same reaction as in the eleventh step.
(13th process)
The invention compound (a-12) can be obtained by carrying out the same reaction as the tenth step on the invention compound (a-13).
The compound (a-5) can also be synthesized by the method described below.

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

(First step)
Compound (a-2) is converted to diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme or the like ether under a hydrogen atmosphere or in the presence of potassium formate (1 to 5 equivalents) or the like; alcohols such as methanol, ethanol or 2-propanol; In a solvent such as water or acetic acid or a mixed solvent thereof, a metal catalyst, for example, a nickel catalyst such as Raney nickel, palladium-activated carbon (Pd / C) and palladium such as 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 under reflux for 1 to 24 hours.
(Second step)
Compound (a-15) can be synthesized in the same manner as the second step in the synthesis of compound (a-3) from compound (a-2).
(Third step) and (Fourth step)
Compound (a-15) and compound (a-5) are synthesized in the same manner as the third step in the synthesis of compound (a-4) from compound (a-3). You can

(Method A-2) In the general formula (I), Y is a carbonyl group (C = O) or thiocarbonyl group (C = S), Z is a bond or an ethenylene group which may have a substituent or ethynylene. When the group m is 1, the invention compounds (a-19) to (a-22) can be obtained by the methods described below.

(In the formula, M is a halogen atom, Z is a bond, an ethenylene group which may have a substituent or an ethynylene group, and R ¹ to R ⁶ , R ¹² to R ¹⁴ , Y and n are the same as those described above. Show the one.)

(First step)
Inventive compound (a-11) obtained by (Method A-1) is supplemented with aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme: dichloromethane, chloroform, Halogenated hydrocarbons such as carbon tetrachloride: Alcohols such as methanol and ethanol; Aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin; Aprotic substances such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, etc. In a polar solvent, the acid halide represented by (a-18) was treated with N, N-dimethylaminopyridine, trimethylamine, triethylamine, tributylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaniline, N- Methylpiperidine Organic bases such as N-methylmorpholine, diethylamine, cyclohexylamine, and procaine: In the presence or absence of an inorganic base such as potassium carbonate and lithium carbonate, the reaction is performed at 0 ° C. to reflux under heating for 1 to 12 hours, or a-17), a carboxylic acid represented by O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU), O- (Benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU), N, N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (WSC), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4- Inventive compound (a-19) is synthesized by reacting at 0 ° C. to under reflux for 1 to 12 hours in the presence or absence of a condensing agent such as methylmorpholinium chloride n hydrate (DMT-MM). can do. Inventive compound (a-19) is aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; halogenated carbonization such as dichloromethane, chloroform and carbon tetrachloride. Hydrogen: In an aliphatic hydrocarbon such as pentane, hexane, heptane, ligroin, etc., using a generally known sulfidizing agent such as diphosphorus pentasulfide, Lawesson's reagent, Davy's reagent, Japanese reagent, Bereau's reagent, etc., heating at 0 ° C to reflux. The compound (a-20) of the invention can be converted by reacting under the condition of 1 to 12 hours.
(Second step)
When R ⁶ is a C _1-6 alkoxy group, the compound of the present invention (a-19) or (a-20) is subjected to a reaction similar to the eleventh step of (Method A-1) to give the compound of the present invention ( a-21) or (a-22) can be obtained, respectively.

(Method A-3) When Y is a carbonyl group (C═O), Z is NR ¹⁵ or an oxygen atom, and m is 1 in the general formula (I), the compound of the invention (a-23) is prepared by the method described below. , (A-24) and (a-27) to (a-28) can be obtained.

(In the formula, Z represents NR ¹⁵ or an oxygen atom, A in the methylating agent (Me-A) represents halogen, trifluoromethanesulfonate, etc., A ⁻ represents its counter anion, R ¹ to R ⁶ , R ¹² to R ¹⁵ , Z and n are the same as above.)

(First step)
Inventive compound (a-11) obtained by (Method A-1), aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme: dichloromethane, chloroform , Halogenated hydrocarbons such as carbon tetrachloride: alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin; aprotons such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide In polar polar solvent, N, N-dimethylaminopyridine, trimethylamine, triethylamine, tributylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylami , Cyclohexylamine, procaine, etc .: Inventive compound (a-23) is obtained by reacting carbonyldiimidazole in the presence of an inorganic base such as potassium carbonate, lithium carbonate, etc. at 0 ° C. to under reflux for 1 to 12 hours. Can be synthesized.
(Second step)
Inventive compound (a-23) includes aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme: halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride. Kinds: Alcohols such as methanol and ethanol; Aliphatic hydrocarbons such as pentane, hexane, heptane and ligroin; N, N-dimethyl in aprotic polar solvents such as acetonitrile, N, N-dimethylformamide and dimethylsulfoxide Aminopyridine, trimethylamine, triethylamine, tributylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine Organic base such as procaine: In the presence or absence of an inorganic base such as potassium carbonate or lithium carbonate, a methylating agent such as methyl iodide, dimethyl sulfate, trifluoromethanesulfonate, meerwein reagent is heated at 0 ° C. to reflux under heating. The compound (a-24) of the invention can be synthesized by reacting for 12 to 48 hours.
(Third step)
Inventive compound (a-24), aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc. Aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin; N, N-dimethylaminopyridine, trimethylamine, triethylamine, N, in aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide Organic bases such as N-diisopropylethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine and procaine: potassium carbonate, charcoal The compound of the invention is obtained by reacting the amine represented by (a-25) or the alcohol represented by (a-26) in the presence of an inorganic base such as lithium at 0 ° C. to under reflux for 1 to 12 hours. (A-27) can be synthesized.
(Fourth 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.

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

(First step)
Inventive compound (a-11) obtained by (Method A-1), aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme: dichloromethane, chloroform , Halogenated hydrocarbons such as carbon tetrachloride: alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin; aprotons such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide Polar solvent; in a solvent such as acetic acid or in a mixed solvent thereof, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, tri (sec-butyl) borohydride lithium, trihydride (sec) -Butyl) potassium borohydride reduction Under the presence, it can be synthesized by reacting for 1-12 hours the aldehyde represented under 0 ° C. ~ heated to reflux (a-23), Compound (a-30).
(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 is a C _6-10 aryl group or heteroaryl group which may have a substituent: Invention compounds (a-32) to (a-33) can be obtained by the method described.

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

(First step)
Inventive compound (a-11) obtained by (Method A-1), aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme: dichloromethane, chloroform , Halogenated hydrocarbons such as carbon tetrachloride: alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin; aprotons such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide In a polar solvent or a mixed solvent thereof,
In the presence of a palladium catalyst such as tetrakistriphenylphosphine palladium (0), palladium (II) acetate, bis (dibenzylideneacetone) 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 (dppf), 2-dicyclohexylphos Phino-2 ′, 4 ′, 6′-triisopropylbiphenyl (Xphos), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (Sphos), 4,5′-bis (diphenylphosphino) -9, In the presence of a phosphorus ligand such as 9'-dimethylxanthene (xantphos) In the absence of N, N-dimethylaminopyridine, trimethylamine, triethylamine, tributylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, Organic bases such as procaine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide; in the presence or absence of bases such as inorganic bases such as potassium carbonate and lithium carbonate, B-hal and room temperature to The compound (a-32) of the invention can be synthesized by reacting under heating under reflux for 1 to 24 hours.
(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 taken together to form a carbonyl group (C═O), R ¹⁰ and R ¹¹ are hydrogen atoms, X is a nitrogen atom, and a solid line. Inventive Compounds (b-1) to (b-2) can be obtained by the method described below when the double line consisting of and the broken line is a single bond.

(In the formula, R ¹ to R ⁶ have the same meanings as described 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 hydrolysis with an acid, for example, ethers such as tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, N, N-dimethylformamide and dimethylsulfoxide; acetic acid and the like. 1 to 6 equivalents or a solvent amount of 1 to 12 mol / L of an inorganic acidic aqueous solution such as hydrochloric acid or sulfuric acid in the mixed solvent or solvent-free solvent, and reacted at room temperature to under reflux for 1 to 24 hours This can be done by In the case of hydrolysis with a base, for example, ethers such as tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and 2-propanol; an aprotic polar solvent such as dimethyl sulfoxide; a solvent such as water or a mixed solvent thereof. In addition, 1 to 6 equivalents of an inorganic base such as sodium hydroxide or potassium hydroxide or an aqueous solution thereof can be reacted at room temperature to under reflux for 1 to 24 hours.
(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) Production method in which R ⁷ is a hydroxy group, R ⁸ to R ¹¹ are hydrogen atoms, X is a nitrogen atom in the general formula (I), and a double line consisting of a solid line and a broken line is a single bond Invention compounds (c-1) to (c-3) can be obtained by the method described above.

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

(First step)
Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme to the invented compound (b-1) obtained by (Method B): dichloromethane, chloroform, tetra Halogenated hydrocarbons such as carbon chloride: In aliphatic hydrocarbons such as pentane, hexane, heptane, and ligroin, a borane-dimethyl sulfide complex, borane-tetrahydrofuran complex tetrahydrofuran solution or a reducing agent such as lithium aluminum hydride at room temperature is used. The invention compound (c-1) can be synthesized by reacting under heating to reflux for 2 to 24 hours.
(Second step)
The compound (c-2) of the invention can be synthesized by carrying out the same reaction as the method described in (Method A-2) to (Method A-5) on the compound (c-1) of the invention. it 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), R ⁷ to R ¹¹ are hydrogen atoms, X is a nitrogen atom, Y is a sulfonyl group (SO ₂ ), a double line consisting of a solid line and a broken line is a single bond, and m is 1. Case manufacturing method

(In the formula, Z represents a bond, an ethenylene group or an ethynylene group, and R ¹ to R ⁶ , R ¹² to R ¹⁴ , n and hal are the same as above.)

(First step)
Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; and dichloromethane, chloroform, Halogenated hydrocarbons such as carbon tetrachloride; aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin; aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, (a-1 ) Is a sulfonyl chloride represented by N, N-dimethylaminopyridine, trimethylamine, triethylamine, tributylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine. , Shi Organic bases such as lohexylamine and procaine: Inventive compound (d-1) by reacting in the presence or absence of an inorganic base such as potassium carbonate and lithium carbonate at 0 ° C. to reflux under heating for 1 to 12 hours. Can be synthesized.
(Second step)
When R ⁶ is a C _1-6 alkoxy group, the invented compound (d-2) can be obtained from the invented compound (d-1) in the same manner as in the eleventh step of (Method A-1).

Further, the substituent of the sulfonylamide of the invention compound (d-1) is represented by Ar, and the invention compound (d-4) in which Ar is a 2-nitrophenyl group or a 2,4-dinitrophenyl group is Can also be synthesized. Further, the invented compound (d-4) can be converted to the invented compound (a-11) in one step.

(In the formula, Ar represents a 2-nitrophenyl or 2,4-dinitrophenyl group, and R ¹ to R ⁶ and hal are the same as above.)

(First step)
Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; Halogenated hydrocarbons such as carbon tetrachloride; Aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin; 2-Nitrobenzenesulfonyl in aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, etc. Chloride or 2,4-dinitrobenzenesulfonyl chloride was added to N, N-dimethylaminopyridine, trimethylamine, triethylamine, tributylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaniline, N-methylpipette. Organic bases such as gin, N-methylmorpholine, diethylamine, cyclohexylamine and procaine: by reacting in the presence or absence of an inorganic base such as potassium carbonate or lithium carbonate at 0 ° C. to reflux under heating for 1 to 12 hours , Compound (d-3) can be synthesized.

(Second step)
Compound (d-3) with aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride; Aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin; trialkylphosphines such as tritert-butylphosphine and triphenylphosphine in aprotic polar solvents such as acetonitrile, N, N-dimethylformamide and dimethylsulfoxide, or Inventive compound (d-4) is obtained by reacting diethyl azodicarboxylate, diisopropyl azodicarboxylate and ditert-butyl azodicarboxylate in the presence of triarylphosphines at 0 ° C. to under reflux for 1 to 12 hours. It can be synthesized.

(Third step)
The compound (d-4) of the invention is treated with an organic base such as potassium tert-butoxide or sodium tert-butoxide in an aprotic polar solvent such as N, N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone or dimethylsulfoxide; By reacting 1-propanethiol, 1-dodecanethiol, thiophenol, 4-mercaptobenzoic acid, etc. at room temperature to 180 ° C. for 30 minutes to 24 hours in the presence of an inorganic base such as potassium, lithium carbonate or sodium carbonate. Inventive compound (a-11) can be obtained.

(Method E) Production method in the case where X is N oxide and the double line consisting of a solid line and a broken line is a single bond in the general formula (I), the compound (e-2) of the invention can be obtained by the method described below. it can.

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

(First step)
The compound (e-1) of the invention obtained by the method described in the above (Method A-1) to (Method A-5), (Method B), (Method C) and (Method D) was diluted with dichloromethane, chloroform and In a halogenated hydrocarbon solvent such as carbon tetrachloride, 1 to 2 equivalents of an aqueous solution of hydrogen peroxide (H ₂ O ₂ ) or m-chloroperbenzoic acid (mCPBA) is added at 0 ° C. to room temperature for 30 minutes or more. The compound (e-2) of the invention can be synthesized by reacting for 24 hours.

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 compound (I) of the invention can be prepared by dissolving the compound (I) in an organic solvent such as ethyl acetate: an alcohol such as methanol or 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 benzenesulfone. It is carried out by heating at room temperature or appropriately in the presence of an acid, an organic sulfonic acid such as p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.

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

Examples of solid preparations 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 the excipient, lactose, D-mannitol, crystalline cellulose, glucose and the like, as the disintegrant, starch, carboxymethyl cellulose calcium (CMC-Ca) and the like, and as the lubricant, magnesium stearate, Talc or the like, and 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. The tablets and pills may be enteric coated.

Examples of the form of the composition of the present invention for injection include pharmaceutically acceptable sterile water or non-aqueous solution, suspension or emulsion. Examples of suitable non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. Such compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, soothing agents, buffers, preservatives and dispersing agents.
These compositions are reduced, for example, by filtration through a bacteria-retaining filter, or by incorporating the sterilant in the form of a sterile solid composition which may be dissolved in the sterilant or some other sterile injectable medium immediately before use. Can be fungi.

The formulation for eye drop administration may preferably contain a solubilizing agent, a preservative, an isotonicity agent, a thickening agent and the like in addition to the compound of the present invention.

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

Formulations for rectal administration may preferably contain, in addition to a compound of this invention, an excipient such as cocoa butter or a suppository wax.

The dose is usually, in adults, the morphinan derivative represented by the above general formula (I) which is an active ingredient, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. The solvate is 0.01 μg to 1 g / day, preferably 0.0001 to 200 mg / day for an injection, and 0.1 μg to 10 g / day for an oral administration, preferably 0.001 to 2000 mg / day. It is administered, but it can be increased or decreased depending on the age, symptoms and the like. If desired, this daily dose can be divided into 2 to 4 divided doses for administration.

Examples of diseases and symptoms related to κ opioid receptors include cardiovascular disorders, digestive system disorders, blood system disorders, respiratory system disorders, liver disorders, nervous system disorders, urinary system disorders, pain, cough, pruritus, Examples include ischemic brain disease and drug dependence. Since the compound of the present invention has a high κ opioid receptor selectivity and a strong agonist activity to the κ opioid receptor, it is effective in treating, ameliorating and preventing 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-ethano-4,12- Synthesis of methanobenzofuro [3,2-e] isoquinolin-14-one (1)

(Method a)
(4R, 7aR, 12bS) -3- (Cyclopropylmethyl) -7,9-dimethoxy-2,3,4,7a-tetrahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinoline (J. 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 63 mmol) in 1,2-dichloroethane (10 mL) was placed in a vial for microwave reaction, 2-chloroacrylonitrile (4.5 mL, 56.6 mmol) was added, and three sealed ones were prepared. Microwave synthesizer was used to irradiate each with microwave, and the reaction was performed for 30 minutes under the conditions of 180 ° C. and 10 bar. After cooling, 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), 1M aqueous sodium hydroxide solution (36 mL) was added, and the mixture was heated under reflux for 3 hr. 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.

(Method b)
(4R, 7aR, 12bS) -3- (Cyclopropylmethyl) -7,9-dimethoxy-2,3,4,7a-tetrahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinoline (19 g, Sodium hydrogen carbonate (42 g, 540 mmol) and 2-chloroacrylonitrile (34.4 mL, 432 mmol) were added to a xylene (180 mL) solution of 54 mmol), 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 obtain the title compound (15.2 g, 71%) as a pale yellow solid.

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 = 3,13 Hz, 1H), 2.07 (ddd, J = 5, 13, 13 Hz, 1H), 2.17 (d, J = 19 Hz, 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 = 9 Hz, 1 H), 5.88-5.93 (m, 1 H), 6.57 (d, J = 8 Hz, 1 H), 6.66 (d, J = 8 Hz, 1) ).

(Reference example 2)
(4R, 4aR, 7R, 7aR, 12bS) -3- (Cyclopropylmethyl) -7,9-dimethoxy-1,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12- Synthesis of methanobenzofuro [3,2-e] isoquinolin-14-one oxime (2)

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) in ethanol (116 mL) / water. The (58 mL) mixed solution was heated under reflux for 5.5 hours. The reaction mixture was allowed to cool, concentrated under reduced pressure, 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 to obtain a crude product of the title compound (7.22 g, quantitative) as a pale yellow solid.

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, 13 Hz, 1H), 2.02 (ddd, J = 6, 13, 13 Hz, 1H), 2.10 (d, J = 18 Hz, 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 = 9 Hz, 1H), 6.00 (dd, J = 1, 9 Hz, 1H), 6.54 (d, J = 8 Hz, 1H), 6.63 (d, J = 8) z, 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-methanobenzofuro Synthesis of [3,2-e] isoquinolin-4a-yl) acetonitrile (3)

To a solution of compound 2 (700 mg, 1.71 mmol) in dichloromethane (6 mL) under ice cooling, triethylamine (477.7 μL, 3.43 mmol) and methanesulfonyl chloride (265.3 μL, 3.43 mmol) were added, and the mixture was added at room temperature to 20. 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 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution to make it basic, and 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 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 = 17 Hz, 1H), 3.14 (d, J = 16 Hz, 1H), 3.38 (d, J = 5 Hz, 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 = 11 Hz, 1H), 6.69 (d, J = 8 Hz, 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-Methanobenzofuro [3,2-e] isoquinolin-4a-yl) acetonitrile (4)

To a mixed solution of compound 3 (5.64 g, 15 mmol) in ethanol (150 mL) / tetrahydrofuran (150 mL) was added 10% palladium-activated carbon (55% wet) (1.5 g), and the mixture was kept under a hydrogen atmosphere at room temperature for 4 hours. It was 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.

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, 14 Hz, 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 0.02 (d, J = 18 Hz, 1H), 3.35 (d, J = 6 Hz, 1H), 3.89 (s, 3H), 4.09 (dd, J = 1, 16 Hz, 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 Synthesis of -4,12-methanobenzofuro [3,2-e] isoquinolin-4a-yl) acetonitrile (5)

A 1M L-selectride-tetrahydrofuran solution (5.3 mL, 5.28 mmol) was added to a tetrahydrofuran (26 mL) solution of compound 4 (1 g, 2.64 mmol), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The combined extracts were dried over sodium sulfate and 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 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 = 6 Hz, 1 H), 3.87 (s, 3 H), 3.99-4.06 (m, 2 H), 4.60 (d, J = 5 Hz, 1 H), 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-methanobenzofuro [3,2-e] isoquinolin-4a-yl) ethyl) carbamate (6)

A 0.94 M borane-tetrahydrofuran solution (15.1 mL, 14.2 mmol) was added to a tetrahydrofuran (28 mL) solution of compound 5 (1.08 g, 2.84 mmol), 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 with ethyl acetate three times. 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.

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 0.75-2.85 (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, = 12 Hz, 1 H), 5.38 (br s, 1 H), 6.60 (d, J = 8 Hz, 1 H), 6.71 (d, J = 8 Hz, 1 H), 7.27-7.40 ( m, 5H).

(Reference example 7)
(4R, 4aS, 7S, 7aR, 12bS) -4a- (2-(((benzyloxy) carbonyl) amino) ethyl) -3- (cyclopropylmethyl) -9-methoxy-2,3,4,4a, Synthesis of 5,6,7,7a-octahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinolin-7-yl methanesulfonate (7)

Triethylamine (598.7 μL, 4.29 mmol) and methanesulfonyl chloride (331.3 μL, 4.29 mmol) were added to a dichloromethane (21 mL) solution of compound 6 (1.11 g, 2.14 mmol), 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.

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 = 8 Hz, 1H), 6.72 (d, J = 8 Hz, 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxylate (8)

Potassium tert-butoxide (39 mg, 0.35 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 7 (173 mg, 0.29 mmol), 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.

¹ H-NMR (400 MHz, 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 = 6 Hz, 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).

(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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (9)

To a solution of compound 8 (614.9 mg, 1.23 mmol) in methanol (12 mL) was added 20% palladium hydroxide-activated carbon (50% wet) (120 mg), 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 H-NMR (400 MHz, 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, 12 Hz, 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 Synthesis of -4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (1H-imidazol-1-yl) methanone (10)

A solution of Compound 9 (155 mg, 0.42 mmol) in N, N-dimethylformamide (4 mL) was added with N, N-diisopropylethylamine (368.3 μL, 2.11 mmol) and carbonyldiimidazole (342.9 mg, 2.11 mmol). 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 with saturated aqueous sodium hydrogen carbonate solution three times. 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 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 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carbonyl) -3-methyl-1H-imidazol-3-ium iodide (11)

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. The obtained concentrated residue was not purified, and a crude product of the title compound (255.4 mg, quantitative) was obtained as a colorless amorphous substance.

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, 18 Hz, 1H), 2.65 (d, J = 8 Hz, 1H), 2.86-2.99 (m, 1H), 2.99 (D, J = 18 Hz, 1H), 3.10 (d, J = 6 Hz, 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 = 8 Hz, 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)

To a solution of tert-butyl (2-formylpyridin-3-yl) carbamate (134 mg, 0.60 mmol) in methanol (1.5 mL) was added a 2M methylamine-methanol solution (0.36 mL, 0.72 mmol) under ice cooling. In addition, it stirred at room temperature for 2.5 hours. Sodium borohydride (34.7 mg, 0.92 mmol) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 3.5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform three times. The combined extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained concentrated residue was not purified, and a crude product of the title compound (145 mg, quantitative) was obtained as a pale yellow oil.

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

(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-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxamido) methyl) pyridin-3-yl) carbamate (13) Synthesis of

A tetrahydrofuran (1.5 mL) solution of compound 11 (15 mg, 0.025 mmol), compound 12 (12.3 mg, 0.052 mmol) and triethylamine (21 μL, 0.15 mmol) 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 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, 14 Hz, 1H), 3.54 (ddd, J = 4, 4, 14 Hz, 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, 8 Hz, 1H), 8.20 (dd, J = 1, 4 Hz, 1H), 8.42 (d, J = 8 Hz, 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (14) Synthesis of

Trifluoroacetic acid (0.5 mL) was added to a dichloromethane (1 mL) solution of compound 13 (16.1 mg, 0.025 mmol) under ice cooling, 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 3 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 H-NMR (400 MHz, 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, 14 Hz, 1H), 3.55 (ddd, J = 4, 4, 14 Hz, 1H), 3.87 (s, 3H), 4.09-4.12 (m, 1H) , 4.51 (d, J = 14 Hz, 1H), 4.60 (d, J = 14 Hz, 1H), 4.61 (s, 1H), 6.60 (d, J = 8 Hz, 1H), 6 ． 3 (d, J = 8 Hz, 1H), 7.26 (dd, J = 5, 8 Hz, 1H), 8.25 (dd, J = 1, 5 Hz, 1H), 8.71 (dd, J = 1) , 8 Hz, 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-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (15) Synthesis of

To a solution of compound 14 (9.8 mg, 0.017 mmol) in dichloromethane (1.5 mL) was added 1M 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 H-NMR (400 MHz, 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, 14 Hz, 1H), 3.55 (ddd, J = 4, 4, 14 Hz, 1H), 4.06-4.09 (m, 1H), 4.53 (d, J = 14 Hz, 1 H), 4.60 (s, 1 H), 4.64 (d, J = 14 Hz, 1 H), 6.53 (d, J = 8 Hz, 1 H), 6.70 (d, J = 8 Hz, H), 7.27 (dd, J = 5, 8 Hz, 1H), 8.26 (dd, J = 1, 5 Hz, 1H), 8.74 (dd, J = 1, 8 Hz, 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 Of 6,6,8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (16)

To a solution of compound 11 (13.8 mg, 0.023 mmol) and 1- (2-fluoro-6-methoxyphenyl) -N-methylmethanamine (11.6 mg, 0.069 mmol) in dichloromethane (1 mL) was added triethylamine (9 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 dichloromethane (1 mL) solution of the obtained crude product 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 H-NMR (400 MHz, 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 = 6 Hz, 1H), 3.38-3.47 (m, 1H), 3.55-3.62 (m, 1H), 4.05 (br s, 1H), 4.35 (d, J = 15 Hz, 1H), 4.45 (d, J = 15 Hz, 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) picolinaldehyde (17)

A solution of 6- (trifluoromethyl) pyridin-2-yl) methanol (synthesized by the method described in WO2010059393) (944 mg, 5.28 mmol) in ethyl acetate (20 mL) was added to manganese dioxide (4.62 g, 53.1 mmol). ) 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 H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.93 (dd, J = 1, 8 Hz, 1 H), 8.10 (dd, J = 8, 8 Hz, 1 H), 8.16 (dd , J = 1,8 Hz, 1H), 10.1 (s, 1H).

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

According to the method described in Reference Example 8, the title compound was obtained from compound 17.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.45 (s, 3H), 3.95 (s, 2H), 7.53 to 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-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxamide ( 19) Synthesis

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

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 = 17 Hz, 1H), 4.56 (d, J = 17 Hz, 1H), 4.60 (s, 1H), 6.48 (d, J = 8 Hz, 1H), 6.73 (d, J = 8 Hz) , 1H), 7. 6 (dd, J = 8,8Hz, 2H), 7.82 (dd, J = 8,8Hz, 1H).

(Reference example 11)
Synthesis of 2-((methylamino) methyl) pyridin-3-ol (20)

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

¹ H-NMR (400 MHz, 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).

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

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

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 = 14 Hz, 1H), 4.63 (d, J) = 14 Hz, 1H), 4.65 (s, 1H), 6.53 (d, J = 8 Hz, 1H), 6.71 (d, J = 8 Hz, 1H), 7.18 (dd, J = 5) , 8Hz, 1H), .25-7.28 (m, 1H), 8.06 (dd, J = 1,5Hz, 1H), 11.5 (br s, 1H).

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

A solution of tert-butyl (pyrimidin-2-ylmethyl) carbamate (synthesized by the method described in WO2013013238) (494 mg, 2.36 mmol) in N, N-dimethylformamide (8 mL) was added with sodium hydride (55%) under ice cooling. Oil dispersion) (126 mg, 2.89 mmol) was added and 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 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- (pyrimidin-2-yl) methanamine dihydrochloride (23)

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

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- (pyrimidin-2-ylmethyl) -1,2,3,4,5,6,6 Synthesis of 8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (24)

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

¹ H-NMR (400 MHz, 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 = 17 Hz, 1 H), 2.96 (s, 3 H), 3.01 (d, J = 6 Hz, 1 H), 3.42 (ddd, J = 4, 11, 14 Hz, 1 H), 3.73. (Ddd, J = 4,5,14 Hz, 1H), 4.10-4.15 (m, 1H), 4.58 (d, J = 17 Hz, 1H), 4.65 (d, J = 17 Hz, 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 = 5 Hz, 2H).

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

According to the method described in Example 8, the title compound was obtained from compound 11 and N-methyl-1- (pyrimidin-4-yl) methanamine dihydrochloride.
¹ H-NMR (400 MHz, 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- (pyrimidin-5-ylmethyl) -1,2,3,4,5,6,6 Synthesis of 8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (26)

According to the method described in Example 8, the title compound was obtained from compound 11 and N-methyl-1- (pyrimidin-5-yl) methanamine dihydrochloride.

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), 1.02-1.13 (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, 5,14 Hz, 1H), 4.03-4.07 (m, 1H), 4.34 (d, J = 16 Hz, 1H), 4.38 (d, J = 16 z, 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 (pyrazin-2-ylmethyl) carbamate (27)

According to the method described in Reference Example 12, the title compound was obtained from tert-butyl (pyrazin-2-ylmethyl) carbamate (synthesized by the method described in WO201212422).

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- (pyrazin-2-yl) methanamine dihydrochloride (28)

According to the method described in Reference Example 13, the title compound was obtained from compound 27.

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

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

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

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 = 19 Hz, 1H), 3.03 (d, J = 6 Hz, 1H), 3.42 (ddd, J = 4, 12, 15 Hz, 1H), 3.69. (Ddd, J = 4, 4, 14 Hz, 1H), 4.04-4.10 (m, 1H), 4.53 (s, 2H), 4.63 (s, 1H), 5.47 (br s, 1H) 6.52 (d, J = 8 Hz, 1H), 6.70 (d, J = 8 Hz, 1H), 8.50 (d, J = 3 Hz, 1H), 8.53-8.55 (m, 1H) ), 8.68 (s, 1H).

(Reference Example 16)
Synthesis of N-methyl-1- (pyridazin-3-yl) methanamine (30)

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

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 = 2,8 Hz, 1H) 9.11 (dd, J = 2.5 Hz, 1H).

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

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

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 = 6 Hz, 1H), 3.42 (ddd, J = 4, 11, 14 Hz, 1H), 3.63 (ddd, J = 4, 4, 14 Hz, 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 ( , J = 8 Hz, 1 H), 6.71 (d, J = 8 Hz, 1 H), 7.49 (dd, J = 5, 9 Hz, 1 H), 7.71 (dd, J = 2, 9 Hz, 1 H) , 9.12 (dd, J = 2.5 Hz, 1H).

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

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

¹ H-NMR (400 MHz, 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 = 19 Hz, 1H), 2.98 (d, J = 6 Hz, 1H), 3.18-3.49 (m, 1H), 3.52-3.63 (m, 1H), 3.89 (s , 1H), 4.03 (d, J = 16 Hz, 1H), 4.08 (d, J = 16 Hz, 1H), 4.49 (s, 1H), 6.13 (d, J = 7 Hz, 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) methanamine (33)

According to the method described in Reference Example 8, from 1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole-2-carbaldehyde (synthesized by the method described in Journal of Organic Chemistry 2006, 71, 8807) The compound was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): −0.01 (s, 9H), 0.90 (t, J = 8 Hz, 2H), 2.44 (s, 3H), 3.50 (T, J = 8 Hz, 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-methanobenzofuro [2,3-c] pyrido [4,3 Synthesis of -d] azepine-7-carboxamide (34)

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

¹ H-NMR (400 MHz, 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 = 18 Hz, 1H), 3.03 (d, J = 6 Hz, 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 = 15 z, 1H), 4.60-4.70 (m, 1H), 5.34 (d, J = 10 Hz, 1H), 5.37 (d, J = 10 Hz, 1H), 6.58 (d, J = 8 Hz, 1H), 6.71 (d, J = 8 Hz, 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 Of 5,5,6,8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (35)

According to the method described in Example 7, the title compound was obtained from compound 34.

¹ H-NMR (400 MHz, 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) , 12 Hz, 1 H), 3.60-3.70 (m, 1 H), 4.00-4.10 (m, 1 H), 4.19 (d, J = 15 Hz, 1 H), 4.41 (d , J = 15 Hz, 1H), 4.60-4.70 (m, 1H), 6.54 (d, J = 8 Hz, 1H), 6.73 (d, J = 8 Hz, 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (36 ) Synthesis

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

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 = 12 Hz, 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 = 5 Hz, 1H), 3.39 (dt, J = 4, 11 Hz, 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 = 5 Hz, 1 H), 4.58-4.62 (m, 1 H), 6.58 (d, J = 8 Hz, 1 H), 6.72 (d, J = 8 Hz, 1 H), 6.85 (d, J = 1 Hz, 1H), 6.96 (d, J = 1 Hz, 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (37 ) Synthesis

According to the method described in Example 7, the title compound was obtained from compound 36.

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 = 14 Hz, 1H), 4.51 (d, J = 14 Hz, 1H), 4.61 (s, 1H), 6.52 (d, J = 8 Hz, 1H), 6.70 (d, J = 8 Hz, 1H), 6.86 (d, J = 1 Hz, 1H), 6.97 (d, J = 1 Hz, 1H).

(Example 21)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-methoxy-N-methyl-N-((1-methyl-1H-pyrazol-3-yl) methyl) -1,2 , 3,4,5,6,8,8a-Octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (38 ) Synthesis

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

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, 14 Hz, 1H), 3.65 (ddd, J = 4, 4, 14 Hz, 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-pyrazol-3-yl) methyl) -1,2 , 3,4,5,6,8,8a-Octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (39 ) Synthesis

According to the method described in Example 7, the title compound was obtained from compound 38.

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, 14 Hz, 1H), 3.68 (ddd, J = 4, 4, 14 Hz, 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- (oxazol-2-yl) methanamine (40)

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

¹ H-NMR (400 MHz, 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- (oxazol-2-ylmethyl) -1,2,3,4,5,6,6 Synthesis of 8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (41)

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

¹ H-NMR (400 MHz, 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, 14 Hz, 1 H), 3.68 (ddd, J = 4, 4, 14 Hz, 1 H), 3.87 (s, 3 H), 4.09-4.12 (m, 1 H) , 4.44 (d, J = 16 Hz, 1H), 4.49 (d, J = 16 Hz, 1H), 4.64-4.65 (m, 1H), 6.58 (d, J = 8 Hz, 1 ), 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- (oxazol-2-ylmethyl) -1,2,3,4,5,6,6 Synthesis of 8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (42)

According to the method described in Example 7, the title compound was obtained from compound 41.

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 to 1.09 (m, 1H), 1.24 to 1.72 (m, 5H), 2.20 to 2.39 (m, 5H), 2.60 to 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 = 8 Hz, 1H), 6.70 (d, J = 8 Hz, 1H), 7.10 (s, 1H), 7.65 (s, 1H).

(Reference Example 19)
Synthesis of N-methyl-1- (oxazol-4-yl) methanamine (43)

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

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

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

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

¹ H-NMR (400 MHz, 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, 14 Hz, 1H), 4.06-4.11 (m, 1H), 4.22 (d, J = 16 Hz, 1H), 4.28 (d, J = 16 Hz, 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- (thiazol-2-ylmethyl) -1,2,3,4,5,6,6 Synthesis of 8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (45)

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

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, 14 Hz, 1H), 3.67 (ddd, J = 4, 4, 14 Hz, 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- (thiazol-2-ylmethyl) -1,2,3,4,5,6,6 Synthesis of 8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (46)

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

¹ H-NMR (400 MHz, 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), 1.6-1.72. (M, 1H), 2.21-2.42 (m, 5H), 2.60-2.67 (m, 1H), 2.84-2.92 (m, 4H), 2.96 (d , J = 18 Hz, 1 H), 3.05 (d, J = 6 Hz, 1 H), 3.45 (ddd, J = 4, 11, 14 Hz, 1 H), 3.67-3.74 (m, 1 H) , 4.09-4.12 (m, 1H), 4.61-4.70 (m, 3H), 6.53 (d, J = 8Hz, 1H), 6.71 (d, J = 8Hz, 1H), 7.3 (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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxylate (47)

To a solution of compound 8 (14 mg, 0.028 mmol) in dichloromethane (3 mL) was added 1M 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 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), 5.10-5.25 (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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxylate (48)

A solution of compound 9 (12.0 mg, 0.033 mmol) in tetrahydrofuran (1 mL) was added to N, N-diisopropylethylamine (30.0 μL, 0.17 mmol) and phenyl chloroformate (12.5 μL, 0.099 mmol) 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 H-NMR (400 MHz, 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, 14 Hz, 0.7H), 3.58 (ddd, J = 4, 12, 14 Hz, 0.3H), 3.87 (s, 3H), 4.13-4 .25 ( , 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 = 9 Hz, 0.7 H), 7.10-7.15 (m, 2 H), 7, 19 (dd, J = 7, 7 Hz, 1 H), 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxylate (49)

According to the method described in Example 7, the title compound was obtained from compound 48.

¹ H-NMR (400 MHz, 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 = 18 Hz, 1H), 3.03-3.09 (m, 1H), 3.46 (ddd, J = 4, 11, 14 Hz, 0.6H), 3.54 (ddd, J = 3, 11, 14 Hz, 0.4 H), 4.11-4.32 (m, 1.4 H), 4.35-4.41 (m, 0.6 H), 4.61 (s, 0.4 H), 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 = 8 Hz, 0.4 H), 7.11-7.17 (m, 2 H), 7.20 (t, J = 7 Hz, 1 H), 7.37 (t, J = 8 Hz, 2 H) ).

(Example 31)
Oxazol-2-ylmethyl (4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a Of 8-, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxylate (50)

A solution of compound 11 (9.8 mg, 0.016 mmol), oxazol-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. It was 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 H-NMR (400 MHz, 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)
Oxazol-2-ylmethyl (4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a Of, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxylate (51)

To a solution of compound 50 (6.4 mg, 0.013 mmol) in dichloromethane (1.5 mL) was added 1M 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 H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.12 (m, 2H), 0.44-0.52 (m, 2H), 0.73-0.82 (m , 1H), 1.03 to 1.09 (m, 1H), 1.26 to 1.72 (m, 5H), 2.18 to 2.39 (m, 5H), 2.58 to 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 = 8 Hz, 1 H), 6.69 (d, J = 8 Hz, 0.6 H), 6.71 (d, J = 8 Hz, 0.4 H), 7.14 (s). , 0.6H), 7.15 ( , 0.4H), 7.67 (s, 0.6H), 7.68 (s, 0.4H).

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

According to the method described in Example 31, the title compound was obtained from compound 11 and oxazol-5-ylmethanol (synthesized by the method described in WO2015138895).

¹ H-NMR (400 MHz, 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 = 18 Hz, 1H), 3.01 (d, J = 6 Hz, 1H), 3.37 (ddd , J = 4, 11, 14 Hz, 1H), 3.86 (s, 1.8H), 3.88 (s, 1.2H), 3.93-3.99 (m, 0.4H), 4 0.07-4.14 (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 = 8 Hz, 1H), 7.14 (s, 1H), 7.88 (s, 0.6H), 7.89 (s, 0.4H).

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

According to the method described in Example 32, the title compound was obtained from compound 52.

¹ H-NMR (400 MHz, 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 = 8 Hz, 1H), 6.6 (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)
Thiazol-2-ylmethyl (4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a Of, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxylate (54)

According to the method described in Example 31, compound 11 and thiazol-2-ylmethanol (synthesized by the method described in WO2040666795) gave the title compound.

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) = 8 Hz, 0.6 H), 6.7 (D, J = 8 Hz, 1 H), 7.34 (d, J = 3 Hz, 0.6 H), 7.36 (d, J = 3 Hz, 0.4 H), 7.77 (d, J = 3 Hz, 0.6H), 7.79 (d, J = 3Hz, 0.4H).

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

According to the method described in Example 32, the title compound was obtained from compound 54.

¹ H-NMR (400 MHz, 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 = 8 Hz, 1 H), 6.70 (d, J = 8 Hz, 0.6 H), 6.72 (d, J = 8 Hz, 0.4 H), 7.35-7.39 (m, 1 H), 7 0.78-7.82 (m, H).

(Example 37)
Pyrimidin-2-ylmethyl (4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a , 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxylate (56)

According to the method described in Example 31, the title compound was obtained from compound 11 and 2-pyrimidinemethanol.

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)
Pyrimidin-2-ylmethyl (4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a , 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxylate (57)

According to the method described in Example 32, the title compound was obtained from compound 56.

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) pyridin-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-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxylate (58)

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) to give 2- (hydroxymethyl) pyridin-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-methanobenzofuro [2,3-c] pyrido [4 A crude product of, 3-d] 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 H-NMR (400 MHz, 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 = 8 Hz, 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (59)

According to the method described in Example 32, the title compound was obtained from compound 47.

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, 12 Hz, 1H), 2.25-2.47 (m, 4H), 2.63 (Dd, J = 5,12 Hz, 1H), 2.74-2.88 (m, 4H), 2.93 (d, J = 18 Hz, 1H), 2.98 (d, J = 6 Hz, 1H) , 3.66 (d, J = 14 Hz, 1H), 3.77 (d, J = 14 Hz, 1H), 4.55 (s, 1H), 6.48 (d, J = 8 Hz, 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-ethano-4,13- Synthesis of methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (60)

According to the method described in Example 2, the title compound was obtained from compound 59.

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 = 5,5,16 Hz, 1H), 1.75-1.88 (m, 1H), 2.29-2.45 (m, 4H), 2.50 (dd, J = 6, 19 Hz, 1H) ), 2.68-2.81 (m, 1H), 3.03 (d, J = 19 Hz, 1H), 3.03-3.14 (m, 1H), 3.19-3.40 (m , 3H), 3.62 (d, J = 2 Hz, 1H), 4.73 (s, 1H), 6.57 (d, J = 8 Hz, 1H), 6.67 (d, J = 8 Hz, 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (3-fluoropyridin-2-yl) methanone (61)

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 monohydrate (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 082 mmol) of N, N-dimethylformamide (1 mL) 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 obtain the title compound (15 mg, quantitative) as a colorless oily substance.

¹ H-NMR (400 MHz, 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 (dd , J = 5, 5, 14 Hz, 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, 5 Hz, 0.3H), 8.47 (Ddd, J = 1, 1, 5 Hz, 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (3-fluoropyridin-2-yl) methanone (62)

According to the method described in Example 7, the title compound was obtained from compound 61.

¹ H-NMR (400 MHz, 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 = 18 Hz, 1 H), 3.03 (d, J = 6 Hz, 0.8 H), 3.07 (d, J = 6 Hz, 0.2 H), 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 = 8 Hz, 0.8 H), 7.39 (ddd, J = 4, 4, 8 Hz, 1 H), 7.52 (ddd, J = 1, 8, 8 Hz, 1 H), 8.14 (Ddd, J = 1, 1, 4 Hz, 0.2H), 8.49 (ddd, J = 1, 1, 4 Hz, 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 Synthesis of -4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (pyrimidin-2-yl) methanone (63)

Compound 9 (14 mg, 0.038 mmol), pyrimidine-2-carboxylic acid (14.2 mg, 0.11 mmol), N, N-dimethylaminopyridine (2.3 mg, 0.019 mmol), 1-hydroxybenztriazole monohydrate Of solvate (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 with saturated aqueous sodium hydrogen carbonate solution three times and saturated brine once. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. To a solution of the obtained crude product in dichloromethane (1 mL) was added 1M boron tribromide-dichloromethane solution (200 μL, 0.20 mmoL) 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 (400 MHz, 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 = 6 Hz, 0.7 H), 3.08 (d, J = 6 Hz, 0.3 H), 3.38-3.54 (m, 1.7 H), 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, = 8 Hz, 0.3 H), 6.54 (d, J = 8 Hz, 0.7 H), 6.65 (d, J = 8 Hz, 0.3 H), 6.73 (d, J = 8 Hz, 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (pyrimidin-4-yl) methanone (64)

Compound 60 (5.7 mg, 0.016 mmol), pyrimidine-4-carboxylic acid (6 mg, 0.049 mmol), N, N-dimethylaminopyridine (1.1 mg, 0.008 mmol), 1-hydroxybenztriazole monohydrate Sate (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 0.049 mmol) of N, N-dimethylformamide (0.5 mL) 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, then 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 obtain the title compound (5.9 mg, 80%) as a colorless oily substance.

¹ H-NMR (400 MHz, 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 = 6 Hz, 0.7 H), 3.08 (d, J = 6 Hz, 0.3 H), 3.43-3.58 (m, 1 H), 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) .3 H), 8.89 (d, J = 5 Hz, 0.7 H), 8.90 (d, J = 5 Hz, 0.3 H), 9.28 (br s, 0.7 H), 9.32 ( d, J = 1 Hz, 0.3 H).

(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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (pyrimidin-5-yl) methanone (65)

Following the method described in Example 42, the title compound was obtained from compound 9 and pyrimidine-5-carboxylic acid.

¹ H-NMR (400 MHz, 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 = 6,18 Hz, 1H), 2.66 (dd, J = 5,12 Hz, 1H), 2.83-2.94 (m, 1H), 3.01 (d, J = 19 Hz, 1H), 3 .05 (d, J = 6 Hz, 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (pyrimidin-5-yl) methanone (65)

According to the method described in Example 7, the title compound was obtained from compound 65.

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, 14 Hz, 1H), 1.73-1.85 (m, 1H), 2.13-2.44 (m, 5H), 2.65. (Dd, J = 4, 11 Hz, 1H), 2.81-2.92 (m, 1H), 2.98 (d, J = 18 Hz, 1H), 3.03 (d, J = 6 Hz, 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (pyridazin-3-yl) methanone (67)

Following the method described in Example 45, the title compound was obtained from compound 60 and pyridazine-3-carboxylic acid.

¹ H-NMR (400 MHz, 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (pyridazin-4-yl) methanone (68)

Following the method described in Example 45, the title compound was obtained from compound 60 and pyridazine-4-carboxylic acid.

¹ H-NMR (400 MHz, 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 = 8 Hz, 1H), 6.75 (d, J = 8 Hz, 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (pyrazin-2-yl) methanone (69)

Following the method described in Example 42, the title compound was obtained from compound 9 and pyrazine-2-carboxylic acid.

¹ H-NMR (400 MHz, 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 = 8 Hz, 0.3 H), 6.75 (d, J = 8 Hz, 0.7 H), 7.55-7.65 (m, 1 H), 7.74 (dt , J = 2, 8 Hz, 0.3 H), 7.8 2 (dt, J = 2, 8 Hz, 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 Synthesis of -4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (pyrazin-2-yl) methanone (70)

According to the method described in Example 7, the title compound was obtained from compound 69.

¹ H-NMR (400 MHz, 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 = 1 Hz, .7H), 8.94 (d, J = 1Hz, 0.3H).

(Example 52)
6-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,6,7,8,8a-octahydro-5H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-carbonyl) pyridin-2 (1H) -one (71) synthesis

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

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 = 6 Hz, 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 = 6 Hz, 1H), 6.60 (d, J = 9 Hz, 1H), 6.61 (d, J = 8 Hz, 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 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-carbonyl) pyridin-2 (1H) -one (72)

According to the method described in Example 7, the title compound was obtained from compound 71.

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 = 18 Hz, 1H), 3.02 (d, J = 5 Hz, 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 = 8 Hz, 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (6-hydroxypyridin-3-yl) methanone (73)

According to the method described in Example 42, the title compound was obtained from compound 9 and 6-hydroxynicotinic acid.

¹ H-NMR (400 MHz, 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, 11 Hz, 1H), 2.81-2.92 (m, 1H), 2.99 (D, J = 19 Hz, 1H), 3.06 (d, J = 6 Hz, 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 = 8H , 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (6-hydroxypyridin-3-yl) methanone (74)

According to the method described in Example 7, the title compound was obtained from compound 73.

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 = 18 Hz, 1H), 3.04 (d, J = 6 Hz, 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, = 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (2-hydroxypyridin-3-yl) methanone (75)

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

¹ H-NMR (400 MHz, 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 0.59 (d, J = 8 Hz, 1H), 6.6 (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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (2-hydroxypyridin-3-yl) methanone (76)

According to the method described in Example 7, the title compound was obtained from compound 75.

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 = 6 Hz, 0.8 H), 3.13 (d, J = 6 Hz, 0.2 H), 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) = 8 Hz, 0.8 H), 7. 4 (d, J = 6Hz, 1H), 7.60-7.73 (m, 1H).

(Example 58)
6-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,6,7,8,8a-octahydro-5H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-carbonyl) -1-methylpyridin-2 (1H) -one (77)

According to the method described in Example 42, 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).

¹ H-NMR (400 MHz, 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. 0.88 (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 (d , J = 1, 7 Hz, 0.6 H), 6.56-6.65 (m, 2 H), 7.26 (d, J = 8 Hz, 1 H), 7.32 (dd, J = 7, 9 Hz, 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 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-carbonyl) -1-methylpyridin-2 (1H) -one (78)

According to the method described in Example 7, the title compound was obtained from compound 77.

¹ H-NMR (400 MHz, 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 = 6 Hz, 0.4H), 3.08 (d, J = 6 Hz, 0.6H), 3.46-3.61 (m, 2H), 3.48 (s, 1.H). 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, 7 Hz, 0.4 H), 6.14 (dd, J = 1, 7 Hz, 0.6 H), 6.56 (d, J = 8 Hz, 1 H), 6.63 (dd, J = 1) , 9 Hz, 0.4 H), 6.63 (dd, J = 1, 9 Hz, 0.6 H), 6.75 (d, J = 8 Hz, 0.4 H), 6.75 (d, J = 8 Hz, 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (oxazol-2-yl) methanone (79)

A solution of compound 9 (7.5 mg, 0.021 mmol) and oxazole-2-carboxylic acid (11.7 mg, 0.10 mmol) in N, N-dimethylformamide (1.5 mL) was added with N, N-diisopropylethylamine (35 μL). , 0.20 mmol) and O- (7-azabenzotriazol-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 with ethyl acetate three times. 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 (400 MHz, 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, 14 Hz, 0.3H), 3.79 (ddd, J = 4, 11, 14 Hz, 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), 6.7 (D, J = 8 Hz, 0.3 H), 6.74 (d, J = 8 Hz, 0.7 H), 7.26-7.30 (m, 1 H), 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (oxazol-2-yl) methanone (80)

According to the method described in Example 7, the title compound was obtained from compound 79.

¹ H-NMR (400 MHz, 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (oxazol-4-yl) methanone (81)

Following the method described in Example 60, the title compound was obtained from compound 9 and oxazole-4-carboxylic acid.

¹ H-NMR (400 MHz, 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 = 8 Hz, 0.4 H), 6.73 (d, J = 8 Hz, 0.4 H), 6.74 (d, J = 8 Hz, 0.6 H), 7.89 (s, 0.6H), 7.91 (s, 0.4 ), 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (oxazol-4-yl) methanone (82)

According to the method described in Example 7, the title compound was obtained from compound 81.

¹ H-NMR (400 MHz, 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, 14 Hz, 0.6 H), 4.54-4.83 (m, 3 H), 6.54 (d, J = 8 Hz, 0.6 H), 6.55 (d, J = 8 Hz, 0.4 H), 6.71 (d, J = 8 Hz, 0.4H), 6.72 (d, J = 8 Hz, 0.6H), 7.90 (s, 0.6H), 7.95 (s, 0.4H) ), 8.21 ( , 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (isoxazol-5-yl) methanone (83)

Following the method described in Example 60, the title compound was obtained from compound 9 and isoxazole-5-carboxylic acid.

¹ H-NMR (400 MHz, 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (isoxazol-5-yl) methanone (84)

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

¹ H-NMR (400 MHz, 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 Synthesis of -4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (thiazol-2-yl) methanone (85)

Following the method described in Example 45, the title compound was obtained from compound 60 and thiazole-2-carboxylic acid.

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 = 8 Hz, 1 H), 6.69-6.76 (m, 1 H), 7.50-7.60 (m, 1 H), 7.91 (d, J = 3 Hz, 0.6 H), 7 .99 (d, J = 3 Hz, 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-yl thiazol-4-carboxylate (86)

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

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 0.03 (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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (thiazol-4-yl) methanone (87)

To a solution of compound 86 (7.5 mg, 0.013 mmol) in methanol (1 mL) was added 2M aqueous sodium hydroxide solution (0.1 mL, 0.10 mmol), and the mixture was stirred at room temperature for 1 hour. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted three times with a chloroform / methanol mixed 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 (400 MHz, 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 = 8 Hz, 1 H), 6.66-6.75 (m, 1 H), 7.93 (d, J = 2 Hz, 0.7 H), 8.04 (d, J = 2 Hz, 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-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (thiazol-5-yl) methanone (88)

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 Of the solvate (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) A solution of N, N-dimethylformamide (1 mL) was stirred at room temperature overnight. 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, then 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 obtain the title compound (6.3 mg, 68%) as a colorless solid.

¹ H-NMR (400 MHz, 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 = 8 Hz, 1 H), 6.73 (d, J = 8 Hz, 1 H), 8.06-8.26 (m, 1 H), 8.90 (s, 1 H).

(Example 69)
((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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (isothiazol-4-yl) methanone (89)

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

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 = 8 Hz, 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (isothiazol-5-yl) methanone (90)

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

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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (isothiazol-5-yl) methanone (91)

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

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.17 (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 Synthesis of -4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (1H-indol-2-yl) methanone (92)

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

¹ H-NMR (400 MHz, 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 Synthesis of -4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (1H-indol-2-yl) methanone (93)

According to the method described in Example 7, the title compound was obtained from compound 92.

¹ H-NMR (400 MHz, 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 = 8 Hz, 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-chloropyrimidin-2-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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) methanone (94)

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

¹ H-NMR (400 MHz, 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 to 3.56 (m, 1.6H), 3.68 to 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 = 8 Hz, 0.4H). 6.75 (d, J = 8 Hz, 0.6H), 8.74-8.82 (m, 2H).

(Example 75)
(5-chloropyrimidin-2-yl) ((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a -Octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) methanone (95)

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

¹ H-NMR (400 MHz, 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 = 8 Hz, 0.3 H), 6.73 (d, J = 8 Hz, 0.7 H), 8.77-8.82 (m, 1 H).

(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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (5-fluoropyrimidin-2-yl) methanone (96)

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

¹ H-NMR (400 MHz, 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), 2.58-2.69 (m, 1H), 2.85-3.14. (M, 3H), 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 = 8 Hz, 0.4 H), 6.75 (d, J = 8 Hz, 0.6 H), 8.64-8.71 (m, 2 H).

(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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (5-fluoropyrimidin-2-yl) methanone (97)

According to the method described in Example 7, the title compound was obtained from compound 96.

¹ H-NMR (400 MHz, 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 = 8 Hz, 0.3 H), 6.73 (d, J = 8 Hz, 0.7 H), 8.66-8.73 (m, 2 H).

(Example 78)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (pyrimidin-2-yl) ethan-1-one (98)

According to the method described in Example 44, the title compound was obtained from compound 9 and 2- (pyrimidin-2-yl) acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.13 (m, 2H), 0.43-0.51 (m, 2H), 0.70-0.81 (m , 1H), 1.03 to 1.12 (m, 1H), 1.17 to 1.33 (m, 1H), 1.34 to 1.54 (m, 3H), 1.60 to 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 = 8 Hz, 0.3 H), 6.69 d, J = 8 Hz, 0.3 H), 6.70 (d, J = 8 Hz, 0.7 H), 7.19-7.23 (m, 1 H), 8.72 (d, J = 8 Hz, 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 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (pyrimidin-5-yl) ethan-1-one (99)

According to the method described in Example 44, the title compound was obtained from compound 9 and 2- (pyrimidin-5-yl) acetic acid.

¹ H-NMR (400 MHz, 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, 15 Hz, 0.5H), 3.56 (ddd, J = 4, 11, 15 Hz, 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 = 5,5,14H , 0.5H), 4.50 (s, 1H), 4.60-4.65 (m, 0.5H), 6.58 (d, J = 8Hz, 0.5H), 6.65 (d , J = 8 Hz, 0.5 H), 6.73 (d, J = 8 Hz, 0.5 H), 6.76 (d, J = 8 Hz, 0.5 H), 8.68 (s, 2 H), 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 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (pyrimidin-5-yl) ethan-1-one (100)

According to the method described in Example 7, the title compound was obtained from Compound 99.

¹ H-NMR (400 MHz, 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 = 18 Hz, 0.3 H), 3.03 (d, J = 6 Hz, 0.7 H), 3.06 (d, J = 6 Hz, 0.3 H), 3.45 ( ddd, J = 5, 11, 15 Hz, 0.3H), 3.58 (ddd, J = 4, 12, 15 Hz, 0.7H), 3.72-3.86 (m, 0.7H), 3 ． 7 (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 = 8 Hz, 0.7 H), 6.73 (d, J = 8 Hz, 0.3 H), 8.69 (s, 1.4 H), 8.70 (s, 0.6 H), 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 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (pyrazin-2-yl) ethan-1-one (101) synthesis

According to the method described in Example 45, the title compound was obtained from compound 60 and 2- (pyrazin-2-yl) acetic acid.

¹ H-NMR (400 MHz, 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, 13 Hz, 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 = 6 Hz, 0.7 H), 3.05 (d, J = 6 Hz, 0.3 H), 3.43 (ddd, J = 4, 10, 14 Hz, 0.3 H), 3.55 (ddd , J = , 12, 15 Hz, 0.7 H), 3.86-3.93 (m, 0.7 H), 4.01 (d, J = 15 Hz, 1 H), 4.06 (d, J = 15 Hz, 1 H) , 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 = 8 Hz, 0.3 H), 6.70 (d, J = 8 Hz, 0.7 H), 6.71 (d, J = 8 Hz, 0.3 H), 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 Of ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (1H-imidazol-2-yl) ethan-1-one (102) Synthesis

According to the method described in Example 60, the title compound was obtained from compound 9 and 2- (1H-imidazol-2-yl) acetic acid hydrochloride.

¹ H-NMR (400 MHz, 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 = 8 Hz, 0.6 H), 6.6 (D, J = 8 Hz, 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 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (1H-imidazol-2-yl) ethan-1-one dihydrochloride ( 103) Synthesis

According to the method described in Example 7, the free form of the title compound was obtained from compound 102 (11.0 mg, 0.023 mmol). The obtained free form was dissolved in methanol (1 mL), 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 on 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 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (isoxazol-3-yl) ethan-1-one (104)

According to the method described in Example 42, the title compound was obtained from compound 9 and 2- (isoxazol-3-yl) acetic acid.

¹ H-NMR (400 MHz, 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), 4.4 (S, 0.6H), 4.52 (s, 0.4H), 4.59-4.64 (m, 0.6H), 6.46 (s, 1H), 6.57 (d, J = 9 Hz, 0.6 H), 6.63 (d, J = 9 Hz, 0.4 H), 6.72 (d, J = 9 Hz, 0.6 H), 6.75 (d, J = 9 Hz, 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 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (isoxazol-3-yl) ethan-1-one (105)

According to the method described in Example 7, the title compound was obtained from compound 104.

¹ H-NMR (400 MHz, 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 (dddd, J = 4, 4, 10, 14Hz, 0.2H), 3.54 (dddd, J = 3, 3, 11, 14 Hz, 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 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (oxazol-4-yl) ethan-1-one (106)

According to the method described in Example 60, the title compound was obtained from compound 9 and 2- (oxazol-4-yl) acetic acid.

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 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (oxazol-4-yl) ethan-1-one (107)

According to the method described in Example 7, the title compound was obtained from compound 106.

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] oxazol-2-yl) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5 , 6,8,8a-Octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) ethan-1-one (108 ) Synthesis

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

¹ H-NMR (400 MHz, 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 = 8 Hz, 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] oxazol-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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) ethan-1-one (109 ) Synthesis

According to the method described in Example 7, the title compound was obtained from compound 108.

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 = 8 Hz, 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 Of ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (1H-indol-3-yl) ethan-1-one (110) Synthesis

According to the method described in Example 60, the title compound was obtained from compound 9 and 2- (1H-indol-3-yl) acetic acid.

¹ H-NMR (400 MHz, 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 Of ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (1H-indol-3-yl) ethan-1-one (111) Synthesis

According to the method described in Example 7, the title compound was obtained from compound 110.

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 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (thiazol-2-yl) ethan-1-one (112)

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

¹ H-NMR (400 MHz, 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, 14 Hz, 0.4H), 3.57 (ddd, J = 4, 11, 14 Hz, 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. 7 (d, J = 8 Hz, 0.6 H), 6.62 (d, J = 8 Hz, 0.4 H), 6.72 (d, J = 8 Hz, 0.6 H), 6.74 (d, J) = 8 Hz, 0.4 H), 7.29 (d, J = 3 Hz, 0.4 H), 7.32 (d, J = 3 Hz, 0.6 H), 7.71 (d, J = 3 Hz, 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 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (thiazol-2-yl) ethan-1-one (113)

According to the method described in Example 7, the title compound was obtained from compound 112.

¹ H-NMR (400 MHz, 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 = 4,11,14 Hz, 0.3H), 3.56 (ddd, J = 4,11,14 Hz, 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 = 8 Hz, 0.3 H), 6.71 (d, J = 8 Hz, 1 H), 7.32 (d, J = 3 Hz, 0.3 H), 7.33 (d, J = 3 Hz) , 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 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (thiazol-5-yl) ethan-1-one (114)

According to the method described in Example 60, the title compound was obtained from compound 9 and 2- (thiazol-5-yl) acetic acid.

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 = 8Hz, 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 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (thiazol-5-yl) ethan-1-one (115)

According to the method described in Example 7, the title compound was obtained from compound 114.

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 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (thiazol-4-yl) ethan-1-one (116)

According to the method described in Example 60, the title compound was obtained from compound 9 and 2- (thiazol-4-yl) acetic acid.

¹ H-NMR (400 MHz, 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 = 8 Hz, 0.6 H), 6.62 (d J = 8 Hz, 0.4 H), 6.72 (d, J = 8 Hz, 0.6 H), 6.74 (d, J = 8 Hz, 0.4 H), 7.23 (s, 0.4 H), 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 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (thiazol-4-yl) ethan-1-one (117)

According to the method described in Example 7, the title compound was obtained from compound 116.

¹ H-NMR (400 MHz, 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 = 8 Hz, 1 H), 7.26-7.29 (m, 1 H), 8.77 (d, J = 2 Hz, 0.3 H), 8.80 (d, J = 2Hz, 0.7H).

(Example 98)
2- (5-chloropyrimidin-2-yl) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,5 6,8,8a-Octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) ethan-1-one (118) Synthesis of

According to the method described in Example 60, the title compound was obtained from compound 9 and 2- (5-chloropyrimidin-2-yl) acetic acid.

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 to 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-chloropyrimidin-2-yl) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,5 6,8,8a-Octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) ethan-1-one (119) Synthesis of

According to the method described in Example 7, the title compound was obtained from compound 118.

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 Of ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (1H-imidazol-1-yl) ethan-1-one (120) Synthesis

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

¹ H-NMR (400 MHz, 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 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (1H-pyrazol-1-yl) ethan-1-one (121) Synthesis

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

¹ H-NMR (400 MHz, 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 = 8 Hz, 0.7 H), 6.63 (d, J = 8 Hz, 0.3 H), 6.70-6.78 (m, 1 H), 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 Of ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (1H-pyrazol-1-yl) ethan-1-one (122) Synthesis

According to the method described in Example 7, the title compound was obtained from compound 121.

¹ H-NMR (400 MHz, 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, H), 7.52-7.58 (m, 2H).

(Example 103)
(E) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H -4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -3- (pyrimidin-2-yl) prop-2-en-1 -Synthesis of one (123)

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

¹ H-NMR (400 MHz, 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 = 8 Hz, 0.6 H), 6.74 (d, J = 8 Hz, 0.4 H), 6.75 (d, J = 8 Hz, 0.6 H), 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 = 15 Hz, 0.6 H), 8.75 (d, J = 4 Hz, 1.2 H), 8.76 (d, J = 4 Hz, 0.8 H).

(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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -3- (pyrimidin-2-yl) prop-2-en-1 -Synthesis of one (124)

According to the method described in Example 7, the title compound was obtained from compound 123.

¹ H-NMR (400 MHz, 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 = 18 Hz, 1 H), 3.03 (d, J = 6 Hz, 0.6 H), 3.06 (d, J = 6 Hz, 0.4 H), 4.01-4.09 (m, 0.0. 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. 4 (d, J = 8 Hz, 0.4 H), 6.56 (d, J = 8 Hz, 0.6 H), 6.71 (d, J = 8 Hz, 0.4 H), 6.73 (d, J = 8 Hz, 0.6 H), 7.21 (t, J = 5 Hz, 1 H), 7.60 (d, J = 15 Hz, 0.6 H), 7.73 (d, J = 15 Hz, 0.4 H) , 7.80 (d, J = 15 Hz, 0.6 H), 7.81 (d, J = 15 Hz, 0.4 H), 8.77 (d, J = 5 Hz, 1.2 H), 8.78 ( d, J = 5 Hz, 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -3- (furan-3-yl) prop-2-en-1 -Synthesis of one (125)

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

¹ H-NMR (400 MHz, 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 to 1.39 (m, 1H), 1.40 to 1.57 (m, 3H), 1.65 to 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 = 18 Hz, 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 ( , 0.5H), 6.51-6.76 (m, 4H), 7.43 (s, 1H), 7.58 (d, J = 16Hz, 0.5H), 7.64 (d, J) = 6 Hz, 1 H), 7.68 (d, J = 15 Hz, 0.5 H).

(Example 106)
(E) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H -4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -3- (oxazol-2-yl) prop-2-en-1 -Synthesis of one (126)

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

¹ H-NMR (400 MHz, 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, 1H), 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 ( , 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -3- (oxazol-2-yl) prop-2-en-1 -Synthesis of one (127)

According to the method described in Example 7, the title compound was obtained from compound 126.

¹ H-NMR (400 MHz, 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 = 6 Hz, 0.4 H), 3.46-3.53 (m, 0.4 H), 3.58-3.66 (m, 0.6 H), 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, 0.6 ), 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 = 8 Hz, 0.6 H), 7.26-7.27 (m, 1 H), 7.34 (d, J = 15 Hz, 0.4 H), 7.37 (d, J = 15 Hz, 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-1,2,3,4,5,6,8,8a-octahydro-7H -4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -3- (oxazol-4-yl) prop-2-en-1 -On (128) synthesis

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

¹ H-NMR (400 MHz, 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), 1.6-1.90 (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, 15 Hz, 0.5 H), 3.89 (s, 3 H), 4.02 (ddd, J = 4, 4, 14 Hz, 0.5 H), 4.26-4.31 (m, 0.5 H), 4.37 (ddd, J = 5, 5, 14 Hz, 0.5H), 4.57 (s, 0.5H), 4.58 (s, 0.5H), 4.72-4.77 (m , 0.5H , 6.58 (d, J = 8 Hz, 0.5H), 6.62 (d, J = 8 Hz, 0.5H), 6.73 (d, J = 8 Hz, 0.5H), 6.75 ( d, J = 8 Hz, 0.5 H), 7.21 (d, J = 15 Hz, 0.5 H), 7.24 (d, J = 15 Hz, 0.5 H), 7.55 (d, J = 15 Hz) , 0.5H), 7.61 (d, J = 15 Hz, 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -3- (oxazol-4-yl) prop-2-en-1 -Synthesis of one (129)

According to the method described in Example 7, the title compound was obtained from compound 128.

¹ H-NMR (400 MHz, 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 = 6 Hz, 0.4 H), 3.48 (ddd, J = 5, 11, 15 Hz, 0.4 H), 3.60 (ddd, J = 4, 12, 16 Hz, 0.6 H), 4.05 (ddd, J = 3, 4, 15 Hz, 0.6 H), 4.22-4.27 (m, 0.4 H), 4.41 (ddd, J = 5, 5, 14 Hz, 0. Four ), 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 = 15 Hz, 0.4 H), 7.26 (d, J = 15 Hz, 0.6 H), 7.55 (d, J = 15 Hz, 0.6 H), 7.62 (d , J = 15 Hz, 0.4 H), 7.79 (s, 0.6 H), 7.81 (s, 0.4 H), 7.91 (s, 0.6 H), 7.92 (s, 0) .4H).

(Example 110)
(E) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H -4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -3- (thiazol-2-yl) prop-2-en-1 -Synthesis of on (130)

Following the method described in Example 60, the title compound was obtained from compound 9 and (E) -3- (thiazol-2-yl) acrylic acid.

¹ H-NMR (400 MHz, 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 = 8 Hz, 0.5 H), 6.63 (d, J = 8 Hz, 0.5 H), 6.73 (d, J = 8 Hz, 0.5 H), 6.75 ( d, J = 8 Hz, 0.5 H), 7. 0-7.41 (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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -3- (thiazol-2-yl) prop-2-en-1 -Synthesis of one (131)

According to the method described in Example 7, the title compound was obtained from compound 130.

¹ H-NMR (400 MHz, 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 = 6 Hz, 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 = 8 Hz, 0.4 H), 6.71 (d, J = 8 Hz, 0.4 H), 6.72 (d, J = 8 Hz, 0.6 H), 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) ).

(Example 112)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -3-phenylprop-2-yn-1-one (132)

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

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 = 18 Hz, 1 H), 3.06 (d, J = 6 Hz, 1 H), 3.38 (ddd, J = 5, 11, 15 Hz, 0.4 H), 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (133)

To a solution of compound 9 (13.5 mg, 0.037 mmol) in N, N-dimethylformamide (1 mL) was added potassium carbonate (25.7 mg, 0.19 mmol) and 3-phenylpropyl bromide (17 μL, 0.11 mmol). , 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 with ethyl acetate three times. 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 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, 13 Hz, 1H), 2.24-2.43 (m, 4H), 2.53 (T, J = 7 Hz, 2H), 2.58-2.67 (m, 1H), 2.64 (t, J = 7Hz, 2H), 2.68-2.91 (m, 4H), 2 .95 (d, J = 18 Hz, 1H), 2.99 (d, J = 6 Hz, 1H), 3.85 (s, 3H), 4.55 (s, 1H), 6.55 (d, J = 8Hz, 1H), .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) -1,2,3,4,6,7,8,8a-octahydro-5H-4a Of 8-, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (134)

According to the method described in Example 7, the title compound was obtained from compound 133.

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 = 18 Hz, 1H), 2.99 (d, J = 6 Hz, 1H), 4.56 (s, 1H), 6.50 (d, J = 8 Hz, 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- (pyrimidin-2-ylmethyl) -1,2,3,4,6,7,8,8a- Synthesis of octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (135)

To a solution of compound 9 (14 mg, 0.038 mmol) in dichloromethane (1 mL), pyrimidine-2-carbaldehyde (20.6 mg, 0.19 mmol) and sodium triacetoxyborohydride (40.5 mg, 0.19 mmol) were added. The mixture was stirred at room temperature for 2 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 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 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 (dd, 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 = 5,11 Hz, 1H), 2.90-3.02 (m, 6H), 3.81 (s, 3H), 4.00 (d, J = 15 Hz, 1H) , 4.05 (d, J = 15 Hz, 1H), 4.73 (s, 1H), 6.55 (d, J = 8 Hz, 1H), 6.67 (d, J = 8 Hz, 1H), 7 ． 7 (t, J = 5Hz, 1H), 8.72 (d, J = 5Hz, 2H).

(Example 116)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -7- (pyrimidin-2-ylmethyl) -1,2,3,4,6,7,8,8a-octahydro-5H- Synthesis of 4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (136)

According to the method described in Example 7, the title compound was obtained from compound 135.

¹ H-NMR (400 MHz, 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 = 8 Hz, 1 H), 6.65 (d, J = 8 Hz, 1 H), 7.19 (t, J = 5 Hz, 1 H), 8.73 (d, J = 5 Hz, 2 H).

(Example 117)
(4R, 4aS, 8R, 8aR, 13bS) -7- (5-Bromopyrimidin-2-yl) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,6,7,8 Synthesis of, 8a-octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (137)

A solution of compound 9 (5.0 mg, 0.014 mmol) in acetonitrile (0.5 mL) was added with N, N-diisopropylethylamine (10.0 μL, 0.056 mmol) and 5-bromo-2-chloropyrimidine (8.0 mg, 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 with saturated aqueous sodium hydrogen carbonate solution three times. 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.

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), 1.00-1.20 (m, 1H), 1.20-1.80 (m, 5H), 2.00-2.50 (m, 5H), 2.59 (dd, J = 6,11 Hz, 1H), 2.70-2.90 (m, 1H), 2.98 (d, J = 18 Hz, 1H), 3.04 (d, J = 6 Hz, 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 = 8 Hz, 1H), 8.28 (s, 2H).

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

According to the method described in Example 7, the title compound was obtained from compound 137.

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), 1.00-2.40 (m, 11H), 2.61 (dd, J = 4, 11 Hz, 1H), 2.70-2.90 (m, 1H), 2.97 (d , J = 18 Hz, 1 H), 3.05 (d, J = 6 Hz, 1 H), 3.30-3.50 (m, 1 H), 4.45 (s, 1 H), 4.57 (s, 1 H) ), 4.70-4.90 (m, 1H), 6.55 (d, J = 8 Hz, 1H), 6.71 (d, J = 8 Hz, 1H), 8.33 (s, 2H).

(Example 119)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-methoxy-7- (pyrimidin-2-yl) -1,2,3,4,6,7,8,8a- Synthesis of octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (139)

According to the method described in Example 117, the title compound was obtained from compound 9 and 2-chloropyrimidine.

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), 1.00-1.20 (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 = 12 Hz, 1 H), 3.88 (s, 3 H), 4.53 (s, 1 H), 4.75 (s, 2 H), 6.45 (t, J = 5 Hz, 1 H), 6. 58 (d, J = 8 Hz, 1H), 6.73 (d, J = 8 Hz, 1H), 8.30 (d, J = 5 Hz, 2H).

(Example 120)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -7- (pyrimidin-2-yl) -1,2,3,4,6,7,8,8a-octahydro-5H- Synthesis of 4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (140)

According to the method described in Example 7, the title compound was obtained from compound 139.

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 = 12 Hz, 1H), 1.20-1.70 (m, 4H), 1.79 (t, J = 11 Hz, 1H), 2.10-2.50. (M, 5H), 2.60 (dd, J = 6, 10 Hz, 1H), 2.83 (dt, J = 5, 13 Hz, 1H), 2.96 (d, J = 18 Hz, 1H), 3 .05 (d, J = 6 Hz, 1H), 3.40-3.50 (m, 1H), 4.50-4.60 (m, 1H), 4.65 (q, J = 3 Hz, 1H) , 4.83 (dq, J = 3, 14 Hz, 1H), 6.48 (t, J = 5 Hz, 1H), 6.54 (d, J = 8 Hz, 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- (pyrimidin-2-yl) acetyl) -1,2,3,4,6,7,8,8a -Octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-yl Synthesis of trifluoromethanesulfonate (141)

A solution of the compound 98 (35 mg, 0.074 mmol) in N, N-dimethylformamide (0.7 mL) was added with potassium carbonate (31 mg, 0.22 mmol) and N-phenylbis (trifluoromethanesulfonimide) (79 mg, 0.22 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. 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.

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. -4.99 (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-Methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (pyrimidin-2-yl) ethan-1-one (142)

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) in N, N-dimethylformamide ( 0.6 mL) solution, triethylsilane (24 μL, 0.15 mmol) was added, 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 3 times with ethyl acetate, and then potassium carbonate was added to the aqueous layer to adjust the pH to 10. After that, extraction was performed 3 times with ethyl acetate, and the organic layer was washed with saturated saline. 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 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-ethano-4,12- Synthesis of methanobenzofuro [3,2-e] isoquinolin-6 (5H) -one (143)

To a solution of compound 1 (2.35 g, 5.97 mmol) in ethanol (60 mL) was added 5% palladium-activated carbon (1.2 g), and the mixture was stirred at 70 ° C for 19 hours under a hydrogen atmosphere. The reaction solution was allowed to cool and then 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 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 to 1.06 (m, 1H), 1.26 (ddd, J = 6, 13, 13 Hz, 1H), 1.50 to 1.57 (m, 1H), 1.68 (Dd, J = 3, 13 Hz, 1H), 1.71-1.81 (m, 1H), 2.02 (ddd, J = 6, 13, 13 Hz, 1H), 2.22 (d, J = 20 Hz, 1 H), 2.30-2.41 (m, 4 H), 2.71 (dd, J = 6,12 Hz, 1 H), 3.07 (d, J = 18 Hz, 1 H), 3.13 ( d, J = 7 Hz, 1H), 3.51 (dd, J = 4, 20 Hz, 1H), 3.53 (s, 3H), 3.89 (s, 3H), 4.60 ( , 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-ethano-4,12- Synthesis of methanobenzofuro [3,2-e] isoquinolin-6 (5H) -one oxime (144)

According to the method described in Reference Example 2, the title compound was obtained from compound 143.

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), 1.10-1.20 (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, 21 Hz, 1H), 3.89 (s, 3H), 4.60 (d, J = 2 Hz, 1H), 6.60. (D, J = 8 Hz, 1H), 6.73 (d, J = 8 Hz, 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-methanobenzofuro [3 , 2-e] Isoquinolin-4a-yl) acetonitrile (145)

To a solution of compound 144 (30 mg, 0.073 mmol) in dichloromethane (1 mL) under ice cooling, triethylamine (20.4 μL, 0.15 mmol) and methanesulfonyl chloride (11.3 μL, 0.15 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. 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 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, 12 Hz, 1H), 2.31 (dd, J = 7, 13 Hz, 1H), 2.40 (dd, J = 6, 13 Hz, 1H), 2.53 (dd, J = 6, 18 Hz, 1 H), 2.61 (d, J = 16 Hz, 1 H), 2.67 (dd, J = 5, 12 Hz, 1 H), 3.01 (d, J = 18 Hz, 1 H), 3. 47 (d, J = 6 Hz, 1H), 3.52 (s, 3H), 3.71 (dd, J = 2, 16 Hz, 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-6 (7H) -one (146)

(Method a)
A solution of compound 4 (219.6 mg, 0.58 mmol) in 6M hydrochloric acid (5 mL) 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 tetrahydrofuran (1 mL) solution of the compound 145 (30 mg, 0.076 mmol), 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 H-NMR (400 MHz, 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, 20 Hz, 1H), 4.41 (d, J = 1 Hz, 1H), 6.12 (br s, 1H), 6.66 (d, J = 8Hz, 1 ), 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-ethano-4,13- Synthesis of methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-8 (8aH) -ol (147)

0.94 mol / L borane-tetrahydrofuran complex tetrahydrofuran solution (319 μL, 0.30 mmol) was added to a tetrahydrofuran (3 mL) solution of compound 146 (20 mg, 0.050 mmol), 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 hr. 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 H-NMR (400 MHz, 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) = 8 Hz, 1H), 6.73 (d, J = 8 Hz, 1H).

(Reference Example 25)
(4R, 4aS, 7S, 7aR, 12bS) -4a- (2-aminoethyl) -3- (cyclopropylmethyl) -9-methoxy-2,3,4,4a, 5,6,7,7a-octahydro Synthesis of -1H-4,12-methanobenzofuro [3,2-e] isoquinolin-7-ol (148)

0.94M borane-tetrahydrofuran solution (44.6 mL, 41.9 mmol) was added to a tetrahydrofuran (84 mL) solution of compound 5 (3.19 g, 8.38 mmol), and the mixture was heated under reflux for 3 hours. The reaction mixture was allowed to cool and then concentrated under reduced pressure. 6M Hydrochloric acid (15 mL) was added to the concentrated residue, and the mixture was heated under reflux for 1 hr. The reaction mixture was allowed to cool, basified with sodium carbonate and extracted with ethyl acetate three times and chloroform three times. 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 (silica gel bearing amino group, 1-10% methanol / chloroform) to give the title compound (3.07 g, 95%) as a colorless solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.16 (m, 2H), 0.46-0.55 (m, 2H), 0.77-0.87 (m , 1H), 0.93-1.05 (m, 1H), 1.11-1.19 (m, 1H), 1.22-1.31 (m, 1H), 1.39-1.72. (M, 3H), 2.13 (ddd, J = 4, 12, 12Hz, 1H), 2.22-2.35 (m, 3H), 2.41 (dd, J = 6, 18Hz, 1H) , 2.62-2.74 (m, 2H), 2.80-2.93 (m, 3H), 3.11 (d, J = 6Hz, 1H), 3.86 (s, 3H), 4 12-4.19 (m, 1H), 4.62 (d, J = 5Hz, 1H), 6.60 (d, J = 8Hz, 1H), 6.71 (d, J = 8Hz, 1H) ．

(Reference Example 26)
N- (2-((4R, 4aS, 7S, 7aR, 12bS) -3- (cyclopropylmethyl) -7-hydroxy-9-methoxy-1,2,3,4,5,6,7,7a- Synthesis of octahydro-4aH-4,12-methanobenzofuro [3,2-e] isoquinolin-4a-yl) ethyl) -2-nitrobenzenesulfonamide (149)

Triethylamine (150 μL, 1.08 mmol) and 2-nitrobenzenesulfonyl chloride (144 mg, 0.65 mmol) were added to a solution of the compound 148 (208 mg, 0.54 mmol) in tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for 50 minutes. 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 with saturated brine and water, 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 (305 mg, 99%) as a pale green amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02-0.08 (m, 2H), 0.42-0.47 (m, 2H), 0.75-0.84 (m , 1H), 0.89-1.02 (m, 1H), 1.12-1.21 (m, 1H), 1.31-1.39 (m, 1H), 1.41-1.47 (M, 2H), 2.07-2.19 (m, 3H), 2.33-2.46 (m, 3H), 2.72-2.84 (m, 2H), 2.92 (d , J = 18 Hz, 1H), 3.05 (d, J = 6 Hz, 1H), 3.15-3.23 (m, 1H), 3.29-3.37 (m, 1H), 3.85 (S, 3H), 3.86-3.94 (m, 1H), 4.52 (d, J = 5Hz, 1H), 5.92 (br s, 1H), 6.60 (d, J = 8Hz, 1H), 6.71 d, J = 8Hz, 1H), 7.22-7.78 (m, 2H), 7.83-7.89 (m, 1H), 8.14-8.19 (m, 1H).

(Example 124)
(4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-7-((2-nitrophenyl) sulfonyl) -1,2,3,4,6,7,8, Synthesis of 8a-octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (150)

A solution of compound 149 (286 mg, 0.50 mmol) in tetrahydrofuran (5 mL) was charged with triphenylphosphine (659 mg, 2.51 mmol) and di-tert-butyl azodicarboxylate (20% toluene solution) (2.89 g, 2.51 mmol). ) Was added and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (10-60% ethyl acetate / heptane) to give the title compound (258 mg, 93%) as a colorless amorphous substance.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.15 (m, 2H), 0.43-0.54 (m, 2H), 0.73-0.84 (m , 1H), 1.00-1.10 (m, 1H), 1.21-1.43 (m, 2H), 1.44-1.63 (m, 3H), 2.24 (dd, J = 7,13Hz, 1H), 2.28-2.36 (m, 3H), 2.37 (dd, J = 6,19Hz, 1H), 2.58-2.69 (m, 1H), 2 0.96-3.06 (m, 1H), 2.98 (d, J = 19Hz, 1H), 3.03 (d, J = 6Hz, 1H), 3.35-3.44 (m, 1H) , 3.81 (ddd, J = 4, 4, 13 Hz, 1H), 3.86 (s, 3H), 4.01-4.05 (m, 1H), 4.61-4.64 (m, 1H), 6 59 (d, J = 8Hz, 1H), 6.72 (d, J = 8Hz, 1H), 7.61-7.72 (m, 3H), 8.08-8.13 (m, 1H).

(Example 125)
(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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (9)

4-Mercaptobenzoic acid (14.5 mg, 0.094 mmol) and potassium carbonate (26 mg, 0.19 mmol) were added to a solution of compound 150 (25.9 mg, 0.047 mmol) in N, N-dimethylformamide (1 mL). The mixture was stirred at 40 ° C for 1.5 hours. The reaction mixture was allowed to cool, diluted with water, and extracted with ethyl acetate. The organic layer was washed with 2M aqueous potassium carbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: 10% ammonia-methanol solution = 95: 5) to give the title compound (16.3 mg, 95%) as a colorless oily substance.
¹ H-NMR of compound 9:
The same NMR data as in Example 2 is shown.

(Example 126)
(4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -1,2,3,4,6,7,8,8a-octahydro-5H-4a, 8-ethano-4,13- Synthesis of methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (60)

To a solution of the compound 150 (568 mg, 1.0 mmol) in N, N-dimethylacetamide (10 mL), 1-dodecanethiol (2.39 mL, 10 mmol) and potassium tert-butoxide (1.12 g, 10 mmol) were added, and the temperature was changed to 150 ° C. And stirred for 90 minutes. 1M hydrochloric acid was added to the reaction mixture under ice-cooling, and the mixture was washed three times with heptane, and 28% aqueous ammonia was added to make the mixture basic. The resulting mixture was extracted with ethyl acetate three times. 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 silica gel column chromatography (silica gel supporting amino group, 0-30% methanol / ethyl acetate) to give the title compound (300 mg, 85%) as a pale-yellow amorphous.

¹ H-NMR of compound 60:
The same NMR data as in Example 41 was shown.

(Example 127)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -1,2,3,4,6,7,8,8a-octahydro-5H-4a, 8-ethano-4,13- Methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (60) and (4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -7-methyl-1 , 2,3,4,6,7,8,8a-Octahydro-5H-4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol Synthesis of (151)

To a solution of compound 9 (116 mg, 0.32 mmol) in chloroform (6 mL) was added 1M boron tribromide-dichloromethane solution (1.5 mL, 1.5 mmol) under ice cooling, and the mixture was stirred at room temperature for 45 minutes. Then, methanol (6 mL) was added under ice cooling, and the mixture was stirred at room temperature for 15 minutes. 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 resulting crude product was purified by preparative thin layer chromatography (chloroform: 2M ammonia-methanol solution = 100: 15) to give compound 60 (79 mg, 71%) as a pale yellow amorphous compound 151 (9.4 mg). , 8%) as colorless amorphous.
¹ H-NMR of compound 60:
The same NMR data as in Example 41 was shown.

Compound 151:
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.14 (m, 2H), 0.41-0.56 (m, 2H), 0.73-1.40 (m , 5H), 1.48-1.75 (m, 2H), 2.20 (dd, J = 7, 13 Hz, 1H), 2.24-2.43 (m, 4H), 2.45 (s. , 3H), 2.56-2.79 (m, 4H), 2.80-2.91 (m, 1H), 2.93 (d, J = 18Hz, 1H), 3.01 (d, J = 6 Hz, 1 H), 4.63 (s, 1 H), 5.35 (br s, 1 H), 6.50 (d, J = 8 Hz, 1 H), 6.67 (d, J = 8 Hz, 1 H) ．

(Example 128)
(4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -1,2,3,4,6,7,8,8a-octahydro-5H-4a, 8-ethano-4,13- Methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (60) and (4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1 , 2,3,4,5,6,8,8a-Octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carba Synthesis of Ludehide (152)

To a solution of compound 150 (260 mg, 0.71 mmol) in N, N-dimethylformamide (10 mL) was added 1-dodecanethiol (1.68 mL, 7.1 mmol) and potassium tert-butoxide (796 mg, 7.1 mmol), Stirred at 150 ° C. for 1 hour. 1M hydrochloric acid was added to the reaction mixture under ice cooling, washed twice with heptane, and then 28% aqueous ammonia was added to make the mixture basic. The resulting 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 (silica gel carrying amino groups, 0-20% methanol / chloroform) to give compound 60 (206 mg, 82%) as a colorless amorphous compound 152 (60 mg, 22%). Was obtained as a colorless solid.

¹ H-NMR of compound 60:
The same NMR data as in Example 41 was shown.

Compound 152:
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.17 (m, 2H), 0.43-0.53 (m, 2H), 0.74-0.84 (m , 1H), 1.06-1.19 (m, 1H), 1.22-1.75 (m, 5H), 2.12-2.44 (m, 5H), 2.63 (dd, J = 5,18 Hz, 1H), 2.80-2.92 (m, 1H), 2.97 (d, J = 19 Hz, 1H), 3.05 (d, J = 6 Hz, 1H), 3.47 -3.59 (m, 2H), 4.40-4.46 (m, 1H), 4.49 (s, 1H), 4.77 (br s, 1H), 6.52-6.59 ( m, 1H), 6.72 (d, J = 8Hz, 1H), 8.10 (s, 0.9H), 8.21 (s, 0.1H).

(Example 129)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 Of ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (1H-indazol-5-yl) ethan-1-one (153) Synthesis

According to the method described in Example 60, the title compound was obtained from compound 9 and 2- (1H-indazol-5-yl) acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.19 (m, 2H), 0.36-0.55 (m, 2H), 0.62-0.93 (m , 1H), 0.97-1.82 (m, 6H), 1.86-1.98 (m, 0.6H), 2.09-2.56 (m, 5.6H), 2.60. -2.68 (m, 0.4H), 2.76-3.13 (m, 2.4H), 3.26-3.53 (m, 1H), 3.71-3.82 (m, 0.6H), 3.83-4.00 (m, 5H), 4.08-4.18 (m, 0.4H), 4.39-4.58 (m, 1.4H), 4. 59-4.73 (m, 0.6H), 6.55 (d, J = 8Hz, 0.6H), 6.62 (d, J = 8Hz, 0.4H), 6.66-6.77 (M, 1H), 7.34 (d, J = 1H , 0.4H), 7.37 (d, J = 1 Hz, 0.6H), 7.39-7.55 (m, 1H), 7.59-7.72 (m, 1H), 7.98. -8.07 (m, 1H).

(Example 130)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (1H-indazol-5-yl) ethan-1-one (154) Synthesis

According to the method described in Example 7, the title compound was obtained from compound 153.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.17 (m, 2H), 0.38-0.54 (m, 2H), 0.62-0.93 (m , 1H), 0.97-1.80 (m, 6H), 1.86-1.98 (m, 0.7H), 2.09-2.57 (m, 5.7H), 2.59 -2.67 (m, 0.3H), 2.78-3.02 (m, 2H), 3.04 (d, J = 6Hz, 0.3H), 3.30-3.57 (m, 1H), 3.71-3.99 (m, 2.7H), 4.05-4.18 (m, 0.3H), 4.38-4.63 (m, 2H), 6.51 ( d, J = 8Hz, 0.7H), 6.55 (d, J = 8Hz, 0.3H), 6.65-6.75 (m, 1H), 7.30-7.38 (m, 1H) ), 7.39-7.55 (m, 1H , 7.61-7.68 (m, 1H), 7.99-8.07 (m, 1H).

(Example 131)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 Of ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (1H-indazol-6-yl) ethan-1-one (155) Synthesis

The title compound was obtained from compound 9 and 2- (1H-indazol-6-yl) acetic acid according to the method described in Example 44.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.18 (m, 2H), 0.38-0.54 (m, 2H), 0.62-0.93 (m , 1H), 0.97-1.80 (m, 6H), 1.86-1.98 (m, 0.8H), 2.09-2.57 (m, 6H), 2.59-2 .67 (m, 0.2H), 2.77-3.10 (m, 2H), 3.26-3.53 (m, 1H), 3.73-3.88 (m, 0.8H) , 3.90-4.02 (m, 2H), 4.03-4.10 (m, 0.2H), 4.39-4.64 (m, 2H), 6.47-6.58 ( m, 1H), 6.66-6.75 (m, 1H), 7.03-7.15 (m, 1H), 7.45 (s, 0.2H), 7.57 (s, 0. 8H), 7.67-7.77 (m, 1H) 8.00-8.08 (m, 1H).

(Example 132)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (2H-1,2,3-triazol-2-yl) ethane-1 Synthesis of one-on (156)

According to the method described in Example 60, the title compound was obtained from compound 9 and 2- (2H-1,2,3-triazol-2-yl) acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.80 (m, 5H), 2.10-2.50 (m, 5H), 2.60-2.70. (M, 1H), 2.70-2.90 (m, 1H), 2.90-3.10 (m, 2H), 3.40-3.45 (m, 0.5H), 3.45 -3.50 (m, 0.5H), 3.50-3.55 (m, 0.5H), 3.86 (s, 1.5H), 3.88 (s, 1.5H), 3 .95-4.00 (m, 0.5H), 4.25-4.35 (m, 0.5H), 4.50-4.60 (m, 1.5H), 5.30-5. 50 (m, 2H), 6.57 (d, J = 8H , 0.5H), 6.64 (d, J = 8Hz, 0.5H), 6.71 (d, J = 8Hz, 0.5H), 6.75 (d, J = 8Hz, 0.5H) , 7.70 (s, 1H), 7.71 (s, 1H).

(Example 133)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (2H-1,2,3-triazol-2-yl) ethane-1 -Synthesis of one (157)

According to the method described in Example 7, the title compound was obtained from compound 156.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.90 (m, 5H), 2.10-2.45 (m, 5H), 2.50-3.10. (M, 4H), 3.40-3.80 (m, 1.7H), 3.90-4.00 (m, 0.3H), 4.20-4.30 (m, 0.3H) , 4.50-4.60 (m, 1.7H), 5.30-5.50 (m, 2H), 6.51 (d, J = 8Hz, 0.7H), 6.56 (d, J = 8 Hz, 0.3H), 6.60-6.70 (m, 1H), 7.65-7.75 (m, 2H).

(Example 134)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 Of ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (1H-indazol-3-yl) ethan-1-one (158) Synthesis

According to the method described in Example 60, the title compound was obtained from compound 9 and 2- (1H-indazol-3-yl) acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.17 (m, 2H), 0.39-0.56 (m, 2H), 0.66-1.90 (m , 6.7H), 2.08-2.51 (m, 6.3H), 2.59-2.70 (m, 0.3H), 2.79-3.14 (m, 2.4H) , 3.34-3.56 (m, 1H), 3.83-3.89 (m, 3H), 3.91-4.03 (m, 0.7H), 4.09-4.45 ( m, 3.6H), 4.50-4.69 (m, 1H), 6.52 (d, J = 8Hz, 0.7H), 6.61 (d, J = 8Hz, 0.3H), 6.69 (d, J = 8 Hz, 0.7H), 6.73 (d, J = 8 Hz, 0.3H), 7.11-7.22 (m, 1H), 7.33-7.51 (M, 2H), 7.78-7.84 m, 0.3H), 7.87-7.94 (m, 0.7H).

(Example 135)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 Of ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (1H-indazol-3-yl) ethan-1-one (159) Synthesis

According to the method described in Example 7, the title compound was obtained from compound 158.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.19 (m, 2H), 0.38-0.55 (m, 2H), 0.64-0.82 (m , 1H), 0.84-1.81 (m, 6H), 2.01-2.45 (m, 6.6H), 2.54-2.67 (m, 0.2H), 2.72 -3.09 (m, 2.2H), 3.23-3.55 (m, 1H), 3.91-4.07 (m, 0.8H), 4.08-4.47 (m, 3.4H), 4.49-4.63 (m, 0, 8H), 4.76 (br s, 1H), 6.48 (d, J = 8Hz, 0.8H), 6.54 (d , J = 8 Hz, 0.2H), 6.64-6.74 (m, 1H), 7.13-7.26 (m, 1H), 7.32-7.50 (m, 2H), 7 .85-7.94 (m, 1H).

(Example 136)
(E) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H -4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -3- (oxazol-2-yl) prop-2-en-1 -Synthesis of on (160)

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

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.16 (m, 2H), 0.44-0.55 (m, 2H), 0.73-0.86 (m , 1H), 1.08-1.79 (m, 6H), 2.11-2.46 (m, 5H), 2.59-2.69 (m, 1H), 2.85-2.95. (M, 1H), 2.99 (d, J = 18Hz, 0.4H), 3.00 (d, J = 19Hz, 0.6H), 3.05 (d, J = 7Hz, 0.4H) , 3.07 (d, J = 6 Hz, 0.6 H), 3.47 (ddd, J = 5, 11, 15 Hz, 0.6 H), 3.64 (ddd, J = 4, 11, 15 Hz, 0 .4H), 3.89 (s, 1.2H), 3.89 (s, 1.8H), 3.91-3.99 (m, 0.4H), 4.21-4.26 (m , 0.6H) 4.44 (ddd, J = 5, 5, 14 Hz, 0.6H), 4.51-4.54 (m, 0.6H), 4.57-4.59 (m, 0.4H), 4 .71-4.75 (m, 0.4H), 6.59 (d, J = 8Hz, 0.4H), 6.65 (d, J = 8Hz, 0.6H), 6.74 (d, J = 8 Hz, 0.4 H), 6.76 (d, J = 8 Hz, 0.6 H), 7.25 (s, 0.4 H), 7.25 (s, 0.6 H), 7.33 ( d, J = 15 Hz, 0.6 H), 7.38 (d, J = 15 Hz, 0.4 H), 7.43 (d, J = 15 Hz, 0.4 H), 7.55 (d, J = 15 Hz) , 0.6H), 7.68 (s, 0.6H), 7.69 (s, 0.4H).

(Example 137)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -3- (oxazol-2-yl) propan-1-one (161)

To a solution of compound 160 (4.6 mg, 0.0094 mmol) in ethanol (1 mL), 10% palladium-activated carbon (55% wet) (1.1 mg, 0.0057 mmol) was added, and the mixture was heated at room temperature under a hydrogen atmosphere for 18 hours. It was stirred. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give a crude product of the title compound (5.0 mg) as a colorless oily substance.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.16 (m, 2H), 0.43-0.55 (m, 2H), 0.73-0.86 (m , 1H), 1.04-1.15 (m, 1H), 1.19-1.75 (m, 5H), 2.12-2.44 (m, 5H), 2.59-2.67. (M, 1H), 2.75-3.33 (m, 7.5H), 3.53 (ddd, J = 4, 11, 15Hz, 0.5H), 3.75-3.83 (m, 0.5H), 3.87 (s, 1.5H), 3.87 (s, 1.5H), 4.03-4.06 (m, 0.5H), 4.41-4.50 ( m, 1H), 4.54-4.57 (m, 0.5H), 4.59-4.64 (m, 0.5H), 6.57 (d, J = 8Hz, 0.5H), 6.62 (d, J = 8 Hz, 0. H), 6.72 (d, J = 8 Hz, 0.5 H), 6.74 (d, J = 8 Hz, 0.5 H), 7.01 (d, J = 7 Hz, 1 H), 7.56 ( d, J = 7 Hz, 0.5 H), 7.56 (d, J = 7 Hz, 0.5 H).

(Example 138)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -3- (oxazol-2-yl) propan-1-one (162)

According to the method described in Example 7, the title compound was obtained from compound 161.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.15 (m, 2H), 0.43-0.54 (m, 2H), 0.73-0.83 (m , 1H), 1.03-1.13 (m, 1H), 1.21-1.71 (m, 5H), 2.13-2.42 (m, 5H), 2.59-2.67. (M, 1H), 2.76-3.05 (m, 5H), 3.09-3.27 (m, 2H), 3.32 (ddd, J = 5, 11, 15Hz, 0.4H) , 3.51 (ddd, J = 4, 11, 15 Hz, 0.6H), 3.82 (ddd, J = 3, 5, 15 Hz, 0.6H), 4.01-4.04 (m, 0 .4H), 4.36-4.44 (m, 0.4H), 4.45-4.48 (m, 0.6H), 4.51-4.55 (m, 0.6H), 4 .56-4.58 m, 0.4H), 4.97 (br s, 1H), 6.52 (d, J = 8Hz, 0.6H), 6.53-6.57 (m, 0.4H), 6.70. (D, J = 8 Hz, 0.4 H), 6.71 (d, J = 8 Hz, 0.6 H), 7.00-7.03 (m, 1 H), 7.56-7.58 (m, 1H).

(Example 139)
((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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (3-hydroxypyridin-2-yl) methanone (163)

According to the method described in Example 44, the title compound was obtained from compound 9 and 3-hydroxypicolinic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.14 (m, 2H), 0.41-0.53 (m, 2H), 0.71-0.85 (m , 1H), 1.02-1.15 (m, 1H), 1.20-1.50 (m, 3.3H), 1.51-1.60 (m, 0.7H), 1.65 -1.81 (m, 1H), 2.10-2.43 (m, 5H), 2.50-2.68 (m, 1H), 2.84-3.11 (m, 3H), 3 .36-3.45 (m, 0.3H), 3.62-3.78 (m, 0.7H), 4.56-5.18 (m, 3H), 6.49-6.56 ( m, 1H), 6.68-6.76 (m, 1H), 7.20-7.36 (m, 2H), 8.00-8.12 (m, 0.7H), 8.19- 8.22 (m, 0.3H).

(Reference Example 27)
(4R, 4aS, 7S, 7aR, 12bS) -3- (Cyclopropylmethyl) -7,9-dimethoxy-5-methyl-1,2,3,4,7,7a-hexahydro-4a, 7-ethano- Synthesis of 4,12-methanobenzofuro [3,2-e] isoquinolin-6 (5H) -one (164)

To an anhydrous tetrahydrofuran solution of compound 143 (323 mg, 0.558 mmol), 11% KHMDS toluene solution (3.5 mL, 1.76 mmol) was added dropwise under ice bath, and the mixture was stirred under nitrogen atmosphere for 10 minutes under ice bath. Iodomethane (110 μL, 1.76 mmol) was added dropwise at the same temperature and the mixture was stirred for 30 minutes, then warmed to room temperature and stirred for 16 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture under an ice bath, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (15-30% ethyl acetate / heptane) to give the title compound (141 mg, 59%) as a white solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.18 (m, 2H), 0.41-0.60 (m, 2H), 0.73-0.91 (m , 2H), 1.17 (d, J = 7 Hz, 3H), 1.23-1.63 (m, 2H), 1.64-1.79 (m, 2H), 2.09-2.45. (M, 5H), 2.64 (dd, J = 6, 12 Hz, 1H), 3.07 (d, J = 18 Hz, 1H), 3.25 (d, J = 6 Hz, 1H), 3.32 -3.42 (m, 1H), 3.52 (s, 3H), 3.89 (s, 3H), 4.67 (d, J = 2Hz, 1H), 6.64 (d, J = 8Hz) , 1H), 6.76 (d, J = 8 Hz, 1H).

(Reference Example 28)
(4R, 4aS, 7R, 7aR, 12bS) -3- (Cyclopropylmethyl) -7,9-dimethoxy-5-methyl-1,2,3,4,7,7a-hexahydro-4a, 7-ethano- Synthesis of 4,12-methanobenzofuro [3,2-e] isoquinolin-6 (5H) -one oxime (165)

According to the method described in Reference Example 2, the title compound was obtained from compound 164.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.18 (m, 2H), 0.41-0.72 (m, 3H), 0.77-0.91 (m , 1H), 1.26 (d, J = 7 Hz, 3H), 1.38-1.77 (m, 4H), 1.98-2.11 (m, 1H), 2.14-2.44. (M, 4H), 2.59 (dd, J = 6, 12Hz, 1H), 3.05 (d, J = 18Hz, 1H), 3.29 (d, J = 7Hz, 1H), 3.48 (S, 3H), 3.88 (s, 3H), 4.02-4.13 (m, 1H), 4.43 (d, J = 1 Hz, 1H), 6.59 (d, J = 8 Hz) , 1H), 6.74 (d, J = 8 Hz, 1H), 7.12 (br s, 1H).

(Reference Example 29)
2-((4R, 4aS, 7aR, 12bS) -3- (cyclopropylmethyl) -9-methoxy-7-oxo-1,2,3,4,5,6,7,7a-octahydro-4aH-4 Of 12,12-Methanobenzofuro [3,2-e] isoquinolin-4a-yl) propanenitrile (166)

According to the method described in Reference Example 3, the title compound was obtained from compound 165.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.19 (m, 2H), 0.45-0.61 (m, 2H), 0.71-0.93 (m , 1H), 1.33 (d, J = 7Hz, 0.6H), 1.42 (d, J = 7Hz, 2.4H), 1.48-1.67 (m, 2H), 1.68 -1.76 (m, 0.2H), 1.83-1.93 (m, 0.8H), 2.08-2.48 (m, 6H), 2.62-2.74 (m, 1H), 2.91-3.09 (m, 1.6H), 3.13 (d, J = 6Hz, 0.8H), 3.17-3.26 (m, 0.2H), 3. 30 (d, J = 6 Hz, 0.2H), 3.40-3.47 (m, 0.2H), 3.90 (s, 3H), 4.55 (s, 0.2H), 4. 90-5.12 (m, 1H), 5.2 (S, 0.8H), 6.56-6.78 (m, 2H).

(Reference Example 30)
2-((4R, 4aS, 7S, 7aR, 12bS) -3- (cyclopropylmethyl) -7-hydroxy-9-methoxy-1,2,3,4,5,6,7,7a-octahydro-4aH Synthesis of -4,12-methanobenzofuro [3,2-e] isoquinolin-4a-yl) propanenitrile (167)

According to the method described in Reference Example 5, the title compound was obtained from compound 166.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.19 (m, 2H), 0.38-0.58 (m, 2H), 0.64-1.72 (m , 7H), 2.02-2.50 (m, 6H), 2.55-2.69 (m, 1H), 2.87-3.05 (m, 2H), 3.47-3.58. (M, 0.2H), 3.80-3.99 (m, 3H), 4.05-4.16 (m, 2H), 4.32-4.40 (m, 0.8H), 4 0.83-5.03 (m, 1.2H), 5.19 (d, J = 6Hz, 0.8H), 6.52-6.66 (m, 1H), 6.68-6.77 ( m, 1H).

(Reference example 31)
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-methanobenzofuro [3,2-e] isoquinolin-4a-yl) propyl) carbamate (168)

According to the method described in Reference Example 6, the title compound was obtained from compound 167.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.18 (m, 2H), 0.41-0.54 (m, 2H), 0.68-1.76 (m , 9H), 1.97-2.56 (m, 5H), 2.58-2.76 (m, 2H), 2.82-3.05 (m, 2H), 3.18-3.36. (M, 3H), 3.80-3.94 (m, 4H), 4.68-4.82 (m, 1H), 4.87-5.01 (m, 1H), 5.06-5 .22 (m, 2H), 6.61 (d, J = 8Hz, 1H), 6.71 (d, J = 8Hz, 1H), 7.23-7.44 (m, 5H).

(Reference Example 32)
(4R, 4aS, 7S, 7aR, 12bS) -4a- (1-(((benzyloxy) carbonyl) amino) propan-2-yl) -3- (cyclopropylmethyl) -9-methoxy-2,3,4 , 4a, 5,6,7,7a-Octahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinolin-7-yl methanesulfonate (169)

According to the method described in Reference Example 7, the title compound was obtained from compound 168.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.17 (m, 2H), 0.42-0.55 (m, 2H), 0.71-1.07 (m , 4H), 1.12-1.78 (m, 5H), 1.94-2.55 (m, 5H), 2.59-2.73 (m, 1H), 2.85-3.44. (M, 8H), 3.87 (s, 3H), 4.67-5.03 (m, 3H), 5.07-5.28 (m, 2H), 6.60 (d, J = 8Hz) , 1H), 6.72 (d, J = 8 Hz, 1H), 7.21-7.45 (m, 5H).

(Example 140)
Benzyl (4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-5-methyl-1,2,3,4,5,6,8,8a-octahydro-7H-4a Of, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxylate (170)

According to the method described in Example 1, the title compound was obtained from compound 169.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.17 (m, 2H), 0.42-0.54 (m, 2H), 0.77-0.99 (m , 5H), 1.21-1.73 (m, 4H), 2.12-2.40 (m, 5H), 2.63-3.14 (m, 5H), 3.81-3.92. (M, 3H), 3.94-4.55 (m, 3H), 5.05-5.27 (m, 2H), 6.52-6.63 (m, 1H), 6.66-6 0.78 (m, 1H), 7.22-7.46 (m, 5H).

(Example 141)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-methoxy-5-methyl-1,2,3,4,6,7,8,8a-octahydro-5H-4a, Synthesis of 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (171)

According to the method described in Example 2, the title compound was obtained from compound 170.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02-0.18 (m, 2H), 0.40-0.57 (m, 2H), 0.66-0.98 (m , 5H), 1.17-1.80 (m, 4H), 2.14-2.50 (m, 5H), 2.58-3.28 (m, 7H), 3.78-3.92. (M, 3H), 4.44 (s, 0.9H), 4.53 (s, 0.1H), 6.50-6.61 (m, 1H), 6.65-6.76 (m , 1H).

(Example 142)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-5-methyl-1,2,3,4,5,6,8,8a-octahydro-7H -4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (pyrimidin-2-yl) ethan-1-one (172 ) Synthesis

According to the method described in Example 60, the title compound was obtained from compound 171 and 2- (pyrimidin-2-yl) acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.18 (m, 2H), 0.41-0.58 (m, 2H), 0.75-1.76 (m , 8H), 2.13-2.43 (m, 5H), 2.51-2.87 (m, 2.4H), 2.92-3.18 (m, 3H), 3.60-3. .72 (m, 0.6H), 3.82-3.91 (m, 3H), 4.04-4.30 (m, 3H), 4.48-4.65 (m, 2H), 6 .55 (d, J = 8 Hz, 0.6 H), 6.61 (d, J = 8 Hz, 0.4 H), 6.67-6.77 (m, 1 H), 7.14-7.27 ( m, 1H), 8.66-8.78 (m, 2H).

(Example 143)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-5-methyl-1,2,3,4,5,6,8,8a-octahydro-7H -4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (pyrimidin-2-yl) ethan-1-one (173 ) Synthesis

According to the method described in Example 7, the title compound was obtained from compound 172.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02-0.18 (m, 2H), 0.41-0.56 (m, 2H), 0.74-1.73 (m , 8H), 2.00-2.85 (m, 8H), 2.87-3.18 (m, 3H), 3.67 (dd, J = 5, 15Hz, 0.7H), 4.02. -4.29 (m, 2.3H), 4.48-4.64 (m, 2.3H), 4.75 (s, 0.7H), 6.51 (d, J = 8Hz, 0. 7H), 6.55 (d, J = 8Hz, 0.3H), 6.66-6.74 (m, 1H), 7.15-7.29 (m, 1H), 8.68-8. 79 (m, 2H).

(Example 144)
2- (5-Bromopyrimidin-2-yl) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,5 6,8,8a-Octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) ethan-1-one (174) Synthesis of

According to the method described in Example 42, the title compound was obtained from compound 9 and 2- (5-bromopyrimidin-2-yl) acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.15 (m, 2H), 0.43-0.54 (m, 2H), 0.72-0.85 (m , 1H), 1.04-1.58 (m, 5H), 1.62-1.79 (m, 1H), 2.11-2.46 (m, 5H), 2.59-2.68. (M, 1H), 2.69-2.79 (m, 0.6H), 2.81-2.90 (m, 0.4H), 2.97 (d, J = 17Hz, 0.6H) , 3.00 (d, J = 18 Hz, 0.4 H), 3.00 (d, J = 6 Hz, 0.6 H), 3.06 (d, J = 6 Hz, 0.4 H), 3.40 ( ddd, J = 4, 10, 14 Hz, 0.4H), 3.54 (ddd, J = 4, 11, 15 Hz, 0.6H), 3.70-3.79 (m, 0.6H), 3 .87 (s, H), 4.11-4.15 (m, 0.4H), 4.12 (d, J = 15Hz, 0.6H), 4.13 (d, J = 15Hz, 0.4H), 4. 14 (d, J = 15 Hz, 0.4 H), 4.15 (d, J = 15 Hz, 0.6 H), 4.39 (ddd, J = 5, 5, 14 Hz, 0.4 H), 4.56 -4.59 (m, 0.6H), 4.61-4.67 (m, 1H), 6.57 (d, J = 8Hz, 0.6H), 6.63 (d, J = 8Hz, 0.4H), 6.72 (d, J = 8Hz, 0.6H), 6.74 (d, J = 8Hz, 0.4H), 8.75 (s, 0.8H), 8.78 ( s, 1.2H).

(Example 145)
2- (5-Bromopyrimidin-2-yl) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,5 6,8,8a-Octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) ethan-1-one (175) Synthesis of

According to the method described in Example 7, the title compound was obtained from compound 174.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.15 (m, 2H), 0.43-0.54 (m, 2H), 0.71-0.83 (m , 1H), 1.02-1.13 (m, 1H), 1.17-1.55 (m, 4H), 1.59-1.74 (m, 1H), 2.09-2.42. (M, 5H), 2.57-2.64 (m, 1H), 2.65-2.75 (m, 0.7H), 2.78-2.88 (m, 0.3H), 2 .94 (d, J = 18 Hz, 0.7 H), 2.95 (d, J = 19 Hz, 0.3 H), 2.98 (d, J = 6 Hz, 0.7 H), 3.04 (d, J = 6 Hz, 0.3 H), 3.39 (ddd, J = 5, 11, 15 Hz, 0.3 H), 3.52 (ddd, J = 4, 12, 15 Hz, 0.7 H), 3.76 (Ddd, = 3,5,15 Hz, 0.7H), 4.07-4.18 (m, 0.3H), 4.12 (d, J = 16Hz, 1H), 4.17 (d, J = 16Hz, 0.7H), 4.17 (d, J = 16Hz, 0.3H), 4.36 (ddd, J = 5, 5,14Hz, 0.3H), 4.52-4.60 (m, 1) .7H), 6.50 (d, J = 8Hz, 0.7H), 6.52 (d, J = 9Hz, 0.3H), 6.69 (d, J = 9Hz, 0.3H), 6 .69 (d, J = 8 Hz, 0.7H), 8.75 (s, 0.6H), 8.76 (s, 1.4H).

(Example 146)
((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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (pyrrolidin-1-yl) methanone (176)

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

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.75 (m, 5H), 1.75-1.90 (m, 4H), 2.20-2.45. (M, 5H), 2.55-2.65 (m, 1H), 2.75-2.90 (m, 1H), 2.90-3.00 (m, 1H), 3.04 (d , J = 6 Hz, 1H), 3.30-3.50 (m, 4H), 3.60-3.70 (m, 1H), 3.87 (s, 3H), 3.95-4.05. (M, 1H), 4.55-4.65 (m, 1H), 5.00 (br s, 1H), 6.58 (d, J = 8 Hz, 1H), 6.71 (d, J = 8 Hz, 1H).

(Example 147)
((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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (pyrrolidin-1-yl) methanone (177)

According to the method described in Example 7, the title compound was obtained from compound 176.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.80 (m, 9H), 2.20-2.40 (m, 5H), 2.45-2.55. (M, 1H), 2.80-2.90 (m, 1H), 2.94 (d, J = 18Hz, 1H), 3.03 (d, J = 6Hz, 1H), 3.10-3 .20 (m, 4H), 3.35-3.45 (m, 1H), 3.55-3.65 (m, 1H), 4.00-4.10 (m, 1H), 4.55 -4.65 (m, 1H), 5.00 (br s, 1H), 6.51 (d, J = 8Hz, 1H), 6.69 (d, J = 8Hz, 1H).

(Example 148)
((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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (piperidin-1-yl) methanone (178)

According to the method described in Example 5, the title compound was obtained from compound 11 and piperidine.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.80 (m, 10H), 2.20-2.45 (m, 5H), 2.55-2.70. (M, 1H), 2.80-3.10 (m, 3H), 3.10-3.25 (m, 4H), 3.30-3.45 (m, 1H), 3.55-3 .65 (m, 1H), 3.65-3.80 (m, 1H), 3.87 (s, 3H), 4.05-4.10 (m, 1H), 4.55-4.60. (M, 1H), 6.56 (d, J = 8Hz, 1H), 6.71 (d, J = 8Hz, 1H).

(Example 149)
((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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (piperidin-1-yl) methanone (179)

According to the method described in Example 7, the title compound was obtained from compound 178.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.80 (m, 12H), 2.15-2.45 (m, 5H), 2.55-2.65. (M, 1H), 2.80-2.90 (m, 1H), 2.95 (d, J = 18Hz, 1H), 3.04 (d, J = 6Hz, 1H), 3.10-3 .20 (m, 3H), 3.35-3.45 (m, 1H), 3.55-3.65 (m, 1H), 4.00-4.10 (m, 1H), 4.60. -4.65 (m, 1H), 5.00 (br s, 1H), 6.52 (d, J = 8Hz, 1H), 6.70 (d, J = 8Hz, 1H).

(Example 150)
Azepan-1-yl ((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H- Synthesis of 4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) methanone (180)

According to the method described in Example 5, the title compound was obtained from compound 11 and hexamethyleneimine.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.80 (m, 13H), 2.15-2.45 (m, 5H), 2.60-2.70. (M, 1H), 2.80-3.10 (m, 3H), 3.25-3.40 (m, 4H), 3.40-3.50 (m, 1H), 3.65-3 .80 (m, 1H), 3.87 (s, 3H), 3.90-4.00 (m, 1H), 4.55-4.60 (m, 1H), 6.57 (d, J) = 8 Hz, 1H), 6.71 (d, J = 8 Hz, 1H).

(Example 151)
Azepan-1-yl ((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H- Synthesis of 4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) methanone (181)

According to the method described in Example 7, the title compound was obtained from compound 180.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm) 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m, 1H), 1.00-1.15 (m, 1H), 1.20-1.90 (m, 13H), 2.10-2.45 (m, 5H), 2.55-2.70 ( m, 1H), 2.80-3.00 (m, 2H), 3.00-3.10 (m, 1H), 3.30-3.45 (m, 5H), 3.45-3. 55 (m, 1H), 3.95-4.05 (m, 1H), 4.55-4.65 (m, 1H), 6.51 (d, J = 8Hz, 1H), 6.68 ( d, J = 8 Hz, 1H).

(Example 152)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-methoxy-7- (pyridin-3-ylsulfonyl) -1,2,3,4,6,7,8,8a -Synthesis of octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (182)

To a solution of compound 9 (22.8 mg, 0.062 mmol) in dichloromethane (1 mL) was added triethylamine (17.3 μL, 0.12 mmol) and pyridine-3-sulfonyl chloride (20 mg, 0.093 mmol), and the mixture was kept at room temperature for 10 minutes. It was stirred. 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 with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: methanol = 20: 1) to obtain the title compound (30.3 mg, 96%) as a colorless oily substance.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.13 (m, 2H), 0.45-0.55 (m, 2H), 0.74-0.83 (m , 1H), 0.93 to 1.03 (m, 1H), 1.08 to 1.19 (m, 2H), 1.20 to 1.31 (m, 1H), 1.47 (ddd, J = 4, 4, 15 Hz, 1H), 1.51-1.59 (m, 1H), 2.20-2.39 (m, 5H), 2.59-2.68 (m, 1H), 2 .93-3.06 (m, 3H), 3.11-3.20 (m, 1H), 3.81-3.89 (m, 1H), 3.86 (s, 3H), 4.02 -4.06 (m, 1H), 4.56-4.59 (m, 1H), 6.58 (d, J = 8Hz, 1H), 6.71 (d, J = 8Hz, 1H), 7 .44-7.49 (m, H), 8.08-8.12 (m, 1H), 8.80 (dd, J = 2,5Hz, 1H), 9.03 (dd, J = 1,2Hz, 1H).

(Example 153)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -7- (pyridin-3-ylsulfonyl) -1,2,3,4,6,7,8,8a-octahydro-5H Of -4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (183)

According to the method described in Example 7, the title compound was obtained from compound 182.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.15 (m, 2H), 0.42-0.55 (m, 2H), 0.73-0.83 (m , 1H), 0.93-1.04 (m, 1H), 1.06-1.20 (m, 2H), 1.21-1.33 (m, 1H), 1.46 (ddd, J = 3,3,15 Hz, 1H), 1.51-1.60 (m, 1H), 2.19-2.37 (m, 5H), 2.60-2.70 (m, 1H), 2 .94 (d, J = 19 Hz, 1H), 2.95-3.05 (m, 2H), 3.12 (ddd, J = 3, 12, 12 Hz, 1H), 3.83-3.90 ( m, 1H), 3.99-4.03 (m, 1H), 4.58-4.62 (m, 1H), 5.66 (br s, 1H), 6.52 (d, J = 8Hz) , 1H), .69 (d, J = 8 Hz, 1H), 7.50 (dd, J = 5, 8 Hz, 1H), 8.13 (ddd, J = 1, 2, 8 Hz, 1H), 8.81 (dd, J = 1,5 Hz, 1H), 9.06 (d, J = 2 Hz, 1H).

(Example 154)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2-methylpropan-1-one (184)

According to the method described in Example 60, the title compound was obtained from compound 9 and isobutyric acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.80 (m, 11H), 2.05-2.45 (m, 5H), 2.55-2.70 (m, 1H), 2.70-3.10. (M, 5H), 3.20-3.30 (m, 0.5H), 3.45-3.55 (m, 0.5H), 3.70-3.90 (m, 0.5H) , 3.86 (s, 3H), 4.00-4.10 (m, 0.5H), 4.35-4.50 (m, 1.5H), 4.55-4.60 (m, 0.5H), 6.55 (d, J = 8Hz, 0.5H), 6.60 (d, J = 8Hz, 0.5H), 6.95-7.20 (m, 1H).

(Example 155)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2-methylpropan-1-one (185)

According to the method described in Example 7, the title compound was obtained from compound 184.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.80 (m, 12H), 2.05-2.40 (m, 5H), 2.55-2.65 (m, 1H), 2.70-3.10. (M, 4H), 3.25-3.35 (m, 0.3H), 3.40-3.55 (m, 0.7H), 3.75-3.85 (m, 0.7H) , 3.90-4.00 (m, 0.3H), 4.35-4.60 (m, 2H), 6.50 (d, J = 8Hz, 0.7H), 6.54 (d, J = 8 Hz, 0.3H), 6.65-6.75 (m, 1H).

(Reference Example 33)
Synthesis of ethyl 2- (5- (methylamino) pyrimidin-2-yl) acetate (186)

Following the method described in Example 115, the title compound was obtained from ethyl 2- (5-aminopyrimidin-2-yl) acetate and 75% granular paraformaldehyde.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.26 (t, J = 7 Hz, 3 H), 2.89 (d, J = 6 Hz, 3 H), 3.74 (br s, 1 H) , 3.91 (s, 2H), 4.20 (q, J = 7Hz, 2H), 8.09 (s, 2H).

(Reference Example 34)
Synthesis of ethyl 2- (5- (dimethylamino) pyrimidin-2-yl) acetate (187)

Following the method described in Example 115, the title compound was obtained from compound 186 and 75% granular paraformaldehyde.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.27 (t, J = 7 Hz, 3 H), 2.99 (s, 6 H), 3.91 (s, 2 H), 4.20 ( q, J = 7 Hz, 2H), 8.18 (s, 2H).

(Example 156)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (5- (dimethylamino) pyrimidin-2-yl) ethan-1-one Synthesis of (188)

Lithium hydroxide monohydrate (4.2 mg, 0.10 mmol) and water (0.5 mL) were added to a solution of compound 187 (10 mg, 0.050 mmol) in methanol (0.5 mL), and the mixture was stirred at room temperature for 3 hours. After that, it was concentrated under reduced pressure. Then, according to the method described in Example 60, the title compound (9.4 mg, 54%) was obtained as a yellow oily substance from the obtained concentrated residue and compound 9 (12 mg, 0.033 mmol).

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.18 (m, 2H), 0.39-0.57 (m, 2H), 0.69-0.93 (m , 1H), 1.00-1.88 (m, 6H), 2.07-2.47 (m, 5H), 2.55-2.69 (m, 1.4H), 2.77-3. .10 (m, 8.6H), 3.36-3.57 (m, 1H), 3.62-4.47 (m, 6.6H), 4.57-4.73 (m, 1.H). 4H), 6.52-6.65 (m, 1H), 6.67-6.77 (m, 1H), 8.14-8.23 (m, 2H).

(Example 157)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (5- (dimethylamino) pyrimidin-2-yl) ethan-1-one Synthesis of (189)

According to the method described in Example 7, the title compound was obtained from compound 188.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.17 (m, 2H), 0.40-0.55 (m, 2H), 0.69-0.93 (m , 1H), 1.00-1.80 (m, 6H), 2.02-2.45 (m, 5H), 2.52-2.70 (m, 1.7H), 2.73-3 .19 (m, 8.3H), 3.35-3.54 (m, 1H), 3.74-3.87 (m, 0.7H), 3.98-4.20 (m, 2.H). 3H), 4.29-4.44 (m, 0.3H), 4.52-4.92 (m, 2.7H), 6.51 (d, J = 8Hz, 0.7H), 6. 55 (d, J = 8 Hz, 0.3H), 6.66-6.73 (m, 1H), 8.16-8.23 (m, 2H).

(Example 158)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-methoxy-N- (2-methoxyethyl) -N-methyl-1,2,3,4,5,6,8 , 8a-Octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (190)

According to the method described in Example 5, the title compound was obtained from compound 11 and 2-methoxy-N-methylethan-1-amine.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.15 (m, 2H), 0.43-0.54 (m, 2H), 0.73-0.84 (m , 1H), 1.00-1.10 (m, 1H), 1.23-1.44 (m, 4H), 1.49-1.57 (m, 1H), 2.20-2.32. (M, 3H), 2.33-2.42 (m, 2H), 2.57-2.67 (m, 1H), 2.83-2.93 (m, 1H), 2.91 (s , 3H), 2.97 (d, J = 18 Hz, 1H), 3.04 (d, J = 6 Hz, 1H), 3.31-3.36 (m, 1H), 3.35 (s, 3H). ), 3.38 (t, J = 6 Hz, 2H), 3.55 (t, J = 6 Hz, 2H), 3.57-3.61 (m, 1H), 3.87 (s, 3H), 4.01-4.05 (m 1H), 4.60 (dd, J = 2,2Hz, 1H), 6.58 (d, J = 8Hz, 1H), 6.72 (d, J = 8Hz, 1H).

(Example 159)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-hydroxy-N- (2-hydroxyethyl) -N-methyl-1,2,3,4,5,6,8 , 8a-Octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (191)

According to the method described in Example 7, the title compound was obtained from compound 190.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.15 (m, 2H), 0.41-0.54 (m, 2H), 0.73-0.82 (m , 1H), 1.00-1.10 (m, 1H), 1.20-1.45 (m, 3H), 1.48-1.55 (m, 1H), 1.60-1.71 (M, 1H), 2.18-2.40 (m, 5H), 2.57-2.65 (m, 1H), 2.76-2.87 (m, 1H), 2.94 (d , J = 18 Hz, 1H), 2.95 (s, 3H), 3.02 (d, J = 6 Hz, 1H), 3.17-3.25 (m, 1H), 3.37-3.47. (M, 1H), 3.51-3.67 (m, 2H), 3.73-3.81 (m, 1H), 3.82-3.89 (m, 1H), 3.94-4 0.00 (m, 1H), 4.6 -4.64 (m, 1H), 6.51 (d, J = 8Hz, 1H), 6.70 (d, J = 8Hz, 1H).

(Example 160)
((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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (1- (pyrimidin-2-yl) cyclopropyl) methanone (192)

According to the method described in Example 68, the title compound was obtained from compound 60 and 1- (pyrimidin-2-yl) cyclopropane-1-carboxylic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.17 (m, 2H), 0.37-0.54 (m, 2H), 0.64-0.92 (m , 1H), 0.99-1.81 (m, 10H), 2.10-2.43 (m, 5H), 2.52-2.72 (m, 2H), 2.85-3.10. (M, 2H), 3.28-3.55 (m, 1H), 3.84-3.99 (m, 1H), 4.55-5.06 (m, 3H), 6.46-6 .58 (m, 1H), 6.61-6.76 (m, 1H), 7.05-7.16 (m, 1H), 8.57-8.69 (m, 2H).

(Reference Example 35)
Synthesis of methyl 2- (5-ethynylpyrimidin-2-yl) acetate (193)

Ethyl 2- (5-bromopyrimidin-2-yl) acetate (141 mg, 0.57 mmol), bis (triphenylphosphine) palladium (II) dichloride (20 mg, 0.028 mmol), copper (I) iodide (11 mg, 0.060 mmol), triethylamine (0.32 mL, 2.3 mmol) and trimethylsilylacetylene (0.16 mL, 1.2 mmol) in tetrahydrofuran (2 mL) were stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, filtered through Celite, and the filtrate was concentrated under reduced pressure. Potassium carbonate (159 mg, 1.2 mmol) was added to a solution of the obtained crude product in methanol / tetrahydrofuran (v / v = 2/1, 3 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, water was added, and the mixture was extracted 3 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 (20-50% ethyl acetate / heptane) to give the title compound (11 mg, 10%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.39 (s, 1H), 3.75 (s, 3H), 4.06 (s, 2H), 8.79 (s, 2H) ．

(Reference Example 35)
Synthesis of 2- (5-ethynylpyrimidin-2-yl) acetic acid (194)

Lithium hydroxide monohydrate (2.8 mg, 0.067 mmol) was added to a tetrahydrofuran / water (v / v = 2/1, 1.5 mL) solution of compound 193, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 ° C., 1M hydrochloric acid (3 mL) was added, and the mixture was extracted 3 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 to obtain a crude product of the title compound (8.8 mg, 90%) as a pale-yellow solid.

¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 3.98 (s, 1H), 4.01 (s, 2H), 8.82 (s, 2H).

(Example 161)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (5-ethynylpyrimidin-2-yl) ethan-1-one (195) Synthesis of

According to the method described in Example 42, the title compound was obtained from compound 9 and compound 194.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.16 (m, 2H), 0.43-0.55 (m, 2H), 0.72-0.84 (m , 1H), 1.04-1.80 (m, 6H), 2.11-2.46 (m, 5H), 2.59-2.79 (m, 1.6H), 2.81-2 .91 (m, 0.4H), 2.97 (d, J = 18Hz, 0.6H), 2.99 (d, J = 6Hz, 0.6H), 3.00 (d, J = 18Hz, 0.4H), 3.06 (d, J = 6Hz, 0.4H), 3.36 (s, 0.4H), 3.37-3.45 (m, 0.4H), 3.38 ( s, 0.6H), 3.53 (ddd, J = 4, 11, 15Hz, 0.6H), 3.70-3.78 (m, 0.6H), 3.87 (s, 3H), 4.11-4.19 (m 1.4H), 4.20 (d, J = 15Hz, 0.4H), 4.21 (d, J = 16Hz, 0.6H), 4.40 (ddd, J = 5, 5, 14Hz, 0) .4H), 4.57-4.60 (m, 0.6H), 4.62-4.68 (m, 1H), 6.57 (d, J = 8Hz, 0.6H), 6.63 (D, J = 8 Hz, 0.4 H), 6.72 (d, J = 8 Hz, 0.6 H), 6.74 (d, J = 8 Hz, 0.4 H), 8.77 (s, 0. 8H), 8.80 (s, 1.2H).

(Example 162)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (5-ethynylpyrimidin-2-yl) ethan-1-one (196) Synthesis of

According to the method described in Example 32, the title compound was obtained from compound 195.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.16 (m, 2H), 0.43-0.54 (m, 2H), 0.71-0.83 (m , 1H), 1.03 to 1.16 (m, 1H), 1.18 to 1.80 (m, 5H), 2.12 to 2.43 (m, 5H), 2.58 to 2.75. (M, 1.7H), 2.80-2.89 (m, 0.3H), 2.93-3.00 (m, 0.3H), 2.95 (d, J = 18Hz, 0. 7H), 2.99 (d, J = 6Hz, 0.7H), 3.05 (d, J = 6Hz, 0.3H), 3.36-3.46 (m, 0.3H), 3. 36 (s, 0.3H), 3.38 (s, 0.7H), 3.52 (ddd, J = 4, 12, 15Hz, 0.7H), 3.72-3.81 (m, 0) .7H), 4.08-4.2 (M, 0.3H), 4.18 (d, J = 16Hz, 0.7H), 4.19 (d, J = 16Hz, 0.3H), 4.22 (d, J = 16Hz, 1H) , 4.37 (ddd, J = 5,5,14 Hz, 0.3H), 4.56-4.62 (m, 1.7H), 6.52 (d, J = 8 Hz, 0.7H), 6.55 (d, J = 8 Hz, 0.3 H), 6.70 (d, J = 8 Hz, 0.3 H), 6.70 (d, J = 8 Hz, 0.7 H), 8.79 (s) , 0.6H), 8.80 (s, 1.4H).

(Example 163)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -N- (2- (dimethylamino) ethyl) -10-hydroxy-N-methyl-1,2,3,4,5,5 Synthesis of 6,8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carboxamide (197)

According to the method described in Example 8, the title compound was obtained from Compound 11 and N ¹ , N ¹ , N ² -trimethylethane-1,2-diamine.

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), 0.99-1.10 (m, 1H), 1.19-1.42 (m, 3H), 1.49-1.55 (m, 1H), 1.59-1.70. (M, 1H), 2.19-2.39 (m, 5H), 2.28 (s, 6H), 2.46-2.58 (m, 2H), 2.59-2.64 (m , 1H), 2.80-2.92 (m, 1H), 2.86 (s, 3H), 2.94 (d, J = 18Hz, 1H), 3.02 (d, J = 6Hz, 1H ), 3.26-3.41 (m, 1H), 3.30 (t, J = 7 Hz, 2H), 3.52-3.59 (m, 1H), 3.97-4.01 (m , 1H), 4.60-4. 4 (m, 1H), 6.51 (d, J = 8Hz, 1H), 6.68 (d, J = 8Hz, 1H).

(Example 164)
((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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (3-methylpyrazin-2-yl) methanone (198)

According to the method described in Example 60, the title compound was obtained from compound 9 and 3-methylpyrazine-2-carboxylic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-2.00 (m, 5H), 2.10-2.50 (m, 5H), 2.50-2.70 (m, 4H), 2.80-3.20. (M, 4H), 3.25-3.75 (m, 2H), 3.79 (s, 1.2H), 3.90 (s, 1.8H), 4.45-4.60 (m , 0.4H), 4.65-4.90 (m, 1.6H), 6.60 (d, J = 8Hz, 1H), 6.69 (d, J = 8Hz, 0.4H), 6 0.75 (d, J = 8 Hz, 0.6H), 8.30-8.60 (m, 2H).

(Example 165)
((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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (3-methylpyrazin-2-yl) methanone (199)

According to the method described in Example 7, the title compound was obtained from compound 198.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.20 (m, 1H), 1.25-1.75 (m, 4H), 1.75-1.90 (m, 0.7H), 2.15-2 .45 (m, 5.3H), 2.58 (s, 0.9H), 2.60-2.70 (m, 3.1H), 2.80-2.90 (m, 0.7H) , 2.90-3.15 (m, 2.3H), 3.30-3.65 (m, 2H), 4.50-5.00 (m, 3H), 6.50-6.60 ( m, 1H), 6.64 (d, J = 8Hz, 0.3H), 6.73 (d, J = 8Hz, 0.7H), 8.40-8.45 (m, 1H), 8. 50-8.55 (m, 1H).

(Example 166)
((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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (3,6-methylpyrazin-2-yl) methanone (200)

According to the method described in Example 60, the title compound was obtained from compound 9 and 3,6-dimethylpyrazine-2-carboxylic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.90 (m, 7H), 2.15-2.50 (m, 5H), 2.50-2.60. (M, 6H), 2.60-2.70 (m, 0.7H), 2.80-2.90 (m, 0.3H), 2.90-3.15 (m, 1H), 3 .30-3.40 (m, 0.7H), 3.40-3.55 (m, 0.7H), 3.60-3.70 (m, 0.3H), 3.70-3. 75 (m, 0.3H), 3.81 (s, 0.9H), 3.91 (s, 2.1H), 4.40-4.50 (m, 0.3H), 4.60- 4.70 (m, 0.3H), 4.70-4. 0 (m, 0.7H), 4.80-4.90 (m, 0.7H), 6.60 (d, J = 8Hz, 1H), 6.70 (d, J = 8Hz, 0.3H ), 6.76 (d, J = 8 Hz, 0.7 H), 8.38 (s, 0.3 H), 8.39 (s, 0.7 H).

(Example 167)
((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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (3,6-dimethylpyrazin-2-yl) methanone (201)

According to the method described in Example 7, the title compound was obtained from compound 200.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.70 (m, 4H), 1.70-1.90 (m, 1H), 2.15-2.45. (M, 5H), 2.56 (s, 3H), 2.58 (s, 3H), 2.60-2.70 (m, 1H), 2.75-2.85 (m, 1H), 2.90-3.15 (m, 2H), 3.25-3.65 (m, 2H), 4.60-4.75 (m, 2H), 6.50-6.60 (m, 1H) ), 6.64 (d, J = 8 Hz, 0.2 H), 6.73 (d, J = 8 Hz, 0.8 H), 8.39 (s, 0.8 H), 8.40 (s, 0) .2H).

(Example 168)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (5-methoxypyrimidin-2-yl) ethan-1-one (202) Synthesis of

Compound 174 (33 mg, 0.058 mmol), cesium carbonate (38 mg, 0.12 mmol) and [(2-di-tert-butylphosphino-3,6-dimethoxy-2 ′, 4 ′, 6′-triisopropyl- Anhydrous methanol (23 μL, 0.58 mmol) was added to a solution of 1,1′-biphenyl) -2- (2′-amino-1,1′-biphenyl)] palladium (II) methanesulfonic acid in anhydrous toluene (1 mL). The mixture was stirred at 90 ° C for 4 hours. After allowing to cool, it was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (1-3% methanol / chloroform) to give the title compound (27 mg, 90%) as a pale-yellow solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02-0.19 (m, 2H), 0.41-0.56 (m, 2H), 0.69-0.94 (m , 1H), 1.01-1.81 (m, 6H), 2.11-2.48 (m, 5H), 2.56-2.76 (m, 1.6H), 2.78-3 .10 (m, 2.4H), 3.36-3.60 (m, 1H), 3.70-3.98 (m, 6.6H), 4.04-4.22 (m, 2.H). 4H), 4.33-4.45 (m, 0.4H), 4.54-4.72 (m, 1.6H), 6.56 (d, J = 8Hz, 0.6H), 6. 63 (d, J = 8 Hz, 0.4H), 6.67-6.77 (m, 1H), 8.32-8.43 (m, 2H).

(Example 169)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (5-methoxypyrimidin-2-yl) ethan-1-one (203) Synthesis of

According to the method described in Example 7, the title compound was obtained from compound 202.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.16 (m, 2H), 0.40-0.55 (m, 2H), 0.69-0.95 (m , 1H), 1.01-1.81 (m, 6H), 2.08-2.44 (m, 5H), 2.56-2.71 (m, 1.7H), 2.75-3 0.08 (m, 2.3H), 3.33-3.58 (m, 1H), 3.71-3.84 (m, 0.7H), 3.88-3.96 (m, 3H) , 4.05-4.21 (m, 2H), 4.33-4.45 (m, 0.3H), 4.54-4.87 (m, 3H), 6.52 (d, J = 8 Hz, 0.7 H), 6.56 (d, J = 8 Hz, 0.3 H), 6.67-6.74 (m, 1 H), 8.38 (s, 0.6 H), 8.40 ( s, 1.4H).

(Example 170)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (dimethylamino) ethan-1-one (204)

According to the method described in Example 42, the title compound was obtained from compound 9 and dimethylglycine.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.16 (m, 2H), 0.44-0.57 (m, 2H), 0.74-0.84 (m , 1H), 1.13-1.20 (m, 1H), 1.22-1.34 (m, 1H), 1.36-1.48 (m, 2H), 1.49-1.57 (M, 1H), 1.61-1.72 (m, 1H), 2.12-2.44 (m, 5H), 2.30 (s, 4.2H), 2.33 (s, 1) .8H), 2.57-2.67 (m, 1H), 2.74-2.90 (m, 1H), 2.98 (d, J = 18Hz, 1H), 3.03-3.29. (M, 3.3H), 3.51 (ddd, J = 4, 13, 13Hz, 0.7H), 3.88 (s, 3H), 4.00 (ddd, J = 4, 4, 14Hz, 0.7H), 4.1 -4.18 (m, 0.3H), 4.44-4.51 (m, 1.3H), 4.58-4.62 (m, 0.7H), 6.57 (d, J = 8 Hz, 0.7 H), 6.62 (d, J = 8 Hz, 0.3 H), 6.70-6.76 (m, 1 H).

(Example 171)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (dimethylamino) ethan-1-one (205)

According to the method described in Example 7, the title compound was obtained from compound 204.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.15 (m, 2H), 0.44-0.55 (m, 2H), 0.72-0.83 (m , 1H), 1.03 to 1.14 (m, 1H), 1.19 to 1.32 (m, 1H), 1.34 to 1.54 (m, 3H), 1.58 to 1.68 (M, 1H), 2.10-2.41 (m, 5H), 2.31 (s, 4.2H), 2.35 (s, 1.8H), 2.55-2.64 (m , 1H), 2.75-2.86 (m, 1H), 2.94 (d, J = 18Hz, 1H), 3.01-3.07 (m, 1H), 3.12 (d, J) = 13 Hz, 1H), 3.21 (d, J = 13 Hz, 0.7H), 3.23 (d, J = 13 Hz, 0.3H), 3.27-3.35 (m, 0.3H) , 3.44-3.54 m, 0.7H), 3.94-4.03 (m, 0.7H), 4.16-4.20 (m, 0.3H), 4.36-4.49 (m, 1.3H) ), 4.50-4.57 (m, 0.7H), 5.47-5.73 (m, 1H), 6.48-6.54 (m, 1H), 6.72 (d, J) = 8 Hz, 1H).

(Example 172)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (5-cyclopropylpyrimidin-2-yl) ethan-1-one (206 ) Synthesis

According to the method described in Example 42, the title compound was obtained from compound 9 and 2- (5-cyclopropylpyrimidin-2-yl) acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.16 (m, 2H), 0.42-0.54 (m, 2H), 0.70-0.84 (m , 3H), 1.02-1.12 (m, 3H), 1.13-1.58 (m, 4H), 1.61-1.78 (m, 1H), 1.80-1.91. (M, 1H), 2.09-2.45 (m, 5H), 2.56-2.70 (m, 1.6H), 2.80-2.90 (m, 0.4H), 2 .96 (d, J = 18 Hz, 0.6 H), 2.97 (d, J = 6 Hz, 0.6 H), 2.99 (d, J = 19 Hz, 0.4 H), 3.06 (d, J = 6 Hz, 0.4 H), 3.41 (ddd, J = 4, 10, 15 Hz, 0.4 H), 3.51 (ddd, J = 4, 11, 15 Hz, 0.6 H), 3.71 -3.80 m, 0.6H), 3.87 (s, 3H), 4.11-4.18 (m, 0.4H), 4.12 (d, J = 15Hz, 1H), 4.15 (d, J = 15 Hz, 1 H), 4.40 (ddd, J = 4, 4, 15 Hz, 0.4 H), 4.58-4.61 (m, 0.6 H), 4.64-4.68 (m , 1H), 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 = 8 Hz, 0.4H), 8.42 (s, 0.8H), 8.46 (s, 1.2H).

(Example 173)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (5-cyclopropylpyrimidin-2-yl) ethan-1-one (207 ) Synthesis

According to the method described in Example 7, the title compound was obtained from compound 206.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.16 (m, 2H), 0.41-0.53 (m, 2H), 0.69-0.84 (m , 3H), 1.01-1.13 (m, 3H), 1.16-1.54 (m, 4H), 1.59-1.74 (m, 1H), 1.80-1.90. (M, 1H), 2.08-2.42 (m, 5H), 2.54-2.66 (m, 1.7H), 2.78-2.88 (m, 0.3H), 2 .93 (d, J = 18 Hz, 0.7 H), 2.95 (d, J = 17 Hz, 0.3 H), 2.96 (d, J = 7 Hz, 0.7 H), 3.04 (d, J = 6 Hz, 0.3 H), 3.41 (ddd, J = 4, 10, 14 Hz, 0.3 H), 3.49 (ddd, J = 4, 12, 15 Hz, 0.7 H), 3.71 -3.81 m, 0.7H), 4.08-4.23 (m, 2.3H), 4.31-4.39 (m, 0.3H), 4.53-4.62 (m, 1.7H) ), 6.50 (d, J = 8 Hz, 0.7 H), 6.50-6.53 (m, 0.3 H), 6.67-6.72 (m, 0.3 H), 6.70. (D, J = 8 Hz, 0.7H), 8.43 (s, 0.6H), 8.45 (s, 1.4H).

(Example 174)
6-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,6,7,8,8a-octahydro-5H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-carbonyl) pyrazin-2 (1H) -one (208) synthesis

According to the method described in Example 60, the title compound was obtained from compound 9 and 6-oxo-1,6-dihydropyrazine-2-carboxylic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-2.00 (m, 5H), 2.20-3.20 (m, 10H), 3.50-3.75 (m, 1H), 3.80-4.00. (M, 4H), 4.55-4.80 (m, 2H), 6.63 (d, J = 8Hz, 1H), 6.76 (d, J = 8Hz, 1H), 7.80 (s , 1H), 8.26 (s, 1H).

(Example 175)
(6-aminopyrazin-2-yl) ((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a -Octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) methanone (209)

A 1M boron tribromide-dichloromethane solution (140 μL, 0.14 mmol) was added to a dichloromethane (0.5 mL) solution of the compound 208 (13 mg, 0.027 mmol), and the mixture was stirred for 2 hours. Aqueous 10% ammonia 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 = 5: 1) to obtain the title compound (3.3 mg, 26%) as a colorless amorphous substance.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.90 (m, 4H), 2.20-2.45 (m, 4H), 2.60-2.70. (M, 1H), 2.80-3.15 (m, 3H), 3.40-3.60 (m, 1H), 3.70-3.80 (m, 0.8H), 3.95 -4.05 (m, 0.2H), 4.45-4.55 (m, 0.2H), 4.60-5.00 (m, 3.8H), 6.50-6.60 ( m, 1H), 6.68 (d, J = 8Hz, 0.2H), 6.73 (d, J = 8Hz, 0.8H), 8.04 (s, 0.8H), 8.06 ( s, 0.2H), 8.11 (s, 0. H), 8.20 (s, 0.2H).

(Example 176)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2-morpholinoethan-1-one (210)

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

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.19 (m, 2H), 0.41-0.58 (m, 2H), 0.71-0.93 (m , 1H), 1.03-1.87 (m, 6H), 1.97-2.45 (m, 5H), 2.46-2.68 (m, 5H), 2.71-3.11. (M, 3H), 3.13-3.34 (m, 2.4H), 3.45-3.97 (m, 8.2H), 4.02-4.25 (m, 0.4H) , 4.41-4.67 (m, 2H), 6.57 (d, J = 8Hz, 0.6H), 6.62 (d, J = 8Hz, 0.4H), 6.68-6. 79 (m, 1H).

(Example 177)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2-morpholinoethane-1-one (211) synthesis

According to the method described in Example 7, the title compound was obtained from compound 210.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.17 (m, 2H), 0.41-0.56 (m, 2H), 0.70-0.94 (m , 1H), 1.01-1.83 (m, 6H), 1.97-2.43 (m, 5H), 2.45-2.68 (m, 5H), 2.70-3.10. (M, 3H), 3.12-3.35 (m, 2.3H), 3.42-3.57 (m, 0.7H), 3.69-3.83 (m, 4H), 3 .86-3.99 (m, 0.7H), 4.07-4.17 (m, 0.3H), 4.38-4.98 (m, 3H), 6.47-6.60 ( m, 1H), 6.65-6.76 (m, 1H).

(Example 178)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (1-methyl-1H-indazol-3-yl) ethan-1-one Synthesis of (212)

According to the method described in Example 44, the title compound was obtained from compound 9 and 2- (1-methyl-1H-indazol-3-yl) acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.01-0.17 (m, 2H), 0.40-0.55 (m, 2H), 0.64-1.84 (m , 7H), 2.08-2.44 (m, 5.8H), 2.57-2.67 (m, 0.2H), 2.75-3.10 (m, 2H), 3.29. -3.54 (m, 1H), 3.96-4.81 (m, 9H), 6.47 (d, J = 8Hz, 0.8H), 6.55 (d, J = 8Hz, 0. 2H), 6.64-6.74 (m, 1H), 7.10-7.20 (m, 1H), 7.30-7.44 (m, 2H), 7.80-7.91 ( m, 1H).

(Example 179)
(4R, 4aS, 8R, 8aR, 13bS) -7- (azetidin-3-yl) -3- (cyclopropylmethyl) -1,2,3,4,6,7,8,8a-octahydro-5H- Synthesis of 4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (213)

A solution of compound 60 (32.0 mg, 0.091 mmol) in chloroform (2 mL) was added to tert-butyl 3-oxoazetidine-1-carboxylate (23.3 mg, 0.14 mmol) and acetic acid (15.6 μL, 0.27 mmol). And sodium triacetoxyborohydride (57.6 mg, 0.27 mmol) were added, and the mixture was stirred at room temperature for 2 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 dried over sodium sulfate and then concentrated under reduced pressure. Then, it was dissolved in trifluoroacetic acid (1 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained crude product was purified by preparative thin layer chromatography (chloroform: 2M ammonia-methanol solution = 100: 25) to give the title compound (27.2 mg, 74%). Was obtained as a colorless amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.16 (m, 2H), 0.41-0.54 (m, 2H), 0.73-0.84 (m , 1H), 0.73 to 0.84 (m, 1H), 0.93 to 1.05 (m, 1H), 1.08 to 1.22 (m, 2H), 1.28 to 1.39 (M, 1H), 1.47-1.62 (m, 1H), 2.21 (dd, J = 7, 13 Hz, 1H), 2.26-2.42 (m, 4H), 2.43 -2.66 (m, 4H), 2.73-2.86 (m, 1H), 2.93 (d, J = 18Hz, 1H), 2.99 (d, J = 6Hz, 1H), 3 .51-3.75 (m, 5H), 4.54 (s, 1H), 6.50 (d, J = 8Hz, 1H), 6.67 (d, J = 8Hz, 1H).

(Example 180)
(3-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, Synthesis of 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) azetidin-1-yl) (phenyl) methanone (214)

According to the method described in Example 60, the title compound was obtained from compound 213 and benzoic acid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.16 (m, 2H), 0.41-0.55 (m, 2H), 0.70-0.79 (m , 7H), 2.14-2.44 (m, 5H), 2.48-3.05 (m, 7H), 3.51-3.70 (m, 1H), 3.98-4.34. (M, 4H), 4.50-4.61 (m, 1H), 4.90-5.14 (m, 1H), 6.51 (d, J = 8Hz, 1H), 6.63-6 .71 (m, 1H), 7.37-7.55 (m, 3H), 7.58-7.73 (m, 2H).

(Example 181)
2- (5- (benzyloxy) pyrimidin-2-yl) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4 5,6,8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) ethan-1-one ( 215) Synthesis

According to the method described in Example 168, the title compound was obtained from compound 174 and benzyl alcohol.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.17 (m, 2H), 0.39-0.57 (m, 2H), 0.69-0.93 (m , 1H), 1.01-1.84 (m, 6H), 2.07-2.51 (m, 5H), 2.55-3.13 (m, 4H), 3.33-3.59 (M, 1H), 3.70-3.97 (m, 3.4H), 4.01-4.24 (m, 2.6H), 4.33-4.46 (m, 0.4H) , 4.54-4.70 (m, 1.6H), 5.08-5.20 (m, 2H), 6.56 (d, J = 8Hz, 0.6H), 6.62 (d, J = 8 Hz, 0.4 H), 6.68-6.77 (m, 1 H), 7.31-7.48 (m, 5 H), 8.42 (s, 0.8 H), 8.45 ( s, 1.2H).

(Example 182)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (5-hydroxypyrimidin-2-yl) ethan-1-one (216) Synthesis of

According to the method described in Example 7, the title compound was obtained from compound 215.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02-0.18 (m, 2H), 0.40-0.56 (m, 2H), 0.69-2.44 (m , 12.5H), 2.53-3.15 (m, 3.5H), 3.28-4.64 (m, 6H), 5.02-5.62 (m, 2H), 6.45 -6.57 (m, 1H), 6.65-6.78 (m, 1H), 8.07-8.28 (m, 2H).

(Example 183)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (6-methoxypyridin-2-yl) ethan-1-one (217) Synthesis of

According to the method described in Example 60, the title compound was obtained from compound 60 and 2- (6-methoxypyridin-2-yl) acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.80 (m, 5H), 1.85-1.95 (m, 1H), 2.15-2.40. (M, 4H), 2.50-2.70 (m, 1H), 2.80-3.10 (m, 3H), 3.30-3.60 (m, 1H), 3.80-4 .10 (m, 5H), 4.30-4.70 (m, 3H), 6.50 (d, J = 8Hz, 0.7H), 6.54 (d, J = 8Hz, 0.3H) , 6.55-6.65 (m, 1H), 6.65-6.75 (m, 1H), 6.85-6.95 (m, 1H), 7.40-7.60 (m, 1H).

(Example 184)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (5-methylpyrimidin-2-yl) ethan-1-one (218) Synthesis of

Compound 174 (20 mg, 0.036 mmol), tetrakis (triphenylphosphine) palladium (0) (13 mg, 0.012 mmol), potassium carbonate (16 mg, 0.12 mmol) and trimethylboroxine (27 μL, 0.19 mmol) in toluene / Water (v / v = 30/1, 1.6 mL) solution was degassed by ultrasonic waves and then stirred at 90 ° C. for 18 hours. The reaction mixture was allowed to cool to room temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-20% methanol / chloroform) to give the title compound (9.3 mg, 52%) as a yellow oily substance.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.16 (m, 2H), 0.41-0.54 (m, 2H), 0.70-0.85 (m , 1H), 1.03-1.16 (m, 1H), 1.18-1.59 (m, 4H), 1.62-1.80 (m, 1H), 2.12-2.46. (M, 5H), 2.29 (s, 1.2H), 2.31 (s, 1.8H), 2.57-2.74 (m, 1.6H), 2.80-2.90 (M, 0.4H), 2.96 (d, J = 19Hz, 0.6H), 2.98 (d, J = 6Hz, 0.6H), 2.99 (d, J = 17Hz, 0. 4H), 3.06 (d, J = 6Hz, 0.4H), 3.42 (ddd, J = 4, 11, 15Hz, 0.4H), 3.51 (ddd, J = 4, 11, 15Hz) , 0.6H) 3.72-3.81 (m, 0.6H), 3.87 (s, 3H), 4.10-4.21 (m, 0.4H), 4.12 (d, J = 15Hz, 1H ), 4.16 (d, J = 15 Hz, 1H), 4.40 (ddd, J = 4, 4, 15 Hz, 0.4H), 4.58-4.62 (m, 0.6H), 4 .64-4.70 (m, 1H), 6.56 (d, J = 8Hz, 0.6H), 6.62 (d, J = 8Hz, 0.4H), 6.72 (d, J = 8 Hz, 0.6 H), 6.74 (d, J = 8 Hz, 0.4 H), 8.53 (s, 0.8 H), 8.56 (s, 1.2 H).

(Example 185)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (5-methylpyrimidin-2-yl) ethan-1-one (219) Synthesis of

According to the method described in Example 32, the title compound was obtained from compound 218.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.16 (m, 2H), 0.41-0.54 (m, 2H), 0.69-0.83 (m , 1H), 1.10-1.15 (m, 1H), 1.17-1.47 (m, 3H), 1.48-1.56 (m, 1H), 1.59-1.71. (M, 1H), 2.11-2.42 (m, 5H), 2.30 (s, 0.9H), 2.31 (s, 2.1H), 2.56-2.70 (m , 1.7H), 2.78-2.88 (m, 0.3H), 2.94 (d, J = 19Hz, 0.7H), 2.96 (d, J = 18Hz, 0.3H) , 2.97 (d, J = 7 Hz, 0.7 H), 3.04 (d, J = 6 Hz, 0.3 H), 3.41 (ddd, J = 4, 10, 14 Hz, 0.3 H), 3.50 (ddd, J 4,12,15Hz, 0.7H), 3.78 (ddd, J = 3, 5,15Hz, 0.7H), 4.08-4.22 (m, 2.3H), 4.37 (ddd , J = 5,5,15 Hz, 0.3 H), 4.56-4.62 (m, 0.7 H), 4.58 (s, 1 H), 6.51 (d, J = 8 Hz, 0. 7H), 6.54 (d, J = 8Hz, 0.3H), 6.70 (d, J = 8Hz, 0.3H), 6.70 (d, J = 8Hz, 0.7H), 8. 54 (s, 0.6H), 8.56 (s, 1.4H).

(Example 186)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -7- (tetrahydro-2H-pyran-4-yl) -1,2,3,4,6,7,8,8a- Synthesis of octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (220)

According to the method described in Example 115, the title compound was obtained from compound 60 and tetrahydro-4H-pyran-4-one.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.16 (m, 2H), 0.41-0.54 (m, 2H), 0.73-1.81 (m , 11H), 2.21 (dd, J = 7, 12 Hz, 1H), 2.24-2.42 (m, 4H), 2.58-2.86 (m, 4H), 2.93 (d , J = 18 Hz, 1H), 2.94-3.14 (m, 3H), 3.29-3.42 (m, 2H), 3.98-4.06 (m, 2H), 4.44. (S, 1H), 4.95 (br s, 1H), 6.49 (d, J = 8Hz, 1H), 6.67 (d, J = 8Hz, 1H).

(Example 187)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (pyridin-2-yl) ethan-1-one (221) synthesis

According to the method described in Example 42, the title compound was obtained from compound 60 and 2- (pyridin-2-yl) acetic acid hydrochloride.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.14 (m, 2H), 0.40-0.52 (m, 2H), 0.69-0.82 (m , 1H), 0.93-1.70 (m, 6H), 1.97 (ddd, J = 6, 13, 13Hz, 0.7H), 2.13-2.40 (m, 4.3H). , 2.49-2.63 (m, 1.7H), 2.77-2.98 (m, 2H), 3.02 (d, J = 6Hz, 0.3H), 3.34-3. 53 (m, 1H), 3.90-4.10 (m, 2.7H), 4.22-4.38 (m, 0.6H), 4.43-4.49 (m, 0.7H) ), 4.52-4.59 (m, 1H), 6.50 (d, J = 8Hz, 0.7H), 6.51-6.53 (m, 0.3H), 6.70 (d , J = 8Hz, 0.7H), 6 71-6.76 (m, 0.3H), 7.13-7.21 (m, 1H), 7.36-7.41 (m, 0.3H), 7.38 (d, J = 8Hz , 0.7H), 7.56-7.70 (m, 1H), 8.51-8.59 (m, 1H).

(Example 188)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (piperidin-1-yl) ethan-1-one (222)

Following the method described in Example 68, the title compound was obtained from compound 60 and 2- (piperidin-1-yl) acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.20 (m, 2H), 0.40-0.59 (m, 2H), 0.71-0.92 (m , 1H), 0.99-1.83 (m, 12H), 1.96-2.68 (m, 10H), 2.71-3.33 (m, 5H), 3.40-3.60. (M, 1H), 3.96-4.23 (m, 1H), 4.37-4.67 (m, 2H), 6.47-6.59 (m, 1H), 6.66-6 .76 (m, 1H).

(Example 189)
7- (2-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H- Synthesis of 4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2-oxoethyl) quinolin-2 (1H) -one (223)

The title compound was obtained from compound 60 and 2- (2-oxo-1,2-dihydroquinolin-7-yl) acetic acid according to the method described in Example 68.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.17 (m, 2H), 0.34-0.52 (m, 2H), 0.62-2.41 (m , 12.6H), 2.44-2.78 (m, 2H), 2.82-3.07 (m, 2H), 3.15-3.27 (m, 0.4H), 3.38. -3.58 (m, 1H), 3.63-3.99 (m, 2.6H), 4.02-4.17 (m, 0.8H), 4.44-4.67 (m, 1.6H), 6.45-6.57 (m, 1H), 6.64-6.80 (m, 2H), 7.06-7.33 (m, 2H), 7.48-7. 58 (m, 1H), 7.73-7.85 (m, 1H), 11.47 (br s, 0.6H), 11.99 (br s, 0.4H).

(Example 190)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (3-methoxypyridin-2-yl) ethan-1-one (224) Synthesis of

According to the method described in Example 68, the title compound was obtained from compound 60 and 2- (3-methoxypyridin-2-yl) acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.15 (m, 2H), 0.41-0.54 (m, 2H), 0.70-0.83 (m , 1H), 1.00-1.13 (m, 0.7H), 1.16-1.55 (m, 4.3H), 1.59-1.79 (m, 1H), 2.12 -2.42 (m, 5H), 2.55-2.71 (m, 1.7H), 2.77-2.87 (m, 0.3H), 2.89-2.99 (m, 1.7H), 3.03 (d, J = 6Hz, 0.3H), 3.32-3.41 (m, 0.3H), 3.42-3.53 (m, 0.7H), 3.69-3.80 (m, 0.7H), 3.84 (s, 0.9H), 3.85 (s, 2.1H), 3.91-4.10 (m, 2.3H) ), 4.33-4.44 (m, 0.3H), .53-4.66 (m, 1.7H), 6.46-6.54 (m, 1H), 6.69 (d, J = 8Hz, 1H), 7.12-7.21 (m, 2H), 8.11-8.19 (m, 1H).

(Example 191)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -7- (piperidin-4-yl) -1,2,3,4,6,7,8,8a-octahydro-5H- Synthesis of 4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (225)

According to the method described in Example 179, the title compound was obtained from compound 60 and tert-butyl 4-oxopiperidine-1-carboxylate.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.16 (m, 2H), 0.40-0.53 (m, 2H), 0.72-1.03 (m , 2H), 1.12 to 1.57 (m, 7H), 1.85-1.95 (m, 2H), 2.21 (dd, J = 7, 12Hz, 1H), 2.25-3 .37 (m, 16H), 4.37 (s, 1H), 6.48 (d, J = 8Hz, 1H), 6.65 (d, J = 8Hz, 1H).

(Example 192)
(4R, 4aS, 8R, 8aR, 13bS) -7- (1-benzylpiperidin-4-yl) -3- (cyclopropylmethyl) -1,2,3,4,6,7,8,8a-octahydro Synthesis of -5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (226)

Following the method described in Example 115, the title compound was obtained from compound 225 and benzaldehyde.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.16 (m, 2H), 0.40-0.54 (m, 2H), 0.71-0.97 (m , 2H), 1.11-1.35 (m, 3H), 1.41-1.57 (m, 3H), 1.62-1.84 (m, 3H), 1.89-2.01 (M, 2H), 2.20 (dd, J = 7, 12 Hz, 1H), 2.22-2.42 (m, 4H), 2.44-2.54 (m, 1H), 2.56 -2.64 (m, 1H), 2.65-2.84 (m, 2H), 2.86-3.05 (m, 5H), 3.08 (dt, J = 3, 11Hz, 1H) , 3.47 (d, J = 13 Hz, 1H), 3.53 (d, J = 13 Hz, 1H), 4.42 (s, 1H), 6.46 (d, J = 8 Hz, 1H), 6 .62 (d, = 8Hz, 1H), 7.21-7.34 (m, 5H).

(Example 193)
(4-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, Synthesis of 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) piperidin-1-yl) (phenyl) methanone (227)

Following the method described in Example 60, the title compound was obtained from compound 225 and benzoic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.16 (m, 2H), 0.40-0.54 (m, 2H), 0.71-3.29 (m , 26H), 3.71-3.92 (m, 1H), 4.31-4.48 (m, 1H), 4.66-5.33 (m, 2H), 6.49 (d, J). = 8 Hz, 1H), 6.67 (d, J = 8 Hz, 1H), 7.33-7.45 (m, 5H).

(Example 194)
6- (2-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H- Synthesis of 4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2-oxoethyl) pyridin-2 (1H) -one (228)

33% Hydrogen bromide-acetic acid solution (0.5 mL) was added to compound 217 (10 mg, 0.02 mmol), and the mixture was stirred at 80 ° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, 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 = 5: 1) to obtain the title compound (1.9 mg, 19%) as a colorless amorphous substance.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.80 (m, 4H), 2.10-2.50 (m, 5H), 2.55-2.65. (M, 1H), 2.75-2.85 (m, 1H), 2.90-3.10 (m, 2H), 3.30-3.65 (m, 1H), 3.65-3 .80 (m, 3H), 3.95-4.05 (m, 0.5H), 4.25-4.40 (m, 1H), 4.40-4.60 (m, 1.5H) , 6.05-6.15 (m, 1H), 6.40-6.60 (m, 2H), 6.72 (d, J = 8Hz, 1H), 7.30-7.45 (m, 1H).

(Example 195)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -7- (2- (pyrimidin-2-yl) acetyl) -1,2,3,4,6,7,8,8a -Octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-10-carbonitrile (229)

Compound 141 (25 mg, 0.041 mmol), zinc cyanide (10 mg, 0.082 mmol), tris (dibenzylideneacetone) dipalladium (0) (38 mg, 0.041 mmol), (±) -2,2′-bis (Diphenylphosphino) -1,1′-binaphthyl (56 mg, 0.09 mmol) was suspended in N, N-dimethylformamide (0.5 mL) and stirred at 150 ° C. for 3 hours. The reaction solution was diluted with ethyl acetate (20 mL), washed with water (20 mL) three times, the organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-10% methanol / chloroform) to give the title compound (20 mg, 100%) as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.90 (m, 5H), 2.15-2.55 (m, 5H), 2.60-2.75. (M, 1.4H), 2.90-3.15 (m, 2.6H), 3.30-3.60 (m, 1H), 3.75-3.85 (m, 0.3H) , 4.10-4.30 (m, 2.7H), 4.40-4.50 (m, 0.6H), 4.60-4.80 (m, 1.4H), 6.67 ( d, J = 8Hz, 0.7H), 6.73 (d, J = 8Hz, 0.3H), 6.75-6.85 (m, 1H), 7.20-7.40 (m, 1H) ), 8.73 (d, J = 5 Hz, 0. H), 8.75 (d, J = 5Hz, 1.4H).

(Example 196)
(4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -7- (2- (pyrimidin-2-yl) acetyl) -1,2,3,4,6,7,8,8a -Octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-10-carboxamide (230)

Compound 229 (20 mg, 0.041 mmol), acetaldoxime (8 μL, 0.14 mmol), tetrakis (triphenylphosphine) palladium (0) (16 mg, 0.014 mmol) were suspended in toluene (0.7 mL), and at 80 ° C. Stir for 3 hours. The reaction solution was diluted with ethyl acetate (20 mL), washed with water (20 mL) three times, the organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (10% methanol / chloroform) to give the title compound (2.0 mg, 10%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.90 (m, 6H), 2.00-2.80 (m, 6H), 2.90-3.30 (m, 3H), 3.40-3.60. (M, 3H), 3.80-3.90 (m, 1H), 4.45-4.65 (m, 2H), 6.55 (d, J = 8Hz, 1H), 6.73 (d , J = 8 Hz, 1H), 7.95-8.05 (m, 1H), 8.15-8.25 (m, 2H).

(Example 197)
6-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,6,7,8,8a-octahydro-5H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-carbonyl) pyrazin-2 (1H) -one (231) synthesis

According to the method described in Example 7, the title compound was obtained from compound 208.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.90 (m, 5H), 2.00-2.15 (m, 2H), 2.15-2.50 (m, 4H), 2.60-2.80. (M, 1H), 3.00-3.15 (m, 2H), 4.05-4.35 (m, 3H), 4.60-4.80 (m, 2H), 5.67 (br s, 1H), 6.76 (d, J = 8Hz, 1H), 7.84 (d, J = 8Hz, 1H), 8.70-8.80 (m, 2H).

(Example 198)
(4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -7- (1- (5-fluoropyrimidin-2-yl) piperidin-4-yl) -1,2,3,4 Synthesis of 6,7,8,8a-octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (232)

According to the method described in Example 117, the title compound was obtained from compound 225 and 2-chloro-5-fluoropyrimidine.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.17 (m, 2H), 0.40-0.55 (m, 2H), 0.72-0.99 (m , 2H), 1.14-1.95 (m, 9H), 2.20 (dd, J = 7, 12Hz, 1H), 2.24-2.42 (m, 4H), 2.57-2. .66 (m, 1H), 2.71-3.01 (m, 8H), 3.07-3.18 (m, 1H), 4.42 (s, 1H), 4.59 (br s, 1H), 4.70-4.78 (m, 2H), 6.48 (d, J = 8Hz, 1H), 6.65 (d, J = 8Hz, 1H), 8.17 (s, 2H) ．

(Example 199)
((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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (morpholino) methanone (233)

According to the method described in Example 5, the title compound was obtained from compound 11 and morpholine.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.18 (m, 2H), 0.41-0.57 (m, 2H), 0.70-0.92 (m , 1H), 0.99-1.14 (m, 1H), 1.19-1.79 (m, 5H), 2.13-2.45 (m, 5H), 2.57-2.68. (M, 1H), 2.81-3.09 (m, 3H), 3.15-3.30 (m, 4H), 3.33-3.47 (m, 1H), 3.58-3 .79 (m, 5H), 3.82-3.95 (m, 3H), 4.02-4.21 (m, 1H), 4.57 (s, 1H), 6.58 (d, J = 8 Hz, 1 H), 6.72 (d, J = 8 Hz, 1 H).

(Example 200)
((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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (morpholino) methanone (234)

According to the method described in Example 7, the title compound was obtained from compound 233.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02-0.17 (m, 2H), 0.40-0.57 (m, 2H), 0.70-0.93 (m , 1H), 0.99-1.13 (m, 1H), 1.18-1.79 (m, 5H), 2.13-2.44 (m, 5H), 2.58-2.68. (M, 1H), 2.76-3.09 (m, 3H), 3.11-3.30 (m, 4H), 3.31-3.47 (m, 1H), 3.58-3 0.82 (m, 5H), 3.99-4.18 (m, 1H), 4.53-4.85 (m, 2H), 6.53 (d, J = 8Hz, 1H), 6.70 (D, J = 8 Hz, 1H).

(Example 201)
1- (2-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H- Synthesis of 4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2-oxoethyl) pyridin-2 (1H) -one (235)

Following the method described in Example 44, the title compound was obtained from compound 9 and 2- (2-oxopyridin-1 (2H) -yl) acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.13 (m, 2H), 0.42-0.54 (m, 2H), 0.71-0.82 (m , 1H), 1.01-1.12 (m, 1H), 1.18-1.50 (m, 4H), 1.55-1.73 (m, 1H), 2.09-2.39. (M, 5H), 2.51-2.64 (m, 1H), 2.76-2.86 (m, 0.4H), 2.87-3.03 (m, 2.6H), 3 .30-3.40 (m, 0.4H), 3.50-3.62 (m, 0.6H), 3.71-3.85 (m, 0.6H), 4.04-4. 09 (m, 0.4H), 4.21-4.32 (m, 0.4H), 4.38-4.48 (m, 1.2H), 4.62-4.75 (m, 1) .4H), 4.93 (d, J = 15 Hz, 0 6H), 5.01 (d, J = 15Hz, 0.4H), 6.18-6.25 (m, 1H), 6.48 (d, J = 8Hz, 0.6H), 6.49 ( d, J = 8 Hz, 0.4H), 6.55-6.61 (m, 1H), 6.67-6.74 (m, 1H), 7.30-7.42 (m, 2H).

(Example 202)
tert-Butyl 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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) pyrrolidine-1-carboxylate (diastereomer A (236) and diastereomer Synthesis of B (237))

According to the method described in Example 115, the title compound was obtained from compound 9 and tert-butyl 3-oxopyrrolidine-1-carboxylate, respectively.

Diastereomer A (236):
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08-0.15 (m, 2H), 0.42-0.55 (m, 2H), 0.72-1.03 (m , 2H), 1.12-2.42 (m, 15H), 2.56-3.70 (m, 17H), 3.86 (s, 3H), 4.42-4.55 (m, 2H) ), 6.57 (d, J = 8 Hz, 1H), 6.70 (d, J = 8 Hz, 1H).

Diastereomer B (237):
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.19 (m, 2H), 0.42-0.56 (m, 2H), 0.73-1.03 (m , 2H), 1.11-3.71 (m, 32H), 3.86 (s, 3H), 4.42-4.58 (m, 2H), 6.52-6.64 (m, 1H) ), 6.71 (d, J = 8 Hz, 1H).

(Example 203)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-methoxy-7- (pyrrolidin-3-yl) -1,2,3,4,6,7,8,8a- Synthesis of octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (238)

Compound 236 (23.3 mg, 0.043 mmol) was dissolved in trifluoroacetic acid (1 mL), the mixture was stirred at room temperature for 1 hr, and the reaction mixture was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (silica gel bearing amino group, 0-20% methanol / chloroform) to give the title compound (16 mg, 85%) as a colorless solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.17 (m, 2H), 0.41-0.56 (m, 2H), 0.72-1.03 (m , 2H), 1.10-1.73 (m, 5H), 1.87-2.04 (m, 2H), 2.21 (dd, J = 7, 12Hz, 1H), 2.22-2 .44 (m, 4H), 2.57-2.83 (m, 5H), 2.87-3.07 (m, 5H), 3.09-3.24 (m, 2H), 3.86. (S, 3H), 4.56 (s, 1H), 6.56 (d, J = 8Hz, 1H), 6.70 (d, J = 8Hz, 1H).

(Example 204)
(4R, 4aS, 8R, 8aR, 13bS) -7- (1-benzylpyrrolidin-3-yl) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,6,7,8 , 8a-Octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (239)

Following the method described in Example 115, the title compound was obtained from compound 238 and benzaldehyde.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.14 (m, 2H), 0.41-0.53 (m, 2H), 0.72-1.00 (m , 2H), 1.09-1.88 (m, 7H), 1.96-2.09 (m, 1H), 2.15-2.50 (m, 7H), 2.56-2.62. (M, 1H), 2.62-2.84 (m, 4H), 2.86-3.07 (m, 4H), 3.24-3.36 (m, 1H), 3.59 (s , 1H), 3.86 (s, 3H), 4.54 (s, 1H), 6.55 (d, J = 8Hz, 1H), 6.70 (d, J = 8Hz, 1H), 7. 21-7.40 (m, 5H).

(Example 205)
(4R, 4aS, 8R, 8aR, 13bS) -7- (1-benzylpyrrolidin-3-yl) -3- (cyclopropylmethyl) -1,2,3,4,6,7,8,8a-octahydro Synthesis of -5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (240)

According to the method described in Example 7, the title compound was obtained from compound 239.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.14 (m, 2H), 0.38-0.53 (m, 2H), 0.71-1.37 (m , 5H), 1.43-1.79 (m, 3H), 1.98-2.13 (m, 1H), 2.16-2.39 (m, 6H), 2.44-2.86. (M, 6H), 2.87-2.99 (m, 4H), 3.28-3.41 (m, 1H), 3.56-3.70 (m, 2H), 4.56 (s , 1H), 6.49 (d, J = 8 Hz, 1H), 6.66 (d, J = 8 Hz, 1H), 7.20-7.36 (m, 5H).

(Example 206)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-methoxy-7- (pyrrolidin-3-yl) -1,2,3,4,6,7,8,8a- Synthesis of octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (241)

According to the method described in Example 203, the title compound was obtained from compound 237.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.17 (m, 2H), 0.41-0.58 (m, 2H), 0.71-1.04 (m , 2H), 1.09-1.41 (m, 3H), 1.47-1.72 (m, 3H), 1.91-2.44 (m, 6H), 2.56-2.65. (M, 1H), 2.68-3.26 (m, 11H), 3.86 (s, 3H), 4.56 (s, 1H), 6.56 (d, J = 8Hz, 1H), 6.70 (d, J = 8 Hz, 1H).

(Example 207)
(4R, 4aS, 8R, 8aR, 13bS) -7- (1-benzylpyrrolidin-3-yl) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,6,7,8 , 8a-Octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (242)

According to the method described in Example 115, the title compound was obtained from compound 241 and benzaldehyde.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.16 (m, 2H), 0.41-0.55 (m, 2H), 0.72-1.00 (m , 2H), 1.10-1.85 (m, 6H), 1.98-2.12 (m, 1H), 2.16-2.42 (m, 7H), 2.49-2.85. (M, 6H), 2.88-3.07 (m, 3H), 3.28-3.41 (m, 1H), 3.52 (d, J = 13Hz, 1H), 3.62 (d , J = 13 Hz, 1H), 3.85 (s, 3H), 4.52 (s, 1H), 6.55 (d, J = 8 Hz, 1H), 6.69 (d, J = 8 Hz, 1H) ), 7.21-7.34 (m, 5H).

(Example 208)
(4R, 4aS, 8R, 8aR, 13bS) -7- (1-benzylpyrrolidin-3-yl) -3- (cyclopropylmethyl) -1,2,3,4,6,7,8,8a-octahydro Synthesis of -5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (243)

According to the method described in Example 7, the title compound was obtained from compound 242.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.15 (m, 2H), 0.41-0.55 (m, 2H), 0.71-1.79 (m , 9H), 2.01-2.24 (m, 2H), 2.25-2.42 (m, 5H), 2.46-2.88 (m, 6H), 2.92 (d, J). = 18 Hz, 1H), 2.96 (d, J = 6 Hz, 1H), 3.14-3.34 (m, 2H), 3.54 (d, J = 12 Hz, 1H), 3.88 (d , J = 12 Hz, 1 H), 4.40 (s, 1 H), 6.49 (d, J = 8 Hz, 1 H), 6.64 (d, J = 8 Hz, 1 H), 7.22-7.36. (M, 5H).

(Example 209)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -3-morpholinopropan-1-one (244)

Following the method described in Example 44, the title compound was obtained from compound 9 and 3-morpholinopropanoic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.22 (m, 2H), 0.41-0.62 (m, 2H), 0.71-0.94 (m , 1H), 0.99-1.15 (m, 1H), 1.19-1.87 (m, 5H), 1.99-3.11 (m, 18H), 3.32-3.58. (M, 1H), 3.64-3.83 (m, 4.7H), 3.93-4.02 (m, 0.3H), 4.22-4.37 (m, 0.3H) , 4.44-4.57 (m, 1.7H), 6.47-6.59 (m, 1H), 6.66 (d, J = 8Hz, 0.3H), 6.71 (d, J = 8 Hz, 0.7H).

(Example 210)
2-chloro-1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H Of -4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) ethan-1-one (245)

To a solution of compound 9 (15 mg, 0.041 mmol) in chloroform (1 mL), triethylamine (28 μL, 0.21 mmol) and chloroacetyl chloride (6.5 μL, 0.082 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. . Water was added to the reaction mixture under ice cooling, and the mixture was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-3% methanol / chloroform) to give the title compound (17 mg, 95%) as a pale-yellow amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.18 (m, 2H), 0.42-0.56 (m, 2H), 0.71-0.91 (m , 1H), 1.05-1.18 (m, 1H), 1.22-1.83 (m, 5H), 2.11-2.48 (m, 5H), 2.56-2.69. (M, 1H), 2.76-3.12 (m, 3H), 3.27-3.44 (m, 0.3H), 3.51-3.66 (m, 0.7H), 3 .69-3.80 (m, 0.7H), 3.84-3.93 (m, 3H), 3.98-4.24 (m, 2.3H), 4.34-4.63 ( m, 2H), 6.59 (d, J = 8Hz, 0.7H), 6.64 (d, J = 8Hz, 0.3H), 6.69-6.79 (m, 1H).

(Example 211)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (3,3-difluoropiperidin-1-yl) ethan-1-one ( 246) synthesis

A solution of compound 245 (17.3 mg, 0.039 mmol) in acetonitrile (1 mL) was added with N, N-diisopropylethylamine (33 μL, 0.20 mmol), 3,3-difluoropiperidine hydrochloride (9.2 mg, 0.059 mmol) and Sodium iodide (0.6 mg, 0.0039 mmol) was added, and the mixture was stirred at room temperature for 40 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-3% methanol / chloroform) to give the title compound (16.8 mg, 81%) as a pale-yellow gum-like substance.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.17 (m, 2H), 0.40-0.58 (m, 2H), 0.73-0.93 (m , 1H), 1.01-1.16 (m, 1H), 1.7-1.99 (m, 9H), 2.06-3.08 (m, 13H), 3.20-3.43. (M, 2.2H), 3.45-3.59 (m, 0.8H), 3.80-3.98 (m, 3.8H), 4.06-4.19 (m, 0. 2H), 4.36-4.66 (m, 2H), 6.52-6.65 (m, 1H), 6.68-6.78 (m, 1H).

(Example 212)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (3,3-difluoropiperidin-1-yl) ethan-1-one ( 247) Synthesis

According to the method described in Example 7, the title compound was obtained from compound 246.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.21 (m, 2H), 0.41-0.58 (m, 2H), 0.71-0.95 (m , 1H), 1.01-1.14 (m, 1H), 1.18-2.00 (m, 9H), 2.08-2.44 (m, 5H), 2.48-3.12 (M, 8H), 3.19-3.59 (m, 3H), 3.85-3.99 (m, 0.8H), 4.06-4.12 (m, 0.2H), 4 .36-4.88 (m, 3H), 6.49-6.59 (m, 1H), 6.65-6.76 (m, 1H).

(Example 213)
tert-Butyl (S) -2-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,6,7,8,8a- Synthesis of octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carbonyl) pyrrolidine-1-carboxylate (248)

According to the method described in Example 60, the title compound was obtained from compound 9 and (tert-butoxycarbonyl) -L-proline.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.80 (m, 14H), 1.80-2.00 (m, 3H), 2.00-2.50. (M, 7H), 2.60-2.70 (m, 1H), 2.80-3.10 (m, 3H), 3.40-3.80 (m, 3H), 3.87 (s) , 1.5H), 3.88 (s, 1.5H), 3.95-4.05 (m, 0.5H), 4.45-4.80 (m, 2.5H), 6.55. -6.65 (m, 1H), 6.70-6.80 (m, 1H).

(Example 214)
(4R, 4aS, 8R, 8aR, 13bS) -7- (L-prolyl) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,6,7,8,8a-octahydro- Synthesis of 5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (249)

Compound 248 (48 mg, 0.082 mmol) was dissolved in trifluoroacetic acid (0.5 mL), and the mixture was stirred at room temperature for 1 hr. The reaction solvent in the reaction solution was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, 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 chromatography (0-10% methanol / chloroform) to give the title compound (38 mg, 100%) as a pale-yellow amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-2.00 (m, 9H), 2.05-2.50 (m, 6H), 2.55-2.70. (M, 1H), 2.75-2.95 (m, 2H), 2.95-3.10 (m, 2H), 3.15-3.30 (m, 1H), 3.45-3 .55 (m, 0.7H), 3.70-3.85 (m, 1H), 3.89 (s, 3H), 3.90-4.00 (m, 1.3H), 4.10 -4.20 (m, 0.3H), 4.50-4.65 (m, 1.7H), 6.58 (d, J = 8Hz, 0.7H), 6.63 (d, J = 8Hz, 0.3H), 6.70-6.8 (M, 1H).

(Example 215)
(4R, 4aS, 8R, 8aR, 13bS) -7- (L-prolyl) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,6,7,8,8a-octahydro- Synthesis of 5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (250)

According to the method described in Example 7, the title compound was obtained from compound 249.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.20-1.35 (m, 1H), 1.40-2.00 (m, 8H), 2.05-2.20 (m, 2H), 2.20-2.50. (M, 4H), 2.55-2.60 (m, 1H), 2.80-3.10 (m, 4H), 3.10-3.25 (m, 1H), 3.50-3 .70 (m, 2H), 4.05-4.15 (m, 1H), 4.33 (s, 1H), 4.40 (s, 1H), 6.51 (d, J = 8Hz, 1H ), 6.68 (d, J = 8 Hz, 1H).

(Example 216)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-methoxy-7- (pyrimidin-2-yl-L-prolyl) -1,2,3,4,6,7, Synthesis of 8,8a-octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (251)

Compound 249 (10 mg, 0.022 mmol), 2-chloropyrimidine (8 mg, 0.066 mmol) and N, N-diisopropylethylamine (15 μL, 0.088 mmol) were dissolved in acetonitrile (0.5 mL), and the mixture was dissolved at 60 ° C. at 16 ° C. Stir for hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (20 mL), and then washed with water (20 mL) three times. 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 (0-10% methanol / chloroform) to give the title compound (12 mg, 100%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.80 (m, 5H), 2.00-2.60 (m, 9H), 2.60-2.70. (M, 1H), 2.80-3.15 (m, 3H), 3.45-3.60 (m, 0.7H), 3.70-3.80 (m, 1.3H), 3 .80-4.00 (m, 5H), 4.50-4.70 (m, 2H), 4.90-5.00 (m, 1H), 6.41 (t, J = 5Hz, 0. 3H), 6.47 (t, J = 5Hz, 0.7H), 6.56 (d, J = 8Hz, 0.7H), 6.64 (d, J = 8Hz, 0.3H), 6. 71 (d, J = 8Hz, 0.7H , 6.75 (d, J = 8Hz, 0.3H), 8.00-8.10 (m, 0.3H), 8.20-8.40 (m, 1.7H).

(Example 217)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-hydroxy-7- (pyrimidin-2-yl-L-prolyl) -1,2,3,4,6,7, Synthesis of 8,8a-octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (252)

According to the method described in Example 7, the title compound was obtained from compound 251.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-2.60 (m, 14H), 2.60-2.70 (m, 1H), 2.90-3.15. (M, 3H), 3.45-3.60 (m, 0.7H), 3.60-3.80 (m, 1.3H), 3.80-4.00 (m, 2H), 4 .40-4.50 (m, 1.7H), 4.50-4.60 (m, 0.3H), 4.80-4.90 (m, 0.3H), 4.90-5. 00 (m, 0.7H), 6.40-6.60 (m, 2H), 6.65-6.75 (m, 1H), 8.15-8.40 (m, 2H).

(Example 218)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-methoxy-7-((pyrimidin-2-ylmethyl) -L-prolyl) -1,2,3,4,6,6 Synthesis of 7,8,8a-octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (253)

To a solution of the compound 249 (10 mg, 0.022 mmol) in dichloromethane (0.5 mL) was added pyrimidine-2-carbaldehyde (7 mg, 0.066 mmol) and sodium triacetoxyborohydride (19 mg, 0.088 mmol) at room temperature. It was stirred for 16 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 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 (12 mg, 100%) as a colorless amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.70 (m, 5H), 1.80-2.10 (m, 3H), 2.10-2.45. (M, 6H), 2.55-2.75 (m, 2H), 2.80-2.95 (m, 1H), 2.95-3.05 (m, 2H), 3.20-3 .40 (m, 1H), 3.40-3.80 (m, 1H), 3.80-3.85 (m, 0.3H), 3.88 (s, 3H), 3.90-4 0.25 (m, 3.7H), 4.40-4.60 (m, 1.7H), 4.80-4.90 (d, J = 5H, 0.3H), 6.55 (d, J = 8 Hz, 0.7 H), 6.10 (d J = 8 Hz, 0.3 H), 6.65-6.80 (m, 1 H), 7.13 (t, J = 5 Hz, 0.3 H), 7.18 (t, J = 5 Hz, 0.7 H ), 8.67 (d, J = 5 Hz, 0.7 H), 8.70-8.80 (m, 1.3 H).

(Example 219)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-hydroxy-7-((pyrimidin-2-ylmethyl) -L-prolyl) -1,2,3,4,6,6 Synthesis of 7,8,8a-octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (254)

According to the method described in Example 7, the title compound was obtained from compound 253.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-2.10 (m, 8H), 2.10-2.45 (m, 6H), 2.60-2.75. (M, 2H), 2.75-2.90 (m, 1H), 2.90-3.05 (m, 2H), 3.25-3.55 (m, 3H), 3.80-3 .90 (m, 0.3H), 3.90-4.25 (m, 2.7H), 4.40-4.60 (m, 2H), 6.45-6.55 (m, 1H) , 6.65-6.75 (m, 1H), 7.10-7.25 (m, 1H), 8.68 (d, J = 5Hz, 0.3H), 8.70-8.85 ( m, 1.7H).

(Example 220)
(R) -5-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,6,7,8,8a-octahydro-5H Of -4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-carbonyl) pyrrolidin-2-one (255)

Following the method described in Example 42, the title compound was obtained from compound 9 and (R) -5-oxopyrrolidine-2-carboxylic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.17 (m, 2H), 0.43-0.56 (m, 2H), 0.72-0.85 (m , 1H), 1.06-1.17 (m, 1H), 1.21-1.74 (m, 5H), 1.93-2.68 (m, 9.7H), 2.73-2. .89 (m, 1H), 2.95-3.03 (m, 0.3H), 2.99 (d, J = 18Hz, 0.7H), 3.05-3.10 (m, 0. 3H), 3.08 (d, J = 6 Hz, 0.7H), 3.09-3.19 (m, 0.3H), 3.48-3.59 (m, 0.7H), 3. 63-3.73 (m, 1H), 3.84-3.90 (m, 0.3H), 3.87 (s, 2.1H), 3.88 (s, 0.9H), 4. 37-4.40 (m, 0.3H), 4. 2-4.45 (m, 0.7H), 4.53-4.63 (m, 2H), 5.92 (br s, 0.3H), 6.13 (br s, 0.7H), 6.59 (d, J = 8 Hz, 0.7 H), 6.64 (d, J = 8 Hz, 0.3 H), 6.73 (d, J = 8 Hz, 0.7 H), 6.75 (d , J = 8 Hz, 0.3H).

(Example 221)
(R) -5-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,6,7,8,8a-octahydro-5H Of -4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-carbonyl) pyrrolidin-2-one (256)

According to the method described in Example 32, the title compound was obtained from compound 255.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.16 (m, 2H), 0.41-0.56 (m, 2H), 0.71-0.82 (m , 1H), 1.06-1.18 (m, 1H), 1.21-1.37 (m, 1.2H), 1.39-1.71 (m, 3.8H), 1.98. -2.53 (m, 8.2H), 2.54-2.65 (m, 1.8H), 2.73-2.90 (m, 1H), 2.96 (d, J = 18Hz, 1H), 3.03-3.10 (m, 0.2H), 3.06 (d, J = 6Hz, 0.8H), 3.43-3.58 (m, 1H), 3.63- 3.72 (m, 0.8H), 3.96-4.01 (m, 0.2H), 4.16-4.25 (m, 0.2H), 4.35-4.40 (m , 0.8H), 4.45-4.53 ( , 1H), 4.62 (dd, J = 6, 8Hz, 0.8H), 4.69 (dd, J = 4, 8Hz, 0.2H), 6.39 (brs, 0.8H), 6.49-6.57 (m, 0.2H), 6.53 (d, J = 8Hz, 0.8H), 6.55 (d, J = 8Hz, 0.2H), 6.73 (d , J = 8 Hz, 1H).

(Example 222)
2-((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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -1-morpholinoethan-1-one (257)

(Sn2 from NH, OH body)

According to the method described in Example 211, the title compound was obtained from compound 60 and 2-chloro-1-morpholinoethane-1-one.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.17 (m, 2H), 0.42-0.56 (m, 2H), 0.72-0.84 (m , 1H), 0.92-1.02 (m, 1H), 1.05-1.28 (m, 2H), 1.30-1.40 (m, 1H), 1.48-1.61 (M, 1H), 1.65-1.80 (m, 1H), 2.20 (dd, J = 7, 12 Hz, 1H), 2.24-2.42 (m, 4H), 2.57 -2.67 (m, 1H), 2.68-2.91 (m, 4H), 2.93 (d, J = 18Hz, 1H), 3.00 (d, J = 6Hz, 1H), 3 .37 (s, 2H), 3.53 to 3.80 (m, 8H), 4.52 (s, 1H), 5.15 (br s, 1H), 6.50 (d, J = 8Hz, 1H), 6.68 ( , J = 8Hz, 1H).

(Example 223)
2-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -1- (piperidin-1-yl) ethan-1-one (258)

According to the method described in Example 211, the title compound was obtained from compound 60 and 2-chloro-1- (piperidin-1-yl) ethan-1-one (synthesized by the method described in WO2018148576).

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.16 (m, 2H), 0.41-0.55 (m, 2H), 0.71-0.84 (m , 1H), 0.90-1.00 (m, 1H), 1.04-1.38 (m, 3H), 1.48-1.80 (m, 8H), 2.19 (dd, J = 7, 13 Hz, 1H), 2.25-2.42 (m, 4H), 2.55-2.65 (m, 1H), 2.69-2.88 (m, 4H), 2.93 (D, J = 18 Hz, 1H), 3.02 (d, J = 6 Hz, 1H), 3.36 (s, 2H), 3.39-3.51 (m, 2H), 3.59-3 .71 (m, 2H), 4.57 (s, 1H), 5.00 (br s, 1H), 6.50 (d, J = 8Hz, 1H), 6.68 (d, J = 8Hz, 1H).

(Example 224)
(S) -5-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,6,7,8,8a-octahydro-5H Of -4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carbonyl) pyrrolidin-2-one (259)

The title compound was obtained from compound 9 and (S) -5-oxopyrrolidine-2-carboxylic acid according to the method described in Example 42.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.16 (m, 2H), 0.44-0.55 (m, 2H), 0.72-0.84 (m , 1H), 1.09-1.18 (m, 1H), 1.21-1.59 (m, 4H), 1.61-1.71 (m, 1H), 2.07-2.69 (M, 10H), 2.85-2.96 (m, 1H), 2.99 (d, J = 18Hz, 0.7H), 3.00 (d, J = 19Hz, 0.3H), 3 .04 (d, J = 6 Hz, 0.7 H), 3.07 (d, J = 6 Hz, 0.3 H), 3.53 (ddd, J = 4, 11, 15 Hz, 0.7 H), 3. 60-3.70 (m, 1H), 3.87 (s, 2.1H), 3.88 (s, 0.9H), 3.96-4.00 (m, 0.3H), 4. 02-4.11 (m 0.3H), 4.47-4.59 (m, 2.7H), 5.98 (br s, 0.3H), 6.01 (br s, 0.7H), 6.59 (d, J = 8 Hz, 0.7 H), 6.65 (d, J = 8 Hz, 0.3 H), 6.73 (d, J = 8 Hz, 0.7 H), 6.75 (d, J = 8 Hz, 0) .3H).

(Example 225)
(S) -5-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,6,7,8,8a-octahydro-5H Of -4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-carbonyl) pyrrolidin-2-one (260)

According to the method described in Example 32, the title compound was obtained from compound 259.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.17 (m, 2H), 0.38-0.54 (m, 2H), 0.70-0.84 (m , 1H), 1.06-1.69 (m, 6H), 2.00-2.67 (m, 10H), 2.82-3.09 (m, 1H), 2.94 (d, J = 19 Hz, 1H), 3.01 (d, J = 6 Hz, 1H), 3.45-3.58 (m, 1H), 3.61-3.71 (m, 1H), 4.47-4 .64 (m, 3H), 6.51 (d, J = 8Hz, 1H), 6.72 (d, J = 8Hz, 1H).

(Example 226)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (pyrrolidin-1-yl) ethan-1-one (261)

According to the method described in Example 60, the title compound was obtained from compound 9 and 2- (pyrrolidin-1-yl) acetic acid hydrochloride.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.18 (m, 2H), 0.40-0.56 (m, 2H), 0.70-0.92 (m , 1H), 1.01-2.00 (m, 10H), 2.06-2.46 (m, 5H), 2.51-3.10 (m, 8H), 3.17-3.36. (M, 1H), 3.37-3.57 (m, 2H), 3.80-3.99 (m, 3.6H), 4.11 (s, 0.4H), 4.37-4 0.78 (m, 2H), 6.57 (d, J = 8Hz, 0.6H), 6.62 (d, J = 8Hz, 0.4H), 6.67-6.79 (m, 1H) ．

(Example 227)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (pyrrolidin-1-yl) ethan-1-one (262)

According to the method described in Example 7, the title compound was obtained from compound 261.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02-0.18 (m, 2H), 0.41-0.58 (m, 2H), 0.71-0.94 (m , 1H), 1.01-2.44 (m, 15H), 2.54-2.88 (m, 6H), 2.89-3.09 (m, 2H), 3.19-3.36. (M, 1H), 3.37-3.57 (m, 2H), 3.88-4.00 (m, 0.7H), 4.06-4.17 (m, 0.3H), 4 .40-4.57 (m, 2H), 6.48-6.58 (m, 1H), 6.66-6.77 (m, 1H).

(Example 228)
2-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -N- (pyrimidin-2-yl) acetamide (263)

The title compound was obtained from compound 60 and 2-chloro-N- (pyrimidin-2-yl) acetamide according to the method described in Example 211.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.17 (m, 2H), 0.42-0.56 (m, 2H), 0.74-0.84 (m , 1H), 0.97-1.10 (m, 1H), 1.15-1.33 (m, 2H), 1.37-1.47 (m, 1H), 1.57-1.81. (M, 2H), 2.16-2.50 (m, 5H), 2.66 (dd, J = 5, 12Hz, 1H), 2.80-3.02 (m, 5H), 3.04 (D, J = 6 Hz, 1 H), 3.40 (d, J = 17 Hz, 1 H), 3.44 (d, J = 17 Hz, 1 H), 4.70 (s, 1 H), 4.94 (br s, 1H), 6.53 (d, J = 8Hz, 1H), 6.69 (d, J = 8Hz, 1H), 7.05 (t, J = 5Hz, 1H), 8.67 (d, J = 5Hz 2H), 9.97 (br s, 1H).

(Example 229)
2- (azepan-1-yl) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8 Of 8, 8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) ethan-1-one (264)

According to the method described in Example 44, a crude product of the title compound was obtained from compound 9 (8.0 mg, 0.023 mmol) and 2- (azepan-1-yl) acetic acid (5.5 mg, 0.035 mmol). To a solution of the obtained crude product in methanol (1 mL) was added 10% palladium-activated carbon (55% wet) (2 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 17 hours. The reaction mixture was filtered with a membrane filter, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-5% methanol / chloroform) to give the title compound (6.1 mg, 53%) as a pale-yellow solid substance.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.18 (m, 2H), 0.41-0.56 (m, 2H), 0.71-0.94 (m , 1H), 1.01-1.92 (m, 14H), 2.07-2.42 (m, 5H), 2.57-3.07 (m, 8H), 3.18-3.57. (M, 3H), 3.98-4.19 (m, 0.8H), 4.25-4.35 (m, 0.2H), 4.40-4.66 (m, 2H), 6 .48-6.59 (m, 1H), 6.67-6.76 (m, 1H).

(Example 230)
tert-Butyl (R) -3- (2-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8 , 8a-Octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2-oxoethyl) morpholine-4-carboxylate Synthesis of (265)

According to the method described in Example 60, the title compound was obtained from compound 9 and (R) -2- (4- (tert-butoxycarbonyl) morpholin-3-yl) acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.18 (m, 2H), 0.41-0.57 (m, 2H), 0.71-0.93 (m , 1H), 1.02-1.83 (m, 15H), 2.08-3.32 (m, 12H), 3.38-4.23 (m, 10H), 4.30-4.74. (M, 3H), 6.52-6.66 (m, 1H), 6.67-6.81 (m, 1H).

(Example 231)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2-((R) -morpholin-3-yl) ethan-1-one (266 ) Synthesis

According to the method described in Example 7, the title compound was obtained from compound 265.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02-0.20 (m, 2H), 0.40-0.56 (m, 2H), 0.68-2.51 (m , 14H), 2.54-3.12 (m, 6H), 3.24-3.46 (m, 3H), 3.53-3.96 (m, 4H), 4.23-4.39. (M, 0.2H), 4.41-4.50 (m, 1H), 4.54-4.64 (m, 0.8H), 6.46-6.58 (m, 1H), 6 .63-6.72 (m, 1H).

(Example 232)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (4,4-difluoropiperidin-1-yl) ethan-1-one ( 267) Synthesis

The title compound was obtained from compound 245 and 4,4-difluoropiperidine according to the method described in Example 211.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.19 (m, 2H), 0.40-0.57 (m, 2H), 0.66-0.95 (m , 1H), 1.02-1.75 (m, 6H), 1.93-2.47 (m, 9H), 2.53-2.92 (m, 6H), 2.93-3.14. (M, 2H), 3.18-3.40 (m, 2.4H), 3.44-3.60 (m, 0.6H), 3.77-3.94 (m, 3.6H) , 4.05 (s, 0.4H), 4.38-4.66 (m, 2H), 6.58 (d, J = 8Hz, 0.6H), 6.62 (d, J = 0. 4H), 6.68-6.78 (m, 1H).

(Example 233)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (4,4-difluoropiperidin-1-yl) ethan-1-one ( 268) Synthesis

According to the method described in Example 7, the title compound was obtained from compound 267.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.18 (m, 2H), 0.43-0.58 (m, 2H), 0.71-0.98 (m , 1H), 1.04-1.76 (m, 6H), 1.95-2.44 (m, 9H), 2.55-2.89 (m, 6H), 2.91-3.10. (M, 2H), 3.17-3.39 (m, 2H), 3.43-3.57 (m, 1H), 3.81-3.95 (m, 0.8H), 4.03. -4.18 (m, 0.2H), 4.39-4.93 (m, 3H), 6.49-6.59 (m, 1H), 6.67-6.76 (m, 1H) ．

(Example 234)
(4R, 4aS, 8R, 8aR, 13bS) -7-((1H-imidazol-3-yl) methyl) -3- (cyclopropylmethyl) -1,2,3,4,6,7,8,8a -Octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-ol (269)

The title compound was obtained from compound 60 and 1H-indazole-3-carbaldehyde according to the method described in Example 115.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.16 (m, 2H), 0.40-0.54 (m, 2H), 0.71-0.85 (m , 1H), 0.86-1.09 (m, 2H), 1.12-1.71 (m, 4H), 2.20 (dd, J = 7, 12Hz, 1H), 2.24-2 .43 (m, 4H), 2.55-2.66 (m, 1H), 2.80-2.95 (m, 5H), 2.98 (d, J = 6Hz, 1H), 4.06 (D, J = 14 Hz, 1 H), 4.12 (d, J = 14 Hz, 1 H), 4.44 (s, 1 H), 6.47 (d, J = 8 Hz, 1 H), 6.64 (d , J = 8 Hz, 1 H), 7.14-7.21 (m, 1 H), 7.34-7.43 (m, 2 H), 7.97 (d, J = 8 Hz, 1 H), 10.01 (Br s 1H).

(Example 235)
2- (7-azabicyclo [2.2.1] heptane-7-yl) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1, 2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) Synthesis of ethane-1-one (270)

The title compound was obtained from compound 245 and 7-azabicyclo [2.2.1] heptane according to the method described in Example 211.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.90 (m, 14H), 2.10-2.50 (m, 5H), 2.60-2.70. (M, 1H), 2.70-3.10 (m, 3H), 3.20-3.40 (m, 3H), 3.45-3.60 (m, 1H), 3.88 (s , 3H), 4.00-4.20 (m, 1H), 4.45-4.65 (m, 2H), 6.57 (d, J = 8 Hz, 0.5H), 6.62 (d , J = 8 Hz, 0.5 H), 6.70-6.80 (m, 1 H).

(Example 236)
2- (7-azabicyclo [2.2.1] heptan-7-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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) Synthesis of ethane-1-one (271)

According to the method described in Example 7, the title compound was obtained from compound 270.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.90 (m, 13H), 2.10-2.45 (m, 5H), 2.55-2.65. (M, 1H), 2.70-3.10 (m, 3H), 3.15-3.25 (m, 1H), 3.30-3.40 (m, 3H), 3.40-3 .55 (m, 1H), 4.00-4.10 (m, 1H), 4.45-4.60 (m, 2H), 6.50-6.60 (m, 1H), 6.65 -6.75 (m, 1H).

(Example 237)
2- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy -1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7 Synthesis of -yl) ethan-1-one (272)

The title compound was obtained from compound 245 and 3-oxa-8-azabicyclo [3.2.1] octane hydrochloride according to the method described in Example 211.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.80 (m, 7H), 1.90-2.10 (m, 4H), 2.15-2.45. (M, 5H), 2.55-2.65 (m, 1H), 2.90-3.30 (m, 6H), 3.50-3.65 (m, 2H), 3.70-3 .95 (m, 5H), 4.00-4.20 (m, 1H), 4.40-4.55 (m, 1H), 4.55-4.70 (m, 1H), 6.55. -6.65 (m, 1H), 6.70-6.80 (m, 1H).

(Example 238)
2- (3-oxa-8-azabicyclo [3.2.1] octane-8-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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7 Synthesis of -yl) ethan-1-one (273)

According to the method described in Example 7, the title compound was obtained from compound 272.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.80 (m, 7H), 1.90-2.45 (m, 7H), 2.55-2.70. (M, 1H), 2.90-3.30 (m, 6H), 3.45-3.60 (m, 4H), 3.75-3.85 (m, 2H), 4.00-4 .15 (m, 0.7H), 4.20-4.35 (m, 0.3H), 4.40-4.55 (m, 1.7H), 4.60-4.70 (m, 0.3H), 6.50-6.60 (m, 1H), 6.65-6.75 (m, 1H).

(Example 239)
tert-Butyl (S) -3- (2-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8 , 8a-Octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2-oxoethyl) morpholine-4-carboxylate Synthesis of (274)

According to the method described in Example 60, the title compound was obtained from compound 9 and (S) -2- (4- (tert-butoxycarbonyl) morpholin-3-yl) acetic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.21 (m, 2H), 0.41-0.60 (m, 2H), 0.71-0.94 (m , 1H), 1.01-1.85 (m, 15H), 1.99-2.50 (m, 6H), 2.56-2.70 (m, 1H), 2.73-3.38. (M, 5H), 3.39-4.25 (m, 10H), 4.26-4.75 (m, 3H), 6.57 (d, J = 8Hz, 0.5H), 6.62 (D, J = 8 Hz, 0.5H), 6.67-6.80 (m, 1H).

(Example 240)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2-((S) -morpholin-3-yl) ethan-1-one (275 ) Synthesis

According to the method described in Example 7, the title compound was obtained from compound 274.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.16 (m, 2H), 0.40-0.54 (m, 2H), 0.70-0.93 (m , 1H), 1.01-1.93 (m, 6H), 2.01-2.66 (m, 8H), 2.72-3.09 (m, 5H), 3.27-3.87. (M, 6.8H), 3.91-3.98 (m, 0.2H), 4.23-4.33 (m, 0.2H), 4.37-4.47 (m, 1H) , 4.65 (d, J = 2 Hz, 0.8H), 6.47-6.57 (m, 1H), 6.63-6.76 (m, 1H).

(Example 241)
(4R, 4aS, 8R, 8aR, 13bS) -7- (2-amino-9H-purin-6-yl) -3- (cyclopropylmethyl) -1,2,3,4,6,7,8, Synthesis of 8a-octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (276)

The title compound was obtained from compound 60 and 6-chloro-9H-purin-2-amine according to the method described in Example 117.

¹ H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.02-0.14 (m, 2H), 0.37-0.50 (m, 2H), 0.72-3.47 ( m, 19H), 4.46 (s, 1H), 5.67 (s, 2H), 6.45 (d, J = 8Hz, 1H), 6.58 (d, J = 8Hz, 1H), 7 .68 (s, 1H).

(Example 242)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2-((S) -4-methylmorpholin-3-yl) ethane-1- On (277) synthesis

Following the method described in Example 115, the title compound was obtained from compound 275 and a 36% aqueous formaldehyde solution.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02-0.19 (m, 2H), 0.41-0.58 (m, 2H), 0.71-0.95 (m , 1H), 1.01-1.90 (m, 6H), 2.01-2.52 (m, 10H), 2.56-3.10 (m, 7H), 3.31-3.59 (M, 2H), 3.62-3.90 (m, 3.7H), 3.96-4.05 (m, 0.3H), 4.24-4.38 (m, 0.3H) , 4.41-4.62 (m, 1.7H), 6.47-6.60 (m, 1H), 6.64-6.77 (m, 1H).

(Example 243)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (2-oxa-6-azaspiro [3.3] heptane-6- Synthesis of (yl) ethane-1-one (278)

To a solution of compound 60 (10 mg, 0.028 mmol) in chloroform (1 mL) was added N, N-diisopropylethylamine (48 μL, 0.28 mmol) and chloroacetyl chloride (6.8 μL, 0.085 mmol) under ice cooling, and the mixture was cooled to room temperature. It was stirred for 2 hours. Next, 2-oxa-6-azaspiro [3.3] heptane (17 mg, 0.17 mmol), sodium iodide (8.5 mg, 0.057 mmol) and acetonitrile (1 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 69 hours. It was stirred. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (silica gel bearing amino group, 3-12% methanol / chloroform) to give the title compound (11 mg, 78%) as a colorless solid substance.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.18 (m, 2H), 0.39-0.57 (m, 2H), 0.70-0.93 (m , 1H), 1.02-1.14 (m, 1H), 1.7-1.80 (m, 5H), 2.01-2.43 (m, 5H), 2.54-2.66. (M, 1H), 2.69-2.86 (m, 1H), 2.89-3.11 (m, 2H), 3.15-3.71 (m, 7.7H), 3.79. -3.88 (m, 0.3H), 4.35-4.53 (m, 2H), 4.65-4.95 (m, 4H), 6.47-6.58 (m, 1H) , 6.65-6.75 (m, 1H).

(Example 244)
2- (3- (chloromethyl) -3- (hydroxymethyl) azetidin-1-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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7- Synthesis of (yl) ethan-1-one dihydrochloride (279)

Compound 278 (11 mg, 0.022 mmol) was dissolved in ethyl acetate (1 mL), 1 M hydrochloric acid-diethyl ether solution (0.5 mL) was added, and the mixture was concentrated under reduced pressure. Water (0.2 mL) was added to the obtained concentrated residue, followed by freezing and lyophilization to give the title compound (13 mg, 95%) as a white powder.

¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 0.38-0.98 (m, 4H), 1.02-1.38 (m, 2H), 1.39-1.94 ( m, 5H), 2.42-2.64 (m, 1H), 2.75-3.15 (m, 3H), 3.16-3.49 (m, 7H), 3.54-3. 94 (m, 5H), 3.95-4.33 (m, 4H), 4.35-4.76 (m, 3H), 6.60-6.83 (m, 2H).

(Example 245)
(4R, 4aS, 8R, 8aR, 13bS) -7-((1H-pyrrolo [3,2-b] pyridin-3-yl) methyl) -3- (cyclopropylmethyl) -1,2,3,4 Of 6,6,7,8,8a-octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (280)

The title compound was obtained from compound 60 and 1H-pyrrolo [3,2-b] pyridine-3-carbaldehyde according to the method described in Example 115.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.13 (m, 2H), 0.38-0.54 (m, 2H), 0.69-1.65 (m , 7H), 2.13-2.40 (m, 5H), 2.50-2.61 (m, 1H), 2.79-3.04 (m, 6H), 4.02 (s, 2H). ), 4.58 (s, 1H), 6.46 (d, J = 8Hz, 1H), 6.68 (d, J = 8Hz, 1H), 6.98-7.05 (m, 1H), 7.39 (s, 1H), 7.59 (d, J = 8Hz, 1H), 8.40 (d, J = 5Hz, 1H), 9.01 (br s, 1H).

(Example 246)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -7- (quinolin-2-ylmethyl) -1,2,3,4,6,7,8,8a-octahydro-5H- Synthesis of 4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (281)

The title compound was obtained from compound 60 and quinoline-2-carbaldehyde according to the method described in Example 115.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.16 (m, 2H), 0.41-0.55 (m, 2H), 0.73-1.80 (m , 7H), 2.21 (dd, J = 7, 12 Hz, 1H), 2.26-2.49 (m, 4H), 2.64 (dd, J = 5, 12 Hz, 1H), 2.75. -2.98 (m, 5H), 2.99 (d, J = 6Hz, 1H), 4.01 (d, J = 15Hz, 1H), 4.06 (d, J = 15Hz, 1H), 4 .57 (s, 1H), 5.31 (br s, 1H), 6.48 (d, J = 8 Hz, 1H), 6.65 (d, J = 8 Hz, 1H), 7.47-7. 56 (m, 1H), 7.64-7.72 (m, 1H), 7.74 (d, J = 8Hz, 1H), 7.81 (d, J = 8Hz, 1H), 8.05 ( d J = 8Hz, 1H), 8.13 (d, J = 8Hz, 1H).

(Example 247)
(4R, 4aS, 8R, 8aR, 13bS) -7-((1H-indazol-6-yl) methyl) -3- (cyclopropylmethyl) -1,2,3,4,6,7,8,8a -Synthesis of octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (282)

The title compound was obtained from compound 60 and 1H-indazole-6-carbaldehyde according to the method described in Example 115.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08-0.13 (m, 2H), 0.44-0.52 (m, 2H), 0.72-1.72 (m , 7H), 2.16-2.48 (m, 5H), 2.64 (dd, J = 4, 12Hz, 1H), 2.81-2.98 (m, 5H), 3.00 (d , J = 6 Hz, 1 H), 3.78 (d, J = 14 Hz, 1 H), 3.90 (d, J = 14 Hz, 1 H), 4.58 (s, 1 H), 6.49 (d, J = 8 Hz, 1 H), 6.64 (d, J = 8 Hz, 1 H), 7.22 (d, J = 8 Hz, 1 H), 7.49 (s, 1 H), 7.70 (d, J = 8 Hz) , 1H), 8.05 (s, 1H).

(Example 248)
(4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -7-((2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) methyl) -1,2 , 3,4,6,7,8,8a-octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (283 ) Synthesis

The title compound was obtained from compound 60 and 2,3-dihydrobenzo [b] [1,4] dioxin-6-carbaldehyde according to the method described in Example 115.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.17 (m, 2H), 0.40-0.54 (m, 2H), 0.72-1.39 (m , 5H), 1.45-1.71 (m, 2H), 1.95-2.46 (m, 5H), 2.63 (dd, J = 5, 11Hz, 1H), 2.72-2. .90 (m, 4H), 2.92 (d, J = 18Hz, 1H), 2.98 (d, J = 6Hz, 1H), 3.53 (d, J = 13Hz, 1H), 3.65. (D, J = 13 Hz, 1H), 4.21-4.29 (m, 4H), 4.53 (s, 1H), 6.48 (d, J = 8 Hz, 1H), 6.61-6 .67 (m, 1H), 6.77-6.92 (m, 3H).

(Example 249)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2-((R) -4-methylmorpholin-3-yl) ethane-1- On (284) synthesis

Following the method described in Example 115, the title compound was obtained from compound 266 and a 36% aqueous formaldehyde solution.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02-0.18 (m, 2H), 0.42-0.57 (m, 2H), 0.71-0.93 (m , 1H), 1.02-1.75 (m, 6H), 2.01-2.52 (m, 10H), 2.55-3.12 (m, 7H), 3.26-3.60 (M, 2H), 3.64-3.88 (m, 3.7H), 3.98-4.06 (m, 0.3H), 4.32-4.49 (m, 1.3H) , 4.51-4.58 (m, 0.7H), 4.74 (br s, 1H), 6.45-6.60 (m, 1H), 6.65-6.76 (m, 1H) ).

(Example 250)
tert-Butyl (R) -2-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,6,7,8,8a- Synthesis of octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine-7-carbonyl) pyrrolidine-1-carboxylate (285)

According to the method described in Example 60, the title compound was obtained from compound 9 and (tert-butoxycarbonyl) -D-proline.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-2.50 (m, 24H), 2.50-2.70 (m, 1H), 2.70-2.90. (M, 1H), 2.90-3.15 (m, 2H), 3.35-3.70 (m, 2H), 3.70-4.00 (m, 4H), 4.00-4 .20 (m, 0.3H), 4.30-4.85 (m, 2.7H), 6.50-6.65 (m, 1H), 6.65-6.80 (m, 1H) ．

(Example 251)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-methoxy-7- (pyrimidin-2-yl-D-prolyl) -1,2,3,4,6,7, Synthesis of 8,8a-octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (286)

According to the method described in Example 214, a crude product (30 mg, 80%) of the de-Boc form of compound 285 was obtained as a pale yellow amorphous form from compound 285 (50 mg, 0.082 mmol). Then, according to the method described in Example 216, the title compound (10 mg, 0.066 mmol) and a portion of the crude de-Boc derivative of compound 285 (10 mg, 0.022 mmol) were used. 84%, colorless amorphous) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.80 (m, 4H), 1.90-2.10 (m, 3H), 2.10-2.50. (M, 7H), 2.60-2.90 (m, 2H), 2.90-3.10 (m, 3H), 3.70-3.80 (m, 1H), 3.80-3 .90 (m, 4H), 4.00-4.15 (m, 1H), 4.45-4.80 (m, 1H), 4.95-5.05 (m, 1H), 5.61 (S, 1H), 6.40-6.50 (m, 1H), 6.50-6.70 (m, 1H), 6.70-6.80 (m, 1H), 8.15-8 0.25 (m, 1H), 8.25-8 35 (m, 1H).

(Example 252)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-hydroxy-7- (pyrimidin-2-yl-D-prolyl) -1,2,3,4,6,7, Synthesis of 8,8a-octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (287)

According to the method described in Example 7, the title compound was obtained from compound 286.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.90 (m, 4H), 1.90-2.60 (m, 9H), 2.60-2.90. (M, 2H), 2.90-3.10 (m, 2.8H), 3.45-3.55 (m, 0.2H), 3.65-3.80 (m, 1H), 3 .80-4.10 (m, 2H), 4.45-4.55 (m, 1H), 4.60-4.90 (m, 1H), 4.90-5.00 (m, 0. 8H), 5.00-5.10 (m, 0.2H), 5.61 (s, 1H), 6.40-6.50 (m, 1H), 6.50-6.60 (m, 1H), 6.65-6.75 (m, 1H , 8.15-8.40 (m, 2H).

(Example 253)
(4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-7-((pyrimidin-2-ylmethyl) -D-prolyl) -1,2,3,4,6 Synthesis of 7,8,8a-octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (288)

According to the method described in Example 214, a crude product (30 mg, 80%) of the de-Boc form of compound 285 was obtained as a pale yellow amorphous form from compound 285 (50 mg, 0.082 mmol). Then, according to the method described in Example 115, a portion of the crude de-Boc derivative of compound 285 (10 mg, 0.022 mmol) and pyrimidine-2-carbaldehyde (7 mg, 0.066 mmol) were used to give the title compound (5 mg , 41%, colorless amorphous) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-2.50 (m , 16H), 2.50-2.70 (m, 2H), 2.70-2.90 (m, 1H), 2.90-3.10 (m, 2H), 3.20-3.40. (M, 1H), 3.40-4.20 (m, 8H), 4.40-4.50 (m, 0.5H), 4.50-4.60 (m, 0.5H), 4 .60-4.80 (m, 1H), 6.55 (d, J = 8Hz, 0.5H), 6.61 (d, J = 8Hz, 0.5H), 6.65-6.80 ( m, 1H), 7.10-7.20 (m, 1H), 8.70-8.80 (m, 2H).

(Example 254)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-hydroxy-7-((pyrimidin-2-ylmethyl) -D-prolyl) -1,2,3,4,6,6 Synthesis of 7,8,8a-octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (289)

According to the method described in Example 7, the title compound was obtained from compound 288.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-2.10 (m, 6H), 2.10-2.45 (m, 6H), 2.45-3.20. (M, 5H), 3.20-3.50 (m, 2H), 3.60-4.10 (m, 4H), 4.10-4.30 (m, 1.7H), 4.40. -4.70 (m, 2.3H), 6.45-6.55 (m, 1H), 6.65-6.75 (m, 1H), 7.10-7.30 (m, 1H) , 8.72 (d, J = 5 Hz, 2H).

(Example 255)
2- (8-Azabicyclo [3.2.1] octane-8-yl) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2 , 3,4,5,6,8,8a-Octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) ethane Synthesis of 1-one (290)

The title compound was obtained from compound 245 and 8-azabicyclo [3.2.1] octane hydrochloride according to the method described in Example 211.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.85 (m, 14H), 1.90-2.05 (m, 2H), 2.10-2.45. (M, 4.4H), 2.55-2.65 (m, 0.6H), 2.70-2.85 (m, 0.4H), 2.90-3.10 (m, 2.H). 6H), 3.10-3.40 (m, 4.4H), 3.50-3.60 (m, 0.6H), 3.88 (s, 1.8H), 3.88 (s, 1.2H), 4.10-4.20 (m, 0.6H), 4.20-4.30 (m, 0.4H), 4.40-4.70 (m, 2H), 6. 56 (d, J = 8 Hz, 0.6 H), 6.6 (D, J = 8Hz, 0.4H), 6.70-6.75 (m, 1H).

(Example 256)
2- (8-Azabicyclo [3.2.1] octane-8-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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) ethane Synthesis of 1-one (291)

According to the method described in Example 7, the title compound was obtained from compound 290.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-2.10 (m, 10H), 2.10-2.45 (m, 6H), 2.55-2.65. (M, 1H), 2.70-3.10 (m, 3.3H), 3.15-3.40 (m, 4.7H), 3.45-3.55 (m, 1H), 3 .60-3.90 (m, 3H), 4.10-4.25 (m, 0.7H), 4.25-4.35 (m, 0.3H), 4.45-4.55 ( m, 1.7H), 4.65-4.75 (m, 0.3H), 6.50-6.55 (m, 1H), 6.71 (d, J = 8Hz, 1H).

(Example 257)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -7- (thiazol-2-ylmethyl) -1,2,3,4,6,7,8,8a-octahydro-5H- Synthesis of 4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (292)

The title compound was obtained from compound 60 and thiazole-2-carbaldehyde according to the method described in Example 115.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.14 (m, 2H), 0.42-0.53 (m, 2H), 0.73-0.84 (m , 1H), 0.90-0.99 (m, 1H), 1.00-1.10 (m, 1H), 1.15-1.25 (m, 1H), 1.31-1.40 (M, 1H), 1.48-1.61 (m, 2H), 2.17-2.44 (m, 5H), 2.62 (dd, J = 5, 11Hz, 1H), 2.84. -2.96 (m, 5H), 2.99 (d, J = 6Hz, 1H), 3.93 (d, J = 15Hz, 1H), 3.95 (d, J = 15Hz, 1H), 4 .55-4.59 (m, 1H), 5.45 (br s, 1H), 6.49 (d, J = 8Hz, 1H), 6.66 (d, J = 8Hz, 1H), 7. 25 (d, J 2Hz, 1H), 8.78 (d, J = 2Hz, 1H).

(Example 258)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -3- (pyrrolidin-1-yl) propan-1-one (293)

According to the method described in Example 68, the title compound was obtained from compound 60 and 3- (pyrrolidin-1-yl) propanoic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.19 (m, 2H), 0.40-0.58 (m, 2H), 0.72-2.41 (m , 16H), 2.53-3.16 (m, 12H), 3.42-3.68 (m, 1H), 3.71-3.83 (m, 0.5H), 3.87-4. 0.06 (m, 1H), 4.44-4.60 (m, 1.5H), 6.41-6.58 (m, 1.5H), 6.70 (d, J = 8Hz, 0. 5H).

(Example 259)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -3- (piperidin-1-yl) propan-1-one (294)

According to the method described in Example 68, the title compound was obtained from compound 60 and 3- (piperidin-1-yl) propanoic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02-0.19 (m, 2H), 0.40-0.57 (m, 2H), 0.71-1.88 (m , 13H), 1.99-3.23 (m, 17H), 3.41-3.58 (m, 0.5H), 3.59-3.82 (m, 1H), 3.84-3. .97 (m, 1H), 4.44-4.58 (m, 1.5H), 6.41-6.58 (m, 1.5H), 6.70 (d, J = 8Hz, 0. 5H).

(Example 260)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -7- (thiazol-4-ylmethyl) -1,2,3,4,6,7,8,8a-octahydro-5H- Synthesis of 4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (295)

The title compound was obtained from compound 60 and thiazole-4-carbaldehyde according to the method described in Example 115.

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), 0.92-1.02 (m, 1H), 1.05-1.16 (m, 1H), 1.18-1.27 (m, 1H), 1.31-1.39 (M, 1H), 1.53 to 1.59 (m, 1H), 1.62-1.72 (m, 1H), 2.16-2.24 (m, 1H), 2.26-2 .48 (m, 4H), 2.64 (dd, J = 5, 11 Hz, 1H), 2.82-2.98 (m, 5H), 3.00 (d, J = 6 Hz, 1H), 4 .04 (s, 2H), 4.62-4.65 (m, 1H), 6.49 (d, J = 8Hz, 1H), 6.66 (d, J = 8Hz, 1H), 7.28 (D, J = 3Hz, 1 ), 7.70 (d, J = 3Hz, 1H).

(Example 261)
((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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (1H-indazol-3-yl) methanone (296)

According to the method described in Example 60, the title compound was obtained from compound 60 and 1H-indazole-3-carboxylic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.17 (m, 2H), 0.38-0.57 (m, 2H), 0.69-0.88 (m , 1H), 0.95-1.92 (m, 6H), 2.17-2.44 (m, 5H), 2.56-2.70 (m, 1H), 2.82-3.11. (M, 3H), 3.27-3.43 (m, 0.5H), 3.60-3.77 (m, 0.5H), 4.50-4.67 (m, 0.5H) , 4.68-4.85 (m, 2H), 4.95-5.07 (m, 0.5H), 6.55 (d, J = 8Hz, 0.5H), 6.59 (d, J = 8 Hz, 0.5 H), 6.75 (d, J = 8 Hz, 0.5 H), 6.77 (d, J = 8 Hz, 0.5 H), 7.17-7.28 (m, 1 H ), 7.31-7.46 (m, 1 5H), 7.52 (d, J = 9Hz, 0.5H), 8.07 (d, J = 8Hz, 0.5H), 8.18 (d, J = 8Hz, 0.5H), 10. 64 (br s, 0.5H), 10.83 (br s, 0.5H).

(Example 262)
2-((1S, 4S) -2-oxa-5-azabicyclo [2.2.2] octan-5-yl) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropyl Methyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3 Synthesis of -d] azepin-7-yl) ethan-1-one (297)

The title compound was obtained from compound 245 and (1S, 4S) -2-oxa-5-azabicyclo [2.2.2] octane oxalate according to the method described in Example 211.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.90 (m, 12H), 2.00-2.50 (m, 7H), 2.50-3.30. (M, 4H), 3.40-3.60 (m, 2H), 3.60-4.00 (m, 5H), 4.25-4.35 (m, 1H), 4.40-4 .70 (m, 2H), 6.50-6.65 (m, 1H), 6.70-6.80 (m, 1H).

(Example 263)
2-((1S, 4S) -2-oxa-5-azabicyclo [2.2.2] octan-5-yl) -1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropyl Methyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3 Synthesis of -d] azepin-7-yl) ethan-1-one (298)

According to the method described in Example 7, the title compound was obtained from compound 297.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-1.90 (m , 12H), 1.90-2.45 (m, 10H), 2.55-3.20 (m, 3H), 3.40-4.00 (m, 4H), 4.25-4.35. (M, 1H), 4.40-4.55 (m, 2H), 6.50-6.55 (m, 1H), 6.65-6.80 (m, 1H).

(Example 264)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-methoxy-7- (2- (pyridin-2-yl) ethyl) -1,2,3,4,6,7 Of 8,8,8a-octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepine (299)

According to the method described in Example 211, the title compound was obtained from compound 9 and 2- (pyridin-2-yl) ethyl 4-methylbenzenesulfonate.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.16 (m, 2H), 0.42-0.54 (m, 2H), 0.73-0.85 (m , 1H), 0.91-1.02 (m, 1H), 1.11-1.36 (m, 3H), 1.45-1.55 (m, 1H), 1.63-1.74. (M, 1H), 2.21 (dd, J = 7, 12 Hz, 1H), 2.24-2.47 (m, 4H), 2.55-2.66 (m, 1H), 2.74 -3.06 (m, 10H), 3.86 (s, 3H), 4.47-4.54 (m, 1H), 6.56 (d, J = 8Hz, 1H), 6.70 (d , J = 8 Hz, 1H), 7.08-7.13 (m, 1H), 7.16-7.21 (m, 1H), 7.56-7.62 (m, 1H), 8.50. -8.55 (m, 1H .

(Example 265)
(4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -7- (2- (pyridin-2-yl) ethyl) -1,2,3,4,6,7,8,8a -Synthesis of octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (300)

According to the method described in Example 32, the title compound was obtained from compound 299.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.15 (m, 2H), 0.42-0.53 (m, 2H), 0.73-0.84 (m , 1H), 0.91-1.00 (m, 1H), 1.07-1.35 (m, 3H), 1.45-1.53 (m, 1H), 1.59-1.71. (M, 1H), 2.20 (dd, J = 7, 13 Hz, 1H), 2.24-2.40 (m, 4H), 2.53-2.65 (m, 1H), 2.74 -3.08 (m, 10H), 4.47-4.52 (m, 1H), 6.49 (d, J = 8Hz, 1H), 6.68 (d, J = 8Hz, 1H), 7 .12 (ddd, J = 1, 5, 8 Hz, 1H), 7.17-7.21 (m, 1H), 7.60 (ddd, J = 1, 8, 8 Hz, 1H), 8.50- 8.54 (m 1H).

(Example 266)
1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (cis-2,6-dimethylpiperidin-1-yl) ethane-1- On (301) synthesis

According to the method described in Example 211, the title compound was obtained from compound 245 and cis-2,6-dimethylpiperidine.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.17 (m, 2H), 0.43-0.57 (m, 2H), 0.74-0.84 (m , 1H), 1.02-1.15 (m, 6H), 1.18-1.71 (m, 6H), 1.58 (s, 6H), 2.08-2.45 (m, 5H ), 2.56-2.68 (m, 1H), 2.76-2.89 (m, 1H), 2.97 (d, J = 19Hz, 1H), 3.01-3.19 (m , 2H), 3.03 (d, J = 6Hz, 0.4H), 3.08 (d, J = 6Hz, 0.6H), 3.38 (ddd, J = 4, 10, 15Hz, 0. 4H), 3.48 (ddd, J = 4, 11, 14 Hz, 0.6H), 3.68 (s, 2H), 3.74-3.82 (m, 0.6H), 3.88 ( s, 3H), 3 96-4.00 (m, 0.4H), 4.22-4.31 (m, 0.4H), 4.44-4.51 (m, 1H), 4.56-4.61 (m , 0.6H), 6.56 (d, J = 8Hz, 0.6H), 6.61 (d, J = 8Hz, 0.4H), 6.72 (d, J = 8Hz, 0.6H) , 6.73 (d, J = 8 Hz, 0.4H).

(Example 267)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (cis-2,6-dimethylpiperidin-1-yl) ethane-1- On (302) synthesis

According to the method described in Example 32, the title compound was obtained from compound 301.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.16 (m, 2H), 0.43-0.57 (m, 2H), 0.73-0.85 (m , 1H), 1.02-1.16 (m, 6H), 1.19-1.73 (m, 12H), 2.02-2.45 (m, 5H), 2.56-2.68. (M, 1H), 2.74-2.89 (m, 1H), 2.96 (d, J = 18Hz, 1H), 3.03 (d, J = 6Hz, 0.3H), 3.08 (D, J = 6 Hz, 0.7H), 3.10-3.21 (m, 2H), 3.33-3.52 (m, 1H), 3.63-3.75 (m, 2H) , 3.76-3.86 (m, 0.7H), 3.95-4.01 (m, 0.3H), 4.22-4.31 (m, 0.3H), 4.43- 4.56 (m, 1.7H), .53 (d, J = 8 Hz, 0.7 H), 6.55 (d, J = 8 Hz, 0.3 H), 6.72 (d, J = 8 Hz, 0.3 H), 6.73 (d, J = 8 Hz, 0.7H).

(Example 268)
(4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -7- (2- (piperidin-1-yl) ethyl) -1,2,3,4,6,7,8,8a -Octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (303)

The title compound was obtained from compound 60 and 1- (2-chloroethyl) piperidine hydrochloride according to the method described in Example 211.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.01-0.21 (m, 2H), 0.39-0.56 (m, 2H), 0.72-0.83 (m , 1H), 0.89-0.99 (m, 1H), 1.01-1.33 (m, 3H), 1.35-1.82 (m, 8H), 2.10-3.05 (M, 20H), 4.46-4.59 (m, 1H), 6.49 (d, J = 8Hz, 1H), 6.66 (d, J = 8Hz, 1H).

(Example 269)
((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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (1H-pyrazol-4-yl) methanone (304)

Following the method described in Example 42, the title compound was obtained from compound 60 and 1H-pyrazole-4-carboxylic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.14 (m, 2H), 0.40-0.53 (m, 2H), 0.70-0.83 (m , 1H), 1.02-1.15 (m, 1H), 1.20-1.51 (m, 4H), 1.56-1.78 (m, 1H), 2.08-2.41 (M, 5H), 2.51-2.62 (m, 1H), 2.73-2.86 (m, 1H), 2.94 (d, J = 19Hz, 1H), 3.00-3 0.08 (m, 1H), 3.10-3.24 (m, 0.7H), 3.53-3.69 (m, 0.7H), 4.08-4.19 (m, 1H) , 4.51-4.62 (m, 1.3H), 4.66-4.74 (m, 0.3H), 6.48-6.58 (m, 1H), 6.76 (d, J = 8Hz, 1H), 7.85-7 94 (m, 1H), 7.96-8.04 (m, 1H).

(Example 270)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2-((R) -4-ethylmorpholin-3-yl) ethane-1- On (305) synthesis

Following the method described in Example 115, the title compound was obtained from compound 266 and acetaldehyde.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02-0.17 (m, 2H), 0.40-0.56 (m, 2H), 0.72-0.96 (m , 1H), 1.03-1.80 (m, 9H), 1.99-2.89 (m, 13H), 2.91-3.07 (m, 2H), 3.19-3.38. (M, 1.3H), 3.45-3.61 (m, 1.7H), 3.66-3.89 (m, 3.7H), 4.04-4.17 (m, 0. 3H), 4.33-4.48 (m, 1.3H), 4.51-4.60 (m, 0.7H), 6.46-6.60 (m, 1H), 6.65- 6.74 (m, 1H).

(Example 271)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2-((R) -4- (cyclopropylmethyl) morpholin-3-yl) Synthesis of ethane-1-one (306)

The title compound was obtained from compound 266 and cyclopropanecarbaldehyde according to the method described in Example 115.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02-0.19 (m, 4H), 0.42-0.60 (m, 4H), 0.71-0.95 (m , 2H), 1.02-1.15 (m, 1H), 1.18-1.79 (m, 5H), 2.00-2.89 (m, 13H), 2.90-3.10. (M, 2H), 3.22-3.42 (m, 1.3H), 3.45-3.60 (m, 1.7H), 3.66-3.88 (m, 3.7H) , 4.01-4.18 (m, 0.3H), 4.32-5.04 (m, 3H), 6.48-6.59 (m, 1H), 6.66-6.75 ( m, 1H).

(Example 272)
((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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (1,3,4-thiadiazol-2-yl) methanone (307)

According to the method described in Example 42, the title compound was obtained from compound 9 and 1,3,4-thiadiazole-2-carboxylic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.15 (m, 2H), 0.43-0.54 (m, 2H), 0.73-0.85 (m , 1H), 1.11-1.21 (m, 1H), 1.30-1.41 (m, 1H), 1.47-1.58 (m, 3H), 1.76-1.88. (M, 1H), 2.18-2.37 (m, 4H), 2.38-2.47 (m, 1H), 2.61-2.69 (m, 1H), 2.97-3 .11 (m, 3H), 3.69-3.78 (m, 0.2H), 3.84-3.93 (m, 0.8H), 3.86 (s, 0.6H), 3 .89 (s, 2.4H), 4.34 (ddd, J = 5, 5, 15Hz, 0.2H), 4.63-4.66 (m, 0.8H), 4.73-4. 77 (m, 0.8H), 4.79- .81 (m, 0.2H), 4.90 (ddd, J = 5, 5, 15Hz, 0.8H), 4.96-5.00 (m, 0.2H), 6.59-6. 63 (m, 0.2H), 6.61 (d, J = 8Hz, 0.8H), 6.73 (d, J = 8Hz, 0.2H), 6.75 (d, J = 8Hz, 0) .8H), 9.22 (s, 0.2H), 9.24 (s, 0.8H).

(Example 273)
(4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -7- (imino (1,3,4-thiadiazol-2-yl) methyl) -1,2,3,4,6 Synthesis of 7,8,8a-octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (308)

According to the method described in Example 175, the title compound was obtained from compound 307.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.13 (m, 2H), 0.41-0.52 (m, 2H), 0.70-0.80 (m , 1H), 1.07-1.17 (m, 1H), 1.24-1.40 (m, 2H), 1.42-1.60 (m, 2H), 1.72-1.84 (M, 1H), 2.19-2.40 (m, 5H), 2.57-2.66 (m, 1H), 2.83-2.94 (m, 1H), 2.95 (d , J = 18 Hz, 1H), 3.02 (d, J = 6 Hz, 1H), 3.50-3.60 (m, 1H), 3.69-3.95 (m, 1H), 4.22 -4.34 (m, 1H), 4.71-4.76 (m, 1H), 6.51 (d, J = 8Hz, 1H), 6.70 (d, J = 8Hz, 1H), 9 .22 (s, 1H).

(Example 274)
(4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -7- (imidazo [1,2-a] pyrimidin-3-ylmethyl) -1,2,3,4,6,7, Synthesis of 8,8a-octahydro-5H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-10-ol (309)

The title compound was obtained from compound 60 and imidazo [1,2-a] pyrimidine-3-carbaldehyde according to the method described in Example 115.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.01-0.16 (m, 2H), 0.37-0.54 (m, 2H), 0.70-1.72 (m , 7H), 2.13-2.38 (m, 5H), 2.51-2.63 (m, 1H), 2.69-2.89 (m, 4H), 2.91 (d, J). = 18 Hz, 1H), 2.97 (d, J = 6 Hz, 1H), 4.00 (s, 2H), 4.28 (s, 1H), 6.47 (d, J = 8 Hz, 1H), 6.68 (d, J = 8 Hz, 1H), 6.84-6.94 (m, 1H), 7.64 (s, 1H), 8.55-8.60 (m, 1H), 8. 76 (d, J = 6 Hz, 1H).

(Example 275)
((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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (4-methoxypyrimidin-2-yl) methanone (310)

According to the method described in Example 60, the title compound was obtained from compound 60 and 4-methoxypyrimidine-2-carboxylic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.18 (m, 2H), 0.37-0.57 (m, 2H), 0.66-0.94 (m , 1H), 1.02-1.88 (m, 5H), 1.94-2.46 (m, 6H), 2.58-2.72 (m, 1H), 2.86-3.14. (M, 3H), 3.35-3.68 (m, 2H), 3.97-4.09 (m, 3H), 4.50-5.00 (m, 2H), 6.49-6 0.59 (m, 1H), 6.66 (d, J = 8Hz, 0.4H), 6.70-6.79 (m, 1.6H), 8.46-8.53 (m, 1H) ．

(Example 276)
((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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (4- (dimethylamino) pyrimidin-2-yl) methanone (311)

According to the method described in Example 60, the title compound was obtained from compound 60 and 4- (dimethylamino) pyrimidine-2-carboxylic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.18 (m, 2H), 0.39-0.56 (m, 2H), 0.69-0.94 (m , 1H), 1.01-1.86 (m, 6H), 2.12-2.44 (m, 5H), 2.57-2.70 (m, 1H), 2.84-3.27. (M, 9H), 3.35-3.56 (m, 1.7H), 3.69-3.78 (m, 0.3H), 4.47-5.01 (m, 3H), 6 .36-6.43 (m, 1H), 6.48-6.57 (m, 1H), 6.65 (d, J = 8Hz, 0.3H), 6.72 (d, J = 8Hz, 0.7H), 8.19-8.27 (m, 1H).

(Example 277)
((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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (4- (pyrrolidin-1-yl) pyrimidin-2-yl) methanone (312)

According to the method described in Example 60, the title compound was obtained from compound 60 and 4- (pyrrolidin-1-yl) pyrimidine-2-carboxylic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.19 (m, 2H), 0.38-0.56 (m, 2H), 0.68-0.95 (m , 1H), 0.99-1.86 (m, 6H), 1.88-2.45 (m, 9H), 2.57-2.73 (m, 1H), 2.86-3.11. (M, 3H), 3.24-3.82 (m, 6H), 4.40-5.05 (m, 3H), 6.21-6.30 (m, 1H), 6.48-6 .57 (m, 1H), 6.65 (d, J = 8Hz, 0.3H), 6.72 (d, J = 8Hz, 0.7H), 8.15-8.24 (m, 1H) ．

(Example 278)
((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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (4,6-dimethoxypyrimidin-2-yl) methanone (313)

According to the method described in Example 60, the title compound was obtained from compound 60 and 4,6-dimethoxypyrimidine-2-carboxylic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.18 (m, 2H), 0.40-0.56 (m, 2H), 0.68-0.95 (m , 1H), 1.03-1.90 (m, 5H), 2.13-2.53 (m, 6H), 2.56-2.74 (m, 1H), 2.88-3.13. (M, 3H), 3.34-3.52 (m, 1.7H), 3.57-3.66 (m, 0.3H), 3.90-4.08 (m, 6H), 4 .36-5.05 (m, 3H), 6.06 (s, 0.7H), 6.07 (s, 0.3H), 6.49-6.59 (m, 1H), 6.66 (D, J = 8 Hz, 0.3 H), 6.73 (d, J = 8 Hz, 0.7 H).

(Example 279)
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-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (4,4-dimethyl-1,4-azacylinan-1-yl) ethane Synthesis of 1-one (314)

According to the method described in Example 243, the title compound was obtained from compound 60 and 4,4-dimethyl-1,4-azasilinane.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.00-0.23 (m, 8H), 0.40-0.56 (m, 2H), 0.72-0.98 (m , 5H), 1.01-1.14 (m, 1H), 1.18-1.94 (m, 5H), 2.02-2.49 (m, 5H), 2.56-3.08 (M, 8H), 3.16-3.37 (m, 2.2H), 3.39-3.57 (m, 0.8H), 3.99-4.25 (m, 1H), 4 .38-4.73 (m, 2H), 6.46-6.60 (m, 1H), 6.66-6.77 (m, 1H).

(Test Example 1)
Functional test of opioid receptor <br /> The functional activity of the compound of the present invention to κ opioid receptor was examined.
Method: It was carried out according to a predetermined method using Lance Ultra cAMP kit (Perkin Elmer). In the evaluation of agonist activity, CHO cells expressing human κ opioid receptor (Catalog No. CT6606, accession No. NM — 000912) and a test compound were assay buffer (1 × HBSS, 5 mM HEPES, pH 7.4) in the presence of 10 μM forskolin. , 0.5 mM IBMX (Isobutylmethylxanthine), 0.1% BSA) for 30 minutes. Subsequently, the cAMP detection reagent in the kit was added, and 1 hour later, time-resolved fluorescence measurement was performed using an EnVision plate reader (Perkin Elmer). The test compounds were evaluated in the kappa opioid receptor function test in the concentration range of 10 ⁻¹⁴ to 10 ⁻⁷ M.

As shown in Tables 1 and 2, it was confirmed that the compound of the present invention exhibits a strong agonist activity for the kappa opioid receptor.

(Test Example 2)
Metabolic stability test (test method)
Human liver microsomes were allowed to react with the test substance for a certain period of time (0 to 60 minutes), and the residual amount of the unchanged substance of the test substance in the reaction sample was measured to determine the residual rate. Remaining rate of unchanged form at 0 hours of reaction time was set to 100%, and residual rate after incubation was log-linear plotted against time, and regression line (y = 100e ^−kt , k = slope of straight line: disappearance rate constant) Was calculated and metabolic clearance CL _int (mL / min / kg) was calculated using the following formula.
Further, the compound (C) described in paragraph [0006] was used as a comparative compound for comparison. Comparative compound (C) was synthesized by the method described in Non-Patent Document 1 and the like.

CL _int * = k (−min) × 45 (mg MS protein / g river) × 21 (g liver / kg) / MS protein (mg MS protein / mL)

*: Yamazaki S. Skiptason J .; Romero D .; Vekich S .; Jones HM. Tan W .; Wilner KD. Koudriakova T .; Drug Metab. Dispos. 2011 Mar; 39 (3): 383-393.

(Test results)
The test results are shown in Table 3.

From the above results, the compound of the present invention showed excellent metabolic stability to the comparative compound (C). From the above, the excellent κ opioid receptor agonist activity and metabolic stability of the compound of the present invention were confirmed.

Claims

The following general formula (I),

(In the formula, R 1 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, or a substituent C 3-6 cycloalkyl C 1-6 alkyl group, aryl group optionally having substituent (s), heteroaryl group optionally having substituent (s), aralkyl optionally having substituent (s) Group, heteroarylalkyl group optionally having substituent (s), C 2-6 alkenyl group optionally having substituent (s), C 2-6 alkynyl group optionally having substituent (s), substituent (s) Represents an acyl group or an amino protecting group which may have,
R 2 and R 3 are the same or different and each is 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, a halogen atom, a hydroxy group. Or R 2 and R 3 together represent a carbonyl group or a thiocarbonyl group, or R 2 and R 3 are bonded to each other to represent a cyclic ketal which may have a substituent,
R 4 and R 5 are the same or different and each have 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, and a substituent. Optionally represents an amino group, a halogen atom or a hydroxy group,
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, a carboxylic acid ester group Or a carbamoyl group which may have a substituent,
R 7 represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group or a hydroxy group,
R 8 and R 9 are the same or different and each is 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, a halogen atom or a hydroxy group. Or R 8 and R 9 together represent a carbonyl group or a thiocarbonyl group, or R 8 and R 9 are bonded to each other to form a C 3-6 saturated hydrocarbon ring which may have a substituent or a substituent. Indicates a cyclic ketal that may have,
R 10 and R 11 are the same or different and each is 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, a halogen atom, a hydroxy group. Or R 10 and R 11 together represent a carbonyl group or a thiocarbonyl group, or R 10 and R 11 are bonded to each other to form a C 3-6 saturated hydrocarbon ring which may have a substituent or a substituent. Indicates a cyclic ketal that may have,
R 12 and R 13 are the same or different and each represent a hydrogen atom, an optionally substituted C 1-6 alkyl group, or R 12 and R 13 together represent a carbonyl group or a thiocarbonyl group. Or R 12 and R 13 on the same carbon are bonded to each other to represent a C 3-6 saturated hydrocarbon ring which may have a substituent, a saturated heterocyclic ring which may have a substituent, or n In the case where is 2 to 3, a pair of adjacent R 12 is bonded to form a C 3-6 saturated hydrocarbon ring which may have a substituent or a saturated heterocycle which may have a substituent. Can be formed,
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, or a C 2 which may have a substituent. -4 alkenyl group, optionally substituted C 2-4 alkynyl group, optionally substituted C 1-6 alkoxy group, optionally substituted amino group, 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 or a saturated heterocyclic group which may have a substituent,
X represents a nitrogen atom or N-oxide,
Y represents C = O, C = S, C = NR 16 or SO 2 ,
R 16 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group,
Z represents NR 15 , an oxygen atom, a bond, an ethenylene group which may have a substituent or an ethynylene group,
R 15 represents a hydrogen atom, a C 1-6 alkyl group which may have a substituent, or a nitrogen-containing saturated heterocycle which may have a substituent by the combination of R 15 and R 14. ,
A double line consisting of a solid line and a broken line represents a single bond or a double bond, and m represents an integer of 0 to 1,
n represents an integer of 0 to 3. )
The morphinan derivative represented by, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
The morphinan derivative according to claim 1, wherein R 6 is a hydroxy group or a C 1-6 alkoxy group which may have a substituent, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable form thereof. Salts or solvates thereof.
The morphinan derivative according to claim 1, wherein R 6 is a hydroxy group, a tautomer, a stereoisomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. .
The morphinan derivative according to any one of claims 1 to 3, wherein R 7 is a hydrogen atom, a tautomer, a stereoisomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof.
Z is NR 15 , an oxygen atom, a bond or an ethenylene group which may have a substituent, The morphinan derivative according to claims 1 to 4, a tautomer or stereoisomer of the compound, or a compound thereof. A pharmaceutical composition containing a pharmaceutically acceptable salt or a solvate thereof as an active ingredient.
The morphinan derivative according to any one of claims 1 to 5, wherein Z is NR 15 or a bond, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or them. A pharmaceutical composition containing as an active ingredient the solvate of.
R 14 has an amino group which may have a substituent, a C 6-10 aryl group which may have a substituent, a heteroaryl group which may have a substituent or has a substituent. The morphinan derivative according to any one of claims 1 to 6, which is an optionally saturated heterocyclic group, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition containing as an active ingredient the solvate of.
The morphinan derivative according to claim 7, wherein the C 6-10 aryl group which may have a substituent according to claim 7 is a phenyl group, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable form thereof. A pharmaceutical composition containing an acceptable salt or a solvate thereof as an active ingredient.
The heteroaryl group which may have a substituent according to claim 7, wherein the furanyl group, thienyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, 1,3,4-thiadiazolyl group , 6-membered heteroaryl groups such as isothiazolyl group, triazolyl group, pyridyl group, pyridazinyl group, pyrazinyl group, pyrimidyl group, 2-oxopyridyl group, 4-oxopyridyl group, 2-oxopyrazinyl group, quinolyl group, isoquinolyl group, Indolyl group, indazolyl group, benzofuranyl group, benzothienyl group, benzoxazolyl group, benzothiazolyl group, imidazopyridinyl group, imidazo [1,2-a] pyrimidyl group, pyrazolopyridinyl group, purine, adenine, The morphinan inducer according to claim 7, which is one of guanine. Body, a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing them solvate as an active ingredient.
The saturated heterocyclic group which may have a substituent according to claim 7 is a cyclic amino group, the morphinan derivative according to claim 7, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition containing the salt or a solvate thereof as an active ingredient.
The cyclic amino group which may have a substituent according to claim 10 is an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, an azepanyl group, a morpholinyl group, a thiomorpholinyl group, 7-azabicyclo [2.2.1] heptyl. Group, 3-oxa-8-azabicyclo [2.2.2] octyl group, 3-oxa-8-azabicyclo [3.2.1] octyl group, 8-azabicyclo [3.2.1] octyl group The pharmaceutical composition containing the morphinan derivative according to claim 10, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
X is a nitrogen atom, a morphinan derivative according to any one of claims 1 to 11, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof or a solvate thereof. A pharmaceutical composition containing as an active ingredient.
The morphinan derivative according to any one of claims 1 to 12, wherein Y is C = O, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof. A pharmaceutical composition containing as an active ingredient.
A pharmaceutical composition comprising the morphinan derivative according to any one of claims 1 to 14, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. .
The medicine according to claim 14, which is a therapeutic, ameliorating, or prophylactic agent for diseases associated with κ opioid receptors.
The medicine according to claim 14 or 15, which is an analgesic.
The medicine according to claim 14 or 15, which is an antipruritic drug.